tbuckley/cabot-search huggingface dataset:
Predictors of Outcomes in Medically Treated Patients With Acute Coronary Syndromes After Angiographic Triage
Authors: Kenji Goto, Alexandra J. Lansky, Martin Fahy, Ecatarina Cristea, Frederick Feit, E. Magnus Ohman, Harvey D. White, Karen P. Alexander, Michel E. Bertrand, Walter Desmet, Martial Hamon, Roxana Mehran, Gregg W. Stone
Journal: Circulation (2010)

Outcomes of patients presenting with acute coronary syndromes are improved with an early invasive approach; however, approximately one third of these patients are treated medically after angiographic screening. We sought to assess the predictors of adverse cardiac events in patients with acute coronary syndrome assigned to medical management.This substudy of the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial included 4491 acute coronary syndrome patients treated medically after angiographic triage. Rates of bleeding and composite ischemia (death, myocardial infarction, revascularization) were compared among the 3 antithrombotic treatment arms. Composite ischemia occurred in 399 patients (9.5%) at 1 year. Treatment with bivalirudin glycoprotein IIb/IIIa inhibitors significantly reduced major bleeding at 30 days (2.5% bivalirudin monotherapy; P=0.005, 2.0% bivalirudin plus glycoprotein IIb/IIIa inhibitors; P=0.0002 versus 4.4% heparin with glycoprotein IIb/IIIa inhibitors). Composite ischemic events at 1 year were not significantly different in the 3 groups (bivalirudin monotherapy, 9.6%; bivalirudin plus glycoprotein IIb/IIIa inhibitors, 9.7%; heparin plus glycoprotein IIb/IIIa inhibitors, 9.1%). Independent predictors of composite ischemia were mostly angiographic factors at 30 days, including jeopardy score and coronary ectasia, and at 1 year, including previous percutaneous coronary intervention, jeopardy score, coronary ectasia, and increasing number of diseased vessels.Among the ACUITY acute coronary syndrome patients treated medically after angiographic triage, bivalirudin therapy significantly reduced bleeding complications compared with heparin without any negative impact on ischemic outcomes at 1 year. The most powerful predictors of ischemic outcomes were angiographic rather than traditional clinical parameters, supporting the early use of angiographic screening in the moderate- and high-risk but medically treated acute coronary syndrome population. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00093158.
Reactive airways dysfunction syndrome (RADS) following exposure to toxic gases of a swine confinement building
Authors: Y Cormier, B Coll, M Laviolette, LP Boulet
Journal: European Respiratory Journal (1996)

We describe the case of a 58 year old male, who developed a reactive airways dysfunction syndrome (RADS) after exposure to a high level of toxic gases in a swine confinement building. This previously healthy, nonatopic man developed moderate, partially reversible, airway obstruction and increased responsiveness within a month after the toxic exposure. The circumstances of the incident and the concomitant death of two sows make it likely that hydrogen sulphide was the causative agent. To our knowledge, this is the first case of reactive airways dysfunction syndrome reported from swine confinement buildings and, therefore, should raise awareness of this potential risk in that work environment.
Protective effects of thromboxane synthetase inhibitors in rats in endotoxic shock.
Authors: W C Wise, J A Cook, P V Halushka, D R Knapp
Journal: Circulation Research (1980)

To evaluate the pathogenic role of thromoboxane (Tx) in endotoxic shock, the potential protective effects of the Tx synthetase inhibitor, 7-(l-imidazolyl)-heptanoic acid (7-IHA) was assessed and compared to that of imidazole in the rat.7-IHA (30 mg/kg) administered iv 30 minutes prior to Salmonella enteritidis endotoxin (20 mg/kg, iv) improved the survival rate from 42% (n = 24) at 5 hours in the vehicle-treated rats to 100% (n = 11).By 24 hours, only 8% of the vehicle-treated rats survived, whereas 80% of the treated group survived.Venous plasma thromboxane B 2 elevation did not occur if 7-IHA (30 mg/kg) was administered iv 30 minutes prior to endotoxin (20 mg/kg, iv).However, 7-IHA did not inhibit endotoxin-induced elevations in plasma prostaglandin E. Endotoxin induced a significant reduction in the platelet counts in vehicle-treated rats from 780 ± 64 x 10 3 /mm 3 to 179 ± 18 x 10 3 /mm 3 (n = 6, P< 0.01) by 15 minutes, whereas, in imidazole-pretreated rats, the platelet count fell significantly less to 402 ± 55 x 10 3 /mm 3 (n = 6, P < 0.05), and in the 7-IHA-pretreated rats, the platelet count fell to 541 ± 91 x 10 3 /mm 3 (n = 5, P < 0.05).Fibrinogen/fibrin degradation products were significantly increased (P < 0.01) in response to endotoxic shock, but both imidazole and 7-IHA significantly decreased (P< 0.05) this elevation.Imidazole and 7-IHA pretreatment prevented lysosomal labilization in endotoxic shock as denoted by significantly decreased elevations in serum acid phosphatase and figlucuronidase.Similarly, reduction in hepatic cellular damage, as assessed by decreased elevations of serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase, was apparent.These results are consistent with the hypothesis that TxA 2 plays a significant role in the pathogenesis of endotoxic shock.
The Human Cervical Cancer Oncogene Protein Is a Biomarker for Human Hepatocellular Carcinoma
Authors: Seung Kew Yoon, Nam Kyu Lim, Seon-Ah Ha, Yong Gyu Park, Jong Young Choi, Kyu Won Chung, Hee Sik Sun, Myung Ja Choi, Junho Chung, Jack R. Wands, Jin Woo Kim
Journal: Cancer Research (2004)

Abstract Human cervical cancer oncogene (HCCR) was identified and appeared to function as a negative regulator of p53 gene. The objective of this study was to validate HCCR expression as a candidate marker for human hepatocellular carcinoma. HCCR epitope was identified as Y355LGTRR360. According to immunofluorescence study, HCCR was predominantly localized in the plasma membrane and cytoplasm of hepatocellular carcinoma. HCCR proteins were overexpressed in the tumorous compared with the nontumorous cirrhosis tissues. However, HCCR was not detected in normal liver tissue. Concentration of HCCR protein in the serum was measured in a total of 570 subjects, and comparisons were made to α-fetoprotein. Serological studies revealed 78.2% sensitivity of HCCR (cutoff value, 15 μg/ml), which was significantly higher than 64.6% of α-fetoprotein (P = 0.0098) and 95.7% specificity for hepatocellular carcinoma. Forty of 52 (76.9%) patients with carcinoma negative for α-fetoprotein showed positive values for HCCR. A positive rate of 69.2% in carcinoma patients with tumor sizes &amp;lt;2 cm was found to be a higher rate than measurement of α-fetoprotein. Furthermore, HCCR expression was also detected in liver cirrhosis at an intermediate level between carcinoma and normal groups, which gave 88.1% sensitivity and 79.0% specificity using 8 μg/ml as a cutoff value. In summary, the HCCR assay may have an advantage over the α-fetoprotein assay in that it is elevated according to disease progression from liver cirrhosis to carcinoma, and it is more frequently positive in patients with early, small hepatocellular carcinoma.
Human Adolescent Nephronophthisis
Authors: HEYMUT OMRAN, KARSTEN HA[Combining Diaeresis]FFNER, SUSE BURTH, CARMEN FERNANDEZ, BERNARDO FARGIER, AMINTA VILLAQUIRAN, HANS-GERD NOTHWANG, SUSANNE SCHNITTGER, HANS LEHRACH, DAVID WOO, MATTHIAS BRANDIS, RALF SUDBRAK, FRIEDHELM HILDEBRANDT
Journal: Journal of the American Society of Nephrology (2001)

In a large Venezuelan kindred, a new type of nephronophthisis was recently identified: Adolescent nephronophthisis (NPH3) is a late-onset recessive renal cystic disorder of the nephronophthisis/medullary cystic group of diseases causing end-stage renal disease at a median age of 19 yr. With the use of a homozygosity mapping strategy, the gene (NPHP3) was previously localized to chromosome 3q22 within a critical interval of 2.4 cM. In the current study, the NPHP3 genetic region was cloned and seven genes, eight expressed sequence-tagged sites, and seven microsatellites were physically localized within the critical disease interval. By human-mouse synteny analysis based on expressed genes, synteny between the human NPHP3 locus on chromosome 3q and the pcy locus on mouse chromosome 9 was clearly demonstrated, thus providing the first evidence of synteny between a human and a spontaneous murine renal cystic disease. By fluorescence in situ hybridization the chromosomal assignment of NPHP3 to chromosome 3q21-q22 was refined. Renal pathology in NPH3 was found to consist of tubular basement membranes changes, tubular atrophy and dilation, and sclerosing tubulointerstitial nephropathy. This pathology clearly resembled findings observed in the recessive pcy mouse model of late-onset polycystic kidney disease. In analogy to pcy, renal cyst development at the corticomedullary junction was found to be an early sign of the disease. Through cloning of the NPH3 critical region and mapping of expressed genes, synteny between human NPH3 and murine pcy was established, thus generating the hypothesis that both diseases are caused by recessive mutations of homologous genes.
The Prediction of Small Airway Dimensions Using Computed Tomography
Authors: Yasutaka Nakano, Jonathan C. Wong, Pim A. de Jong, Lilliana Buzatu, Taishi Nagao, Harvey O. Coxson, W. Mark Elliott, James C. Hogg, Peter D. Paré
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

Chronic obstructive pulmonary disease is characterized by destruction of the lung parenchyma and/or small airway narrowing. To determine whether the dimensions of relatively large airways assessed using computed tomography (CT) reflect small airway dimensions measured histologically, we assessed these variables in nonobstructed or mild to moderately obstructed patients having lobar resection for a peripheral tumor. For both CT and histology, the square root of the airway wall area (Aaw) was plotted versus lumen perimeter to estimate wall thickness. The wall area percentage was calculated as wall area/lumen area + wall area x 100. Although CT overestimated Aaw, the slopes of the relationships between the square root of Aaw and internal perimeter (Pi) measured with both techniques were related (CT slope = 0.2059 histology slope + 0.1701, R2 = 0.32, p < 0.01). The mean wall area percentage measured by CT for airways with a Pi of greater than 0.75 cm predicted the mean dimensions of the small airways with an internal diameter of 1.27 mm (R2 = 0.57, p < 0.01). We conclude that CT measurements of airways with a Pi of 0.75 cm or more could be used to estimate the dimensions of the small conducting airways, which are the site of airway obstruction in chronic obstructive pulmonary disease.
Relationship between six-minute walk distance and chronic obstructive pulmonary disease assessment test
Authors: Selina Dürr, Stefanie Zogg, Sabrina Maier, Esther Helen Steveling, David Miedinger, Jörg Daniel Leuppi
Journal: European Respiratory Journal (2012)

Background: Many patients with chronic obstructive pulmonary disease (COPD) are affected by the impairment in the ability to perform daily physical activities due to exercise intolerance, which can lead to a poor health-related quality of life.

Aims and objectives: Our aim was to investigate the association of the six-minute walk distance (6MWD) and the COPD assessment test (CAT). We hypothesized that physical capacity has a more relevant association with quality of life than lung function.

Methods: This cross-sectional study was conducted in 2011 at the University Hospital of Basel, Switzerland. Patients with COPD stages I to IV were investigated. Functional exercise capacity was measured by the six-minute walk test according to the guidelines of the American Thoracic Society. Spirometry was performed according to current guidelines. Health status was assessed by the CAT. A forced entry multiple regression analysis was calculated. The regression included 6MWD, forced expiratory volume in one second in % of predicted (FEV1%predicted), age and Body-Mass-Index (BMI). The dependent variable was the CAT-score.

Results: Complete data were available for 73 individuals (age 67.0 ±9.8yrs, 58.9% male, FEV1%predicted 69.7 ±23.7%, 6MWD 434.5 ±99.1m, CAT-score 12.5 ±6.8, BMI 25.7 ±5.5). Age and 6MWD significantly contributed to the model (β= -0.49 respectively β= -0.46, p<0.01). BMI and FEV1%predicted did not significantly influence the CAT-score (β= -0.14 respectively β= -0.13).

Conclusion: The association of the 6MWD and the CAT-score indicates that higher physical fitness level is related to improved health status and thus decreased impact of COPD on an individual's life.
The CFTR and EGFR relationship in airway vascular growth, and its importance in cystic fibrosis
Authors: Jay A. Nadel
Journal: European Respiratory Journal (2013)

Describing the battle between lung defences and atmospheric invaders e.g.viruses: the winner determines our viability http://ow.ly/p7y0HIn this issue of the European Respiratory Journal, MARTIN et al. [1] focus on the life-threatening complication of haemoptysis in cystic fibrosis (CF).The authors examine the role of vascular endothelial growth factor (VEGF)-A on angiogenesis in the normal state and in CF.They report that CF airways at transplantation show increased vascularity and increased VEGF-A expression.In normal human airway epithelial cells they report that VEGF-A synthesis is produced via activation of the epidermal growth factor receptor (EGFR) and is suppressed by a selective EGFR inhibitor.Most novel and exciting are the findings that in airway epithelial cells containing cystic fibrosis transmembrane conductance regulator (CFTR), inhibition of CFTR increases EGFR activation and that an inhibitor of EGFR activation prevents the VEGF-A synthesis induced by suppression of CFTR, suggesting that there is a reciprocal relationship between CFTR and EGFR.Both CFTR and EGFR coexist on the airway epithelial surface.EGFR activation results in ''pro-inflammatory responses''; in addition to VEGF-A, this includes other products such as interleukin-8 (a potent neutrophil chemoattractant) [2] and mucins [3].The fact that inhibition of CFTR results in exaggerated production of VEGF-A suggests that CFTR normally suppresses the EGFR ''inflammatory'' responses.VEGF-A production occurs in response to EGFR activation.The study by MARTIN et al. [1] found that suppression of CFTR increased EGFR activation, but only after 8 h.This suggests that a complicated series of signalling events is involved in the activation of EGFR as a consequence of CFTR suppression.Research on the signalling pathways involved remains to be investigated.The study by MARTIN et al. [1] describes the role of airway epithelial cell signalling in the regulation of bronchial vessel growth.Activation of EGFR promotes peribronchial angiogenesis, and the presence of CFTR on the epithelial surface inhibits this host response (the production of new bronchial vessels).The details of the cell signalling involved in the interactions of EGFR and CFTR remain unknown and may extend to a variety of actions.Furthermore, they can also provide insights into novel regulatory functions of CFTR.CFTR gene malfunction in CF is a topic of great interest.In addition, recent studies suggest that changes in CFTR activity can also occur in subjects without CF.For example, DRANSFIELD et al. [4] recently reported that smokers have reduced lower airway CFTR activity compared to healthy nonsmokers.The authors suggest that acquired CFTR dysfunction may contribute to COPD pathogenesis.It should also be noted that chronic smoking results in increased expression of EGFR, which could suppress CFTR activity.Thus, the level of activity of EGFR could modulate the expression and activity of CFTR.
Hedgehog and Notch Signaling Regulate Self-Renewal of Undifferentiated Pleomorphic Sarcomas
Authors: Chang Ye Yale Wang, Qingxia Wei, Ilkyu Han, Shingo Sato, Ronak Ghanbari- Azarnier, Heather Whetstone, Raymond Poon, Jiayi Hu, Feifei Zheng, Phil Zhang, Weishi Wang, Jay S. Wunder, Benjamin A. Alman
Journal: Cancer Research (2012)

Like many solid tumors, sarcomas are heterogeneous and include a small fraction of the so-called side population (SP) cells with stem-like tumor-initiating potential. Here, we report that SP cells from a soft tissue tumor of enigmatic origin termed undifferentiated pleomorphic sarcoma (also known as malignant fibrous histiocytoma or MFH sarcoma) display activation of both the Hedgehog and Notch pathways. Blockade to these pathways in murine xenograft models, this human cancer decreased the proportion of SP cells present and suppressed tumor self-renewal, as illustrated by the striking inability of xenograft tumors subjected to pathway blockade to be serially transplanted to new hosts. In contrast, conventional chemotherapies increased the proportion of SP cells present in tumor xenografts and did not affect their ability to be serially transplanted. SP cells from these tumors displayed an unexpectedly high proliferation rate which was selectively inhibited by Hedgehog and Notch blockade compared with conventional chemotherapies. Together, our findings deepen the concept that Hedgehog and Notch signaling are fundamental drivers of tumor self-renewal, acting in a small population of tumor-initiating cells present in tumors. Furthermore, our results suggest not only novel treatment strategies for deadly recurrent unresectable forms of this soft tumor subtype, but also potential insights into its etiology which has been historically controversial.
Effect of arginase II on L-arginine depletion and cell growth in murine cell lines of renal cell carcinoma
Authors: David J Tate, Derek J Vonderhaar, Yupanqui A Caldas, Toye Metoyer, John R Patterson, Diego H Aviles, Arnold H Zea
Journal: Journal of Hematology & Oncology (2008)

Abstract Background L-arginine is the common substrate for the two isoforms of arginase. Arginase I, highly expressed in the liver and arginase II mainly expressed in the kidney. Arginase I-producing myeloid derived suppressor cells have been shown to inhibit T-cell function by the depletion of L-arginine. On the other hand, arginase II has been detected in patients with cancer and is thought to metabolize L-arginine to L-ornithine needed to sustain rapid tumor growth; however its role in L-arginine depletion is unclear. Thus, in tumor biology, L-arginine metabolism may play a dual role in tumor growth and in the induction of T cell dysfunction. Therefore, we studied in murine renal cell carcinoma (RCC) cell lines, the effect of arginase II on tumor cell proliferation and L-arginine depletion. The effect of arginase inhibitors on cell proliferation was also tested. Methods Three murine renal cell carcinoma (mRCC) cell lines were tested for the presence of arginase. nor-NOHA, an arginase inhibitor was used to substantiate the effect of arginase on cell growth and L-arginine depletion. Amino acid levels were tested by HPLC. Results Our results show that mRCC cell lines express only arginase II and were able to deplete L-arginine from the medium. Cell growth was independent of the amount of arginase activity expressed by the cells. nor-NOHA significantly ( P = 0.01) reduced arginase II activity and suppressed cell growth in cells exhibiting high arginase activity. The depletion of L-arginine by mRCC induced the decrease expression of CD3ζ a key element for T-cell function. Conclusion The results of this study show for the first time that arginase II produced by RCC cell lines depletes L-arginine resulting in decreased expression of CD3ζ. These results indicate that RCC cell lines expressing arginase II can modulate the L-arginine metabolic pathway to regulate both cell growth and T-cell function. Blocking arginase may lead to a decrease in RCC cell growth and aid in restoring immune function by increasing L-arginine availability for T-cell use. Understanding the interplay between arginase II and its interaction with the immune system may provide future therapeutic benefits to treat patients with RCC.
Bronchiolar wall structure is altered in adult mice following neonatal hyperoxia
Authors: Megan O'Reilly, Foula Sozo, Richard Harding
Journal: European Respiratory Journal (2012)

Background:  Very preterm infants often require supplemental oxygen, and can have an increased risk of poor lung function and asthma in later life. Follow-up studies suggest that factors associated with very preterm birth can cause long-term changes in the the small conducting airways.   Aim:  To determine if bronchiolar wall structure is persistently affected by neonatal exposure to hyperoxic gas.   Methods:  Neonatal mice (C57BL/6J) breathed 65% O 2  from birth until postnatal day 7 (P7), after which they lived in room air until P56 (n=26). Controls breathed room air from birth (n=27). Bronchiolar walls, lung parenchyma and bronchoalveolar fluid (BALF) were analysed at P56. In bronchioles, we measured epithelial thickness, proportions of proliferating epithelial cells, ciliated and Clara cells, the amount of collagen and airway smooth muscle (ASM), and the number of alveolar-bronchiolar attachments. In lung parenchyma, we measured percent tissue space and mean linear intercept (MLI).   Results:  In bronchioles, adult mice exposed to neonatal hyperoxia had significantly thicker epithelium, more ASM and more collagen than controls (p   Conclusions:  Exposing the developing lung to hyperoxic gas results in persistent airway remodelling and increased numbers of pulmonary immune cells suggesting on-going inflammation in adulthood.
Activation of the<b><i>MDR1</i></b>Upstream Promoter in Breast Carcinoma as a Surrogate for Metastatic Invasion
Authors: Selina Raguz, Manuela Tamburo De Bella, Gopichani Tripuraneni, Martin J. Slade, Christopher F. Higgins, R. Charles Coombes, Ernesto Yagüe
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Activation of the MDR1 upstream promoter (USP) has been described previously in four lymphoblastic leukemia patients, where it is the major MDR1 promoter associated with P-glycoprotein overexpression. We asked whether MDR1 USP-derived transcripts were also present in breast carcinoma and assessed their potential as a biomarker. Experimental Design: We developed a sensitive method for detecting transcripts derived from the MDR1 USP and used it to identify MDR1 USP-derived transcripts in cell model systems, in 61 breast carcinoma biopsies of the primary tumor, and in isolated malignant epithelial cells both from the primary tumor and from the associated invaded lymph nodes. Results: The MDR1 USP was not active in several independent leukemic and breast cancer cell lines or nucleated peripheral blood cells (n = 9). However, transcripts derived from the MDR1 USP were detected in some drug-resistant cell lines and a high proportion of primary breast tumors (71.6%; n = 61), whereas they were present at low frequency in normal breast tissue (10%; n = 10). Activation of MDR1 USP was not due to chromosomal amplifications or rearrangements at the MDR1 locus. Transcription from the MDR1 USP correlated with metastatic node invasion [N = 0–3 versus N &amp;gt; 3 (N = number of lymph nodes invaded); Fisher’s exact test, P = 0.011] and was detected in malignant epithelial cells from the primary tumor and those that metastasized to the lymph nodes. Conclusions: MDR1 USP activation is a surrogate marker for breast carcinoma progression and can be used as a marker to study breast cancer susceptibility.