tbuckley/cabot-search huggingface dataset:
Myeloperoxidase Genotypes and Enhanced Efficacy of Chemotherapy for Early-Stage Breast Cancer in SWOG-8897
Authors: Christine B. Ambrosone, William E. Barlow, Wanda Reynolds, Robert B. Livingston, I-Tien Yeh, Ji-Yeob Choi, Warren Davis, James M. Rae, Li Tang, Laura R. Hutchins, Peter M. Ravdin, Silvana Martino, C. Kent Osborne, Alan P. Lyss, Daniel F. Hayes, Kathy S. Albain
Journal: Journal of Clinical Oncology (2009)

Myeloperoxidase (MPO) generates reactive oxygen species and also activates xenobiotics. In a rigorous clinical trial (Southwest Oncology Group SWOG-8897), we examined relationships between genotypes and disease-free survival (DFS) among women treated for breast cancer, as well as those who did not receive adjuvant chemotherapy.Patients were assigned to risk groups according to standard prognostic features; the low-risk group (n = 753 genotyped) received follow-up only, and the high-risk group (n = 401 genotyped) was randomly assigned to adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) or cyclophosphamide, doxorubicin, and fluorouracil (CAF), with or without tamoxifen. DNA from archived normal lymph node tissue was genotyped, and Cox proportional hazard models were used to calculate DFS associated with MPO genotypes.Among women in the treatment arm, those with MPO G alleles had more than a two-fold reduction in hazard of recurrence (adjusted hazard ratio [HR] for GA genotypes, 0.51; 95% CI, 0.21 to 0.99; HR for GG genotypes, 0.41; 95% CI, 0.21 to 0.77). Effects were greatest among women who were further randomly assigned to tamoxifen (HR for GA genotypes, 0.28; 95% CI, 0.12 to 0.69; HR for GG genotypes, 0.19; 95% CI, 0.08 to 0.45). There were no significant associations between genotypes and DFS among women in the untreated arm, and relationships between genotypes and DFS did not differ by CAF or CMF.These results, observed in two independent study populations, indicate that high-activity MPO genotypes are associated with better survival among women receiving cyclophosphamide-containing therapy, particularly when followed by tamoxifen therapy. MPO can be inhibited and/or upregulated by commonly used drugs; thus, our findings merit further investigation for optimization of therapeutics for breast cancer.
Antisense Oligonucleotide Inhibition of Tumor Necrosis Factor Receptor 1 Protects the Liver from Radiation-Induced Apoptosis
Authors: Xiao W. Huang, Jiong Yang, Aleksandar F. Dragovic, Hong Zhang, Theodore S. Lawrence, Ming Zhang
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Liver damage by radiation limits its efficacy in cancer treatment. As radiation can generate apoptotic signals, we wished to examine the potential to protect the liver by inhibiting apoptosis through two key mediators, FAS and tumor necrosis factor receptor 1 (TNFR1). Experimental Design: Radiation-induced liver damage was assessed by serum aspartate aminotransferase and alanine aminotransferase, hepatocyte micronucleus formation, and apoptosis assays (terminal nucleotidyl transferase–mediated nick end labeling and caspase-3 cleavage) in mice. Protection was evaluated by pretreating mice with antisense oligonucleotides (ASO) for FAS or TNFR1 prior to radiation. TNF-α production in liver and in Kupffer cells were determined by ELISA. Results: Radiation increased liver FAS and TNFR1 transcription in a dose- and time-dependent manner (maximized at 25 Gy and 8 hours postirradiation). Pretreatment with ASOs for FAS and TNFR1 resulted in the inhibition of liver FAS and TNFR1 by 78% and 59%, respectively. Inductions of serum aspartate aminotransferase and alanine aminotransferase were observed at 2 hours after radiation and could be reduced by pretreating mice with ASO for TNFR1 but not FAS or control oligonucleotide. Radiation-induced liver apoptosis (terminal nucleotidyl transferase–mediated nick end labeling staining and caspase-3 activation on Western blot) and hepatocyte micronucleus formation were reduced by pretreatment with ASO for TNFR1. In addition, radiation stimulated TNF-α production both in irradiated liver and in cultured Kupffer cells by &amp;gt;50% and 100%, respectively. Conclusion: This study suggests that ionizing radiation activates apoptotic signaling through TNFR1 in the liver, and thus provides a rationale for anti-TNFR1 apoptotic treatment to prevent radiation-induced liver injury.
17β-Estradiol Decreases Endothelin-1 Levels in the Coronary Circulation of Postmenopausal Women With Coronary Artery Disease
Authors: Carolyn M. Webb, Mohammad A. Ghatei, John G. McNeill, None DCRR, Peter Collins
Journal: Circulation (2000)

Background —Estrogen reverses acetylcholine-induced coronary vasoconstriction via the possible facilitation of endothelium-derived NO. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the effects of 17β-estradiol on coronary vasomotor responses to substance P (SP), and coronary sinus endothelin-1 and NO metabolite levels in postmenopausal women with coronary heart disease. Methods and Results —We studied 20 women; 14 received estrogen (mean age 65±2 years) and 6 served as ethanol control subjects (age 63±3 years). Intracoronary infusions of papaverine (8 mg) and SP were administered before and 20 minutes after 50 pg/min 17β-estradiol or 0.2 μL/min control. Coronary blood flow was calculated from the diameter, as measured with quantitative coronary angiography, and flow velocity, as measured with intracoronary Doppler. Coronary sinus plasma endothelin-1 and nitrite/nitrate (NO 2 /NO 3 ) were measured at baseline, at peak velocity response to each infusion, and every 5 minutes during the estradiol infusion. Endothelin-1 levels were decreased after 20 minutes of estradiol (1.12±0.18 versus 0.86±0.17 pmol/L baseline2 versus estradiol, P =0.05). Endothelin-1 levels to SP decreased after 17β-estradiol (1.29±0.18 versus 1.04±0.15 and 1.3±0.16 versus 0.99±0.17 pmol/L for before versus after estradiol, 10 and 25 pmol/min SP; both P &lt;0.05). NO 2 /NO 3 levels did not change. There was no change in vasomotor responses to estradiol alone or to papaverine or SP before versus after estradiol. Conclusions —Short-term intracoronary 17β-estradiol administration decreases coronary endothelin-1 levels. There was no enhancement of vasomotor responses to SP after the administration of estrogen, suggesting that the effects of estrogen on coronary acetylcholine responses may be a specific and not a generalized effect on coronary vasoreactivity.
Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases
Authors: Robert Visse, Hideaki Nagase
Journal: Circulation Research (2003)

Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration. Currently 23 MMP genes have been identified in humans, and most are multidomain proteins. This review describes the members of the matrixin family and discusses substrate specificity, domain structure and function, the activation of proMMPs, the regulation of matrixin activity by tissue inhibitors of metalloproteinases, and their pathophysiological implication.
Greater Fish, Fruit, and Vegetable Intakes Are Related to Lower Incidence of Venous Thromboembolism
Authors: Lyn M. Steffen, Aaron R. Folsom, Mary Cushman, David R. Jacobs, Wayne D. Rosamond
Journal: Circulation (2006)

Little is known about the role of dietary intake in the development of deep vein thrombosis or pulmonary embolus (venous thromboembolism [VTE]). Homocysteine, factor VIII, and von Willebrand factor levels, risk factors for VTE, are influenced by dietary intake. We tested the hypothesis that foods rich in B vitamins and omega-3 fatty acids are negatively associated and meat intake is positively associated with incidence of VTE.In a prospective study over 12 years, 14,962 middle-aged adults participating in the Atherosclerosis Risk in Communities study were followed up for incident VTE. All hospitalizations were identified, and 196 VTEs were validated by chart review. A food frequency questionnaire assessed dietary intake at baseline and year 6. In separate proportional hazards regression analyses, risk of developing VTE was computed across quintiles of selected nutrients, major food groups, and the Western diet pattern, with adjustment for demographic and lifestyle factors, body mass index, and diabetes. Hazard ratios and 95% confidence intervals of VTE incidence across quintiles of fruit and vegetable intake were 1.0 (reference), 0.73 (0.48 to 1.11), 0.57 (0.37 to 0.90), 0.47 (0.29 to 0.77), and 0.59 (0.36 to 0.99) (P(trend)=0.03). Eating fish 1 or more times per week was associated with 30% to 45% lower incidence of VTE for quintiles 2 to 5 compared with quintile 1, suggestive of a threshold effect. Hazard ratios of VTE across quintiles of red and processed meat intake were 1.0, 1.24 (0.78 to 1.98), 1.21 (0.74 to 1.98), 1.09 (0.64 to 1.87), and 2.01 (1.15 to 3.53) (P(trend)=0.02). Hazard ratios were attenuated only slightly after adjustment for factors VIIc and VIIIc and von Willebrand factor.A diet including more plant food and fish and less red and processed meat is associated with a lower incidence of VTE.
A phase III comparison of CHOP vs. m-BACOD vs. ProMACE-CytaBOM vs. MACOP-B in patients with intermediate- or high-grade non-Hodgkin's lymphoma: Results of SWOG-8516 (Intergroup 0067), the National High-Priority Lymphoma Study
Authors: R.I. Fisher, E.R. Gaynor, S. Dahlberg, M.M. Oken, T.M. Grogan, E.M. Mize, J.H. Glick, C.A. Coltman, T.P. Miller
Journal: Annals of Oncology (1994)
Arterio-venous Aneurysm, Anastomosis of Vein, and Suture of Artery
Authors: H. J. Godwin
Journal: BMJ (1915)

Captain Addinsell uoticedthat there was diffuse pulsation, with a thrill over the base of Scarpa's triangle.No operation was attempted.When I saw the case, two days after admission, there was s-light swelling over the base of Scarpa's triangle, a very marked thirill, and a bruit so loud that it cotld be heard by approaching the ear to the thigh without toucljing it.The murmur was conducted to the tibial vessels and upwards to the abdominal norta.The whole leg was slightly oedematous.Although rest by sandbags and elevation of the limb were used, the leg and tihigh became progressively more oedematous, and the pain .persisted.After tenldays this gradually passed away and the l)osterior tibial and dorsalis pedis arteries became palpable.'lTe point of maximum intensity of thrill and murmur became niore localized to a point just below Poupart's ligament.He vas evacuated to Enigland on October 8th, 1915, I,ith his leg normal in size, less pain, and in good general condition.Having briefly related the symptoms and lhistory of these cases, I should like to colmipare some points with the description given in Keen's Surgery (edition 1914).
Sinus mucosal IL-8 gene expression in chronic rhinosinusitis
Authors: Chan Rhyoo, Scherer P. Sanders, Donald A. Leopold, David Proud
Journal: Journal of Allergy and Clinical Immunology (1999)

Background: Epithelial hyperplasia and mucosal infiltration of leukocytes are common features of chronic rhinosinusitis. The epithelium can produce chemoattractant cytokines that may contribute to leukocyte infiltration in rhinosinusitis. Objective: We sought to determine whether mucosal IL-8 gene expression is increased in chronic rhinosinusitis and to relate IL-8 gene expression to disease severity. Methods: We used both a noncompetitive and a quantitative, competitive reverse transcription-polymerase chain reaction to examine IL-8 gene expression in samples of sinus mucosal tissue obtained during surgery from 22 patients with chronic rhinosinusitis and 9 normal control subjects. IL-8 gene expression was related to disease severity assessed by sinus computed tomography (CT) scores and to symptom scores assessed by means of a questionnaire. Results: Sinus mucosal IL-8 gene expression was not detected in any of the control subjects but was present in 12 of 22 (55%) patients with rhinosinusitis. Sinus CT scores and symptom scores were both significantly higher in patients with positive mucosal IL-8 gene expression than in subjects with no detectable IL-8 gene expression. Positive IL-8 gene expression was not predicted by history of prior surgery nor by atopic or asthmatic status. In 9 subjects with positive IL-8 gene expression, levels of mRNA expression, assessed by competitive reverse transcription-polymerase chain reaction, correlated significantly (rho = 0.72, P < .05) with sinus CT scores. Conclusion: Sinus mucosal expression of the gene for IL-8 is increased in patients with chronic rhinosinusitis, and the level of IL-8 gene expression correlates with disease severity. (J Allergy Clin Immunol 1999;103:395-400.)
Increased <i>MET</i> Gene Copy Number Negatively Affects Survival of Surgically Resected Non–Small-Cell Lung Cancer Patients
Authors: Federico Cappuzzo, Antonio Marchetti, Margaret Skokan, Elisa Rossi, Sujatha Gajapathy, Lara Felicioni, Maela del Grammastro, Maria Grazia Sciarrotta, Fiamma Buttitta, Matteo Incarbone, Luca Toschi, Giovanna Finocchiaro, Annarita Destro, Luigi Terracciano, Massimo Roncalli, Marco Alloisio, Armando Santoro, Marileila Varella-Garcia
Journal: Journal of Clinical Oncology (2009)

To investigate the prognostic role of genomic gain for MET and epidermal growth factor receptor (EGFR) genes in surgically resected non-small-cell lung cancer (NSCLC).This retrospective study included 447 NSCLC patients with available tumor tissue from primary lung tumor and survival data. EGFR and MET status was evaluated by fluorescent in situ hybridization (FISH) in tissue microarray sections.EGFR FISH results were obtained in 376 cases. EGFR gene amplification and high polysomy (EGFR FISH+) were observed in 10.4% and 32.4% of cases, respectively. EGFR FISH-positive patients had a nonsignificant shorter survival than EGFR FISH-negative patients (P = .4). Activating EGFR mutations were detected in 9.7% of 144 stage I-II disease with no impact on survival. MET FISH analysis was performed in 435 cases. High MET gene copy number (mean > or = 5 copies/cell) was observed in 48 cases (MET+, 11.1%), including 18 cases with true gene amplification (4.1%). MET+ status was associated with advanced stage (P = .01), with grade 3 (P = .016) and with EGFR FISH+ result (P < .0001). No patient with activating EGFR mutation resulted MET+. In the whole population, MET-positive patients had shorter survival than MET-negative patients (P = .005). Multivariable model confirmed that MET-negative patients had a significant reduction in the risk of death than MET-positive patients (hazard ratio, 0.66; P = .04).MET increased gene copy number is an independent negative prognostic factor in surgically resected NSCLC. EGFR gene gain does not impact survival after resection.
An apPEAling new therapeutic for ulcerative colitis?
Authors: Declan P McKernan, David P Finn
Journal: Gut (2013)

<h3>Abstract</h3> Secretory preproteins of the Sec pathway bear signal peptides and are targeted post-translationally to cross the plasma membrane or ER through translocases. After translocation and signal peptide cleavage, mature domains fold to native states in the bacterial periplasm or after further trafficking. During cytoplasmic transit, mature domains must remain non-folded for translocase recognition and translocation. Here, we sought the structural basis for the delayed folding mechanism of mature domains and how this is regulated by signal peptides. To address this, we compared how evolution diversified a periplasmic peptidyl-prolyl isomerase PpiA mature domain from its structural twin cytoplasmic PpiB. Using global and local hydrogen deuterium exchange mass spectrometry we showed that PpiA is a slower folder. We defined at near-residue resolution hierarchical folding initiated by similar foldons in the twins, that displayed different order and rates. Folding is delayed in PpiA by less hydrophobic/bulky native contacts, frustrated residues and a critical β -turn in the early folding region and by signal peptide-driven disorder, which disrupts foldon hierarchy. When selected PpiA residues and its signal peptide were grafted onto PpiB they converted it into a slow folder with enhanced <i>in vivo</i> secretion. These data reveal the structural basis of non-folding in a secretory protein, that allows its trafficking.
Effects of alkaline protease or restrictocin deficient mutants of Aspergillus fumigatus on human polymorphonuclear leukocytes
Authors: Y Ikegami, R Amitani, T Murayama, R Nawada, WJ Lee, R Kawanami, F Kuze
Journal: European Respiratory Journal (1998)

Several substances including proteases and restrictocin have been suggested as candidates for virulence determinants in invasive pulmonary aspergillosis. However, the roles of such substances are not well understood. This study compared the in vitro suppressive effects of Aspergillus fumigatus culture filtrates (ACFs), on the functions of human polymorphonuclear leukocytes (PMNLs), the principal cells in the host defence against aspergillus hyphae, from a clinically isolated wild-type and isogenic mutant strains which lack production of elastolytic alkaline protease (Alp) and/or restrictocin. ACFs were obtained by culturing conidia of each strain in Medium- 199 at 37 degrees C for 5 days. ACFs of the wild-type significantly (p<0.01) suppressed chemotaxis, superoxide anion (O2-) release and PMNL-mediated hyphal damage, compared with the control (Medium-199). ACFs of the mutant strains that lack Alp or restrictocin significantly (p<0.01) suppressed chemotaxis and O2(-)-release, but did not suppress hyphal damage, compared with the control. The wild-type significantly (p<0.01) suppressed chemotaxis of PMNLs compared with the mutant strains lacking Alp or restrictocin, whereas there were no significant differences in suppression of O2(-)-release and hyphal damage by PMNLs. ACF of a mutant strain that lacks both Alp and restrictocin had much less activity, but significantly (p<0.01) suppressed chemotaxis of PMNLs compared with the control. In conclusion, alkaline protease and restrictocin may play roles in the suppressive effect of Aspergillus fumigatus culture filtrates on the functions of human polymorphonuclear leukocytes. Other antiphagocytic substances produced by Aspergillus fumigatus remain to be identified.
Nicholson insists he will oversee NHS reorganisation, despite calls for resignation
Authors: A. O'Dowd
Journal: BMJ (2013)

The head of the NHS in England has told MPs that he was determined to continue to steer the NHS as controversial changes come into effect next month, despite calls for his resignation in the wake of the Mid Staffordshire NHS Foundation Trust scandal.1 2

At a fiery session of the parliamentary health select committee on 5 March, MPs questioned the NHS chief executive, David Nicholson, for almost three hours about the recent report of the public inquiry by Robert Francis QC into Mid Staffs and asked whether it was time for someone else to take charge.

The GP and committee member Sarah Wollaston, the Conservative MP for Totnes, asked, “How far do you take personal responsibility for an organisation that’s been shown to minimise patient complaints, gag whistleblowers, massage mortality data, bury bad news, …
Upregulation of Phosphodiesterase 1A1 Expression Is Associated With the Development of Nitrate Tolerance
Authors: Dongsoo Kim, Sergei D. Rybalkin, Xinchun Pi, Yining Wang, Changxi Zhang, Thomas Munzel, Joseph A. Beavo, Bradford C. Berk, Chen Yan
Journal: Circulation (2001)

Background The efficacy of nitroglycerin (NTG) as a vasodilator is limited by tolerance, which develops shortly after treatment begins. In vascular smooth muscle cells (VSMCs), NTG is denitrated to form nitric oxide (NO), which activates guanylyl cyclase and generates cGMP. cGMP plays a key role in nitrate-induced vasodilation by reducing intracellular Ca 2+ concentration. Therefore, one possible mechanism for development of nitrate tolerance would be increased activity of the cGMP phosphodiesterase (PDE), which decreases cGMP levels. Methods and Results To test this hypothesis, rats were made tolerant by continuous infusion of NTG for 3 days (10 μg · kg −1 · min −1 SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca 2+ /calmodulin (CaM)–stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca 2+ /CaM-stimulated PDE revealed that PDE1A1 was increased 2.3-fold in NTG-tolerant rat aortas. Increased PDE1A1 was due to mRNA upregulation as measured by relative quantitative reverse transcription–polymerase chain reaction. The PDE1-specific inhibitor vinpocetine partially restored the sensitivity of the tolerant vasculature to subsequent NTG exposure. In cultured rat aortic VSMCs, angiotensin II (Ang II) increased PDE1A1 activity, and vinpocetine blocked the effect of Ang II on decrease in cGMP accumulation. Conclusions Induction of PDE1A1 in nitrate-tolerant vessels may be one mechanism by which NO/cGMP-mediated vasodilation is desensitized and Ca 2+ -mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.
Modulation of heparan sulfate in the glomerular endothelial glycocalyx decreases leukocyte influx during experimental glomerulonephritis
Authors: Angelique LWMM Rops, Markus A. Loeven, Jasper J. van Gemst, Iris Eversen, Xander M. Van Wijk, Henry B. Dijkman, Toin H. van Kuppevelt, Jo H.M. Berden, Ton J. Rabelink, Jeffrey D. Esko, Johan van der Vlag
Journal: Kidney International (2014)
Genetically Encoded Immunophotosensitizer 4D5scFv-miniSOG is a Highly Selective Agent for Targeted Photokilling of Tumor Cells in<i> Vitro</i>
Authors: Kristina E. Mironova, Galina M. Proshkina, Anastasiya V. Ryabova, Oleg A. Stremovskiy, Sergey A. Lukyanov, Rem V. Petrov, Sergey M. Deyev
Journal: Theranostics (2013)

Tumor-targeted delivery of cytotoxins presents considerable advantages over their passive transport. Chemical conjugation of cytotoxic module to antibody is limited due to insufficient reproducibility of synthesis, and recombinant immunotoxins are aimed to overcome this disadvantage. We obtained genetically encoded immunophotosensitizer 4D5scFv-miniSOG and evaluated its photocytotoxic effect in vitro. A single-chain variable fragment (scFv) of humanized 4D5 antibody was used as a targeting vehicle for selective recognition of the extracellular domain of human epidermal growth factor receptor 2 (HER2/neu) overexpressed in many human carcinomas. As a phototoxic module we used a recently described photoactivated fluorescent flavoprotein miniSOG. We found that recombinant protein 4D5scFv-miniSOG exerts a highly specific photo-induced cytotoxic effect on HER2/neu-positive human breast adenocarcinoma SK-BR-3 cells (IC50= 160 nM). We demonstrated that the 4D5scFv-miniSOG specifically binds to HER2-positive cells and internalizes via receptor-mediated endocytosis. Co-treatment of breast cancer cells with 4D5scFv-miniSOG and Taxol or junction opener protein JO-1 produced remarkable additive effects.