tbuckley/cabot-search huggingface dataset:
The role of oxygen-derived free radicals in ischemia-induced increases in canine skeletal muscle vascular permeability.
Authors: R J Korthuis, D N Granger, M I Townsley, A E Taylor
Journal: Circulation Research (1985)

Previous studies indicate that vascular permeability is increased in skeletal muscle subjected to 4 hours of inflow occlusion. However, the mechanism(s) underlying the increase in permeability are unknown. The aim of this study was to assess the role of oxygen-derived free radicals and histamine as putative mediators of the increased permeability in skeletal muscle subjected to 4 hours of inflow occlusion. The osmotic reflection coefficient for total plasma proteins and isogravimetric capillary pressure were estimated in canine gracilis muscle for the following conditions: control, ischemia, and ischemia plus pretreatment with allopurinol (a xanthine oxidase inhibitor), catalase (a peroxidase that reduces hydrogen peroxide to water and molecular oxygen), superoxide dismutase (a superoxide anion scavenger), dimethyl sulfoxide (a hydroxyl radical scavenger), diphenhydramine (a histamine H1-receptor blocker), or cimetidine (a histamine H2-receptor blocker). Ischemia, followed by reperfusion, significantly reduced the reflection coefficient from 0.94 +/- 0.02 to 0.64 +/- 0.02 and isogravimetric capillary pressure from 13.8 +/- 1.0 mm Hg to 6.9 +/- 0.4 mmHg, indicating a dramatic increase in microvascular permeability. Prior treatment with diphenhydramine or cimetidine did not significantly alter the permeability increase induced by ischemia. However, pretreatment with allopurinol, catalase, superoxide dismutase, or dimethylsulfoxide did significantly attenuate the increase in vascular permeability. The results of this study indicate that oxygen radicals are primarily responsible for the increased vascular permeability produced by ischemia-reperfusion, that the hydroxyl radical may represent the primary damaging radical, and that xanthine oxidase may represent the primary source of oxygen-derived free radicals in ischemic skeletal muscle.
Altering the spectrum of immunoglobulin V gene somatic hypermutation by modifying the active site of AID
Authors: Meng Wang, Cristina Rada, Michael S. Neuberger
Journal: The Journal of Experimental Medicine (2010)

High-affinity antibodies are generated by somatic hypermutation with nucleotide substitutions introduced into the IgV in a semirandom fashion, but with intrinsic mutational hotspots strategically located to optimize antibody affinity maturation. The process is dependent on activation-induced deaminase (AID), an enzyme that can deaminate deoxycytidine in DNA in vitro, where its activity is sensitive to the identity of the 5′-flanking nucleotide. As a critical test of whether such DNA deamination activity underpins antibody diversification and to gain insight into the extent to which the antibody mutation spectrum is dependent on the intrinsic substrate specificity of AID, we investigated whether it is possible to change the IgV mutation spectrum by altering AID’s active site such that it prefers a pyrimidine (rather than a purine) flanking the targeted deoxycytidine. Consistent with the DNA deamination mechanism, B cells expressing the modified AID proteins yield altered IgV mutation spectra (exhibiting a purine→pyrimidine shift in flanking nucleotide preference) and altered hotspots. However, AID-catalyzed deamination of IgV targets in vitro does not yield the same degree of hotspot dominance to that observed in vivo, indicating the importance of features beyond AID’s active site and DNA local sequence environment in determining in vivo hotspot dominance.
American Society of Clinical Oncology 2008 Clinical Practice Guideline Update: Use of Chemotherapy and Radiation Therapy Protectants
Authors: Martee L. Hensley, Karen L. Hagerty, Tarun Kewalramani, Daniel M. Green, Neal J. Meropol, Todd H. Wasserman, Gary I. Cohen, Bahman Emami, William J. Gradishar, R. Brian Mitchell, J. Tate Thigpen, Andy Trotti, Daniel von Hoff, Lynn M. Schuchter
Journal: Journal of Clinical Oncology (2008)

To update a clinical practice guideline on the use of chemotherapy and radiation therapy protectants for patients with cancer.An update committee reviewed literature published since the last guideline update in 2002.Thirty-nine reports met the inclusion criteria: palifermin and dexrazoxane, three reports (two studies) each; amifostine, 33 reports (31 studies); and mesna, no published randomized trials identified since 2002.Dexrazoxane is not recommended for routine use in breast cancer (BC) in adjuvant setting, or metastatic setting with initial doxorubicin-based chemotherapy. Consider use with metastatic BC and other malignancies, for patients who have received more than 300 mg/m(2) doxorubicin who may benefit from continued doxorubicin-containing therapy. Cardiac monitoring should continue in patients receiving doxorubicin. Amifostine may be considered for prevention of cisplatin-associated nephrotoxicity, reduction of grade 3 to 4 neutropenia (alternative strategies are reasonable), and to decrease acute and late xerostomia with fractionated radiation therapy alone for head and neck cancer. It is not recommended for protection against thrombocytopenia, prevention of platinum-associated neurotoxicity or ototoxicity or paclitaxel-associated neuropathy, prevention of radiation therapy-associated mucositis in head and neck cancer, or prevention of esophagitis during concurrent chemoradiotherapy for non-small-cell lung cancer. Palifermin is recommended to decrease severe mucositis in autologous stem-cell transplantation (SCT) for hematologic malignancies with total-body irradiation (TBI) conditioning regimens, and considered for patients undergoing myeloablative allogeneic SCT with TBI-based conditioning regimens. Data are insufficient to recommend use in the non-SCT setting.
TREM-like transcript-1 protects against inflammation-associated hemorrhage by facilitating platelet aggregation in mice and humans
Authors: A. Valance Washington, Sébastien Gibot, Ismael Acevedo, James Gattis, Laura Quigley, Robert Feltz, Alina De La Mota, Rebecca L. Schubert, Julio Gomez-Rodriguez, Jun Cheng, Amalia Dutra, Evgenia Pak, Oleg Chertov, Linette Rivera, Jessica Morales, Jacek Lubkowski, Robert Hunter, Pamela L. Schwartzberg, Daniel W. McVicar
Journal: Journal of Clinical Investigation (2009)

Triggering receptor expressed on myeloid cells-like (TREM-like) transcript-1 (TLT-1), a type 1 single Ig domain orphan receptor specific to platelet and megakaryocyte alpha-granules, relocates to the platelet surface upon platelet stimulation. We found here that patients diagnosed with sepsis, in contrast to healthy individuals, had substantial levels of soluble TLT-1 (sTLT-1) in their plasma that correlated with the presence of disseminated intravascular coagulation. sTLT-1 bound to fibrinogen and augmented platelet aggregation in vitro. Furthermore, the cytoplasmic domain of TLT-1 could also bind ezrin/radixin/moesin family proteins, suggesting its ability to link fibrinogen to the platelet cytoskeleton. Accordingly, platelets of Treml1-/- mice failed to aggregate efficiently, extending tail-bleeding times. Lipopolysaccharide-treated Treml1-/- mice developed higher plasma levels of TNF and D-dimers than wild-type mice and were more likely to succumb during challenge. Finally, Treml1-/- mice were predisposed to hemorrhage associated with localized inflammatory lesions. Taken together, our findings suggest that TLT-1 plays a protective role during inflammation by dampening the inflammatory response and facilitating platelet aggregation at sites of vascular injury. Therefore, therapeutic modulation of TLT-1-mediated effects may provide clinical benefit to patients with hypercoagulatory conditions, including those associated with inflammation.
Hypoxia Inducible Factor-1–Independent Pathways in Tumor Angiogenesis
Authors: Yusuke Mizukami, Yutaka Kohgo, Daniel C. Chung
Journal: Clinical Cancer Research (2007)

Among the factors that can stimulate angiogenesis, vascular endothelial growth factor has emerged as one of the most important, and inhibition of vascular endothelial growth factor has recently shown efficacy in the treatment of advanced colorectal cancer. Hypoxia develops within solid tumors and is one of the most potent stimuli of vascular endothelial growth factor expression. This effect is mediated primarily by hypoxia inducible factor-1 (HIF-1), often considered a master regulator of angiogenesis in hypoxia. Consequently, inhibition of HIF-1 has been proposed as a strategy to block tumor angiogenesis therapeutically. However, accumulating evidence indicates that HIF-independent pathways can also control angiogenesis. This review highlights some of the key signaling pathways independent of HIF-1 that can stimulate angiogenesis in hypoxia. Understanding the full spectrum of molecular pathways that control tumor angiogenesis is critical for the optimal design of targeted therapies.
Sleep Disturbances in Midlife Unrelated to 32-Year Diabetes Incidence
Authors: Cecilia Björkelund, Dorota Bondyr-Carlsson, Leif Lapidus, Lauren Lissner, Jörgen Månsson, Ingmar Skoog, Calle Bengtsson
Journal: Diabetes Care (2005)

OBJECTIVE—To study the relation between diabetes incidence and sleep problems in a population-based sample of women followed for 32 years. RESEARCH DESIGN AND METHODS—The researchers conducted a prospective population study initiated in 1968–1969, with follow-ups in 1974–1975, 1980–1981, 1992–1993, and 2000–2001 in Gothenburg, Sweden. A total of 1,462 women born in 1908, 1914, 1918, 1922, and 1930, representative of women of the same ages in the general population, initially participated (90% participation rate). Reported sleep duration, sleep problems, and use of sleeping medication were related to incident diabetes from 1968 to 2000. Associations between sleep problems and diabetes were corrected for waist-to-hip ratio (WHR), BMI, subscapular skinfold, fasting blood glucose and serum lipid concentrations, blood pressure, heart rate, smoking, physical activity, education, and socioeconomic status. Additionally, associations between BMI, WHR, and sleep problems were examined. RESULTS—Over 32 years, 126 women (8.7%) developed diabetes. Associations between diabetes and initial sleep problems were tested in a Cox regression analysis, taking into consideration factors associated (P &amp;lt; 0.1) with diabetes. Sleep problems in 1968 did not increase risk of developing diabetes during the following 32 years. Obesity, particularly centralized, was associated with sleep problems. CONCLUSIONS—No association between sleep problems and developing diabetes was seen in this 32-year follow-up of middle-aged women. Obesity, on the other hand, known to cause increased risk of diabetes, was associated with current sleep problems.
Targeted therapy for glioblastoma multiforme neoplastic meningitis with intrathecal delivery of an oncolytic recombinant poliovirus.
Authors: Hidenobu Ochiai, Stephanie A Campbell, Gary E Archer, Tracy A Chewning, Eugenia Dragunsky, Alexander Ivanov, Matthias Gromeier, John H Sampson
Journal: Clinical Cancer Research (2006)

Abstract PURPOSE: The toxicity and antitumor activity of regional intrathecal delivery of an oncolytic recombinant poliovirus, PVS-RIPO, was evaluated in rodent models of glioblastoma multiforme neoplastic meningitis. EXPERIMENTAL DESIGN: To evaluate for toxicity, PVS-RIPO was administered into the spinal cord of transgenic mice that express the human poliovirus receptor, CD155, and into the intrathecal space of athymic rats without tumor. To evaluate efficacy, two different doses of PVS-RIPO were administered intrathecally 3 days after athymic rats were inoculated intrathecally with an aggressive human glioblastoma multiforme xenograft. RESULTS: No clinical or histologic evidence of toxicity was found. In efficacy studies, median survival was increased by 174.47% from 8.5 days in the group treated with UV light-inactivated virus to 15 days in the rats treated with 1.0 x 10(7) plaque-forming units (pfu) of PVS-RIPO (P &amp;lt; 0.0001). A similar increase in median survival was seen in the group receiving 1.0 x 10(9) pfu PVS-RIPO (P &amp;lt; 0.0001); however, there was no statistically significant dose-response relationship (P = 0.345). In addition, 1 of 10 rats in lower-dose PVS-RIPO-treated group and 3 of 10 rats in higher-dose PVS-RIPO-treated group survived &amp;gt;60 days after tumor cell inoculation and had no evidence of residual tumor at autopsy. CONCLUSION: These results suggest that intrathecal treatment with PVS-RIPO may be useful for treatment of neoplastic meningitis in patients with glioblastoma multiforme and provides a rationale for clinical trials in this area.
Prediction of sudden cardiac death after myocardial infarction in the beta-blocking era
Authors: Heikki V Huikuri, Jari M Tapanainen, Kai Lindgren, Pekka Raatikainen, Timo H Mäkikallio, K.E Juhani Airaksinen, Robert J Myerburg
Journal: Journal of the American College of Cardiology (2003)
In Silico Characterization and Molecular Evolutionary Analysis of a Novel Superfamily of Fungal Effector Proteins
Authors: Ioannis Stergiopoulos, Yiannis A.I. Kourmpetis, Jason C. Slot, Freek T. Bakker, Pierre J.G.M. De Wit, Antonis Rokas
Journal: Molecular Biology and Evolution (2012)

Most fungal plant pathogens secrete effector proteins during pathogenesis to manipulate their host's defense and promote disease. These are so highly diverse in sequence and distribution, they are essentially considered as species-specific. However, we have recently shown the presence of homologous effectors in fungal species of the Dothideomycetes class. One such example is Ecp2, an effector originally described in the tomato pathogen Cladosporium fulvum but later detected in the plant pathogenic fungi Mycosphaerella fijiensis and Mycosphaerella graminicola as well. Here, using in silico sequence-similarity searches against a database of 135 fungal genomes and GenBank, we extend our queries for homologs of Ecp2 to the fungal kingdom and beyond, and further study their history of diversification. Our analyses show that Ecp2 homologs are members of an ancient and widely distributed superfamily of putative fungal effectors, which we term Hce2 for Homologs of C. fulvum Ecp2. Molecular evolutionary analyses show that the superfamily originated and diversified within the fungal kingdom, experiencing multiple lineage-specific expansions and losses that are consistent with the birth-and-death model of gene family evolution. Newly formed paralogs appear to be subject to diversification early after gene duplication events, whereas at later stages purifying selection acts to preserve diversity and the newly evolved putative functions. Some members of the Hce2 superfamily are fused to fungal Glycoside Hydrolase family 18 chitinases that show high similarity to the Zymocin killer toxin from the dairy yeast Kluyveromyces lactis, suggesting an analogous role in antagonistic interactions. The observed high rates of gene duplication and loss in the Hce2 superfamily, combined with diversification in both sequence and possibly functions within and between species, suggest that Hce2s are involved in adaptation to stresses and new ecological niches. Such findings address the need to rationalize effector biology and evolution beyond the perspective of solely host-microbe interactions.
Molecular activity of sirolimus and its possible application in tuberous sclerosis treatment
Authors: Jaroslaw Jozwiak, Sergiusz Jozwiak, Monika Oldak
Journal: Medicinal Research Reviews (2005)

Abstract Sirolimus is one of the intensively investigated drugs with pluripotent activities. It binds to its intracellular receptor FKBP12 (FK506‐binding protein 12), a member of the family of FK506‐binding proteins, and inhibits the activity of mTOR, a serine/threonine kinase involved in numerous cell processes linked to cell growth control. The drug is currently registered for the prophylaxis of organ rejection and for use in coronary stents. However, unique characteristics of sirolimus make it a good candidate for anti‐cancer therapy. Indeed, phase II and III clinical studies in humans with several types of neoplasms are already under way. The review describes molecular activity of sirolimus and its analogs, characteristic for specific applications, in view of very recent advances involving tuberous sclerosis complex (TSC)‐mediated signaling pathways. Current studies with sirolimus performed in tuberous sclerosis animal models are presented. Possible application of sirolimus for treating tuberous sclerosis, disease caused by mutations of TSC proteins, is discussed. © 2005 Wiley Periodicals, Inc. Med Res Rev
Improved left ventricular diastolic filling in patients with coronary artery disease after percutaneous transluminal coronary angioplasty.
Authors: R O Bonow, K M Kent, D R Rosing, L C Lipson, S L Bacharach, M V Green, S E Epstein
Journal: Circulation (1982)

Left ventricular (LV) diastolic filling is abnormal at rest in many patients with coronary artery disease (CAD), even in the presence of normal resting LV systolic function. To determine the effects of improved myocardial perfusion on impaired. LV diastolic filling, we studied 25 patients with one-vessel CAD by high-temporal-resolution radionuclide angiography before and after percutaneous transluminal coronary angioplasty (PTCA). No patient had ECG evidence of previous myocardial infarction. Despite normal regional and global LV systolic function at rest in all patents, LV diastolic filling was abnormal (peak LV filling rate [PFR] less than 2.5 end-diastolic volumes (EDV)/sec or time to PFR greater than 180 msec) in 17 of 25 patients. Twenty-three patients had abnormal LV systolic function during exercise. After successful PTCA, LV ejection fraction and heart rate at rest were unchanged, but LV ejection fraction during exercise increased, from 52 +/- 8% (+/- SD) to 63 +/- 5% (p less than 0.001). LV diastolic filling at rest improved: PFR increased from 2.3 +/- 0.6 to 2.8 +/- 0.5 EDV/sec (p less than 0.001) and time to PFR decreased from 181 +/- 22 to 160 +/- 18 msec (p less than 0.001). Thus, a reduction in exercise-induced LV systolic dysfunction after PTCA, reflecting a reduction in reversible ischemia, was associated with improved LV diastolic filling at rest. These data suggest that in many CAD patients with normal resting LV systolic function and without previous infarction, abnormalities of resting LV diastolic filling are not fixed, but appear to be reversible manifestations of impaired coronary flow.
The Effect of Soybean Sterols on the Absorption of Cholesterol by the Rat
Authors: RAY H. ROSENMAN, SANFORD O. BYERS, MEYER FRIEDMAN
Journal: Circulation Research (1954)

Mixed soybean sterols (80 per cent sitosterols) were fed to rats simultaneously with cholesterol in acute and chronic experiments. In acute experiments, concurrent feeding of a test dose of soybean sterols and cholesterol did not diminish the usual fraction of cholesterol absorption into the thoracic duct lymph. In chronic experiments the addition of 2 or 10 per cent soybean sterols to a diet which induces chronic hypercholesteremia in rats failed to inhibit the development or magnitude of chronic hypercholesteremia.
Minimally invasive parathyroidectomy
Authors: F Fausto Palazzo, Gregory P Sadler
Journal: BMJ (2004)

Heralds a new era in the treatment of primary hyperparathyroidism 

Primary hyperparathyroidism is a more prevalent condition than many perceive. The overall incidence is 25 per 100 000 of the United Kingdom's population.1 However, in women over the age of 45 it may affect one in 500, and more than 1% of post-menopausal women have raised serum concentrations of calcium.2 Parathyroidectomy is the treatment of choice in symptomatic primary hyperparathyroidism. It cures fatigue and the bone, abdominal, urological, and mental symptoms associated with hypercalcaemia. Parathyroidectomy also results in a quantifiable improvement in health related quality of life.3 Additionally a 25 year follow up of patients with untreated “asymptomatic disease” showed a notable increase in cardiovascular deaths compared with age matched normocalcaemic controls.2 Support for an operative approach is further provided by lack of an effective medical treatment and the cost and doctor hours involved in the follow up of conservatively managed patients.

Traditionally parathyroidectomy involves a collar incision, bilateral exploration of the neck, identification of all four parathyroid glands, and removal of the diseased gland or glands. This approach, in experienced hands in large volume centres, has enabled cure rates of up to 97% with minimal morbidity, …
Phase II Study of the Farnesyl Transferase Inhibitor R115777 in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Alex A. Adjei, Ann Mauer, Laura Bruzek, Randolph S. Marks, Shauna Hillman, Susan Geyer, Lorelei J. Hanson, John J. Wright, Charles Erlichman, Scott H. Kaufmann, Everett E. Vokes
Journal: Journal of Clinical Oncology (2003)

This phase II study was undertaken to define the efficacy and pharmacodynamics of R115777, a farnesyl transferase inhibitor, in the first-line treatment of patients with advanced non-small-cell lung cancer.Forty-four patients with measurable stage IIIB (pleural effusion) or stage IV disease received 193 courses of treatment (median, 2.0; range, 1 to 22) with R115777 300 mg administered orally twice daily for 21 of every 28 days. Buccal mucosa samples and peripheral blood mononuclear cells (PBMCs) were collected before and after 8 days of treatment to evaluate inhibition of farnesyl transferase in vivo.No objective complete or partial responses were documented. Seven patients (16%; 95% confidence interval [CI], 8% to 31%) had disease stabilization for greater than 6 months. Median survival was 7.7 months (95% CI, 6.5 to 10.5) and time to progression was 2.7 months (95% CI, 1.9 to 3.1). The most severe toxicity was neutropenia (9% grade 3, 7% grade 4) and the most common toxicities were anemia (50% grade 1 or 2, 5% grade 3) and anorexia (50% grade 1 or 2, 2% grade 3). Mild peripheral neuropathy occurred in 25% of patients. Evidence of farnesyl transferase inhibition was documented in 83% of patients.Single-agent R115777 was well tolerated in patients with advanced NSCLC, but demonstrated minimal clinical activity. Inhibition of farnesylation in vivo was consistently documented. On the basis of promising results of farnesyl transferase inhibitor combinations with standard chemotherapy agents, future studies of this agent in NSCLC should be in combination with systemic chemotherapy.
I<scp>mmunological</scp>M<scp>emory to</scp>V<scp>iral</scp>I<scp>nfections</scp>
Authors: Raymond M. Welsh, Liisa K. Selin, Eva Szomolanyi-Tsuda
Journal: Annual Review of Immunology (2004)

The purpose of immunological memory is to protect the host from reinfection, to control persistent infections, and, through maternal antibody, to protect the host's immunologically immature offspring from primary infections. Immunological memory is an exclusive property of the acquired immune system, where in the presence of CD4 T cell help, T cells and B cells clonally expand and differentiate to provide effector systems that protect the host from pathogens. Here we describe how T and B cell memory is generated in response to virus infections and how these cells respond when the host is infected again by similar or different viruses.