tbuckley/cabot-search huggingface dataset:
Eukaryotic Pyruvate Formate Lyase and Its Activating Enzyme Were Acquired Laterally from a Firmicute
Authors: C. W. Stairs, A. J. Roger, V. Hampl
Journal: Molecular Biology and Evolution (2011)

Most of the major groups of eukaryotes have microbial representatives that thrive in low oxygen conditions. Those that have been studied in detail generate ATP via pathways involving anaerobically functioning enzymes of pyruvate catabolism that are typically absent in aerobic eukaryotes and whose origins remain controversial. These enzymes include pyruvate:ferredoxin oxidoreductase, pyruvate:NADP+ oxidoreductase, and pyruvate formate lyase (Pfl). Pfl catalyzes the nonoxidative generation of formate and acetyl-Coenzyme A (CoA) from pyruvate and CoA and is activated by Pfl activating enzyme (Pfla). Within eukaryotes, this extremely oxygen-sensitive pathway was first described in the hydrogenosomes of anaerobic chytrid fungi and has more recently been characterized in the mitochondria and chloroplasts of the chlorophyte alga Chlamydomonas reinhardtii. To clarify the origins of this pathway, we have comprehensively searched for homologs of Pfl and Pfla in publicly available large-scale eukaryotic genomic and cDNA sequencing data, including our own from the anaerobic amoebozoan Mastigamoeba balamuthi. Surprisingly, we find that these enzymes are widely distributed and are present in diverse facultative or obligate anaerobic eukaryotic representatives of the archaeplastidan, metazoan, amoebozoan, and haptophyte lineages. Using maximum likelihood and Bayesian phylogenetic methods, we show that the eukaryotic Pfl and Pfla sequences each form monophyletic groups that are most closely related to homologs in firmicute gram-positive bacteria. Topology tests exclude both α-proteobacterial and cyanobacterial affinities for these genes suggesting that neither originated from the endosymbiotic ancestors of mitochondria or chloroplasts. Furthermore, the topologies of the eukaryote portion of the Pfl and Pfla trees significantly differ from well-accepted eukaryote relationships. Collectively, these results indicate that the Pfl pathway was first acquired by lateral gene transfer into a eukaryotic lineage most probably from a firmicute bacterial lineage and that it has since been spread across diverse eukaryotic groups by more recent eukaryote-to-eukaryote transfer events.
Estimation of Clotting Accelerator Activity in Plasma after Ingestion of Fat
Authors: JOHN H. TILDEN, R. E. SHIPLEY
Journal: Circulation Research (1957)

A relatively simple method is presented which permits a quantitative estimation of a "coagulation accelerator activity" which appears in plasma of human and dog blood after oral ingestion of various fats. Accelerator activity and increased plasma turbidity were observed after ingestion of cream, peanut oil, cocoanut oil, linseed oil, or sodium oleate. Peak responses were seen between 3 and 5 hours after fat intake with gradual return toward control levels in 7 hours.
Phase I Pharmacokinetic, Food Effect, and Pharmacogenetic Study of Oral Irinotecan Given as Semisolid Matrix Capsules in Patients with Solid Tumors
Authors: Otto Soepenberg, Herlinde Dumez, Jaap Verweij, Floris A. de Jong, Maja J.A. de Jonge, José Thomas, Ferry A.L.M. Eskens, Ron H.N. van Schaik, Johan Selleslach, Judith ter Steeg, Patricia Lefebvre, Sylvie Assadourian, Ger-Jan Sanderink, Alex Sparreboom, Allan T. van Oosterom
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To characterize the maximum-tolerated dose, recommended dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and food effect of orally administered irinotecan formulated as new semisolid matrix capsules. Experimental Design: Irinotecan was given orally in fasted patients once daily for 5 consecutive days and repeated every 3 weeks. Patients were randomly assigned to take the drug along with a high-fat, high-calorie breakfast for the administration at day 1 of the first or second cycle. Dosages tested were 70 and 80 mg/m2/day. Results: Twenty-five patients received 101 cycles of therapy (median two cycles, range 1-15). During the first cycle, grade 3 delayed diarrhea and grade 3 fever were the DLTs at the dosage of 80 mg/m2/day in three out of five patients. Hematologic and nonhematologic toxicities were mild to moderate. Exposure to the active metabolite SN-38 was relatively high compared with i.v. infusion, but no relevant accumulation was observed. Food had no significant effect on irinotecan pharmacokinetics. One confirmed partial remission and 10 disease stabilizations were observed in previously treated patients. No association was found between the UGT1A1*28 genotype and the risk of severe irinotecan-induced toxicity. Conclusions: For oral irinotecan, a dose of 70 mg/m2/day for 5 consecutive days every 3 weeks is recommended for further studies. Delayed diarrhea was the main DLT, similar to that observed with intravenously administered irinotecan. This study confirms that oral administration of irinotecan is feasible and may have favorable pharmacokinetic characteristics.
Increased glutaredoxin-1 and decreased protein<i>S</i>-glutathionylation in sputum of asthmatics
Authors: Ine Kuipers, Renaud Louis, Maité Manise, Mieke A. Dentener, Charles G. Irvin, Yvonne M.W. Janssen-Heininger, Christopher E. Brightling, Emiel F.M. Wouters, Niki L. Reynaert
Journal: European Respiratory Journal (2013)

Increased glutaredoxin-1 and decreased protein S-glutathionylation in sputum of asthmaticsTo the Editor:Total reduced glutathione (GSH), the main pulmonary antioxidant, is increased in asthma patients and, in some studies, increased amounts of oxidised glutathione (GSSG) were also found.In addition, enzymes that regulate the GSH redox cycle are altered in asthmatics (reviewed in [1]).
Connexin 43 and ischemic preconditioning
Authors: R Schulz
Journal: Cardiovascular Research (2004)

Connexin 43 (Cx43) is the essential protein to form hemichannels and gap junctions in the myocardium. The phosphorylation status of Cx43 which is regulated by a variety of protein kinases and phosphatases determines hemichannel and/or gap junction conductance and permeability. Gap junctions are involved in cell–cell coupling while hemichannels contribute to cardiomyocyte volume regulation. Cx43-formed channels are involved in ischemia/reperfusion injury, since blockade of a large portion of Cx43-formed channels attenuates ischemic hypercontracture, infarct development and post myocardial infarction remodeling. Ischemic preconditioning's protection also depends on functional Cx43-formed channels, since uncoupling of channels or genetic Cx43 deficiency abolishes infarct size reduction by ischemic preconditioning. The exact underlying mechanism(s) how Cx43 mediates protection remain to be established.
A long-distance runner with lateral knee pain
Authors: C M Nusman, M C de Jonge, A Navas Canete, M Maas
Journal: British Journal of Sports Medicine (2010)

A 25-year-old female marathon runner, who trained three times a week, consulted an orthopaedic surgeon due to lateral knee pain. It had been bothering her for 7 weeks. The onset was gradual. After several visits to her physiotherapist, where she performed exercises for coordination, strength and stability, she decided to seek further advice, because the problem was gradually getting worse. She experienced a sharp pain on the outside of the left knee. The pain worsened during activity after an often pain-free start and was exacerbated on running downhill. The pain disappeared hours after the exercise, and in rest she had no complaints at all.

Physical examination revealed a healthy female (1.70 m, 55 kg). Inspection of the knee showed a diffuse lateral swelling without erythema. There was no effusion. On palpation, there was tenderness over the whole lateral side of the knee, with the tenderest point being the lateral femoral condyl. The range of motion was normal.

When putting full weight on the injured leg during the Renne test, the lateral knee pain occurred. The Noble test (manual compression of the iliotibial band (ITB) on the lateral femur condyl during flexion and extension of the knee) was positive; the patient experienced pain at 30° of flexion during motion from 90° flexion to full extension. The McMurray test for a meniscal tear was not painful. Performance of the Ober test showed moderate tightness of the ITB. Neurovascular examination was normal.

The patient was referred …
Functional Synergies yet Distinct Modulators Affected by Genetic Alterations in Common Human Cancers
Authors: Marina Bessarabova, Olga Pustovalova, Weiwei Shi, Tatiana Serebriyskaya, Alex Ishkin, Kornelia Polyak, Victor E. Velculescu, Tatiana Nikolskaya, Yuri Nikolsky
Journal: Cancer Research (2011)

Abstract An important general concern in cancer research is how diverse genetic alterations and regulatory pathways can produce common signaling outcomes. In this study, we report the construction of cancer models that combine unique regulation and common signaling. We compared and functionally analyzed sets of genetic alterations, including somatic sequence mutations and copy number changes, in breast, colon, and pancreatic cancer and glioblastoma that had been determined previously by global exon sequencing and SNP (single nucleotide polymorphism) array analyses in multiple patients. The genes affected by the different types of alterations were mostly unique in each cancer type, affected different pathways, and were connected with different transcription factors, ligands, and receptors. In our model, we show that distinct amplifications, deletions, and sequence alterations in each cancer resulted in common signaling pathways and transcription regulation. In functional clustering, the impact of the type of alteration was more pronounced than the impact of the kind of cancer. Several pathways such as TGF-β/SMAD signaling and PI3K (phosphoinositide 3-kinase) signaling were defined as synergistic (affected by different alterations in all four cancer types). Despite large differences at the genetic level, all data sets interacted with a common group of 65 “universal cancer genes” (UCG) comprising a concise network focused on proliferation/apoptosis balance and angiogenesis. Using unique nodal regulators (“overconnected” genes), UCGs, and synergistic pathways, the cancer models that we built could combine common signaling with unique regulation. Our findings provide a novel integrated perspective on the complex signaling and regulatory networks that underlie common human cancers. Cancer Res; 71(10); 3471–81. ©2011 AACR.
An EZH2 polymorphism is associated with clinical outcome in metastatic colorectal cancer patients
Authors: F. Crea, L. Fornaro, E. Paolicchi, G. Masi, P. Frumento, F. Loupakis, L. Salvatore, C. Cremolini, M. Schirripa, F. Graziano, M. Ronzoni, V. Ricci, W.L. Farrar, A. Falcone, R. Danesi
Journal: Annals of Oncology (2011)
Airway Responses to Aerosolized Brevetoxins in an Animal Model of Asthma
Authors: William M. Abraham, Andrea J. Bourdelais, Juan R. Sabater, Ashfaq Ahmed, Troy A. Lee, Irakli Serebriakov, Daniel G. Baden
Journal: American Journal of Respiratory and Critical Care Medicine (2004)

10.1164/rccm.200406-735OCFlorida red tide brevetoxins are sodium channel neurotoxins produced by the dinoflagellate Karenia brevis. When aerosolized, the toxin causes airway symptoms in normal individuals and patients with airway disease, but systematic exposures to define the pulmonary consequences and putative mechanisms are lacking. Here we report the effects of airway challenges with lysed cultures of Karenia brevis (crude brevetoxin), pure brevetoxin-2, brevetoxin-3, and brevetoxin-tbm (brevetoxin-2 minus the side chain) on pulmonary resistance and tracheal mucus velocity, a marker of mucociliary clearance, in allergic and nonallergic sheep. Picogram concentrations of toxin caused bronchoconstriction in both groups of sheep. Brevetoxin-tbm was the least potent, indicating the importance of the side chain for maximum effect. Both histamine H1– and cholinergic-mediated pathways contributed to the bronchoconstriction. A synthetic antagonist, β-naphthoyl-brevetoxin-3, and brevenal, a natural antagonist, inhibited the bronchoconstriction. Only crude brevetoxin and brevetoxin-3 decreased tracheal mucus velocity; both antagonists prevented this. More importantly, picomolar concentrations of the antagonists alone improved tracheal mucus velocity to the degree seen with mM concentrations of the sodium channel blocker amiloride. Thus, Karenia brevis, in addition to producing toxins that adversely affect the airways, may be a source of agents for treating mucociliary dysfunction.
Cellular Source and Amount of Vascular Endothelial Growth Factor and Platelet-Derived Growth Factor in Tumors Determine Response to Angiogenesis Inhibitors
Authors: Barbara Sennino, Frank Kuhnert, Sebastien P. Tabruyn, Michael R. Mancuso, Dana D. Hu-Lowe, Calvin J. Kuo, Donald M. McDonald
Journal: Cancer Research (2009)

Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and their receptors are important targets in cancer therapy based on angiogenesis inhibition. However, it is unclear whether inhibition of VEGF and PDGF together is more effective than inhibition of either one alone. Here, we used two contrasting tumor models to compare the effects of inhibiting VEGF or PDGF alone, by adenovirally generated soluble receptors, to the effects of inhibiting both together. In RIP-Tag2 tumors, VEGF and PDGF inhibition together reduced tumor vascularity and abundance of pericytes. However, VEGF inhibition reduced tumor vascularity without decreasing pericyte density, and PDGF inhibition reduced pericytes without reducing tumor vascularity. By contrast, in Lewis lung carcinomas (LLC), inhibition of VEGF or PDGF reduced blood vessels and pericytes to the same extent as did inhibition of both together. Similar results were obtained using tyrosine kinase inhibitors AG-013736 and imatinib. In LLC, VEGF expression was largely restricted to pericytes and PDGF was largely restricted to endothelial cells, but, in RIP-Tag2 tumors, expression of both growth factors was more widespread and significantly greater than in LLC. These findings suggest that inhibition of PDGF in LLC reduced pericytes, and then tumor vessels regressed because pericytes were the main source of VEGF. The vasculature of RIP-Tag2 tumors, in which most VEGF is from tumor cells, was more resistant to PDGF inhibition. The findings emphasize the interdependence of pericytes and endothelial cells in tumors and the importance of tumor phenotype in determining the cellular effects of VEGF and PDGF inhibitors on tumor vessels.
Bone marrow transplantation in a patient with myelodysplasia associated with diffuse eosinophilic fasciitis
Authors: Martin S. Tallman, Robert W. McGuffin, Celestia S. Higano, Gordon Starkebaum, Steven J. Collins, Harold Johnston, Jack W. Singer, David J. Perry, Arthur Kunath
Journal: American Journal of Hematology (1987)

Abstract A 34‐year‐old man with diffuse eosinophilic fasciitis and a hypocellular myelodysplastic syndrome underwent marrow transplantation from an HLA‐identical brother. Prompt hematopoietic reconstitution was observed, strongly suggesting that the marrow hypocellularity was caused by neither a serum inhibitory factor nor a microenvironmental disorder. The patient died of disseminated cytomegalovirus infection too early to evaluate the impact of hematopoietic reconstitution on the eosinophilic fasciitis. Nevertheless, marrow transplantation may offer a therapeutic option for those patients with this disorder who develop severe hematopoietic dysfunction and who have a suitable marrow donor.
Clonal Expansion and Loss of Heterozygosity at Chromosomes 9p and 17p in Premalignant Esophageal (Barrett's) Tissue
Authors: Patricia C. Galipeau, Laura J. Prevo, Carissa A. Sanchez, Gary M. Longton, Brian J. Reid
Journal: JNCI Journal of the National Cancer Institute (1999)

Background: Abnormalities involving the p16 (also known as cyclin-dependent kinase N2 [CDKN2], p16 [INK4a], or MTS1) and p53 (also known as TP53) tumor suppressor genes are highly prevalent in esophageal adenocarcinomas.Loss of heterozygosity (LOH) at 9p21 and 17p13 chromosomes (locations for p16 and p53 genes, respectively) is frequently observed in the premalignant condition, Barrett's esophagus.We studied extensively the distribution and heterogeneity of LOH at 9p and 17p chromosomes throughout the Barrett's segment in patients who have not yet developed esophageal adenocarcinoma.Methods: We evaluated 404 samples from 61 consecutive patients enrolled in the Seattle Barrett's Esophagus Study from February 1995 through September 1998.All patients had high-grade dysplasia but no diagnosis of cancer.The samples were assayed for LOH at 9p and 17p chromosomes after amplification of genomic DNA by use of polymerase chain reaction and DNA genotyping.The cell fractions were purified by flow cytometry on the basis of DNA content and proliferation-associated antigen labeling.Association between LOH at 9p and LOH at 17p with flow cytometric abnormalities was determined by chi-squared test, and logistic regression models were used to model and test for the extent to which a particular genotype was found in 2-cm intervals.Results and Conclusions: LOH at 9p and 17p chromosomes are highly prevalent somatic genetic lesions in premalignant Barrett's tissue.LOH at 9p is more common than LOH at 17p in diploid samples and can be detected over greater regions of Barrett's epithelium.In most patients with high-grade dysplasia, the Barrett's mucosa contains a mosaic of clones and subclones with different patterns of LOH.Some clones had expanded to involve extensive regions of Barrett's epithelium.LOH at 9p and 17p chromosomes may be useful biomarkers to stratify patients' risk of progression to esophageal cancer.Barrett's esophagus is a premalignant condition in which the normal squamous epithelium of the esophagus is replaced by metaplastic columnar epithelium (1).Barrett's esophagus predisposes patients to the development of esophageal adenocarcinoma, a cancer whose incidence has been increasing rapidly in the United States and in regions of Western Europe
German health reforms hang in the balance
Authors: Annette Tuffs
Journal: BMJ (2007)

The German coalition government is still struggling to push through its ambitious but highly criticised health reform plans (bmj.com, 15 Jul 2006, News Extra). 

At the beginning of January Volker Kauder, the parliamentary leader of Chancellor Angela Merkel's conservative party, the Christian Democrats, announced that the final decision on the reforms would be delayed and be brought to the vote in parliament on 29 January at the earliest. 

Karl Lauterbach, an expert on health care for the party's coalition partners, the Social …
Influence of Simulated Altitude on the Performance of Five Blood Glucose Meters
Authors: Jean-Francois Gautier, Andre Xavier Bigard, Philippe Douce, Alain Duvallet, Gerard Cathelineau
Journal: Diabetes Care (1996)

OBJECTIVE To determine the reliability of five blood glucose meters (BGMs) at various simulated altitudes using a hypobaric chamber. RESEARCH DESIGN AND METHODS Blood glucose levels (ranged from 1.5 to 26.3 mmol/l, according to the reference method) were measured in 18 venous blood samples by each BGM at 200, 1,000, and every 500 m up to 4,000 m in a hypobaric chamber, where temperature and humidity were held constant. RESULTS Four BGMs underestimated and one overestimated blood glucose concentration while barometric pressure decreased. The average percent error varied in relation to simulated altitude from 0.26 ± 4.8% (SD) at 200 m to −28.9 ± 4.5% at 4,000 m (Glucometer 3; P &amp;lt; 0.05), from 28.4 ± 5.7 to 49.3 ± 5.9% (Accu-Chek Easy; P &amp;lt; 0.05), from −10.5 ± 2.6 to 19.8 ± 4.3% (Tracer, P &amp;lt; 0.05), from −5.5 ± 2.6 to −11.2 ± 3.0% (Reflolux; NS), and from 17.8 ± 4.3 to 14.8 ± 3.6% (One Touch; NS). The most accurate seemed to be the Reflolux, except for high blood glucose levels at simulated high altitudes. The One Touch II showed a good agreement, whatever the barometric pressure and the range of blood glucose concentrations. The highest underestimation was seen with the Glucometer 3. CONCLUSIONS Except for the Accu-Chek Easy, low barometric pressure underestimated the BGM results in comparison with measurements taken at simulated low altitudes. The lack of accuracy and consistency of performance &amp;gt; 2,000 m should be known by diabetic patients practicing sports activities, such as trekking or skiing at high altitudes.
Website of the week: Traffic congestion
Authors: T. Jackson
Journal: BMJ (2003)

The introduction of congestion charging on the streets of central London, the subject of an editorial in this week's BMJ (p 345), has already polarised public opinion. And supporters and opponents of mayor Ken Livingstone's brave scheme, which is set to take effect from 17 February, already have a formidable web presence. Among the more colourful anti-charge sites are Sod-U-Ken.co.uk, whose petition has so far collected several thousand signatures, and www.london-congestioncharge.co.uk, which flaunts the slogan “Kill Kenny's New Poll Tax.” Lining up in favour of the charge are, not surprisingly, Friends of the Earth (www.foe.co.uk/campaigns/transport/news/congestion_charging/) and campaign group Transport 2000 (www.transport2000.org.uk/).

But London's congestion charging is of far wider interest: civic leaders around the world will be monitoring the progress of the scheme to see whether they can implement something similar to beat gridlock. Until then, the internet can offer drivers, town planners, and public health workers the chance to monitor traffic flows. The Athens Real-Time Traffic Map (www.transport.ntua.gr/map/), which is updated every 15 minutes, displays congestion on the city's streets using a spectrum of colour, from green for light traffic to red for heavy. There are similar sites for other built up areas, such as Gary, Chicago, and the Milwaukee Corridor (www.gcmtravel.com/gcm/maps_chicago.jsp) and Seattle (www.cityofseattle.net/html/traffic.htm).

Some great cities, such as Venice, Siena, Parma, and Groningen in the Netherlands, are almost completely car free or have already gone much further than London towards restricting traffic from their streets. At carfree.com you can find out more about car free cities and how they can be built, as well as a valuable set of international links to sites about urban planning, bicycle advocacy, and a range of social and environmental issues.

Meanwhile, those who think they can run London's transport better than Ken Livingstone should try the virtual learning arcade at Biz/ed (www.bized.ac.uk/virtual/vla/transport/index.htm). Here you can select various options (for example, increase road pricing and introduce bus lanes) to see what effect this has on traffic flows. Whatever you choose to do, few disagree that something has to be done to ensure that not only is there no more jam today, but that there is no jam tomorrow.