tbuckley/cabot-search huggingface dataset:
Abstract OT1-1-13: A Phase 2, randomized, open-label, multicenter, safety and efficacy study of oral lucitanib in patients with metastatic breast cancer with alterations in the FGF pathway
Authors: Maysa Abu-Khalaf, Ingrid Mayer, Jason B Litten, Mitch Raponi, Andrew R Allen, Lajos Pusztai, Carlos L Arteaga
Journal: Cancer Research (2015)

Abstract BACKGROUND: Lucitanib is a potent, oral inhibitor of the tyrosine kinase activity of Fibroblast Growth Factor Receptors 1-3 (FGFR1-3), Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR1-3) and Platelet-Derived Growth Factor Receptors A/B (PDGFRA/B). Aberrant FGF signaling, as defined as FGFR1 and/or 11q amplification, is a hallmark genomic alteration in breast cancer, observed at a combined frequency of up to 25% of patients. Breast cancer patients with measurable disease and aberrant FGF signaling treated in the ongoing Phase 1/2 clinical trial of lucitanib monotherapy experienced an ORR of 50% and a DCR of 100%. This compelling clinical activity has led to the initiation of a global clinical development program for lucitanib in breast cancer. TRIAL DESIGN: The current study is comparing PFS for doses of lucitanib (10 or 15 mg daily) in patients with FGF-aberrant metastatic breast cancer after failure of currently available standard therapies. Approximately 160 patients will be randomized 1:1 to the 10 mg and 15 mg daily dosing groups and stratified by FGF pathway alteration (FGFR1 or 11q amplification) and prior anti-VEGF therapy (yes or no). FGFR1 and 11q (containing the FGF ligands 3, 4, and 19) amplification is determined locally for patient enrolment and confirmed by central laboratory fluorescent in situ hybridization (FISH) testing. A total of 130 PFS events provides 80% power at a 2-sided significance level of 0.05 to detect a hazard ratio of 0.60 for comparing the 10 mg and 15 mg dose groups. Secondary objectives are ORR, DoR, DCR, OS, PROs, safety and population PK. Exploratory endpoints include tissue and blood-based biomarkers that may be predictive of response or primary resistance to treatment with lucitanib. ELIGIBILITY CRITERIA: Histologically or cytologically confirmed FGF-aberrant metastatic breast cancer relapsed or refractory to approved standard available treatment. ECOG 0 or 1. Normal organ function. Patients with uncontrolled hypertension are excluded. Citation Format: Maysa Abu-Khalaf, Ingrid Mayer, Jason B Litten, Mitch Raponi, Andrew R Allen, Lajos Pusztai, Carlos L Arteaga. A Phase 2, randomized, open-label, multicenter, safety and efficacy study of oral lucitanib in patients with metastatic breast cancer with alterations in the FGF pathway [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-1-13.
VML 295 (LY-293111), a novel LTB4 antagonist, is not effective in the prevention of relapse in psoriasis
Authors: J.M. Mommers, M.M. Van Rossum, M.E. Kooijmans-Otero, G.L. Parker, P.C.M. Van De Kerkhof
Journal: British Journal of Dermatology (2000)

Journal Article VML 295 (LY‐293111), a novel LTB4 antagonist, is not effective in the prevention of relapse in psoriasis Get access J.M. Mommers, J.M. Mommers University Hospital Nijmegen, Department of Dermatology, PO Box 9101, 6500 HB Nijmegen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar M.M. Van Rossum, M.M. Van Rossum University Hospital Nijmegen, Department of Dermatology, PO Box 9101, 6500 HB Nijmegen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar M.E. Kooijmans‐Otero, M.E. Kooijmans‐Otero University Hospital Nijmegen, Department of Dermatology, PO Box 9101, 6500 HB Nijmegen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar G.L. Parker, G.L. Parker Vanguard Medica Ltd, Surrey, U.K. Search for other works by this author on: Oxford Academic Google Scholar P.C.M. Van De Kerkhof P.C.M. Van De Kerkhof University Hospital Nijmegen, Department of Dermatology, PO Box 9101, 6500 HB Nijmegen, the Netherlands Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 2, 1 February 2000, Pages 259–266, https://doi.org/10.1046/j.1365-2133.2000.03295.x Published: 01 February 2000
Spanish doctors warn others off their territory
Authors: Xavier Bosch
Journal: BMJ (2001)

Spain's Organisation of Medical Colleges, which brings together most official medical colleges, has started a campaign to prevent pharmacists and, to a lesser extent opticians, from encroaching on doctors' work.

With the slogan “Your doctor, as ever. His unique interest is yours,” the campaign was launched in Madrid by the health minister, Ms Celia Villalobos. The campaign is costing seven million pesetas (£27 000; $40 000), which will be spent on a million leaflets and over 200 000 posters, to be distributed to health centres nationwide. Leaflets will be handed to patients going to health centres, especially primary healthcare centres, …
Relationship of serum sodium concentration to mortality in a wide spectrum of heart failure patients with preserved and with reduced ejection fraction: an individual patient data meta‐analysis†
Authors: Dan Rusinaru, Christophe Tribouilloy, Colin Berry, A. Mark Richards, Gillian A. Whalley, Nikki Earle, Katrina K. Poppe, Marco Guazzi, Stella M. Macin, Michel Komajda, Robert N. Doughty
Journal: European Journal of Heart Failure (2012)
Activating mutations in the epidermal growth factor receptor underlie responsiveness of non-small cell lung cancer to the tyrosine kinase inhibitor Gefitinib
Authors: Daniel A. Haber
Journal: Cancer Research (2005)

PL6  The Epidermal Growth Factor Receptor (EGFR) is commonly expressed at high levels in multiple epithelial cancers, but treatment with the novel EGFR tyrosine kinase inhibitor Gefitinib has produced only modest results in most cancer types. However, approximately 10% of patients with non-small cell lung cancer (NSCLC) have dramatic clinical responses following treatment with Gefitinib. Gefitinib-responsive tumors are most commonly bronchoalveolar in histology and are more frequent in non-smokers and in women, suggesting the possibility of a distinct genetic etiology. We have recently shown that virtually all Gefitinib-responsive tumors harbor specific activating mutations in the kinase domain of EGFR. These somatic mutations are clustered around the ATP binding cleft of the kinase, and mediate both altered ligand-dependent signaling, as well as enhanced binding by the inhibitor. Of note, EGF binding to the mutant receptor results is greatly increased signaling through the anti-apoptotic AKT and STAT pathways, compared with the wild-type receptor, whereas proliferative signals mediated through the ERK pathway are unaltered. The possibility that mutant EGFRs mediate critical survival signals on which the Gefitinib-responsive cancers have become dependent is further supported by the observation that siRNA-mediated knockdown of the mutant EGFR allele triggers massive apoptosis in lung cancer cells harboring the mutant receptor. Taken together, these observations have direct implications for the treatment of patients with NSCLC with EGFR mutations, and more broadly for the design and application of molecular targeted therapy of cancer.
Abstract 17241: Impaired Left Atrioventricular Coupling Compromises Cardiac Performance in Heart Failure With Preserved Ejection Fraction
Authors: Rosita Zakeri, Hiroyuki Takahama, Philip A Araoz, Hon-Chi Lee, Margaret M Redfield
Journal: Circulation (2014)

Background: In heart failure with preserved ejection fraction (HFpEF), left ventricular (LV) systolic elastance (Ees) increases in tandem with increases in arterial elastance (Ea), which maintains ejection fraction but limits systolic reserve and precipitates volume sensitivity. The left atrium (LA) lies in series with the LV and contributes to LV stroke volume. We hypothesized that HFpEF is associated with increased LA systolic elastance (E LA ) and deranged atrioventricular (AV) coupling which may additionally compromise cardiac performance. Methods: HFpEF was modeled by experimental hypertension (bilateral renal wrap + DOCA) in elderly dogs (n=9). LA and LV structure, function (echo, MRI) and invasively assessed pressure-volume relationships (PVR, open-chest; pericardiotomy; admittance catheter) were compared to sham-operated young dogs (control; n=13). Results: As compared to controls, HFpEF dogs displayed concentric remodeling, with increased diastolic stiffness, Ea and Ees (p&lt;0.05 for all) and reduced Ea/Ees (p=0.03). LA maximum volume (28±3 vs 23±3mL, p=0.007), LA stroke volume (4±1 vs2±1mL, p=0.006), LA active emptying fraction (18±6 vs 12±2%, p=0.03) and LA ejection rate (51±14 vs 30±16mL/s) were higher in HFpEF versus controls, suggesting increased LA stroke work and inotropy. At matched heart rate and LA pressure, E LA was steeper in HFpEF than control (2.7±0.9 vs 1.5±0.6mmHg/mL, p=0.01) and positively correlated with Ees (r=0.6, p=0.005) and Ea (r=0.66, p=0.002). However AV mismatch occurred as increases in E LA were not proportionate to increases in Ees (Ees/E LA 1.3±0.4 HFpEF vs 0.8±0.4 control, p&lt;0.05). On linear regression, worse AV coupling (i.e. higher Ees/E LA ) was associated with lower LV stroke volume ( Figure ). Conclusion: In experimental HFpEF, despite enhanced LA contractility, AV coupling was deranged. Worse AV coupling may further contribute to reserve dysfunction, LA pressure rise, and susceptibility to pulmonary edema in HFpEF.
Interleukin-15 enhances neutrophil functional activity in patients with human immunodeficiency virus infection
Authors: Claudio M. Mastroianni, Gabriella d'Ettorre, Gabriele Forcina, Miriam Lichtner, Fabio Mengoni, Claudia D'Agostino, Angela Corpolongo, Anna P. Massetti, Vincenzo Vullo
Journal: Blood (2000)
Abstract 5400: Increase In Actin <i>O</i> -GlcNAcylation After Acute Exposure to N-Acetyl-D Glucosamine Influences Myofilament Calcium Sensitivity
Authors: Genaro A Ramirez Correa, Wenhai Jin, Zihao Wang, Zhong Xin, Wei D Gao, Gerald W Hart, Anne M Murphy
Journal: Circulation (2008)

Recently, we have identified specific sites of O -GlcNAcylation in major cardiac myofilament proteins. We used a methodology based on GalNaz-Biotin labeling followed by DTT switch and LC-MS/MS site mapping. As a result, 42 O- GlcNAc peptides from cardiac myofilaments were identified, corresponding to 32 of cardiac myosin heavy chain (MHC), 6 of α-sarcomeric actin, 2 of myosin light chain 1 (MLC1), 1 of MLC2, and 1 of troponin I (cTnI). Most of the identified O -GlcNAcylation sites are novel post-translational modification sites. To assess the potential physiological role of myofilament GlcNAcylation, Force-Calcium relationships studies were performed on skinned rat trabeculae. We have previously reported that exposure to GlcNAc but not Glycerol significantly decreases calcium sensitivity, further investigation confirm these preliminary findings (pCa 50 1.81 ± 0.13 μM for Control vs. 3.83 ± 0.44 μM for GlcNAc, n =7, P &lt;=.001), and in addition demonstrate that maximal force (F max ) and Hill coefficient ( n ) are not significantly changed. Troponin I phosphorylation at Ser23, 24 was determined in three pooled trabeculea by WB using a specific antibody phosphor-TnI (Cell Signaling) normalized to actin signal (GlcNAc 0.722 vs Glycerol 0.667 A.U., n=3, p=NS). Phosphorylation at this PKA sites was ruled out as responsible for myofilament desensitization. Acute exposure of cardiac myofilaments to GlcNAc significantly increased α-sarcomeric actin O -GlcNAcylation from 27.6±4.2% to 35.1±2.36% ( n = 4, p&lt;0.05) whereas total GlcNAcylation levels were unchanged. Additionally, we showed by immunofluoresence that O-GlcNAc transferase (OGT) and O-GlcNAcase (OGase) are abundant in rat hearts, OGT localizes predominantly in cardiac nuclei and less in cytoplasm, whereas OGase shows the opposite pattern. These studies provides the first site mapping of O -GlcNAcylation sites in cardiac myofilament proteins, and demonstrates their potential role in regulating myocardial contractile function. Regulation of myofilament O -GlcNAcylation may represent a novel and useful therapeutic target in heart failure, especially in diabetic cardiomyopathy.
Role for the Nuclear Factor κB Pathway in Transforming Growth Factor-β1 Production in Idiopathic Myelofibrosis: Possible Relationship with FK506 Binding Protein 51 Overexpression
Authors: Emiko Komura, Carole Tonetti, Virginie Penard-Lacronique, Hédia Chagraoui, Catherine Lacout, Jean Pierre LeCouédic, Philippe Rameau, Najet Debili, William Vainchenker, Stéphane Giraudier
Journal: Cancer Research (2005)

Abstract The release of transforming growth factor-β1 (TGF-β1) in the bone marrow microenvironment is one of the main mechanisms leading to myelofibrosis in murine models and probably in the human idiopathic myelofibrosis (IMF). The regulation of TGF-β1 synthesis is poorly known but seems regulated by nuclear factor κB (NF-κB). We previously described the overexpression of an immunophilin, FK506 binding protein 51 (FKBP51), in IMF megakaryocytes. Gel shift and gene assays show that FKBP51's overexpression in a factor-dependent hematopoietic cell line, induces a sustained NF-κB activation after cytokine deprivation. This activation correlates with a low level of IκBα. A spontaneous activation of NF-κB was also detected in proliferating megakaryocytes and in circulating CD34+ patient cells. In normal cells, NF-κB activation was only detected after cytokine treatment. The expression of an NF-κB superrepressor in FKBP51 overexpressing cells and in derived megakaryocytes from CD34+ of IMF patients revealed that NF-κB activation was not involved in the resistance to apoptosis after cytokine deprivation of these cells but in TGF-β1 secretion. These results highlight the importance of NF-κB's activation in the fibrosis development of this disease. They also suggest that FKBP51's overexpression in IMF cells could play an important role in the pathogenesis of this myeloproliferative disorder.
EGCG inhibits activation of the IGF/IGF-1R system in human colon cancer and hepatoma cells
Authors: Masahito Shimizu, Yohei Shirakami, I. Bernard Weinstein, Hisataka Moriwaki
Journal: Cancer Research (2006)

4887  The insulin like growth factor (IGF)/IGF-1 receptor (IGF-1R) system, which includes IGF, IGF-1R, and IGF binding proteins (IGFBPs), plays an important role in the development of human malignancies. We previously reported that in the HT29 and SW837 human colon cancer cell lines EGCG, the major biologically active component of green tea, inhibits activation of the receptor tyrosine kinases (RTKs) EGFR, HER2, and HER3, and that this is associated with inhibition of multiple downstream signaling pathways (Shimizu, M., et al. Clin Cancer Res 11, 2005). Since IGF-1R is also a RTK, in this study we examined the effects of EGCG on the activity of IGF/IGF-1R system in human colon cancer and hepatoma cells. We found that the colon cancer cell line SW837 and the hepatoma cell line HepG2 express high levels of the IGF-1R protein, and that both cell lines display constitutive activation of this receptor. Treatment of both cell lines with EGCG caused a decrease in the phosphorylated (i.e., activated) form of the IGF-1R protein, a decrease in the levels of both IGF-1 protein and mRNA, and an increase in the levels of both IGFBP-3 protein and mRNA. When SW837 cells were treated with EGCG for a longer time, i. e., 96 hours, a very low concentration (1.0 μg/ml) of EGCG also caused inhibition of activation of the IGF-1R, a decrease in the IGF-1 protein, and an increase in the IGFBP-3 protein. EGCG also caused a decrease in the levels of mRNA that encode MMPs-7 and -9, proteins that proteolyze IGFBP-3. In addition, treatment with EGCG caused a transient increase in the expression of TGF-β2, an inducer of IGFBP-3 expression in SW837 cells. We also found that IGF-1 and IGF-2 stimulate the growth of HepG2 cells and EGCG caused a decrease in the phosphorylated forms of the ERK and Akt proteins which are downstream signaling molecules in the IGF/IGF1-R system. These findings suggest that EGCG can overcome the stimulatory effects of IGF on the IGF-1R dependent signaling pathway, thus expanding the roles of EGCG as an inhibitor of critical RTKs involved in cell proliferation. These results provide further evidence that EGCG may be useful in the chemoprevention or treatment of both colorectal and liver cancer.
Communicating Life Expectancy to Patients With Terminal IllnessCommunicating Life Expectancy to Patients With Terminal Illness
Authors: Gary N Fox
Journal: JAMA (2003)

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Short communication: Lupin allergy in peanut‐allergic children and teenagers
Authors: J. Shaw, G. Roberts, K. Grimshaw, S. White, J. Hourihane
Journal: Allergy (2007)

Lupin has now been introduced into food production in the UK. There is a concern that, on account of cross-reactivity, peanut-allergic children are at high risk for lupin allergy.To investigate the prevalence of lupin sensitization and allergy in children with peanut allergy compared with atopic controls.Children (<18 years) were recruited. Peanut-allergic subjects either had a convincing history of peanut allergy with diagnostic peanut skin prick test (SPT) or specific-immunoglobulin E (IgE) results or a positive food challenge. Control subjects were atopic but not peanut-allergic. All subjects had SPT to peanut and lupin. Sensitized subjects were offered a randomized, double-blind, placebo-controlled lupin challenge. Lupin allergy was defined as objective immediate hypersensitivity reaction at food challenge.Forty-seven peanut-allergic children and 46 atopic controls were recruited. Sixteen peanut-allergic children were sensitized to lupin [34%, 95% confidence interval (CI): 21-49%]. Nine were challenged to lupin. Two reacted (itchy mouth and urticaria; itchy mouth and 20% drop in peak expiratory flow rate) giving a minimum prevalence of lupin allergy in peanut-allergic children of 4.0% (95% CI: 1-15%). Atopic controls were significantly (P = 0.001) less likely to be sensitized to lupin (4%, 95% CI: 1-15%) and had smaller wheals and serum-specific IgE results. None of the atopic controls reacted on lupin challenge, giving a rate of allergy in the atopic controls of 0% (95% CI: 0-8%).A small but significant number of children with peanut allergy are allergic to lupin. Sensitization to lupin is much rarer in nonpeanut-allergic atopic subjects.
Telemental health: A status update
Authors: Elias Aboujaoude, Wael Salame, Lama Naim
Journal: World Psychiatry (2015)

A rather large body of literature now exists on the use of telemental health services in the diagnosis and management of various psychiatric conditions. This review aims to provide an up-to-date assessment of telemental health, focusing on four main areas: computerized CBT (cCBT), Internet-based CBT (iCBT), virtual reality exposure therapy (VRET), and mobile therapy (mTherapy). Four scientific databases were searched and, where possible, larger, better-designed meta-analyses and controlled trials were highlighted. Taken together, published studies support an expanded role for telepsychiatry tools, with advantages that include increased care access, enhanced efficiency, reduced stigma associated with visiting mental health clinics, and the ability to bypass diagnosis-specific obstacles to treatment, such as when social anxiety prevents a patient from leaving the house. Of technology-mediated therapies, cCBT and iCBT possess the most efficacy evidence, with VRET and mTherapy representing promising but less researched options that have grown in parallel with virtual reality and mobile technology advances. Nonetheless, telepsychiatry remains challenging because of the need for specific computer skills, the difficulty in providing patients with a deep understanding or support, concerns about the "therapeutic alliance", privacy fears, and the well documented problem of patient attrition. Future studies should further test the efficacy, advantages and limitations of technology-enabled CBT, as well as explore the online delivery of other psychotherapeutic and psychopharmacological modalities.
Regionalization of Cardiac Surgery in the United States and Canada
Authors: Kevin Grumbach
Journal: JAMA (1995)

<h3>Objective.</h3> —To determine how regionalization of facilities for coronary artery bypass surgery (CABS) affects geographic access to CABS and surgical outcomes. <h3>Design.</h3> —Computerized hospital discharge records were used to measure hospital CABS volume and in-hospital post-CABS mortality rates. Relationships between surgical volume and age- and sex-adjusted mortality rates were compared using χ<sup>2</sup>tests. Small-area analysis of the association between CABS rates and distances to nearest CABS hospital was performed using multivariate linear regression methods. <h3>Setting.</h3> —All nonfederal hospitals in New York, California, Ontario, Manitoba, and British Columbia. <h3>Patients.</h3> —All adult residents of the five jurisdictions who underwent CABS in a hospital in their jurisdiction from 1987 through 1989. <h3>Results.</h3> —In New York and Canada, approximately 60% of all CABS operations took place in hospitals performing 500 or more CABS operations per year, compared with only 26% in California. The highest mortality rates were found among California hospitals performing fewer than 100 CABS operations per year (adjusted 14-day in-hospital mortality was 4.7% compared with 2.4% in high-volume California hospitals,<i>P</i>&lt;.001). The percentage of the population residing within 25 miles of a CABS hospital was 91% in California, 82% in New York, and less than 60% in Canada. Eliminating very low-volume (&lt;100 cases per year) CABS hospitals in California would increase travel distances to a CABS hospital only slightly for a small number of residents. The Canadian degree of regionalization was not associated with lower CABS rates within provinces for populations living at more remote distances from the nearest CABS hospital. <h3>Conclusion.</h3> —Regionalization of CABS facilities in New York and Canada largely avoids the problem of low-volume outlier hospitals with high postoperative mortality rates found in California. New York has avoided the redundancy of facilities that exists in California while still providing residents a geographically convenient selection of CABS hospitals. Stricter regionalization in Canada may leave residents with a more narrow choice of facilities, but does not disproportionately affect access to surgery for populations living at remote distances from CABS facilities. (<i>JAMA</i>. 1995;274:1282-1288)