tbuckley/cabot-search huggingface dataset:
Pazopanib, a Multikinase Angiogenesis Inhibitor, in Patients With Relapsed or Refractory Advanced Soft Tissue Sarcoma: A Phase II Study From the European Organisation for Research and Treatment of Cancer–Soft Tissue and Bone Sarcoma Group (EORTC Study 62043)
Authors: Stefan Sleijfer, Isabelle Ray-Coquard, Zsuzsa Papai, Axel Le Cesne, Michelle Scurr, Patrick Schöffski, Françoise Collin, Lini Pandite, Sandrine Marreaud, Annick De Brauwer, Martine van Glabbeke, Jaap Verweij, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2009)

PURPOSE Given the importance of angiogenesis in soft tissue sarcoma (STS), pazopanib, an oral angiogenesis inhibitor that targets vascular endothelial growth factor receptor and platelet-derived growth factor receptor, was explored in patients with advanced STS. PATIENTS AND METHODS Patients with intermediate- or high-grade advanced STS who were ineligible for chemotherapy or who had received no more than two prior cytotoxic agents for advanced disease, who had documented progression, who had adequate performance status, and who had good organ function were eligible. Pazopanib 800 mg was given daily. The primary end point was progression-free rate at 12 weeks (PFR(12 weeks)). Secondary end points were response, safety, and overall survival. Four different strata were studied: adipocytic STS, leiomyosarcomas, synovial sarcomas, and other STS types. A Simon two-stage design was applied (P1 = 40%; P0 = 20%; alpha = beta = .1) for each stratum. Results One hundred forty-two patients were enrolled. The adipocytic STS stratum was closed after the first stage, given insufficient activity (PFR(12 weeks), five [26%] of19). PFR(12 weeks) was 18 (44%) of 41 patients in the leiomyosarcoma cohort, 18 (49%) of 37 in the synovial sarcomas, and 16 (39%) of 41 in the other STS types. Compared with historical controls who were treated with second-line chemotherapy, progression-free and overall survivals were prolonged in the three cohorts in which the primary end point was reached. The most frequent drug-related toxicities were hypertension, fatigue, hypopigmentation, and nausea. Other toxicities included liver enzyme elevations, myelosuppression, and proteinuria, all of which were mostly grades 1 to 2. The most frequent grades 3 to 4 toxicities were hyperbilirubinemia (6.3%), hypertension (7.7%), and fatigue (7.7%). CONCLUSION Pazopanib is well tolerated in patients with relapsed, advanced STS and demonstrates interesting activity that warrants additional study in patients with leiomyosarcomas, synovial sarcomas, and other STS types.
Bronchiolitis obliterans following haematopoietic stem cell transplantation
Authors: A. O. Soubani, J. P. Uberti
Journal: European Respiratory Journal (2007)

The aim of the present article is to review the available clinical data on bronchiolitis obliterans following haematopoietic stem cell transplantation (HSCT). The data sources used were the Medline database and references from the identified articles related to bronchiolitis obliterans, noninfectious pulmonary complications and HSCT. HSCT is an important treatment for a variety of malignant and nonmalignant conditions. However, the procedure is limited by significant complications that may involve every organ of the body. Pulmonary complications are seen in 40–60% of HSCT recipients. The recent advances in prophylaxis and treatment of infectious complications have increased the significance of late noninfectious pulmonary conditions. Currently, bronchiolitis obliterans is one of the most challenging pulmonary complications facing clinicians who are taking care of haematopoietic stem cell transplantation recipients. This article reviews the clinical and pathological features of this condition, sheds some light on potential mechanisms of pathogenesis, and discusses the available management options.
Hybrid Cells Derived From Fusion of TA3-Ha Ascites Carcinoma With Normal Fibroblasts. I. Malignancy, Karyotype, and Formation of Isoantigenic Variants 2
Authors: George Klein, Sten Friberg, Francis Wiener, Henry Harris
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Hybrid Cells Derived From Fusion of TA3-Ha Ascites Carcinoma With Normal Fibroblasts. I. Malignancy, Karyotype, and Formation of Isoantigenic Variants Get access George Klein, George Klein Department of Tumor Biology, Karolinska Institutet Medical School, S 104 01 Stockholm 60, Sweden and Sir William Dunn School of Pathology, University of Oxford, Oxford, England Search for other works by this author on: Oxford Academic PubMed Google Scholar Sten Friberg, Jr., Sten Friberg, Jr. Department of Tumor Biology, Karolinska Institutet Medical School, S 104 01 Stockholm 60, Sweden and Sir William Dunn School of Pathology, University of Oxford, Oxford, England Search for other works by this author on: Oxford Academic PubMed Google Scholar Francis Wiener, Francis Wiener Department of Tumor Biology, Karolinska Institutet Medical School, S 104 01 Stockholm 60, Sweden and Sir William Dunn School of Pathology, University of Oxford, Oxford, England Search for other works by this author on: Oxford Academic PubMed Google Scholar Henry Harris Henry Harris Department of Tumor Biology, Karolinska Institutet Medical School, S 104 01 Stockholm 60, Sweden and Sir William Dunn School of Pathology, University of Oxford, Oxford, England Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 50, Issue 5, May 1973, Pages 1259–1268, https://doi.org/10.1093/jnci/50.5.1259 Published: 01 May 1973 Article history Received: 12 September 1972 Accepted: 31 January 1973 Published: 01 May 1973
Survey of general practitioners' views of consultants' non-urgent referral of outpatients to other consultants
Authors: S Bridger, S R Cairns
Journal: BMJ (1996)

Standard definitions of diagnosis and inter- ventions in general practice are unclear * 81% of general practice can be described as evidence based using this method of assessment * Evidence derived from different methodologies may be important for the assessment of the evidence base of general practice the value of a coffee future-likely to be altered by tomorrow's experience.Furthermore, some inter- ventions were originally assessed within secondary care but their main use is in the community. THE SEARCH FOR APPROPRIATE PARADIGMSDespite the healthy debate resulting from the Oxford study,`5 both patients and policy makers might want doctors to try to base as many of their interventions as possible on evidence from clinical trials.There may be a temptation to produce a league table of specialties and settings-for example, inpatient medicine might be found to be "better than" general practice by 1%.We could question whether it is feasible or even desirable to pursue the goal of 100% evidence based practice.Much of the work within general practice, as well as in other settings, consists of medicine that combines science with art, sociology, mythology, and pastoral care.These aspects of care must be incorporated into an appropriate paradigm of evidence based practice rather than that determined solely by clinical trials.Linked to this is the search for appropriateness of the methods used to provide the evidence.We believe that for general practice, and possibly in other settings too, the most important evidence may be found in developing alternative methodologies which comple- ment conclusions from randomised controlled trials.We thank staff at The Street Lane Practice for their help.
Delayed Arteriogenesis in Hypercholesterolemic Mice
Authors: Daniela Tirziu, Karen L. Moodie, Zhen W. Zhuang, Katie Singer, Armin Helisch, Jeff F. Dunn, Weiming Li, Jaipal Singh, Michael Simons
Journal: Circulation (2005)

Background— Hypercholesterolemia has been reported to inhibit ischemia-induced angiogenesis. To address its effects on arteriogenesis, we investigated arterial growth in hypercholesterolemic low-density lipoprotein receptor −/− /ApoB-48 −/− (HCE) mice. Methods and Results— The extent and the time course of arteriogenesis after femoral artery ligation was evaluated in HCE and strain-matched control mice. Distal limb perfusion was measured by laser Doppler imaging, whereas MRI was used to visualize arterial flow and micro-computed tomography to assess vascular growth. After femoral artery ligation, serial laser Doppler imaging demonstrated significantly delayed restoration of perfusion in untreated HCE compared with control mice (day 3, 0.09 versus 0.19, P &lt;0.05). Treatment with Ad-PR39 in control mice led to a significant restoration of arterial blood flow and tissue perfusion at day 3, whereas in HCE mice, hindlimb perfusion began increasing only by day 7. Micro-CT analysis confirmed increased growth of smaller arterioles (16 to 63 μm in diameter) in the Ad-PR39–treated control compared with HCE mice. The delay in arteriogenesis in HCE mice correlated with delayed tissue appearance of F4/80 + cells. Analysis of gene expression after Ad-PR39 treatment demonstrated that HCE mice had significantly reduced expression of FGF receptor 1, hypoxia-inducible factor-1α, vascular cell adhesion molecule-1, macrophage scavenger receptor-1, and cyclophilin A compared with controls 3 days after arterial ligation that equalized by day 7, mimicking relative changes in arteriogenesis and tissue perfusion. Conclusions— Hypercholesterolemia results in delayed native arteriogenesis because of reduced early monocyte/macrophage influx and delayed and impaired arterial growth response to growth factor therapy.
Small molecules and targeted therapies in distant metastatic disease
Authors: P. Hersey, L. Bastholt, V. Chiarion-Sileni, G. Cinat, R. Dummer, A.M.M. Eggermont, E. Espinosa, A. Hauschild, I. Quirt, C. Robert, D. Schadendorf
Journal: Annals of Oncology (2009)

Chemotherapy, biological agents or combinations of both have had little impact on survival of patients with metastatic melanoma. Advances in understanding the genetic changes associated with the development of melanoma resulted in availability of promising new agents that inhibit specific proteins up-regulated in signal cell pathways or inhibit anti-apoptotic proteins. Sorafenib, a multikinase inhibitor of the RAF/RAS/MEK pathway, elesclomol (STA-4783) and oblimersen (G3139), an antisense oligonucleotide targeting anti-apoptotic BCl-2, are in phase III clinical studies in combination with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib, dasatinib, sunitinib) may have a role in treatment of patients with melanoma harbouring c-Kit mutations. Although often studied as single agents with disappointing results, new targeted drugs should be more thoroughly evaluated in combination therapies. The future of rational use of new targeted agents also depends on successful application of analytical techniques enabling molecular profiling of patients and leading to selection of likely therapy responders.
Six- and Twelve-Month Results From First Human Experience Using Everolimus-Eluting Stents With Bioabsorbable Polymer
Authors: Eberhard Grube, Shinjo Sonoda, Fumiaki Ikeno, Yasuhiro Honda, Saibal Kar, Charles Chan, Ulrich Gerckens, Alexandra J. Lansky, Peter J. Fitzgerald
Journal: Circulation (2004)

Everolimus, an active immunosuppressive and antiproliferative agent of the same family as sirolimus (rapamycin), has demonstrated significant reduction of neointimal proliferation in animal studies. The First Use To Underscore restenosis Reduction with Everolimus (FUTURE) I trial was the first in-human experience to evaluate the safety and efficacy of everolimus-eluting stents (EES), coated with a bioabsorbable polymer, compared with bare metal stents (BMS).FUTURE I was a prospective, single-blind, randomized trial that enrolled 42 patients with de novo coronary lesions (EES 27, BMS 15). Patient and lesion characteristics were comparable between the groups. Major adverse cardiac event rates were low at 30 days and 6 months, without any early or late stent thrombosis for either group (P=NS). Between 6 and 12 months, there were no additional reports of major adverse cardiac events. The 6-month angiographic in-stent restenosis rate was 0% versus 9.1% (1 patient) (P=NS), with an associated late loss of 0.11 mm versus 0.85 mm (P<0.001), and the in-segment restenosis rate was 4% (1 patient) and 9.1% (1 patient) (P=NS) for EES and BMS, respectively. Intravascular ultrasound analysis revealed a significant reduction of percent neointimal volume in EES compared with BMS (2.9+/-1.9 mm3/mm versus 22.4+/-9.4 mm3/mm, P<0.001). There was no late stent malapposition in either group. The safety and efficacy of the EES appeared to be sustained at 12 months.In this initial clinical experience, EES with bioabsorbable polymer demonstrated a safe and efficacious method to reduce in-stent neointimal hyperplasia and restenosis.
Effect of Calcium Carbonate on the Absorption of Levothyroxine
Authors: Nalini Singh
Journal: JAMA (2000)

The effect of calcium carbonate on the absorption of levothyroxine has not been studied systematically. Such a potential drug interaction merits investigation because concurrent treatment with both drugs is common, particularly in postmenopausal women.To investigate the potential interference of calcium carbonate in the absorption of levothyroxine.Prospective cohort study conducted from November 1998 to June 1999, supplemented with an in vitro study of thyroxine (T(4)) binding to calcium carbonate.Veterans Affairs Medical Center in West Los Angeles, Calif.Twenty patients (age range, 27-78 years; n=11 men) with hypothyroidism who were taking a stable long-term regimen of levothyroxine were included in the study. All patients had serum free T(4) and thyrotropin values in the normal range before beginning the study.Subjects were instructed to take 1200 mg/d of elemental calcium as calcium carbonate, ingested with their levothyroxine, for 3 months.Levels of free T(4), total T(4), total triiodothyronine (T(3)), and thyrotropin, measured in all subjects at baseline (while taking levothyroxine alone), at 2 and 3 months (while taking calcium carbonate and levothyroxine), and 2 months after calcium carbonate discontinuation (while continuing to take levothyroxine).Mean free T(4) and total T(4) levels were significantly reduced during the calcium period and increased after calcium discontinuation. Mean free T(4) levels were 17 pmol/L (1.3 ng/dL) at baseline, 15 pmol/L (1.2 ng/dL) during the calcium period, and 18 pmol/L (1.4 ng/dL) after calcium discontinuation (overall P<.001); mean total T(4) levels were 118 nmol/L (9.2 microg/dL) at baseline, 111 nmol/L (8.6 microg/dL) during the calcium period, and 120 nmol/L (9.3 microg/dL) after calcium discontinuation (overall P=.03). Mean thyrotropin levels increased significantly, from 1.6 mIU/L at baseline to 2.7 mIU/L during the calcium period, and decreased to 1. 4 mIU/L after calcium discontinuation (P=.008). Twenty percent of patients had serum thyrotropin levels higher than the normal range during the calcium period; the highest observed level was 7.8 mIU/L. Mean T(3) levels did not change during the calcium period. The in vitro study of T(4) binding to calcium showed that adsorption of T(4) to calcium carbonate occurs at acidic pH levels.This study of 20 patients receiving long-term levothyroxine replacement therapy indicates that calcium carbonate reduces T(4) absorption and increases serum thyrotropin levels. Levothyroxine adsorbs to calcium carbonate in an acidic environment, which may reduce its bioavailability. JAMA. 2000;283:2822-2825
Extensive and selective mutation of a rearranged VH5 gene in human B cell chronic lymphocytic leukemia.
Authors: J Cai, C Humphries, A Richardson, P W Tucker
Journal: The Journal of Experimental Medicine (1992)

B cell chronic lymphocytic leukemia (CLL) is the malignant, monoclonal equivalent of a human CD5+ B cell. Previous studies have shown that the VH and VL genes rearranged and/or expressed in CLL have few and apparently random mutations. However, in this study, we have found that the rearranged VH251 gene, one of the three-membered VH5 family, has extensive and selective mutations in B-CLL cells. Somatic mutation at the nucleotide level is 6.03% in B-CLLs whereas the somatic mutation levels are much lower in CD5+ and CD5- cord B cells, adult peripheral blood B cells, and Epstein-Barr virus-transformed CD5+ B cell lines (0.45, 0.93, and 1.92%, respectively). Complementary determining region 1 (CDR1) mutation in CLLs is particularly prevalent, and interchanges in CDRs often lead to acquisition of charge. Analysis of somatic mutations and mutations to charged residues demonstrated that the mutations in CLLs are highly selected.
Maple syrup urine disease in Mennonites. Evidence that the Y393N mutation in E1 alpha impedes assembly of the E1 component of branched-chain alpha-keto acid dehydrogenase complex.
Authors: C R Fisher, J L Chuang, R P Cox, C W Fisher, R A Star, D T Chuang
Journal: Journal of Clinical Investigation (1991)

Maple Syrup Urine Disease (MSUD) in Mennonites is associated with homozygosity for a T to A transversion in the E1 alpha gene of the branched-chain alpha-keto acid dehydrogenase complex. This causes a tyrosine to asparagine substitution at position 393 (Y393N). To assess the functional significance of this missense mutation, we have carried out transfection studies using E1 alpha-deficient MSUD lymphoblasts (Lo) as a host. The level of E1 beta subunit is also greatly reduced in Lo cells. Efficient episomal expression in lymphoblasts was achieved using the EBO vector. The inserts employed were chimeric bovine-human cDNAs which encode mitochondrial import competent E1 alpha subunit precursors. Transfection with normal E1 alpha cDNA into Lo cells restored decarboxylation activity of intact cells. Western blotting showed that both E1 alpha and E1 beta subunits were markedly increased. Introduction of Y393N mutant E1 alpha cDNA failed to produce any measurable decarboxylation activity. Mutant E1 alpha subunit was expressed at a normal level, however, the E1 beta subunit was undetectable. These results provide the first evidence that Y393N mutation is the cause of MSUD. Moreover, this mutation impedes the assembly of E1 alpha with E1 beta into a stable alpha 2 beta 2 structure, resulting in the degradation of the free E1 beta subunit.
Patient Autonomy for the Management of Chronic Conditions: A Two-Component Re-Conceptualization
Authors: Aanand D. Naik, Carmel B. Dyer, Mark E. Kunik, Laurence B. McCullough
Journal: The American Journal of Bioethics (2009)

The clinical application of the concept of patient autonomy has centered on the ability to deliberate and make treatment decisions (decisional autonomy) to the virtual exclusion of the capacity to execute the treatment plan (executive autonomy). However, the one-component concept of autonomy is problematic in the context of multiple chronic conditions. Adherence to complex treatments commonly breaks down when patients have functional, educational, and cognitive barriers that impair their capacity to plan, sequence, and carry out tasks associated with chronic care. The purpose of this article is to call for a two-component re-conceptualization of autonomy and to argue that the clinical assessment of capacity for patients with chronic conditions should be expanded to include both autonomous decision-making and autonomous execution of the agreed-upon treatment plan. We explain how the concept of autonomy should be expanded to include both decisional and executive autonomy, describe the biopsychosocial correlates of the two-component concept of autonomy, and recommend diagnostic and treatment strategies to support patients with deficits in executive autonomy.
Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study
Authors: C P Bearcroft, D Perrett, M J G Farthing
Journal: Gut (1998)

Background —Increased concentrations of 5-hydroxytryptamine (5-HT) can be detected in the systemic circulation after a meal and may be involved in the physiological control of gastrointestinal motility. Abnormalities of 5-HT release after a meal might explain some of the postprandial symptoms associated with the irritable bowel syndrome (IBS). Aim —To investigate the effect of a standard meal on plasma 5-HT and urinary 5-hydroxyindole acetic acid (5-HIAA) concentrations in patients with diarrhoea predominant IBS and in healthy volunteers. Methods —After an overnight fast, six volunteers and five patients with IBS were given a carbohydrate-rich meal. Blood and urine samples were taken before and for four hours after the meal. Platelet-poor plasma 5-HT and urinary 5-HIAA were analysed by reversed phase high performance liquid chromatography with fluorometric detection. 5-HIAA was expressed as a ratio with urinary creatinine concentration, which was measured by spectrophotometry. Results —During the four hour postprandial period, 5-HT concentrations were significantly higher in patients with IBS than in healthy volunteers at 0.5 hours (p&lt;0.05), 2 hours (p&lt;0.05) and 2.5 hours (p&lt;0.05). 5-HT was not detected in the plasma in the fasting state in patients or volunteers. Median peak 5-HT in patients with IBS (359 (198–796) nmol/l) was significantly greater than volunteers (83 (7–190)) (p&lt;0.05). “Area under the curve” for 5-HT detection was greater for patients with IBS (317 (138–771)) than for healthy volunteers (51 (4–129); p&lt;0.05).The duration of the 5-HT peak was significantly longer in patients with IBS (3 (1–3) hours) than in the healthy volunteers (1 (1–1) hours; p&lt;0.01). Postprandial urinary median 5-HIAA values in controls (5.6 (5.5–5.8) μmol/mmol creatinine) and patients with IBS (3.0 (2.5–6.8) μmol/mmol creatinine) were not significantly different from preprandial values (controls: 5.9 (5.5–6.6) μmol/mmol creatinine; patients with IBS: (6.2 (2.4–9.3) μmol/mmol creatinine). Conclusion —These findings indicate that there may be a difference in the way that 5-HT is released in patients with diarrhoea predominant IBS, and could suggest a possible role for 5-HT in the postprandial symptoms of these patients.
Identification of a calmodulin-binding domain in Sema4D that regulates its exodomain shedding in platelets
Authors: Peipei Mou, Zhao Zeng, Qiang Li, Xiaohui Liu, Xiaoran Xin, Kenneth M. Wannemacher, Changgeng Ruan, Renhao Li, Lawrence F. Brass, Li Zhu
Journal: Blood (2013)
Heparin‐mediated neutralization of platelet antiaggregatory activity of prostacyclin (PGI<sub>2</sub>): Studies on mechanism
Authors: Sabiha R. Saba, Hussain I. Saba
Journal: American Journal of Hematology (1985)

Abstract Prostacyclin (PGI 2 ) is a well‐known potent inhibitor of platelet aggregation. Its role has been implicated in physiological and pathological states of hemostasis. Heparin blocks the prostacyclin‐mediated antiaggregatory activity on platelets. Prior treatment of heparin with heparinase as well as with protamine destroyed heparin's ability to neutralize PGI 2 . Studies on the mechanism of heparin blocking of PGI 2 activity suggested that heparin interacted directly with PGI 2 , as shown by the loss of PGI 2 mobility on thin layer chromatography concomitant with the loss of PGI 2 ‐mediated inhibition of platelet aggregation. PGI 2 in this combination with heparin, nevertheless, retained its time‐dependent ability to be hydrolyzed to 6‐keto‐PGF 1α . Findings of these studies may have implications in thrombosis and hemostasis, particularly in heparin‐mediated abnormalities of circulating platelets.