tbuckley/cabot-search huggingface dataset:
Magnetic Resonance Imaging Characteristics Predict Epidermal Growth Factor Receptor Amplification Status in Glioblastoma
Authors: Manish Aghi, Paola Gaviani, John W. Henson, Tracy T. Batchelor, David N. Louis, Fred G. Barker
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Two clinical-molecular glioblastoma subtypes have been described: “primary” glioblastomas arise de novo in older patients and often overexpress epidermal growth factor receptor (EGFR); “secondary” glioblastomas progress from lower-grade tumors in younger patients and commonly have TP53 mutations. EGFR overexpression correlates in experimental gliomas with increased angiogenesis, edema, and invasion. No radiographic predictors of molecular glioblastoma subtype are known. Experimental Design: We retrospectively reviewed 75 glioblastomas, classified as TP53-mutated (n = 11), EGFR-amplified (n = 31), or neither (non-TP53/non-EGFR; n = 33). Four variables were derived from preoperative magnetic resonance imaging: (a) T2/T1, the ratio of T2-bright volume to enclosed T1-enhancing volume; (b) percentage of tumor volume that was necrosis; and (c and d) T1 and T2 border sharpness coefficients (BSC), the rates of change in grayscale intensity of adjacent 0.02-cm2 voxels traversing the anterior, posterior, and lateral borders on T1-enhanced and T2 images. Results and Conclusions: Mean T2/T1 was 4.7 for EGFR-amplified glioblastomas, greater than that of TP53-mutated glioblastomas (2.3) or non-TP53/non-EGFR glioblastomas (2.6; P &amp;lt; 0.00005). All four tumors with T2/T1 &amp;gt; 7.2 were EGFR-amplified; 0 of 15 with T2/T1 &amp;lt; 4.7 underwent gross total resection. The mean T2 BSC of EGFR-amplified glioblastomas was 33.7, less sharp (P &amp;lt; 0.0000005) than TP53-mutated (72.2) and non-TP53/non-EGFR glioblastomas (81.2). All 15 glioblastomas with T2 BSC &amp;lt; 30.8 were EGFR-amplified. Percentage necrosis and T1 BSC did not differ between glioblastoma subtypes. The increased T2/T1 ratio and decreased T2 BSC in EGFR-overexpressing tumors are the first radiographic distinctions described between glioblastoma molecular subtypes. These findings may reflect increased angiogenesis, edema, and/or invasion in EGFR-overexpressing tumors.
IPF: time for the (ciliary) beat generation?
Authors: Sarah Wiscombe, Ian A Forrest, A John Simpson
Journal: Thorax (2013)

Idiopathic pulmonary fibrosis (IPF), the most common of the idiopathic interstitial pneumonias remains a disabling, progressive lung disease with extremely poor prognosis, in which no pharmacological intervention significantly alters outcome.1 A relatively poor understanding of the complex pathophysiology of IPF continues to hinder the identification of effective therapies, and of patients most likely to benefit from existing treatments.

Usual interstitial pneumonia is the histological hallmark of IPF, characterised by temporospatial heterogeneity in which normal lung is interspersed with areas of subpleural interstitial fibrosis, loss of normal alveolar architecture and the presence of fibroblastic foci.2 Histological sections may also show ‘bronchiolisation’ of the distal airway with alveolar structures replaced by enlarged airspaces (forming characteristic honeycomb cysts) lined by epithelial cells more akin to proximal airway epithelium, often ciliated and mucus producing.3 ,4 The potential importance of mucus production in the pathogenesis of IPF has been highlighted by a landmark study demonstrating that a common variant within the putative promoter region of MUC5B (an airway mucin gene) is strongly associated with familial interstitial pneumonia and IPF.5 Moreover, subjects with IPF had significantly higher expression of MUC5B protein levels compared with controls, and this was localised to areas of lung fibrosis. It has been hypothesised that excessive MUC5B may impair the host response to alveolar injury through excess mucus plugging and impaired clearance of inhaled substances and micro-organisms. Alternative theories propose that MUC5B may interfere directly with alveolar repair mechanisms, either through disruption of interactions between type II alveolar epithelial cells and extracellular matrix, or …
Phase I and Pharmacokinetic Study of the Novel Oral Cell-Cycle Inhibitor Ro 31-7453 in Patients With Advanced Solid Tumors
Authors: Jakob Dupont, Bryan Bienvenu, Carol Aghajanian, Sandra Pezzulli, Paul Sabbatini, Phothisath Vongphrachanh, Christine Chang, Christina Perkell, Kenneth Ng, Sharon Passe, Lars Breimer, Jianguo Zhi, Mark DeMario, David Spriggs, Steven L. Soignet
Journal: Journal of Clinical Oncology (2004)

Purpose To determine maximum tolerated dose, pharmacokinetics (PK), and safety of Ro 31-7453, a novel, oral cell-cycle inhibitor. Patients and Methods Using an accelerated dose-escalation schedule, 48 patients with advanced solid tumors were treated with doses of Ro 31-7453 ranging from 25 to 800 mg/m 2 /d given for 4 consecutive days, every 3 weeks. The total daily dose was taken as a single dose (schedule A) or divided into two equal doses taken 12 hours apart (schedule B). PK samples of blood and urine were collected on the first and last days of dosing in cycles 1 and 2. Results Forty-five patients completed at least one cycle of therapy. Myelosuppression and stomatitis were dose-limiting toxicities, occurring at the 800 mg/m 2 /d dose level for both schedules. Toxicity was independent of body-surface area, leading to the recommended phase II flat dose of 1,000 mg daily for 4 days for both schedules. Common adverse events included diarrhea, nausea, vomiting, fatigue, alopecia, and elevated liver-function tests. One death, related to neutropenic sepsis, occurred on study. The PK of the parent compound and major metabolites were apparently linear, with a half-life of approximately 9 hours and a maximum concentration of approximately 4 hours. Minor antitumor activity was observed against carcinoma of the lung, breast, pancreas, and ovary. Conclusion Ro 31-7453 was well tolerated, with manageable adverse effects. Significant PK variability (absorption, metabolism, and excretion) was observed, and a substantial number of additional patients are needed to confirm the recommended phase II dose. Additional pharmacology and phase II studies are under way to explore the dose-toxicity relationship.
Vascular endothelial growth factor and angiopoietin-2 play a major role in the pathogenesis of vascular leakage in cirrhotic rats
Authors: P Melgar-Lesmes, S Tugues, J Ros, G Fernandez-Varo, M Morales-Ruiz, J Rodes, W Jimenez
Journal: Gut (2008)

<h3>Background and aims:</h3> The extent and molecular mechanisms governing plasma extravasation and formation of ascites in cirrhosis are unknown. Vascular endothelial growth factor-A (VEGF-A) and angiopoietin-2 (Ang-2) are endogenous substances with powerful vascular permeability effects. We assessed regional blood flow, vascular leakage, mRNA and tissular expression of VEGF-A and Ang-2 and vascular permeability following VEGF receptor 2 blockade in control and cirrhotic rats to define the vascular territories showing altered vascular permeability in cirrhosis and to determine whether VEGF-A and Ang-2 are involved in this phenomenon. <h3>Methods:</h3> Arterial blood flow was analysed with the coloured microsphere method. Vascular leakage was measured and visualised with the dye Evan's Blue and colloidal carbon techniques, respectively. VEGF-A and Ang-2 expression were determined by real-time polymerase chain reaction (RT-PCR), immunohistochemistry and western blot. The effect on vascular permeability induced by VEGFR<sub>2</sub> blockade was assessed by administration of the receptor inhibitor SU11248. <h3>Results:</h3> Arterial blood flow was increased in the mesentery, pancreas and small intestine but not in the kidney and spleen of cirrhotic rats as compared to controls. Increased vascular leakage was observed in the mesentery and liver, where colloidal carbon spread from microvessels to the adjacent fibrotic tracts. Increased hepatic and mesenteric expression of VEGF-A and Ang-2 was found in cirrhotic rats as compared to controls. Blockade of VEGFR<sub>2</sub> markedly reduced hepatic and mesenteric vascular leakage in cirrhotic rats. <h3>Conclusions:</h3> Enhanced endothelial permeability is restricted to the hepatic and mesenteric vascular beds in cirrhotic rats with ascites and VEGF-A and Ang-2 are key factors in the signalling pathways regulating this dysfunction.
Reduction in Diabetic Amputations Over 11 Years in a Defined U.K. Population
Authors: Singhan Krishnan, Fiona Nash, Neil Baker, Duncan Fowler, Gerry Rayman
Journal: Diabetes Care (2007)

To assess changes in diabetic lower-extremity amputation rates in a defined relatively static population over an 11-year period following the introduction of a multidisciplinary foot team.All diabetic patients with foot problems admitted to Ipswich Hospital, a large district general hospital, were identified by twice-weekly surveillance of all relevant in-patient areas and outcomes including amputations recorded.The incidence of major amputations fell 62%, from 7.4 to 2.8 per 100,000 of the general population. Total amputation rates also decreased (40.3%) but to a lesser extent due to a small increase in minor amputations. Expressed as incidence per 10,000 people with diabetes, total amputations fell 70%, from 53.2 to 16.0, and major amputations fell 82%, from 36.4 to 6.7.Significant reductions in total and major amputation rates occurred over the 11-year period following improvements in foot care services including multidisciplinary team work.
Curcumin Blocks RON Tyrosine Kinase–Mediated Invasion of Breast Carcinoma Cells
Authors: Madhusudhanan Narasimhan, Sudhakar Ammanamanchi
Journal: Cancer Research (2008)

Abstract We have recently shown that macrophage-stimulating protein (MSP) promotes the invasion of recepteur d'origine nantais (RON), a tyrosine kinase receptor–positive MDA-MB-231, MDA-MB-468 breast cancer cells, and also identified the regulatory elements required for RON gene expression. In this report, we have analyzed the efficacy of a chemopreventive agent, curcumin, in blocking RON tyrosine kinase–mediated invasion of breast cancer cells. Reverse transcription-PCR and Western analysis indicated the down-regulation of the RON message and protein, respectively, in MDA-MB-231 and MDA-MB-468 cells. Significantly, curcumin-mediated inhibition of RON expression resulted in the blockade of RON ligand, MSP-induced invasion of breast cancer cells. We have identified two putative nuclear factor-κB p65 subunit binding sites on the RON promoter. Using chromatin immunoprecipitation analysis and site-directed mutagenesis of the RON promoter, we have confirmed the binding of p65 to the RON promoter. Our data show that curcumin reduces RON expression by affecting p65 protein expression and transcriptional activity. Treatment of MDA-MB-231 cells with pyrrolidine dithiocarbamate, an inhibitor of p65, or small interfering RNA knockdown of p65, blocked RON gene expression and MSP-mediated invasion of MDA-MB-231 cells. This is the first report showing the regulation of human RON gene expression by nuclear factor-κB and suggests a potential therapeutic role for curcumin in blocking RON tyrosine kinase–mediated invasion of carcinoma cells. [Cancer Res 2008;68(13):5185–92]
High-Density Lipoproteins and Endothelial Function
Authors: Brian J. O’Connell, Jacques Genest
Journal: Circulation (2001)

Elevated plasma levels of HDL cholesterol or apolipoprotein A-I, the major protein moiety of HDL particles, are protective against coronary artery disease. HDL particles remove cholesterol from peripheral cells and transfer it to the liver for bile acid synthesis. The interaction between lipoproteins is not mediated through simple contact between 2 phospholipid membranes but involves specific protein-receptor interactions, charged phospholipid-phospholipid contact, and activation of cellular signaling pathways. These lead to regulation of genes or the modification of proteins involved in vasomotor function, platelet activation, thrombosis and thrombolysis, cell adhesion, apoptosis and cell proliferation, and cellular cholesterol homeostasis.
Accelerated Radiotherapy With Carbogen and Nicotinamide for Laryngeal Cancer: Results of a Phase III Randomized Trial
Authors: Geert O. Janssens, Saskia E. Rademakers, Chris H. Terhaard, Patricia A. Doornaert, Hendrik P. Bijl, Piet van den Ende, Alim Chin, Henri A. Marres, Remco de Bree, Albert J. van der Kogel, Ilse J. Hoogsteen, Johannes Bussink, Paul N. Span, Johannes H. Kaanders
Journal: Journal of Clinical Oncology (2012)

To report the results from a randomized trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen inhalation and nicotinamide (ARCON) in laryngeal cancer.Patients with cT2-4 squamous cell laryngeal cancer were randomly assigned to AR (68 Gy within 36 to 38 days) or ARCON. To limit the risk of laryngeal necrosis, ARCON patients received 64 Gy on the laryngeal cartilage. The primary end point was local control. Secondary end points were regional control, larynx preservation, toxicity, disease-free survival, and overall survival. In a translational side study, the hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies.From April 2001 to February 2008, 345 patients were accrued. After a median follow-up of 44 months, local tumor control rate at 5 years was 78% for AR versus 79% for ARCON (P = .80), with larynx preservation rates of 84% and 87%, respectively (P = .48). The 5-year regional control was significantly better with ARCON (93%) compared with AR (86%, P = .04). The improvement in regional control was specifically observed in patients with hypoxic tumors and not in patients with well-oxygenated tumors (100% v 55%, respectively; P = .01). AR and ARCON produced equal levels of toxicity.Despite lack of benefit in local tumor control for advanced laryngeal cancers, a significant gain in regional control rate, with equal levels of toxicity, was observed in favor of ARCON. The poor regional control of patients with hypoxic tumors is specifically countered by ARCON treatment.
THE RELATION OF FATTY DEGENERATION TO THE OXIDATION OF PURINES BY LIVER CELLS
Authors: H. Gideon Wells
Journal: The Journal of Experimental Medicine (1910)

These experiments show that it is possible to cause, by the proper use of hydrazine and phosphorus, a very high degree of fatty change in the liver with a minimum of necrosis, involving alike both peripheral and central portions of the lobule and thus eliminating the " factor of safety" or residual normal cells. Nevertheless, it is found that such fatty liver tissue has not lost in the least its power to oxidize uric acid when acting upon it in vitro with abundant air supply, nor is the power to oxidize xanthine to uric acid noticeably diminished. Since these two enzymes, and especially the uricolytic enzyme, are about the last to appear in the development of the animal kingdom and also of the individual mammal, it is to be expected that they will be among the first of the enzymes to be destroyed by injurious agencies, but evidently they are not affected by conditions that lead to the highest degree of fatty metamorphosis of the cytoplasm of the hepatic cells. While these experiments merely prove that extreme fatty degeneration does not destroy or appreciably diminish the power of liver cells to oxidize uric acid and xanthine in vitro, yet they suggest that in general fatty degeneration is probably not essentially incompatible with a high degree of metabolic activity by the affected cells. It is possible that in the living tissue functional activity may be decreased secondarily by fatty metamorphosis, as, for example, by the enlarged fatty cells compressing the capillaries and reducing circulatory activity, or by modification of diffusion through the cell by the fat deposits, independent of any deleterious influence upon the cellular enzymes themselves. Other experiments will be required to determine whether steatogenic poisons leave intrahepatic enzymes other than the uricase equally unaffected, but as it has already been shown by Jacoby that the autolytic enzymes and aldehydase in the liver cells are not destroyed by phosphorus poisoning, and Abderhalden and Schittenhelm* found that peptids are hydrolyzed fully as rapidly by phosphorus livers as by normal livers, it seems probable that extreme fatty metamorphosis is not associated with any serious injury to the enzymes by which the liver cells perform their metabolic functions, with the possible exception of those enzymes concerned with the metabolism of fats.
Antibodies to neutrophil cytoplasmic antigens in Wegener's granulomatosis and other conditions.
Authors: D J Harrison, R Simpson, R Kharbanda, V E Abernethy, G Nimmo
Journal: Thorax (1989)

The use of serum antibodies to neutrophil cytoplasmic antigens (ANCA) as a diagnostic marker for Wegener's granulomatosis and other forms of vasculitis has been assessed. Although ANCA have been described by several groups the precise antigenic targets are unknown, and detection of ANCA still relies on an indirect immunofluorescence assay technique. Several different patterns of fluorescence have been produced by using sera from different groups of patients, and insufficient information is available on the frequency of positive results and of the patterns of immunofluorescence obtained when serum from patients with vasculitis as a part of a generalised connective tissue disease is used. A study was carried out on serum from 240 patients, including 23 patients with Wegener's granulomatosis, 12 with microscopic polyarteritis, and 30 with various connective tissue diseases. Three patterns of fluorescence were observed: bright coarsely granular cytoplasmic, bright non-granular cytoplasmic, and weak diffuse cytoplasmic. The bright, coarsely granular pattern was 86% specific for Wegener's granulomatosis in this series and was observed in 18 of 23 cases. Other patterns of fluorescence were found in various conditions and were not of diagnostic value. The technique is simple, inexpensive, rapid, and reproducible.
Every case of essential thrombocythemia should be tested for the Philadelphia chromosome
Authors: Lawrence Rice, Uday Popat
Journal: American Journal of Hematology (2004)

Essential thrombocythemia (ET) and chronic myelogenous leukemia (CML) usually present with distinctive features. Citing experience with cases that overlap, the Polycythemia Vera Study Group recommends that negative tests for the Philadelphia chromosome be obtained before diagnosing ET. We describe two young women presenting with features absolutely typical for ET, including extreme thrombocytosis, no leukocytosis, no basophilia, no peripheral immature cells, and no splenomegaly. Severe thrombotic complications ensued: multiple cerebrovascular thromboemboli, pulmonary emboli, and miscarriage in one and myocardial infarction in the other. By 4 years, both developed leukocytosis, extreme basophilia, and circulating blasts, typical of accelerated CML. Cytogenetic studies were then performed, revealing the Philadelphia chromosome. Imatinib produced rapid clearing of blasts and basophils, but one woman later succumbed after allogeneic bone marrow transplant and the other has not achieved a major cytogenetic response. We conclude that CML can present in identical fashion as ET. The mandate for routine Philadelphia chromosome testing is magnified by the availability of targeted therapy and its greater efficacy in early stage disease. Am. J. Hematol. 78:71–73, 2005. © 2004 Wiley-Liss, Inc.
Positive Surgical Margins in Radical Prostatectomy: Outlining the Problem and Its Long-Term Consequences
Authors: Ofer Yossepowitch, Anders Bjartell, James A. Eastham, Markus Graefen, Bertrand D. Guillonneau, Pierre I. Karakiewicz, Rodolfo Montironi, Franceso Montorsi
Journal: European Urology (2008)
The B cell in systemic lupus erythaematosus: a rational target for more effective therapy
Authors: C B Driver, M Ishimori, M H Weisman
Journal: Annals of the Rheumatic Diseases (2007)

Current treatment options for systemic lupus erythaematosus (SLE) are diverse and poorly defined, and aggressive therapy can be associated with serious toxicity and tolerability issues. There is, therefore, a need for new and improved treatments to be studied thoroughly in well-designed controlled trials. B Cell dysfunction has emerged as a key pathophysiological component of SLE and is a prime target for the development of new agents for a wide range of lupus severity, including advanced disease. Although many current drugs appear to modify B cell function, the advent of new, targeted therapies offers the hope of improved efficacy and a better long-term tolerability profile.
Long-term Idiotype Vaccination Combined with Interleukin-12 (IL-12), or IL-12 and Granulocyte Macrophage Colony-Stimulating Factor, in Early-Stage Multiple Myeloma Patients
Authors: Lotta Hansson, Amir Osman Abdalla, Ali Moshfegh, Aniruddha Choudhury, Hodjattallah Rabbani, Bo Nilsson, Anders Osterborg, Håkan Mellstedt
Journal: Clinical Cancer Research (2007)

Abstract Purpose and Experimental Design: Twenty-eight patients with immunoglobulin G myeloma stages I to II were immunized i.d. over 110 weeks with autologous M protein combined with interleukin-12 (IL-12; n = 15) or with IL-12 and granulocyte macrophage colony-stimulating factor (GM-CSF; n = 13). Idiotype-specific T-cell responses were assessed by [3H]thymidine incorporation, enzyme-linked immunospot assay, and delayed-type hypersensitivity reaction. Results: Based on these three assays, idiotype-specific immune responses were noted in 5 of 15 (33%) patients in the IL-12 group and in 11 of 13 (85%) patients in the GM-CSF/IL-12 group (P &amp;lt; 0.01). Immune response was seen only in patients with M-component concentration of &amp;lt;50 g/L. Three of 16 (19%) responders showed a gradually increasing idiotype-specific T-cell response, whereas 11 of 16 (69%) patients showed initial response, which then disappeared rapidly; the latter pattern was frequently associated with subsequent progressive disease. Immune nonresponse was associated with an increase in the numbers of CD4+/CD25+ cells (regulatory T cells), which was absent in responding patients. Median time to progression for immune responders (n = 16) was 108 weeks compared with 26 weeks for nonresponders (n = 12; P = 0.03). Conclusions: These results indicate that idiotype immunization of myeloma patients with GM-CSF and IL-12 may induce specific T-cell response more frequently than with IL-12 alone and that immune response may correlate with time to progression and nonresponse with increased numbers of regulatory T cells.
Calcifications in the cuff: take it or leave it?
Authors: Dirk-Jan Hofstee, Taco Gosens, Michel Bonnet, Jan De Waal Malefijt
Journal: British Journal of Sports Medicine (2007)

Objectives: The aim of this study was to evaluate whether removing the calcifications in the rotator cuff tendons during surgical subacromial decompression improves outcome in patients with calcific tendonitis. Methods: Two groups of 20 patients with a subacromial impingement syndrome and cuff calcifications were operated on. In group A, patients had an anterolateral acromioplasty according to Neer with excision of calcifications. In group B, the same procedure was performed without additional excision of calcifications. After a minimum follow-up of 3 years the patients were assessed with the disabilities of arm, shoulder and hand score (DASH), the visual analogue scale (VAS) for pain, measurements of range of motion (ROM) in all planes, and satisfaction with treatment. Results: The results for the DASH score, ROM, VAS and satisfaction with treatement showed no significant difference between the two groups. Conclusion: The results of our study suggest that removal of calcific deposits with anterolateral acromioplasty does not influence patient outcome. Further prospective studies are needed to determine the optimal surgical treatment for calcific tendonitis.