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Sample records for 111ll iiiii iiiii

  1. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 14 2014-07-01 2014-07-01 false Applicability of General Provisions to Subpart IIIII 10 Table 10 to Subpart IIIII of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED)...

  2. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 13 2011-07-01 2011-07-01 false Applicability of General Provisions to Subpart IIIII 10 Table 10 to Subpart IIIII of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED)...

  3. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 14 2012-07-01 2011-07-01 true Applicability of General Provisions to Subpart IIIII 10 Table 10 to Subpart IIIII of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED)...

  4. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 13 2010-07-01 2010-07-01 false Applicability of General Provisions to Subpart IIIII 10 Table 10 to Subpart IIIII of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED)...

  5. 40 CFR Table 10 to Subpart IIIii... - Applicability of General Provisions to Subpart IIIII

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 14 2013-07-01 2013-07-01 false Applicability of General Provisions to Subpart IIIII 10 Table 10 to Subpart IIIII of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES (CONTINUED)...

  6. 40 CFR Appendixes II-Iii to Part 264 - [Reserved

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 25 2010-07-01 2010-07-01 false II Appendixes II-III to Part 264 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) SOLID WASTES (CONTINUED) STANDARDS FOR OWNERS AND OPERATORS OF HAZARDOUS WASTE TREATMENT, STORAGE, AND DISPOSAL FACILITIES Appendixes II-III...

  7. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... vent hose; open-top container where liquid mercury is not covered by an aqueous liquid; end box...

  8. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... vent hose; open-top container where liquid mercury is not covered by an aqueous liquid; end box...

  9. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 2 Table 2 to Subpart IIIII of Part 63—Work... must . . . 1. Each vent hose on each mercury cell Half day A leaking vent hose Take action...

  10. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... vent hose; open-top container where liquid mercury is not covered by an aqueous liquid; end box...

  11. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... CATEGORIES (CONTINUED) National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 2 Table 2 to Subpart IIIII of Part 63—Work... must . . . 1. Each vent hose on each mercury cell Half day A leaking vent hose Take action...

  12. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 14 2012-07-01 2011-07-01 true Requirements for Cell Room Monitoring... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  13. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 7 Table 7 to Subpart IIIII of Part 63... following as part of your plan . . . 1. Center aisles of cell rooms A description of the manner of washdown... baskets 6. Hydrogen system piping 7. Basement floor of cell rooms 8. Tanks 9. Pillars and beams in...

  14. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 7 Table 7 to Subpart IIIII of Part 63... following as part of your plan . . . 1. Center aisles of cell rooms A description of the manner of washdown... baskets 6. Hydrogen system piping 7. Basement floor of cell rooms 8. Tanks 9. Pillars and beams in...

  15. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 2 Table 2 to Subpart IIIII of Part 63—Work... must . . . 1. Each vent hose on each mercury cell Half day A leaking vent hose Take action immediately... mercury seal pot stopper securely in place. 6. Cell room floors Month Cracks, spalling, or...

  16. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 13 2010-07-01 2010-07-01 false Requirements for Cell Room Monitoring... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  17. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 14 2014-07-01 2014-07-01 false Requirements for Cell Room Monitoring... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  18. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 14 2013-07-01 2013-07-01 false Requirements for Cell Room Monitoring... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  19. 40 CFR Table 8 to Subpart IIIii of... - Requirements for Cell Room Monitoring Program

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 13 2011-07-01 2011-07-01 false Requirements for Cell Room Monitoring... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 8 Table 8 to Subpart IIIII of Part 63—Requirements for Cell Room Monitoring Program As stated in § 63.8192(g)(1), your mercury monitoring system...

  20. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 9 Table 9 to Subpart IIIII of Part 63... other deficiency in a cell room floor, pillar, or beam that could cause liquid mercury to become trapped.... f. If you take a cell off line or isolate the leaking equipment, the date and time you take the...

  1. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  2. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Problem Identification, Leak Detection and Mercury Vapor 6 Table 6 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII..., Leak Detection and Mercury Vapor As stated in Tables 1 and 2 of Subpart IIIII, examples of...

  3. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  4. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  5. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  6. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Problem Identification, Leak Detection and Mercury Vapor 6 Table 6 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII..., Leak Detection and Mercury Vapor As stated in Tables 1 and 2 of Subpart IIIII, examples of...

  7. 40 CFR Table 4 to Subpart IIIii of... - Work Practice Standards-Requirements for Mercury Liquid Collection

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... for Mercury Liquid Collection 4 Table 4 to Subpart IIIII of Part 63 Protection of Environment... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 4 Table 4 to Subpart IIIII of Part 63—Work Practice Standards—Requirements for Mercury Liquid Collection As stated...

  8. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII... and Cell Room Monitoring Plans Your Floor-Level Mercury Vapor Measurement Plan required by §...

  9. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII... and Cell Room Monitoring Plans Your Floor-Level Mercury Vapor Measurement Plan required by §...

  10. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII... and Cell Room Monitoring Plans Your Floor-Level Mercury Vapor Measurement Plan required by §...

  11. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII... and Cell Room Monitoring Plans Your Floor-Level Mercury Vapor Measurement Plan required by §...

  12. 40 CFR Table 5 to Subpart IIIii of... - Required Elements of Floor-Level Mercury Vapor Measurement and Cell Room Monitoring Plans

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Mercury Vapor Measurement and Cell Room Monitoring Plans 5 Table 5 to Subpart IIIII of Part 63 Protection... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII... and Cell Room Monitoring Plans Your Floor-Level Mercury Vapor Measurement Plan required by §...

  13. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 13 2011-07-01 2011-07-01 false Work Practice Standards-Design, Operation, and Maintenance Requirements 1 Table 1 to Subpart IIIII of Part 63 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) NATIONAL EMISSION STANDARDS FOR HAZARDOUS AIR POLLUTANTS FOR SOURCE CATEGORIES...

  14. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Hazardous Air Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII...; cracks or spalling in cell room floors, pillars, or beams; caustic leaks; liquid mercury accumulations or... through a detection cell where ultraviolet light at 253.7 nanometers (nm) is directed...

  15. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... during transport. h. Store carbon from decomposers in accordance with the requirements in 40 CFR part 265... mercury-containing wastes in process vessels or in accordance with the requirements in 40 CFR part 265... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 1 Table 1...

  16. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... during transport. h. Store carbon from decomposers in accordance with the requirements in 40 CFR part 265... mercury-containing wastes in process vessels or in accordance with the requirements in 40 CFR part 265... Pollutants: Mercury Emissions From Mercury Cell Chlor-Alkali Plants Pt. 63, Subpt. IIIII, Table 1 Table 1...

  17. Effect of Pulse Duration on Polytetrafluoroethylene Shocked above the Crystalline Phase II-Iii Transition

    NASA Astrophysics Data System (ADS)

    Brown, E. N.; Gray, G. T.; Rae, P. J.; Trujillo, C. P.; Bourne, N. K.

    2007-12-01

    We present an experimental study of crystalline structure evolution of polytetrafluoroethylene (PTFE) due to pressure-induced phase transitions in a semi-crystalline polymer using soft-recovery, shock-loading techniques coupled with mechanical and chemical post-shock analysis. Gas-launched, plate impact experiments have been performed on pedigreed PTFE 7C, mounted in momentum-trapped, shock assemblies, with impact pressures above and below the phase II to phase III crystalline transition. Below the phase transition only subtle changes were observed in the crystallinity, microstructure, and mechanical response of PTFE. Shock loading of PTFE 7C above the phase II-III transition was seen to cause both an increase in crystallinity from 38% to ˜53% and a finer crystalline microstructure, and changed the yield and flow stress behavior. We particularly focus on the effect of pulse duration on the microstructure evolution.

  18. Shock Pulse Effects in PTFE Shocked Through the Crystalline Phase II--III Transition

    NASA Astrophysics Data System (ADS)

    Brown, Eric N.; Gray, George T., III; Rae, Philip J.; Bourne, Neil K.

    2008-03-01

    We present an experimental study of crystalline structure evolution of polytetrafluoroethylene (PTFE) due to pressure-induced phase transitions in a semi-crystalline polymer using soft-recovery, shock-loading techniques coupled with mechanical and chemical post-shock analysis. Gas-launched, plate impact experiments have been performed on pedigreed PTFE 7C, mounted in momentum-trapped, shock assemblies, with impact pressures above and below the phase II to phase III crystalline transition. Below the phase transition only subtle changes were observed in the crystallinity, microstructure, and mechanical response of PTFE. Shock loading of PTFE 7C above the phase II--III transition was seen to cause both an increase in crystallinity from 38% to ˜53% (by Differential Scanning Calorimetry, DSC) and a finer crystalline microstructure, and changed the yield and flow stress behavior. We particularly focus on the effect of pulse duration on the microstructure evolution.

  19. Effect of Pulse Duration on Polytetrafluoroethylene Shocked Above the Crystalline Phase II--III Transition

    NASA Astrophysics Data System (ADS)

    Brown, Eric N.; Gray, George T., III; Rae, Philip J.; Trujillo, Carl P.; Bourne, Neil K.

    2007-06-01

    We present an experimental study of crystalline structure evolution of polytetrafluoroethylene (PTFE) due to pressure-induced phase transitions in a semi-crystalline polymer using soft-recovery, shock-loading techniques coupled with mechanical and chemical post-shock analysis. Gas-launched, plate impact experiments have been performed on pedigreed PTFE 7C, mounted in momentum-trapped, shock assemblies, with impact pressures above and below the phase II to phase III crystalline transition. Below the phase transition only subtle changes were observed in the crystallinity, microstructure, and mechanical response of PTFE. Shock loading of PTFE 7C above the phase II--III transition was seen to cause both an increase in crystallinity from 38% to ˜53% (by Differential Scanning Calorimetry, DSC) and a finer crystalline microstructure, and changed the yield and flow stress behavior. We particularly focus on the effect of pulse duration on the microstructure evolution.

  20. A varying-stage adaptive phase II/III clinical trial design.

    PubMed

    Dong, Gaohong

    2014-04-15

    Currently, adaptive phase II/III clinical trials are typically carried out with a strict two-stage design. The first stage is a learning stage called phase II, and the second stage is a confirmatory stage called phase III. Following phase II analysis, inefficacious or harmful dose arms are dropped, then one or two promising dose arms are selected for the second stage. However, there are often situations in which researchers are in dilemma to make 'go or no-go' decision and/or to select 'best' dose arm(s), as data from the first stage may not provide sufficient information for their decision making. In this case, it is challenging to follow a strict two-stage plan. Therefore, we propose a varying-stage adaptive phase II/III clinical trial design, in which we consider whether there is a need to have an intermediate stage to obtain more data, so that a more informative decision could be made. Hence, the number of further investigational stages in our design is determined on the basis of data accumulated to the interim analysis. With respect to adaptations, we consider dropping dose arm(s), switching another plausible endpoint as the primary study endpoint, re-estimating sample size, and early stopping for futility. We use an adaptive combination test to perform final analyses. By applying closed testing procedure, we control family-wise type I error rate at the nominal level of α in the strong sense. We delineate other essential design considerations including the threshold parameters and the proportion of alpha allocated in the two-stage versus three-stage setting. PMID:24273128

  1. Unbiased estimation in seamless phase II/III trials with unequal treatment effect variances and hypothesis-driven selection rules.

    PubMed

    Robertson, David S; Prevost, A Toby; Bowden, Jack

    2016-09-30

    Seamless phase II/III clinical trials offer an efficient way to select an experimental treatment and perform confirmatory analysis within a single trial. However, combining the data from both stages in the final analysis can induce bias into the estimates of treatment effects. Methods for bias adjustment developed thus far have made restrictive assumptions about the design and selection rules followed. In order to address these shortcomings, we apply recent methodological advances to derive the uniformly minimum variance conditionally unbiased estimator for two-stage seamless phase II/III trials. Our framework allows for the precision of the treatment arm estimates to take arbitrary values, can be utilised for all treatments that are taken forward to phase III and is applicable when the decision to select or drop treatment arms is driven by a multiplicity-adjusted hypothesis testing procedure. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. PMID:27103068

  2. Soft recovery of polytetrafluoroethylene shocked through the crystalline phase II-III transition

    NASA Astrophysics Data System (ADS)

    Brown, E. N.; Trujillo, C. P.; Gray, G. T.; Rae, P. J.; Bourne, N. K.

    2007-01-01

    Polymers are increasingly being utilized as monolithic materials and composite matrices for structural applications historically reserved for metals. High strain-rate applications in aerospace, defense, and the automotive industries have lead to interest in the shock response of polytetrafluoroethylene (PTFE) and the ensuing changes in polymer structure due to shock prestraining. We present an experimental study of crystalline structure evolution due to pressure-induced phase transitions in a semicrystalline polymer using soft-recovery, shock loading techniques coupled with mechanical and chemical postshock analyses. Gas-launched, plate impact experiments have been performed on pedigreed PTFE 7C, mounted in momentum trapped, shock assemblies, with impact pressures above and below the phase II to phase III crystalline transition. Below the phase transition only subtle changes were observed in the crystallinity, microstructure, and mechanical response of PTFE. Shock loading of PTFE 7C above the phase II-III transition was seen to cause both an increase in crystallinity from 38% to ˜53% (by differential scanning calorimetry) and a finer crystalline microstructure, and changed the yield and flow stress behavior.

  3. ROTATION OF THE K3 II-III GIANT STAR {alpha} HYDRA

    SciTech Connect

    Gray, David F.

    2013-08-01

    Fundamental spectroscopic determination of projected rotation rates of slowly rotating stars is challenging because the rotational broadening of the spectral lines is often comparable to, or smaller than, the broadening from other sources, most notably macroturbulence. Fourier techniques have the advantage over direct profile matching when the observed profiles are complete, but when the profiles are severely blended, the Fourier analysis is compromised. A process of modeling partial profiles for determining the rotation rate for stars having blended spectral lines is investigated and applied to the evolved star {alpha} Hya (K3 II-III). Projected rotation higher than 5 km s{sup -1} can be definitively ruled out for this star. Not all lines are equally good, depending on the amount of blending and also depending on the strength of the line, as the balance between the thermal and non-thermal components changes. A modest ambiguity arises between macroturbulence and rotational broadening, but a careful look at the differences between the observations and the models allows one to measure the rotation with acceptable precision. The result for {alpha} Hya is v sin i = 2.6 {+-} 0.3 km s{sup -1}.

  4. World Health Organization grade II-III astrocytomas consist of genetically distinct tumor lineages.

    PubMed

    Hattori, Natsuki; Hirose, Yuichi; Sasaki, Hikaru; Nakae, Shunsuke; Hayashi, Saeko; Ohba, Shigeo; Adachi, Kazuhide; Hayashi, Takuro; Nishiyama, Yuya; Hasegawa, Mitsuhiro; Abe, Masato

    2016-08-01

    Recent investigations revealed genetic analysis provides important information in management of gliomas, and we previously reported grade II-III gliomas could be classified into clinically relevant subgroups based on the DNA copy number aberrations (CNAs). To develop more precise genetic subgrouping, we investigated the correlation between CNAs and mutational status of the gene encoding isocitrate dehydrogenase (IDH) of those tumors. We analyzed the IDH status and CNAs of 174 adult supratentorial gliomas of astrocytic or oligodendroglial origin by PCR-based direct sequencing and comparative genomic hybridization, respectively. We analyzed the relationship between genetic subclassification and clinical features. We found the most frequent aberrations in IDH mutant tumors were the combined whole arm-loss of 1p and 19q (1p/19q codeletion) followed by gain on chromosome arm 7q (+7q). The gain of whole chromosome 7 (+7) and loss of 10q (-10q) were detected in IDH wild-type tumors. Kaplan-Meier estimates for progression-free survival showed that the tumors with mutant IDH, -1p/19q, or +7q (in the absence of +7p) survived longer than tumors with wild-type IDH, +7, or -10q. As tumors with +7 (IDH wild-type) showed a more aggressive clinical nature, they are probably not a subtype that developed from the slowly progressive tumors with +7q (IDH mutant). Thus, tumors with a gain on chromosome 7 (mostly astrocytic) comprise multiple lineages, and such differences in their biological nature should be taken into consideration during their clinical management. PMID:27196377

  5. Detection of methicillin-resistant Staphylococcus pseudintermedius ST169 and novel ST354 SCCmec II-III isolates related to the worldwide ST71 clone.

    PubMed

    Ishihara, K; Koizumi, A; Saito, M; Muramatsu, Y; Tamura, Y

    2016-01-01

    The recent appearance of methicillin-resistant Staphylococcus pseudintermedius (MRSP) is a concern for both veterinary and human healthcare. MRSP clonal lineages with sequence type (ST) 71-spa t02-staphylococcal cassette chromosome mec (SCCmec) II-III and ST68-spa t06-SCCmec V have spread throughout Europe and North America, respectively. The current study compared the molecular characteristics of 43 MRSP isolates from dogs in Japan with those of MRSP from previous reports using multilocus sequence typing based on seven housekeeping genes, SCCmec typing, and detection of antimicrobial resistance genes. Three related clonal lineages, ST71, ST169, and the newly registered ST354, were observed in SCCmec II-III isolates from Japan, despite MRSP SCCmec II-III isolates being thought to belong to a single clonal lineage. The majority of SCCmec II-III isolates belonging to ST169 (9/11) and ST354 (3/3), but not ST71 (0/11), harboured tetM. Four STs were observed for the SCCmec V isolates; however, neither ST68 nor related STs were found in the Japanese MRSP isolates. In conclusion, MRSP SCCmec II-III isolates from Japan belonged to ST71 and related STs (ST169 and ST354). A variety of MRSP SCCmec V clones, including some novel clones, were identified. PMID:26138564

  6. Efficacy of Adjuvant 5-Fluorouracil Therapy for Patients with EMAST-Positive Stage II/III Colorectal Cancer

    PubMed Central

    Hamaya, Yasushi; Guarinos, Carla; Tseng-Rogenski, Stephanie S.; Iwaizumi, Moriya; Das, Ritabrata; Jover, Rodrigo; Castells, Antoni; Llor, Xavier; Andreu, Montserrat; Carethers, John M.

    2015-01-01

    Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutSα (hMSH2-hMSH6 heterodimer) and hMutSβ (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutSα > hMutSβ alone. We tested if patients with EMAST CRCs (hMutSβ defective) had diminished response to adjuvant 5-FU chemotherapy, paralleling in vitro findings. We analyzed 230 patients with stage II/III sporadic colorectal cancers for which we had 5-FU treatment and survival data. Archival DNA was analyzed for EMAST (>2 of 5 markers mutated among UT5037, D8S321, D9S242, D20S82, D20S85 tetranucleotide loci). Kaplan-Meier survival curves were generated and multivariate analysis was used to determine contribution to risk. We identified 102 (44%) EMAST cancers. Ninety-four patients (41%) received adjuvant 5-FU chemotherapy, and median follow-up for all patients was 51 months. Patients with EMAST CRCs demonstrated improved survival with adjuvant 5FU to the same extent as patients with non-EMAST CRCs (P<0.05). We observed no difference in survival between patients with stage II/III EMAST and non-EMAST cancers (P = 0.36). There is improved survival for stage II/III CRC patients after adjuvant 5-FU-based chemotherapy regardless of EMAST status. The loss of contribution of hMSH3 for 5-FU cytotoxicity may not adversely affect patient outcome, contrasting patients whose tumors completely lack DNA MMR function (MSI-H). PMID:25996601

  7. Evidence of active tectonics on a Roman aqueduct system (II-III century A.D.) near Rome, Italy

    NASA Astrophysics Data System (ADS)

    Marra, Fabrizio; Montone, Paola; Pirro, Mario; Boschi, Enzo

    2004-04-01

    In this paper we describe evidence of strong tectonic deformation affecting two aqueducts of Roman age (II-III century A.D.). The channels are located approximately 20 km northeast of Rome along the ancient Via Tiburtina. Brittle and ductile deformation affects these two structures, including extensional joint systems, NE-oriented faults, and horizontal distortion. This deformation is consistent with right-lateral movement on major N-striking faults, and represents the first evidence that tectonic deformation took place in historical times in the vicinity of Rome, with local strike-slip movement superimposed on a regional extensional fault system.

  8. Layer II/III of the prefrontal cortex: inhibition by the serotonin 5-HT1A receptor in development and stress

    PubMed Central

    Goodfellow, Nathalie M.; Benekareddy, Madhurima; Vaidya, Vidita A.; Lambe, Evelyn K.

    2009-01-01

    The modulation of the prefrontal cortex by the neurotransmitter serotonin (5-HT) is thought to play a key role in determining adult anxiety levels. Layer II/III of the prefrontal cortex, which mediates communication across cortical regions, displays a of high level 5-HT1A receptor binding in normal individuals and a significantly lower level in patients with mood and anxiety disorders. Here, we examine how serotonin modulates pyramidal neurons in layer II/III of the rat prefrontal cortex throughout postnatal development and in adulthood. Using whole cell recordings in brain slices of the rat medial prefrontal cortex, we observed that serotonin directly inhibits layer II/III pyramidal neurons through 5-HT1A receptors across postnatal development (P6 to P96). In adulthood, a sex difference in these currents emerges, consistent with human imaging studies of 5-HT1A receptor binding. We examined the effects of early life stress on the 5-HT1A receptor currents in layer II/III. Surprisingly, animals subjected to early life stress displayed significantly larger 5-HT1A-mediated outward currents throughout the third and fourth postnatal weeks following elevated 5-HT1A expression during the second postnatal week. Subsequent exposure to social isolation in adulthood resulted in the almost-complete elimination of 5-HT1A currents in layer II/III neurons suggesting an interaction between early life events and adult experiences. These data represent the first examination of functional 5-HT1A receptors in layer II/III of the prefrontal cortex during normal development as well as after stress. PMID:19675243

  9. Motor Training Promotes Both Synaptic and Intrinsic Plasticity of Layer II/III Pyramidal Neurons in the Primary Motor Cortex

    PubMed Central

    Kida, Hiroyuki; Tsuda, Yasumasa; Ito, Nana; Yamamoto, Yui; Owada, Yuji; Kamiya, Yoshinori; Mitsushima, Dai

    2016-01-01

    Motor skill training induces structural plasticity at dendritic spines in the primary motor cortex (M1). To further analyze both synaptic and intrinsic plasticity in the layer II/III area of M1, we subjected rats to a rotor rod test and then prepared acute brain slices. Motor skill consistently improved within 2 days of training. Voltage clamp analysis showed significantly higher α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/N-methyl-d-aspartate (AMPA/NMDA) ratios and miniature EPSC amplitudes in 1-day trained rats compared with untrained rats, suggesting increased postsynaptic AMPA receptors in the early phase of motor learning. Compared with untrained controls, 2-days trained rats showed significantly higher miniature EPSC amplitude and frequency. Paired-pulse analysis further demonstrated lower rates in 2-days trained rats, suggesting increased presynaptic glutamate release during the late phase of learning. One-day trained rats showed decreased miniature IPSC frequency and increased paired-pulse analysis of evoked IPSC, suggesting a transient decrease in presynaptic γ-aminobutyric acid (GABA) release. Moreover, current clamp analysis revealed lower resting membrane potential, higher spike threshold, and deeper afterhyperpolarization in 1-day trained rats—while 2-days trained rats showed higher membrane potential, suggesting dynamic changes in intrinsic properties. Our present results indicate dynamic changes in glutamatergic, GABAergic, and intrinsic plasticity in M1 layer II/III neurons after the motor training. PMID:27193420

  10. Thymidine phosphorylase and hypoxia-inducible factor 1-α expression in clinical stage II/III rectal cancer: association with response to neoadjuvant chemoradiation therapy and prognosis.

    PubMed

    Lin, Shuhan; Lai, Hao; Qin, Yuzhou; Chen, Jiansi; Lin, Yuan

    2015-01-01

    The aim of this study was to determine whether pretreatment status of thymidine phosphorylase (TP), and hypoxia-inducible factor alpha (HIF-1α) could predict pathologic response to neoadjuvant chemoradiation therapy with oxaliplatin and capecitabine (XELOXART) and outcomes for clinical stage II/III rectal cancer patients. A total of 180 patients diagnosed with clinical stage II/III rectal cancer received XELOXART. The status of TP, and HIF-1α were determined in pretreatment biopsies by immunohistochemistry (IHC). Tumor response was assessed in resected regimens using the tumor regression grade system and TNM staging system. 5-year disease free survival (DFS) and 5-year overall survival (OS) were evaluated with the Kaplan-Meier method and were compared by the log-rank test. Over expression of TP and low expression of HIF-1α were associated with pathologic response to XELOXART and better outcomes (DFS and OS) in clinical stage II/III rectal cancer patients (P < 0.05). Our result suggested that pretreatment status of TP and HIF-1α were found to predict pathologic response and outcomes in clinical stage II/III rectal cancer received XELOXART. Additional well-designed, large sample, multicenter, prospective studies are needed to confirm the result of this study. PMID:26617778

  11. Prognostic Role of BRAF Mutation in Stage II/III Colorectal Cancer Receiving Curative Resection and Adjuvant Chemotherapy: A Meta-Analysis Based on Randomized Clinical Trials

    PubMed Central

    Cao, Ying; Fang, Xuefeng; Zhong, Chenhan; Li, Dan; Yuan, Ying

    2016-01-01

    Background and Objective Studies examining the prognostic value of the BRAF mutation on relapse-free survival (RFS), disease-free survival (DFS) and overall survival (OS) in stage II/III colorectal cancer (CRC) patients receiving curative resection and adjuvant chemotherapy so far showed discrepant results. Therefore, a meta-analysis of relevant studies was performed for clarification. Methods Randomized trials of stage II/III colorectal cancer treated with curative resection followed by adjuvant chemotherapy were selected to conduct a meta-analysis. The necessary descriptive and statistical information such as hazard ratios (HRs) and 95% confidence intervals (CIs) were derived from published survival data. Results Seven phase III randomized clinical trials (RCTs) including 1,035 BRAF mutation stage II/III CRC patients receiving curative resection and adjuvant chemotherapy were analyzed. Overall, BRAF mutation resulted in poorer OS (HR = 1.42, 95% CI: 1.25–1.60; P < 0.00001), and poorer DFS (HR = 1.26, 95% CI: 1.07–1.48, P = 0.006) compared with BRAF wild-type CRC. The prognostic role on RFS could not be elucidated in the meta-analysis because of limited data. Conclusions BRAF mutation was significantly related with shorter DFS and OS among stage II/III CRC patients receiving adjuvant chemotherapy after curative resection. Its prognostic role for RFS needs to be further analyzed when more data is available. PMID:27138801

  12. Measurement of the Flux and Zenith-Angle Distribution of Upward Through-Going Muons in Kamiokande II+III

    NASA Astrophysics Data System (ADS)

    Hatakeyama, S.; Hara, T.; Fukuda, Y.; Hayakawa, T.; Inoue, K.; Ishihara, K.; Ishino, H.; Joukou, S.; Kajita, T.; Kasuga, S.; Koshio, Y.; Kumita, T.; Matsumoto, K.; Nakahata, M.; Nakamura, K.; Okumura, K.; Sakai, A.; Shiozawa, M.; Suzuki, J.; Suzuki, Y.; Tomoeda, T.; Totsuka, Y.; Hirata, K. S.; Kihara, K.; Oyama, Y.; Koshiba, M.; Nishijima, K.; Horiuchi, T.; Fujita, K.; Koga, M.; Maruyama, T.; Suzuki, A.; Mori, M.; Suda, T.; Suzuki, A. T.; Ishizuka, T.; Miyano, K.; Okazawa, H.; Nagashima, Y.; Takita, M.; Yamaguchi, T.; Hayato, Y.; Kaneyuki, K.; Suzuki, T.; Takeuchi, Y.; Tanimori, T.; Tasaka, S.; Ichihara, E.; Miyamoto, S.; Nishikawa, K.

    1998-09-01

    The flux of upward through-going muons of minimum (mean) threshold energy >1.6 (3.0) GeV is measured, based on a total of 372 events observed by the Kamiokande II+III detector during 2456 detector live days. The observed muon flux was Φobs = [1.94+/-0.10\\(stat.\\)+0.07-0.06sys.\\)]×10-13 cm-2 s-1 sr-1, which is compared to an expected value of Φtheo = [2.46+/-0.54\\(theo.\\)]×10-13 cm-2 s-1 sr-1. The observation is in agreement with the prediction within the errors. The zenith-angle dependence of the observed upward through-going muons supports the previous indication of neutrino oscillations made by Kamiokande using sub- and multi-GeV atmospheric neutrino events.

  13. Purification of human immunoglobulins A, G and M from Cohn fraction II/III by small peptide affinity chromatography.

    PubMed

    Liu, Zhuo; Gurgel, Patrick V; Carbonell, Ruben G

    2012-11-01

    This work describes attempts to purify human IgG, IgA and IgM from Cohn fraction II/III using HWRGWV affinity peptide resin. The effects of peptide density and different elution additives on recovery of the three antibodies were investigated. At low peptide density, salting-in salts such as magnesium chloride and calcium chloride facilitated antibody elution. Ethylene glycol, urea and arginine also facilitated elution because of their ability to decrease hydrophobic interactions, hydrogen bonding and electrostatic interactions. However, at high peptide density, no recovery improvements were observed because of increased non-specific hydrophobic interactions. The final elution conditions for each antibody were chosen based on the resulting yields and purities when a 10:2:1mg/mL mixture of human IgG, IgA and IgM was used as starting material. Different pretreatment methods were employed in order to improve the purity of antibodies from Cohn fraction II/III. After pretreatment with caprylic acid precipitation or combination of caprylic acid and polyethylene glycol precipitation, purities over 95% and yields of about 60% were obtained for hIgG, which are comparable to current chromatographic purification methods involving two chromatography steps when hIgG is isolated from plasma fractions. A hIgA-enriched fraction with 42% hIgA and 56% hIgG, as well as a hIgM enriched fraction with 46% hIgM, 28% hIgA and 24% hIgG, were obtained as the by-products. PMID:23026261

  14. Changes in the BDNF-immunopositive cell population of neocortical layers I and II/III after focal cerebral ischemia in rats.

    PubMed

    Choi, Yongwon; Kang, Sung Goo; Kam, Kyung-Yoon

    2015-04-24

    Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family and is widely distributed in the central nervous system, including the cerebral cortex. BDNF plays an important role in normal neural development, survival of existing neurons, and activity-dependent neuroplasticity. BDNF can also be neuroprotective and evoke neurogenesis in certain pathological conditions, such as cerebral ischemia. Neocortical layer I is an important region that can integrate feedforward and feedback information from other cortical areas and subcortical regions. In addition, it has recently been proposed as a possible source of neuronal progenitor cells after ischemia. Therefore, we investigated changes in the BDNF-immunoreactive cell population of neocortical layers I and II/III after middle cerebral artery occlusion (MCAO)-induced cerebral ischemia in rats. In unaffected condition, the number of BDNF(+) cells in layer I was significantly less than in layer II/III in the cingulate cortex and in the motor and sensory areas. The increase in the number of BDNF(+) cells in layer I 8 days after MCAO was more remarkable than layer II/III, in all regions except the area of cingulate cortex farthest from the infarct core. Only BDNF(+)-Ox-42(+) cells showed a tendency to increase consistently toward the infarct core in both layers I and II/III, implying a major source of BDNF for response to ischemic injury. The present study suggests that some beneficial effects during recovery from ischemic injury, such as increased supportive microglia/macrophages, occur owing to a sensitive response of BDNF in layer I. PMID:25681548

  15. High expression of Zinc-finger protein X-linked promotes tumor growth and predicts a poor outcome for stage II/III colorectal cancer patients

    PubMed Central

    Yan, Leilei; Zhu, Qingchao; Liu, Liguo; Xu, Bing; Liu, Sihong; Jin, Zhiming; Gao, Yuping

    2016-01-01

    Zinc-finger protein X-linked (ZFX) was recently identified as a novel oncoprotein in several human malignancies. In this study, we examined the correlation between ZFX expression and the clinical characteristics of stage II/III CRC patients, as well as the molecular mechanism by which ZFX apparently contributes to CRC tumor progression. Using immunohistochemistry, we detected expression of ZFX in CRC tissues collected from stage II/III patients and determined that its expression correlated with tumor differentiation and stage. Survival analysis indicated that patients with high ZFX expression had poorer overall and disease-free survival. ZFX knockdown in SW620 and SW480 CRC cells significantly inhibited cell proliferation and colony formation, enhanced apoptosis and induced cell cycle arrest. It also enhanced the sensitivity of CRC cells to 5-Fu. In a xenograft model, ZFX knockdown suppressed in vivo CRC tumor growth. Microarray analysis revealed the primary target of ZFX to be DUSP5. Whereas ZFX knockdown increased DUSP5 expression, DUSP5 knockdown rescued ZFX-mediated cell proliferation in ZFX knockdown cells. These findings demonstrate that ZFX promotes CRC progression by suppressing DUSP5 expression and suggest that ZFX is a novel prognostic biomarker and potentially useful therapeutic target in stage II/III CRC patients. PMID:26967242

  16. Germline polymorphisms in genes involved in the Hippo pathway as recurrence biomarkers in stages II/III colon cancer.

    PubMed

    Sebio, A; Matsusaka, S; Zhang, W; Yang, D; Ning, Y; Stremitzer, S; Stintzing, S; Sunakawa, Y; Yamauchi, S; Fujimoto, Y; Ueno, M; Lenz, H-J

    2016-08-01

    The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil (5-Fu). In this study, 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56 vs 33%, hazard ratio (HR): 1.87; P=0.017). Patients with TAZ rs3811715 CT or TT genotypes had lower 3-year recurrence rate than patients with a CC genotype (28 vs 40%; HR: 0.66; P=0.07). In left-sided tumors, this association was stronger (HR: 0.29; P=0.011) and a similar trend was found in an independent Japanese cohort. These promising results reveal polymorphisms in the Hippo pathway as biomarkers for stages II and III colon cancer.The Pharmacogenomics Journal advance online publication, 15 September 2015; doi:10.1038/tpj.2015.64. PMID:26370619

  17. Cux1 Enables Interhemispheric Connections of Layer II/III Neurons by Regulating Kv1-Dependent Firing.

    PubMed

    Rodríguez-Tornos, Fernanda M; Briz, Carlos G; Weiss, Linnea A; Sebastián-Serrano, Alvaro; Ares, Saúl; Navarrete, Marta; Frangeul, Laura; Galazo, Maria; Jabaudon, Denis; Esteban, José A; Nieto, Marta

    2016-02-01

    Neuronal subtype-specific transcription factors (TFs) instruct key features of neuronal function and connectivity. Activity-dependent mechanisms also contribute to wiring and circuit assembly, but whether and how they relate to TF-directed neuronal differentiation is poorly investigated. Here we demonstrate that the TF Cux1 controls the formation of the layer II/III corpus callosum (CC) projections through the developmental transcriptional regulation of Kv1 voltage-dependent potassium channels and the resulting postnatal switch to a Kv1-dependent firing mode. Loss of Cux1 function led to a decrease in the expression of Kv1 transcripts, aberrant firing responses, and selective loss of CC contralateral innervation. Firing and innervation were rescued by re-expression of Kv1 or postnatal reactivation of Cux1. Knocking down Kv1 mimicked Cux1-mediated CC axonal loss. These findings reveal that activity-dependent processes are central bona fide components of neuronal TF-differentiation programs and establish the importance of intrinsic firing modes in circuit assembly within the neocortex. PMID:26804994

  18. Germline polymorphisms in genes involved in the Hippo pathway as recurrence biomarkers in stage II/III colon cancer

    PubMed Central

    Sebio, Ana; Matsusaka, Satoshi; Zhang, Wu; Yang, Dongyun; Ning, Yan; Stremitzer, Stefan; Stintzing, Sebastian; Sunakawa, Yu; Yamauchi, Shinichi; Fujimoto, Yoshiya; Ueno, Masashi; Lenz, Heinz-Josef

    2015-01-01

    The Hippo pathway regulates tissue growth and cell fate. In colon cancer, Hippo pathway deregulation promotes cellular quiescence and resistance to 5-Fluorouracil. In this study 14 polymorphisms in 8 genes involved in the Hippo pathway (MST1, MST2, LATS1, LATS2, YAP, TAZ, FAT4 and RASSF1A) were evaluated as recurrence predictors in 194 patients with stages II/III colon cancer treated with 5-Fu-based adjuvant chemotherapy. Patients with a RASSF1A rs2236947 AA genotype had higher 3-year recurrence rate than patients with CA/CC genotypes (56% vs 33%, HR: 1.87; p=0.017). Patients with TAZ rs3811715 CT or TT genotypes had lower 3-year recurrence rate than patients with a CC genotype (28% vs 40%; HR: 0.66; p=0.07). In left-sided tumors, this association was stronger (HR: 0.29; p=0.011) and a similar trend was found in an independent Japanese cohort. These promising results reveal polymorphisms in the Hippo pathway as biomarkers for stage II and III colon cancer. PMID:26370619

  19. Equatorial π-stacking interactions in diruthenium (II,III) tetracarboxylate complexes containing extended π-systems

    NASA Astrophysics Data System (ADS)

    O'Rourke, Natasha F.; Ronaldson, Michael; Stanley Cameron, T.; Wang, Ruiyao; Aquino, Manuel A. S.

    2013-11-01

    The synthesis of three new valent-averaged tetracarboxylatodiruthenium (II,III) complexes, [Ru2(1-naphthylacetate)4(H2O)2](PF6)ṡ4THF, 1ṡ4THF, [Ru2(2-naphthoate)4(THF)2](PF6)ṡ3THF, 2ṡ3THF, and [Ru2(coumarin-3-carboxylate)4(MeOH)2](PF6)ṡMeOHṡH2O, 3ṡMeOHṡH2O, was accomplished using a well documented carboxylate exchange reaction. All three complexes were thoroughly characterized using infrared and UV-Vis spectroscopies, elemental analysis and X-ray diffraction. Due to the extended π-systems present, two of the complexes, 2ṡ3THF and 3ṡMeOHṡH2O, display extensive π-stacking in two dimensions, with similar interactions notably absent in 1ṡ4THF due to the perpendicular orientation of the naphthyl rings. Modest H-bonding is seen in complexes 1ṡ4THF and 3ṡMeOHṡH2O. As these types of complexes are noted secondary building units (SBU's) in the construction of metal-organic frameworks (MOF's), the significance of these interactions in stabilizing even larger, supramolecular structures, are noted.

  20. Randomized phase II/III clinical trial of elpamotide for patients with advanced pancreatic cancer: PEGASUS-PC Study.

    PubMed

    Yamaue, Hiroki; Tsunoda, Takuya; Tani, Masaji; Miyazawa, Motoki; Yamao, Kenji; Mizuno, Nobumasa; Okusaka, Takuji; Ueno, Hideki; Boku, Narikazu; Fukutomi, Akira; Ishii, Hiroshi; Ohkawa, Shinichi; Furukawa, Masayuki; Maguchi, Hiroyuki; Ikeda, Masafumi; Togashi, Yosuke; Nishio, Kazuto; Ohashi, Yasuo

    2015-07-01

    Gemcitabine is a key drug for the treatment of pancreatic cancer; however, with its limitation in clinical benefits, the development of another potent therapeutic is necessary. Vascular endothelial growth factor receptor 2 is an essential target for tumor angiogenesis, and we have conducted a phase I clinical trial using gemcitabine and vascular endothelial growth factor receptor 2 peptide (elpamotide). Based on the promising results of this phase I trial, a multicenter, randomized, placebo-controlled, double-blind phase II/III clinical trial has been carried out for pancreatic cancer. The eligibility criteria included locally advanced or metastatic pancreatic cancer. Patients were assigned to either the Active group (elpamotide + gemcitabine) or Placebo group (placebo + gemcitabine) in a 2:1 ratio by the dynamic allocation method. The primary endpoint was overall survival. The Harrington-Fleming test was applied to the statistical analysis in this study to evaluate the time-lagged effect of immunotherapy appropriately. A total of 153 patients (Active group, n = 100; Placebo group, n = 53) were included in the analysis. No statistically significant differences were found between the two groups in the prolongation of overall survival (Harrington-Fleming P-value, 0.918; log-rank P-value, 0.897; hazard ratio, 0.87, 95% confidence interval [CI], 0.486-1.557). Median survival time was 8.36 months (95% CI, 7.46-10.18) for the Active group and 8.54 months (95% CI, 7.33-10.84) for the Placebo group. The toxicity observed in both groups was manageable. Combination therapy of elpamotide with gemcitabine was well tolerated. Despite the lack of benefit in overall survival, subgroup analysis suggested that the patients who experienced severe injection site reaction, such as ulceration and erosion, might have better survival. PMID:25867139

  1. Phase II Study of Chemoradiotherapy With 5-Fluorouracil and Cisplatin for Stage II-III Esophageal Squamous Cell Carcinoma: JCOG Trial (JCOG 9906)

    SciTech Connect

    Kato, Ken; Muro, Kei; Minashi, Keiko; Ohtsu, Atsushi; Ishikura, Satoshi; Boku, Narikazu; Takiuchi, Hiroya; Komatsu, Yoshito; Miyata, Yoshinori; Fukuda, Haruhiko

    2011-11-01

    Purpose: In this Phase II study, we evaluated the efficacy and toxicity of chemoradiotherapy (CRT) with cisplatin (CDDP) and 5-fluorouracil (5-FU) for Stage II-III esophageal squamous cell carcinoma (ESCC). Patients and Methods: Patients with clinical Stage II-III (T1N1M0 or T2-3N0-1M0) thoracic ESCC were enrolled between April 2000 and March 2002. Chemotherapy comprised two courses of protracted infusion of 5-FU (400 mg/m{sup 2}/day) on Days 1-5 and 8-12, and 2-h infusion of CDDP (40 mg/m{sup 2}) on Days 1 and 8; this regimen was repeated every 5 weeks. Concurrent radiotherapy involved 60-Gy irradiation (30 fractions) for 8 weeks with a 2-week break. Responders received two courses of 5-FU (800 mg/m{sup 2}/day) on Days 1-5 and CDDP (80 mg/m{sup 2}) on Day 1. Final analysis was conducted in March 2007. Survival and late toxicities were monitored for 5 years. Results: The characteristics of the 76 patients enrolled were as follows: median age, 61 years; male/female, 68/8; performance status 0/1, 59/17 patients; Stage IIA/IIB/III, 26/12/38 patients. Of the 74 eligible patients, 46 (62.2%) achieved complete response. Median survival time was 29 months, with 3- and 5-year survival rates of 44.7% and 36.8%, respectively. Acute toxicities included Grade 3/4 esophagitis (17%), nausea (17%), hyponatremia (16%), and infection without neutropenia (12%). Late toxicities comprised Grade 3/4 esophagitis (13%), pericardial (16%) and pleural (9%) effusion, and radiation pneumonitis (4%), causing 4 deaths. Conclusions: CRT is effective for Stage II-III ESCC with manageable acute toxicities and can provide a nonsurgical treatment option. However, further improvement is required for reduction in late toxicity.

  2. Voluntary exercise partially reverses neonatal alcohol-induced deficits in mPFC layer II/III dendritic morphology of male adolescent rats.

    PubMed

    Hamilton, G F; Criss, K J; Klintsova, A Y

    2015-08-01

    Developmental alcohol exposure in humans can produce a wide range of deficits collectively referred to as fetal alcohol spectrum disorders (FASD). FASD-related impairments in executive functioning later in life suggest long-term damage to the prefrontal cortex (PFC). In rodent neonates, moderate to high levels of alcohol exposure decreased frontal lobe brain size and altered medial PFC pyramidal neuron dendritic morphology. Previous research in our lab demonstrated that neonatal alcohol exposure decreased basilar dendritic complexity but did not affect spine density in Layer II/III pyramidal neurons in 26- to 30-day-old rats. The current study adds to the literature by evaluating the effect of neonatal alcohol exposure on mPFC Layer II/III basilar dendritic morphology in adolescent male rats. Additionally, it examines the potential for voluntary exercise to mitigate alcohol-induced deficits on mPFC dendritic complexity. An animal model of binge drinking during the third trimester of pregnancy was used. Rats were intubated with alcohol (alcohol-exposed, AE; 5.25 g kg(-1) day(-1)) on postnatal days (PD) 4-9; two control groups were included (suckle control and sham-intubated). Rats were anesthetized and perfused with heparinized saline solution on PD 42, and brains were processed for Golgi-Cox staining. Developmental alcohol exposure decreased spine density and dendritic complexity of basilar dendrites of Layer II/III neurons in the medial PFC (mPFC) compared to dendrites of control animals. Voluntary exercise increased spine density and dendritic length in AE animals resulting in elimination of the differences between AE and SH rats. Thus, voluntary exercise during early adolescence selectively rescued alcohol-induced morphological deficits in the mPFC. PMID:25967699

  3. Fatigue delamination growth in woven glass/epoxy composite laminates under mixed-mode II/III loading conditions at cryogenic temperatures

    NASA Astrophysics Data System (ADS)

    Takeda, Tomo; Miura, Masaya; Shindo, Yasuhide; Narita, Fumio

    2013-12-01

    We investigate the cryogenic delamination growth behavior in woven glass fiber reinforced polymer (GFRP) composite laminates under mixed-mode II/III fatigue loading. Fatigue delamination tests were conducted with six-point bending plate (6PBP) specimens at room temperature, liquid nitrogen temperature (77 K) and liquid helium temperature (4 K), and the delamination growth rate data for various mixed-mode ratios of Modes II and III were obtained. The energy release rate was evaluated using the three-dimensional finite element method. In addition, the fatigue delamination growth mechanisms were characterized by scanning electron microscopic observations of the specimen fracture surfaces.

  4. A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC)

    PubMed Central

    Oki, E.; Murata, A.; Yoshida, K.; Maeda, K.; Ikejiri, K.; Munemoto, Y.; Sasaki, K.; Matsuda, C.; Kotake, M.; Suenaga, T.; Matsuda, H.; Emi, Y.; Kakeji, Y.; Baba, H.; Hamada, C.; Saji, S.; Maehara, Y.

    2016-01-01

    Backgrounds Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur–uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. Patients and methods The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20–80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500–600 mg/day on days 1–5, followed by 2 days rest) or S-1 (80–120 mg/day on days 1–28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. Results In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63–0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. Conclusion One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection. PMID:27056996

  5. FKBP12 modulation of the binding of the skeletal ryanodine receptor onto the II-III loop of the dihydropyridine receptor.

    PubMed Central

    O'Reilly, Fiona M; Robert, Mylène; Jona, Istvan; Szegedi, Csaba; Albrieux, Mireille; Geib, Sandrine; De Waard, Michel; Villaz, Michel; Ronjat, Michel

    2002-01-01

    In skeletal muscle, excitation-contraction coupling involves a functional interaction between the ryanodine receptor (RyR) and the dihydropyridine receptor (DHPR). The domain corresponding to Thr(671)-Leu(690) of the II-III loop of the skeletal DHPR alpha(1)-subunit is able to regulate RyR properties and calcium release from sarcoplasmic reticulum, whereas the domain corresponding to Glu(724)-Pro(760) antagonizes this effect. Two peptides, covering these sequences (peptide A(Sk) and C(Sk), respectively) were immobilized on polystyrene beads. We demonstrate that peptide A(Sk) binds to the skeletal isoform of RyR (RyR1) whereas peptide C(Sk) does not. Using surface plasmon resonance detection, we show that 1) domain Thr(671)-Leu(690) is the only sequence of the II-III loop binding with RyR1 and 2) the interaction of peptide A(Sk) with RyR1 is not modulated by Ca(2+) (pCa 9-2) nor by Mg(2+) (up to 10 mM). In contrast, this interaction is strongly potentiated by the immunophilin FKBP12 (EC(50) = 10 nM) and inhibited by both rapamycin (IC(50) = 5 nM) and FK506. Peptide A(Sk) induces a 300% increase of the opening probability of the RyR1 incorporated in lipid bilayer. Removal of FKBP12 from RyR1 completely abolishes this effect of domain A(Sk) on RyR1 channel behavior. These results demonstrate a direct interaction of the RyR1 with the discrete domain of skeletal DHPR alpha(1)-subunit corresponding to Thr(671)-Leu(690) and show that the association of FKBP12 with RyR1 specifically modulates this interaction. PMID:11751303

  6. Thyroid Function in Women after Multimodal Treatment for Breast Cancer Stage II/III: Comparison With Controls From a Population Sample

    SciTech Connect

    Reinertsen, Kristin Valborg; Cvancarova, Milada; Wist, Erik; Bjoro, Trine; Dahl, Alv A.; Danielsen, Turi; Fossa, Sophie D.

    2009-11-01

    Purpose: A possible association between thyroid diseases (TD) and breast cancer (BC) has been debated. We examined prevalence and development of TD in women after multimodal treatment for Stage II/III BC compared with women from a general population. Secondarily, we explored the impact of two different radiotherapy (RT) techniques (standardized field arrangements vs. computed tomography [CT]-based dose planning) on TD in BC patients examined 35-120 months after primary BC treatment. Methods and Materials: A total of 403 BC patients completed a questionnaire about TD and had blood samples taken for analyses of thyroid function. All had undergone postoperative RT with or without (2%) adjuvant systemic treatment. The results in the BC patients were compared with a cancer-free, age-matched control group from a general population (CGr). Results: There was higher prevalence of self-reported hypothyroidism in the BC patients as compared with the CGr (18% vs. 6%, p < 0.001). The raised prevalence was predominantly due to a substantial increase in the development of hypothyroidism after BC diagnosis, whereas the prevalence of hypothyroidism before BC diagnosis was similar to that observed in the CGr. Patients treated with CT-based RT showed a trend for increased post-BC development of hypothyroidism as compared with those treated with standardized field arrangements (p = 0.08). Conclusions: Hypothyroidism is significantly increased in women after multimodal treatment for Stage II/III BC. Radiation to the thyroid gland may be a contributing factor. BC patients should be routinely screened for hypothyroidism.

  7. Fluorouracil-based preoperative chemoradiotherapy with or without oxaliplatin for stage II/III rectal cancer: a 3-year follow-up study

    PubMed Central

    Jiao, Dexin; Zhang, Rui; Gong, Zhiqiang; Liu, Fang; Chen, Yue; Yu, Qinrui; Sun, Liping; Duan, Hongyan; Zhu, Shendong; Liu, Fei; Wang, Jian

    2015-01-01

    Background Fluorouracil-based preoperative chemoradiotherapy has become the standard treatment for stage II/III rectal cancer. In order to improve the overall survival (OS) and disease-free survival (DFS), we added oxaliplatin to the standard treatment, and compared the effectiveness of these two treatment patterns. Methods A total of 206 patients enrolled in the prospective study had histologically confirmed rectal cancer of clinical stage II/III during July 2007 to July 2010. They were randomized into the experimental group received oxaliplatin and capecitabine in combination with radiotherapy, and the control group received capecitabine in combination with radiotherapy. All patients received surgery in 6−10 weeks after chemoradiotherapy and adjuvant chemotherapy with mFOLFOX6. The primary endpoints were DFS and OS, and the secondary endpoints included toxicity, compliance, and histopathological response. Results The 3-year OS in the experimental group and the control group was 90.29% vs. 86.41% (P>0.05), and the 3-year DFS was 80.58% vs. 69.90% (P>0.05). The pathological complete remission (pCR) rates were 23.30% and 19.42%, respectively (P=0.497). The 3-year local recurrence rates were 4.85% vs. 5.83% (P=0.694), and the 3-year distant metastasis rates were 16.50% and 28.16%, respectively (P=0.045). There were no significant differences in most grade 3−4 toxicities between two groups, however, grade 3−4 diarrhea occurred in 16.50% (17/103) of the experimental group, compared with 6.80% (7/103) of the control group (P=0.030). Also, the total grade 3−4 acute toxicity showed a significant difference (10.68% vs. 21.36%, P=0.037). Conclusions The experimental treatment did not lead significantly improved OS and DFS, and thus longer follow-up is warranted for our patient cohort. Adding oxaliplatin to capecitabine-based preoperative chemoradiotherapy can significantly reduce metastasis, but has only minimal impact on local recurrence. Although grade 3−4

  8. Exome sequencing identifies NFS1 deficiency in a novel Fe-S cluster disease, infantile mitochondrial complex II/III deficiency.

    PubMed

    Farhan, Sali M K; Wang, Jian; Robinson, John F; Lahiry, Piya; Siu, Victoria M; Prasad, Chitra; Kronick, Jonathan B; Ramsay, David A; Rupar, C Anthony; Hegele, Robert A

    2014-01-01

    Iron-sulfur (Fe-S) clusters are a class of highly conserved and ubiquitous prosthetic groups with unique chemical properties that allow the proteins that contain them, Fe-S proteins, to assist in various key biochemical pathways. Mutations in Fe-S proteins often disrupt Fe-S cluster assembly leading to a spectrum of severe disorders such as Friedreich's ataxia or iron-sulfur cluster assembly enzyme (ISCU) myopathy. Herein, we describe infantile mitochondrial complex II/III deficiency, a novel autosomal recessive mitochondrial disease characterized by lactic acidemia, hypotonia, respiratory chain complex II and III deficiency, multisystem organ failure and abnormal mitochondria. Through autozygosity mapping, exome sequencing, in silico analyses, population studies and functional tests, we identified c.215G>A, p.Arg72Gln in NFS1 as the likely causative mutation. We describe the first disease in man likely caused by deficiency in NFS1, a cysteine desulfurase that is implicated in respiratory chain function and iron maintenance by initiating Fe-S cluster biosynthesis. Our results further demonstrate the importance of sufficient NFS1 expression in human physiology. PMID:24498631

  9. [Value of training-induced effects on arterial vascular system and skeletal muscles in therapy of NYHA II/III heart failure].

    PubMed

    Huonker, M; Keul, J

    2001-11-01

    increase of more glycolytic type 2 fibers. In addition, the volume density and the surface area of the cristae of mitochondria are reduced. All these changes results in a decrease of aerobic skeletal muscle metabolism independent of the blood flow volume, so that the physical fitness of the patients progressively decline. On the basis of the training-induced physiological adaptations of the cardiovascular system, a special exercise therapy supervised by a physician was developed for patients with congestive heart failure NYHA II/III. It have been shown that various exercise programs, which are adjusted to the degree of cardiac function impairment are suitable to restore the endothelial dysfunction of the arterial vessels as well as to cure the disturbed skeletal muscle metabolism in these patients independent of an improvement of cardiac function. Therefore in patients with congestive heart failure NYHA II/III who underwent regularly such an exercise therapy, the secondary impaired physical fitness could be rebuild without an excessive risk for an acute exercise-induced cardiovascular emergency. PMID:11771449

  10. Fibroblast Growth Factor 2-A Predictor of Outcome for Patients Irradiated for Stage II-III Non-Small-Cell Lung Cancer

    SciTech Connect

    Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, Frank

    2012-01-01

    Purpose: The prognostic value of the tumor cell expression of the fibroblast growth factor 2 (FGF-2) in patients with non-small-cell lung cancer (NSCLC) is unclear. The present study investigated the effect of tumor cell expression of FGF-2 on the outcome of 60 patients irradiated for Stage II-III NSCLC. Methods and Materials: The effect of FGF-2 expression and 13 additional factors on locoregional control (LRC), metastasis-free survival (MFS), and overall survival (OS) were retrospectively evaluated. These additional factors included age, gender, Karnofsky performance status, histologic type, histologic grade, T and N category, American Joint Committee on Cancer stage, surgery, chemotherapy, pack-years, smoking during radiotherapy, and hemoglobin during radiotherapy. Locoregional failure was identified by endoscopy or computed tomography. Univariate analyses were performed with the Kaplan-Meier method and the Wilcoxon test and multivariate analyses with the Cox proportional hazard model. Results: On univariate analysis, improved LRC was associated with surgery (p = .017), greater hemoglobin levels (p = .036), and FGF-2 negativity (p <.001). On multivariate analysis of LRC, surgery (relative risk [RR], 2.44; p = .037), and FGF-2 expression (RR, 5.06; p <.001) maintained significance. On univariate analysis, improved MFS was associated with squamous cell carcinoma (p = .020), greater hemoglobin levels (p = .007), and FGF-2 negativity (p = .001). On multivariate analysis of MFS, the hemoglobin levels (RR, 2.65; p = .019) and FGF-2 expression (RR, 3.05; p = .004) were significant. On univariate analysis, improved OS was associated with a lower N category (p = .048), greater hemoglobin levels (p <.001), and FGF-2 negativity (p <.001). On multivariate analysis of OS, greater hemoglobin levels (RR, 4.62; p = .002) and FGF-2 expression (RR, 3.25; p = .002) maintained significance. Conclusions: Tumor cell expression of FGF-2 appeared to be an independent negative predictor

  11. Systemic, postsymptomatic antisense oligonucleotide rescues motor unit maturation delay in a new mouse model for type II/III spinal muscular atrophy

    PubMed Central

    Bogdanik, Laurent P.; Osborne, Melissa A.; Davis, Crystal; Martin, Whitney P.; Austin, Andrew; Rigo, Frank; Bennett, C. Frank; Lutz, Cathleen M.

    2015-01-01

    Clinical presentation of spinal muscular atrophy (SMA) ranges from a neonatal-onset, very severe disease to an adult-onset, milder form. SMA is caused by the mutation of the Survival Motor Neuron 1 (SMN1) gene, and prognosis inversely correlates with the number of copies of the SMN2 gene, a human-specific homolog of SMN1. Despite progress in identifying potential therapies for the treatment of SMA, many questions remain including how late after onset treatments can still be effective and what the target tissues should be. These questions can be addressed in part with preclinical animal models; however, modeling the array of SMA severities in the mouse, which lacks SMN2, has proven challenging. We created a new mouse model for the intermediate forms of SMA presenting with a delay in neuromuscular junction maturation and a decrease in the number of functional motor units, all relevant to the clinical presentation of the disease. Using this new model, in combination with clinical electrophysiology methods, we found that administering systemically SMN-restoring antisense oligonucleotides (ASOs) at the age of onset can extend survival and rescue the neurological phenotypes. Furthermore, these effects were also achieved by administration of the ASOs late after onset, independent of the restoration of SMN in the spinal cord. Thus, by adding to the limited repertoire of existing mouse models for type II/III SMA, we demonstrate that ASO therapy can be effective even when administered after onset of the neurological symptoms, in young adult mice, and without being delivered into the central nervous system. PMID:26460027

  12. Mastectomy With Immediate Expander-Implant Reconstruction, Adjuvant Chemotherapy, and Radiation for Stage II-III Breast Cancer: Treatment Intervals and Clinical Outcomes

    SciTech Connect

    Wright, Jean L.; Cordeiro, Peter G.; Ben-Porat, Leah; Van Zee, Kimberly J.; Hudis, Clifford; Beal, Kathryn; McCormick, Beryl

    2008-01-01

    Purpose: To determine intervals between surgery and adjuvant chemotherapy and radiation in patients treated with mastectomy with immediate expander-implant reconstruction, and to evaluate locoregional and distant control and overall survival in these patients. Methods and Materials: Between May 1996 and March 2004, 104 patients with Stage II-III breast cancer were routinely treated at our institution under the following algorithm: (1) definitive mastectomy with axillary lymph node dissection and immediate tissue expander placement, (2) tissue expansion during chemotherapy, (3) exchange of tissue expander for permanent implant, (4) radiation. Patient, disease, and treatment characteristics and clinical outcomes were retrospectively evaluated. Results: Median age was 45 years. Twenty-six percent of patients were Stage II and 74% Stage III. All received adjuvant chemotherapy. Estrogen receptor staining was positive in 77%, and 78% received hormone therapy. Radiation was delivered to the chest wall with daily 0.5-cm bolus and to the supraclavicular fossa. Median dose was 5040 cGy. Median interval from surgery to chemotherapy was 5 weeks, from completion of chemotherapy to exchange 4 weeks, and from exchange to radiation 4 weeks. Median interval from completion of chemotherapy to start of radiation was 8 weeks. Median follow-up was 64 months from date of mastectomy. The 5-year rate for locoregional disease control was 100%, for distant metastasis-free survival 90%, and for overall survival 96%. Conclusions: Mastectomy with immediate expander-implant reconstruction, adjuvant chemotherapy, and radiation results in a median interval of 8 weeks from completion of chemotherapy to initiation of radiation and seems to be associated with acceptable 5-year locoregional control, distant metastasis-free survival, and overall survival.

  13. Japanese POEMS syndrome with Thalidomide (J-POST) Trial: study protocol for a phase II/III multicentre, randomised, double-blind, placebo-controlled trial

    PubMed Central

    Katayama, Kanako; Misawa, Sonoko; Sato, Yasunori; Sobue, Gen; Yabe, Ichiro; Watanabe, Osamu; Nishizawa, Masatoyo; Kusunoki, Susumu; Kikuchi, Seiji; Nakashima, Ichiro; Ikeda, Shu-ichi; Kohara, Nobuo; Kanda, Takashi; Kira, Jun-ichi; Hanaoka, Hideki; Kuwabara, Satoshi

    2015-01-01

    Introduction Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a fatal systemic disorder associated with plasma cell dyscrasia and the overproduction of the vascular endothelial growth factor (VEGF). Recently, the prognosis of POEMS was substantially improved by introduction of therapeutic intervention for myeloma. However, no randomised clinical trial has been performed because of the rarity and severity of the disease. Methods and analysis The Japanese POEMS syndrome with Thalidomide (J-POST) Trial is a phase II/III multicentre, double-blinded, randomised, controlled trial that aims to evaluate the efficacy and safety of a 24-week treatment with thalidomide in POEMS syndrome, with an additional 48-week open-label safety study. Adults with POEMS syndrome who have no indication for transplantation are assessed for eligibility at 12 tertiary neurology centres in Japan. Patients who satisfy the eligibility criteria are randomised (1:1) to receive thalidomide (100–300 mg daily) plus dexamethasone (12 mg/m2 on days 1–4 of a 28-day cycle) or placebo plus dexamethasone. Both treatments were administered for 24 weeks (six cycles; randomised comparative study period). Patients who complete the randomised study period or show subacute deterioration during the randomised period participate in the subsequent 48-week open-label safety study (long-term safety period). The primary end point of the study is the reduction rate of serum VEGF levels at 24 weeks. Ethics and dissemination The protocol was approved by the Institutional Review Board of each hospital. The trial was notified and registered at the Pharmaceutical and Medical Devices Agency, Japan (No. 22-1716). The J-POST Trial is currently ongoing and is due to finish in August 2015. The findings of this trial will be disseminated through peer-reviewed publications and conference presentations and will also be disseminated to participants. Trial registration number

  14. Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and Niemann-Pick C1 disease - Lysosomal storage disorders caused by defects of non-lysosomal proteins.

    PubMed

    Dierks, Thomas; Schlotawa, Lars; Frese, Marc-André; Radhakrishnan, Karthikeyan; von Figura, Kurt; Schmidt, Bernhard

    2009-04-01

    Multiple sulfatase deficiency (MSD), mucolipidosis (ML) II/III and Niemann-Pick type C1 (NPC1) disease are rare but fatal lysosomal storage disorders caused by the genetic defect of non-lysosomal proteins. The NPC1 protein mainly localizes to late endosomes and is essential for cholesterol redistribution from endocytosed LDL to cellular membranes. NPC1 deficiency leads to lysosomal accumulation of a broad range of lipids. The precise functional mechanism of this membrane protein, however, remains puzzling. ML II, also termed I cell disease, and the less severe ML III result from deficiencies of the Golgi enzyme N-acetylglucosamine 1-phosphotransferase leading to a global defect of lysosome biogenesis. In patient cells, newly synthesized lysosomal proteins are not equipped with the critical lysosomal trafficking marker mannose 6-phosphate, thus escaping from lysosomal sorting at the trans Golgi network. MSD affects the entire sulfatase family, at least seven members of which are lysosomal enzymes that are specifically involved in the degradation of sulfated glycosaminoglycans, sulfolipids or other sulfated molecules. The combined deficiencies of all sulfatases result from a defective post-translational modification by the ER-localized formylglycine-generating enzyme (FGE), which oxidizes a specific cysteine residue to formylglycine, the catalytic residue enabling a unique mechanism of sulfate ester hydrolysis. This review gives an update on the molecular bases of these enigmatic diseases, which have been challenging researchers since many decades and so far led to a number of surprising findings that give deeper insight into both the cell biology and the pathobiochemistry underlying these complex disorders. In case of MSD, considerable progress has been made in recent years towards an understanding of disease-causing FGE mutations. First approaches to link molecular parameters with clinical manifestation have been described and even therapeutical options have been

  15. Feasibility of radiotherapy after high-dose dense chemotherapy with epirubicin, preceded by dexrazoxane, and paclitaxel for patients with high-risk Stage II-III breast cancer

    SciTech Connect

    De Giorgi, Ugo . E-mail: ugo_degiorgi@yahoo.com; Giannini, Massimo; Frassineti, Luca; Kopf, Barbara; Palazzi, Silvia; Giovannini, Noemi; Zumaglini, Federica; Rosti, Giovanni; Emiliani, Ermanno; Marangolo, Maurizio

    2006-07-15

    Purpose: To verify the feasibility of, and quantify the risk of, pneumonitis from locoregional radiotherapy (RT) after high-dose dense chemotherapy with epirubicin and paclitaxel with peripheral blood progenitor cell support in patients with high-risk Stage II-III breast cancer. Methods and Materials: Treatment consisted of a mobilizing course of epirubicin 150 mg/m{sup 2}, preceded by dexrazoxane (Day 1), paclitaxel 175 mg/m{sup 2} (Day 2), and filgrastim; followed by three courses of epirubicin 150 mg/m{sup 2}, preceded by dexrazoxane (Day 1), paclitaxel 400 mg/m{sup 2} (Day 2), and peripheral blood progenitor cell support and filgrastim, every 16-19 days. After chemotherapy, patients were treated with locoregional RT, which included the whole breast or the chest wall, axilla, and supraclavicular area. Results: Overall, 64 of 69 patients were evaluable. The interval between the end of chemotherapy and the initiation of RT was at least 1.5-2 months (mean 2). No treatment-related death was reported. After a median follow-up of 27 months from RT (range 5-77 months), neither clinically relevant radiation pneumonitis nor congestive heart failure had been reported. Minor and transitory lung and cardiac toxicities were observed. Conclusion: Sequential high doses of epirubicin, preceded by dexrazoxane, and paclitaxel did not adversely affect the tolerability of locoregional RT in breast cancer patients. The risk of pneumonitis was not affected by the use of sequential paclitaxel with an interval of at least 1.5-2 months between the end of chemotherapy and the initiation of RT. Long-term follow-up is needed to define the risk of cardiotoxicity in these patients.

  16. Fougerite and Fe II-III hydroxycarbonate green rust; ordering, deprotonation and/or cation substitution; structure of hydrotalcite-like compounds and mythic ferrosic hydroxide Fe(

    NASA Astrophysics Data System (ADS)

    Génin, Jean-Marie R.; Aïssa, Rabha; Géhin, Antoine; Abdelmoula, Mustapha; Benali, Omar; Ernstsen, Vibeke; Ona-Nguema, Georges; Upadhyay, Chandan; Ruby, Christian

    2005-05-01

    A green rust has been recognised as a new mineral (IMA 2003-057) and given the name fougerite. Its chemical counterpart is Fe II-III hydroxycarbonate GR1(CO32-) compound, which is partially deprotonated since formed by reduction of ferric oxyhydroxides through the activity of dissimilatory iron-reducing bacteria (DIRB) in anaerobic gley soils. Preparation of GR1(CO32-) by co-precipitation of Fe II and Fe III cations in carbonated medium shows by using Mössbauer spectroscopy that the domain of existence of GR1(CO32-) lies within [0.25,0.33] for x={[Fe]/[Fe]} with ordered upper limit [ṡ[. GR1(CO32-) gets oxidised into ferrihydrite evolving to goethite by aerial oxidation, or into ferric green rust GR1(, [ṡ[ by OH - deprotonation. A mass balance of iron ox(yhydrox)ides is drawn accordingly in the carbonated medium. Mössbauer spectra measured at 12 K show quite different magnetic properties and the three quadrupole doublets, comprising 2 ferrous and 1 ferric in GR1(CO32-), become 3 magnetically split ferric sextets in GR1(. Structures of ordered GR1(CO32-), GR1( and GR1(Cl -) hydroxychloride are drawn. Extension to other hydrotalcite-like compounds is proposed whereas occurrences of fougerite mixed with clay minerals are presented. Fougerite is FeII6(1-x)FeIII6x((CO, the partially deprotonated green rust where 1/3⩽x<2/3. Substitution of Fe cations by Mg II or Al III may occur but the proposal advocating a ferrosic hydroxide Fe( is discarded.

  17. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: Results of a prospective randomized phase II/III trial

    PubMed Central

    Heiss, Markus M; Murawa, Pawel; Koralewski, Piotr; Kutarska, Elzbieta; Kolesnik, Olena O; Ivanchenko, Vladimir V; Dudnichenko, Alexander S; Aleknaviciene, Birute; Razbadauskas, Arturas; Gore, Martin; Ganea-Motan, Elena; Ciuleanu, Tudor; Wimberger, Pauline; Schmittel, Alexander; Schmalfeldt, Barbara; Burges, Alexander; Bokemeyer, Carsten; Lindhofer, Horst; Lahr, Angelika; Parsons, Simon L

    2010-01-01

    Malignant ascites is a common manifestation of advanced cancers, and treatment options are limited. The trifunctional antibody catumaxomab (anti-epithelial cell-adhesion molecule x anti-CD3) represents a targeted immunotherapy for the intraperitoneal (i.p.) treatment of malignant ascites secondary to epithelial cancers. In this phase II/III trial (EudraCT 2004-000723-15; NCT00836654), cancer patients (n = 258) with recurrent symptomatic malignant ascites resistant to conventional chemotherapy were randomized to paracentesis plus catumaxomab (catumaxomab) or paracentesis alone (control) and stratified by cancer type (129 ovarian and 129 nonovarian). Catumaxomab was administered as an i.p. infusion on Days 0, 3, 7 and 10 at doses of 10, 20, 50 and 150 μg, respectively. The primary efficacy endpoint was puncture-free survival. Secondary efficacy parameters included time to next paracentesis, ascites signs and symptoms and overall survival (OS). Puncture-free survival was significantly longer in the catumaxomab group (median 46 days) than the control group (median 11 days) (hazard ratio = 0.254: p < 0.0001) as was median time to next paracentesis (77 versus 13 days; p < 0.0001). In addition, catumaxomab patients had fewer signs and symptoms of ascites than control patients. OS showed a positive trend for the catumaxomab group and, in a prospectively planned analysis, was significantly prolonged in patients with gastric cancer (n = 66; 71 versus 44 days; p = 0.0313). Although adverse events associated with catumaxomab were frequent, they were manageable, generally reversible and mainly related to its immunologic mode of action. Catumaxomab showed a clear clinical benefit in patients with malignant ascites secondary to epithelial cancers, especially gastric cancer, with an acceptable safety profile. PMID:20473913

  18. Three-dimensional localization of the α and β subunits and of the II-III loop in the skeletal muscle L-type Ca2+ channel.

    PubMed

    Szpyt, John; Lorenzon, Nancy; Perez, Claudio F; Norris, Ethan; Allen, Paul D; Beam, Kurt G; Samsó, Montserrat

    2012-12-21

    The L-type Ca(2+) channel (dihydropyridine receptor (DHPR) in skeletal muscle acts as the voltage sensor for excitation-contraction coupling. To better resolve the spatial organization of the DHPR subunits (α(1s) or Ca(V)1.1, α(2), β(1a), δ1, and γ), we created transgenic mice expressing a recombinant β(1a) subunit with YFP and a biotin acceptor domain attached to its N- and C- termini, respectively. DHPR complexes were purified from skeletal muscle, negatively stained, imaged by electron microscopy, and subjected to single-particle image analysis. The resulting 19.1-Å resolution, three-dimensional reconstruction shows a main body of 17 × 11 × 8 nm with five corners along its perimeter. Two protrusions emerge from either face of the main body: the larger one attributed to the α(2)-δ1 subunit that forms a flexible hook-shaped feature and a smaller protrusion on the opposite side that corresponds to the II-III loop of Ca(V)1.1 as revealed by antibody labeling. Novel features discernible in the electron density accommodate the atomic coordinates of a voltage-gated sodium channel and of the β subunit in a single docking possibility that defines the α1-β interaction. The β subunit appears more closely associated to the membrane than expected, which may better account for both its role in localizing the α(1s) subunit to the membrane and its suggested role in excitation-contraction coupling. PMID:23118233

  19. HLA-G 3’UTR Polymorphisms Impact the Prognosis of Stage II-III CRC Patients in Fluoropyrimidine-Based Treatment

    PubMed Central

    Garziera, Marica; Bidoli, Ettore; Cecchin, Erika; Mini, Enrico; Nobili, Stefania; Lonardi, Sara; Buonadonna, Angela; Errante, Domenico; Pella, Nicoletta; D’Andrea, Mario; De Marchi, Francesco; De Paoli, Antonino; Zanusso, Chiara; De Mattia, Elena; Tassi, Renato; Toffoli, Giuseppe

    2015-01-01

    An important hallmark of CRC is the evasion of immune surveillance. HLA-G is a negative regulator of host’s immune response. Overexpression of HLA-G protein in primary tumour CRC tissues has already been associated to worse prognosis; however a definition of the role of immunogenetic host background is still lacking. Germline polymorphisms in the 3’UTR region of HLA-G influence the magnitude of the protein by modulating HLA-G mRNA stability. Soluble HLA-G has been associated to 3’UTR +2960 Ins/Ins and +3035 C/T (lower levels) and +3187 G/G (high levels) genotypes. HLA-G 3’UTR SNPs have never been explored in CRC outcome. The purpose of this study was to investigate if common HLA-G 3’UTR polymorphisms have an impact on DFS and OS of 253 stage II-III CRC patients, after primary surgery and ADJ-CT based on FL. The 3’UTR was sequenced and SNPs were analyzed for their association with survival by Kaplan-Meier and multivariate Cox models; results underwent internal validation using a resampling method (bootstrap analysis). In a multivariate analysis, we estimated an association with improved DFS in Ins allele (Ins/Del +Ins/Ins) carriers (HR 0.60, 95% CI 0.38–0.93, P = 0.023) and in patients with +3035 C/T genotype (HR 0.51, 95% CI 0.26–0.99, P = 0.045). The +3187 G/G mutated carriers (G/G vs A/A+A/G) were associated to a worst prognosis in both DFS (HR 2.46, 95% CI 1.19–5.05, P = 0.015) and OS (HR 2.71, 95% CI 1.16–6.63, P = 0.022). Our study shows a prognostic and independent role of 3 HLA-G 3’UTR SNPs, +2960 14-bp INDEL, +3035 C>T, and +3187 A>G. PMID:26633805

  20. Prognostic Impact of Erythropoietin Expression and Erythropoietin Receptor Expression on Locoregional Control and Survival of Patients Irradiated for Stage II/III Non-Small-Cell Lung Cancer

    SciTech Connect

    Rades, Dirk; Setter, Cornelia; Dahl, Olav; Schild, Steven E.; Noack, Frank

    2011-06-01

    Purpose: Prognostic factors can guide the physician in selecting the optimal treatment for an individual patient. This study investigates the prognostic value of erythropoietin (EPO) and EPO receptor (EPO-R) expression of tumor cells for locoregional control and survival in non-small-cell lung cancer (NSCLC) patients. Methods and Materials: Fourteen factors were investigated in 62 patients irradiated for stage II/III NSCLC, as follows: age, gender, Karnofsky performance score (KPS), histology, grading, TNM/American Joint Committee on Cancer (AJCC) stage, surgery, chemotherapy, pack years (average number of packages of cigarettes smoked per day multiplied by the number of years smoked), smoking during radiotherapy, hemoglobin levels during radiotherapy, EPO expression, and EPO-R expression. Additionally, patients with tumors expressing both EPO and EPO-R were compared to those expressing either EPO or EPO-R and to those expressing neither EPO nor EPO-R. Results: On univariate analysis, improved locoregional control was associated with AJCC stage II cancer (p < 0.048), surgery (p < 0.042), no smoking during radiotherapy (p = 0.024), and no EPO expression (p = 0.001). A trend was observed for a KPS of >70 (p = 0.08), an N stage of 0 to 1 (p = 0.07), and no EPO-R expression (p = 0.10). On multivariate analysis, AJCC stage II and no EPO expression remained significant. No smoking during radiotherapy was almost significant. On univariate analysis, improved survival was associated with N stage 0 to 1 (p = 0.009), surgery (p = 0.039), hemoglobin levels of {>=}12 g/d (p = 0.016), and no EPO expression (p = 0.001). On multivariate analysis, N stage 0 to 1 and no EPO expression maintained significance. Hemoglobin levels of {>=}12 g/d were almost significant. On subgroup analyses, patients with tumors expressing both EPO and EPO-R had worse outcomes than those expressing either EPO or EPO-R and those expressing neither EPO nor RPO-R. Conclusions: EPO expression of tumor cells

  1. Paclitaxel injection concentrate for nanodispersion versus nab-paclitaxel in women with metastatic breast cancer: a multicenter, randomized, comparative phase II/III study.

    PubMed

    Jain, Minish M; Gupte, Smita U; Patil, Shekhar G; Pathak, Anand B; Deshmukh, Chetan D; Bhatt, Niraj; Haritha, Chiramana; Govind Babu, K; Bondarde, Shailesh A; Digumarti, Raghunadharao; Bajpai, Jyoti; Kumar, Ravi; Bakshi, Ashish V; Bhattacharya, Gouri Sankar; Patil, Poonam; Subramanian, Sundaram; Vaid, Ashok K; Desai, Chirag J; Khopade, Ajay; Chimote, Geetanjali; Bapsy, Poonamalle P; Bhowmik, Shravanti

    2016-02-01

    Paclitaxel is widely used in the treatment of patients with metastatic breast cancer (MBC). Formulations of paclitaxel contain surfactants and solvents or albumin derived from human blood. The use of co-solvents such as polyoxyethylated castor oil is thought to contribute to toxicity profile and hypersensitivity reactions as well as leaching of plasticizers from polyvinyl chloride bags and infusion sets. Currently, nab-paclitaxel, an albumin-bound paclitaxel in nanometer range continues to be the preferred taxane formulation used in clinic. This study (CTRI/2010/091/001116) investigated the efficacy and tolerability of a polyoxyethylated castor oil- and albumin-free formulation of paclitaxel [paclitaxel injection concentrate for nanodispersion (PICN)] compared with nab-paclitaxel in women with refractory MBC. The current study was a multicenter, open-label, parallel-group, randomized, comparative phase II/III trial evaluating the efficacy and safety of PICN (260 mg/m(2) [n = 64] and 295 mg/m(2) [n = 58] every 3 weeks) compared with nab-paclitaxel (260 mg/m(2) every 3 weeks [n = 58]) in women 18 and 70 years old with confirmed MBC. Overall response rate (ORR) was assessed with imaging every 2 cycles. An independent analysis of radiologic data was performed for evaluable patients. Progression-free survival (PFS) was a secondary efficacy measure. Independent radiologist-assessed ORRs in the evaluable population of women aged ≥70 years were 35, 49, and 43 % in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Median PFS in the evaluable population was 23, 35, and 34 weeks in the PICN 260 mg/m(2), PICN 295 mg/m(2), and nab-paclitaxel 260 mg/m(2) arms, respectively. Adverse events occurred in similar proportions of patients across treatment arms. Hypersensitivity reactions were not frequently observed with the clinical use of PICN across the treatment cohorts. In women with metastatic breast cancer, PICN at 260 and 295 mg/m(2

  2. The Role of Postmastectomy Radiation Therapy After Neoadjuvant Chemotherapy in Clinical Stage II-III Breast Cancer Patients With pN0: A Multicenter, Retrospective Study (KROG 12-05)

    SciTech Connect

    Shim, Su Jung; Park, Won; Huh, Seung Jae; Choi, Doo Ho; Shin, Kyung Hwan; Lee, Nam Kwon; Suh, Chang-Ok; Keum, Ki Chang; Kim, Yong Bae; Ahn, Seung Do; Kim, Su Ssan; Ha, Sung W.; Chie, Eui Kyu; Kim, Kyubo; Shin, Hyun Soo; Kim, Jin Hee; Lee, Hyung-Sik

    2014-01-01

    Purpose: The purpose of this study was to investigate the role of postmastectomy radiation therapy (PMRT) after neoadjuvant chemotherapy (NAC) in clinical stage II-III breast cancer patients with pN0. Methods and Materials: We retrospectively identified 417 clinical stage II-III breast cancer patients who achieved an ypN0 at surgery after receiving NAC between 1998 and 2009. Of these, 151 patients underwent mastectomy after NAC. The effect of PMRT on disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), and overall survival (OS) was evaluated by multivariate analysis including known prognostic factors using the Kaplan-Meier method and compared using the log–rank test and Cox proportional regression analysis. Results: Of the 151 patients who underwent mastectomy, 105 (69.5%) received PMRT and 46 patients (30.5%) did not. At a median follow-up of 59 months, 5 patients (3.3%) developed LRR (8 sites of recurrence) and 14 patients (9.3%) developed distant metastasis. The 5-year DFS, LRRFS, and OS rates were 91.2, 98.1, and 93.3% with PMRT and 83.0%, 92.3%, and 89.9% without PMRT, respectively (all P values not significant). By univariate analysis, only age (≤40 vs >40 years) was significantly associated with decreased DFS (P=.027). By multivariate analysis, age (≤40 vs >40 years) and pathologic T stage (0-is vs 1 vs 2-4) were significant prognostic factors affecting DFS (hazard ratio [HR] 0.353, 95% confidence interval [CI] 0.135-0.928, P=.035; HR 2.223, 95% CI 1.074-4.604, P=.031, respectively). PMRT showed no correlation with a difference in DFS, LRRFS, or OS by multivariate analysis. Conclusions: PMRT might not be necessary for pN0 patients after NAC, regardless of clinical stage. Prospective randomized clinical trial data are needed to assess whether PMRT can be safely omitted in pN0 patients after NAC and mastectomy for clinical stage II-III breast cancer.

  3. A Phase II/III Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Ginger (Zingiber officinale) for Nausea Caused by Chemotherapy for Cancer: A Currently Accruing URCC CCOP Cancer Control Study.

    PubMed

    Hickok, Jane T; Roscoe, Joseph A; Morrow, Gary R; Ryan, Julie L

    2007-09-01

    Despite the widespread use of 5-HT3 receptor antagonist antiemetics such as ondansetron and granistron, up to 70% of patients with cancer receiving highly emetogenic chemotherapy agents experience postchemotherapy nausea and vomiting. Delayed postchemotherapy nausea (nausea that occurs >/= 24 hours after chemotherapy administration) and anticipatory nausea (nausea that develops before chemotherapy administration, in anticipation of it) are poorly controlled by currently available antiemetic agents. Scientific studies suggest that ginger (Zingiber officinale) might have beneficial effects on nausea and vomiting associated with motion sickness, surgery, and pregnancy. In 2 small studies of patients with cancer receiving chemotherapy, addition of ginger to standard antiemetic medication further reduced the severity of postchemotherapy nausea. This article describes a phase II/III randomized, dose-finding, placebo-controlled, double-blind clinical trial to assess the efficacy of ginger for nausea associated with chemotherapy for cancer. The study is currently being conducted by private practice oncology groups that are funded by the National Cancer Institute's Community Clinical Oncology Program and affiliated with the University of Rochester Cancer Center Community Clinical Oncology Program Research Base. PMID:18632524

  4. Long-term Survival Outcomes Following Internal Mammary Node Irradiation in Stage II-III Breast Cancer: Results of a Large Retrospective Study With 12-Year Follow-up

    SciTech Connect

    Chang, Jee Suk; Park, Won; Kim, Yong Bae; Lee, Ik Jae; Keum, Ki Chang; Lee, Chang Geol; Choi, Doo Ho; Suh, Chang-Ok; Huh, Seung Jae

    2013-08-01

    Purpose: To examine the effect of internal mammary node irradiation (IMNI) on disease-free survival (DFS) and overall survival (OS) in breast cancer patients treated with modified radical mastectomy and postoperative radiation therapy. Methods and Materials: Between 1994 and 2002, 396 patients with stage II-III breast cancer were treated with postmastectomy radiation therapy with (n=197) or without (n=199) IMNI. Patients who received neoadjuvant chemotherapy were excluded. IMNI was administered at the clinical discretion of the treating physician. Median RT dose was 50.4 Gy (range, 45.0-59.4 Gy) in 28 fractions, with inclusion of the supraclavicular fossa in 96% of patients. Adjuvant chemotherapy was administered to 99.7% of the patients and endocrine therapy to 53%. Results: The median follow-up was 149 months (range, 124-202). IMNI patients had more advanced nodal stage and non-high grade tumors than those without IMNI (P<.001). Otherwise, disease and treatment characteristics were well balanced. The 10-year DFS with and without IMNI was 65% and 57%, respectively (P=.05). Multivariate analysis demonstrated that IMNI was an independent, positive predictor of DFS (hazard ratio [HR], 0.70; P=.02). Benefits of IMNI in DFS were seen most apparently in N2 patients (HR, 0.44; 95% confidence interval [CI], 0.26-0.74) and inner/central tumors (HR, 0.55; 95% CI, 0.34-0.90). The 10-year OS with and without IMNI was 72% and 66%, respectively (P=.62). The 10-year DFS and OS were 61%, and 69%, respectively. Conclusions: Internal mammary node irradiation significantly improved DFS in postmastectomy breast cancer patients. Pending long-term results from randomized trials, treatment of internal mammary nodes should be considered in postmastectomy radiation therapy.

  5. Phase II Results of RTOG 0537: A Phase II/III Study Comparing Acupuncture-like Transcutaneous Electrical Nerve Stimulation Versus Pilocarpine in Treating Early Radiation-Induced Xerostomia

    PubMed Central

    Wong, Raimond K. W.; James, Jennifer L.; Sagar, Stephen; Wyatt, Gwen; Nguyen-Tân, Phuc Felix; Singh, Anurag K.; Lukaszczyk, Barbara; Cardinale, Francis; Yeh, Alexander M.; Berk, Lawrence

    2011-01-01

    Purpose This phase II component of a multi-institutional phase II/III randomized trial assessed the feasibility and preliminary efficacy of acupuncture-like transcutaneous electrical nerve stimulation (ALTENS) in reducing radiation-induced xerostomia. Methods Head and neck cancer patients who were 3–24 months from completing radiotherapy ± chemotherapy (RT±C) and experiencing xerostomia symptoms with basal whole saliva production ≥0.1 ml/min and without recurrence were eligible. Patients received twice weekly ALTENS sessions (24 over 12 weeks) using a Codetron™ unit. The primary objective assessed the feasibility of ALTENS treatment. A patient was considered compliant if 19/24 ALTENS were delivered, with a targeted 85% compliance rate. Secondary objectives measured treatment-related toxicities and ALTENS effect on overall radiation-induced xerostomia burden using the University of Michigan Xerostomia-Related Quality of Life Scale (XeQOLS). Results Of 48 accrued patients, 47 were evaluable. Median age was 60 years; 84% were male, 70% completed RT±C for > 12 months and 21% had received prior pilocarpine. All ALTENS sessions were completed in 34 patients, but 9 and 1 completed 20–23 and 19 sessions respectively, representing a 94% total compliance rate. 6-month XeQOLS scores were available for 35 patients; 30 (86%) achieved a positive treatment response with a mean reduction of 35.9% (SD 36.1). Five patients developed grade 1–2 gastrointestinal toxicity and one had grade 1 pain event. Conclusions ALTENS treatment for radiation-induced xerostomia can be uniformly delivered in a cooperative multicenter setting and has possible beneficial treatment response. Given these results, the phase III component of this study was initiated. PMID:22252927

  6. Ozone loss rates in the Arctic winter stratosphere during 1994-2000 derived from POAM II/III and ILAS observations: Implications for relationships among ozone loss, PSC occurrence, and temperature

    NASA Astrophysics Data System (ADS)

    Terao, Yukio; Sugita, Takafumi; Sasano, Yasuhiro

    2012-03-01

    Quantitative chemical ozone loss rates at the 475 K isentropic surface inside the Arctic polar vortex are evaluated for six winters (January through March) using a satellite-based Match technique. Satellite observational data are taken from the Polar Ozone and Aerosol Measurement (POAM) II for 1994-1996, the Improved Limb Atmospheric Spectrometer (ILAS) for 1997, and the POAM III for 1999-2000. The largest ozone loss rates were observed in the end of January 1995 (˜50 ± 20 ppbv d-1), February 1996 (˜40-50 ± 15 ppbv d-1), February 1997 (˜40 ± 8 ppbv d-1), January 2000 (˜60 ± 30 ppbv d-1), and early March 2000 (˜40 ± 10 ppbv d-1). The probability of polar stratospheric cloud (PSC) existence is estimated using aerosol extinction coefficient data from POAM II/III and ILAS. Ozone loss and the PSC probability are strongly correlated and an absolute increase of 10% in the PSC probability is found to amplify the chemical ozone loss rate during Arctic winter by approximately 25 ± 6 ppbv per day or 3.2 ± 0.7 ppbv per sunlit hour. Relationships between average Arctic winter ozone loss rates and various PSC- and temperature-related indices are investigated, including the area of polar vortex that is colder than the threshold temperature for PSC existence (APSC), the PSC formation potential (PFP), and the potential for activation of chlorine (PACl). Of these three, PACl provides the best proxy representation of interannual variability in Arctic ozone loss at the 475 K level. Large ozone loss occurred primarily for air masses that experienced low temperatures between 187 K and 195 K within the previous 10 days and the ozone loss rates clearly increase with decreasing the minimum temperature. The particularly large ozone losses of ˜9 ± 3 ppbv per sunlit hour in February 1996 and January 2000 were associated with low minimum temperatures of 187-189 K, simultaneously with high PSC probabilities.

  7. Adult Education in Israel, II-III.

    ERIC Educational Resources Information Center

    Kirmayer, Paul, Ed.; Pinnes, Noy, Ed.

    This is the second booklet in English that deals with adult education in Israel. The following papers are included: "Editors' Notes" (Paul Kirmayer, Noy Pinnes); "Introduction" (Meir Peretz); "Defining 'Adult Education'" (Yehezkel Cohen); "Planning Study Programs for Adults" (Rachel Tokatli); "The Role of Adult Education: Changing the Individual…

  8. Role of Postmastectomy Radiation After Neoadjuvant Chemotherapy in Stage II-III Breast Cancer

    SciTech Connect

    Fowble, Barbara L.; Einck, John P.; Kim, Danny N.; McCloskey, Susan; Mayadev, Jyoti; Yashar, Catheryn; Chen, Steven L.; Hwang, E. Shelley

    2012-06-01

    Purpose: To identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regional failure (LRF). Methods and Materials: Seven breast cancer physicians from University of California cancer centers created 14 hypothetical clinical case scenarios, identified, reviewed, and abstracted the available literature (MEDLINE and Cochrane databases), and formulated evidence tables with endpoints of LRF, disease-free survival, and overall survival. Using the American College of Radiology appropriateness criteria methodology, appropriateness ratings for postmastectomy radiation were assigned for each scenario. Finally, an overall summary risk assessment table was developed. Results: Of 24 sources identified, 23 were retrospective studies from single institutions. Consensus on the appropriateness rating, defined as 80% agreement in a category, was achieved for 86% of the cases. Distinct LRF risk categories emerged. Clinical stage II (T1-2N0-1) patients, aged >40 years, estrogen receptor-positive subtype, with pathologic complete response or 0-3 positive nodes without lymphovascular invasion or extracapsular extension, were identified as having {<=}10% risk of LRF without radiation. Limited data support stage IIIA patients with pathologic complete response as being low risk. Conclusions: In the absence of randomized trial results, existing data can be used to guide the use of PMRT in the neoadjuvant chemotherapy setting. Using available studies to inform appropriateness ratings for clinical scenarios, we found a high concordance of treatment recommendations for PMRT and were able to identify a cohort of women with a low risk of LRF without radiation. These low-risk patients will form the basis for future planned studies within University of California Athena Breast Health Network.

  9. CHEMICAL INTERACTIONS OF ARSENATE, ARSENITE, PHOSPHATE, AND SILICATE WITH IRON (II,III) HYDROXYCARBONATE GREEN RUST

    EPA Science Inventory

    Granular zerovalent iron has been proposed to be used as a medium in permeable reactive barriers (PRBs) to remove arsenic from contaminated groundwater. Iron(II, III) hydroxycarbonate green rust (carbonate green rust, or CGR) is a major corrosion product of zerovalent iron under ...

  10. dBase II/III Books for Scholars: An Introduction to dBase Literature.

    ERIC Educational Resources Information Center

    Slatta, Richard W.

    1986-01-01

    Critically reviews more than 20 of the best books for scholars on Ashton-Tate's dBase II and dBase III relational database management programs for microcomputers. Books are arranged by category: beginning and advanced programming guidance, program listings, and reference. A comprehensive bibliography of dBase books in print is also included. (56…

  11. Multipurpose Wetlands Phase II/III: final design and ongoing research investigations

    USGS Publications Warehouse

    Babbitt, Bruce; Beard, Daniel P.; Hancock, Lawrence F.

    1994-01-01

    The Eastern Municipal Water District (EMWD), the Bureau of Reclamation (USBR), and the National Biological Survey (NBS), in consultation with other governmental agencies, the academic community, and environmental groups, are involved in a cooperative wetlands research and demonstration effort. This report reflects progress through the first 3 years of a 5-year program. The goal of the Multipurpose Wetlands Research and Demonstration Project is to evaluate and expand the use of reclaimed water and contaminated ground water through the incorporation of multipurpose constructed wetlands into EMWD's total water resources management program. The focus of the wetlands is the development of design, construction, and operation criteria that will provide a cost-effective and innovative alternative for managing water resources and provide other public benefits in arid areas. The program also recognizes the fact that naturally-occurring wetlands, both coastal and inland, have been disappearing at an alarming rate.

  12. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... hydrogen cooler, and all other vessels, piping, and equipment in liquid mercury service in the cell room... subpart. 12. Each decomposer and all hydrogen piping up to the hydrogen header Half day Equipment that is leaking hydrogen and/or mercury vapor Take the required action specified in Table 3 to this subpart....

  13. [Thiotriazoline in the Treatment of Stable Angina Pectoris of II-III Functional Class].

    PubMed

    Kadin, D V; Chumak, B A; Filippov, A E; Shustov, S B

    2015-01-01

    Trimetazidine is a metabolic agent of proven efficacy in improving myocardial ischemia and angina. A comparative international multicenter randomized trial, assessed anti-anginal anti ischemic efficacy and safety of Trimetazidine (60 mg/d) and Thiotriazoline (600 mg/d) in symptomatic patients with chronic ischemic heart disease receiving the first line therapy. The study assessed the efficacy of the two drugs on total exercise duration, time to 1-mm ST segment depression, the number of angina attacks and nitroglycerin tablets consumed amount. Both drugs have demonstrated clinical efficacy equal for all primary and secondary endpoints. PMID:26761968

  14. 40 CFR Table 2 to Subpart IIIii of... - Work Practice Standards-Required Inspections

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... hydrogen cooler, and all other vessels, piping, and equipment in liquid mercury service in the cell room... subpart. 12. Each decomposer and all hydrogen piping up to the hydrogen header Half day Equipment that is leaking hydrogen and/or mercury vapor Take the required action specified in Table 3 to this subpart....

  15. 40 CFR Table 9 to Subpart IIIii of... - Required Records for Work Practice Standards

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 13 2010-07-01 2010-07-01 false Required Records for Work Practice...—Required Records for Work Practice Standards As stated in § 63.8256(c), you must keep the records (related to the work practice standards) specified in the following table: For each . . . You must record...

  16. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 14 2013-07-01 2013-07-01 false Required Elements of Washdown Plans 7...—Required Elements of Washdown Plans As stated in § 63.8192, your written washdown plan must address the elements contained in the following table: For each of the following areas . . . You must establish...

  17. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 13 2011-07-01 2011-07-01 false Required Elements of Washdown Plans 7...—Required Elements of Washdown Plans As stated in § 63.8192, your written washdown plan must address the elements contained in the following table: For each of the following areas . . . You must establish...

  18. 40 CFR Table 7 to Subpart IIIii of... - Required Elements of Washdown Plans

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 14 2012-07-01 2011-07-01 true Required Elements of Washdown Plans 7...—Required Elements of Washdown Plans As stated in § 63.8192, your written washdown plan must address the elements contained in the following table: For each of the following areas . . . You must establish...

  19. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... its concentration in the air stream. c. Portable mercury vapor analyzer—gold film amalgamation detector A sample of gas is drawn through a detection cell containing a gold film detector. Elemental mercury amalgamates with the gold film, changing the resistance of the detector in proportion to...

  20. Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER).

    PubMed

    Merrill, Jt; Buyon, Jp; Furie, Ra; Latinis, Km; Gordon, C; Hsieh, H-J; Brunetta, P

    2011-06-01

    The EXPLORER study was designed to assess the response to rituximab versus placebo in patients with moderate to severe extrarenal systemic lupus erythematosus (SLE) receiving background immunosuppression. The definition of response required reduced clinical activity without subsequent flares over 52 weeks, and the study did not meet its efficacy endpoint. The current exploratory analysis assessed flare rates in patients who achieved initial low disease activity response (British Isles Lupus Assessment Group [BILAG] C or better in all organs) during the study. Exploratory reanalysis of data from the EXPLORER trial was conducted, considering alternative definitions for flare. No difference was found between rituximab and placebo in preventing or delaying moderate to severe flares. However, when severe (BILAG A) flares alone were examined, rituximab reduced the risk of a subsequent first A flare (hazard ratio = 0.61; p = 0.052) and lowered mean ± SD annualized A flare rates (0.86 ± 1.47 vs. 1.41 ± 2.14; p = 0.038). Eighty-four (49.7%) rituximab-treated patients achieved low disease activity without subsequent A flares versus 31 (35.2%) placebo-treated patients (p = 0.027). Prednisone rescue for A flares was similar in rituximab- (24%) and placebo-treated (14%) patients (p = 0.204). This post hoc analysis evaluates the hypothesis that assessment of BILAG A flares may distinguish potential treatment effects with greater sensitivity than assessment of BILAG B flares. PMID:21478286

  1. Fulvestrant and/or Anastrozole in Treating Postmenopausal Patients With Stage II-III Breast Cancer Undergoing Surgery

    ClinicalTrials.gov

    2016-09-15

    Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; Invasive Ductal Breast Carcinoma; Invasive Lobular Breast Carcinoma; Recurrent Breast Cancer; Stage II Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  2. Control of intramolecular electron transfer by protonation: Dimers and polymers containing ruthenium II/III and 44' azopyridine

    NASA Astrophysics Data System (ADS)

    Launay, Jean-Pierre; Marvaud, Valérie

    1992-07-01

    The association of pentammine ruthenium(II) with the reducible ligand 44' azopyridine leads to a pH induced redox reaction in which ruthenium is oxidized to the III state, while 44' azopyridine is reduced to hydrazopyridine. In this process, the conjugated ligand is transformed in a nonconjugated one, with loss of its intramolecular electron transfer properties. In order to exploit this control of an intramolecular electron transfer by a protonation process, we have prepared ``shish-kebab'' polymers by first inserting ruthenium in tetrakis (3,5-diterbutyl 4-hydroxyphenyl) porphyrin under a CO atmosphere. The resulting Ru(CO)porphyrin complex is photochemically decarbonylated in the presence of bridging ligands (44×azopyridine or pyrazine). Polymers are thus obtained, which can be oxidized by iodine, giving rise to intervalence transitions between ruthenium(II) and (III) in the near-infrared. This provides a convenient way to monitor electron transfer along the polymer chain. In the case of 44' azopyridine, the pH induced redox reaction is again observed. Starting from a homovalent ruthenium(II) chain, this gives the possibility to switch ``ON'' or ``OFF'' the intervalence transition by a protonation/deprotonation reaction.

  3. 40 CFR Table 6 to Subpart IIIii of... - Examples of Techniques for Equipment Problem Identification, Leak Detection and Mercury Vapor

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... its concentration in the air stream. c. Portable mercury vapor analyzer—gold film amalgamation detector A sample of gas is drawn through a detection cell containing a gold film detector. Elemental mercury amalgamates with the gold film, changing the resistance of the detector in proportion to...

  4. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... the end box and maintain the temperature of the aqueous liquid below its boiling point, maintain a... its boiling point. 9. Open-top containers holding liquid mercury Maintain a layer of aqueous liquid... during transport. h. Store carbon from decomposers in accordance with the requirements in 40 CFR part...

  5. 40 CFR Table 1 to Subpart IIIii of... - Work Practice Standards-Design, Operation, and Maintenance Requirements

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... the end box and maintain the temperature of the aqueous liquid below its boiling point, maintain a... its boiling point. 9. Open-top containers holding liquid mercury Maintain a layer of aqueous liquid... during transport. h. Store carbon from decomposers in accordance with the requirements in 40 CFR part...

  6. Bevacizumab, Fluorouracil, Leucovorin Calcium, and Oxaliplatin Before Surgery in Treating Patients With Stage II-III Rectal Cancer

    ClinicalTrials.gov

    2015-10-24

    Mucinous Adenocarcinoma of the Rectum; Signet Ring Adenocarcinoma of the Rectum; Stage IIA Rectal Cancer; Stage IIB Rectal Cancer; Stage IIC Rectal Cancer; Stage IIIA Rectal Cancer; Stage IIIB Rectal Cancer; Stage IIIC Rectal Cancer

  7. Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3).

    PubMed

    Jäger, Michael; Schoberth, Alexandra; Ruf, Peter; Hess, Juergen; Hennig, Michael; Schmalfeldt, Barbara; Wimberger, Pauline; Ströhlein, Michael; Theissen, Bettina; Heiss, Markus M; Lindhofer, Horst

    2012-01-01

    Patients with malignant ascites secondary to primary carcinomas benefit from intraperitoneal therapy with the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3). Here, we report the analysis of peritoneal fluid samples from 258 patients with malignant ascites randomized to catumaxomab or control groups to investigate the molecular effects of catumaxomab treatment. In the catumaxomab group, tumor cell numbers and peritoneal levels of VEGF decreased, whereas the activation status of CD4(+) and CD8(+) T-cell populations increased more than two-fold after treatment. Notably, CD133(+)/EpCAM(+) cancer stem cells vanished from the catumaxomab samples but not from the control samples. In vitro investigations indicated that catumaxomab eliminated tumor cells in a manner associated with release of proinflammatory Th1 cytokines. Together, our findings show that catumaxomab therapy activates peritoneal T cells and eliminates EpCAM(+) tumor cells, establishing a molecular and cellular basis to understand in vivo efficacy within the immunosuppressed malignant ascites tissue microenvironment. PMID:22044753

  8. Akt Inhibitor MK-2206 and Anastrozole With or Without Goserelin Acetate in Treating Patients With Stage II-III Breast Cancer

    ClinicalTrials.gov

    2016-03-30

    Estrogen Receptor Positive; HER2/Neu Negative; Recurrent Breast Carcinoma; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer

  9. A phase II/III double-blind, dose-finding clinical trial of a combination of mefloquine, sulfadoxine, and pyrimethamine (Fansimef) in falciparum malaria

    PubMed Central

    de Souza, J. M.; Sheth, U. K.; Wernsdorfer, W. H.; Trigg, P. I.; Doberstyn, E. B.

    1987-01-01

    Fansimef is a combination of 250 mg mefloquine (base), 500 mg sulfadoxine, and 25 mg pyrimethamine per tablet. One hundred and fifty adult male Brazilian patients at Belém (Pará), who had peripheral blood smears positive for Plasmodium falciparum, with or without clinical symptoms of falciparum malaria, were treated in a double-blind randomized fashion with either one, two or three tablets of Fansimef. Of those receiving one tablet (48 patients), 81% were cured and 19% exhibited RI recrudescences. All the patients receiving two or three tablets of Fansimef (49 patients in each group) were cured. The rates of initial clearance of parasitaemia and fever were similar in all treatment groups. Tolerance was good at all dose levels. The main side-effects included nausea, vomiting, dizziness, diarrhoea and abdominal pain, but these were mild and transient and required no specific treatment. The incidence of vomiting and nausea was highest in patients given the three-tablet dose. The results of various haematological, biochemical and urine analyses were not adversely altered by the administration of Fansimef. PMID:3311438

  10. Vaccine Therapy and Cyclophosphamide in Treating Patients With Stage II-III Breast or Stage II-IV Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-01-07

    Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IIA Breast Cancer; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Breast Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Breast Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Breast Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Breast Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  11. Whole genome sequencing of a recombinant type II/III Toxoplasma gondii strain from Uganda reveals chromosome sorting and local allelic variants.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Toxoplasma gondii is a zoonotic parasite of global importance. In common with many protozoan parasites it has the capacity for sexual recombination, but current evidence suggests this is rarely employed. The global population structure is dominated by a small number of clonal genotypes, which exhib...

  12. Bevacizumab and Intravenous or Intraperitoneal Chemotherapy in Treating Patients With Stage II-III Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-07-05

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Undifferentiated Ovarian Carcinoma

  13. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks 3 Table 3 to... Standards—Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks... cell back into service until the leaking equipment is repaired. 3. A decomposer or hydrogen...

  14. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks 3 Table 3 to... Standards—Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks... cell back into service until the leaking equipment is repaired. 3. A decomposer or hydrogen...

  15. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks 3 Table 3 to... Standards—Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks... cell back into service until the leaking equipment is repaired. 3. A decomposer or hydrogen...

  16. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks 3 Table 3 to... Standards—Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks... cell back into service until the leaking equipment is repaired. 3. A decomposer or hydrogen...

  17. lLong-Term Outcomes after Proton Therapy, with Concurrent Chemotherapy, for Stage II-III Inoperable Non-Small Cell Lung Cancer

    PubMed Central

    Nguyen, Quynh-Nhu; Ly, Ngoc Bui; Komaki, Ritsuko; Levy, Lawrence B.; Gomez, Daniel R.; Chang, Joe Y.; Allen, Pamela K.; Mehran, Reza J.; Lu, Charles; Gillin, Michael; Liao, Zhongxing; Cox, James D.

    2016-01-01

    Purpose We report long-term disease control, survival, and toxicity for patients with locally advanced non-small cell lung cancer prospectively treated with concurrent proton therapy and chemotherapy on a nonrandomized case-only obervational study. Methods All patients received passive-scatter proton therapy, planned with 4D-CT–based simulation; all received proton therapy concurrent with weekly chemotherapy. Endpoints were local and distant control, disease-free survival (DFS), and overall survival (OS). Results The 134 patients (21 stage II, 113 stage III; median age 69 years) had a median gross tumor volume (GTV) of 70 cm3 (range, 5-753 cm3); 77 patients (57%) received 74 Gy(RBE), and 57 (42% received 60–72 Gy(RBE) (range, 60-74.1 Gy(RBE)). At a median follow-up time of 4.7 years, median OS times were 40.4 months (stage II) and 30.4 months (stage III). Five-year DFS rates were 17.3% (stage II) and 18.0% (stage III). OS, DFS, and local and distant control rates at 5 years did not differ by disease stage. Age and GTV were related to OS and DFS. Toxicity was tolerable, with 1 grade 4 esophagitis and 16 grade 3 events (2 pneumonitis, 6 esophagitis, 8 dermatitis). Conclusion This report of outcomes after proton therapy for 134 patients indicated that this regimen produced excellent OS with tolerable toxicity. PMID:26028228

  18. Carboplatin and Paclitaxel With or Without Atezolizumab Before Surgery in Treating Patients With Newly Diagnosed, Stage II-III Triple-Negative Breast Cancer

    ClinicalTrials.gov

    2016-08-29

    Estrogen Receptor Negative; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-Negative Breast Carcinoma

  19. Postoperative radiotherapy and tumor recurrence after complete resection of stage II/III thymic tumor: a meta-analysis of cohort studies

    PubMed Central

    Ma, Jietao; Sun, Xin; Huang, Letian; Xiong, Zhicheng; Yuan, Meng; Zhang, Shuling; Han, Cheng-Bo

    2016-01-01

    Background Whether postoperative radiotherapy (PORT) is effective for reducing the recurrence risk in patients who received complete resection of the stage II or III thymic tumors has not been determined. A meta-analysis was performed by combining the results of all available controlled trials. Methods PubMed, Cochrane’s Library, and the Embase databases were searched for studies which compared the recurrence data for patients with complete resection of the stage II or III thymic tumors assigned to an observing group, or a PORT group. A random effect model was applied to combine the results. Results Nineteen studies, all designed as retrospective cohort studies were included. These studies included 663 patients of PORT group and 617 patients of observing group. The recurrence rate for the patients in PORT group and observing group were 12.4% and 11.5%, respectively. Results of our study indicated that PORT has no significant influence on recurrent risk in patients with stage II or III thymic tumor after complete resection (odds ratio 1.02, 95% confidence interval 0.55–1.90, P=0.96). When stratified by stages, our meta-analyses did not indicate any significant effects of PORT on recurrent outcomes in either the stage II or the stage III patients. Moreover, subsequent analysis limited to studies only including patients with thymoma or thymic carcinoma also did not support the benefits of PORT on recurrent outcomes. Conclusion Although derived from retrospective cohort studies, current evidence did not support any benefit of PORT on recurrent risk in patients with complete resection of the stage II or III thymic tumors. PMID:27524907

  20. Concomitant boost IMRT-based neoadjuvant chemoradiotherapy for clinical stage II/III rectal adenocarcinoma: results of a phase II study

    PubMed Central

    2014-01-01

    Aim This study was designed to evaluate the efficacy and toxicities of concomitant boost intensity-modulated radiation therapy (IMRT) along with capecitabine and oxaliplatin, followed by a cycle of Xelox, in neoadjuvant course for locally advanced rectal cancer. Materials and methods Patients with histologically confirmed, newly diagnosed, locally advanced rectal adenocarcinoma (cT3-T4 and/or cN+) located within 12 cm of the anal verge were included in this study. Patients received IMRT to the pelvis of 50 Gy and a concomitant boost of 5 Gy to the primary tumor in 25 fractions, and concurrent with oxaliplatin (50 mg/m2 d1 weekly) and capecitabine (625 mg/m2 bid d1–5 weekly). One cycle of Xelox (oxaliplatin 130 mg/m2 on d1 and capecitabine 1000 mg/m2 twice daily d1–14) was given two weeks after the completion of chemoradiation, and radical surgery was scheduled eight weeks after chemoradiation. Tumor response was evaluated by tumor regression grade (TRG) system and acute toxicities were evaluated by NCI-CTC 3.0 criteria. Survival curves were estimated using the Kaplan-Meier method and compared with Log-rank test. Results A total of 78 patients were included between March 2009 and May 2011 (median age 54 years; 62 male). Seventy-six patients underwent surgical resection. Twenty-eight patients underwent sphincter-sparing lower anterior resection and 18 patients (23.7%) were evaluated as pathological complete response (pCR). The incidences of grade 3 hematologic toxicity, diarrhea, and radiation dermatitis were 3.8%, 10.3%, and 17.9%, respectively. The three-year LR (local recurrence), DFS (disease-free survival) and OS (overall survival) rates were 14.6%, 63.8% and 77.4%, respectively. Initial clinical T stage and tumor regression were independent prognostic factors to DFS. Conclusion An intensified regimen of concomitant boost radiotherapy plus concurrent capecitabine and oxaliplatin, followed by one cycle of Xelox, can be safely administered in patients with locally advanced rectal cancer, and produces a high rate of pCR. A prognostic score model is helpful to distinguish different long-term prognosis groups in early stage. PMID:24606870

  1. Effect of cariprazine across the symptoms of mania in bipolar I disorder: Analyses of pooled data from phase II/III trials.

    PubMed

    Vieta, Eduard; Durgam, Suresh; Lu, Kaifeng; Ruth, Adam; Debelle, Marc; Zukin, Stephen

    2015-11-01

    Bipolar I disorder is a chronic disorder characterized by episodic recurrences of mania, depression, and mixed affective states interspersed with periods of full or partial remission; subsyndromal residual symptoms between episodes are common and disabling. Cariprazine, an atypical antipsychotic, is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. Post-hoc analyses of pooled data from 3 positive trials were conducted to evaluate the effect of cariprazine 3-12 mg/d on the symptoms of mania in inpatients (18-65 years) with bipolar I disorder and a current manic episode. Analyses were based on the pooled intent-to-treat (ITT) population (placebo=429; cariprazine=608). Mean change from baseline to the end of treatment on individual Young Mania Rating Scale (YMRS) items was analysed using a mixed-effects model for repeated measures (MMRM); categorical symptom severity shifts were analysed using logistic regression. Statistically significant improvement in mean change was seen for cariprazine versus placebo on all 11 YMRS items (p<0.0001); significantly more cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment on 11 YMRS items (p<0.0001) and concurrently on the 4 YMRS core symptoms (irritability, speech, content, and disruptive-aggressive behaviour) (p<0.0001). Significantly more cariprazine- versus placebo-treated patients shifted from a Moderate/Worse or Marked/Worse Symptoms categories to Mild/No Symptoms on all 11 (p<0.0001) and 9 of 11 YMRS items (p<0.05), respectively. Results suggest that cariprazine treatment improved mania across YMRS symptoms; a significant percentage of cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment. PMID:26419293

  2. 40 CFR Table 3 to Subpart IIIii of... - Work Practice Standards-Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks 3 Table 3 to... Standards—Required Actions for Liquid Mercury Spills and Accumulations and Hydrogen and Mercury Vapor Leaks... cell back into service until the leaking equipment is repaired. 3. A decomposer or hydrogen...

  3. Transthoracic versus abdominal-transhiatal resection for treating Siewert type II/III adenocarcinoma of the esophagogastric junction: a meta-analysis

    PubMed Central

    Zheng, Zhi; Cai, Jun; Yin, Jie; Zhang, Jun; Zhang, Zhong-Tao; Wang, Kang-Li

    2015-01-01

    Our study aimed to explore the differences in short and long-term outcomes about the transthoracic (TH) and abdominal-transhiatal (TH) approaches for treating esophagogastric junction (AEG). A systematic review of PubMed, EMbase, Cochrane Library, China National Knowledge Infrastructure and CBMdisc was performed. All original articles comparing TH with TA were included in the study. Meta-analysis was conducted using odd ratios (OR) and weighted mean differences (WMDs).Thirteen studies including 2489 patients with adenocarcinoma of the esophagogastric junction, with 1050 patients underwent TA and 1437 patients underwent TH were pooled for this study. There were no significant difference between two approaches concerning duration of operation, blood loss, anastomotic leakage and positive of proximal incisal margin. Lymph node excised also showed no significant differences between two procedures in RCTs while in TA group of Non-RCTs, the number of lymph node dissection is higher. TH approach was associated with a longer length of hospital stay and had higher incidence of respiratory and cardiovascular complications and early postoperative mortality. Overall analysis of 1, 3, 5-year survival showed no significant difference between two approaches. Based on the study, TA approach had a positive impact than TH for AEG with respect to respiratory and cardiovascular complications, hospital stay and early mortality rates. There were no significant differences between the two approaches for long-term survival. Therefore, two surgical approaches are acceptable, and the elders with poor cardiopulmonary function, we recommended TA approach for treating it. PMID:26770310

  4. Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin Followed by Surgery and Paclitaxel in Treating Patients With Triple Negative Stage II-III Breast Cancer

    ClinicalTrials.gov

    2016-03-08

    Estrogen Receptor-negative Breast Cancer; HER2-negative Breast Cancer; Progesterone Receptor-negative Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

  5. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.

    PubMed

    Weller, Michael; Weber, Ruthild G; Willscher, Edith; Riehmer, Vera; Hentschel, Bettina; Kreuz, Markus; Felsberg, Jörg; Beyer, Ulrike; Löffler-Wirth, Henry; Kaulich, Kerstin; Steinbach, Joachim P; Hartmann, Christian; Gramatzki, Dorothee; Schramm, Johannes; Westphal, Manfred; Schackert, Gabriele; Simon, Matthias; Martens, Tobias; Boström, Jan; Hagel, Christian; Sabel, Michael; Krex, Dietmar; Tonn, Jörg C; Wick, Wolfgang; Noell, Susan; Schlegel, Uwe; Radlwimmer, Bernhard; Pietsch, Torsten; Loeffler, Markus; von Deimling, Andreas; Binder, Hans; Reifenberger, Guido

    2015-05-01

    Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status. PMID:25783747

  6. Phase II Study of Intraperitoneal Paclitaxel Plus Cisplatin and Intravenous Paclitaxel Plus Bevacizumab As Adjuvant Treatment of Optimal Stage II/III Epithelial Ovarian Cancer

    PubMed Central

    Konner, Jason A.; Grabon, Diana M.; Gerst, Scott R.; Iasonos, Alexia; Thaler, Howard; Pezzulli, Sandra D.; Sabbatini, Paul J.; Bell-McGuinn, Katherine M.; Tew, William P.; Hensley, Martee L.; Spriggs, David R.; Aghajanian, Carol A.

    2011-01-01

    Purpose Intraperitoneal (IP) cisplatin and intravenous (IV) or IP paclitaxel constitute a standard therapy for optimally debulked ovarian cancer. Bevacizumab prolongs progression-free survival (PFS) when included in first-line IV chemotherapy. In this study, the safety and feasibility of adding bevacizumab to a first-line IP regimen were assessed. Patients and Methods Treatment was as follows: paclitaxel 135 mg/m2 IV over 3 hours day 1, cisplatin 75 mg/m2 IP day 2, and paclitaxel 60 mg/m2 IP day 8. Bevacizumab 15 mg/kg IV was given after paclitaxel on day 1 beginning in cycle 2. After six cycles of chemotherapy, bevacizumab was given every 3 weeks for 17 additional treatments. The primary end point was safety and tolerability determined by whether 60% of patients completed six cycles of IV/IP chemotherapy. Results Of 41 treated patients, 30 (73%) received six cycles of IV/IP chemotherapy and 35 (85%) received at least four cycles. Three (27%) of those who discontinued chemotherapy did so because of complications related to bevacizumab (hypertension, n = 2; perforation, n = 1). Grades 3 to 4 toxicities included neutropenia (34%), vasovagal syncope (10%), hypertension (7%), nausea/vomiting (7%), hypomagnesemia (7%), and abdominal pain (7%). There were three grade 3 small bowel obstructions (7%) during cycles 3, 9, and 15. One patient died following rectosigmoid anastomotic dehiscence during cycle 4. Estimated median PFS is 28.6 months (95% CI, 19.1 to 38.9 months). Three patients (7%) had IP port malfunction. Conclusion The addition of bevacizumab to this IP regimen is feasible; however, bevacizumab may increase the risk of bowel obstruction/perforation. The observed median PFS is similar to that seen with IP/IV chemotherapy alone. PMID:22067389

  7. Efficacy and safety analysis of trastuzumab and paclitaxel based regimen plus carboplatin or epirubicin as neoadjuvant therapy for clinical stage II-III, HER2-positive breast cancer patients: a phase 2, open-label, multicenter, randomized trial.

    PubMed

    Huang, Liang; Chen, Sheng; Yang, Wentao; Xu, Binghe; Huang, Tao; Yang, Hongjian; Zheng, Hong; Wang, Yongsheng; Song, Erwei; Zhang, Jin; Cui, Shude; Pang, Da; Tang, Lili; Lei, Yutao; Geng, Cuizhi; Shao, Zhiming

    2015-07-30

    This trial was designed to compare the efficacy and safety between epirubicin (E) and carboplatin (C) in combination with paclitaxel (P) and trastuzumab (H) in neoadjuvant setting. In 13 Chinese cancer centers, 100 patients with HER2-positive, locally advanced breast cancer were 1:1 randomized to receive medication as follows: trastuzumab and paclitaxel weekly combined with carboplatin weekly for PCH group, or epirubicin every 3 weeks for PEH group. Patients were given 4 to 6 cycles of chemotherapy. The primary endpoint was pathologic complete response (pCR) rate, which was no significant difference in PCH and PEH regimen (39.1% vs. 48.8%; p=0.365). However, PEH regimen achieved higher pCR in luminal-B (HER2-poitive) subgroup (55.0% vs. 24.0%; p = 0.033), but not in ERBB2+ subgroup (42.9% vs. 57.1%; p = 0.355). PEH regimen showed a favorable efficacy in PIK3CA mutated subgroup (69.2% vs.23.5%, p=0.012). No significant difference was observed in the subgroup analysis of TP53 mutation status, PTEN expression, FCGR2A SNP and FCGR3A SNP. Both regimens as neoadjuvant chemotherapy achieve similar efficacy and safety. PEH might improve pCR rate, especially in the luminal-B subtype and PIK3CA mutation subtype. PEH is feasible and less likely to increase the incidence of acute cardiac events compared to PCH. PMID:26084292

  8. Phase II-I-II Study of Two Different Doses and Schedules of Pralatrexate, a High-Affinity Substrate for the Reduced Folate Carrier, in Patients With Relapsed or Refractory Lymphoma Reveals Marked Activity in T-Cell Malignancies

    PubMed Central

    O'Connor, Owen A.; Horwitz, Steven; Hamlin, Paul; Portlock, Carol; Moskowitz, Craig H.; Sarasohn, Debra; Neylon, Ellen; Mastrella, Jill; Hamelers, Rachel; MacGregor-Cortelli, Barbara; Patterson, Molly; Seshan, Venkatraman E.; Sirotnak, Frank; Fleisher, Martin; Mould, Diane R.; Saunders, Mike; Zelenetz, Andrew D.

    2009-01-01

    Purpose To determine the maximum-tolerated dose (MTD) and efficacy of pralatrexate in patients with lymphoma. Patients and Methods Pralatrexate, initially given at a dose of 135 mg/m2 on an every-other-week basis, was associated with stomatitis. A redesigned, weekly phase I/II study established an MTD of 30 mg/m2 weekly for six weeks every 7 weeks. Patients were required to have relapsed/refractory disease, an absolute neutrophil greater than 1,000/μL, and a platelet count greater than 50,000/μL for the first dose of any cycle. Results The every-other-week, phase II experience was associated with an increased risk of stomatitis and hematologic toxicity. On a weekly schedule, the MTD was 30 mg/m2 weekly for 6 weeks every 7 weeks. This schedule modification resulted in a 50% reduction in the major hematologic toxicities and abrogation of the grades 3 to 4 stomatitis. Stomatitis was associated with elevated homocysteine and methylmalonic acid, which were reduced by folate and vitamin B12 supplementation. Of 48 assessable patients, the overall response rate was 31% (26% by intention to treat), including 17% who experienced complete remission (CR). When analyzed by lineage, the overall response rates were 10% and 54% in patients with B- and T-cell lymphomas, respectively. All eight patients who experienced CR had T-cell lymphoma, and four of the six patients with a partial remission were positron emission tomography negative. The duration of responses ranged from 3 to 26 months. Conclusion Pralatrexate has significant single-agent activity in patients with relapsed/refractory T-cell lymphoma. PMID:19652067

  9. BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial.

    PubMed Central

    Butler, Karina; Inshaw, Jamie; Ford, Deborah; Bernays, Sarah; Scott, Karen; Kenny, Julia; Klein, Nigel; Turkova, Anna; Harper, Lynda; Nastouli, Eleni; Paparini, Sara; Choudhury, Rahela; Rhodes, Tim; Babiker, Abdel; Gibb, Diana

    2016-01-01

    BACKGROUND For human immunodeficiency virus (HIV)-infected adolescents facing lifelong antiretroviral therapy (ART), short-cycle therapy (SCT) with long-acting agents offers the potential for drug-free weekends, less toxicity, better adherence and cost savings. OBJECTIVES To determine whether or not efavirenz (EFV)-based ART in short cycles of 5 days on and 2 days off is as efficacious (in maintaining virological suppression) as continuous EFV-based ART (continuous therapy; CT). Secondary objectives included the occurrence of new clinical HIV events or death, changes in immunological status, emergence of HIV drug resistance, drug toxicity and changes in therapy. DESIGN Open, randomised, non-inferiority trial. SETTING Europe, Thailand, Uganda, Argentina and the USA. PARTICIPANTS Young people (aged 8-24 years) on EFV plus two nucleoside reverse transcriptase inhibitors and with a HIV-1 ribonucleic acid level [viral load (VL)] of < 50 copies/ml for > 12 months. INTERVENTIONS Young people were randomised to continue daily ART (CT) or change to SCT (5 days on, 2 days off ART). MAIN OUTCOME MEASURES Follow-up was for a minimum of 48 weeks (0, 4 and 12 weeks and then 12-weekly visits). The primary outcome was the difference between arms in the proportion with VL > 50 copies/ml (confirmed) by 48 weeks, estimated using the Kaplan-Meier method (12% non-inferiority margin) adjusted for region and age. RESULTS In total, 199 young people (11 countries) were randomised (n = 99 SCT group, n = 100 CT group) and followed for a median of 86 weeks. Overall, 53% were male; the median age was 14 years (21% ≥ 18 years); 13% were from the UK, 56% were black, 19% were Asian and 21% were Caucasian; and the median CD4% and CD4 count were 34% and 735 cells/mm(3), respectively. By week 48, only one participant (CT) was lost to follow-up. The SCT arm had a 27% decreased drug exposure as measured by the adherence questionnaire and a MEMSCap(™) Medication Event Monitoring System (MEMSCap Inc., Durham, NC, USA) substudy (median cap openings per week: SCT group, n = 5; CT group, n = 7). By 48 weeks, six participants in the SCT group and seven in the CT group had a confirmed VL > 50 copies/ml [difference -1.2%, 90% confidence interval (CI) -7.3% to 4.9%] and two in the SCT group and four in the CT group had a confirmed VL > 400 copies/ml (difference -2.1%, 90% CI -6.2% to 1.9%). All six participants in the SCT group with a VL > 50 copies/ml resumed daily ART, of whom five were resuppressed, three were on the same regimen and two with a switch; two others on SCT resumed daily ART for other reasons. Overall, three participants in the SCT group and nine in the CT group (p = 0.1) changed ART regimen, five because of toxicity, four for simplification reasons, two because of compliance issues and one because of VL failure. Seven young people (SCT group, n = 2; CT group, n = 5) had major non-nucleoside reverse transcriptase inhibitor mutations at VL failure, of whom two (n = 1 SCT group, n = 1 CT group) had the M184V mutation. Two young people had new Centers for Disease Control B events (SCT group, n = 1; CT group, n = 1). There were no significant differences between SCT and CT in grade 3/4 adverse events (13 vs. 14) or in serious adverse events (7 vs. 6); there were fewer ART-related adverse events in the SCT arm (2 vs. 14; p = 0.02). At week 48 there was no evidence that SCT led to increased inflammation using an extensive panel of markers. Young people expressed a strong preference for SCT in a qualitative substudy and in pre- and post-trial questionnaires. In total, 98% of the young people are taking part in a 2-year follow-up extension of the trial. CONCLUSIONS Non-inferiority of VL suppression in young people on EFV-based first-line ART with a VL of < 50 copies/ml was demonstrated for SCT compared with CT, with similar resistance, safety and inflammatory marker profiles. The SCT group had fewer ART-related adverse events. Further evaluation of the immunological and virological impact of SCT is ongoing. A limitation of the trial is that the results cannot be generalised to settings where VL monitoring is either not available or infrequent, nor to use of low-dose EFV. Two-year extended follow-up of the trial is ongoing to confirm the durability of the SCT strategy. Further trials of SCT in settings with infrequent VL monitoring and with other antiretroviral drugs such as tenofovir alafenamide, which has a long intracellular half-life, and/or dolutegravir, which has a higher barrier to resistance, are planned. TRIAL REGISTRATION Current Controlled Trials ISRCTN97755073; EUDRACT 2009-012947-40; and CTA 27505/0005/001-0001. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme (projects 08/53/25 and 11/136/108), the European Commission through EuroCoord (FP7/2007/2015), the Economic and Social Research Council, the PENTA Foundation, the Medical Research Council and INSERM SC10-US19, France, and will be published in full in Health Technology Assessment; Vol. 20, No. 49. See the NIHR Journals Library website for further project information. PMID:27377073

  10. Relationship Between Tumor Gene Expression and Recurrence in Four Independent Studies of Patients With Stage II/III Colon Cancer Treated With Surgery Alone or Surgery Plus Adjuvant Fluorouracil Plus Leucovorin

    PubMed Central

    O'Connell, Michael J.; Lavery, Ian; Yothers, Greg; Paik, Soonmyung; Clark-Langone, Kim M.; Lopatin, Margarita; Watson, Drew; Baehner, Frederick L.; Shak, Steven; Baker, Joffre; Cowens, J. Wayne; Wolmark, Norman

    2010-01-01

    Purpose These studies were conducted to determine the relationship between quantitative tumor gene expression and risk of cancer recurrence in patients with stage II or III colon cancer treated with surgery alone or surgery plus fluorouracil (FU) and leucovorin (LV) to develop multigene algorithms to quantify the risk of recurrence as well as the likelihood of differential treatment benefit of FU/LV adjuvant chemotherapy for individual patients. Patients and Methods We performed quantitative reverse transcription polymerase chain reaction (RT-qPCR) on RNA extracted from fixed, paraffin-embedded (FPE) tumor blocks from patients with stage II or III colon cancer who were treated with surgery alone (n = 270 from National Surgical Adjuvant Breast and Bowel Project [NSABP] C-01/C-02 and n = 765 from Cleveland Clinic [CC]) or surgery plus FU/LV (n = 308 from NSABP C-04 and n = 508 from NSABP C-06). Overall, 761 candidate genes were studied in C-01/C-02 and C-04, and a subset of 375 genes was studied in CC/C-06. Results A combined analysis of the four studies identified 48 genes significantly associated with risk of recurrence and 66 genes significantly associated with FU/LV benefit (with four genes in common). Seven recurrence-risk genes, six FU/LV-benefit genes, and five reference genes were selected, and algorithms were developed to identify groups of patients with low, intermediate, and high likelihood of recurrence and benefit from FU/LV. Conclusion RT-qPCR of FPE colon cancer tissue applied to four large independent populations has been used to develop multigene algorithms for estimating recurrence risk and benefit from FU/LV. These algorithms are being independently validated, and their clinical utility is being evaluated in the Quick and Simple and Reliable (QUASAR) study. PMID:20679606

  11. Valproic acid, compared to other antiepileptic drugs, is associated with improved overall and progression-free survival in glioblastoma but worse outcome in grade II/III gliomas treated with temozolomide.

    PubMed

    Redjal, Navid; Reinshagen, Clemens; Le, Andrew; Walcott, Brian P; McDonnell, Erin; Dietrich, Jorg; Nahed, Brian V

    2016-05-01

    Valproic acid (VPA) is an anti-epileptic drug with properties of a histone deacetylase inhibitor (HDACi). HDACi play a key role in epigenetic regulation of gene expression and have been increasingly used as anticancer agents. Recent studies suggest that VPA is associated with improved survival in high-grade gliomas. However, effects on lower grade gliomas have not been examined. This study investigates whether use of VPA correlates with tumor grade, histological progression, progression-free and overall survival (OS) in grade II, III, and IV glioma patients. Data from 359 glioma patients (WHO II-IV) treated with temozolomide plus an antiepileptic drug (VPA or another antiepileptic drug) between January 1997 and June 2013 at the Massachusetts General Hospital was analyzed retrospectively. After confounder adjustment, VPA was associated with a 28 % decrease in hazard of death (p = 0.031) and a 28 % decrease in the hazard of progression or death (p = 0.015) in glioblastoma. Additionally, VPA dose correlated with reduced hazard of death by 7 % (p = 0.002) and reduced hazard of progression or death by 5 % (p < 0.001) with each 100 g increase in total dose. Conversely, in grade II and III gliomas VPA was associated with a 118 % increased risk of tumor progression or death (p = 0.014), and every additional 100 g of VPA raised the hazard of progression or death by 4 %, although not statistically significant (p = 0.064). Moreover, grade II and III glioma patients taking VPA had 2.17 times the risk of histological progression (p = 0.020), although this effect was no longer significant after confounder adjustment. In conclusion, VPA was associated with improved survival in glioblastoma in a dose-dependent manner. However, in grade II and III gliomas, VPA was linked to histological progression and decrease in progression-free survival. Prospective evaluation of VPA treatment for glioma patients is warranted to confirm these findings. PMID:26830093

  12. Image-Guided Hypofractionated Radiation Therapy With Stereotactic Body Radiation Therapy Boost and Combination Chemotherapy in Treating Patients With Stage II-III Non-Small Cell Lung Cancer That Cannot Be Removed By Surgery

    ClinicalTrials.gov

    2016-09-07

    Adenocarcinoma of the Lung; Adenosquamous Cell Lung Cancer; Large Cell Lung Cancer; Recurrent Non-small Cell Lung Cancer; Squamous Cell Lung Cancer; Stage IIA Non-small Cell Lung Cancer; Stage IIB Non-small Cell Lung Cancer; Stage IIIA Non-small Cell Lung Cancer; Stage IIIB Non-small Cell Lung Cancer

  13. 77 FR 27272 - Environmental Impact Statement: Hamilton and Clermont Counties, OH

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-09

    ... Segment 3 of the proposed Oasis Rail Line which would share the right-of-way with relocated SR-32. Tier 1... proposed Segments II-III SR 32 project and proposed Oasis Rail Line Segment 3 will involve more detailed... Oasis rail transit (a portion of which parallels the Segment II-III corridor), a ] multi-modal...

  14. REVIEW OF THE NEGOTIATION OF THE MODEL PROTOCOL ADDITIONAL TO THE AGREEMENT(S) BETWEEN STATE(S) AND THE INTERNATIONAL ATOMIC ENERGY AGENCY FOR THE APPLICATION OF SAFEGUARDS, INFCIRC/540 (Corrected) VOLUME II/III IAEA COMMITTEE 24, Major Issues Underlying the Model Additional Protocol (1996-1997).

    SciTech Connect

    Rosenthal, M.D.; Saum-Manning, L.; Houck, F.

    2010-01-01

    Volume I of this Review traces the origins of the Model Additional Protocol. It covers the period from 1991, when events in Iraq triggered an intensive review of the safeguards system, until 1996, when the IAEA Board of Governors established Committee 24 to negotiate a new protocol to safeguards agreement. The period from 1991-1996 set the stage for this negotiation and shaped its outcome in important ways. During this 5-year period, many proposals for strengthening safeguards were suggested and reviewed. Some proposals were dropped, for example, the suggestion by the IAEA Secretariat to verify certain imports, and others were refined. A rough consensus was established about the directions in which the international community wanted to go, and this was reflected in the draft of an additional protocol that was submitted to the IAEA Board of Governors on May 6, 1996 in document GOV/2863, Strengthening the Effectiveness and Improving the Efficiency of the Safeguards System - Proposals For Implementation Under Complementary Legal Authority, A Report by the Director General. This document ended with a recommendation that, 'the Board, through an appropriate mechanism, finalize the required legal instrument taking as a basis the draft protocol proposed by the Secretariat and the explanation of the measures contained in this document.'

  15. Acquired antithrombin III deficiency in patients with glomerular proteinuria.

    PubMed

    Thaler, E; Balzar, E; Kopsa, H; Pinggera, W F

    1978-01-01

    Antithrombin III (AT II/III) was determined immunologically and by means of a heparin cofactor assay in plasma samples and 24-hour urine of 15 patients with various degrees of proteinuria, being predominantly of glomerular origin. In urine the AT II/III concentrations were significantly correlated to the concentrations of albumin, plasminogen and IgG. One third of the patients had AT II/III plasma levels below the normal range. The plasma levels showed a significant inverse correlation to the AT II/III and albumin clearance rates. Similarily, the plasminogen concentrations in plasma were decreased in two thirds of the patients, being inversely correlated to the renal plasminogen clearance values. It is proposed that AT II/III deficiency in the nephrotic syndrome is an important pathogenetic factor in venous thrombosis. PMID:689489

  16. Interleukin-1 Blockade With Canakinumab to Improve Exercise Capacity in Patients With Chronic Systolic Heart Failure and Elevated High Sensitivity C-reactive Protein (Hs-CRP)

    ClinicalTrials.gov

    2016-08-22

    Prior Acute Myocardial Infarction; Evidence of Systemic Inflammation (C Reactive Protein Plasma >2 mg/l); Reduced Left Ventricle Ejection Fraction (<50%); Symptoms of Heart Failure (NYHA Class II-III)

  17. Uncoupling of Cav1.2 From Ca2+-Induced Ca2+ Release and SK Channel Regulation in Pancreatic β-Cells

    PubMed Central

    Wang, Yuchen; Jarrard, Rachel E.; Pratt, Evan P.S.; Guerra, Marcy L.; Salyer, Amy E.; Lange, Allison M.; Soderling, Ian M.

    2014-01-01

    We investigated the role of Cav1.2 in pancreatic β-cell function by expressing a Cav1.2 II-III loop/green fluorescent protein fusion in INS-1 cells (Cav1.2/II-III cells) to disrupt channel-protein interactions. Neither block of KATP channels nor stimulation of membrane depolarization by tolbutamide was different in INS-1 cells compared with Cav1.2/II-III cells, but whole-cell Cav current density was significantly increased in Cav1.2/II-III cells. Tolbutamide (200 μM) stimulated insulin secretion and Ca2+ transients in INS-1 cells, and Cav1.2/II-III cells were completely blocked by nicardipine (2 μM), but thapsigargin (1 μM) blocked tolbutamide-stimulated secretion and Ca2+ transients only in INS-1 cells. Tolbutamide-stimulated endoplasmic reticulum [Ca2+] decrease was reduced in Cav1.2/II-III cells compared with INS-1 cells. However, Ca2+ transients in both INS-1 cells and Cav1.2/II-III cells were significantly potentiated by 8-pCPT-2′-O-Me-cAMP (5 μM), FPL-64176 (0.5 μM), or replacement of extracellular Ca2+ with Sr2+. Glucose (10 mM) + glucagon-like peptide-1 (10 nM) stimulated discrete spikes in [Ca2+]i in the presence of verapamil at a higher frequency in INS-1 cells than in Cav1.2/II-II cells. Glucose (18 mM) stimulated more frequent action potentials in Cav1.2/II-III cells and primary rat β-cells expressing the Cav1.2/II-II loop than in control cells. Further, apamin (1 μM) increased glucose-stimulated action potential frequency in INS-1 cells, but not Cav1.2/II-III cells, suggesting that SK channels were not activated under these conditions in Cav1.2/II-III loop-expressing cells. We propose the II-III loop of Cav1.2 as a key molecular determinant that couples the channel to Ca2+-induced Ca2+ release and activation of SK channels in pancreatic β-cells. PMID:24506535

  18. ProEx™ C is a useful ancillary study for grading anal intraepithelial neoplasia alone and in combination with other biomarkers.

    PubMed

    Larson, Brent K; Mohanty, Sambit K; Wu, Julie M; Bose, Shikha; Walts, Ann E

    2016-03-01

    Anal intraepithelial neoplasia (AIN) is a precursor to invasive anal squamous cell carcinoma. Histologic evaluation is hampered by intra- and interobserver variability. Various biomarkers have been investigated to improve the accuracy and reproducibility of diagnosis and grading, but interpretation can be challenging. ProEx™ C is an antibody cocktail for proteins upregulated in cervical intraepithelial neoplasia. This study investigated ProEx™ C's role alone and with p16 and Ki-67 in the diagnosis and grading of AIN. Sixty-seven anal tissue samples (22 AIN I, 25 AIN II/III, and 20 non-dysplastic) were stained for ProEx™ C, Ki-67, and p16. Staining patterns were recorded and correlated with morphologic diagnoses. Considering AIN II/III vs I, full-thickness ProEx™ C staining was more frequent in AIN II/III (p = 0.0373), and showed the highest sensitivity of the biomarkers. In combination with Ki-67, sensitivity was lower, but specificity for AIN II/III rose to 83%. For differentiating non-dysplasia from AIN I, negative ProEx™ C staining correlated with non-dysplasia (p < 0.0001) and had the highest sensitivity (90%). In combination with Ki-67, sensitivity dropped to 80%, but specificity was high (96%). ProEx™ C is useful for diagnosing and grading AIN, performing as well or better than other markers at identifying AIN II/III and non-dysplastic epithelium. PMID:26590011

  19. Solar Occultation Retrieval Algorithm Development

    NASA Technical Reports Server (NTRS)

    Lumpe, Jerry D.

    2004-01-01

    This effort addresses the comparison and validation of currently operational solar occultation retrieval algorithms, and the development of generalized algorithms for future application to multiple platforms. initial development of generalized forward model algorithms capable of simulating transmission data from of the POAM II/III and SAGE II/III instruments. Work in the 2" quarter will focus on: completion of forward model algorithms, including accurate spectral characteristics for all instruments, and comparison of simulated transmission data with actual level 1 instrument data for specific occultation events.

  20. Platelet mitochondrial evaluation during cytochrome c and dichloroacetate treatments of MELAS.

    PubMed

    Nakano, Kazutoshi; Tarashima, Mikako; Tachikawa, Emiko; Noda, Naoko; Nakayama, Tomohiro; Sasaki, Kaori; Mizoguchi, Eriko; Matsuzaki, Mihoko; Osawa, Makiko

    2005-12-01

    We hypothesized that serial changes in platelet (PLT) mitochondrial enzyme (ME) activities might correspond to the effects of medications for mitochondrial encephalomyopathy and stroke-like episodes (MELAS). Cytochrome c and sodium dichloroacetate (DCA) were given to a 7-year-old girl with MELAS who had an A3243G mitochondrial DNA mutation. The effects were evaluated with whole PLT-ME assays, developed by our group, using a microplate-reader. During cytochrome c treatment, complex II+III (II+III), complex IV (IV) and citrate synthase (CS) activities showed gradual but statistically significant decrease. II+III activity dropped below normal. II+III/CS activity was initially below normal, followed by a transient improvement, then decreased again before the appearance of central nervous system symptoms. II+III, IV, II+III/CS and IV/CS activities reached their lowest levels in association with a stroke-like episode, then increased with DCA treatment. Our results suggest that progressive mitochondrial dysfunction may occur before the stroke-like episodes in MELAS and that DCA treatment may increase mitochondrial activities. Our whole PLT-ME assay system may be useful for serially evaluating mitochondrial functions in relation to clinical symptoms. PMID:16290150

  1. 76 FR 13851 - National Emission Standards for Hazardous Air Pollutants: Mercury Emissions From Mercury Cell...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-14

    ... 19, 2003, EPA promulgated the 2003 Mercury Cell NESHAP (40 CFR part 63, subpart IIIII, 68 FR 70904... proposed in 2008? On June 11, 2008 (73 FR 33257), EPA responded to NRDC's petition for reconsideration. In... supporting them, please see the preamble for the June 11, 2008 proposal (73 FR 33258). The 2008...

  2. Is Obesity Stigmatizing? Body Weight, Perceived Discrimination, and Psychological Well-Being in the United States

    ERIC Educational Resources Information Center

    Carr, Deborah; Friedman, Michael A.

    2005-01-01

    We investigate the frequency and psychological correlates of institutional and interpersonal discrimination reported by underweight, normal weight, overweight, obese I, and obese II/III Americans. Analyses use data from the Midlife Development in the United States study, a national survey of more than 3,000 adults ages 25 to 74 in 1995. Compared…

  3. Symmetrical osteoporosis (spongy hyperostosis) in a prehistoric skull from New Mexico.

    PubMed

    Jarcho, S; Simon, N; Jaffe, H L

    1965-01-01

    Fragments of an Anasazi skull (Pueblo II-III) from New Mexico are described. Lesions of symmetrical osteoporosis were found and their anatomical and roentgenographic characteristics are discussed. The term symmetrical osteoporosis has led to confusion with the unrelated disease osteoporosis and should be replaced by the designation spongy hyperostosis. PMID:19588580

  4. Mediterranean and Black Sea organisms and algae from mariculture as sources of antitumor drugs.

    PubMed

    Apryshko, Galina N; Ivanov, Valeriy N; Milchakova, Natalya A; Nekhoroshev, Mikhail V

    2005-06-01

    Mussels and tunicates cultivated in Mediterranean and Black Sea are the sources of antitumor drugs. Three compounds isolated from these animals (ET-743, aplidin and bryostatin-1) are on the II-III stages of clinical trials. Carotenoid fucoxantin that is present in edible brown algae possesses antitumor activity. The consumption of brown macrophyts decreases the risk of cancer development. PMID:15995624

  5. 77 FR 18793 - Spectrum Sharing Innovation Test-Bed Pilot Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-28

    ... Pilot Program, 73 FR 76,002 (Dec. 15, 2008). \\3\\ The final Phase I test plan and additional information... National Telecommunications and Information Administration Spectrum Sharing Innovation Test-Bed Pilot... conduct in Phase II/III of the Spectrum Sharing Innovation Test-Bed pilot program to assess...

  6. Greenhouse evaluation of commercial soybean cultivars adapted to the northern United States for resistance to charcoal rot

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Thirty (30) and sixty-seven (67) commercially available soybean (Glycine max (L.) Merr) cultivars from Wisconsin (Maturity group (MG) I-II) and Indiana (MG II-III), respectively, were evaluated for charcoal rot (CR; Macrophomina phaseolina (Tassi) Goid) resistance using a cut-stem greenhouse assay. ...

  7. Dendrites and Cognition: A Negative Pilot Study in the Rat.

    ERIC Educational Resources Information Center

    Anderson, Britt

    1995-01-01

    The dendritic structure of layer II-III pyramidal neurons of the parietal cortex in 41 Long-Evans rats was compared to behavioral assessments of attention to novelty, response flexibility, and reasoning. A significant correlation between dendritic arborization and behavioral performance was not demonstrated. (SLD)

  8. Is obesity stigmatizing? Body weight, perceived discrimination, and psychological well-being in the United States.

    PubMed

    Carr, Deborah; Friedman, Michael A

    2005-09-01

    We investigate the frequency and psychological correlates of institutional and interpersonal discrimination reported by underweight, normal weight, overweight, obese I, and obese II/III Americans. Analyses use data from the Midlife Development in the United States study, a national survey of more than 3,000 adults ages 25 to 74 in 1995. Compared to normal weight persons, obese II/III persons (body mass index of 35 or higher) are more likely to report institutional and day-to-day interpersonal discrimination. Among obese II/III persons, professional workers are more likely than nonprofessionals to report employment discrimination and interpersonal mistreatment. Obese II/III persons report lower levels of self-acceptance than normal weight persons, yet this relationship is fully mediated by the perception that one has been discriminated against due to body weight or physical appearance. Our findings offer further support for the pervasive stigma of obesity and the negative implications of stigmatized identities for life chances. PMID:16259147

  9. Vocational Education and Training in Finland.

    ERIC Educational Resources Information Center

    Bergstrom, Heidi; Katajisto, Jukka; Kimari, Matti; Kyro, Matti; Rahikainen, Elisa; Sulamaa, Kaarle; Walls, Leena; Ogren, Marjatta

    This monograph describes development of the Finnish system of vocational education and training and discusses its future outlook. Chapter I provides background information on political and administrative structures, population, and the economy and labor force. Chapters II-III describe the education system and its development and the vocational…

  10. HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

    PubMed

    Richman, Susan D; Southward, Katie; Chambers, Philip; Cross, Debra; Barrett, Jennifer; Hemmings, Gemma; Taylor, Morag; Wood, Henry; Hutchins, Gordon; Foster, Joseph M; Oumie, Assa; Spink, Karen G; Brown, Sarah R; Jones, Marc; Kerr, David; Handley, Kelly; Gray, Richard; Seymour, Matthew; Quirke, Philip

    2016-03-01

    HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome. Pathological material was obtained from 1914 patients in the QUASAR stage II-III trial and 1342 patients in stage IV trials (FOCUS and PICCOLO). Tissue microarrays were created for HER2 immunohistochemistry. HER2-amplification was assessed using FISH and copy number variation. KRAS/BRAF mutation status was assessed by pyrosequencing. Progression-free survival (PFS) and overall survival (OS) data were obtained for FOCUS/PICCOLO and recurrence and mortality for QUASAR; 29/1342 (2.2%) stage IV and 25/1914 (1.3%) stage II-III tumours showed HER2 protein overexpression. Of the HER2-overexpressing cases, 27/28 (96.4%) stage IV tumours and 20/24 (83.3%) stage II-III tumours demonstrated HER2 amplification by FISH; 41/47 (87.2%) also showed copy number gains. HER2-overexpression was associated with KRAS/BRAF wild-type (WT) status at all stages: in 5.2% WT versus 1.0% mutated tumours (p < 0.0001) in stage IV and 2.1% versus 0.2% in stage II-III tumours (p = 0.01), respectively. HER2 was not associated with OS or PFS. At stage II-III, there was no significant correlation between HER2 overexpression and 5FU/FA response. A higher proportion of HER2-overexpressing cases experienced recurrence, but the difference was not significant. HER2-amplification/overexpression is identifiable by immunohistochemistry, occurring infrequently in stage II-III CRC, rising in stage IV and further in KRAS/BRAF WT tumours. The value of HER2-targeted therapy in patients with HER2-amplified CRC must be tested in a clinical trial. © 2015 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society

  11. agr Dysfunction Affects Staphylococcal Cassette Chromosome mec Type-Dependent Clinical Outcomes in Methicillin-Resistant Staphylococcus aureus Bacteremia

    PubMed Central

    Kang, Chang Kyung; Cho, Jeong Eun; Choi, Yoon Jeong; Jung, Younghee; Kim, Nak-Hyun; Kim, Chung-Jong; Kim, Taek Soo; Song, Kyoung-Ho; Choe, Pyoeng Gyun; Park, Wan Beom; Bang, Ji-Hwan; Kim, Eu Suk; Park, Kyoung Un; Park, Sang Won; Kim, Nam-Joong; Oh, Myoung-don

    2015-01-01

    Staphylococcal cassette chromosome mec element (SCCmec) type-dependent clinical outcomes may vary due to geographical variation in the presence of virulence determinants. We compared the microbiological factors and mortality attributed to methicillin-resistant Staphylococcus aureus (MRSA) bacteremia between SCCmec types II/III and type IV. All episodes of MRSA bacteremia in a tertiary-care hospital (South Korea) over a 4.5-year period were reviewed. We studied the microbiological factors associated with all blood MRSA isolates, including spa type, agr type, agr dysfunction, and the genes for Panton-Valentine leukocidin (PVL) and phenol-soluble modulin (PSM)-mec, in addition to SCCmec type. Of 195 cases, 137 involved SCCmec types II/III, and 58 involved type IV. The mortality attributed to MRSA bacteremia was less frequent among the SCCmec type IV (5/58) than that among types II/III (39/137, P = 0.002). This difference remained significant when adjusted for clinical factors (adjusted odds ratio [aOR], 0.14; 95% confidence interval [CI], 0.04 to 0.49; P = 0.002). Of the microbiological factors tested, agr dysfunction was the only significant factor that showed different positivity between the SCCmec types, and it was independently associated with MRSA bacteremia-attributed mortality (aOR, 4.71; 95% CI, 1.72 to 12.92; P = 0.003). SCCmec type IV is associated with lower MRSA bacteremia-attributed mortality than are types II/III, which might be explained by the high rate of agr dysfunction in SCCmec types II/III in South Korea. PMID:25779574

  12. Proton Beam Therapy of Stage II and III Non-Small-Cell Lung Cancer

    SciTech Connect

    Nakayama, Hidetsugu; Satoh, Hiroaki; Sugahara, Shinji; Kurishima, Koichi; Tsuboi, Koji; Sakurai, Hideyuki; Ishikawa, Shigemi; Tokuuye, Koichi

    2011-11-15

    Purpose: The present retrospective study assessed the role of proton beam therapy (PBT) in the treatment of patients with Stage II or III non-small-cell lung cancer who were inoperable or ineligible for chemotherapy because of co-existing disease or refusal. Patients and Methods: Between November 2001 and July 2008, PBT was given to 35 patients (5 patients with Stage II, 12 with Stage IIIA, and 18 with Stage IIIB) whose median age was 70.3 years (range, 47.4-85.4). The median proton dose given was 78.3 Gy (range, 67.1-91.3) (relative biologic effectiveness). Results: Local progression-free survival for Stage II-III patients was 93.3% at 1 year and 65.9% at 2 years during a median observation period of 16.9 months. Four patients (11.4%) developed local recurrence, 13 (37.1%) developed regional recurrence, and 7 (20.0%) developed distant metastases. The progression-free survival rate for Stage II-III patients was 59.6% at 1 year and 29.2% at 2 years. The overall survival rate of Stage II-III patients was 81.8% at 1 year and 58.9% at 2 years. Grade 3 or greater toxicity was not observed. A total of 15 patients (42.9%) developed Grade 1 and 6 (17.1%) Grade 2 toxicity. Conclusion: PBT for Stage II-III non-small-cell lung cancer without chemotherapy resulted in good local control and low toxicity. PBT has a definite role in the treatment of patients with Stage II-III non-small-cell lung cancer who are unsuitable for surgery or chemotherapy.

  13. Ascending aortic Doppler velocity and the prediction of exercise capacity in post-infarction left ventricular dysfunction.

    PubMed

    Coats, A J; Adamopoulos, S; Isea, J E; Conway, J; Murphy, C; Sleight, P

    1992-03-01

    A system to improve analysis of the aortic pulsed Doppler velocity signal has been developed and used to study cardiac performance during a 4 min, 25 W incremental stage supine bicycle exercise to exhaustion. Twenty-two male subjects with stable chronic ischaemic heart disease were studied (15 with NYHA class II/III heart failure, and seven age-matched class I subjects). None had evidence of reversible ischaemia. Peak velocity (PV) from the intensity weighted mean velocity profile, early acceleration (eA) and stroke distance (SD) were all significantly lower at rest in class II/III compared to class I. For the change from rest to 50 W, PV did not alter, eAC increased significantly (P less than 0.05) and to a similar extent in both groups (18.6% class II/III vs 16.4% class I) and SD was reduced from 7.8 to 5.9 in class II/III (P less than 0.01) but did not change in class I (12.4 vs 11.8, ns). There was also a greater increase in heart rate (HR) in class II/III subjects (P less than 0.05). The duration of exercise was correlated with resting PV (r = 0.48, P less than 0.025) but was correlated best with the change in blood momentum (PV x Stroke volume x HR) between rest and peak exercise (r = 0.80, P less than 0.001). Thus Doppler velocimetry can give quantitative information on the response to exercise which discriminates between grades of ventricular dysfunction and is predictive of exercise capacity. PMID:1597222

  14. Post-mastectomy breast reconstruction and its subsequent complications: a comparison between obese and non-obese women with breast cancer.

    PubMed

    Huo, Jinhai; Smith, Benjamin D; Giordano, Sharon H; Reece, Gregory P; Shih, Ya-Chen Tina

    2016-06-01

    To compare the utilization pattern of breast reconstruction between obese and non-obese patients and assess the association between obesity and postoperative complications as well as healthcare costs. Using MarketScan databases, we identified 2558 breast cancer patients who underwent mastectomy between 2009 and 2012. Temporal trends in breast reconstruction were assessed using the Cochran-Armitage test. Logistic regression models were performed to determine the association between obesity and the occurrence of postoperative complications. Healthcare costs were compared using a generalized linear model. Among 2558 patients treated with mastectomy, the breast reconstruction rate of non-obese patients (76.2 %) was significantly higher than patients in obese class I and class II&III (63.3 and 60.2 %, respectively; P < 0.001). Compared with non-obese patients, obese patients had significantly higher rates of infection (OR 1.53, for obese class I, and OR 1.60, for obese class II&III, both P < 0.01), wound (OR 1.51, P = 0.01 for obese class I, and OR 1.98, P < 0.001 for obese class II&III), and perfusion complications (OR 1.73, P = 0.01 for obese class I, and OR 2.21, P < 0.01 for obese class II&III). The mean postoperative complication cost for non-obese patients ($4684) was significantly lower than those for obese class I patients ($6250) and obese class II&III patients ($7868; P < 0.001). Our analysis demonstrated a significant gap in breast reconstruction between obese and non-obese patients, and our finding underscores the need for careful preoperative assessment of obese patients and call for additional research to minimize the risk of complications. PMID:27178333

  15. A goitrogenic agent from millet (Pennisetum typhoides) in Darfur Province, Western Sudan.

    PubMed

    Osman, A K; Basu, T K; Dickerson, J W

    1983-01-01

    Serum samples from girls from an elementary school in Western Sudan with grades O, I and II/III goitre were examined for their thiocyanate, cysteine, thyroxine, TSH and T3 concentrations. The concentrations of thiocyanate in all girls was higher than that reported in the literature for Nigerians, but the concentrations of thiocyanate were nevertheless significantly elevated, and those of thyroxine significantly lowered in girls with grades I and II/III goitre as compared with grade O. There were no significant differences between any of the groups in the concentrations of cysteine or TSH and T3. The predominant staple food eaten in this area of Sudan is millet and evidence is produced that this contains a goitrogenic thionamide which could be a factor in causing the endemic goitre. PMID:6830139

  16. Spaceflight induces changes in the synaptic circuitry of the postnatal developing neocortex

    NASA Technical Reports Server (NTRS)

    DeFelipe, J.; Arellano, J. I.; Merchan-Perez, A.; Gonzalez-Albo, M. C.; Walton, K.; Llinas, R.

    2002-01-01

    The establishment of the adult pattern of neocortical circuitry depends on various intrinsic and extrinsic factors, whose modification during development can lead to alterations in cortical organization and function. We report the effect of 16 days of spaceflight [Neurolab mission; from postnatal day 14 (P14) to P30] on the neocortical representation of the hindlimb synaptic circuitry in rats. As a result, we show, for the first time, that development in microgravity leads to changes in the number and morphology of cortical synapses in a laminar-specific manner. In the layers II/III and Va, the synaptic cross-sectional lengths were significantly larger in flight animals than in ground control animals. Flight animals also showed significantly lower synaptic densities in layers II/III, IV and Va. The greatest difference was found in layer II/III, where there was a difference of 344 million synapses per mm(3) (15.6% decrease). Furthermore, after a 4 month period of re-adaptation to terrestrial gravity, some changes disappeared (i.e. the alterations were transient), while conversely, some new differences also appeared. For example, significant differences in synaptic density in layers II/III and Va after re-adaptation were no longer observed, whereas in layer IV the density of synapses increased notably in flight animals (a difference of 185 million synapses per mm(3) or 13.4%). In addition, all the changes observed only affected asymmetrical synapses, which are known to be excitatory. These results indicates that terrestrial gravity is a necessary environmental parameter for normal cortical synaptogenesis. These findings are fundamental in planning future long-term spaceflights.

  17. Substrate-controlled Rh(II)-catalyzed single-electron-transfer (SET): divergent synthesis of fused indoles.

    PubMed

    Chen, Kai; Zhu, Zi-Zhong; Liu, Jia-Xin; Tang, Xiang-Ying; Wei, Yin; Shi, Min

    2016-01-01

    Rh(II)-catalyzed diversified ring expansions controlled by single-electron-transfer (SET) have been disclosed in this communication, producing a series of indole-fused azetidines and 1H-carbazoles or related derivatives in moderate to good yields via Rh2(III,II) nitrene radical intermediates. The direction of ring expansion branches according to different ring sizes of methylenecycloalkanes. PMID:26548476

  18. Fluorescence Resonance Energy Transfer-based Structural Analysis of the Dihydropyridine Receptor α1S Subunit Reveals Conformational Differences Induced by Binding of the β1a Subunit.

    PubMed

    Mahalingam, Mohana; Perez, Claudio F; Fessenden, James D

    2016-06-24

    The skeletal muscle dihydropyridine receptor α1S subunit plays a key role in skeletal muscle excitation-contraction coupling by sensing membrane voltage changes and then triggering intracellular calcium release. The cytoplasmic loops connecting four homologous α1S structural domains have diverse functions, but their structural arrangement is poorly understood. Here, we used a novel FRET-based method to characterize the relative proximity of these intracellular loops in α1S subunits expressed in intact cells. In dysgenic myotubes, energy transfer was observed from an N-terminal-fused YFP to a FRET acceptor, ReAsH (resorufin arsenical hairpin binder), targeted to each α1S intracellular loop, with the highest FRET efficiencies measured to the α1S II-III loop and C-terminal tail. However, in HEK-293T cells, FRET efficiencies from the α1S N terminus to the II-III and III-IV loops and the C-terminal tail were significantly lower, thus suggesting that these loop structures are influenced by the cellular microenvironment. The addition of the β1a dihydropyridine receptor subunit enhanced FRET to the II-III loop, thus indicating that β1a binding directly affects II-III loop conformation. This specific structural change required the C-terminal 36 amino acids of β1a, which are essential to support EC coupling. Direct FRET measurements between α1S and β1a confirmed that both wild type and truncated β1a bind similarly to α1S These results provide new insights into the role of muscle-specific proteins on the structural arrangement of α1S intracellular loops and point to a new conformational effect of the β1a subunit in supporting skeletal muscle excitation-contraction coupling. PMID:27129199

  19. Bd +60 73 = Igr J00370+6122

    NASA Astrophysics Data System (ADS)

    Negueruela, Ignacio; Reig, Pablo

    2004-05-01

    A classification spectrum of BD +60 73, reported to be the optical counterpart to IGR J00370+6122 (ATel #281), was taken on the night of 2003 July 7th with the 2.5-m Issac Newton telescope at La Palma. The derived spectral type is BN0.5II-III, where the composite luminosity class indicates an intermediate luminosity. The Nitrogen enhancement is moderately high, with numerous NII lines being rather stronger than corresponds to the spectral type.

  20. Inhibition of TRPV1 channels enables long-term potentiation in the entorhinal cortex.

    PubMed

    Banke, Tue G

    2016-04-01

    The transient receptor potential vanilloid 1 (TRPV1) channel is a non-selective cation channel that is mainly found in nociceptive neurons of the peripheral nervous system; however, these channels have also been located within the CNS, including the entorhinal cortex. Whole-cell patch-clamp recordings of principal entorhinal cortex (EC) layers II/III neurons revealed that evoked inhibitory postsynaptic currents were depressed by application of the TRPV1 agonist capsaicin (CAP), accompanied by a change in the pair-pulse ratio (PPR). In addition, recordings of miniature inhibitory postsynaptic currents (mIPSCs) revealed that inter-event intervals but not amplitude were decreased in wild-type (WT) after application of CAP. This suggests that TRPV1 channels are functional in the entorhinal cortex and are located on inhibitory neurons with their axonal arborization within layers II/III. In order to study TRPV1 channels and their involvement in long-term potentiation (LTP) induction in a more intact circuit, extracellular field potential recordings were performed in EC layers II/III. It was found that activated TRPV1 channels preclude induction of long-term potentiation. In sharp contrast, clear LTP was observed when antagonizing TRPV1 channels or recording from TRPV1 knock-out mice. Thus, these results suggests that signaling through activating inhibitory presynaptic TRPV1 channels represents a novel mechanism by which a shift in feed-forward inhibition of layers II/III cortical principal neurons prompt changes in synaptic strength and thereby contribute to a change of information storage within the brain. PMID:26729265

  1. Statewide land cover derived from multiseasonal Landsat TM data: A retrospective of the WISCLAND project

    USGS Publications Warehouse

    Reese, H.M.; Lillesand, T.M.; Nagel, D.E.; Stewart, J.S.; Goldmann, R.A.; Simmons, T.E.; Chipman, J.W.; Tessar, P.A.

    2002-01-01

    Landsat Thematic Mapper (TM) data were the basis in production of a statewide land cover data set for Wisconsin, undertaken in partnership with U.S. Geological Survey's (USGS) Gap Analysis Program (GAP). The data set contained seven classes comparable to Anderson Level I and 24 classes comparable to Anderson Level II/III. Twelve scenes of dual-date TM data were processed with methods that included principal components analysis, stratification into spectrally consistent units, separate classification of upland, wetland, and urban areas, and a hybrid supervised/unsupervised classification called "guided clustering." The final data had overall accuracies of 94% for Anderson Level I upland classes, 77% for Level II/III upland classes, and 84% for Level II/III wetland classes. Classification accuracies for deciduous and coniferous forest were 95% and 93%, respectively, and forest species' overall accuracies ranged from 70% to 84%. Limited availability of acceptable imagery necessitated use of an early May date in a majority of scene pairs, perhaps contributing to lower accuracy for upland deciduous forest species. The mixed deciduous/coniferous forest class had the lowest accuracy, most likely due to distinctly classifying a purely mixed class. Mixed forest signatures containing oak were often confused with pure oak. Guided clustering was seen as an efficient classification method, especially at the tree species level, although its success relied in part on image dates, accurate ground troth, and some analyst intervention. ?? 2002 Elsevier Science Inc. All rights reserved.

  2. Rotigotine in Combination with the MAO-B Inhibitor Selegiline in Early Parkinson’s Disease: A Post Hoc Analysis

    PubMed Central

    Giladi, Nir; Asgharnejad, Mahnaz; Bauer, Lars; Grieger, Frank; Boroojerdi, Babak

    2016-01-01

    Background: Monoamine oxidase B (MAO-B) inhibitors and dopamine receptor agonists are common first-line treatment options in early Parkinson’s disease (PD). Objective: To evaluate the efficacy and safety of rotigotine transdermal patch as an add-on therapy to an MAO-B inhibitor in patients with early-PD. Methods: In two Phase III, randomized, double-blind, placebo-controlled studies in early-PD (SP512, SP513), patients were randomized to rotigotine (titrated to optimal dose ≤8 mg/24 h) or placebo, and maintained for 24 (SP512) or 33 (SP513) weeks. Post hoc analyses were performed on pooled data for patients receiving an MAO-B inhibitor (selegiline) at a stable dose at randomization and throughout the studies, with groups defined as “Selegiline+Rotigotine” and “Selegiline+Placebo”. Outcome measures included change from baseline in Unified Parkinson’s Disease Rating Scale (UPDRS) II (activities of daily living), III (motor), UPDRS II+III and responders (patients achieving ≥20%, ≥25% or ≥30% decrease in UPDRS II+III). As post hoc analyses, p-values are exploratory. Results: 130 patients were evaluable for efficacy analyses (“Selegiline+Rotigotine”: 84, “Selegiline+Placebo”: 46). Combined treatment with rotigotine and selegiline improved UPDRS III and UPDRS II+III scores versus selegiline alone (LS-mean [95% CI] treatment difference for UPDRS III: –4.89 [–7.87 to –1.91], p = 0.0015; for UPDRS II+III: –5.76 [–9.71 to –1.82], p = 0.0045). Higher proportion of patients in the “Selegiline+Rotigotine” group were classified as ≥20%, ≥25% or ≥30% responders (all p < 0.001). Combined treatment appeared more effective in patients aged ≤65 years versus > 65 years (although patient numbers in the subgroups were low). Adverse event profile was consistent with the known safety profile of rotigotine. Conclusions: In these post hoc analyses, adjunctive treatment with rotigotine in patients already receiving an

  3. Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology.

    PubMed

    Di Jeso, Bruno; Arvan, Peter

    2016-02-01

    Thyroglobulin (Tg) is a vertebrate secretory protein synthesized in the thyrocyte endoplasmic reticulum (ER), where it acquires N-linked glycosylation and conformational maturation (including formation of many disulfide bonds), leading to homodimerization. Its primary functions include iodide storage and thyroid hormonogenesis. Tg consists largely of repeating domains, and many tyrosyl residues in these domains become iodinated to form monoiodo- and diiodotyrosine, whereas only a small portion of Tg structure is dedicated to hormone formation. Interestingly, evolutionary ancestors, dependent upon thyroid hormone for development, synthesize thyroid hormones without the complete Tg protein architecture. Nevertheless, in all vertebrates, Tg follows a strict pattern of region I, II-III, and the cholinesterase-like (ChEL) domain. In vertebrates, Tg first undergoes intracellular transport through the secretory pathway, which requires the assistance of thyrocyte ER chaperones and oxidoreductases, as well as coordination of distinct regions of Tg, to achieve a native conformation. Curiously, regions II-III and ChEL behave as fully independent folding units that could function as successful secretory proteins by themselves. However, the large Tg region I (bearing the primary T4-forming site) is incompetent by itself for intracellular transport, requiring the downstream regions II-III and ChEL to complete its folding. A combination of nonsense mutations, frameshift mutations, splice site mutations, and missense mutations in Tg occurs spontaneously to cause congenital hypothyroidism and thyroidal ER stress. These Tg mutants are unable to achieve a native conformation within the ER, interfering with the efficiency of Tg maturation and export to the thyroid follicle lumen for iodide storage and hormonogenesis. PMID:26595189

  4. Origin of natural gases in the Paleozoic-Mesozoic basement of the Polish Carpathian Foredeep

    NASA Astrophysics Data System (ADS)

    Kotarba, Maciej

    2012-08-01

    Hydrocarbon gases from Upper Devonian and Lower Carboniferous reservoirs in the Paleozoic basement of the Polish Carpathian Foredeep were generated mainly during low-temperature thermogenic processes ("oil window"). They contain only insignificant amounts of microbial methane and ethane. These gaseous hydrocarbons were generated from Lower Carboniferous and/or Middle Jurassic mixed Type III/II kerogen and from Ordovician-Silurian Type II kerogen, respectively. Methane, ethane and carbon dioxide of natural gas from the Middle Devonian reservoir contain a significant microbial component whereas their small thermogenic component is most probably genetically related to Ordovician-Silurian Type II kerogen. The gaseous hydrocarbons from the Upper Jurassic and the Upper Cretaceous reservoirs of the Mesozoic basement were generated both by microbial carbon dioxide reduction and thermogenic processes. The presence of microbial methane generated by carbon dioxide reduction suggests that in some deposits the traps had already been formed and sealed during the migration of microbial methane, presumably in the immature source rock environment. The traps were successively supplied with thermogenic methane and higher hydrocarbons generated at successively higher maturation stages of kerogen. The higher hydrocarbons of the majority of deposits were generated from mixed Type III/II kerogen deposited in the Middle Jurassic, Lower Carboniferous and/or Devonian strata. Type II or mixed Type II/III kerogen could be the source for hydrocarbons in both the Tarnów and Brzezówka deposits. In the Cenomanian sandstone reservoir of the Brzezowiec deposit and one Upper Jurassic carbonate block of the Lubaczów deposit microbial methane prevails. It migrated from the autochthonous Miocene strata.

  5. LAYER I NEOCORTICAL ECTOPIA: CELLULAR ORGANIZATION AND LOCAL CORTICAL CIRCUITRY

    PubMed Central

    Gabel, Lisa Ann

    2011-01-01

    Focal cortical dysplasia (FCD) are associated with neurological disorders and cognitive impairments in humans. Molecular layer ectopia, clusters of misplaced cells in layer I of the neocortex, have been identified in patients with developmental dyslexia and psychomotor retardation. Mouse models of this developmental disorder display behavioral impairments and increased seizure susceptibility. Although there is a correlation between cortical malformations and neurological dysfunction, little is known about the morphological and physiological properties of cells within cortical malformations. In the present study we used electrophysiological and immunocytochemical analyses to examine the distribution of neuronal and non-neuronal cell types within and surrounding layer I neocortical ectopia in NXSMD/EiJ mice. We show that cells within ectopia have membrane properties of both pyramidal and a variety of nonpyramidal cell types, including fast-spiking cells. Immunocytochemical analysis for different interneuronal subtypes demonstrates that ectopia contain nonpyramidal cells immunoreactive for calbindin-D28K (CALB), parvalbumin (PARV), and calretinin (CR). Ectopia also contain astrocytes, positive for glial fibrillary acidic protein (GFAP) and oligodendrocyte precursor cells positive for NG2 proteoglycan (NG2). Lastly, we provide electrophysiological and morphological evidence to demonstrate that cells within ectopia receive input from cells within layers I, upper and deeper II/III, and V and provide outputs to cells within deep layer II/III and layer V, but not layers I and upper II/III. These results indicate that ectopia contain cells of different lineages with diverse morphological and physiological properties, and appear to cause disruptions in local cortical circuitry. PMID:21256119

  6. Immunological monitoring of anticancer vaccines in clinical trials

    PubMed Central

    Ogi, Chizuru; Aruga, Atsushi

    2013-01-01

    Therapeutic anticancer vaccines operate by eliciting or enhancing an immune response that specifically targets tumor-associated antigens. Although intense efforts have been made for developing clinically useful anticancer vaccines, only a few Phase III clinical trials testing this immunotherapeutic strategy have achieved their primary endpoint. Here, we report the results of a retrospective research aimed at clarifying the design of previously completed Phase II/III clinical trials testing therapeutic anticancer vaccines and at assessing the value of immunological monitoring in this setting. We identified 17 anticancer vaccines that have been investigated in the context of a completed Phase II/III clinical trial. The immune response of patients receiving anticancer vaccination was assessed for only 8 of these products (in 15 distinct studies) in the attempt to identify a correlation with clinical outcome. Of these studies, 13 were supported by a statistical correlation study (Log-rank test), and no less than 12 identified a positive correlation between vaccine-elicited immune responses and disease outcome. Six trials also performed a Cox proportional hazards analysis, invariably demonstrating that vaccine-elicited immune responses have a positive prognostic value. However, despite these positive results in the course of early clinical development, most therapeutic vaccines tested so far failed to provide any clinical benefit to cancer patients in Phase II/III studies. Our research indicates that evaluating the immunological profile of patients at enrollment might constitute a key approach often neglected in these studies. Such an immunological monitoring should be based not only on peripheral blood samples but also on bioptic specimens, whenever possible. The evaluation of the immunological profile of cancer patients enrolled in early clinical trials will allow for the identification of individuals who have the highest chances to benefit from anticancer vaccination

  7. A Metabolic Study of Huntington’s Disease

    PubMed Central

    Kalliolia, Eirini; Ottolenghi, Chris; Hindmarsh, Peter; Hill, Nathan R.; Costelloe, Seán J.; Martin, Nicholas G.; Positano, Vincenzo; Watt, Hilary C.; Frost, Chris; Björkqvist, Maria; Warner, Thomas T.

    2016-01-01

    Background Huntington’s disease patients have a number of peripheral manifestations suggestive of metabolic and endocrine abnormalities. We, therefore, investigated a number of metabolic factors in a 24-hour study of Huntington’s disease gene carriers (premanifest and moderate stage II/III) and controls. Methods Control (n = 15), premanifest (n = 14) and stage II/III (n = 13) participants were studied with blood sampling over a 24-hour period. A battery of clinical tests including neurological rating and function scales were performed. Visceral and subcutaneous adipose distribution was measured using magnetic resonance imaging. We quantified fasting baseline concentrations of glucose, insulin, cholesterol, triglycerides, lipoprotein (a), fatty acids, amino acids, lactate and osteokines. Leptin and ghrelin were quantified in fasting samples and after a standardised meal. We assessed glucose, insulin, growth hormone and cortisol concentrations during a prolonged oral glucose tolerance test. Results We found no highly significant differences in carbohydrate, protein or lipid metabolism markers between healthy controls, premanifest and stage II/III Huntington’s disease subjects. For some markers (osteoprotegerin, tyrosine, lysine, phenylalanine and arginine) there is a suggestion (p values between 0.02 and 0.05) that levels are higher in patients with premanifest HD, but not moderate HD. However, given the large number of statistical tests performed interpretation of these findings must be cautious. Conclusions Contrary to previous studies that showed altered levels of metabolic markers in patients with Huntington’s disease, our study did not demonstrate convincing evidence of abnormalities in any of the markers examined. Our analyses were restricted to Huntington’s disease patients not taking neuroleptics, anti-depressants or other medication affecting metabolic pathways. Even with the modest sample sizes studied, the lack of highly significant results

  8. Multiple functional involvement of thymosin beta-4 in tooth germ development.

    PubMed

    Ookuma, Yukiko F; Kiyoshima, Tamotsu; Kobayashi, Ieyoshi; Nagata, Kengo; Wada, Hiroko; Fujiwara, Hiroaki; Yamaza, Haruyoshi; Nonaka, Kazuaki; Sakai, Hidetaka

    2013-02-01

    Thymosin beta-4 (Tβ4) is known to be ubiquitously involved in the actin monomer sequestering on the cytoskeleton. Our previous study showed specific temporal and special in situ expression pattern of Tβ4 mRNA in dental epithelial and mesenchymal cells in the developing tooth germ of the mouse lower first molar. In this study, we examined the functional implications of Tβ4 in the developmental course of the mouse lower first molar. An inhibition assay using Tβ4 antisense sulfur-substituted oligodeoxynucleotide (AS S-ODN) in cultured embryonic day 11.0 (E11.0) mandibles showed a significant growth inhibition of the tooth germ. However, no growth arrest of the cultured E15.0 tooth germ was observed by using Tβ4 AS S-ODN. The Tβ4 knockdown led to significantly decreased expression levels of type II/III runt-related transcription factor 2 (Runx2) and nucleolin (Ncl) in the cultured E11.0 mandibles. Since our previous studies proved that the inhibition of type II/III Runx2 and Ncl translations resulted in the developmental arrest of the tooth germ in the cultured E11.0 mandible, Tβ4 appears to play roles in tooth germ development via the regulation of the type II/III Runx2 and Ncl expressions. Tβ4 knockdown also resulted in decreased secretion of matrix metalloproteinase (Mmp)-2, a reduced cell motility activity and upregulation of E-cadherin in dental epithelial mDE6 cells. These results suggest that Tβ4 plays multiple functional roles in odontogenic epithelial cells in the early stages of tooth germ development by regulating the expression of odontogenesis-related genes. PMID:23052839

  9. Altered production of tumour necrosis factors alpha and beta and interferon gamma by HIV-infected individuals.

    PubMed Central

    Vyakarnam, A; Matear, P; Meager, A; Kelly, G; Stanley, B; Weller, I; Beverley, P

    1991-01-01

    In vitro studies shows that recombinant tumour necrosis factor (TNF) alpha and beta, and interferon-gamma (IFN-gamma) can enhance HIV replication, and peripheral blood mononuclear cells (PBMC) infected with HIV in vitro secrete high levels of the same cytokines. As T cells secrete all three mediators, the capacity of T cell activation signals to trigger cytokine production in PBMC from HIV-infected individuals was investigated as such patients may be immunocompromised. We demonstrate that asymptomatic seropositives in CDC group II/III as well as patients who have progressed to CDC group IV of the disease proliferate efficiently to anti-CD3 antibody, recombinant interleukin-2 (rIL-2), phytohaemagglutinin (PHA), PHA plus phorbol 12,13 dibutyrate (PMA) but secrete significantly (P less than 0.05) higher amounts of TNF-alpha, TNF-beta and IFN-gamma compared with controls in response to the same stimulants. We also show a difference between group II/III and group IV patients with the latter secreting more TNF-alpha and IFN-gamma. The kinetics of TNF-alpha and -beta, and IFN-gamma production was stimulus dependent with overall levels varying in time for each stimulus. Furthermore, the kinetics of the response to all three stimulants were altered in seropositives; CDC group II/III and group IV patients secreted higher levels of cytokines over several time points compared to controls. The altered production of these mediators by HIV-infected patients may contribute to disease progression and to the pathogenesis of AIDS. PMID:1901776

  10. EphA2 expression is a key driver of migration and invasion and a poor prognostic marker in colorectal cancer

    PubMed Central

    Blayney, Jaine K.; McArt, Darragh G.; Redmond, Keara L.; Weir, Jessica-Anne; Bradley, Conor A.; Sasazuki, Takehiko; Shirasawa, Senji; Wang, Tingting; Srivastava, Supriya; Ong, Chee Wee; Arthur, Ken; Salto-Tellez, Manuel; Wilson, Richard H.

    2015-01-01

    Purpose EphA2, a member of the Eph receptor tyrosine kinases family, is an important regulator of tumour initiation, neo-vascularization and metastasis in a wide range of epithelial and mesenchymal cancers, however its role in colorectal cancer (CRC) recurrence and progression is unclear. Experimental Design EphA2 expression was determined by immunohistochemistry in stage II/III colorectal tumours (N=338), and findings correlated with clinical outcome. The correlation between EphA2 expression and stem cell markers CD44 and Lgr5 was examined. The role of EphA2 in migration/invasion was assessed using a panel of KRAS wild-type (WT) and mutant (MT) parental and invasive CRC cell line models. Results Colorectal tumours displayed significantly higher expression levels of EphA2 compared with matched normal tissue, which positively correlated with high CD44 and Lgr5 expression levels. Moreover, high EphA2 mRNA and protein expression were found to be associated with poor overall survival in stage II/III CRC tissues, in both univariate and multivariate analyses. Pre-clinically, we found that EphA2 was highly expressed in KRASMT CRC cells and that EphA2 levels are regulated by the KRAS-driven MAPK and RalGDS-RalA pathways. Moreover, EphA2 levels were elevated in several invasive daughter cell lines and down-regulation of EphA2 using RNAi or recombinant EFNA1, suppressed migration and invasion of KRASMT CRC cells. Conclusions These data show that EpHA2 is a poor prognostic marker in stage II/III CRC, which may be due to its ability to promote cell migration and invasion, providing support for the further investigation of EphA2 as a novel prognostic biomarker and therapeutic target. PMID:26283684

  11. Differential columnar processing in local circuits of barrel and insular cortices.

    PubMed

    Sato, Hajime; Shimanuki, Yasushi; Saito, Mitsuru; Toyoda, Hiroki; Nokubi, Takashi; Maeda, Yoshinobu; Yamamoto, Takashi; Kang, Youngnam

    2008-03-19

    The columnar organization is most apparent in the whisker barrel cortex but seems less apparent in the gustatory insular cortex. We addressed here whether there are any differences between the two cortices in columnar information processing by comparing the spatiotemporal patterns of excitation spread in the two cortices using voltage-sensitive dye imaging. In contrast to the well known excitation spread in the horizontal direction in layer II/III induced in the barrel cortex by layer IV stimulation, the excitation caused in the insular cortex by stimulation of layer IV spread bidirectionally in the vertical direction into layers II/III and V/VI, displaying a columnar image pattern. Bicuculline or picrotoxin markedly extended the horizontal excitation spread in layer II/III in the barrel cortex, leading to a generation of excitation in the underlying layer V/VI, whereas those markedly increased the amplitude of optical responses throughout the whole column in the insular cortex, subsequently widening the columnar image pattern. Such synchronous activities as revealed by the horizontal and vertical excitation spreads were consistently induced in the barrel and insular cortices, respectively, even by stimulation of different layers with varying intensities. Thus, a unique functional column existed in the insular cortex, in which intracolumnar communication between the superficial and deep layers was prominent, and GABA(A) action is involved in the inhibition of the intracolumnar communication in contrast to its involvement in intercolumnar lateral inhibition in the barrel cortex. These results suggest that the columnar information processing may not be universal across the different cortical areas. PMID:18354011

  12. Comparison of core decompression and conservative treatment for avascular necrosis of femoral head at early stage: a meta-analysis

    PubMed Central

    Hong, Yu-Cai; Zhong, Hui-Ming; Lin, Tiao; Shi, Jian-Bin

    2015-01-01

    The purpose of the current meta-analysis was to compare the efficacy of core decompression (CD) and conservative treatment (CT) for saving femoral heads in patients with avascular necrosis of femoral head (ANFH). Four RCTs and two CCTs involving 323 hips with 24- to 48-months follow-up were included in this review. Our results suggested CD had a trend of favorable results in contrast to other CT (OR 3.28; 95% CI 0.77-14.02; P = 0.11) but saved much less hips compared to biophysical treatments [odds ratio (OR) 0.37; 95% CI 0.18-0.74; P = 0.005]. In the stratified survival rate analysis by ANFH stage, interestingly, CD group got a significantly higher successful rate of hip joint conservation than other CT group in both stage I and stage II-III (stage I: OR 4.43; 95% CI 1.34-14.65; P = 0.01; stage II-III: OR 6.75; 95% CI 2.18-20.90; P = 0.0009). In the biophysical stimulation subgroup, however, an even higher frequency of survived hips were observed compared to CD group at stage II-III (CD vs. biophysical stimulation: OR 0.34; 95% CI 0.17-0.67; P = 0.002). In conclusion, performing CD for ANFH is effective for preventing femoral collapse within a short-term follow-up, but an even higher successful rate were expected by biophysical stimulations. Nevertheless, the short-term follow-up, the small sample size of the current meta-analysis only provide limited quality of evidence, which required confirmation from further large-scale, well-designed RCT with longer follow-up. PMID:26131094

  13. Perioperative and postoperative outcomes of perforated diverticulitis Hinchey II and III: open Hartmann's procedure vs. laparoscopic lavage and drainage in the elderly.

    PubMed

    Gentile, Valentina; Ferrarese, Alessia; Marola, Silvia; Surace, Alessandra; Borello, Alessandro; Ferrara, Yuri; Enrico, Stefano; Martino, Valter; Nano, Mario; Solej, Mario

    2014-01-01

    Hartmann's procedure (HP) is the most performed technique for acute diverticulitis. Laparoscopic lavage and drainage (LLD) is an option evaluated as definitive treatment for diverticulitis Hinchey grade II-III. Aim of the study is to analyze and compare LLD vs HP outcomes. From January 1st 2009 and December 31st 2012 we prospectively enrolled 30 patients with diagnosis of acute diverticulitis Hinchey grade II-III. Fourteen patients underwent to LLD (LLD group, LLDG) and 16 patients to HP (Hartmann group, HG). We evaluated: demographic variables, comorbidities, admission clinical status, radiological imaging, intraoperative outcomes (operative time), postoperative outcomes (admission to ICU, timing of drainage removal, restore of bowel functions, timing of oral solid intake), mortality rate (perioperative and after 12 months) and morbidity rate (surgical, infectious, cardiovascular, renal and systemic complications). Exclusion criteria were: other diseases, colon cancer's suspect or diagnosis, conversion to HP. Patients' mean age was 64.8 years in HG and 62.6 in LLDG. M:F ratio was 6:10 in HG, 8:6 in LLDG. Data showed improved outcomes in LLDG for: total operative time (p < 0.0001), admission to ICU (p 0.0447), restoration of bowel functions (p 0.0035 for gases, p 0.0152 for feces), mobilization (p 0.0087) and length of hospital stay (p 0.0132). According to literature, LLD is related to operative risk, morbidity and mortality rate and length of stay lower than HP. LLD also gives the possibility to avoid stoma. Despite limits of our study, we consider LLD as a "safe and effective" treatment for Hinchey grade II-III acute diverticulitis. PMID:25172780

  14. Long-term follow up of patients with implantable cardioverter-defibrillators and mild, moderate, or severe impairment of left ventricular function.

    PubMed Central

    Trappe, H. J.; Wenzlaff, P.; Pfitzner, P.; Fieguth, H. G.

    1997-01-01

    OBJECTIVE: To determine whether patients with life threatening ventricular tachyarrhythmias, impaired left ventricular function, and severe heart failure will benefit from implantable cardioverter-defibrillator (ICD) treatment. DESIGN: 410 patients were followed up after ICD implant. Left ventricular function was assessed by the New York Heart Association (NYHA) functional class of heart failure: 50 patients (12%) were in NYHA I-II, 151 (37%) in NYHA II, 117 (29%) in NYHA II-III, and 92 (22%) in NYHA III. Epicardial ICD implantation was performed in 209 patients (51%) and 201 patients (49%) received non-thoracotomy ICDs. RESULTS: Perioperatively, 12 patients (3%) died, more often after epicardial ICD implant (11/209 patients, 5%) than after transvenous implant (1/201 patients, < 1%) (P < 0.05). During a mean (SD) follow up of 28 (24) months (range < 1 to 114 months), 90 patients (23%) died: nine (2%) died from sudden arrhythmia; five (1%) also died suddenly but probably not from arrhythmic causes; 55 (14%) died from cardiac causes (congestive heart failure, myocardial reinfarction); 21 (5%) died from non-cardiac causes. The three year, five year, and seven year survival was 92-96% for arrhythmic mortality in NYHA class I, II and III, compared to a three year survival of 94% and a five year and seven year survival of 84% for patients in NYHA class II-III. 338 patients (82%) received ICD shocks (21 (SD 43) shocks per patient); patients in NYHA class II (83%), class II-III (84%), and class III (90%) received ICD discharges more often than those in class I-II (64%) (P < 0.05). The mean (SD) time interval between ICD implant and the first ICD shock was shorter in NYHA class II (16 (17) months), class II-III (19 (27) months), and class III (16 (19) months) than in class 0-I (22 (24) months) (P < 0.05). CONCLUSIONS: Patients with mild, moderate, and severe left ventricular dysfunction benefit from ICD treatment and these patients survive for a considerable time after the

  15. [Results of surgical treatment of generalized emphysema of the lungs].

    PubMed

    Iaitskiĭ, N A; Varlamov, V V; Gorbunkov, S D; Akopov, A L; Chernyĭ, S M; Lukina, O V; Chermenskiĭ, A G; Gembitskaia, T E

    2014-01-01

    An analysis of examination and treatment results was made in 123 patients with generalized emphysema of the lungs and respiratory failure of II-III degree. The patients were divided into two groups according to the age: younger than 40 years old (group A - 9 patients),40 years old and older (group B - 114). A surgical reduction of lung volume was performed to correct the respiratory failure in 69 patients. The rate of postoperative complications consisted of 14.7% in group A and it was 42.2% in group B. PMID:25055526

  16. Intermittent preventive treatment for malaria in pregnancy in Africa: What's new, what's needed?

    PubMed Central

    Vallely, Andrew; Vallely, Lisa; Changalucha, John; Greenwood, Brian; Chandramohan, Daniel

    2007-01-01

    Falciparum malaria is an important cause of maternal, perinatal and neonatal morbidity in high transmission settings in Sub-Saharan Africa. Intermittent preventive treatment with sulphadoxine-pyrimethamine (SP-IPT) has proven efficacious in reducing the burden of pregnancy-associated malaria but increasing levels of parasite resistance mean that the benefits of national SP-IPT programmes may soon be seriously undermined in much of the region. Hence, there is an urgent need to develop alternative drug regimens for IPT in pregnancy. This paper reviews published safety and efficacy data on various antimalarials and proposes several candidate combination regimens for assessment in phase II/III clinical trials. PMID:17306014

  17. Transcatheter Embolization of a Renal Artery Aneurysm Using Ethylene Vinyl Alcohol Copolymer

    SciTech Connect

    Rautio, Riitta Haapanen, Arto

    2007-04-15

    Our aim was to treat a clinically silent renal artery aneurysm. The patient was a 76-year-old man with elevated prostate-specific antigen and prostata biopsies with a gradus II-III adenocarcinoma who was incidentally found to have an aneurysm in his right renal artery. We performed a successful transcatheter embolization of the aneurysm using ethylene vinyl alcohol copolymer (Onyx). To avoid migration of the liquid material into the parent artery, a balloon was inflated in the orifice of the neck of the aneurysm while the liquid was injected. Five-month follow-up computed tomography (CT) imaging confirmed total occlusion of the aneurysm.

  18. Raman spectra of solid benzene under high pressure

    NASA Technical Reports Server (NTRS)

    Thiery, M.-M.; Kobashi, K.; Spain, I. L.

    1985-01-01

    Raman spectra of solid benzene have been measured at room temperature up to about 140 kbar, using the diamond anvil cell. Effort has been focused upon the lattice vibration spectra at pressures above that of phase II. It is found that a change in slopes occurs in the frequency-pressure curves at about 40 kbar. Furthermore, a new band appears above 90 kbar. These features probably correspond respectively to the II-III phase transition, which has been reported previously, and a III-IV phase transition, reported here for the first time.

  19. CpG and TpA frequencies in the plant system.

    PubMed Central

    Boudraa, M; Perrin, P

    1987-01-01

    Higher plant nuclear sequences reveal avoidance of CpG and TpA doublets. Chloroplast sequences avoid the TpA doublet in all codon positions. The chloroplast genome is not methylated but codon positions II-III and untranslated regions avoid CpG. The mitochondrial genome, also unmethylated, avoids CpG in all codon positions. We therefore deduce that methylation is not sufficient to explain CpG avoidance in the higher plant systems. Other factors must be taken into account such as amino acid composition, codon choices and perhaps stability of the DNA helix. PMID:3497385

  20. Valvular dysplasia and congestive heart failure in a juvenile African penguin (Spheniscus demersus).

    PubMed

    McNaughton, Allyson; Frasca, Salvatore; Mishra, Neha; Tuttle, Allison D

    2014-12-01

    Abstract: An aquarium-housed, 6-mo-old African penguin (Spheniscus demersus) presented with acute respiratory distress. Auscultation revealed a grade II-III systolic murmur in the absence of adventitial sounds, and an enlarged heart without pulmonary edema was seen radiographically. Echocardiographic evaluation revealed atrioventricular (AV) valvular dysplasia and ventricular enlargement. The penguin was treated with enalapril, furosemide, and pimobendan but died within 3 wk of detection of the murmur. Congenital dysplasia of the right AV valve with right atrial and ventricular dilation and ventricular hypertrophy were diagnosed on postmortem examination. PMID:25632699

  1. Laminar-dependent dendritic spine alterations in the motor cortex of adult rats following callosal transection and forced forelimb use.

    PubMed

    Adkins, DeAnna L; Bury, Scott D; Jones, Theresa A

    2002-07-01

    Previously, the authors found that partial denervation of the motor cortex in adult animals can enhance this region's neuronal growth response to relevant behavioral change. Rats with partial corpus callosum transections that were forced to rely on one forelimb for 18 days had increased dendritic arborization of layer V pyramidal neurons in the opposite motor cortex compared to controls. This was not found as a result of denervation alone or of forced forelimb use alone. However, it seemed possible that each independent manipulation (i.e., forced forelimb use alone and callosal transections alone) resulted in neural structural alterations that were simply not revealed in measurements of dendritic branch number and/or not inclusive of layer V dendrites. This possibility was assessed in the current study with a reexamination of the Golgi-Cox impregnated tissue generated in the previous study. Tissue was quantified from rats that received either partial transections of the rostral two-thirds of the corpus callosum (CCX) or sham operations (Sham) followed either by 18 days of forced use of one forelimb (Use) or unrestricted use of both forelimbs (Cont). Measurements of apical and basilar dendrites from pyramidal neurons of layer II/III and layer V were performed to detect spine addition resulting from either increased spine density or the addition of dendritic material. As hypothesized, significant spine addition was found following forced forelimb use alone (Sham+Use) and callosal transections alone (CCX+Cont). However, forced use primarily increased spines on layer II/III pyramidal neurons, whereas callosal transections primarily increased dendritic spines on layer V pyramidal neurons in comparison to Sham+Cont. A much more robust increase in layer V dendritic spines was found in animals with the combination of forced forelimb use and denervation (CCX+Use). In contrast to the effects of forced use alone, however, CCX+Use rats failed to show major net increases in

  2. Record of a new species of the genus Viridopromontorius Luna de Carvalho (Strepsiptera: Corioxenidae) from India with a revised key to Corioxenidae.

    PubMed

    Roy, Sukhendu; Hazra, Niladri

    2016-01-01

    A new species of the genus Viridopromontorius Luna de Carvalho is described from West Bengal, India. The new species V. aequus differs from the other member of Viridopromontorius by having approximately equal size of antennomeres IV and V, maxillary palp nearly twice the length of base, vein R4 curved towards R2, very small distal process on tarsomeres II-III, tarsomere IV almost trapezoidal and acumen to some extent upwardly bent (in lateral view). A revised key of the family Corioxenidae is also provided. PMID:27615860

  3. Perinatal opiate treatment delays growth of cortical dendrites.

    PubMed

    Ricalde, A A; Hammer, R P

    1990-07-31

    Basilar dendritic arborizations of layer II-III pyramidal neurons in primary somatosensory cortex of 5-day-old male rats were reconstructed following perinatal morphine, morphine/naltrexone, or saline vehicle administration. Morphine treatment was observed to reduce total dendritic length. This effect was limited to higher order dendritic branches, with terminal dendrites manifesting the greatest reduction of length. The action of morphine was presumably mediated by opiate receptors, since concurrent naltrexone administration completely reversed morphine effects on dendritic length and branching. These results suggest that opiates act during late ontogenesis to affect dendritic growth in cerebral cortex. PMID:2172870

  4. Implementing the UCSD PASCAL system on the MODCOMP computer. [deep space network

    NASA Technical Reports Server (NTRS)

    Wolfe, T.

    1980-01-01

    The implementation of an interactive software development system (UCSD PASCAL) on the MODCOMP computer is discussed. The development of an interpreter for the MODCOMP II and the MODCOMP IV computers, written in MODCOMP II assembly language, is described. The complete Pascal programming system was run successfully on a MODCOMP II and MODCOMP IV under both the MAX II/III and MAX IV operating systems. The source code for an 8080 microcomputer version of the interpreter was used as the design for the MODCOMP interpreter. A mapping of the functions within the 8080 interpreter into MODCOMP II assembly language was the method used to code the interpreter.

  5. [The impact of the intravenous He-Ne laser therapy on the antioxidant system in patient with stable exertion angina and postinfarct cardiosclerosis].

    PubMed

    Boev, S S; Selivonenko, V G

    1997-01-01

    The authors' study show that intravenous He-Ne laser therapy (HNLT) in patients with stable angina of effort (functional class II-III) and postinfarction cardiosclerosis irrespective of ejection fraction increased plasma katalase and red cell vitamin A concentrations. HNLT aroused vitamin E concentration in red cells in anginal patients with intact ejection fraction whereas in those with reduced ejection fraction it elevated blood peroxidase, plasma vitamin A and E concentrations. For patients with postinfarction cardiosclerosis there were, respectively, higher levels of blood peroxidase, plasmic vitamin A, red cell vitamin E, plasmic SH-groups and blood peroxidase, plasmic vitamins A and E. PMID:9503808

  6. Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+ /calmodulin-dependent protein kinase II

    PubMed Central

    Yao, Junlan; Davies, Lucinda A.; Howard, Jason D.; Adney, Scott K.; Welsby, Philip J.; Howell, Nancy; Carey, Robert M.; Colbran, Roger J.; Barrett, Paula Q.

    2006-01-01

    Ang II receptor activation increases cytosolic Ca2+ levels to enhance the synthesis and secretion of aldosterone, a recently identified early pathogenic stimulus that adversely influences cardiovascular homeostasis. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a downstream effector of the Ang II–elicited signaling cascade that serves as a key intracellular Ca2+ sensor to feedback-regulate Ca2+ entry through voltage-gated Ca2+ channels. However, the molecular mechanism(s) by which CaMKII regulates these important physiological targets to increase Ca2+ entry remain unresolved. We show here that CaMKII forms a signaling complex with α1H T-type Ca2+ channels, directly interacting with the intracellular loop connecting domains II and III of the channel pore (II-III loop). Activation of the kinase mediated the phosphorylation of Ser1198 in the II-III loop and the positive feedback regulation of channel gating both in intact cells in situ and in cells of the native adrenal zona glomerulosa stimulated by Ang II in vivo. These data define the molecular basis for the in vivo modulation of native T-type Ca2+ channels by CaMKII and suggest that the disruption of this signaling complex in the zona glomerulosa may provide a new therapeutic approach to limit aldosterone production and cardiovascular disease progression. PMID:16917542

  7. Mitochondrial impairment by PPAR agonists and statins identified via immunocaptured OXPHOS complex activities and respiration.

    PubMed

    Nadanaciva, Sashi; Dykens, James A; Bernal, Autumn; Capaldi, Roderick A; Will, Yvonne

    2007-09-15

    Mitochondrial impairment is increasingly implicated in the etiology of toxicity caused by some thiazolidinediones, fibrates, and statins. We examined the effects of members of these drug classes on respiration of isolated rat liver mitochondria using a phosphorescent oxygen sensitive probe and on the activity of individual oxidative phosphorylation (OXPHOS) complexes using a recently developed immunocapture technique. Of the six thiazolidinediones examined, ciglitazone, troglitazone, and darglitazone potently disrupted mitochondrial respiration. In accord with these data, ciglitazone and troglitazone were also potent inhibitors of Complexes II+III, IV, and V, while darglitazone predominantly inhibited Complex IV. Of the six statins evaluated, lovastatin, simvastatin, and cerivastatin impaired mitochondrial respiration the most, with simvastatin and lovastatin impairing multiple OXPHOS Complexes. Within the class of fibrates, gemfibrozil more potently impaired respiration than fenofibrate, clofibrate, or ciprofibrate. Gemfibrozil only modestly inhibited Complex I, fenofibrate inhibited Complexes I, II+III, and V, and clofibrate inhibited Complex V. Our findings with the two complementary methods indicate that (1) some members of each class impair mitochondrial respiration, whereas others have little or no effect, and (2) the rank order of mitochondrial impairment accords with clinical adverse events observed with these drugs. Since the statins are frequently co-prescribed with the fibrates or thiazolidinediones, various combinations of these three drug classes were also analyzed for their mitochondrial effects. In several cases, the combination additively uncoupled or inhibited respiration, suggesting that some combinations are more likely to yield clinically relevant drug-induced mitochondrial side effects than others. PMID:17658574

  8. [The expression of IDH1 (R132H) is positively correlated with cell proliferation and angiogenesis in glioma samples].

    PubMed

    Shi, Jiankuan; Zhao, Yuanlin; Yuan, Yuan; Wang, Chao; Xie, Zhonglin; Gao, Xing; Xiao, Liming; Ye, Jing

    2016-03-01

    Objective To explore the correlations of the expression of mutant isocitrate dehydrogenase (IDH1) (R132H) protein with angiogenesis and cell proliferation in glioma. Methods We performed polymerase chain reaction-based IDH gene mutation screening in 385 glioma samples, and the subcellular localization and expression levels of IDH1 (R132H) was examined by immunohistochemistry (IHC). Ki-67 labeling index was introduced to determine the proliferation of glioma cells, and the microvessel density was measured through CD34 staining. Statistical analyses were performed to show the correlations of IDH1 mutation with cell proliferation and microvessel density. Results The mutant rates of IDH1 were about 50%-60% in grade II-III gliomas and secondary glioblastomas, which were significantly higher than those in pilocytic astrocytoma (grade I) and primary glioblastoma (grade IV). Moreover, the level of IDH1 (R132H) protein was positively correlated with Ki-67 labeling index and microvessel density. Conclusion IDH mutation was common in grade II-III glioma and secondary glioblastoma, and the mutant IDH1 (R132H) might play a critical role in the cell proliferation and angiogenesis of glioma. PMID:26927556

  9. Cooperative behavior during ferroelectric transitions in KNO3 powder

    NASA Astrophysics Data System (ADS)

    Westphal, M. J.

    1993-09-01

    Experimental evidence of cooperative behavior during the ferroelectric phase transitions in granular and powder KNO3 at atmospheric pressure is presented. Three different experimental studies were performed in which phase transitions were detected and characterized by heat flow calorimetry: (1) the distribution of SiC powder in granular KNO3 was varied; (2) the volume fraction of SiC in powdered KNO3 was varied; and (3) pure KNO3 powder was thermally cycled. All three studies provided evidence of cooperative behavior between the KNO3 particles during the III-II phase transition. The cooperative behavior reduced the temperature range of phase III stability from ˜97-124 °C to that characteristic of bulk material (˜110-124 °C). Separate KNO3 particles behaved as individual ferroelectric domains, with each particle making the phase transition independently near the expected Curie temperature. Particles of KNO3 in intimate physical contact tended to behave cooperatively as a single large ferroelectric domain leading to sharper phase transitions more characteristic of single crystals. The degree of cooperative behavior was dependent upon the extent to which the individual particles were in physical contact. The absence of the III-II phase transition in KNO3 powder that has been reported in the literature can be understood from the results obtained using SiC powder to separate KNO3 particles during heat flow calorimetry measurements.

  10. Effects of Mood Stabilizers on Brain Energy Metabolism in Mice Submitted to an Animal Model of Mania Induced by Paradoxical Sleep Deprivation.

    PubMed

    Streck, Emilio L; Scaini, Giselli; Jeremias, Gabriela C; Rezin, Gislaine T; Gonçalves, Cinara L; Ferreira, Gabriela K; Réus, Gislaine Z; Resende, Wilson R; Valvassori, Samira S; Kapczinski, Flávio; Andersen, Mônica L; Quevedo, João

    2015-06-01

    There is a body of evidence suggesting that mitochondrial dysfunction is involved in bipolar disorder (BD) pathogenesis. Studies suggest that abnormalities in circadian cycles are involved in the pathophysiology of affective disorders; paradoxical sleep deprivation (PSD) induces hyperlocomotion in mice. Thus, the present study aims to investigate the effects of lithium (Li) and valproate (VPA) in an animal model of mania induced by PSD for 96 h. PSD increased exploratory activity, and mood stabilizers prevented PSD-induced behavioral effects. PSD also induced a significant decrease in the activity of complex II-III in hippocampus and striatum; complex IV activity was decreased in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex. Additionally, VPA administration was able to prevent PSD-induced inhibition of complex II-III and IV activities in prefrontal cortex, cerebellum, hippocampus, striatum and cerebral cortex, whereas Li administration prevented PSD-induced inhibition only in prefrontal cortex and hippocampus. Regarding the enzymes of Krebs cycle, only citrate synthase activity was increased by PSD in prefrontal cortex. We also found a similar effect in creatine kinase, an important enzyme that acts in the buffering of ATP levels in brain; its activity was increased in prefrontal cortex, hippocampus and cerebral cortex. These results are consistent with the connection of mitochondrial dysfunction and hyperactivity in BD and suggest that the present model fulfills adequate face, construct and predictive validity as an animal model of mania. PMID:25894682

  11. The characterization of neuroenergetic effects of chronic L-tyrosine administration in young rats: evidence for striatal susceptibility.

    PubMed

    Ferreira, Gabriela K; Carvalho-Silva, Milena; Gomes, Lara M; Scaini, Giselli; Teixeira, Leticia J; Mota, Isabella T; Schuck, Patrícia F; Ferreira, Gustavo C; Streck, Emilio L

    2015-02-01

    Tyrosinemia type II is an inborn error of metabolism caused by a deficiency in hepatic cytosolic aminotransferase. Affected patients usually present a variable degree of mental retardation, which may be related to the level of plasma tyrosine. In the present study we evaluated effect of chronic administration of L-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase and complexes I, II, II-III and IV in cerebral cortex, hippocampus and striatum of rats in development. Chronic administration consisted of L-tyrosine (500 mg/kg) or saline injections 12 h apart for 24 days in Wistar rats (7 days old); rats were killed 12 h after last injection. Our results demonstrated that L-tyrosine inhibited the activity of citrate synthase in the hippocampus and striatum, malate dehydrogenase activity was increased in striatum and succinate dehydrogenase, complexes I and II-III activities were inhibited in striatum. However, complex IV activity was increased in hippocampus and inhibited in striatum. By these findings, we suggest that repeated administrations of L-tyrosine cause alterations in energy metabolism, which may be similar to the acute administration in brain of infant rats. Taking together the present findings and evidence from the literature, we hypothesize that energy metabolism impairment could be considered an important pathophysiological mechanism underlying the brain damage observed in patients with tyrosinemia type II. PMID:25252880

  12. Diffusion-Weighted Imaging in Meningioma: Prediction of Tumor Grade and Association with Histopathological Parameters12

    PubMed Central

    Surov, Alexey; Gottschling, Sebastian; Mawrin, Christian; Prell, Julian; Spielmann, Rolf Peter; Wienke, Andreas; Fiedler, Eckhard

    2015-01-01

    OBJECTIVES: To analyze diffusion-weighted imaging (DWI) findings of meningiomas and to compare them with tumor grade, cell count, and proliferation index and to test a possibility of use of apparent diffusion coefficient (ADC) to differentiate benign from atypical/malignant tumors. METHODS: Forty-nine meningiomas were analyzed. DWI was done using a multislice single-shot echo-planar imaging sequence. A polygonal region of interest was drawn on ADC maps around the margin of the lesion. In all lesions, minimal ADC values (ADCmin) and mean ADC values (ADCmean) were estimated. Normalized ADC (NADC) was calculated in every case as a ratio ADCmean meningioma/ADCmean white matter. All meningiomas were surgically resected and analyzed histopathologically. The tumor proliferation index was estimated on Ki-67 antigen–stained specimens. Cell density was calculated. Collected data were evaluated by means of descriptive statistics. Analyses of ADC/NADC values were performed by means of two-sided t tests. RESULTS: The mean ADCmean value was higher in grade I meningiomas in comparison to grade II/III tumors (0.96 vs 0.80 × 10− 3 mm2s− 1, P = .006). Grade II/III meningiomas showed lower NADC values in comparison to grade I tumors (1.05 vs 1.26, P = .015). There was no significant difference in ADCmin values between grade I and II/III tumors (0.69 vs 0.63 × 10− 3 mm2s− 1, P = .539). The estimated cell count varied from 486 to 2091 (mean value, 1158.20 ± 333.74; median value, 1108). There were no significant differences in cell count between grade I and grade II/III tumors (1163.93 vs 1123.86 cells, P = .77). The mean level of the proliferation index was 4.78 ± 5.08%, the range was 1% to 18%, and the median value was 2%. The proliferation index was statistically significant higher in grade II/III meningiomas in comparison to grade I tumors (15.43% vs 3.00%, P = .001). Ki-67 was negatively associated with ADCmean (r = − 0.61, P < .001) and NADC (r = − 0.60, P

  13. Effects of acute and chronic treatment elicited by lamotrigine on behavior, energy metabolism, neurotrophins and signaling cascades in rats.

    PubMed

    Abelaira, Helena M; Réus, Gislaine Z; Ribeiro, Karine F; Zappellini, Giovanni; Ferreira, Gabriela K; Gomes, Lara M; Carvalho-Silva, Milena; Luciano, Thais F; Marques, Scherolin O; Streck, Emilio L; Souza, Cláudio T; Quevedo, João

    2011-12-01

    The present study was aimed to investigate the behavioral and molecular effects of lamotrigine. To this aim, Wistar rats were treated with lamotrigine (10 and 20 mg/kg) or imipramine (30 mg/kg) acutely and chronically. The behavior was assessed using forced swimming test. Brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), Proteina Kinase B (PKB, AKT), glycogen synthase kinase 3 (GSK-3) and B-cell lymphoma 2 (Bcl-2) levels, citrate synthase, creatine kinase and mitochondrial chain (I, II, II-III and IV) activities were assessed in the brain. The results showed that both treatments reduced the immobility time. The BDNF were increased in the prefrontal after acute treatment with lamotrigine (20 mg/kg), and the BDNF and NGF were increased in the prefrontal after chronic treatment with lamotrigine in all doses. The AKT increased and Bcl-2 and GSK-3 decreased after both treatments in all brain areas. The citrate synthase and creatine kinase increased in the amygdala after acute treatment with imipramine. Chronic treatment with imipramine and lamotrigine (10 mg/kg) increased the creatine kinase in the hippocampus. The complex I was reduced and the complex II, II-III and IV were increased, but related with treatment and brain area. In conclusion, lamotrigine exerted antidepressant-like, which can be attributed to its effects on pathways related to depression, such as neurotrophins, metabolism energy and signaling cascade. PMID:22044672

  14. Accident progression event tree analysis for postulated severe accidents at N Reactor

    SciTech Connect

    Wyss, G.D.; Camp, A.L.; Miller, L.A.; Dingman, S.E.; Kunsman, D.M. ); Medford, G.T. )

    1990-06-01

    A Level II/III probabilistic risk assessment (PRA) has been performed for N Reactor, a Department of Energy (DOE) production reactor located on the Hanford reservation in Washington. The accident progression analysis documented in this report determines how core damage accidents identified in the Level I PRA progress from fuel damage to confinement response and potential releases the environment. The objectives of the study are to generate accident progression data for the Level II/III PRA source term model and to identify changes that could improve plant response under accident conditions. The scope of the analysis is comprehensive, excluding only sabotage and operator errors of commission. State-of-the-art methodology is employed based largely on the methods developed by Sandia for the US Nuclear Regulatory Commission in support of the NUREG-1150 study. The accident progression model allows complex interactions and dependencies between systems to be explicitly considered. Latin Hypecube sampling was used to assess the phenomenological and systemic uncertainties associated with the primary and confinement system responses to the core damage accident. The results of the analysis show that the N Reactor confinement concept provides significant radiological protection for most of the accident progression pathways studied.

  15. [High dosage therapy and autologous peripheral stem cell transplantation in breast carcinoma].

    PubMed

    Kier, P; Ruckser, R; Buxhofer, V; Habertheuer, K H; Zelenka, P; Tatzreiter, G; Hübl, G; Kittl, E; Hauser, A; Sebesta, C; Hinterberger, W

    2000-01-01

    42 breast cancer patients were treated by high-dose chemotherapy (HDC) and autologous peripheral stem-cell transplantation (ASTx) in the Donauspital between 1992 and 1999. 24 patients had stage II/III breast cancer with high risk for relapse. The other 18 patients underwent HDC and ASTx in chemosensitive stage IV. After previous conventional chemotherapy peripheral stem-cells were harvested by one cycle of mobilisation chemotherapy (epirubicin/taxol, FEC 120 or cyclophosphamide) followed by cytokine stimulation. 16 patients were treated by a tandem transplantation (conditioning protocol for 1st ASTx was melphalan 200 mg/m2 and for 2nd transplant it was CTC: cyclophosphamide 6 g/m2; thiotepa 500 mg/m2; carboplatin 800 mg/m2). The other 26 patients received one HDC with CTC as conditioning protocol. The HDC was well tolerated by all patients, there was no transplant-related mortality. The median survival and the progression-free survival (PFS) after HDC and ASTx in stage IV breast cancer patients were 28 and 11 months, respectively. The median survival and PFS were not yet reached in stage II/III patients after 55 months. The actuarial survival and PFS in that patient group were 70% after 55 months. Our data confirm the low risk and good efficacy of HDC and ASTx in breast cancer patients. Nevertheless randomised studies are necessary to evaluate the importance of HDC compared to intensified conventional protocols without ASTx. PMID:11261276

  16. Distribution of 28 kDa Calbindin-Immunopositive Neurons in the Cat Spinal Cord

    PubMed Central

    Merkulyeva, Natalia; Veshchitskii, Aleksandr; Makarov, Felix; Gerasimenko, Yury; Musienko, Pavel

    2016-01-01

    The distribution of vitamin D-dependent calcium-binding protein (28 kDa calbindin) was investigated in cat lumbar and sacral spinal cord segments (L1-S3). We observed specific multi-dimensional distributions over the spinal segments for small immunopositive cells in Rexed laminae II-III and medium-to-large cells of varying morphology in lamina I and laminae V-VIII. The small neurons in laminae II-III were clustered into the columns along the dorsal horn curvature. The medium-to-large cells were grouped into four assemblages that were located in (1) the most lateral region of lamina VII at the L1-L4 level; (2) the laminae IV-V boundary at the L5-L7 level; (3) the lamina VII dorsal border at the L5-L7 level; and (4) the lamina VIII at the L5-S3 level. The data obtained suggest that the morphological and physiological heterogeneity of calbindin immunolabeling cells formed morpho-functional clusters over the gray matter. A significant portion of the lumbosacral enlargement had immunopositive neurons within all Rexed laminae, suggesting an important functional role within and among the spinal networks that control hindlimb movements. PMID:26858610

  17. The Body Mass Index-Mortality Link across the Life Course: Two Selection Biases and Their Effects

    PubMed Central

    Zheng, Hui; Dirlam, Jonathan

    2016-01-01

    In this study, we investigated two selection biases that may affect the obesity-mortality link over the life course: mortality selection and healthy participant effects. If these selection mechanisms are stronger among obese adults than among non-obese adults, they may contribute to the weakening obesity-mortality link over the life course. We used data from the National Health and Nutrition Examination Survey 1988–2010 with linked mortality files from 1988–2011. We employed weighted Cox models to test and adjust for these two selection biases. We also used complementary log-log models, adjusted for a normal distribution of frailty, to test for mortality selection effects; accelerated failure-time models to mitigate the mortality selection effect; and ordinary least squares regression to test for healthy participant effects. The link between class II/III obesity and mortality weakens at older ages. We did not find evidence for significant mortality selection or healthy participant effects. Also, even if the healthy participant effects were stronger among obese adults, they are not strong enough to produce a weakening association between obesity and morbidity at higher ages at the time of the survey. Therefore, neither of these selection biases explains the diminishing effect of class II/III obesity on mortality over the life course. PMID:26841215

  18. Characterizing VIP Neurons in the Barrel Cortex of VIPcre/tdTomato Mice Reveals Layer-Specific Differences

    PubMed Central

    Prönneke, Alvar; Scheuer, Bianca; Wagener, Robin J.; Möck, Martin; Witte, Mirko; Staiger, Jochen F.

    2015-01-01

    Neocortical GABAergic interneurons have a profound impact on cortical circuitry and its information processing capacity. Distinct subgroups of inhibitory interneurons can be distinguished by molecular markers, such as parvalbumin, somatostatin, and vasoactive intestinal polypeptide (VIP). Among these, VIP-expressing interneurons sparked a substantial interest since these neurons seem to operate disinhibitory circuit motifs found in all major neocortical areas. Several of these recent studies used transgenic Vip-ires-cre mice to specifically target the population of VIP-expressing interneurons. This makes it necessary to elucidate in detail the sensitivity and specificity of Cre expression for VIP neurons in these animals. Thus, we quantitatively compared endogenous tdTomato with Vip fluorescence in situ hybridization and αVIP immunohistochemistry in the barrel cortex of VIPcre/tdTomato mice in a layer-specific manner. We show that VIPcre/tdTomato mice are highly sensitive and specific for the entire population of VIP-expressing neurons. In the barrel cortex, approximately 13% of all GABAergic neurons are VIP expressing. Most VIP neurons are found in layer II/III (∼60%), whereas approximately 40% are found in the other layers of the barrel cortex. Layer II/III VIP neurons are significantly different from VIP neurons in layers IV–VI in several morphological and membrane properties, which suggest layer-dependent differences in functionality. PMID:26420784

  19. Prenatal Stress Enhances Excitatory Synaptic Transmission and Impairs Long-Term Potentiation in the Frontal Cortex of Adult Offspring Rats

    PubMed Central

    Sowa, Joanna; Bobula, Bartosz; Glombik, Katarzyna; Slusarczyk, Joanna; Basta-Kaim, Agnieszka; Hess, Grzegorz

    2015-01-01

    The effects of prenatal stress procedure were investigated in 3 months old male rats. Prenatally stressed rats showed depressive-like behavior in the forced swim test, including increased immobility, decreased mobility and decreased climbing. In ex vivo frontal cortex slices originating from prenatally stressed animals, the amplitude of extracellular field potentials (FPs) recorded in cortical layer II/III was larger, and the mean amplitude ratio of pharmacologically-isolated NMDA to the AMPA/kainate component of the field potential—smaller than in control preparations. Prenatal stress also resulted in a reduced magnitude of long-term potentiation (LTP). These effects were accompanied by an increase in the mean frequency, but not the mean amplitude, of spontaneous excitatory postsynaptic currents (sEPSCs) in layer II/III pyramidal neurons. These data demonstrate that stress during pregnancy may lead not only to behavioral disturbances, but also impairs the glutamatergic transmission and long-term synaptic plasticity in the frontal cortex of the adult offspring. PMID:25749097

  20. Prognostic role of IDH mutations in gliomas: a meta-analysis of 55 observational studies

    PubMed Central

    Fu, Zhiquan; Feng, Fang; Qiao, Enqi; Li, Qinglin; Sun, Caixing; Ge, Minghua

    2015-01-01

    Background IDH (Isocitrate dehydrogenase) mutations occur frequently in gliomas, but their prognostic impact has not been fully assessed. We performed a meta-analysis of the association between IDH mutations and survival in gliomas. Methods Pubmed and EMBASE databases were searched for studies reporting IDH mutations (IHD1/2 and IDH1) and survival in gliomas. The primary outcome was overall survival (OS); the secondary outcome was progression-free survival (PFS). Hazard ratios (HR) with 95% confidence interval (CI) were determined using the Mantel-Haenszel random-effect modeling. Funnel plot and Egger's test were conducted to examine the risk of publication bias. Results Fifty-five studies (9487 patients) were included in the analysis. Fifty-four and twenty-seven studies investigated the association between IDH1/2 mutations and OS/PFS respectively in patients with glioma. The results showed that patients possessing an IDH1/2 mutation had significant advantages in OS (HR = 0.39, 95%CI: 0.34–0.45; P < 0.001) and PFS (HR = 0.42, 95% CI: 0.35–0.51; P < 0.001). Subgroup analysis showed a consistent result with pooled analysis, and patients with glioma of WHO grade III or II-III had better outcomes. Conclusions These findings provide further indication that patients with glioma harboring IDH mutations have improved OS and PFS, especially for patients with WHO grade III and grade II-III. PMID:26220714

  1. Histological asymmetries of primary motor cortex predict handedness in chimpanzees (Pan troglodytes).

    PubMed

    Sherwood, Chet C; Wahl, Elizabeth; Erwin, Joseph M; Hof, Patrick R; Hopkins, William D

    2007-08-01

    Like humans, chimpanzees display robust and consistent hand preferences during the performance of certain tasks. Although correlations have been demonstrated between gross anatomic measures of primary motor cortex asymmetry and handedness in captive chimpanzees, the relationship between histological architecture and behavioral lateralization has not yet been investigated. Therefore, we examined interhemispheric asymmetry of several different microstructural characteristics of the primary motor cortex in the region of hand representation from 18 chimpanzees tested on a coordinated bimanual task before death. At the population level our data showed leftward bias for higher layer II/III neuron density. Of note, however, there was no population-level asymmetry in the areal fraction of Nissl-stained cell bodies, a finding that differs from previous studies of this cortical region in humans. Nonetheless, we found that asymmetry in the density of layer II/III parvalbumin-immunoreactive interneurons was the best predictor of individual hand preference. These results suggest that histological asymmetries are related to handedness in chimpanzees, while overall patterns of asymmetry at the population level might differ from humans. PMID:17534947

  2. Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function.

    PubMed

    Albera, Carlo; Costabel, Ulrich; Fagan, Elizabeth A; Glassberg, Marilyn K; Gorina, Eduard; Lancaster, Lisa; Lederer, David J; Nathan, Steven D; Spirig, Dominique; Swigris, Jeff J

    2016-09-01

    This post hoc analysis examined the differences in idiopathic pulmonary fibrosis disease progression and the effects of pirfenidone in patients stratified by more preserved versus less preserved baseline lung function status using forced vital capacity (FVC) or GAP (gender, age and physiology) index stage.Efficacy outcomes, i.e. FVC, 6-min walking distance (6MWD) and dyspnoea (University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)), were analysed at 12 months in patients randomised to pirfenidone 2403 mg·day(-1) or placebo in the pooled phase 3 CAPACITY/ASCEND population (n=1247), with subgroups stratified by baseline FVC ≥80% versus <80% or GAP stage I versus II-III. Treatment-by-subgroup interaction was tested based on a rank ANCOVA model; factors in the model included study, region, treatment, subgroup and treatment-by-subgroup interaction term.Patients with both more preserved (FVC ≥80% or GAP stage I) and less preserved (FVC <80% or GAP stage II-III) lung function at baseline demonstrated clinically significant disease progression at 12 months in terms of categorical decline in FVC, 6MWD and UCSD SOBQ. The magnitude of pirfenidone treatment effect was comparable between subgroups, regardless of whether lung function was classified using FVC or GAP index stage.These findings support the initiation of treatment with pirfenidone, irrespective of stage of baseline lung function in this patient population. PMID:27471208

  3. Developmental Origin of Patchy Axonal Connectivity in the Neocortex: A Computational Model

    PubMed Central

    Bauer, Roman; Zubler, Frederic; Hauri, Andreas; Muir, Dylan R.; Douglas, Rodney J.

    2014-01-01

    Injections of neural tracers into many mammalian neocortical areas reveal a common patchy motif of clustered axonal projections. We studied in simulation a mathematical model for neuronal development in order to investigate how this patchy connectivity could arise in layer II/III of the neocortex. In our model, individual neurons of this layer expressed the activator–inhibitor components of a Gierer–Meinhardt reaction–diffusion system. The resultant steady-state reaction–diffusion pattern across the neuronal population was approximately hexagonal. Growth cones at the tips of extending axons used the various morphogens secreted by intrapatch neurons as guidance cues to direct their growth and invoke axonal arborization, so yielding a patchy distribution of arborization across the entire layer II/III. We found that adjustment of a single parameter yields the intriguing linear relationship between average patch diameter and interpatch spacing that has been observed experimentally over many cortical areas and species. We conclude that a simple Gierer–Meinhardt system expressed by the neurons of the developing neocortex is sufficient to explain the patterns of clustered connectivity observed experimentally. PMID:23131803

  4. Neocortical calretinin neurons in primates: increase in proportion and microcircuitry structure

    PubMed Central

    Džaja, Domagoj; Hladnik, Ana; Bičanić, Ivana; Baković, Marija; Petanjek, Zdravko

    2014-01-01

    In this article we first point at the expansion of associative cortical areas in primates, as well as at the intrinsic changes in the structure of the cortical column. There is a huge increase in proportion of glutamatergic cortical projecting neurons located in the upper cortical layers (II/III). Inside this group, a novel class of associative neurons becomes recognized for its growing necessity in both inter-areal and intra-areal columnar integration. Equally important to the changes in glutamatergic population, we found that literature data suggest a 50% increase in the proportion of neocortical GABAergic neurons between primates and rodents. This seems to be a result of increase in proportion of calretinin interneurons in layers II/III, population which in associative areas represents 15% of all neurons forming those layers. Evaluating data about functional properties of their connectivity we hypothesize that such an increase in proportion of calretinin interneurons might lead to supra-linear growth in memory capacity of the associative neocortical network. An open question is whether there are some new calretinin interneuron subtypes, which might substantially change micro-circuitry structure of the primate cerebral cortex. PMID:25309344

  5. Clinical and evolving features of women diagnosed with precancerous cervical lesions, screened and treated in the Amazon region of Brazil.

    PubMed

    Prado, Patricia Rezende do; Koifman, Rosalina Jorge; Silva, Ilce Ferreira da

    2014-09-01

    The objective of the study was to determine the dynamics of precancerous lesions in women of a cohort treated for cervical intraepithelial neoplasia (CIN) and followed up over the next two years. The conditional probability of failure was calculated using the Kaplan-Meier method, and the raw and adjusted hazard ratios (HR) were determined using Cox regression with a p-value entry of < 0.05. Of the 237 women who were treated, 51.5% were accompanied over 24 months, and treatment failed for 21.9% of those accompanied. Women who had five or more pregnancies (adjusted HR = 3.10, 95%CI: 1.28-7.51) or an initial histological diagnosis of CIN II/III demonstrated an independent risk of treatment failure (adjusted HR = 3.14, 95%CI: 1.20-8.19). Being in a stable relationship was a protective factor against treatment failure (adjusted HR = 0.47, 95%CI: 0.24-0.89). A history of more frequent pregnancies and a histological diagnosis of CIN II/III are directly correlated with risk of CIN treatment failure, whereas being in a stable relationship is inversely correlated with this risk. PMID:25317520

  6. High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer

    PubMed Central

    Zheng, Hong-Tu; Shi, De-Bing; Wang, Yu-Wei; Li, Xin-Xiang; Xu, Ye; Tripathi, Pratik; Gu, Wei-Lie; Cai, Guo-Xiang; Cai, San-Jun

    2014-01-01

    Objective: This study sought to investigate the role of the long noncoding RNA MALAT1 in the prognosis of stage II/III colorectal cancer (CRC) patients. Methods: The expression of MALAT1 was evaluated in cancer tissues from 146 stage II/III CRC patients undergoing radical resection and 23 paired normal colonic mucosa samples using quantitative real-time reverse transcriptase PCR. Differences in the expression of MALAT1 between 23 CRC and paired normal colonic mucosa samples were analysed with the Wilcoxon test. Relationships between the expression level of MALAT1, patient clinicopathological parameters and disease-free survival (DFS) and overall survival (OS) were analysed using the univariate Kaplan-Meier method and the multivariate COX regression model. Results: The MALAT1 levels in cancerous tissues were 2.26 times higher than those measured in noncancerous tissues, and this difference was statistically significant (P = 0.0004). Based on their expression level of MALAT1, the patients were divided into a high MALAT1 expression group (n = 73) and a low expression group (n = 73). Patients with tumours harbouring higher expression of MALAT1 showed a significantly worse prognosis with a hazard ratio (HR) of 2.863 (95% CI, 1.659 to 4.943; P < 0.001) for DFS and 3.968 (95% CI, 1.665 to 9.456; P = 0.002) for OS. Furthermore, patients with perineural invasion demonstrated significantly worse DFS (HR = 3.459, 95% CI 2.008 to 5.957; P < 0.001) and OS (HR = 3.750, 95% CI 1.743 to 8.069; P = 0.001) than those without perineural invasion. Multivariate analyses indicated that MALAT1 expression and perineural invasion were two independent prognostic risk factors for patients with CRC. Conclusion: The expression of MALAT1 is upregulated in CRC tissues, and a higher expression level of MALAT1 might serve as a negative prognostic marker in stage II/III CRC patients. PMID:25031737

  7. Primary healthcare worker knowledge related to prenatal and immediate newborn care: a cross sectional study in Masindi, Uganda

    PubMed Central

    2014-01-01

    Background Global neonatal mortality remains unacceptably high. Health workers who attend to prenatal and postnatal mothers need to be knowledgeable in preventive and curative care for pregnant women and their newborn babies. This study aimed to determine the level of knowledge related to prenatal and immediate newborn care among primary healthcare workers in Masindi, Uganda. Methods A cross-sectional study was conducted. Interviews comprised of 25 multiple-choice questions were administered to health workers who were deployed to offer prenatal and postnatal care in Masindi in November 2011. Questions were related to four domains of knowledge: prenatal care, immediate newborn care, management of neonatal infections and identifying and stabilizing Low-Birth Weight (LBW) babies. Corresponding composite variables were derived; level of knowledge among health workers dichotomized as ‘adequate’ or ‘inadequate’. The chi-square statistic test was used to examine associations with independent variables including level of training (nursing assistant, general nurse or midwife), level of care (hospital/health centre level IV or health centre level III/II) and years of service (five years or less, six years or more). Results 183 health workers were interviewed: general nurses (39.3%), midwives (21.9%) and nursing assistants (38.8%). Respectively, 53.6%, 46.5%, 7.1% and 56.3% were considered to have adequate knowledge in prenatal care, newborn care, management of neonatal infections and identifying/stabilizing LBW babies. Being a general nurse was significantly associated with having adequate knowledge in identifying and stabilizing LBW babies (p < 0.001) compared to being a nursing assistant. Level of care being hospital/health centre level IV was not significantly associated with having adequate knowledge in prenatal or newborn care with reference to health centres of level III/II. Conclusion Knowledge regarding prenatal and newborn care among primary healthcare

  8. Imaging of the stroke-related changes in the vascular system of the mouse brain with the use of extended focus optical coherence microscopy

    NASA Astrophysics Data System (ADS)

    Tamborski, Szymon; Lyu, Hong Chou; Bukowska, Danuta; Dolezyczek, Hubert; Wilczynski, Grzegorz; Szlag, Daniel; Lasser, Theo; Wojtkowski, Maciej; Szkulmowski, Maciej

    2016-03-01

    We used Optical Coherence Microscopy (OCM) to monitor structural and functional changes due to ischemic stroke in small animals brains in vivo. To obtain lateral resolution of 2.2 μm over the range of 600 μm we used extended focus configuration of OCM instrument involving Bessel beam. It provided access to detailed 3D information about the changes in brain vascular system up to the level of capillaries across I and II/III layers of neocortex. We used photothrombotic stroke model involving photoactive application of rose bengal to assure minimal invasiveness of the procedure and precise localization of the clot distribution center. We present the comparative analysis involving structural and angiographic maps of the stroke-affected brain enabling in-depth insight to the process of development of the disorder.

  9. [Child abuse in Tlaxcala: a case-control study].

    PubMed

    Herrada-Huidobro, A; Nazar-Beutelspacher, A; Cassaball-Núñez, M; Vega-Ramos, R; Nava-Cruz, C B

    1992-01-01

    A longitudinal, retrospective and descriptive study about child abuse was carried out in the Hospitals of the Tlaxcala Secretariat of Health, Mexico. The information was obtained from hospitalized children's charts between January first and November 30, 1991. The charts included were those belonging to zero to 14 year old children with injuries, poisoning, and II-III degrees of malnutrition. Four child-abuse criteria were established: physical, sexual, non organic malnutrition and mixed (physical and non organic malnutrition). Two control groups were defined. Different patterns were observed between accidental and non accidental injuries, malnutrition and poisoning among the case and the control groups. The study provides useful information for the integral diagnosis of child abuse in hospitalized children. PMID:1475698

  10. Emerging applications of stereotactic body radiotherapy.

    PubMed

    Lo, Simon S; Loblaw, Andrew; Chang, Eric L; Mayr, Nina A; Teh, Bin S; Huang, Zhibin; Yao, Min; Ellis, Rodney J; Biswas, Tithi; Sohn, Jason W; Machtay, Mitchell; Sahgal, Arjun

    2014-05-01

    Stereotactic body radiotherapy (SBRT) has been used extensively in patients with lung, liver and spinal tumors, and the treatment outcomes are very favorable. For certain conditions such as medically inoperable stage I non-small-cell lung cancer, liver and lung oligometastases, primary liver cancer and spinal metastases, SBRT is regarded as one of the standard therapies. In the recent years, the use of SBRT has been extended to other disease conditions and sites such as recurrent head and neck cancer, renal cell carcinoma, prostate cancer, adrenal metastasis, pancreatic cancer, gynecological malignancies, spinal cord compression, breast cancer, and stage II-III non-small-cell lung cancer. Preliminary data in the literature show promising results but the follow-up intervals are short for most studies. This paper will provide an overview of these emerging applications. PMID:24947266

  11. Development of bevacizumab in advanced cervical cancer: pharmacodynamic modeling, survival impact and toxicology.

    PubMed

    Eskander, Ramez N; Tewari, Krishnansu S

    2015-01-01

    Historically, patients with metastatic, persistent or recurrent cervical cancer had limited therapeutic options. Despite several Phase II/III clinical trials, the combination of cisplatin and paclitaxel remained the most effective chemotherapeutic regimen. In 2014, publication of Gynecologic Oncology Group 240 represented the emergence of an alternate and effective therapeutic option. This prospective, randomized, Phase III clinical trial explored the impact of adding the antiangiogenic agent bevacizumab to two separate cytotoxic chemotherapy backbones. Importantly, the study met its primary end point, showing a survival advantage of approximately 4 months without detriment in quality of life. As such, a review of bevacizumab and its application in patients with advanced-stage cervical cancer is warranted. PMID:25760973

  12. VUV Spectra observed in C-2 FRC plasma

    NASA Astrophysics Data System (ADS)

    Osin, Dmitry; Douglass, Jon; Tuszewski, Michel; TAE Team

    2014-10-01

    A grazing incidence flat-field spectrometer was installed for observation of vuv-spectra in C-2 FRC experiment. Wavelength calibration was done by observing spectra of six different gases produced by a hollow-cathode discharge lamp . In addition, in-situ calibration and alignment were performed utilizing neutral-beam heated gases. Wavelength regions between 16 nm and 170 nm was investigated with accuracy of about 0.02 nm. VUV-spectral lines of the most abundant impurity ions were identified both for Plasma Gun and C-2 plasmas. In addition to D spectrum, strong lines of O III-VI, N IV-V, C II-III, and Fe II ions were observed during the plasma lifetime. VUV radiative power losses within energy range from 7.3 eV to 81 eV were estimated based on the calculated FRC dimensions.

  13. Tavaborole 5% Solution: A Novel Topical Treatment for Toenail Onychomycosis.

    PubMed

    Gupta, G; Foley, K A; Gupta, A K

    2015-11-01

    Onychomycosis is a stubborn fungal infection of the nails that can be difficult to effectively manage. One of the challenges with topical therapies is penetrating the nail plate to reach the site of infection. As the first antifungal in a boron-containing class of drugs with a novel mechanism of action, tavaborole is able to penetrate the nail plate more effectively than ciclopirox and amorolfine lacquers. In Phase II/III clinical trials, tavaborole was shown to be safe and clinically effective. Tavaborole 5% solution was approved by the US FDA for the treatment of toenail onychomycosis in July 2014 and is an important addition to the topical treatment arsenal against this stubborn infection. PMID:27224843

  14. Efficient Ab initio Modeling of Random Multicomponent Alloys

    NASA Astrophysics Data System (ADS)

    Jiang, Chao; Uberuaga, Blas P.

    2016-03-01

    We present in this Letter a novel small set of ordered structures (SSOS) method that allows extremely efficient ab initio modeling of random multicomponent alloys. Using inverse II-III spinel oxides and equiatomic quinary bcc (so-called high entropy) alloys as examples, we demonstrate that a SSOS can achieve the same accuracy as a large supercell or a well-converged cluster expansion, but with significantly reduced computational cost. In particular, because of this efficiency, a large number of quinary alloy compositions can be quickly screened, leading to the identification of several new possible high-entropy alloy chemistries. The SSOS method developed here can be broadly useful for the rapid computational design of multicomponent materials, especially those with a large number of alloying elements, a challenging problem for other approaches.

  15. EVALUATING COSTS WITH UNMEASURED CONFOUNDING: A SENSITIVITY ANALYSIS FOR THE TREATMENT EFFECT

    PubMed Central

    Handorf, Elizabeth A.; Bekelman, Justin E.; Heitjan, Daniel F.; Mitra, Nandita

    2014-01-01

    Estimates of the effects of treatment on cost from observational studies are subject to bias if there are unmeasured confounders. It is therefore advisable in practice to assess the potential magnitude of such biases. We derive a general adjustment formula for loglinear models of mean cost and explore special cases under plausible assumptions about the distribution of the unmeasured confounder. We assess the performance of the adjustment by simulation, in particular, examining robustness to a key assumption of conditional independence between the unmeasured and measured covariates given the treatment indicator. We apply our method to SEER-Medicare cost data for a stage II/III muscle-invasive bladder cancer cohort. We evaluate the costs for radical cystectomy vs. combined radiation/chemotherapy, and find that the significance of the treatment effect is sensitive to plausible unmeasured Bernoulli, Poisson and Gamma confounders. PMID:24587844

  16. Five-color band ultraviolet photometry of fourteen close binaries

    NASA Technical Reports Server (NTRS)

    Kondo, Y.; Mccluskey, G. E.; Wu, C.-C.

    1981-01-01

    Photometric observations obtained with the Astronomical Netherlands Satellite in five ultraviolet wavelength regions for 14 close binaries are presented. Strong excess far-ultraviolet flux is detected in four objects. The binaries TT Hya, RX Cas, and SX Cas exhibit a pronounced excess of far-ultraviolet flux, which is thought to be the result of mass transfer phenomena in these systems. Observations of the binary R Ara show very peculair variations; its far ultraviolet flux at 1550 A brightened by 0.4 mag between phases 0.7 and 0.8, while its near ultraviolet flux at 3300 A decreased by 0.5 mag over this same half-day interval. The A0 II-III component in the system RZ Sct is seen to dominate the ultraviolet spectrum.

  17. Sorafenib in radioactive iodine-refractory well-differentiated metastatic thyroid cancer

    PubMed Central

    McFarland, Daniel C; Misiukiewicz, Krzysztof J

    2014-01-01

    Recent Phase III data presented at the American Society of Clinical Oncology (ASCO) 2013 annual conference by Brose et al led to the US Food and Drug Administration (FDA) approval of sorafenib for the treatment of well-differentiated radioactive iodine-resistant metastatic thyroid cancer. This is the second drug in 40 years to be FDA approved for this indication. Recent reviews and a meta-analysis reveal a modest ability to induce a partial remission but substantial ability to halt disease progression. Given the significant activating mutations present in thyroid cancer, many of which are inhibited by sorafenib, the next logical approach may be to combine targeted rational therapies if permitted by collective toxicity profiles. This systematic review aims to summarize the recent Phase II/III data leading to the FDA approval of sorafenib for radioactive iodine therapy differentiated thyroid cancer and highlights recent novel combination therapy trials. PMID:25053887

  18. Cariprazine: First Global Approval.

    PubMed

    McCormack, Paul L

    2015-11-01

    Cariprazine (Vraylar) is an oral atypical antipsychotic originated by Gedeon Richter. It is a potent dopamine D3 and D2 receptor partial agonist, which preferentially binds to the D3 receptor. Cariprazine also has partial agonist activity at serotonin 5-HT1A receptors. In September 2015, cariprazine received its first global approval in the USA for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is also in development in a variety of countries for the treatment of schizophrenia with predominant negative symptoms (phase III), as adjunctive therapy for major depressive disorder (phase II/III) and for the treatment of bipolar depression (phase II). This article summarizes the milestones in the development of cariprazine leading to this first approval for schizophrenia and manic or mixed episodes associated with bipolar I disorder. PMID:26510944

  19. Animal models of rheumatoid arthritis: How informative are they?

    PubMed

    McNamee, Kay; Williams, Richard; Seed, Michael

    2015-07-15

    Animal models of arthritis are widely used to de-convolute disease pathways and to identify novel drug targets and therapeutic approaches. However, the high attrition rates of drugs in Phase II/III rates means that a relatively small number of drugs reach the market, despite showing efficacy in pre-clinical models. There is also increasing awareness of the ethical issues surrounding the use of animal models of disease and it is timely, therefore, to review the relevance and translatability of animal models of arthritis. In this paper we review the most commonly used animal models in terms of their pathological similarities to human rheumatoid arthritis as well as their response to drug therapy. In general, the ability of animal models to predict efficacy of biologics in man has been good. However, the predictive power of animal models for small molecules has been variable, probably because of differences in the levels of target knockdown achievable in vivo. PMID:25824900

  20. Current Standard and Investigational Approaches to the Management of Hormone-Refractory Prostate Cancer

    PubMed Central

    Mendiratta, Prateek; Armstrong, Andrew J; George, Daniel J

    2007-01-01

    Prostate cancer is a common cause of death in men and remains incurable in the metastatic setting. In 2004, 2 landmark trials using docetaxel-based chemotherapy, TAX 327 and SWOG 99-16, showed a survival benefit for the first time in metastatic, hormone-refractory prostate cancer. Current research suggests that several distinct mechanisms of androgen-refractory disease may converge in patients with disease progression on androgen deprivation therapy. These findings have identified several potential targets for therapeutic intervention. Current standard and investigational treatment options for this disease are discussed, including chemotherapy and rapidly evolving therapies in phase II/III trials involving antiangiogenic therapies, signal transduction inhibitors, immunomodulatory agents, and nuclear receptor targets. In light of a growing array of treatment options and an increasingly chronic natural history, this review supports a multidisciplinary care approach to these patients, including medical oncologists, urologists, and radiation oncologists, to optimize survival and quality of life. PMID:17387372

  1. GSK-1605786, a selective small-molecule antagonist of the CCR9 chemokine receptor for the treatment of Crohn's disease.

    PubMed

    Eksteen, Bertus; Adams, David H

    2010-07-01

    GSK-1605786 (CCX-282; Traficet-EN), a selective antagonist of the CC chemokine receptor (CCR9), is being developed by GlaxoSmithKline plc under license from ChemoCentryx Inc for the potential treatment of inflammatory bowel disease, including Crohn's disease and celiac disease. CCR9 is a tissue-specific lymphocyte trafficking molecule that selectively attracts both B- and T-cells to the small gut. Inhibition of CCR9 by GSK-1605786 may inhibit B- and T-cell entry to the small gut and ameliorate inflammation while leaving immune function at other anatomical sites unaffected. GSK-1605786 was assessed as a treatment for moderate-to-severe Crohn's disease in the phase II/III PROTECT-1 trial and as a treatment for celiac disease in a phase II trial. Data suggest that GSK-1605786 is efficacious in patients with Crohn's disease with the advantage of being orally bioavailable. PMID:20582872

  2. Fermentation, Hydrogen, and Sulfur Metabolism in Multiple Uncultivated Bacterial Phyla

    SciTech Connect

    Wrighton, Kelly C.; Thomas, BC; Sharon, I; Miller, CS; Castelle, Cindy J; Verberkmoes, Nathan C; Wilkins, Michael J.; Hettich, Robert {Bob} L; Lipton, Mary S; Williams, Ken; Long, Philip E; Banfield, Jillian F.

    2012-01-01

    BD1-5, OP11, and OD1 bacteria have been widely detected in anaerobic environments, but their metabolisms remain unclear owing to lack of cultivated representatives and minimal genomic sampling. We uncovered metabolic characteristics for members of these phyla, and a new lineage, PER, via cultivation-independent recovery of 49 partial to near-complete genomes from an acetate-amended aquifer. All organisms were nonrespiring anaerobes predicted to ferment. Three augment fermentation with archaeal-like hybrid type II/III ribulose-1,5-bisphosphate carboxylase-oxygenase (RuBisCO) that couples adenosine monophosphate salvage with CO2 fixation, a pathway not previously described in Bacteria. Members of OD1 reduce sulfur and may pump protons using archaeal-type hydrogenases. For six organisms, the UGA stop codon is translated as tryptophan. All bacteria studied here may play previously unrecognized roles in hydrogen production, sulfur cycling, and fermentation of refractory sedimentary carbon.

  3. [YB-1-based virotherapy: A new therapeutic intervention for transitional cell carcinoma of the bladder?].

    PubMed

    Holm, P S; Retz, M; Gschwend, J E; Nawroth, R

    2016-03-01

    Therapeutic intervention using oncolytic viruses is called virotherapy. This type of virus is defined by the ability to replicate in tumor cells only and to destroy these cells upon replication. In addition, this virus type is able to induce a tumor-directed immune response. Early clinical trials have confirmed the safety profile of oncolytic viruses. Currently, different groups are working on the development of oncolytic viruses with a focus on treatment of nonmuscle invasive bladder cancer (NMIBC). A preliminary active recruiting clinical phase II/III trial ongoing in patients with a NMIBC was recently implemented in the United States. Our research group developed an oncolytic adenovirus that will soon enter a clinical phase I trial in patients diagnosed with glioma. This virus is being further modified for the treatment of NMIBC. In this review article, recent developments in the design and use of virotherapy in bladder cancer are summarized. PMID:26556269

  4. [Evaluation of late results of laryngeal cancer treatment with the use of polymer endoprostheses].

    PubMed

    Klochikhin, A L; Trofimov, E I; Davydova, I I

    2010-01-01

    Application of biocompatible polymer-based endoprostheses (EG 1-4, TS 42-2-476-85) for the treatment of laryngeal cancer made it possible to achieve good oncological outcome in the late postoperative period and ensured high-quality functional rehabilitation of the patients. The estimated 3-year survival rate following endoprosthetic treatment amounted to 73.9%, 5-year survival rate was 67.6%, and 10-year survival rate 58.7%. Objective assessment of voice rehabilitation with the use of the software package (Windows 98, 2000, XP) demonstrated restoration of the vocal function in 70% of the patients while the remaining 30% were able to communicate by whisper speech. Resection of the larynx in patients with its stage II-III cancer in combination with the use of polymer endoprostheses yielded good oncological results and ensured the high rate of vocal function rehabilitation. PMID:20436419

  5. Development of InCVAX as a novel in situ autologous vaccine for metastatic cancers (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Hode, Tomas; Alleruzzo, Luciano; Raker, Joseph; Lam, Samuel Siu Kit; Nordquist, Robert E.; Chen, Wei R.

    2016-03-01

    A novel method, an in situ autologous whole-cell cancer vaccine (inCVAX), is being developed by Immunophotonics, Inc., for the treatment of metastatic cancers. inCVAX combines phototherapy and immunotherapy to potentially induce a systemic anti-tumor immune response in the hosts. Immunophotonics and its academic partners have spent years conducting nonclinical research, developing CMC techniques and conducting clinical research. In 2015 the company initiated a late-stage (II/III) clinical trial in South America for advanced breast cancer patients. The process of developing the inCVAX approach from a laboratory setting into clinical trials requires significant efforts from a group of dedicated engineers, scientists, and physicians. The growth of the company and its business advances demonstrated the determination of a group of visionary investors, entrepreneurs, and business leaders. This talk will chronicle the milestones of the scientific achievement, medical progress, and business development of Immunophotonics.

  6. Orthogonal micro-organization of orientation and spatial frequency in primate primary visual cortex.

    PubMed

    Nauhaus, Ian; Nielsen, Kristina J; Disney, Anita A; Callaway, Edward M

    2012-12-01

    Orientation and spatial frequency tuning are highly salient properties of neurons in primary visual cortex (V1). The combined organization of these particular tuning properties in the cortical space will strongly shape the V1 population response to different visual inputs, yet it is poorly understood. In this study, we used two-photon imaging in macaque monkey V1 to demonstrate the three-dimensional cell-by-cell layout of both spatial frequency and orientation tuning. We first found that spatial frequency tuning was organized into highly structured maps that remained consistent across the depth of layer II/III, similarly to orientation tuning. Next, we found that orientation and spatial frequency maps were intimately related at the fine spatial scale observed with two-photon imaging. Not only did the map gradients tend notably toward orthogonality, but they also co-varied negatively from cell to cell at the spatial scale of cortical columns. PMID:23143516

  7. Chandelier neurons within the rabbits' cerebral cortex. A Golgi study.

    PubMed

    Müller-Paschinger, I B; Tömböl, T; Petsche, H

    1983-01-01

    This study has been carried out by light microscopy on 3 Golgi-Kopsch impregnated brains of young adult rabbits. It is shown that chandelier cells exist within the rabbits' cerebral cortex. In the rabbit, the chandelier cell is a medium ranged bipolar interneuron in layer II/III with a characteristic axon which forms a plexus with a diameter of about 350-500 micrometers in the horizontal and 200-350 micrometers in the vertical direction; the end of each ramulus forms the typical "candlestick", a little vertical string of 1-6 boutons on an axon fibre. These boutons form contacts with all parts of pyramidal cells in layer II and the upper part of layer III. Similarities and differences with respect to previous descriptions of these cells in other species are discussed. PMID:6837931

  8. Cholinergic and noradrenergic triggers' in soman induced convulsions

    SciTech Connect

    Shipley, M.T.; Zimmer, L.; Ennis, M.; Etri, M.

    1993-05-13

    Considerable evidence suggests that soman induced seizure's are initiated in the piriform cortex (PC). Consistent with this, PC is the most frequent site of neuropathology in soman treated rats and other species. Previous studies in this laboratory have shown that convulsive doses of soman cause the rapid induction of the immediate early gene protein product, Fos, in piriform cortex (PC). Fos is known to be expressed when neurons undergo sustained excitatory activity. Following soman, Fos is selectively expressed by neurons in layers II Ill of PC. These neurons are known to send excitatory projections to the hippocampus and to thalamus and neocortex. Thus, we have suggested that soman may initially cause seizure activity in layer II-III PC neurons; this seizure activity could then spread to the hippocampus and neocortex. Consistent with this hypothesis, we have observed that Fos is expressed in hippocampus, thalamus and neocortex subsequent to its expression in PC.

  9. Decoding the stellar fossils of the dusty Milky Way progenitors

    NASA Astrophysics Data System (ADS)

    de Bennassuti, M.; Schneider, R.; Valiante, R.; Salvadori, S.

    2014-12-01

    We investigate the metallicity distribution function (MDF) of the Galactic halo and the relative fraction of Carbon-normal and Carbon-rich stars using the semi-analytical code GAMETE. The code reconstructs the hierarchical merger tree of the Milky Way (MW) and follows the star formation history and the metal evolution in individual progenitors, including for the first time the formation and evolution of dust. We predict scaling relations between the dust, metal and gas masses for MW progenitors and compare them with observational data of galaxies at 0 <= z < 6.3. We find that the relative contribution of C-normal and C-enhanced stars to the MDF and its dependence on [Fe/H] allow to discriminate among different Pop III/II transition criteria as well as between different Initial Mass Functions (IMFs) and supernova (SN) yields for Population III stars.

  10. Suvorexant for the treatment of insomnia.

    PubMed

    Jacobson, Laura H; Callander, Gabrielle E; Hoyer, Daniel

    2014-11-01

    Suvorexant (Belsorma(®)) is the first orexin receptor antagonist approved by the US FDA (August 2014) for insomnia treatment. Following comprehensive Phase II/III studies, with up to 12 months of treatment in adult and elderly patients, there is little doubt that suvorexant induces and maintains sleep. However, the FDA and sponsor disagreed about effective versus safe doses (November 2012). The FDA considered that 5-15 mg were efficient and probably safe, whereas the sponsors had proposed 15-40 mg. The final approved doses are 5, 10, 15 and 20 mg. The major issues are next-morning somnolence and safety as seen in driving tests, with possible signs of muscle weakness, weird dreams, sleep walking, other nighttime behaviors and suicidal ideation. Despite its limitations, suvorexant's market entry offers a truly novel treatment for insomnia, paving the way for follow-up compounds and opening therapeutic avenues in other disorders for orexin receptor modulating compounds. PMID:25318834

  11. [The atypical course of syphilis in HIV infection].

    PubMed

    Mahrle, G; Rasokat, H; Kurz, K; Steigleder, G K

    1989-05-15

    We report on 3 HIV patients showing atypical courses of syphilis. Both the history and serology of the first patient proved a recent re-infection with T. pallidum, whereas the histopathological findings corresponded to an advanced stage of the disease (S II-III). The second patient showed the clinical picture of syphilis maligna with slowly converting and slightly positive serological reactions. The third patient had a refractory syphilis and an early relapse. Our observations suggest that syphilis might take an unusual course in HIV patients. Considering our total HIV clientèle (800 patients greater than or equal to WR 2) the frequency of these atypical cases must be rated very low (0.38%). PMID:2741530

  12. The potential for a controlled human infection platform in Singapore

    PubMed Central

    Balasingam, Shobana; Horby, Peter; Wilder-Smith, Annelies

    2014-01-01

    For over 100 years, controlled human infection (CHI) studies have been performed to advance the understanding of the pathogenesis, treatment and prevention of infectious diseases. This methodology has seen a resurgence, as it offers an efficient model for selecting the most promising agents for further development from available candidates. CHI studies are utilised to bridge safety and immunogenicity testing and phase II/III efficacy studies. However, as this platform is not currently utilised in Asia, opportunities to study therapeutics and vaccines for infections that are important in Asia are missed. This review examines the regulatory differences for CHI studies between countries and summarises other regulatory differences in clinical trials as a whole. We found that the regulations that would apply to CHI studies in Singapore closely mirror those in the United Kingdom, and conclude that the regulatory and ethical guidelines in Singapore are compatible with the conduct of CHI studies. PMID:25273928

  13. Recombinant B domain deleted porcine factor VIII for the treatment of bleeding episodes in adults with acquired hemophilia A.

    PubMed

    Gomperts, Edward

    2015-08-01

    Hemophilia A is an inherited deficiency of clotting factor VIII (FVIII) often complicated by inhibitor development (CHAWI) in which neutralizing antibodies block the therapeutic benefit of replacement therapy. Inhibitors to FVIII can also be seen in an auto-immune disease known as acquired hemophilia A (AHA). 'Bypassing' therapies have been shown to provide hemostasis but dosing must be done empirically because current assays cannot measure objective markers of treatment efficacy and safety. A recombinant porcine sequence factor VIII (r-pFVIII) has been developed for the management of AHA. Preclinical, Phase I and Phase II clinical research studies in CHAWI subjects showed therapeutic potential and safety of this agent. A Phase II/III study in AHA with serious bleeding episodes shows a positive response in all subjects after administration. Based on current preclinical and clinical trial data, r-pFVIII should become the first line of treatment in the management of hemorrhage in patients with AHA. PMID:25927594

  14. Positron emission tomography radioligands for in vivo imaging of Aβ plaques

    PubMed Central

    Mason, N. Scott; Mathis, Chester A.; Klunk, William E.

    2014-01-01

    The development of positron emission tomography (PET) radioligands for the non-invasive imaging of amyloid-β plaque burden has been the focus of intense research efforts over the last decade. A variety of structural backbones have been investigated and several radiolabeled molecules have been evaluated in phase I (and later) clinical studies. These efforts have been driven by the desire not only to develop a suitable diagnostic imaging agent but also to develop a means to evaluate potential therapies for Alzheimer’s disease. This review focuses on the development of these ligands, as well as the radiochemistry and current regulatory status of these PET radioligands. Particular attention is given to those ligands that have progressed to the later stages of drug development (phase II/III clinical trial studies) or approved New Drug Application status. PMID:24285314

  15. The potential for a controlled human infection platform in Singapore.

    PubMed

    Balasingam, Shobana; Horby, Peter; Wilder-Smith, Annelies

    2014-09-01

    For over 100 years, controlled human infection (CHI) studies have been performed to advance the understanding of the pathogenesis, treatment and prevention of infectious diseases. This methodology has seen a resurgence, as it offers an efficient model for selecting the most promising agents for further development from available candidates. CHI studies are utilised to bridge safety and immunogenicity testing and phase II/III efficacy studies. However, as this platform is not currently utilised in Asia, opportunities to study therapeutics and vaccines for infections that are important in Asia are missed. This review examines the regulatory differences for CHI studies between countries and summarises other regulatory differences in clinical trials as a whole. We found that the regulations that would apply to CHI studies in Singapore closely mirror those in the United Kingdom, and conclude that the regulatory and ethical guidelines in Singapore are compatible with the conduct of CHI studies. PMID:25273928

  16. Targeting PCSK9 for therapeutic gains.

    PubMed

    Shapiro, Michael D; Fazio, Sergio; Tavori, Hagai

    2015-04-01

    Even though it is only a little over a decade from the discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) as a plasma protein that associates with both hypercholesterolemia and low cholesterol syndromes, a rich literature has developed describing its unique physiology and the impact of antagonism of this molecule on cholesterol metabolism for therapeutic purposes. Indeed, the PCSK9 story is unfolding rapidly, with many answers and more questions. This review summarizes the most recent data from phase II/III clinical trials of PCSK9 inhibition with the three leading antibodies, highlights the clinical significance of the ongoing studies, and suggests future areas of investigation based on recent basic science discoveries on the physiology of PCSK9. PMID:25712137

  17. [The cognitive dysfunction in Parkinson's disease].

    PubMed

    Kanazawa, Akira

    2004-09-01

    Parkinson's disease (PD) is a slowly progressive disorder which begins with motor symptoms. Several cognitive deficits can be observed in nondemented patients with PD during their history. The core symptom in the cognitive deficits in PD is the executive dysfunction. Neuropsychological tests such as Wisconsin Card Sorting Test, Trail Making Test are used to measure the degree of this dysfunction. Executive dysfunction is thought related to abnormalities in the dorsolateral prefrontal circuit which largely passes through the caudate nucleus. The dysfunction emerges as the pathology spreads to the nigrocaudate project corresponding to Hoehn & Yahr stage II-III. Effective therapy for cognitive dysfunction in PD remains elusive, however donepezil, Attention Process Training, Music therapy and Transcranial magnetic stimulation have been reported to have partial efficacy. PMID:15462384

  18. Spatiotemporal distribution of bacterioplankton and bacteriobenthos in the Amur Liman and adjacent sea areas

    NASA Astrophysics Data System (ADS)

    Karetnikova, E. A.; Garetova, L. A.

    2015-09-01

    Data on the abundance and the ecological-trophic structure of bacterioplankton and bacteriobenthos communities in the Amur Liman and adjacent waters collected in June 2007 have been compared to the relevant data of 2006. Interyear changes of bacterioplankton abundance have been found to depend on the intensity of the Amur River runoff. Correlation analysis has revealed a negative dependence of the abundance of bacterioplankton, bacteriobenthos, and their ecological-trophic groups on water salinity, as well as direct relations between these biotic components and organic matter in water and bottom sediments. The microbiological indicators of water quality ranked the studied waters as classes III-IV in 2006 and as classes II-III in 2007. The high total abundance of bacteriobenthos (109-1010 cells/g) is a result of the functioning of a marginal filter rather than the direct pollution of the liman.

  19. Enhanced Vision for All-Weather Operations Under NextGen

    NASA Technical Reports Server (NTRS)

    Bailey, Randall E.; Kramer, Lynda J.; Williams, Steven P.; Bailey, Randall E.; Kramer, Lynda J.; Williams, Steven P.

    2010-01-01

    Recent research in Synthetic/Enhanced Vision technology is analyzed with respect to existing Category II/III performance and certification guidance. The goal is to start the development of performance-based vision systems technology requirements to support future all-weather operations and the NextGen goal of Equivalent Visual Operations. This work shows that existing criteria to operate in Category III weather and visibility are not directly applicable since, unlike today, the primary reference for maneuvering the airplane is based on what the pilot sees visually through the "vision system." New criteria are consequently needed. Several possible criteria are discussed, but more importantly, the factors associated with landing system performance using automatic and manual landings are delineated.

  20. Temperature control of a microspectrophotometer system for monitoring the redox reactions of respiratory pigments in small volumes

    NASA Astrophysics Data System (ADS)

    Kavanagh, Karen Y.; Walsh, James E.; Murphy, J.; Harmey, M.; Farrell, M. A.; Hardimann, O.; Perryman, R.

    1998-05-01

    We report the development of a microspectrophotometer system for use on micro samples of mitochondrial respiratory pigments. A novel optical fiber set-up uses visible spectrophotometry to monitor the reduction of mitochondrial electron carriers. Data is presented for the reduction of cytochrome-c and for the effect of temperature on the levels of complex II/III activity from the mitochondria of rat liver. This in-vivo simulation of the reduction of cytochrome-c can be observed using a fiber optic probe which requires less than twenty (mu) l of sample for analysis. The key features of the system are: front end adaptability, high sensitivity and fast multispectral acquisition which are essential for the biological reactions which are observed.

  1. Efficient Ab initio Modeling of Random Multicomponent Alloys.

    PubMed

    Jiang, Chao; Uberuaga, Blas P

    2016-03-11

    We present in this Letter a novel small set of ordered structures (SSOS) method that allows extremely efficient ab initio modeling of random multicomponent alloys. Using inverse II-III spinel oxides and equiatomic quinary bcc (so-called high entropy) alloys as examples, we demonstrate that a SSOS can achieve the same accuracy as a large supercell or a well-converged cluster expansion, but with significantly reduced computational cost. In particular, because of this efficiency, a large number of quinary alloy compositions can be quickly screened, leading to the identification of several new possible high-entropy alloy chemistries. The SSOS method developed here can be broadly useful for the rapid computational design of multicomponent materials, especially those with a large number of alloying elements, a challenging problem for other approaches. PMID:27015491

  2. Damarane-type Saponins from Gynostemma longipes and their Cytotoxic Activity.

    PubMed

    Anh, Pham Tuan; Ky, Pham Thank; Cue, Nguyen Thi; Nhiem, Nguyen Xuan; Yen, Pham Hai; Ngoc, Tran Minh; Anh, Hoang Le Tuan; Tai, Bui Huu; Trang, Do Thi; Minh, Chau Van; Kiem, Phan Van

    2015-08-01

    Two new damarane-type saponins, named gylongiposides II-III (1 and 2), along with one known compound, (23S)-3β,20ξ,21ξ-trihydroxy-19-oxo-21,23-epoxydammar-24-ene 3-O-α-L-rhamnopyranosyl-(1-->2)-[-D-xylopyranosyl-(1-->3)]-α-L-arabinopyranoside, were isolated from the leaves of Gynostemma longipes C.Y.Wu. Their structures were determined by 1D- and 2D-NMR and HR-ESI-MS spectra. Compounds 1-3 exhibited moderate activity against four human cancer cell lines, A-549, HT-29, OVCAR, and MCF-7, with IC50 values ranging from 9.8 +/- 2.1 to 49.6 +/- 2.6 μM. PMID:26434113

  3. [Pilote strategy to optimize an individual treatment of arterial hypertention and algorithm of the prophylactics of vascular complications].

    PubMed

    Tolstopiatov, S M

    2006-12-01

    Ischemic stroke (IS) and myocardial infarction are very serious complications of arterial hypertention (AH). To prevent such complications it is important to control the level of arterial pressure, state of lipid spectre and to reveal hypercoagulation in blood which is a predictor to the formation of thrombi and after its severity degree to find clinical homeostatic risk factor, individual dose of an antiaggregant medication and its application. 146 patients with II-III stage arterial hypertention were observed using "Koaguloscop-TC" apparatus. 36 parameters reflecting the formation of all phases of coagulation cascade and the fibrinolysis system of these patients have been studied. To optimize individual treatment of arterial hypertention and prophylactics of vascular complications is necessary to prescribe a complex treatment including antihypertensive, hypolypidemic and antiagragative agents. PMID:17427421

  4. Progression of Ebola Therapeutics During the 2014-2015 Outbreak.

    PubMed

    Mendoza, Emelissa J; Qiu, Xiangguo; Kobinger, Gary P

    2016-02-01

    The recent Ebola virus (EBOV) outbreak in West Africa was the deadliest EBOV epidemic in history, highlighting the need for a safe and efficacious treatment against EBOV disease (EVD). In the absence of an approved treatment, experimental drugs were utilized under compassionate grounds hoping to diminish EVD-associated morbidity and mortality. As more data were collected from safety studies, Phase II/III clinical trials were introduced in Guinea, Sierra Leone, and Liberia to test promising candidates, including small-molecule drugs, RNA-based treatments, and antibody-based therapies. In this review, we summarize the use of, and preliminary observations from, current clinical trials with EVD therapeutics, shedding light on experimental drug selection, emergency clinical evaluation, and the impact these factors may have on future infectious disease outbreaks. PMID:26774636

  5. Phosphatidylinositol 3-kinase CB association with preoperative radiotherapy response in rectal adenocarcinoma

    PubMed Central

    Yu, Wei-Dong; Peng, Yi-Fan; Pan, Hong-Da; Wang, Lin; Li, Kun; Gu, Jin

    2014-01-01

    AIM: To examine the correlation of phosphatidylinositol 3-kinase (PIK3) CB expression with preoperative radiotherapy response in patients with stage II/III rectal adenocarcinoma. METHODS: PIK3CB immunoexpression was retrospectively assessed in pretreatment biopsies from 208 patients with clinical stage II/III rectal adenocarcinoma, who underwent radical surgery after 30-Gy/10-fraction preoperative radiotherapy. The relation between PIK3CB expression and tumor regression grade, clinicopathological characteristics, and survival time was statistically analyzed. Western blotting and in vitro clonogenic formation assay were used to detect PIK3CB expression in four colorectal cancer cell lines (HCT116, HT29, LoVo, and LS174T) treated with 6-Gy ionizing radiation. Pharmacological assays were used to evaluate the therapeutic relevance of TGX-221 (a PIK3CB-specific inhibitor) in the four colorectal cancer cell lines. RESULTS: Immunohistochemical staining indicated that PIK3CB was more abundant in rectal adenocarcinoma tissues with poor response to preoperative radiotherapy. High expression of PIK3CB was closely correlated with tumor height (P < 0.05), ypT stage (P < 0.05), and high-degree tumor regression grade (P < 0.001). High expression of PIK3CB was a potential prognostic factor for local recurrence-free survival (P < 0.05) and metastasis-free survival (P < 0.05). High expression of PIK3CB was also associated with poor therapeutic response and adverse outcomes in rectal adenocarcinoma patients treated with 30-Gy/10-fraction preoperative radiotherapy. In vitro, PIK3CB expression was upregulated in all four colorectal cancer cell lines concurrently treated with 6-Gy ionizing radiation, and the PIK3CB-specific inhibitor TGX-221 effectively inhibited the clonogenic formation of these four colorectal cancer cell lines. CONCLUSION: PIK3CB is critically involved in response to preoperative radiotherapy and may serve as a novel target for therapeutic intervention. PMID:25473181

  6. Comprehensive Chronic Laminar Single-Unit, Multi-Unit, and Local Field Potential Recording Performance With Planar Single Shank Electrode Arrays

    PubMed Central

    Kozai, Takashi D. Y.; Du, Zhanhong; Gugel, Zhannetta V.; Smith, Matthew A.; Chase, Steven M.; Bodily, Lance M; Caparosa, Ellen M.; Friedlander, Robert M.; Cui, X. Tracy

    2015-01-01

    Background Intracortical electrode arrays that can record extracellular action potentials from small, targeted groups of neurons are critical for basic neuroscience research and emerging clinical applications. In general, these electrode devices suffer from reliability and variability issues, which have led to comparative studies of existing and emerging electrode designs to optimize performance. Comparisons of different chronic recording devices have been limited to single-unit (SU) activity and employed a bulk averaging approach treating brain architecture as homogeneous with respect to electrode distribution. New Method In this study, we optimize the methods and parameters to quantify evoked multi-unit (MU) and local field potential (LFP) recordings in 8 mice visual cortices. Results These findings quantify the large recording differences stemming from anatomical differences in depth and the layer dependent relative changes to SU and MU recording performance over 6-months. For example, performance metrics in Layer V and stratum pyramidale were initially higher than Layer II/III, but decrease more rapidly. On the other hand, Layer II/III maintained recording metrics longer. In addition, chronic changes at the level of layer IV are evaluated using visually evoked current source density. Comparison with Existing Method(s) The use of MU and LFP activity for evaluation and tracking biological depth provides a more comprehensive characterization of the electrophysiological performance landscape of microelectrodes. Conclusions A more extensive spatial and temporal insight into the chronic electrophysiological performance over time will help uncover the biological and mechanical failure mechanisms of the neural electrodes and direct future research toward the elucidation of design optimization for specific applications. PMID:25542351

  7. Acute administration of l-tyrosine alters energetic metabolism of hippocampus and striatum of infant rats.

    PubMed

    Ramos, Andrea C; Ferreira, Gabriela K; Carvalho-Silva, Milena; Furlanetto, Camila B; Gonçalves, Cinara L; Ferreira, Gustavo C; Schuck, Patrícia F; Streck, Emilio L

    2013-08-01

    Tyrosinemia type II is an inborn error of metabolism caused by mutations in the gene that encodes tyrosine aminotransferase, which leads to increased blood tyrosine levels. Considering that tyrosine levels are highly elevated in fluids of patients with tyrosinemia type II, and that previous studies demonstrated significant alterations in brain energy metabolism of young rats caused by l-tyrosine, the present study aimed to evaluate the effect of acute administration of l-tyrosine on the activities of citrate synthase, malate dehydrogenase, succinate dehydrogenase, and mitochondrial respiratory chain complexes I, II, II-III, and IV in posterior cortex, hippocampus, and striatum of infant rats. Wistar rats (10 days old) were killed 1h after a single intraperitoneal injection of tyrosine (500 mg/kg) or saline. The activities of energy metabolism enzymes were evaluated in brain of rats. Our results demonstrated that acute administration of l-tyrosine inhibited the activity of citrate synthase activity in striatum and increased the activities of malate dehydrogenase and succinate dehydrogenase in hippocampus. On the other hand, these enzymes were not affected in posterior cortex. The activities of complex I and complex II were inhibited by acute administration of l-tyrosine in striatum. On the other hand, the acute administration of l-tyrosine increased the activity of activity of complex II-III in hippocampus. Complex IV was not affected by acute administration of l-tyrosine in infant rats. Our results indicate an alteration in the energy metabolism in hippocampus and striatum of infant rats after acute administration of l-tyrosine. If the same effects occur in the brain of the patients, it is possible that energy metabolism impairment may be contribute to possible damage in memory and cognitive processes in patients with tyrosinemia type II. PMID:23602810

  8. A Novel Form of Compensation in the Tg2576 Amyloid Mouse Model of Alzheimer’s Disease

    PubMed Central

    Somogyi, Attila; Katonai, Zoltán; Alpár, Alán; Wolf, Ervin

    2016-01-01

    One century after its first description, pathology of Alzheimer’s disease (AD) is still poorly understood. Amyloid-related dendritic atrophy and membrane alterations of susceptible brain neurons in AD, and in animal models of AD are widely recognized. However, little effort has been made to study the potential effects of combined morphological and membrane alterations on signal transfer and synaptic integration in neurons that build up affected neural networks in AD. In this study spatial reconstructions and electrophysiological measurements of layer II/III pyramidal neurons of the somatosensory cortex from wild-type (WT) and transgenic (TG) human amyloid precursor protein (hAPP) overexpressing Tg2576 mice were used to build faithful segmental cable models of these neurons. Local synaptic activities were simulated in various points of the dendritic arbors and properties of subthreshold dendritic impulse propagation and predictors of synaptic input pattern recognition ability were quantified and compared in modeled WT and TG neurons. Despite the widespread dendritic degeneration and membrane alterations in mutant mouse neurons, surprisingly little, or no change was detected in steady-state and 50 Hz sinusoidal voltage transfers, current transfers, and local and propagation delays of PSPs traveling along dendrites of TG neurons. Synaptic input pattern recognition ability was also predicted to be unaltered in TG neurons in two different soma-dendritic membrane models investigated. Our simulations predict the way how subthreshold dendritic signaling and pattern recognition are preserved in TG neurons: amyloid-related membrane alterations compensate for the pathological effects that dendritic atrophy has on subthreshold dendritic signal transfer and integration in layer II/III somatosensory neurons of this hAPP mouse model for AD. Since neither propagation of single PSPs nor integration of multiple PSPs (pattern recognition) changes in TG neurons, we conclude that AD

  9. Marked reduction of Na(+), K(+)-ATPase and creatine kinase activities induced by acute lysine administration in glutaryl-CoA dehydrogenase deficient mice.

    PubMed

    Amaral, Alexandre Umpierrez; Cecatto, Cristiane; Seminotti, Bianca; Zanatta, Ângela; Fernandes, Carolina Gonçalves; Busanello, Estela Natacha Brandt; Braga, Luisa Macedo; Ribeiro, César Augusto João; de Souza, Diogo Onofre Gomes; Woontner, Michael; Koeller, David M; Goodman, Stephen; Wajner, Moacir

    2012-09-01

    Glutaric acidemia type I (GA I) is an inherited neurometabolic disorder caused by a severe deficiency of the mitochondrial glutaryl-CoA dehydrogenase activity leading to accumulation of predominantly glutaric (GA) and 3-hydroxyglutaric (3HGA) acids in the brain and other tissues. Affected patients usually present with hypotonia and brain damage and acute encephalopathic episodes whose pathophysiology is not yet fully established. In this study we investigated important parameters of cellular bioenergetics in brain, heart and skeletal muscle from 15-day-old glutaryl-CoA dehydrogenase deficient mice (Gcdh(-/-)) submitted to a single intra-peritoneal injection of saline (Sal) or lysine (Lys - 8 μmol/g) as compared to wild type (WT) mice. We evaluated the activities of the respiratory chain complexes II, II-III and IV, α-ketoglutarate dehydrogenase (α-KGDH), creatine kinase (CK) and synaptic Na(+), K(+)-ATPase. No differences of all evaluated parameters were detected in the Gcdh(-/-) relatively to the WT mice injected at baseline (Sal). Furthermore, mild increases of the activities of some respiratory chain complexes (II-III and IV) were observed in heart and skeletal muscle of Gcdh(-/-) and WT mice after Lys administration. However, the most marked effects provoked by Lys administration were marked decreases of the activities of Na(+), K(+)-ATPase in brain and CK in brain and skeletal muscle of Gcdh(-/-) mice. In contrast, brain α-KGDH activity was not altered in WT and Gcdh(-/-) injected with Sal or Lys. Our results demonstrate that reduction of Na(+), K(+)-ATPase and CK activities may play an important role in the pathogenesis of the neurodegenerative changes in GA I. PMID:22578804

  10. Stereological assessment of the dorsal anterior cingulate cortex in schizophrenia: absence of changes in neuronal and glial densities

    PubMed Central

    Höistad, Malin; Heinsen, Helmut; Wicinski, Bridget; Schmitz, Christoph; Hof, Patrick R.

    2012-01-01

    Aims The prefrontal and anterior cingulate cortices are implicated in schizophrenia, and many studies have assessed volume, cortical thickness, and neuronal densities or numbers in these regions. Available data however are rather conflicting and no clear cortical alteration pattern has been established. Changes in oligodendrocytes and white matter have been observed in schizophrenia, introducing a hypothesis about a myelin deficit as a key event in disease development. Methods We investigated the dorsal anterior cingulate cortex (dACC) in 13 males with schizophrenia and 13 age- and gender-matched controls. We assessed stereologically the dACC volume, neuronal and glial densities, total neuron and glial numbers, and glia/neuron (GNI) ratios in both layers II-III and V-VI. Results We observed no differences in neuronal or glial densities. No changes were observed in dACC cortical volume, total neuron numbers, and total glial numbers in schizophrenia. This contrasts with previous findings and suggests that the dACC may not undergo as severe changes in schizophrenia as is generally believed. However, we observed higher glial densities in layers V-VI than in layers II-III in both controls and patients with schizophrenia, pointing to possible layer-specific effects on oligodendrocyte distribution during development. Conclusions Using rigorous stereological methods, we demonstrate a seemingly normal cortical organization in an important neocortical area for schizophrenia, emphasizing the importance of such morphometric approaches in quantitative neuropathology. We discuss the significance of subregion- and layer-specific alterations in the development of schizophrenia, and the discrepancies between post-mortem histopathological studies and in vivo brain imaging findings in patients. PMID:22860626

  11. Prognostic impact of mutation profiling in patients with stage II and III colon cancer

    PubMed Central

    Shen, Yinchen; Han, Xiaohong; Wang, Jianfei; Wang, Shuai; Yang, Hongying; Lu, Shih-Hsin; Shi, Yuankai

    2016-01-01

    Development of colorectal cancer (CRC) associates with accumulation of genetic mutations include the epidermal growth factor receptor (EGFR) signaling pathway. However, whether mutations in KRAS together with downstream factors BRAF, PIK3CA and NRAS impact prognosis is still unclear for stage II-III colon cancer. In the present study a total of 228 stage II-III colon cancer samples were retrospectively collected, KRAS (codons 12, 13 and 61), BRAF (exon 11 and exon 15), PIK3CA (exon 9 and exon 20) and NRAS (codons 12, 13 and 61) status was detected by Sanger sequencing, 37.89% (86/227) tumors harbored a KRAS mutation, 7.02% (16/228) harbored a BRAF mutation, 13.18% (29/220) harbored a PIK3CA mutation and 0.89% (2/224) harbored a NRAS mutation. NRAS mutations existed only in stage II colon cancer. Older groups harbored a higher KRAS and BRAF mutation (P < 0.05), PIK3CA (exon9) mutations appeared more common in worse differentiation tumors (P = 0.032). Moreover, PIK3CA (E545K) mutation was significantly associated with tumor recurrence (P = 0.031) and acted independently prognostic for poor OS (P = 0.044), while only in stage III colon cancer. KRAS, BRAF and NRAS mutations do not have major prognostic value in stage II and III colon cancer, subtypes of gene mutations should be further investigated for a better understanding in CRC. PMID:27074743

  12. Factors Affecting the Risk of Brain Metastasis in Small Cell Lung Cancer With Surgery: Is Prophylactic Cranial Irradiation Necessary for Stage I-III Disease?

    SciTech Connect

    Gong Linlin; Wang, Q.I.; Zhao Lujun; Yuan Zhiyong; Li Ruijian; Wang Ping

    2013-01-01

    Purpose: The use of prophylactic cranial irradiation (PCI) in small cell lung cancer (SCLC) with surgical resection has not been fully identified. This study undertook to assess the factors affecting the risk of brain metastases in patients with stage I-III SCLC after surgical resection. The implications of PCI treatment for these patients are discussed. Methods and Materials: One hundred twenty-six patients treated with surgical resection for stage I-III SCLC from January 1998-December 2009 were retrospectively analyzed to elucidate the risk factors of brain metastases. Log-rank test and Cox regression model were used to determine the risk factors of brain metastases. Results: The median survival time for this patient population was 34 months, and the 5-year overall survival rate was 34.9%. For the whole group, 23.0% (29/126) of the patients had evidence of metastases to brain. Pathologic stage not only correlated with overall survival but also significantly affected the risk of brain metastases. The 5-year survival rates for patients with pathologic stages I, II, and III were 54.8%, 35.6%, and 14.1%, respectively (P=.001). The frequency of brain metastases in patients with pathologic stages I, II, and III were 6.25% (2/32), 28.2% (11/39), and 29.1% (16/55) (P=.026), respectively. A significant difference in brain metastases between patients with complete resection and incomplete resection was also observed (20.5% vs 42.9%, P=.028). The frequency of brain metastases was not found to be correlated with age, sex, pathologic type, induction chemotherapy, adjuvant chemotherapy, or adjuvant radiation therapy. Conclusions: Stage I SCLC patients with complete resection had a low incidence of brain metastases and a favorable survival rate. Stage II-III disease had a higher incidence of brain metastases. Thus, PCI might have a role for stage II-III disease but not for stage I disease.

  13. Adenocarcinoma of the Esophagogastric Junction: The Pattern of Metastatic Lymph Node Dissemination as a Rationale for Elective Lymphatic Target Volume Definition

    SciTech Connect

    Meier, Iris; Merkel, Susanne; Papadopoulos, Thomas; Sauer, Rolf; Hohenberger, Werner; Brunner, Thomas B.

    2008-04-01

    Purpose: Regional nodal metastasis after neoadjuvant chemoradiation of adenocarcinoma of the esophagogastric junction (AEG) predicts survival. We aimed to clarify the lymph node (LN) distribution of AEG according to location of the tumor mass and invasion of neighboring areas for the selection of radiotherapy planning target volume (PTV) margins. Methods and Materials: Patterns of regional spread were analyzed in pathology reports of 326 patients patients with AEG who had undergone primary resection, with {>=}15 lymph nodes examined. Tumors were classified into AEG types based on endoscopy and pathology reports. Fisher's exact test was used to compare nodal disease and tumor characteristics. Pulmonary dose-volume histograms were tested in 8 patients. Results: Nodes were positive in 81% of T2 to T4 tumors. Type of AEG, tumor size, lymphovascular invasion, and grading significantly influenced nodal distribution. We found that marked esophageal invasion of AEG II/III significantly correlated with paraesophageal nodal disease, and T3 to T4 AEG II/III had a significant rate of splenic hilum/artery nodes. Middle and lower paraesophageal nodes should be treated in T2 to T4 AEG I and AEG II with {>=}15 mm involvement above the Z-line, and T3 to T4 AEG II. The splenic hilum and artery nodes can be spared in T2 AEG tumors, especially Type I tumors. The influence of paraesophageal nodal treatment on the risk of postoperative pulmonary complications can be estimated from dose-volume histograms. Conclusions: Accurate pretherapeutic staging predicts the risk of subclinical nodal disease and should be used to select the appropriate radiotherapeutic PTV. Careful selection of the PTV can be used to maximize the therapeutic window in multimodal therapy for AEG.

  14. Testicular effects of 3-nitro-1,2,4-triazol-5-one (NTO) in mice when exposed orally.

    PubMed

    Mullins, Anna B; Despain, Kenneth E; Wallace, Shannon M; Honnold, Cary L; May Lent, Emily

    2016-02-01

    3-Nitro-1,2,4-triazol-5-one (NTO) is currently being investigated in the development of insensitive munitions. Rats orally exposed to NTO have demonstrated testicular toxicity in both subacute and subchronic studies; however, toxicity has not been verified in mice. Also, previous studies have not demonstrated the nature of NTO-induced testicular toxicity due to the prolonged dosing regimen utilized and effects of maturation depletion. In this study, a time-course design was used and the earliest pathological changes in testes of adult BALB/c mice orally dosed with NTO in corn oil suspensions at 0, 500 or 1000 mg/kg-day NTO for 1, 3, 7 or 14 d were evaluated. The earliest NTO-induced testicular changes occurred in the 1000 mg/kg-day group at day 7 and the 500 mg/kg-day group at day 14 as evident by the presence of bi- and multinucleated giant cells (MNGCs) of almost all spermatids in an isolated stage II-III tubule/step 2-3 and a stage IX tubule/step 9 in the 1000 and 500 mg/kg-day groups, respectively. Testicular toxicity was characterized by degeneration and the presence of bi- and MNGCs of spermatids (stages II-III and IX), which progressed to additional germ cell degeneration as dosing duration increased. Occasional step 16 spermatid retention was also noted in stage XII and I tubules in the day 14, 1000 mg/kg-day group. These data indicate that NTO is a testicular toxicant in mice and that spermatids are the most sensitive cell. The presence of retained spermatids warrants further investigation regarding NTO's role as a direct Sertoli cell toxicant. PMID:26804465

  15. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury.

    PubMed

    Patil, Naeem K; Parajuli, Nirmala; MacMillan-Crow, Lee Ann; Mayeux, Philip R

    2014-04-01

    Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy, and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 h after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 h. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 h post-CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 h. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-h survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI. PMID:24500690

  16. Observing Supernovae and Supernova Remnants with JWST

    NASA Astrophysics Data System (ADS)

    Sonneborn, George; Temim, Tea; Williams, Brian J.; Blair, William P.

    2015-01-01

    The James Webb Space Telescope (JWST) will enable near- and mid-infrared studies of supernovae (SN) and supernova remnants (SNR) in the Milky Way and galaxies throughout the local universe and to high redshift. JWST's instrumentation provides imaging, coronography, and spectroscopy (R<3000) over the wavelength range 1-29 microns. The unprecedented sensitivity and angular resolution will enable spectroscopic study of new and recent supernovae, including molecule and dust formation, in galaxies at least out to 30 Mpc, and imaging to much greater distances. The Target of Opportunity response time can be as short as 48 hours, enabling quick follow-up observations of important SN events. JWST will be ideal for the study of Galactic and Magellanic Clouds supernova remnants, particularly young remnants with hot dust. Its high angular resolution (0.07" at 2 microns, 0.7" at 20 microns) will allow direct comparison between the IR, optical, and X-ray morphologies, identifying sites of dust emission in both the ejecta and the shocked ISM unresolved by previous IR telescopes. There is a rich spectrum of atomic lines (H, He I, [Si I], [Fe II], [Ni I-III], [Co II-III], [S III-IV], [Ar II-III], [Ne II, III, V], [O IV]) and molecules (CO, SiO, H2) of importance for SN and SNR studies. JWST is a large aperture (6.5m), cryogenic, infrared-optimized space observatory under construction by NASA, ESA, and CSA for launch in 2018. The JWST observatory will be placed in an Earth-Sun L2 orbit by an Ariane 5 launch vehicle provided by ESA. The observatory is designed for a 5-year prime science mission, with consumables for 10 years of science operations. The first call for proposals for JWST observations will be released in 2017.

  17. Long-Term Survival and Local Relapse Following Surgery Without Radiotherapy for Locally Advanced Upper Rectal Cancer

    PubMed Central

    Park, Jun Seok; Sakai, Yoshiharu; Simon, NG Siu Man; Law, Wai Lun; Kim, Hyeong Rok; Oh, Jae Hwan; Shan, Hester Cheung Yui; Kwak, Sang Gyu; Choi, Gyu-Seog

    2016-01-01

    Abstract Controversy remains regarding whether preoperative chemoradiation protocol should be applied uniformly to all rectal cancer patients regardless of tumor height. This pooled analysis was designed to evaluate whether preoperative chemoradiation can be safely omitted in higher rectal cancer. An international consortium of 7 institutions was established. A review of the database that was collected from January 2004 to May 2008 identified a series of 2102 patients with stage II/III rectal or sigmoid cancer (control arm) without concurrent chemoradiation. Data regarding patient demographics, recurrence pattern, and oncological outcomes were analyzed. The primary end point was the 5-year local recurrence rate. The local relapse rate of the sigmoid colon cancer (SC) and upper rectal cancer (UR) cohorts was significantly lower than that of the mid/low rectal cancer group (M-LR), with 5-year estimates of 2.5% for the SC group, 3.5% for the UR group, and 11.1% for the M-LR group, respectively. A multivariate analysis showed that tumor depth, nodal metastasis, venous invasion, and lower tumor level were strongly associated with local recurrence. The cumulative incidence rate of local failure was 90.6%, 92.5%, and 94.4% for tumors located within 5, 7, and 9 cm from the anal verge, respectively. Routine use of preoperative chemoradiation for stage II/III rectal tumors located more than 8 to 9 cm above the anal verge would be excessive. The integration of a more individualized approach focused on systemic control is warranted to improve survival in patients with upper rectal cancer. PMID:27258487

  18. Peptide fragments of the dihydropyridine receptor can modulate cardiac ryanodine receptor channel activity and sarcoplasmic reticulum Ca2+ release.

    PubMed Central

    Dulhunty, Angela F; Curtis, Suzanne M; Cengia, Louise; Sakowska, Magdalena; Casarotto, Marco G

    2004-01-01

    We show that peptide fragments of the dihydropyridine receptor II-III loop alter cardiac RyR (ryanodine receptor) channel activity in a cytoplasmic Ca2+-dependent manner. The peptides were AC (Thr-793-Ala-812 of the cardiac dihydropyridine receptor), AS (Thr-671-Leu-690 of the skeletal dihydropyridine receptor), and a modified AS peptide [AS(D-R18)], with an extended helical structure. The peptides added to the cytoplasmic side of channels in lipid bilayers at > or = 10 nM activated channels when the cytoplasmic [Ca2+] was 100 nM, but either inhibited or did not affect channel activity when the cytoplasmic [Ca2+] was 10 or 100 microM. Both activation and inhibition were independent of bilayer potential. Activation by AS, but not by AC or AS(D-R18), was reduced at peptide concentrations >1 mM in a voltage-dependent manner (at +40 mV). In control experiments, channels were not activated by the scrambled AS sequence (ASS) or skeletal II-III loop peptide (NB). Resting Ca2+ release from cardiac sarcoplasmic reticulum was not altered by peptide AC, but Ca2+-induced Ca2+ release was depressed. Resting and Ca2+-induced Ca2+ release were enhanced by both the native and modified AS peptides. NMR revealed (i) that the structure of peptide AS(D-R18) is not influenced by [Ca2+] and (ii) that peptide AC adopts a helical structure, particularly in the region containing positively charged residues. This is the first report of specific functional interactions between dihydropyridine receptor A region peptides and cardiac RyR ion channels in lipid bilayers. PMID:14678014

  19. A 24-Hour Study of the Hypothalamo-Pituitary Axes in Huntington’s Disease

    PubMed Central

    Nambron, Rajasree; Costelloe, Seán J.; Martin, Nicholas G.; Hill, Nathan R.; Frost, Chris; Watt, Hilary C.; Hindmarsh, Peter; Björkqvist, Maria; Warner, Thomas T.

    2015-01-01

    Background Huntington’s disease is an inherited neurodegenerative disorder characterised by motor, cognitive and psychiatric disturbances. Patients exhibit other symptoms including sleep and mood disturbances, muscle atrophy and weight loss which may be linked to hypothalamic pathology and dysfunction of hypothalamo-pituitary axes. Methods We studied neuroendocrine profiles of corticotropic, somatotropic and gonadotropic hypothalamo-pituitary axes hormones over a 24-hour period in controlled environment in 15 healthy controls, 14 premanifest and 13 stage II/III Huntington’s disease subjects. We also quantified fasting levels of vasopressin, oestradiol, testosterone, dehydroepiandrosterone sulphate, thyroid stimulating hormone, free triiodothyronine, free total thyroxine, prolactin, adrenaline and noradrenaline. Somatotropic axis hormones, growth hormone releasing hormone, insulin-like growth factor-1 and insulin-like factor binding protein-3 were quantified at 06:00 (fasting), 15:00 and 23:00. A battery of clinical tests, including neurological rating and function scales were performed. Results 24-hour concentrations of adrenocorticotropic hormone, cortisol, luteinizing hormone and follicle-stimulating hormone did not differ significantly between the Huntington’s disease group and controls. Daytime growth hormone secretion was similar in control and Huntington’s disease subjects. Stage II/III Huntington’s disease subjects had lower concentration of post-sleep growth hormone pulse and higher insulin-like growth factor-1:growth hormone ratio which did not reach significance. In Huntington’s disease subjects, baseline levels of hypothalamo-pituitary axis hormones measured did not significantly differ from those of healthy controls. Conclusions The relatively small subject group means that the study may not detect subtle perturbations in hormone concentrations. A targeted study of the somatotropic axis in larger cohorts may be warranted. However, the lack

  20. Emission lines in the optical spectrum of 3 Cen A

    NASA Astrophysics Data System (ADS)

    Wahlgren, G. M.; Hubrig, S.

    2004-05-01

    Previously, weak emission lines had been detected at red wavelengths in the spectra of a limited sample of mid to late B type main sequence stars. A fuller description of the occurrence and origins of these lines has yet to be forwarded, in part due to the lack of observations detailing the spectral transitions involved. To address this deficiency, we present a line list of weak emission features found in the optical and near infrared spectral region of the chemically peculiar He-weak star 3 Cen A (HD 120709). Nearly 350 features, mostly associated with allowed transitions from high-excitation states of first ions, are catalogued along with identifications. Prominent among the emission lines are the spectra P II, Mn II, Fe II, Ni II and Cu II. Emission lines from Ca II, Si II and Hg II are also evident. Abundances are determined for several elements from synthetic spectrum fitting, with anomalies detected for the ions O I/II, P II/III and Si II/III. The LTE synthetic spectrum fitting also revealed that the low excitation 4s-4p transitions of Fe II predict an abundance that is greater than that determined from higher excitation 4d-4f transitions. Several of these latter transitions have upper energy levels that are found to be associated with emission lines. We also present empirical considerations for the excitation processes leading to the weak emission lines. Based on observations obtained at the European Southern Observatory, La Silla, Chile, No. 65.L-0316 and Paranal, Chile No. 266.D-5655. Tables 2 and 3 are only available in electronic form at the CDS via anonymous ftp to cdsarc.u-strasbg.fr (130.79.128.5) or via http://cdsweb.u-strasbg.fr/cgi-bin/qcat?J/A+A/418/1073

  1. The origin of oil in the Cretaceous succession from the South Pars Oil Layer of the Persian Gulf

    NASA Astrophysics Data System (ADS)

    Rahmani, Omeid; Aali, Jafar; Junin, Radzuan; Mohseni, Hassan; Padmanabhan, Eswaran; Azdarpour, Amin; Zarza, Sahar; Moayyed, Mohsen; Ghazanfari, Parviz

    2013-07-01

    The origin of the oil in Barremian-Hauterivian and Albian age source rock samples from two oil wells (SPO-2 and SPO-3) in the South Pars oil field has been investigated by analyzing the quantity of total organic carbon (TOC) and thermal maturity of organic matter (OM). The source rocks were found in the interval 1,000-1,044 m for the Kazhdumi Formation (Albian) and 1,157-1,230 m for the Gadvan Formation (Barremian-Hauterivian). Elemental analysis was carried out on 36 samples from the source rock candidates (Gadvan and Kazhdumi formations) of the Cretaceous succession of the South Pars Oil Layer (SPOL). This analysis indicated that the OM of the Barremian-Hauterivian and Albian samples in the SPOL was composed of kerogen Types II and II-III, respectively. The average TOC of analyzed samples is less than 1 wt%, suggesting that the Cretaceous source rocks are poor hydrocarbon (HC) producers. Thermal maturity and Ro values revealed that more than 90 % of oil samples are immature. The source of the analyzed samples taken from Gadvan and Kazhdumi formations most likely contained a content high in mixed plant and marine algal OM deposited under oxic to suboxic bottom water conditions. The Pristane/nC17 versus Phytane/nC18 diagram showed Type II-III kerogen of mixture environments for source rock samples from the SPOL. Burial history modeling indicates that at the end of the Cretaceous time, pre-Permian sediments remained immature in the Qatar Arch. Therefore, lateral migration of HC from the nearby Cretaceous source rock kitchens toward the north and south of the Qatar Arch is the most probable origin for the significant oils in the SPOL.

  2. Predictors of recurrence free survival for patients with stage II and III colon cancer

    PubMed Central

    2014-01-01

    Background The aim of this study was to evaluate clinico-pathologic specific predictors of recurrence for stage II/III disease. Improving recurrence prediction for resected stage II/III colon cancer patients could alter surveillance strategies, providing opportunities for more informed use of chemotherapy for high risk individuals. Methods 871 stage II and 265 stage III patients with colon cancers were included. Features studied included surgery date, age, gender, chemotherapy, tumor location, number of positive lymph nodes, tumor differentiation, and lymphovascular and perineural invasion. Time to recurrence was evaluated, using Cox’s proportional hazards models. The predictive ability of the multivariable models was evaluated using the concordance (c) index. Results For stage II cancer patients, estimated recurrence-free survival rates at one, three, five, and seven years following surgery were 98%, 92%, 90%, and 89%. Only T stage was significantly associated with recurrence. Estimated recurrence-free survival rates for stage III patients at one, three, five, and seven years following surgery were 94%, 78%, 70%, and 66%. Higher recurrence rates were seen in patients who didn’t receive chemotherapy (p = 0.023), with a higher number of positive nodes (p < 0.001). The c-index for the stage II model was 0.55 and 0.68 for stage III. Conclusions Current clinic-pathologic information is inadequate for prediction of colon cancer recurrence after resection for stage II and IIII patients. Identification and clinical use of molecular markers to identify the earlier stage II and III colon cancer patients at elevated risk of recurrence are needed to improve prognostication of early stage colon cancers. PMID:24886281

  3. Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas

    PubMed Central

    Healy, Patrick; Reitman, Zachary J.; Lipp, Eric; Rasheed, B. Ahmed; Yang, Rui; Diplas, Bill H.; Wang, Zhaohui; Greer, Paula K.; Zhu, Huishan; Wang, Catherine Y.; Carpenter, Austin B.; Friedman, Henry; Friedman, Allan H.; Keir, Stephen T.; He, Jie; He, Yiping; McLendon, Roger E.; Herndon II, James E.; Yan, Hai; Bigner, Darell D.

    2014-01-01

    Frequent mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) and the promoter of telomerase reverse transcriptase (TERT) represent two significant discoveries in glioma genomics. Understanding the degree to which these two mutations co-occur or occur exclusively of one another in glioma subtypes presents a unique opportunity to guide glioma classification and prognosis. We analyzed the relationship between overall survival (OS) and the presence of IDH1/2 and TERT promoter mutations in a panel of 473 adult gliomas. We hypothesized and show that genetic signatures capable of distinguishing among several types of gliomas could be established providing clinically relevant information that can serve as an adjunct to histopathological diagnosis. We found that mutations in the TERT promoter occurred in 74.2% of glioblastomas (GBM), but occurred in a minority of Grade II-III astrocytomas (18.2%). In contrast, IDH1/2 mutations were observed in 78.4% of Grade II-III astrocytomas, but were uncommon in primary GBM. In oligodendrogliomas, TERT promoter and IDH1/2 mutations co-occurred in 79% of cases. Patients whose Grade III-IV gliomas exhibit TERT promoter mutations alone predominately have primary GBMs associated with poor median OS (11.5 months). Patients whose Grade III-IV gliomas exhibit IDH1/2 mutations alone predominately have astrocytic morphologies and exhibit a median OS of 57 months while patients whose tumors exhibit both TERT promoter and IDH1/2 mutations predominately exhibit oligodendroglial morphologies and exhibit median OS of 125 months. Analyzing gliomas based on their genetic signatures allows for the stratification of these patients into distinct cohorts, with unique prognosis and survival. PMID:24722048

  4. Long-Term Survival and Local Relapse Following Surgery Without Radiotherapy for Locally Advanced Upper Rectal Cancer: An International Multi-Institutional Study.

    PubMed

    Park, Jun Seok; Sakai, Yoshiharu; Simon, Ng Siu Man; Law, Wai Lun; Kim, Hyeong Rok; Oh, Jae Hwan; Shan, Hester Cheung Yui; Kwak, Sang Gyu; Choi, Gyu-Seog

    2016-05-01

    Controversy remains regarding whether preoperative chemoradiation protocol should be applied uniformly to all rectal cancer patients regardless of tumor height. This pooled analysis was designed to evaluate whether preoperative chemoradiation can be safely omitted in higher rectal cancer.An international consortium of 7 institutions was established. A review of the database that was collected from January 2004 to May 2008 identified a series of 2102 patients with stage II/III rectal or sigmoid cancer (control arm) without concurrent chemoradiation. Data regarding patient demographics, recurrence pattern, and oncological outcomes were analyzed. The primary end point was the 5-year local recurrence rate.The local relapse rate of the sigmoid colon cancer (SC) and upper rectal cancer (UR) cohorts was significantly lower than that of the mid/low rectal cancer group (M-LR), with 5-year estimates of 2.5% for the SC group, 3.5% for the UR group, and 11.1% for the M-LR group, respectively. A multivariate analysis showed that tumor depth, nodal metastasis, venous invasion, and lower tumor level were strongly associated with local recurrence. The cumulative incidence rate of local failure was 90.6%, 92.5%, and 94.4% for tumors located within 5, 7, and 9 cm from the anal verge, respectively.Routine use of preoperative chemoradiation for stage II/III rectal tumors located more than 8 to 9 cm above the anal verge would be excessive. The integration of a more individualized approach focused on systemic control is warranted to improve survival in patients with upper rectal cancer. PMID:27258487

  5. Age-dependent actions of dopamine on inhibitory synaptic transmission in superficial layers of mouse prefrontal cortex.

    PubMed

    Paul, Kush; Cox, Charles L

    2013-03-01

    Numerous developmental changes in the nervous system occur during the first several weeks of the rodent lifespan. Therefore, many characteristics of neuronal function described at the cellular level from in vitro slice experiments conducted during this early time period may not generalize to adult ages. We investigated the effect of dopamine (DA) on inhibitory synaptic transmission in superficial layers of the medial prefrontal cortex (PFC) in prepubertal [postnatal age (P; days) 12-20], periadolescent (P30-48), and adult (P70-100) mice. The PFC is associated with higher-level cognitive functions, such as working memory, and is associated with initiation, planning, and execution of actions, as well as motivation and cognition. It is innervated by DA-releasing fibers that arise from the ventral tegmental area. In slices from prepubertal mice, DA produced a biphasic modulation of inhibitory postsynaptic currents (IPSCs) recorded in layer II/III pyramidal neurons. Activation of D2-like receptors leads to an early suppression of the evoked IPSC, which was followed by a longer-lasting facilitation of the IPSC mediated by D1-like DA receptors. In periadolescent mice, the D2 receptor-mediated early suppression was significantly smaller compared with the prepubertal animals and absent in adult animals. Furthermore, we found significant differences in the DA-mediated lasting enhancement of the inhibitory response among the developmental groups. Our findings suggest that behavioral paradigms that elicit dopaminergic release in the PFC differentially modulate inhibition of excitatory pyramidal neuron output in prepuberty compared with periadolescence and adulthood in the superficial layers (II/III) of the cortex. PMID:23221420

  6. A polymorphism at the 3'-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole

    PubMed Central

    2010-01-01

    Background Aromatase (CYP19A1) regulates estrogen biosynthesis. Polymorphisms in CYP19A1 have been related to the pathogenesis of breast cancer (BC). Inhibition of aromatase with letrozole constitutes the best option for treating estrogen-dependent BC in postmenopausal women. We evaluate a series of polymorphisms of CYP19A1 and their effect on response to neoadjuvant letrozole in early BC. Methods We analyzed 95 consecutive postmenopausal women with stage II-III ER/PgR [+] BC treated with neoadjuvant letrozole. Response to treatment was measured by radiology at 4th month by World Health Organization (WHO) criteria. Three polymorphisms of CYP19A1, one in exon 7 (rs700519) and two in the 3'-UTR region (rs10046 and rs4646) were evaluated on DNA obtained from peripheral blood. Results Thirty-five women (36.8%) achieved a radiological response to letrozole. The histopathological and immunohistochemical parameters, including hormonal receptor status, were not associated with the response to letrozole. Only the genetic variants (AC/AA) of the rs4646 polymorphism were associated with poor response to letrozole (p = 0.03). Eighteen patients (18.9%) reported a progression of the disease. Those patients carrying the genetic variants (AC/AA) of rs4646 presented a lower progression-free survival than the patients homozygous for the reference variant (p = 0.0686). This effect was especially significant in the group of elderly patients not operated after letrozole induction (p = 0.009). Conclusions Our study reveals that the rs4646 polymorphism identifies a subgroup of stage II-III ER/PgR [+] BC patients with poor response to neoadjuvant letrozole and poor prognosis. Testing for the rs4646 polymorphism could be a useful tool in order to orientate the treatment in elderly BC patients. PMID:20144226

  7. Inactivation of renal mitochondrial respiratory complexes and manganese superoxide dismutase during sepsis: mitochondria-targeted antioxidant mitigates injury

    PubMed Central

    Patil, Naeem K.; Parajuli, Nirmala; Mayeux, Philip R.

    2014-01-01

    Acute kidney injury (AKI) is a complication of sepsis and leads to a high mortality rate. Human and animal studies suggest that mitochondrial dysfunction plays an important role in sepsis-induced multi-organ failure; however, the specific mitochondrial targets damaged during sepsis remain elusive. We used a clinically relevant cecal ligation and puncture (CLP) murine model of sepsis and assessed renal mitochondrial function using high-resolution respirometry, renal microcirculation using intravital microscopy, and renal function. CLP caused a time-dependent decrease in mitochondrial complex I and II/III respiration and reduced ATP. By 4 h after CLP, activity of manganese superoxide dismutase (MnSOD) was decreased by 50% and inhibition was sustained through 36 h. These events were associated with increased mitochondrial superoxide generation. We then evaluated whether the mitochondria-targeted antioxidant Mito-TEMPO could reverse renal mitochondrial dysfunction and attenuate sepsis-induced AKI. Mito-TEMPO (10 mg/kg) given at 6 h post-CLP decreased mitochondrial superoxide levels, protected complex I and II/III respiration, and restored MnSOD activity by 18 h. Mito-TEMPO also improved renal microcirculation and glomerular filtration rate. Importantly, even delayed therapy with a single dose of Mito-TEMPO significantly increased 96-h survival rate from 40% in untreated septic mice to 80%. Thus, sepsis causes sustained inactivation of three mitochondrial targets that can lead to increased mitochondrial superoxide. Importantly, even delayed therapy with Mito-TEMPO alleviated kidney injury, suggesting that it may be a promising approach to treat septic AKI. PMID:24500690

  8. Patterns of Care and Outcomes of Adjuvant Radiotherapy for Meningiomas: A Surveillance, Epidemiology, and End Results and Medicare Linked Analysis

    PubMed Central

    Ugiliweneza, Beatrice; Burton, Eric; Skirboll, Stephen; Woo, Shiao; Boakye, Max

    2016-01-01

    Background: The role of adjuvant stereotactic radiosurgery (SRS) and fractionated radiotherapy (XRT) are unknown in patients with resected meningiomas. Objective: To identify patterns of care and outcomes of adjuvant radiotherapy for meningiomas in the Linked Surveillance, Epidemiology, and End Results (SEER) Medicare data. Methods: A total of 1,964 patients older than 66 years included in the SEER-Medicare data, who were diagnosed with meningioma, and underwent craniotomy were included for analysis. Results: Patients were less likely to receive adjuvant therapy if they were older than 75 (OR 0.730, 95% CI 0.548-0.973), female sex (OR 0.731, 95% CI 0.547-0.978), or unmarried (OR 0.692, 95% CI 0.515-0.929). Patients were more likely to receive adjuvant treatment for Grade II/III tumors (OR 5.586, 95% CI 2.135-13.589), tumors over 5 cm (OR 1.850, 95% CI 1.332-2.567), or partial resection (OR 3.230, 95% CI 2.327-4.484). Yearly between 2000 and 2009, 10.65 – 19.77% of patients received adjuvant therapy. Although no survival benefit was seen with the addition of adjuvant therapy (p = 0.1236), the subgroup of patients receiving SRS had a decreased risk of death compared to those receiving surgery alone (aHR 0.544, 95% CI 0.318 – 0.929). Conclusion: Utilization of adjuvant XRT and SRS remained stable between 2000 and 2010. Male sex, young age, marriage, partial resection, Grade II/III tumors, and large tumors predicted the use of adjuvant therapy. For all patients, SRS decreased the risk of death compared to craniotomy alone.

  9. Effects of High-Intensity Interval Training versus Continuous Training on Physical Fitness, Cardiovascular Function and Quality of Life in Heart Failure Patients

    PubMed Central

    Benda, Nathalie M. M.; Seeger, Joost P. H.; Stevens, Guus G. C. F.; Hijmans-Kersten, Bregina T. P.; van Dijk, Arie P. J.; Bellersen, Louise; Lamfers, Evert J. P.; Hopman, Maria T. E.; Thijssen, Dick H. J.

    2015-01-01

    Introduction Physical fitness is an important prognostic factor in heart failure (HF). To improve fitness, different types of exercise have been explored, with recent focus on high-intensity interval training (HIT). We comprehensively compared effects of HIT versus continuous training (CT) in HF patients NYHA II-III on physical fitness, cardiovascular function and structure, and quality of life, and hypothesize that HIT leads to superior improvements compared to CT. Methods Twenty HF patients (male:female 19:1, 64±8 yrs, ejection fraction 38±6%) were allocated to 12-weeks of HIT (10*1-minute at 90% maximal workload—alternated by 2.5 minutes at 30% maximal workload) or CT (30 minutes at 60–75% of maximal workload). Before and after intervention, we examined physical fitness (incremental cycling test), cardiac function and structure (echocardiography), vascular function and structure (ultrasound) and quality of life (SF-36, Minnesota living with HF questionnaire (MLHFQ)). Results Training improved maximal workload, peak oxygen uptake (VO2peak) related to the predicted VO2peak, oxygen uptake at the anaerobic threshold, and maximal oxygen pulse (all P<0.05), whilst no differences were present between HIT and CT (N.S.). We found no major changes in resting cardiovascular function and structure. SF-36 physical function score improved after training (P<0.05), whilst SF-36 total score and MLHFQ did not change after training (N.S.). Conclusion Training induced significant improvements in parameters of physical fitness, although no evidence for superiority of HIT over CT was demonstrated. No major effect of training was found on cardiovascular structure and function or quality of life in HF patients NYHA II-III. Trial Registration Nederlands Trial Register NTR3671 PMID:26517867

  10. Improving efficiency and reducing costs: Design of an adaptive, seamless, and enriched pragmatic efficacy trial of an online asthma management program☆,☆☆,★

    PubMed Central

    Lu, Mei; Ownby, Dennis R.; Zoratti, Edward; Roblin, Douglas; Johnson, Dayna; Johnson, Christine Cole; Joseph, Christine L.M.

    2014-01-01

    Clinical trials are critical for medical decision-making, however, under the current paradigm, clinical trials are fraught with problems including low enrollment and high cost. Promising alternatives to increase trial efficiency and reduce costs include the use of (1) electronic initiatives that permit electronic remote data capture (EDC) for direct data collection at a site (2), electronic medical records (EMR) for patient identification and data collection, and (3) adaptive, enrichment designs with pragmatic approaches. We describe the design of a seamless, multi-site randomized Phase II/III trial to evaluate an asthma management intervention in urban adolescents with asthma. Patients are randomized, asked to access four online sessions of the intervention or control asthma management program, and are then followed for one year. The primary efficacy endpoint is self-reported asthma control as measured by the Asthma Control Test (ACT). Comparative effectiveness parametric approaches are utilized to conduct the trial in a real world setting with reduced costs. Escalated electronic initiatives are implemented for patient identification, assent, enrollment and tracking. Patient enrollment takes place during primary care visits. A centralized database with EDC is used for CRF data collection with integration of EMR data. This Phase II/III trial plans to have a total sample size of 500 patients with an interim look at the completion of Phase II (n = 250), The interim analyses include an assessment of the intervention effect, marker(s) identification and the feasibility study of EMR data as the trial CRF data collection. Patient enrollment has begun and is ongoing. PMID:24607295

  11. Verbal Inflectional Morphology in L1 and L2 Spanish: A Frequency Effects Study Examining Storage versus Composition

    PubMed Central

    Bowden, Harriet Wood; Gelfand, Matthew P.; Sanz, Cristina; Ullman, Michael T.

    2009-01-01

    This study examines the storage vs. composition of Spanish inflected verbal forms in L1 and L2 speakers of Spanish. L2 participants were selected to have mid-to-advanced proficiency, high classroom experience, and low immersion experience, typical of medium-to-advanced foreign language learners. Participants were shown the infinitival forms of verbs from either Class I (the default class, which takes new verbs) or Classes II and III (non-default classes), and were asked to produce either first-person singular present-tense or imperfect forms, in separate tasks. In the present tense, the L1 speakers showed inflected-form frequency effects (i.e., higher frequency forms were produced faster, which is taken as a reflection of storage) for stem-changing (irregular) verb-forms from both Class I (e.g., pensar-pienso) and Classes II and III (e.g., perder-pierdo), as well as for non-stem-changing (regular) forms in Classes II/III (e.g., vender-vendo), in which the regular transformation does not appear to constitute a default. In contrast, Class I regulars (e.g., pescar-pesco), whose non-stem-changing transformation constitutes a default (e.g., it is applied to new verbs), showed no frequency effects. L2 speakers showed frequency effects for all four conditions (Classes I and II/III, regulars and irregulars). In the imperfect tense, the L1 speakers showed frequency effects for Class II/III (-ía-suffixed) but not Class I (-aba-suffixed) forms, even though both involve non-stem-change (regular) default transformations. The L2 speakers showed frequency effects for both types of forms. The pattern of results was not explained by a wide range of potentially confounding experimental and statistical factors, and does not appear to be compatible with single-mechanism models, which argue that all linguistic forms are learned and processed in associative memory. The findings are consistent with a dual-system view in which both verb class and regularity influence the storage vs

  12. Differential inhibitory effects of methylmalonic acid on respiratory chain complex activities in rat tissues.

    PubMed

    Pettenuzzo, Leticia F; Ferreira, Gustavo da C; Schmidt, Anna Laura; Dutra-Filho, Carlos S; Wyse, Angela T S; Wajner, Moacir

    2006-02-01

    Methylmalonic acidemia is an inherited metabolic disorder biochemically characterized by tissue accumulation of methylmalonic acid (MMA) and clinically by progressive neurological deterioration and kidney failure, whose pathophysiology is so far poorly established. Previous studies have shown that MMA inhibits complex II of the respiratory chain in rat cerebral cortex, although no inhibition of complexes I-V was found in bovine heart. Therefore, in the present study we investigated the in vitro effect of 2.5mM MMA on the activity of complexes I-III, II, II-III and IV in striatum, hippocampus, heart, liver and kidney homogenates from young rats. We observed that MMA caused a significant inhibition of complex II activity in striatum and hippocampus (15-20%) at low concentrations of succinate in the medium, but not in the peripheral tissues. We also verified that the inhibitory property of MMA only occurred after exposing brain homogenates for at least 10 min with the acid, suggesting that this inhibition was mediated by indirect mechanisms. Simultaneous preincubation with the nitric oxide synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) and catalase (CAT) plus superoxide dismutase (SOD) did not prevent MMA-induced inhibition of complex II, suggesting that common reactive oxygen (superoxide, hydrogen peroxide and hydroxyl radical) and nitric (nitric oxide) species were not involved in this effect. In addition, complex II-III (20-35%) was also inhibited by MMA in all tissues tested, and complex I-III only in the kidney (53%) and liver (38%). In contrast, complex IV activity was not changed by MMA in all tissues studied. These results indicate that MMA differentially affects the activity of the respiratory chain pending on the tissues studied, being striatum and hippocampus more vulnerable to its effect. In case our in vitro data are confirmed in vivo in tissues from methylmalonic acidemic patients, it is feasible that that the present findings may be

  13. Efficacy of Addition of Antiangiogenic Agents to Taxanes-Containing Chemotherapy in Advanced Nonsmall-Cell Lung Cancer

    PubMed Central

    Sheng, Jin; Yang, Yun-Peng; Yang, Bi-Jun; Zhao, Yuan-Yuan; Ma, Yu-Xiang; Hong, Shao-Dong; Zhang, Ya-Xiong; Zhao, Hong-Yun; Huang, Yan; Zhang, Li

    2015-01-01

    Abstract Preclinical researches indicated a potential synergistic effect of taxanes-containing chemotherapy (TCC) and antiangiogenic agents (AAs) on the treatment of advanced nonsmall-cell lung cancer (NSCLC). The advantage of adding AA to TCC in the real world remains confusing. We summarized the current evidences from relevant phase II/III randomized controlled trials (RCTs) by performing this meta-analyses. Electronic databases were searched for eligible literatures. The primary endpoint was overall survival (OS). Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes were calculated using RevMan 5.2. A total of 14 phase II/III RCTs involving 9703 participants were included. Compared to standard TCC, the addition of AA was associated with the significant better OS (HR 0.92, 95% CI 0.87–0.97, P = 0.002), prolonged progression-free survival (HR 0.79, 95% CI 0.71–0.87, P < 0.00001), superior response rate (risk ratio [RR] 1.69, 95% CI 1.47–1.95, P < 0.0001), and disease control rate (RR 1.19, 95% CI 1.08–1.32, P < 0.00001). Subgroup analyses indicated that patient treated with monoclonal antibodies (HR 0.89, 95% CI 0.82–0.96, P = 0.02) as well as application in second-line (HR 0.91, 95% CI 0.85–0.96, P = 0.02) acquired significant OS improvement. Other clinical factors directing significant OS improvement by the combination strategy included nonsquamous cancer (P = 0.002), nonsmokers (P = 0.0005), and female (P = 0.02). Toxicities were greater but generally mild or moderate in the combination group, and were mostly manageable. In summary, the addition of AAs to TCC could improve prognosis of advanced NSCLC. Furthermore, proper selection of patient population and AAs is crucial for clinical trials design and clinical practice in the future. PMID:26252298

  14. Should Splenic Hilar Lymph Nodes be Dissected for Siewert Type II and III Esophagogastric Junction Carcinoma Based on Tumor Diameter?

    PubMed Central

    Lv, Chen-Bin; Huang, Chang-Ming; Zheng, Chao-Hui; Li, Ping; Xie, Jian-Wei; Wang, Jia-Bin; Lin, Jian-Xian; Lu, Jun; Chen, Qi-Yue; Cao, Long-Long; Lin, Mi; Tu, Ru-Hong

    2016-01-01

    Abstract The aim of the study is to identify the value of a spleen-preserving No. 10 lymphadenectomy (SPL) for Siewert type II/III adenocarcinoma of the esophagogastric junction (AEG). From January 2007 to June 2014, 694 patients undergoing radical total gastrectomy for Siewert type II/III AEG were analyzed. Oncologic outcomes were compared between SPL and no SPL (No. 10D+ and No. 10D–) groups. The incidence of No. 10 lymph node metastasis (LNM) was 12.3%. No significant differences in the incidence of No. 10 LNM were found between Siewert type II AEG with tumor diameters of <4 cm and ≥4 cm (P = 0.071). However, Siewert type III AEG with a tumor diameter ≥4 cm showed a significantly higher frequency of No. 10 LNM compared with a tumor diameter <4 cm (P < 0.001). The No. 10D+ group had superior 3-year overall survival (OS) and disease-free survival (DFS) rates compared with the No. 10D− group (P = 0.030 and P = 0.005, respectively). For patients with Siewert type II and type III AEG with a tumor diameter <4 cm, the 3-year OS and DFS rates were similar between the 2 groups. However, the No. 10D+ group had better 3-year OS (66.6% vs 51.1%, P = 0.019) and DFS (63.2% vs 45.9%, P = 0.007) rates for Siewert type III AEG with a tumor diameter ≥4 cm. A multivariate Cox regression showed that SPL was an independent prognostic factor in Siewert type III AEG with a tumor diameter ≥4 cm. SPL may improve the prognosis of Siewert type III AEG with a tumor diameter ≥4 cm, whereas SPL may be omitted without decreasing survival in patients with Siewert type II or type III AEG with a tumor diameter <4 cm. PMID:27227913

  15. Contributions of principal neocortical neurons to magnetoencephalography and electroencephalography signals

    PubMed Central

    Murakami, Shingo; Okada, Yoshio

    2006-01-01

    A realistically shaped three-dimensional single-neuron model was constructed for each of four principal cell types in the neocortex in order to infer their contributions to magnetoencephalography (MEG) and electroencephalography (EEG) signals. For each cell, the soma was stimulated and the resulting intracellular current was used to compute the current dipole Q for the whole cell or separately for the apical and basal dendrites. The magnitude of Q is proportional to the magnetic field and electrical potential far from the neuron. A train of spikes and depolarization shift in an intracellular burst discharge were seen as spikes and an envelope in Q for the layer V and layer II/III pyramidal cells. The stellate cells lacked the envelope. As expected, the pyramidal cells produced a stronger Q than the stellate cells. The spikes produced by the layer V pyramidal cells (n = 4) varied between −0.78 and 2.97 pA m with the majority of the cells showing a current toward the pia (defined as positive). The basal dendrites, however, produced considerable spike currents. The magnitude and direction of dipole moment are in agreement with the distribution of the dendrites. The spikes in Q for the layer V pyramidal cells were produced by the transient sodium conductance and potassium conductance of delayed rectifier type; the conductances distributed along the dendrites were capable of generating spike propagation, which was seen in Q as the tail of a triphasic wave lasting several milliseconds. The envelope was similar in magnitude (−0.41 to −0.90 pA m) across the four layer V pyramidal cells. The spike and envelope for the layer II/III pyramidal cell were 0.47 and −0.29 pA m, respectively; these values agreed well with empirical and theoretical estimates for guinea pig CA3 pyramidal cells. Spikes were stronger for the layer IV spiny stellate (0.27 pA m) than the layer III aspiny stellate cell (0.06 pA m) along their best orientations. The spikes may thus be stronger than

  16. Pharmacogenetic Study in Rectal Cancer Patients Treated With Preoperative Chemoradiotherapy: Polymorphisms in Thymidylate Synthase, Epidermal Growth Factor Receptor, GSTP1, and DNA Repair Genes

    SciTech Connect

    Paez, David; Salazar, Juliana; Pare, Laia; Pertriz, Lourdes; Targarona, Eduardo; Rio, Elisabeth del; Barnadas, Agusti; Marcuello, Eugenio; Baiget, Montserrat

    2011-12-01

    Purpose: Several studies have been performed to evaluate the usefulness of neoadjuvant treatment using oxaliplatin and fluoropyrimidines for locally advanced rectal cancer. However, preoperative biomarkers of outcome are lacking. We studied the polymorphisms in thymidylate synthase, epidermal growth factor receptor, glutathione S-transferase pi 1 (GSTP1), and several DNA repair genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 128 rectal cancer patients treated with preoperative chemoradiotherapy. Methods and Materials: Blood samples were obtained from 128 patients with Stage II-III rectal cancer. DNA was extracted from the peripheral blood nucleated cells, and the genotypes were analyzed by polymerase chain reaction amplification and automated sequencing techniques or using a 48.48 dynamic array on the BioMark system. The germline polymorphisms studied were thymidylate synthase, (VNTR/5 Prime UTR, 2R G>C single nucleotide polymorphism [SNP], 3R G>C SNP), epidermal growth factor receptor (Arg497Lys), GSTP1 (Ile105val), excision repair cross-complementing 1 (Asn118Asn, 8092C>A, 19716G>C), X-ray repair cross-complementing group 1 (XRCC1) (Arg194Trp, Arg280His, Arg399Gln), and xeroderma pigmentosum group D (Lys751Gln). The pathologic response, pathologic regression, progression-free survival, and overall survival were evaluated according to each genotype. Results: The Asterisk-Operator 3/ Asterisk-Operator 3 thymidylate synthase genotype was associated with a greater response rate (pathologic complete remission and microfoci residual tumor, 59% in Asterisk-Operator 3/ Asterisk-Operator 3 vs. 35% in Asterisk-Operator 2/ Asterisk-Operator 2 and Asterisk-Operator 2/ Asterisk-Operator 3; p = .013). For the thymidylate synthase genotype, the median progression-free survival was 103 months for the Asterisk-Operator 3/ Asterisk-Operator 3 patients and 84 months for the Asterisk-Operator 2/ Asterisk-Operator 2 and Asterisk-Operator 2/ Asterisk

  17. Two-Center/Three-Electron Sigma Half-Bonds in Main Group and Transition Metal Chemistry.

    PubMed

    Berry, John F

    2016-01-19

    First proposed in a classic Linus Pauling paper, the two-center/three-electron (2c/3e) σ half-bond challenges the extremes of what may or may not be considered a chemical bond. Two electrons occupying a σ bonding orbital and one electron occupying the antibonding σ* orbital results in bond orders of ∼0.5 that are characteristic of metastable and exotic species, epitomized in the fleetingly stable He2(+) ion. In this Account, I describe the use of coordination chemistry to stabilize such fugacious three-electron bonded species at disparate ends of the periodic table. A recent emphasis in the chemistry of metal-metal bonds has been to prepare compounds with extremely short metal-metal distances and high metal-metal bond orders. But similar chemistry can be used to explore metal-metal bond orders less than one, including 2c/3e half-bonds. Bimetallic compounds in the Ni2(II,III) and Pd2(II,III) oxidation states were originally examined in the 1980s, but the evidence collected at that time suggested that they did not contain 2c/3e σ bonds. Both classes of compounds have been re-examined using EPR spectroscopy and modern computational methods that show the unpaired electron of each compound to occupy a M-M σ* orbital, consistent with 2c/3e Ni-Ni and Pd-Pd σ half-bonds. Elsewhere on the periodic table, a seemingly unrelated compound containing a trigonal bipyramidal Cu3S2 core caused a stir, leaving prominent theorists at odds with one another as to whether the compound contains a S-S bond. Due to my previous experience with 2c/3e metal-metal bonds, I suggested that the Cu3S2 compound could contain a 2c/3e S-S σ half-bond in the previously unknown oxidation state of S2(3-). By use of the Cambridge Database, a number of other known compounds were identified as potentially containing S2(3-) ligands, including a noteworthy set of cyclopentadienyl-supported compounds possessing diamond-shaped Ni2E2 units with E = S, Se, and Te. These compounds were subjected to

  18. Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success.

    PubMed

    Pogue, Brian W; Elliott, Jonathan T; Kanick, Stephen C; Davis, Scott C; Samkoe, Kimberley S; Maytin, Edward V; Pereira, Stephen P; Hasan, Tayyaba

    2016-04-01

    Photodynamic therapy (PDT) can be a highly complex treatment, with many parameters influencing treatment efficacy. The extent to which dosimetry is used to monitor and standardize treatment delivery varies widely, ranging from measurement of a single surrogate marker to comprehensive approaches that aim to measure or estimate as many relevant parameters as possible. Today, most clinical PDT treatments are still administered with little more than application of a prescribed drug dose and timed light delivery, and thus the role of patient-specific dosimetry has not reached widespread clinical adoption. This disconnect is at least partly due to the inherent conflict between the need to measure and understand multiple parameters in vivo in order to optimize treatment, and the need for expedience in the clinic and in the regulatory and commercialization process. Thus, a methodical approach to selecting primary dosimetry metrics is required at each stage of translation of a treatment procedure, moving from complex measurements to understand PDT mechanisms in pre-clinical and early phase I trials, towards the identification and application of essential dose-limiting and/or surrogate measurements in phase II/III trials. If successful, identifying the essential and/or reliable surrogate dosimetry measurements should help facilitate increased adoption of clinical PDT. In this paper, examples of essential dosimetry points and surrogate dosimetry tools that may be implemented in phase II/III trials are discussed. For example, the treatment efficacy as limited by light penetration in interstitial PDT may be predicted by the amount of contrast uptake in CT, and so this could be utilized as a surrogate dosimetry measurement to prescribe light doses based upon pre-treatment contrast. Success of clinical ALA-based skin lesion treatment is predicted almost uniquely by the explicit or implicit measurements of photosensitizer and photobleaching, yet the individualization of treatment

  19. Revisiting photodynamic therapy dosimetry: reductionist & surrogate approaches to facilitate clinical success

    NASA Astrophysics Data System (ADS)

    Pogue, Brian W.; Elliott, Jonathan T.; Kanick, Stephen C.; Davis, Scott C.; Samkoe, Kimberley S.; Maytin, Edward V.; Pereira, Stephen P.; Hasan, Tayyaba

    2016-04-01

    Photodynamic therapy (PDT) can be a highly complex treatment, with many parameters influencing treatment efficacy. The extent to which dosimetry is used to monitor and standardize treatment delivery varies widely, ranging from measurement of a single surrogate marker to comprehensive approaches that aim to measure or estimate as many relevant parameters as possible. Today, most clinical PDT treatments are still administered with little more than application of a prescribed drug dose and timed light delivery, and thus the role of patient-specific dosimetry has not reached widespread clinical adoption. This disconnect is at least partly due to the inherent conflict between the need to measure and understand multiple parameters in vivo in order to optimize treatment, and the need for expedience in the clinic and in the regulatory and commercialization process. Thus, a methodical approach to selecting primary dosimetry metrics is required at each stage of translation of a treatment procedure, moving from complex measurements to understand PDT mechanisms in pre-clinical and early phase I trials, towards the identification and application of essential dose-limiting and/or surrogate measurements in phase II/III trials. If successful, identifying the essential and/or reliable surrogate dosimetry measurements should help facilitate increased adoption of clinical PDT. In this paper, examples of essential dosimetry points and surrogate dosimetry tools that may be implemented in phase II/III trials are discussed. For example, the treatment efficacy as limited by light penetration in interstitial PDT may be predicted by the amount of contrast uptake in CT, and so this could be utilized as a surrogate dosimetry measurement to prescribe light doses based upon pre-treatment contrast. Success of clinical ALA-based skin lesion treatment is predicted almost uniquely by the explicit or implicit measurements of photosensitizer and photobleaching, yet the individualization of treatment

  20. Nitric oxide interacts with mitochondrial complex III producing antimycin-like effects.

    PubMed

    Iglesias, Darío E; Bombicino, Silvina S; Valdez, Laura B; Boveris, Alberto

    2015-12-01

    The effect of NO between cytochromes b and c of the mitochondrial respiratory chain were studied using submitochondrial particles (SMP) from bovine heart and GSNO and SPER-NO as NO sources. Succinate-cytochrome c reductase (complex II-III) activity (222 ± 4 nmol/min. mg protein) was inhibited by 51% in the presence of 500 μM GSNO and by 48% in the presence of 30 μM SPER-NO, in both cases at ~1.25 μM NO. Neither GSNO nor SPER-NO were able to inhibit succinate-Q reductase activity (complex II; 220 ± 9 nmol/min. mg protein), showing that NO affects complex III. Complex II-III activity was decreased (36%) when SMP were incubated with l-arginine and mtNOS cofactors, indicating that this effect is also produced by endogenous NO. GSNO (500 μM) reduced cytochrome b562 by 71%, in an [O2] independent manner. Hyperbolic increases in O2(•-) (up to 1.3 ± 0.1 nmol/min. mg protein) and H2O2 (up to 0.64 ± 0.05 nmol/min. mg protein) productions were observed with a maximal effect at 500 μM GSNO. The O2(•-)/H2O2 ratio was 1.98 in accordance with the stoichiometry of the O2(•-) disproportionation. Moreover, H2O2 production was increased by 72-74% when heart coupled mitochondria were exposed to 500 μM GSNO or 30 μM SPER-NO. SMP incubated in the presence of succinate showed an EPR signal (g=1.99) compatible with a stable semiquinone. This EPR signal was increased not only by antimycin but also by GSNO and SPER-NO. These signals were not modified under N2 atmosphere, indicating that they are not a consequence to the effect of NOx species on complex III area. These results show that NO interacts with ubiquinone-cytochrome b area producing antimycin-like effects. This behaviour comprises the inhibition of electron transfer, the interruption of the oxidation of cytochromes b, and the enhancement of [UQH(•)]ss which, in turn, leads to an increase in O2(•-) and H2O2 mitochondrial production rates. PMID:26456055

  1. c-MYC Copy-Number Gain Is an Independent Prognostic Factor in Patients with Colorectal Cancer

    PubMed Central

    Lee, Kyu Sang; Kwak, Yoonjin; Nam, Kyung Han; Kim, Duck-Woo; Kang, Sung-Bum; Choe, Gheeyoung; Kim, Woo Ho; Lee, Hye Seung

    2015-01-01

    Background The aim of this study was to determine the incidence and clinicopathological significance of c-MYC gene copy-number (GCN) gain in patients with primary colorectal cancer (CRC). Methods The c-MYC GCN was investigated in 367 consecutive CRC patients (cohort 1) by using dual-color silver in situ hybridization. Additionally, to evaluate regional heterogeneity, we examined CRC tissue from 3 sites including the primary cancer, distant metastasis, and lymph-node metastasis in 152 advanced CRC patients (cohort 2). KRAS exons 2 and 3 were investigated for mutations. Results In cohort 1, c-MYC gene amplification, defined by a c-MYC:centromere of chromosome 8 ratio ≥ 2.0, was detected in 31 (8.4%) of 367 patients. A c-MYC GCN gain, defined by ≥ 4.0 c-MYC copies/nucleus, was found in 63 (17.2%) patients and was associated with poor prognosis (P = 0.015). Multivariate Cox regression analysis showed that the hazard ratio for c-MYC GCN gain was 2.35 (95% confidence interval, 1.453–3.802; P < 0.001). In a subgroup of stage II-III CRC patients, c-MYC GCN gain was significantly associated with poor prognosis by univariate (P = 0.034) and multivariate (P = 0.040) analyses. c-MYC protein overexpression was observed in 201 (54.8%) out of 367 patients and weakly correlated with c-MYC GCN gain (ρ, 0.211). In cohort 2, the c-MYC genetic status was heterogenous in advanced CRC patients. Discordance between GCN gain in the primary tumor and either distant or lymph-node metastasis was 25.7% and 30.4%, respectively. A similar frequency for c-MYC GCN gain and amplification was observed in CRC patients with both wild-type and mutated KRAS. Conclusions c-MYC GCN gain was an independent factor for poor prognosis in consecutive CRC patients and in the stage II-III subgroup. Our findings indicate that the status of c-MYC may be helpful in predicting the patients’ outcome and for managing CRC patients. PMID:26426996

  2. [Neoadjuvant radiochemotherapy in the treatment of locally advanced rectal tumors].

    PubMed

    Rápolti, Edit; Szigeti, András; Farkas, Róbert; Bellyei, Szabolcs; Boronkai, Arpád; Papp, András; Gömöri, Eva; Horváth, Ors Péter; Mangel, László

    2009-12-01

    We investigated the response rate and side effects of simultaneous, neoadjuvant radiochemotherapy (RCT) in locally advanced rectal cancer. Between 2005 and 2007, we treated 112 patients in stage II-III rectal carcinoma at the Institute of Oncotherapy, University of Pécs. For staging abdomino-pelvic CT (112) and transrectal US (49) or pelvic MR (10), or PET-CT (1) was performed. Radiation therapy was delivered with 3D CRT-based technique using belly-board with 18 MV photon energy, while patients in prone position. A total dose of 45 Gy (single dose 1.8 Gy) was delivered to the tumor and the pelvic lymph nodes. 5-FU and Ca-folinate was administered concomitantly in the 1st and 5th week of radiotherapy. Four weeks after delivering neoadjuvant RCT the patients' control CT was evaluated according to RECIST criteria. RCT was followed by surgery in 6-9 weeks. We graded the histology using the Mandard regression score system. Side effects were registered using CTCAE v 3.0. Grade 1, 2 or 3 acute gastrointestinal toxicity occurred in 12%, grade 3 hematological toxicity in 9.5% of the patients. The response rate determined by using control CT was 64.85%. According to the Mandard regression score, TRG1 occurred in 15%, TRG2 in 30.4%, TRG3 in 28%, TRG4 in 24% and TRG5 in 2.6% of the cases. Radical surgery was performed in 89 cases, 72 with R0 resection. By assessing the histological samples we found downstaging in 46% of the T and 34.5% of the N stage. We have no information on increased postoperative complications. We followed 86 patients after neoadjuvant therapy. Until March 2009 there was no progression in 48 of our patients. In 13 cases local relapse occurred, and in 25 cases the disease progressed because of distant metastasis, although local control was maintained. 10 patients had local relapse and distant metastases. 17 patients passed away. As a conclusion, neoadjuvant RCT of Stage II-III patients is an effective and well tolerated treatment, allowing for high R0

  3. The master T-operator for the Gaudin model and the KP hierarchy

    NASA Astrophysics Data System (ADS)

    Alexandrov, Alexander; Leurent, Sebastien; Tsuboi, Zengo; Zabrodin, Anton

    2014-06-01

    Following the approach of [1], we construct the master T-operator for the quantum Gaudin model with twisted boundary conditions and show that it satisfies the bilinear identity and Hirota equations for the classical KP hierarchy. We also characterize the class of solutions to the KP hierarchy that correspond to eigenvalues of the master T-operator and study dynamics of their zeros as functions of the spectral parameter. This implies a remarkable connection between the quantum Gaudin model and the classical Calogero-Moser system of particles. The quantum Gaudin model, The classical Kadomtsev-Petviashvili (KP) hierarchy, The classical Calogero-Moser (CM) system of particles. The link (i)-(ii) is a limiting case of the correspondence between quantum spin chains with the Yangian Y(gl(N))-invariant rational R-matrices and the classical modified KP hierarchy based on the construction of the master T-operator [1,2]. The link (ii)-(iii) is a well-known story about dynamics of poles of rational solutions to soliton equations started by Airault, McKean and Moser [3] for the KdV equation, developed by Krichever [4] for the KP equation and extended to the whole KP hierarchy by Shiota [5]. The composition of (i)-(ii) and (ii)-(iii) implies the connection between the quantum Gaudin model and the classical CM model which is a limiting case of the connection between quantum spin chains and classical Ruijsenaars systems found in [1]. The link (i)-(iii) was also earlier established in [6] from a different reasoning.The master T-operator was introduced in [1]. We construct commuting integrals of motion for the gl(N) Gaudin model, with twisted boundary conditions and vector representations at the marked points in the quantum space, corresponding to arbitrary representations in the auxiliary space. They are presented in an explicit form using the matrix derivative operation. We also find functional relations satisfied by them. The master T-operator for the gl(N) Gaudin model is the

  4. Early radionuclide scans for risk assessment in suspected acute myocardial infarction.

    PubMed Central

    Norris, S. L.; Haywood, L. J.; Sobel, E.; Hung, G. L.; deGuzman, M.; Siegel, M.

    1997-01-01

    First-day thallium-201 myocardial perfusion scans and technetium-99m RBC gated scintiangiography were performed during the initial clinical and prognostic evaluation of 69 patients with suspected acute myocardial infarction. Patients were monitored for clinical course, diagnosis confirmation, and use of specialty services (cardiac catheterization, percutaneous balloon angioplasty, and cardiac surgery) during hospitalization. Myocardial infarction, confirmed in 20 patients, was associated with significantly more left ventricular dilatation, lower ejection fractions, lower peak left ventricular filling rates, wall motion abnormalities, and thallium-201 perfusion defects than nonmyocardial infarction patients. Among all patients, left ventricular dilatation carried a relative risk of myocardial infarction of 5.8; low ejection fraction and right ventricular dilatation were strongly associated with myocardial infarction. A logistic model for congestive heart failure included: left ventricular dilation, lower mean left ventricular filling rates and time to peak filling rates, and abnormal thallium-201 lung:heart uptakes. Among nonmyocardial infarction patients, subsequent cardiac catheterization was predicted by the presence of anterior thallium-201 perfusion defects, Killip functional class II-III, and ischemia on ECG. These findings suggest that early detection of myocardial perfusion defects and cardiac dysfunction by radionuclide scans enhances initial evaluation of suspected acute myocardial infarction patients. Additional studies are needed to confirm these findings. PMID:9433058

  5. The scaffold protein Nde1 safeguards the brain genome during S phase of early neural progenitor differentiation

    PubMed Central

    Houlihan, Shauna L; Feng, Yuanyi

    2014-01-01

    Successfully completing the S phase of each cell cycle ensures genome integrity. Impediment of DNA replication can lead to DNA damage and genomic disorders. In this study, we show a novel function for NDE1, whose mutations cause brain developmental disorders, in safeguarding the genome through S phase during early steps of neural progenitor fate restrictive differentiation. Nde1 mutant neural progenitors showed catastrophic DNA double strand breaks concurrent with the DNA replication. This evoked DNA damage responses, led to the activation of p53-dependent apoptosis, and resulted in the reduction of neurons in cortical layer II/III. We discovered a nuclear pool of Nde1, identified the interaction of Nde1 with cohesin and its associated chromatin remodeler, and showed that stalled DNA replication in Nde1 mutants specifically occurred in mid-late S phase at heterochromatin domains. These findings suggest that NDE1-mediated heterochromatin replication is indispensible for neuronal differentiation, and that the loss of NDE1 function may lead to genomic neurological disorders. DOI: http://dx.doi.org/10.7554/eLife.03297.001 PMID:25245017

  6. Impact of the Preoperative Controlling Nutritional Status (CONUT) Score on the Survival after Curative Surgery for Colorectal Cancer

    PubMed Central

    Iseki, Yasuhito; Shibutani, Masatsune; Maeda, Kiyoshi; Nagahara, Hisashi; Ohtani, Hiroshi; Sugano, Kenji; Ikeya, Tetsuro; Muguruma, Kazuya; Tanaka, Hiroaki; Toyokawa, Takahiro; Sakurai, Katsunobu; Hirakawa, Kosei

    2015-01-01

    Background Recently, the preoperative immune-nutritional status has been reported to correlate with the survival rate in patients with colorectal cancer (CRC). However, there have been no reports on the relationship between the controlling nutritional status (CONUT) score and the clinical outcome after curative surgery for CRC. We herein evaluated the prognostic significance of the CONUT score in patients with CRC, and then compared the accuracy of the CONUT score and the prognostic nutritional index (PNI) as a predictor of survival. Methods We retrospectively reviewed a database of 204 patients who underwent curative surgery for Stage II/III CRC. Patients were divided into two groups according to the CONUT score and the PNI. Results The five-year cancer-specific survival (CSS) rate was significantly higher at 92.7% in the low CONUT group, compared to a rate of 81.0% in the high CONUT group (p=0.0016). The five-year CSS was 71.2% in the low PNI group and 92.3% in the high PNI group, which showed a significant difference (p=0.0155). A multivariate analysis showed that lymph node metastasis and the CONUT score were independent risk factors for CSS. Conclusion This study suggested that the CONUT score is a strong independent predictor of the survival among CRC patients. PMID:26147805

  7. Olesoxime, a cholesterol-like neuroprotectant for the potential treatment of amyotrophic lateral sclerosis

    PubMed Central

    Martin, Lee J

    2011-01-01

    Effective therapies are needed for amyotrophic lateral sclerosis (ALS), a debilitating and fatal motor neuron disease. Cell and animal models of ALS are begsinning to reveal possible principles governing the biology of motor neuron-selective vulnerability that implicate mitochondria and the mitochondrial permeability pore (mPTP). Proteins associated with the mPTP are known to be enriched in motor neurons and the genetic deletion of a major regulator of the mPTP has robust effects in ALS transgenic mice, delaying disease onset and extending survival. Thus, the mPTP is a rational, mechanism-based target for the development of drugs designed to treat ALS. Trophos SA has discovered olesoxime (TRO-19622), a small-molecule with a cholesterol-like structure, which has remarkable neuroprotective properties for motor neurons in cell culture and in rodents. Olesoxime appears to act on mitochondria, possibly at the mPTP. Phase I clinical trials of olesoxime have been completed successfully. Olesoxime is well tolerated and achieves levels predicted to be clinically effective when administered orally. It has been granted orphan drug status for the treatment of ALS in the US and for the treatment of spinal muscular atrophy in the EU. Phase II/III clinical trials are in progress in Europe. PMID:20721828

  8. Moving towards treatments for spinal muscular atrophy: hopes and limits.

    PubMed

    Wirth, Brunhilde; Barkats, Martine; Martinat, Cecile; Sendtner, Michael; Gillingwater, Thomas H

    2015-09-01

    Spinal muscular atrophy (SMA), one of the most frequent and devastating genetic disorders causing neuromuscular degeneration, has reached the forefront of clinical translation. The quite unique genetic situation of SMA patients, who lack functional SMN1 but carry the misspliced SMN2 copy gene, creates the possibility of correcting SMN2 splicing by antisense oligonucleotides or drugs. Both strategies showed impressive results in pre-clinical trials and are now in Phase II-III clinical trials. SMN gene therapy approaches using AAV9-SMN vectors are also highly promising and have entered a Phase I clinical trial. However, careful analysis of SMA animal models and patients has revealed some limitations that need to be taken very seriously, including: i) a limited time-window for successful therapy delivery, making neonatal screening of SMA mandatory; ii) multi-organ impairment, requiring systemic delivery of therapies; and iii) a potential need for combined therapies that both increase SMN levels and target pathways that preserve/rescue motor neuron function over the lifespan. Meeting these challenges will likely be crucial to cure SMA, instead of only ameliorating symptoms, particularly in its most severe form. This review discusses therapies currently in clinical trials, the hopes for SMA therapy, and the potential limitations of these new approaches. PMID:25920617

  9. Coronagraphic Polarimetry with NICMOS: Dust grain evolution in T Tauri stars

    NASA Astrophysics Data System (ADS)

    Schneider, Glenn

    2006-07-01

    The formation of planetary systems is intimately linked to the dust population in circumstellar disks, thus understanding dust grain evolution is essential to advancing our understanding of how planets form. By combining {1} the coronagraphic polarimetry capabilities of NICMOS, {2} powerful 3-D radiative transfer codes, and {3} observations of objects known to span the Class II-III stellar evolutionary phases, we will gain crucial insight into dust grain growth. By observing objects representative of a known evolutionary sequence of YSOs, we will be able to investigate how the dust population evolves in size and distribution during the crucial transition from a star+disk system to a system containing planetesimals. When combine with our previous study on dust grain evolution in the Class I-II phase, the proposed study will help to establish the fundamental time scales for the depletion of ISM-like grains: the first step in understanding the transformation from small submicron sized dust grains, to large millimeter sized grains, and untimely to planetary bodies.

  10. Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease

    PubMed Central

    Solfrizzi, Vincenzo; Imbimbo, Bruno P.; Lozupone, Madia; Santamato, Andrea; Zecca, Chiara; Barulli, Maria Rosaria; Bellomo, Antonello; Pilotto, Alberto; Daniele, Antonio; Greco, Antonio

    2016-01-01

    The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT+). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid. PMID:27429978

  11. The effects of chronic fluoxetine treatment following injury of medial frontal cortex in mice.

    PubMed

    McAllister, Brendan B; Spanswick, Simon C; Patel, Payal P; Barneto, Alison A; Dyck, Richard H

    2015-09-01

    Injury of the brain is a leading cause of long-term disability. Recent evidence indicates that the selective serotonin reuptake inhibitor drug fluoxetine may be beneficial when administered following brain injury. However, its potential to promote recovery and the mechanisms by which it might do so require further characterization. In the present experiment, fluoxetine was administered to mice for 4 weeks following injury of medial frontal cortex (MFC). MFC injury altered behavior, reducing locomotion, decreasing swim speed in the Morris water task, and decreasing anxiety-like behavior in the elevated plus maze. Fluoxetine treatment did not affect these behavioral alterations, but it did increase the social dominance of the injured mice, as assessed by the tube test. Fluoxetine treatment also hastened learning of a T-maze position discrimination task, independently of lesion condition. Anatomically, fluoxetine failed to decrease lesion size, increase the survival of cells born 1-week post injury in the hippocampal dentate gyrus, or reverse the reduction in spine density in layer II/III pyramidal neurons in cingulate cortex caused by the lesions. Fluoxetine did, however, increase the dendritic arborization of these cells, which was reduced in the mice with lesions. Thus, while not all the effects of MFC injury were ameliorated, the behavioral outcome of mice with MFC injuries was improved, and one of the neuroanatomical sequelae of the lesions counteracted, by chronic fluoxetine, further contributing to the evidence that fluoxetine could be a useful treatment following brain injury. PMID:25956871

  12. Optical nonlinearity and piezoelectricity in 2,4,6-trimethylpyridinium perchlorate

    NASA Astrophysics Data System (ADS)

    Wojtaś, M.; Czupiński, O.; Tylczyński, Z.; Isakov, D.; Belsley, M.; Jakubas, R.

    2014-09-01

    [(CH3)3C5H2NH][ClO4] exhibits rich polymorphism, it undergoes four structural phase transitions: from phases I to II at 356/327 K (heating/cooling), II-III at 346/326, III-IV at 226 K and IV-V at 182/170 K. [(CH3)3C5H2NH][ClO4] reveals a strong optical nonlinearity over a wide temperature region with the SHG efficiency comparable to that of KDP. The piezoelectric properties were studied macroscopically by series resonance method over the phases III, IV and V as well as microscopically by means of piezoelectric force microscopy (PFM) in ambient conditions. One of the piezoelectric module at phase transition point at 226 K drops to the value twice smaller than in room temperature what up to now was not encountered in literature. Moreover the ferroelastic phase transition IV-V was observed by means of polarizing optical microscope. The choice of the point group of phase I (Pmmm) was confirmed by the SHG measurements. The updated phase diagram is presented.

  13. Hyperviscosity and hypofunction of the seminal vesicles.

    PubMed

    Gonzales, G F; Kortebani, G; Mazzolli, A B

    1993-01-01

    The study was designed to determine whether hyperviscosity of the semen sample is related to dysfunction of the male accessory glands. It was carried out on men who consecutively attended an infertility clinic between June 1989 and June 1991, and the men were grouped according to viscosity of semen samples (normal viscosity or higher viscosity). Semen samples from 229 infertility patients were studied. From these, 155 had normal viscosity and 74 showed hyperviscosity. The effect of hyperviscosity of semen samples on seminal quality and the function of the prostate was evaluated by acid phosphatase measurement, and the seminal vesicles by measurement of corrected fructose. Sperm motility (grades II-III), sperm vitality, and corrected fructose were significantly reduced in samples with high viscosity (p < .05). A high prevalence of hyperviscosity in semen samples was associated with only hypofunction of the seminal vesicles. In fact, 36.5% of subjects with hyperviscosity showed reduced levels of corrected fructose. The same association with hyperviscosity was not observed when only hypofunction of the prostate was present, or when hypofunction of both prostate and seminal vesicles was present (P:NS). Further analysis showed that high viscosity is observed mainly when corrected seminal fructose levels were below 1.5 mg/mL x 10(6) spz/mL. It would appear that hyperviscosity affects sperm motility and is associated with hypofunction of the seminal vesicles. PMID:8420506

  14. Effects of prior treatment with simvastatin on skeletal muscle structure and mitochondrial enzyme activities during early phases of sepsis

    PubMed Central

    Ozkok, Elif; Yorulmaz, Hatice; Ates, Gulten; Serdaroglu-Oflazer, Piraye; Tamer, Ayse Sule

    2014-01-01

    We investigated the effects of the early phase of sepsis and prior treatment of Simvastatin on muscle structure and mitochondrial enzymes treated with lipopolysaccharide (LPS) in rats. We divided rats into control, LPS, simvastatin, simvastatin + LPS groups. Mitochondrial citrate synthase, complex I, II, I + III, II + III, cytochrome c oxidase (COX) activities were measured. Muscle tissue was stained using modified Gomori trichrome (MGT), succinic dehydrogenase (SDH) and cytochrome oxidase (COX). In all treated groups, complex I and citrate synthase activities were higher than in the controls. In the control and LPS groups, COX activity was increased when compared with simvastatins’. Complex II, II-III activities were higher in the LPS group than in the control group. Complex I-III activities were higher in the Simvastatin and Simvastatin + LPS groups than in the control and LPS groups (P < 0.05). Myopathic changes with LPS group were observed in MGT stained sections. Our findings showed improvements in the alterations of enzyme activities and muscle myofibrils after treating rats with LPS that had received a prior dose of simvastatin. PMID:25674200

  15. The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex

    PubMed Central

    Bajo, Victoria M; Leach, Nicholas D; Cordery, Patricia M; Nodal, Fernando R; King, Andrew J

    2014-01-01

    Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus-specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4-SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en-passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing. PMID:24945075

  16. Impairment of electron transfer chain induced by acute carnosine administration in skeletal muscle of young rats.

    PubMed

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I-III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α , and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I-III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α , and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  17. Fenproporex increases locomotor activity and alters energy metabolism, and mood stabilizers reverse these changes: a proposal for a new animal model of mania.

    PubMed

    Rezin, Gislaine T; Furlanetto, Camila B; Scaini, Giselli; Valvassori, Samira S; Gonçalves, Cinara L; Ferreira, Gabriela K; Jeremias, Isabela C; Resende, Wilson R; Cardoso, Mariane R; Varela, Roger B; Quevedo, João; Streck, Emilio L

    2014-04-01

    Fenproporex (Fen) is converted in vivo into amphetamine, which is used to induce mania-like behaviors in animals. In the present study, we intend to present a new animal model of mania. In order to prove through face, construct, and predictive validities, we evaluated behavioral parameters (locomotor activity, stereotypy activity, and fecal boli amount) and brain energy metabolism (enzymes citrate synthase; malate dehydrogenase; succinate dehydrogenase; complexes I, II, II-III, and IV of the mitochondrial respiratory chain; and creatine kinase) in rats submitted to acute and chronic administration of fenproporex, treated with lithium (Li) and valproate (VPA). The administration of Fen increased locomotor activity and decreased the activity of Krebs cycle enzymes, mitochondrial respiratory chain complexes, and creatine kinase, in most brain structures evaluated. In addition, treatment with mood stabilizers prevented and reversed this effect. Our results are consistent with the literature that demonstrates behavioral changes and mitochondrial dysfunction caused by psychostimulants. These findings suggest that chronic administration of Fen may be a potential animal model of mania. PMID:24126971

  18. Impairment of Electron Transfer Chain Induced by Acute Carnosine Administration in Skeletal Muscle of Young Rats

    PubMed Central

    Macarini, José Roberto; Maravai, Soliany Grassi; Cararo, José Henrique; Dimer, Nádia Webber; Gonçalves, Cinara Ludvig; Kist, Luiza Wilges; Bogo, Mauricio Reis; Schuck, Patrícia Fernanda; Streck, Emilio Luiz; Ferreira, Gustavo Costa

    2014-01-01

    Serum carnosinase deficiency is an inherited disorder that leads to an accumulation of carnosine in the brain tissue, cerebrospinal fluid, skeletal muscle, and other tissues of affected patients. Considering that high levels of carnosine are associated with neurological dysfunction and that the pathophysiological mechanisms involved in serum carnosinase deficiency remain poorly understood, we investigated the in vivo effects of carnosine on bioenergetics parameters, namely, respiratory chain complexes (I–III, II, and II-III), malate dehydrogenase, succinate dehydrogenase, and creatine kinase activities and the expression of mitochondrial-specific transcription factors (NRF-1, PGC-1α, and TFAM) in skeletal muscle of young Wistar rats. We observed a significant decrease of complexes I–III and II activities in animals receiving carnosine acutely, as compared to control group. However, no significant alterations in respiratory chain complexes, citric acid cycle enzymes, and creatine kinase activities were found between rats receiving carnosine chronically and control group animals. As compared to control group, mRNA levels of NRF-1, PGC-1α, and TFAM were unchanged. The present findings indicate that electron transfer through the respiratory chain is impaired in skeletal muscle of rats receiving carnosine acutely. In case these findings are confirmed by further studies and ATP depletion is also observed, impairment of bioenergetics could be considered a putative mechanism responsible for the muscle damage observed in serum carnosinase-deficient patients. PMID:24877122

  19. A Novel Operative Procedure for Pelvic Organ Prolapse Utilizing a MRI-Visible Mesh Implant: Safety and Outcome of Modified Laparoscopic Bilateral Sacropexy

    PubMed Central

    Meyberg-Solomayer, Gabriele; Radosa, Julia; Bader, Werner; Schneider, Guenther; Solomayer, Erich

    2015-01-01

    Introduction. Sacropexy is a generally applied treatment of prolapse, yet there are known possible complications of it. An essential need exists for better alloplastic materials. Methods. Between April 2013 and June 2014, we performed a modified laparoscopic bilateral sacropexy (MLBS) in 10 patients using a MRI-visible PVDF mesh implant. Selected patients had prolapse POP-Q stages II-III and concomitant OAB. We studied surgery-related morbidity, anatomical and functional outcome, and mesh-visibility in MRI. Mean follow-up was 7.4 months. Results. Concomitant colporrhaphy was conducted in 1/10 patients. Anatomical success was defined as POP-Q stage 0-I. Apical success rate was 100% and remained stable. A recurrent cystocele was seen in 1/10 patients during follow-up without need for intervention. Out of 6 (6/10) patients with preoperative SUI, 5/6 were healed and 1/6 persisted. De-novo SUI was seen in 1/10 patients. Complications requiring a relaparoscopy were seen in 2/10 patients. 8/10 patients with OAB were relieved postoperatively. The first in-human magnetic resonance visualization of a prolapse mesh implant was performed and showed good quality of visualization. Conclusion. MLBS is a feasible and safe procedure with favorable anatomical and functional outcome and good concomitant healing rates of SUI and OAB. Prospective data and larger samples are required. PMID:25961042

  20. [The clinical pharmacology and efficacy of the new Soviet calcium antagonist foridon].

    PubMed

    Kukes, V G; Rumiantsev, A S; Gneushev, E T; Al'perovich, B R; Svetyĭ, L I; Nasyrov, M N; Taratuta, T V

    1990-01-01

    A total of 56 patients with coronary heart disease (CHD), angina pectoris of effort, functional classes II-III, were placed under observation. All the patients received 20 mg foridon (F), 20 mg corinfar (C), 80 mg anapriline (A). 24 patients were subjected to the continuous treatment with F (20 mg 4 times a day). The antianginal action of the drug was compared to the blood concentration on days 7, 14, 21, 28, 43 and 57 of the treatment with F. In 14 patients with angina pectoris and in 18 patients with essential hypertension, the efficacy of F and C was cross correlated. It has been demonstrated that F can be successfully used for the treatment of patients with CHD, angina pectoris of effort and (or) essential hypertension. The increase of the single dose of foridon from 20 to 40 mg does not result in the potentiation of its hypotensive effect. F and C provoke the highest rise of exercise tolerance with combined angina pectoris. Continuous concomitant administration of F and C with A leads to the potentiation of the antianginal action. PMID:2084878

  1. Demographic characteristics and distribution of lysosomal storage disorder subtypes in Eastern China.

    PubMed

    Chen, Xueru; Qiu, Wenjuan; Ye, Jun; Han, Lianshu; Gu, Xuefan; Zhang, Huiwen

    2016-04-01

    Lysosomal storage disorders (LSDs) are a group of >50 different types of inherited metabolic disorders that result from defects in the lysosome. The aim of this study was to investigate the distribution and demographic characteristics of the different subtypes of LSDs in Eastern China. From 2006 to 2012, 376 out of 1331 clinically suspected patients were diagnosed with 17 different subtypes of LSDs at our hospital. Mucopolysaccharidoses (MPS) were the most common group of LSDs (50.5%), followed by sphingolipidoses (25.4%) and Pompe disease (19.8%). Mucolipidosis type II/III accounted for the remaining 4% of diagnosed LSDs. MPS II was the most common form of MPS, comprising 47.4% of all MPS cases diagnosed, followed by MPS IVA (26.8%) and MPS I (16.3%). Gaucher disease and Niemann-Pick disease type A/B were the two most common forms of sphingolipidoses. There was a large variation in the time between disease onset and eventual diagnosis, from 0.3 years in infantile-onset Pompe disease to 30 years in Fabry disease, highlighting timely and accurate diagnosis of LSDs as the main challenge in China. PMID:26740238

  2. The three-dimensional structural surface of two beta-sheet scorpion toxins mimics that of an alpha-helical dihydropyridine receptor segment.

    PubMed Central

    Green, Daniel; Pace, Suzi; Curtis, Suzanne M; Sakowska, Magdalena; Lamb, Graham D; Dulhunty, Angela F; Casarotto, Marco G

    2003-01-01

    An alpha-helical II-III loop segment of the dihydropyridine receptor activates the ryanodine receptor calcium-release channel. We describe a novel manipulation in which this agonist's activity is increased by modifying its surface structure to resemble that of a toxin molecule. In a unique system, native beta-sheet scorpion toxins have been reported to activate skeletal muscle ryanodine receptor calcium channels with high affinity by binding to the same site as the lower-affinity alpha-helical dihydropyridine receptor segment. We increased the alignment of basic residues in the alpha-helical peptide to mimic the spatial orientation of active residues in the scorpion toxin, with a consequent 2-20-fold increase in the activity of the alpha-helical peptide. We hypothesized that, like the native peptide, the modified peptide and the scorpion toxin may bind to a common site. This was supported by (i) similar changes in ryanodine receptor channel gating induced by the native or modified alpha-helical peptide and the beta-sheet toxin, a 10-100-fold reduction in channel closed time, with a < or = 2-fold increase in open dwell time and (ii) a failure of the toxin to further activate channels activated by the peptides. These results suggest that diverse structural scaffolds can present similar conformational surface properties to target common receptor sites. PMID:12429019

  3. The Impact of Remote Ischemic Preconditioning on Arterial Stiffness and Heart Rate Variability in Patients with Angina Pectoris

    PubMed Central

    Zagidullin, Naufal; Scherbakova, Elena; Safina, Yuliana; Zulkarneev, Rustem; Zagidullin, Shamil

    2016-01-01

    Remote ischemic preconditioning (RIPC) is the set of ischemia episodes that protects against subsequent periods of prolonged ischemia through the cascade of adaptive responses; however, the mechanisms of RIPC are not entirely clear. Here, we aimed to study the impact of RIPC in patients with stable angina pectoris and compare it with healthy individuals with respect to arterial stiffness and heart rate variability. In the randomized, sham-controlled, crossover blind design study, a group of 30 coronary heart disease (CHD) patients (63.9 ± 1.6 years) with stable angina pectoris NYHA II-III and a control group of 20 healthy individuals (58.2 ± 2.49) were both randomly allocated for remote RIPC or sham RIPC. Arterial stiffness, pulse wave velocity (Spygmacor, Australia), and heart rate variability (HRV) were recorded before and after the procedure followed by the crossover examination. In the group of healthy individuals, RIPC showed virtually no impact on the cardiovascular parameters, while, in the CHD group, the systolic and central systolic blood pressure, central pulse pressure, and augmentation decreased, and total power of HRV improved. We conclude that ischemic preconditioning reduces not only systolic blood pressure, but also reduces central systolic blood pressure and improves arterial compliance and heart rate modulation reserve, which may be associated with the antianginal effect of preconditioning. PMID:27348009

  4. Randomized controlled clinical trial to access efficacy and safety of miltefosine in the treatment of cutaneous leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil.

    PubMed

    Chrusciak-Talhari, Anette; Dietze, Reynaldo; Chrusciak Talhari, Carolina; da Silva, Roberto Moreira; Gadelha Yamashita, Ellen Priscila; de Oliveira Penna, Gerson; Lima Machado, Paulo Roberto; Talhari, Sinésio

    2011-02-01

    Miltefosine has been used in the treatment of several new world cutaneous leishmaniasis (CL) species with variable efficacy. Our study is the first evidence on its clinical efficacy in Leishmania (Viannia) guyanensis. In this phase II/III randomized clinical trial, 90 CL patients were randomly allocated (2:1) to oral miltefosine (2.5 mg/kg/day/28 days) (N = 60) or parenteral antimony (15-20 mg/Sb/kg/day/20 days) (N = 30) according to age groups: 2-12 y/o and 13-65 y/o. Patients were human immunodeficiency virus (HIV) noninfected parasitological proven CL without previous treatment. Definitive cure was accessed at 6 months follow-up visit. No severe adverse events occurred. Vomiting was the most frequent adverse event (48.3%) followed by nausea (8.6%) and diarrhea (6.7%). Cure rates were 71.4% (95% confidence interval [CI] = 57.8-82.7) and 53.6% (95% CI = 33.9-72.5) (P = 0.05) for miltefosine and antimonial, respectively. There were no differences in cure rates between age groups within the same treatment arms. Miltefosine was safe and relatively well tolerated and cure rate was higher than antimony. PMID:21292895

  5. [Brazilian biomedical and epidemiological research vis-à-vis the UNGASS targets].

    PubMed

    Bastos, Francisco Inácio; Hacker, Mariana A

    2006-04-01

    The focus of the present study is the Brazilian response within science, technology and innovation to the targets formulated in the UNGASS document. An analysis was made of items 70-73 of the UNGASS Draft Declaration of Commitment on HIV/AIDS (2001), which defined science, technology and innovation targets relating to HIV/AIDS. The main topics listed in these items were put into operation in the form of keywords, in order to guide systematic searches within the standard biomedicine databases, also including the subdivisions of the Web of Science relating to natural and social sciences. The success of Brazilian research within the field of characterization and isolation of HIV-1 is undeniable. Phase II/III vaccine studies have been developed in Rio de Janeiro, Belo Horizonte and São Paulo. Empirical studies on the monitoring of primary resistance have been developed in specific populations, through the Brazilian HIV Resistance Monitoring Network. Within the field of monitoring secondary resistance, initiatives such as the National Genotyping Network have been highlighted. Two national systems--the Mortality Information System and the Notifiable Diseases Information System (Aids)--and some studies with wider coverage have given rise to work on trends within the epidemic. The production of high-quality generic medications and their free distribution to patients have been highlighted. Brazil has implemented a consistent and diversified response within the field of HIV/AIDS, with studies relating to the development of vaccines, new medications and monitoring of the epidemic. PMID:16729157

  6. The broad-spectrum anti-DNA virus agent cidofovir inhibits lung metastasis of virus-independent, FGF2-driven tumors.

    PubMed

    Liekens, Sandra; Noppen, Sam; Gijsbers, Sofie; Sienaert, Rebecca; Ronca, Roberto; Tobia, Chiara; Presta, Marco

    2015-03-10

    The FDA-approved anti-DNA virus agent cidofovir (CDV) is being evaluated in phase II/III clinical trials for the treatment of human papillomavirus (HPV)-associated tumors. However, previous observations had shown that CDV also inhibits the growth of vascular tumors induced by fibroblast growth factor-2 (FGF2)-transformed FGF2-T-MAE cells. Here, we demonstrate that CDV inhibits metastasis induced by FGF2-driven, virus-independent tumor cells. Pre-treatment of luciferase-expressing FGF2-T-MAE cells with CDV reduced single cell survival and anchorage-independent growth in vitro and lung metastasis formation upon intravenous inoculation into SCID mice. This occurred in the absence of any effect on homing of FGF2-T-MAE cells to the lungs and on the growth of subconfluent cell cultures or subcutaneous tumors in mice. Accordingly, CDV protected against lung metastasis when given systemically after tumor cell injection. Lung metastases in CDV-treated mice showed reduced Ki67 expression and increased nuclear accumulation of p53, indicating that CDV inhibits metastasis by affecting single cell survival properties. The anti-metastatic potential of CDV was confirmed on B16-F10 melanoma cells, both in zebrafish embryos and mice. These findings suggest that CDV may have therapeutic potential as an anti-metastatic agent and warrants further study to select those tumor types that are most likely to benefit from CDV therapy. PMID:25609197

  7. Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3.

    PubMed

    Barca, E; Musumeci, O; Montagnese, F; Marino, S; Granata, F; Nunnari, D; Peverelli, L; DiMauro, S; Quinzii, C M; Toscano, A

    2016-08-01

    Inherited ataxias are a group of heterogeneous disorders in children or adults but their genetic definition remains still undetermined in almost half of the patients. However, CoQ10 deficiency is a rare cause of cerebellar ataxia and ADCK3 is the most frequent gene associated with this defect. We herein report a 48 year old man, who presented with dysarthria and walking difficulties. Brain magnetic resonance imaging showed a marked cerebellar atrophy. Serum lactate was elevated. Tissues obtained by muscle and skin biopsies were studied for biochemical and genetic characterization. Skeletal muscle biochemistry revealed decreased activities of complexes I+III and II+III and a severe reduction of CoQ10 , while skin fibroblasts showed normal CoQ10 levels. A mild loss of maximal respiration capacity was also found by high-resolution respirometry. Molecular studies identified a novel homozygous deletion (c.504del_CT) in ADCK3, causing a premature stop codon. Western blot analysis revealed marked reduction of ADCK3 protein levels. Treatment with CoQ10 was started and, after 1 year follow-up, patient neurological condition slightly improved. This report suggests the importance of investigating mitochondrial function and, in particular, muscle CoQ10 levels, in patients with adult-onset cerebellar ataxia. Moreover, clinical stabilization by CoQ10 supplementation emphasizes the importance of an early diagnosis. PMID:26818466

  8. Acute Toxicity of Radiochemotherapy in Rectal Cancer Patients: A Risk Particularly for Carriers of the TGFB1 Pro25 variant

    SciTech Connect

    Schirmer, Markus Anton; Mergler, Caroline Patricia Nadine; Rave-Fraenk, Margret; Herrmann, Markus Karl; Hennies, Steffen; Gaedcke, Jochen; Conradi, Lena-Christin; Jo, Peter; Beissbarth, Tim; Hess, Clemens Friedrich; Becker, Heinz; Ghadimi, Michael; Brockmoeller, Juergen; Christiansen, Hans; Wolff, Hendrik Andreas

    2012-05-01

    Purpose: Transforming growth factor-beta1 is related to adverse events in radiochemotherapy. We investigated TGFB1 genetic variability in relation to quality of life-impairing acute organ toxicity (QAOT) of neoadjuvant radiochemotherapy under clinical trial conditions. Methods and Materials: Two independent patient cohorts (n = 88 and n = 75) diagnosed with International Union Against Cancer stage II/III rectal cancer received neoadjuvant radiation doses of 50.4 Gy combined with 5-fluorouracil-based chemotherapy. Toxicity was monitored according to Common Terminology Criteria for Adverse Events. QAOT was defined as a CTCAE grade {>=}2 for at least one case of enteritis, proctitis, cystitis, or dermatitis. Nine germline polymorphisms covering the common genetic diversity in the TGFB1 gene were genotyped. Results: In both cohorts, all patients carrying the TGFB1 Pro25 variant experienced QAOT (positive predictive value of 100%, adjusted p = 0.0006). In a multivariate logistic regression model, gender, age, body mass index, type of chemotherapy, or disease state had no significant impact on QAOT. Conclusion: The TGFB1 Pro25 variant could be a relevant marker for individual treatment stratification and carriers may benefit from adaptive clinical care or specific radiation techniques.

  9. Sodium Butyrate, a Histone Deacetylase Inhibitor, Reverses Behavioral and Mitochondrial Alterations in Animal Models of Depression Induced by Early- or Late-life Stress.

    PubMed

    Valvassori, Samira S; Resende, Wilson R; Budni, Josiane; Dal-Pont, Gustavo C; Bavaresco, Daniela V; Réus, Gislaine Z; Carvalho, André F; Gonçalves, Cinara L; Furlanetto, Camila B; Streck, Emilio L; Quevedo, João

    2015-01-01

    The aim of the present study was to evaluate the effects of sodium butyrate on depressive-like behavior and mitochondrial alteration parameters in animal models of depression induced by maternal deprivation or chronic mild stress in Wistar rats. maternal deprivation was established by separating pups from their mothers for 3 h daily from postnatal day 1 to day 10. Chronic mild stress was established by water deprivation, food deprivation, restraint stress, isolation and flashing lights. Sodium butyrate or saline was administered twice a day for 7 days before the behavioral tests. Depressive behavior was evaluated using the forced swim test. The activity of tricarboxylic acid cycle enzymes (succinate dehydrogenase and malate dehydrogenase) and of mitochondrial chain complexes (I, II, II-III and IV) was measured in the striatum of rats. From these analyses it can be observed that sodium butyrate reversed the depressive-like behavior observed in both animal models of depression. Additionally, maternal deprivation and chronic mild stress inhibited mitochondrial respiratory chain complexes and increased the activity of tricarboxylic acid cycle enzymes. Sodium butyrate treatment reversed -maternal deprivation and chronic mild stress- induced dysfunction in the striatum of rats. In conclusion, sodium butyrate showed antidepressant effects in maternal deprivation and chronic mild stress-treated rats, and this effect can be attributed to its action on the neurochemical pathways related to depression. PMID:26216027

  10. [Application of photodynamic therapy to reduce the amount of resection for non-small cell lung cancer].

    PubMed

    Akopov, A L; Rusanov, A A; Chistiakov, I V; Urtenova, M A; Kazakov, N V; Gerasin, A V; Papaian, G V

    2013-01-01

    A prospective analysis of results of combined treatment of 22 patients with central stage II-III non-small cell lung cancer (NSCLC) was performed (the defeat of the main bronchi or lower parts of the trachea), which initially had been regarded as unresectable or inoperable (12 patients for functional reasons could not pass pneumonectomy, and in 10 patients a contraindication to primary surgery was the involvement of the distal trachea in tumor), but underwent surgery after preoperative treatment.Combination therapy included preoperative endobronchial photodynamic therapy (PDT) and chemotherapy followed by surgery and intraoperative PDT resection margins. PDT was carried out with the use of chlorine E6 (Radachlorin) and light wavelength of 662 nm. Overall response rate after neoadjuvant treatment was 82 %, endoscopic remission was observed in 21 of 22 patients (95%). 10 patients underwent pneumonectomy, 12--lobectomy. 19 surgical interventions were regarded as radical (R0--86%), 3--as microscopically non-radical (R1--14%). Degree of lymphatic metastasis spreading pN0 was detected in 6 patients (27 %), pN1--in 14 (64%) and pN2--in 2 patients (9%). Surgical lethality was 5%. In the late time of the whole observation period none of the patients developed local recurrence. One-year survival was 95%, 3-year--91%. PDT can play an important role in combination with surgical treatment for NSCLC and reduces the amount of resection in part of initially unresectable or inoperable patients. PMID:24624784

  11. Evolution of increased glia–neuron ratios in the human frontal cortex

    PubMed Central

    Sherwood, Chet C.; Stimpson, Cheryl D.; Raghanti, Mary Ann; Wildman, Derek E.; Uddin, Monica; Grossman, Lawrence I.; Goodman, Morris; Redmond, John C.; Bonar, Christopher J.; Erwin, Joseph M.; Hof, Patrick R.

    2006-01-01

    Evidence from comparative studies of gene expression and evolution suggest that human neocortical neurons may be characterized by unusually high levels of energy metabolism. The current study examined whether there is a disproportionate increase in glial cell density in the human frontal cortex in comparison with other anthropoid primate species (New World monkeys, Old World monkeys, and hominoids) to support greater metabolic demands. Among 18 species of anthropoids, humans displayed the greatest departure from allometric scaling expectations for the density of glia relative to neurons in layer II/III of dorsolateral prefrontal cortex (area 9L). However, the human glia–neuron ratio in this prefrontal region did not differ significantly from allometric predictions based on brain size. Further analyses of glia–neuron ratios across frontal areas 4, 9L, 32, and 44 in a sample of humans, chimpanzees, and macaque monkeys showed that regions involved in specialized human cognitive functions, such as “theory of mind” (area 32) and language (area 44) have not evolved differentially higher requirements for metabolic support. Taken together, these findings suggest that greater metabolic consumption of human neocortical neurons relates to the energetic costs of maintaining expansive dendritic arbors and long-range projecting axons in the context of an enlarged brain. PMID:16938869

  12. Mitochondrial Disorders May Mimic Amyotrophic Lateral Sclerosis at Onset

    PubMed Central

    Finsterer, Josef; Zarrouk-Mahjoub, Sinda

    2016-01-01

    Similarities between a mitochondrial disorder (MID) and amyotrophic lateral sclerosis (ALS) fade with disease progression and the development of mitochondrial multiple organ dysfunction syndrome (MIMODS). However, with mild MIMODS, a MID may still be misinterpreted as ALS. We report a 48-year-old male who presented to the Neurological Hospital Rosenhügel, Vienna, Austria, in February 2001 with slowly progressive weakness, wasting and left upper limb fasciculations which spread to the shoulder girdle and lower limbs. Additionally, he developed tetraspasticity and bulbar involvement. He had been diagnosed with ALS a year previously due to electrophysiological investigations indicative of a chronic neurogenic lesion. However, a muscle biopsy revealed morphological features of a MID and a combined complex-II/III defect. Nerve conduction studies were performed over subsequent years until February 2011. This case demonstrates that MIDs may mimic ALS at onset and begin as a mono-organ disorder but develop into a multi-organ disease with long-term progression. A combined complex II/III defect may manifest with bulbar involvement. PMID:26909222

  13. Multiplexed immunofluorescence delineates proteomic cancer cell states associated with metabolism

    PubMed Central

    Sood, Anup; Miller, Alexandra M.; Brogi, Edi; Sui, Yunxia; Armenia, Joshua; McDonough, Elizabeth; Santamaria-Pang, Alberto; Carlin, Sean; Stamper, Aleksandra; Campos, Carl; Pang, Zhengyu; Li, Qing; Port, Elisa; Graeber, Thomas G.; Schultz, Nikolaus; Ginty, Fiona; Larson, Steven M.; Mellinghoff, Ingo K.

    2016-01-01

    The phenotypic diversity of cancer results from genetic and nongenetic factors. Most studies of cancer heterogeneity have focused on DNA alterations, as technologies for proteomic measurements in clinical specimen are currently less advanced. Here, we used a multiplexed immunofluorescence staining platform to measure the expression of 27 proteins at the single-cell level in formalin-fixed and paraffin-embedded samples from treatment-naive stage II/III human breast cancer. Unsupervised clustering of protein expression data from 638,577 tumor cells in 26 breast cancers identified 8 clusters of protein coexpression. In about one-third of breast cancers, over 95% of all neoplastic cells expressed a single protein coexpression cluster. The remaining tumors harbored tumor cells representing multiple protein coexpression clusters, either in a regional distribution or intermingled throughout the tumor. Tumor uptake of the radiotracer 18F-fluorodeoxyglucose was associated with protein expression clusters characterized by hormone receptor loss, PTEN alteration, and HER2 gene amplification. Our study demonstrates an approach to generate cellular heterogeneity metrics in routinely collected solid tumor specimens and integrate them with in vivo cancer phenotypes. PMID:27182557

  14. Electrocatalytic oxidation of L-tryptophan using copper hexacyanoferrate film modified gold nanoparticle graphite-wax electrode.

    PubMed

    Prabhu, P; Babu, R Suresh; Narayanan, S Sriman

    2011-10-01

    A novel copper hexacyanoferrate (CuHCF) film modification on cysteamine (Cys)-gold nanoparticle (AuNp) graphite-wax (GW) composite electrode was achieved for the quantitative determination of L-Tryptophan (L-Trp) at a reduced overpotential of 400mV in comparison with the bare Cys-AuNp-GW composite electrode. This modified electrode exhibited a well resolved pair of redox peaks corresponding to the hexacyanoferrate (II/III) reactions of CuHCF film at a formal potential of 0.65 V at a scan rate of 20 mV s(-1). Electrochemical impedance spectroscopy (EIS) studies with the modified electrode showed a very low charge transfer resistance to the electron transfer kinetics of Fe(II)/Fe(III) reactions. A linear range of 8.5×10(-7) M to 1.2×10(-4) M with a detection limit of 1.85×10(-8) M was achieved for the determination of L-Trp with a sensitivity of 0.1198 μA/μM. The influence of ultrasonication on the stability of the CuHCF film modified electrode was investigated. In addition, the CuHCF film modified electrode displayed an excellent reproducibility towards the real time analysis of L-Trp in commercial milk samples. PMID:21621399

  15. Detection of novel polymorphisms in the ckit gene of canine patients with lymphoma, melanoma, haemangiosarcoma, and osteosarcoma.

    PubMed

    Gramer, Irina; Kessler, Martin; Geyer, Joachim

    2016-06-01

    Tyrosine kinase inhibitors (TKIs) that specifically target cKIT represent a therapeutic approach for non-resectable canine mast cell tumours (MCTs) grade II/III. The therapeutic benefit of TKIs has been investigated in other tumours based on clinical response rates and identification of gain-of-function mutations. In the present study, cKIT expression in 14 dogs with osteosarcoma, melanoma, haemangiosarcoma, lymphoma, and fibrosarcoma was analysed. Tissue samples were used for cKIT sequencing to (I) detect the cKIT transcript and to (II) identify gain-of-function mutations. The cKIT transcript was detected in ten patients. Four novel amino acid substitutions and five silent polymorphisms were identified. Furthermore, an insertion mutation (GNSK) was discovered in the tissue, but not in the blood sample of one dog. CKIT expression was identified in a variety of canine tumours and, therefore, TKIs might have a broader therapeutic indication apart from treatment of MCTs. Further investigations will be necessary to localize the cKIT protein in the respective tumours and to evaluate the functional consequence of the cKIT variants identified in the present study. PMID:26971271

  16. Palynology, palynofacies and petroleum potential of the Upper Cretaceous-Eocene Matulla, Brown Limestone and Thebes formations, Belayim oilfields, central Gulf of Suez, Egypt

    NASA Astrophysics Data System (ADS)

    El Diasty, W. Sh.; El Beialy, S. Y.; Abo Ghonaim, A. A.; Mostafa, A. R.; El Atfy, H.

    2014-07-01

    Palynological, palynofacies and organic geochemical results of 46 samples retrieved from the Upper Cretaceous - Eocene Matulla, Brown Limestone and Thebes formations, Belayim oilfields, central Gulf of Suez, Egypt are presented. The two latter formations are not dated palynologically as their lithology is not promising for palynological yield. However the Matulla Formation is dated as Turonian-Santonian age, based on the combined evidence of pollen and dinocysts. Palynofacies analysis carried out under both transmitted and fluorescent microscopy indicated that both the Thebes and Brown Limestone formations are deposited under a distal suboxic-anoxic environment. On the other hand, the Turonian-Santonian Matulla Formation supported the existence of a marginal marine deposition under dysoxic-anoxic basin to proximal suboxic-anoxic shelf environments. Rock-Eval pyrolysis and TOC results indicated that most of the studied formations are thermally immature to marginally mature and have a good petroleum potential. They are organically-rich in both oil- and gas-prone kerogen Type-II and II/III, deposited under marine reducing conditions favorable for hydrocarbon generation and expulsion.

  17. The SMS domain of Trs23p is responsible for the in vitro appearance of the TRAPP I complex in Saccharomyces cerevisiae

    PubMed Central

    Brunet, Stephanie; Noueihed, Baraa; Shahrzad, Nassim; Saint-Dic, Djenann; Hasaj, Benedeta; Guan, Tian Lai; Moores, Adrian; Barlowe, Charles; Sacher, Michael

    2012-01-01

    Saccharomyces cerevisiae transport protein particle (TRAPP) is a family of related multisubunit complexes required for endoplasmic reticulum-to-Golgi transport (TRAPP I), endosome-to-Golgi transport (TRAPP II) or cytosol to vacuole targeting (TRAPP III). To gain insight into the relationship between these complexes, we generated random and targeted mutations in the Trs23p core subunit. Remarkably, at physiological salt concentrations only two peaks (TRAPP I and a high molecular weight peak) are detected in wild-type cells. As the salt was raised, the high molecular weight peak resolved into TRAPP II and III peaks. Deletion of a Saccharomycotina-specific domain of Trs23p resulted in destabilization of TRAPP I but had no effect on TRAPP II or III. This mutation had no observable growth phenotype, normal levels of Ypt1p-directed guanine nucleotide exchange factor activity in vivo and did not display any in vivo nor in vitro blocks in membrane traffic. Biochemical analysis indicated that TRAPP I could be produced from the TRAPP II/III peak in vitro by increasing the salt concentration. Our data suggest that the SMS domain of Trs23p is responsible for the in vitro appearance of TRAPP I in S. cerevisiae. The implications of these findings are discussed. PMID:22645708

  18. Emerging drugs for osteoarthritis

    PubMed Central

    Matthews, Gloria

    2013-01-01

    Introduction Osteoarthritis (OA), the most prevalent form of joint disease, affecting as much as 13% of the world’s population. In the United States, it is the leading cause of disability in people over age 65 and is characterized by progressive cartilage loss, bone remodeling, osteophyte formation and synovial inflammation with resultant joint pain and disability. There are no treatments marketed for structural disease modification; current treatments mainly target symptoms, with >75% of patients reporting need for additional symptomatic treatment. Areas covered Drugs in later development (Phase II-III) for osteoarthritis pain and joint structural degeneration are reviewed. Not covered are procedural (e.g. arthrocentesis, physical therapy), behavioral (e.g. weight loss, pain coping techniques) or device (e.g. knee braces, surgical implants) based treatments. Expert opinion More in depth understanding of the pathophysiology of the disease, as well as elucidation of the link between clinical symptomatology and structural changes in the joint will likely lead to development of novel target classes with promising efficacy in the future. Efficacy notwithstanding, there remain significant hurdles to overcome in clinical development of these therapeutics, inherent in the progression pattern of the disease as well as challenges with readouts for both pain and structure modification trials. PMID:21542666

  19. [Study PARADIGM-HF - a paradigm shift in the treatment of chronic heart failure].

    PubMed

    Bělohlávek, Jan

    2015-01-01

    Chronic heart failure is a crucial problem of current cardiology. Despite that, no major development has occurred in the therapy in recent years. In this regard, first results of studies with ARNI inhibitors (angiotensin-receptor neprilysin inhibitors) may be considered hopeful. Dual inhibition of AT1 receptors and neprilysin blocks renin-angiotensin-aldosteron (RAS) axis and concurrently supports natural vasodilatory and diuretic effect of natriuretic peptides. Large-scale prospective randomized multicenter trial PARADIGM-HF with more than 8000 individuals with stabilized chronic heart failure with systolic dysfunction (LV EF 40%, later 35%), mostly in functional class NYHA II-III with elevated BNP/NT-pro BNP has shown 20% decrease in primary endpoint (cardiovascular death or hospitalization for heart failure) in a group treated by ARNI (LCZ696; sacubiltril - valsartan). Beneficial effect of ARNI was consistent also for total and cardiovascular mortality, for hospitalization for heart failure and in other pre-specified subgroup analyses, including quality of life. The treatment was safe, typical adverse event was hypotension, however without a need to interrupt the treatment. Dual RAS and neprilysin inhibition might thus after long time become a change in stable chronic heart failure with systolic dysfunction treatment "paradigm". Czech Republic significantly contributed to this study and all study sites should be congratulated and thanked for their high-quality work provided. PMID:26750622

  20. A combined computational and experimental study of the [Co(bpy)3](2+/3+) complexes as one-electron outer-sphere redox couples in dye-sensitized solar cell electrolyte media.

    PubMed

    Yaghoobi Nia, Narges; Farahani, Pooria; Sabzyan, Hassan; Zendehdel, Mahmoud; Oftadeh, Mohsen

    2014-06-21

    A combined experimental and computational investigation conducted to understand the nature of the interactions between cobalt II/III redox mediators ([Co(bpy)3](2+/3+)) and their impact on the performance of the corresponding dye-sensitized solar cells (DSCs) is reported. The fully optimized equilibrium structures of cobalt(II/III)-tris-bipyridine complexes in the gas phase and acetonitrile solvent are obtained by the density functional B3LYP method using LanL2DZ and 6-31G(d,p) basis sets. The harmonic vibrational frequencies, infrared intensities and Raman scattering activities of the complexes are also calculated. The scaled computational vibrational wavenumbers show very good agreement with the experimental values. Calculations of the electronic properties of the complexes are also performed at the TD-B3LYP/6-31G(p,d)[LanL2DZ] level of theory. Detailed interpretations of the infrared and Raman spectra of the complexes in different phases are reported. Detailed atomic orbital coefficients of the frontier molecular orbitals and their major contributions to electronic excitations of the complexes are also reported. These results are in good agreement with the experimental electrochemical values. Marcus diagram is derived for the electron transfer reaction Co(II) + D35(+)→ Co(III) + D35 using the Co-N bond length as a reaction coordinate. PMID:24802678

  1. Acute Carnosine Administration Increases Respiratory Chain Complexes and Citric Acid Cycle Enzyme Activities in Cerebral Cortex of Young Rats.

    PubMed

    Macedo, Levy W; Cararo, José H; Maravai, Soliany G; Gonçalves, Cinara L; Oliveira, Giovanna M T; Kist, Luiza W; Guerra Martinez, Camila; Kurtenbach, Eleonora; Bogo, Maurício R; Hipkiss, Alan R; Streck, Emilio L; Schuck, Patrícia F; Ferreira, Gustavo C

    2016-10-01

    Carnosine (β-alanyl-L-histidine) is an imidazole dipeptide synthesized in excitable tissues of many animals, whose biochemical properties include carbonyl scavenger, anti-oxidant, bivalent metal ion chelator, proton buffer, and immunomodulating agent, although its precise physiological role(s) in skeletal muscle and brain tissues in vivo remain unclear. The aim of the present study was to investigate the in vivo effects of acute carnosine administration on various aspects of brain bioenergetics of young Wistar rats. The activity of mitochondrial enzymes in cerebral cortex was assessed using a spectrophotometer, and it was found that there was an increase in the activities of complexes I-III and II-III and succinate dehydrogenase in carnosine-treated rats, as compared to vehicle-treated animals. However, quantitative real-time RT-PCR (RT-qPCR) data on mRNA levels of mitochondrial biogenesis-related proteins (nuclear respiratory factor 1 (Nrf1), peroxisome proliferator-activated receptor-γ coactivator 1-α (Ppargc1α), and mitochondrial transcription factor A (Tfam)) were not altered significantly and therefore suggest that short-term carnosine administration does not affect mitochondrial biogenesis. It was in agreement with the finding that immunocontent of respiratory chain complexes was not altered in animals receiving carnosine. These observations indicate that acute carnosine administration increases the respiratory chain and citric acid cycle enzyme activities in cerebral cortex of young rats, substantiating, at least in part, a neuroprotector effect assigned to carnosine against oxidative-driven disorders. PMID:26476839

  2. Risk of adverse events with bevacizumab addition to therapy in advanced non-small-cell lung cancer: a meta-analysis of randomized controlled trials

    PubMed Central

    Lai, Xi-Xi; Xu, Ren-Ai; Yu-Ping, Li; Yang, Han

    2016-01-01

    Background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor ligand, has shown survival benefits in the treatment of many types of malignant tumors, including non-small-cell lung cancer (NSCLC). We conducted this systematic review and meta-analysis to investigate the risk of the most clinically relevant adverse events related to bevacizumab in advanced NSCLC. Methods Databases from PubMed, Web of Science, and Cochrane Library up to August 2015, were searched to identify relevant studies. We included prospective randomized controlled Phase II/III clinical trials that compared therapy with or without bevacizumab for advanced NSCLC. Summary relative risk (RR) and 95% confidence intervals were calculated using random effects or fixed effects according to the heterogeneity among included trials. Results A total of 3,745 patients from nine clinical trials were included in the meta-analysis. Summary RRs showed a statistically significant bevacizumab-associated increased risk in three of the adverse outcomes studied: proteinuria (RR =7.55), hypertension (RR =5.34), and hemorrhagic events (RR =2.61). No statistically significant differences were found for gastrointestinal perforation (P=0.60), arterial and venous thromboembolic events (P=0.35 and P=0.92, respectively), or fatal events (P=0.29). Conclusion The addition of bevacizumab to therapy in advanced NSCLC did significantly increase the risk of proteinuria, hypertension, and hemorrhagic events but not arterial/venous thromboembolic events, gastrointestinal perforation, or fatal adverse events. PMID:27143937

  3. Visual and noxious electrical stimulus-evoked membrane-potential responses in anterior cingulate cortical neurons.

    PubMed

    Ma, Li-Qing; Ning, Li; Wang, Zhiru; Wang, Ying-Wei

    2016-01-01

    Anterior cingulate cortex (ACC) is known to participate in numerous brain functions, such as memory storage, emotion, attention, as well as perception of acute and chronic pain. ACC-dependent brain functions often rely on ACC processing of various forms of environmental information. To understand the neural basis of ACC functions, previous studies have investigated ACC responses to environmental stimulation, particularly complex sensory stimuli as well as award and aversive stimuli, but this issue remains to be further clarified. Here, by performing whole-cell recording in vivo in anaesthetized adult rats, we examined membrane-potential (MP) responses of layer II/III ACC neurons that were evoked by a brief flash of visual stimulation and pain-related electrical stimulation delivered to hind paws. We found that ~54 and ~81 % ACC neurons exhibited excitatory MP responses, subthreshold or suprathreshold, to the visual stimulus and the electrical stimulus, respectively, with no cell showing inhibitory MP responses. We further found that the visually evoked ACC response could be greatly diminished by local lidocaine infusion in the visual thalamus, and only their temporal patterns but not amplitudes could be changed by large-scale visual cortical lesions. Our in vivo whole-cell recording data characterized in ACC neurons a visually evoked response, which was largely dependent on the visual thalamus but not visual cortex, as well as a noxious electrical stimulus-evoked response. These findings may provide potential mechanisms that are used for ACC functions on the basis of sensory information processing. PMID:27585569

  4. Associations of perceived neighborhood safety and crime with cardiometabolic risk factors among a population with type 2 diabetes.

    PubMed

    Tamayo, Aracely; Karter, Andrew J; Mujahid, Mahasin S; Warton, E Margaret; Moffet, Howard H; Adler, Nancy; Schillinger, Dean; Hendrickson O'Connell, Bethany; Laraia, Barbara

    2016-05-01

    Little is known about how neighborhood crime may relate to health in diabetes patients. We examined associations between individuals' perceptions of neighborhood safety or violent crime and stress, physical activity, body mass index (BMI) or hemoglobin A1c (HbA1c) in a sample (n=721) of adults (mean age:63) with diabetes. Self-reported neighborhood safety, violent crime, physical activity, and stress were collected and linked to clinical measures of BMI and HbA1c. Approximately 54% and 15% of patients reported neighborhood safety concerns and violent crimes, respectively. Any neighborhood safety concerns (β=1.14, 95% C.I. 0.04-2.24) and violent crime (β=2.04, 95% C.I. 0.34-3.73) were associated with BMI in adjusted analysis. Any violent crime was associated with class II-III obesity (BMI≥35) (OR=1.34, 95% C.I.: 1.02, 1.75). There were no significant associations between neighborhood safety concerns or violent crime with stress, physical activity, or HbA1c. Neighborhood safety is associated with BMI and obesity. Further studies, including longitudinal designs, are needed to study how people with diabetes may be influenced by a sense of poor personal safety in their neighborhoods. PMID:27060870

  5. Body Shape, Adiposity Index, and Mortality in Postmenopausal Women: Findings from the Women’s Health Initiative

    PubMed Central

    Thomson, Cynthia A.; Garcia, David O.; Wertheim, Betsy C.; Hingle, Melanie D.; Bea, Jennifer W.; Zaslavsky, Oleg; Caire-Juvera, Graciela; Rohan, Thomas; Vitolins, Mara Z.; Thompson, Patricia A.; Lewis, Cora E.

    2016-01-01

    Objective Studies evaluating the relationship between body mass index (BMI) and mortality demonstrate a U-shaped association. To expand, this study evaluated the relationship between adiposity indices, a body shape index (ABSI) and body adiposity index (BAI), and mortality in 77,505 postmenopausal women. Methods A prospective cohort analysis was conducted in the Women’s Health Initiative to ascertain the independent relationships between adiposity indices and mortality in order to inform on the clinical usefulness of alternate measures of mortality risk. ABSI (waist circumference (cm)/[BMI2/3 × height (cm)1/2]), BAI (hip circumference (cm)/[height (m)1.5] − 18), weight, BMI, and waist circumference (WC) were evaluated in relation to mortality risk using adjusted Cox proportional hazards regression models. Results ABSI showed a linear association with mortality (HR, 1.37; 95% CI, 1.28–1.47 for quintile 5 vs. 1) while BMI and BAI had U-shaped relationships with HR of 1.30; 95% CI, 1.20–1.40 for obesity II/III BMI and 1.06, 95% CI, 0.99–1.13 for BAI. Higher WC (HR, 1.21; 95% CI, 1.13–1.29 for quintile 5 vs. 1) showed relationships similar to BMI. Conclusions ABSI appears to be a clinically useful measure for estimating mortality risk, perhaps more so than BAI and BMI in postmenopausal women. PMID:26991923

  6. Umbilical cord blood transplantation for adults using tacrolimus with two-day very-short-term methotrexate for graft-versus-host disease prophylaxis.

    PubMed

    Saito, Bungo; Hattori, Norimichi; Yamamoto, Kohei; Arai, Nana; Kawaguchi, Yukiko; Fujiwara, Shun; Kabasawa, Nobuyuki; Tsukamoto, Hiroyuki; Uto, Yui; Ariizumi, Hirotsugu; Yanagisawa, Kouji; Nakamaki, Tsuyoshi

    2016-08-01

    Cord blood transplantation (CBT) is an alternative approach to allogeneic stem cell transplantation. However, CBT is associated with issues including pre-engraftment immune reaction (PIR), engraftment syndrome (ES), and graft failure (GF). Tacrolimus (TAC) and short-term methotrexate (sMTX: days 1, 3, 6, and/or 11) are used for graft-versus-host disease (GVHD) prophylaxis during CBT; however, sMTX does not accelerate neutrophil engraftment. Therefore, we hypothesized that lower doses of sMTX [very-short-term MTX (vsMTX): 10 and 7mg/m(2) on days 1 and 3, respectively] with TAC reduce the risk of GF without increasing post-transplantation immune reactions during CBT. We retrospectively analyzed 40 patients who received TAC with vsMTX for GVHD prophylaxis. PIR and ES developed in 4 patients. The cumulative incidence of neutrophil engraft at day 60 was 92.5%. No cases of primary graft failure were noted. The cumulative incidence of grades II-III GVHD was 48.1% at day 100, and the cumulative 100-day incidence of nonrelapse mortality was 12.5%. This study suggests that TAC with vsMTX reduces the risk of PIR and ES during CBT and stimulates neutrophil engraftment, but may be associated with slightly higher aGVHD compared with calcineurin inhibitor and sMTX. Therefore, we recommend vsMTX plus TAC as an option for GVHD prophylaxis during CBT. PMID:27376545

  7. Masitinib for the treatment of mild to moderate Alzheimer's disease.

    PubMed

    Folch, Jaume; Petrov, Dmitry; Ettcheto, Miren; Pedrós, Ignacio; Abad, Sonia; Beas-Zarate, Carlos; Lazarowski, Alberto; Marin, Miguel; Olloquequi, Jordi; Auladell, Carme; Camins, Antoni

    2015-06-01

    Alzheimer's disease (AD) is a degenerative neurological disorder that is the most common cause of dementia and disability in older patients. Available treatments are symptomatic in nature and are only sufficient to improve the quality of life of AD patients temporarily. A potential strategy, currently under investigation, is to target cell-signaling pathways associated with neurodegeneration, in order to decrease neuroinflammation, excitotoxicity, and to improve cognitive functions. Current review centers on the role of neuroinflammation and the specific contribution of mast cells to AD pathophysiology. The authors look at masitinib therapy and the evidence presented through preclinical and clinical trials. Dual actions of masitinib as an inhibitor of mast cell-glia axis and a Fyn kinase blocker are discussed in the context of AD pathology. Masitinib is in Phase III clinical trials for the treatment of malignant melanoma, mastocytosis, multiple myeloma, gastrointestinal cancer and pancreatic cancer. It is also in Phase II/III clinical trials for the treatment of multiple sclerosis, rheumatoid arthritis and AD. Additional research is warranted to better investigate the potential effects of masitinib in combination with other drugs employed in AD treatment. PMID:25961655

  8. Comprehensive protein tyrosine phosphatase mRNA profiling identifies new regulators in the progression of glioma.

    PubMed

    Bourgonje, Annika M; Verrijp, Kiek; Schepens, Jan T G; Navis, Anna C; Piepers, Jolanda A F; Palmen, Chantal B C; van den Eijnden, Monique; Hooft van Huijsduijnen, Rob; Wesseling, Pieter; Leenders, William P J; Hendriks, Wiljan J A J

    2016-01-01

    The infiltrative behavior of diffuse gliomas severely reduces therapeutic potential of surgical resection and radiotherapy, and urges for the identification of new drug-targets affecting glioma growth and migration. To address the potential role of protein tyrosine phosphatases (PTPs), we performed mRNA expression profiling for 91 of the 109 known human PTP genes on a series of clinical diffuse glioma samples of different grades and compared our findings with in silico knowledge from REMBRANDT and TCGA databases. Overall PTP family expression levels appeared independent of characteristic genetic aberrations associated with lower grade or high grade gliomas. Notably, seven PTP genes (DUSP26, MTMR4, PTEN, PTPRM, PTPRN2, PTPRT and PTPRZ1) were differentially expressed between grade II-III gliomas and (grade IV) glioblastomas. For DUSP26, PTEN, PTPRM and PTPRT, lower expression levels correlated with poor prognosis, and overexpression of DUSP26 or PTPRT in E98 glioblastoma cells reduced tumorigenicity. Our study represents the first in-depth analysis of PTP family expression in diffuse glioma subtypes and warrants further investigations into PTP-dependent signaling events as new entry points for improved therapy. PMID:27586084

  9. The relation between cardiac output kinetics and skeletal muscle oxygenation during moderate exercise in moderately impaired patients with chronic heart failure.

    PubMed

    Spee, Ruud F; Niemeijer, Victor M; Schoots, Thijs; Wijn, Pieter F; Doevendans, Pieter A; Kemps, Hareld M

    2016-07-01

    Oxygen uptake (V̇o2) kinetics are prolonged in patients with chronic heart failure (CHF). This may be caused by impaired oxygen delivery or skeletal muscle derangements. We investigated whether impaired cardiac output (Q̇) kinetics limit skeletal muscle oxygen delivery relative to the metabolic demands at submaximal exercise in CHF patients by evaluating the relation between Q̇ kinetics and skeletal muscle deoxygenation. Forty-three CHF patients, NYHA II-III, performed a constant-load exercise test at 80% of the ventilatory aerobic threshold (VAT) to assess V̇o2 kinetics (τV̇o2). Q̇ kinetics (τQ̇) were assessed by a radial artery pulse contour analysis method. Skeletal muscle deoxygenation was assessed by near infrared spectroscopy at the m. vastus lateralis, using the minimal value of the tissue saturation index during onset of exercise (TSImin). Patients were categorized in slow and normal Q̇ responders relative to metabolic demands (τQ̇/V̇o2 ≥1 and τQ̇/V̇o2 <1, respectively), τQ̇ (62 ± 29 s), and τV̇o2 (60 ± 21 s) were significantly related (r = 0.66, P = 0.001). There was a significant correlation between τQ̇ and TSImin in the slow Q̇ responders [rs= -0.57, P = 0.005, n = 22 (51%)]. In conclusion, in moderately impaired CHF patients with relatively slow Q̇ kinetics, central hemodynamics may limit skeletal muscle oxygenation during moderate-intensity exercise. PMID:27283909

  10. What Do Effective Treatments for Multiple Sclerosis Tell Us about the Molecular Mechanisms Involved in Pathogenesis?

    PubMed Central

    Buzzard, Katherine A.; Broadley, Simon A.; Butzkueven, Helmut

    2012-01-01

    Multiple sclerosis is a potentially debilitating disease of the central nervous system. A concerted program of research by many centers around the world has consistently demonstrated the importance of the immune system in its pathogenesis. This knowledge has led to the formal testing of a number of therapeutic agents in both animal models and humans. These clinical trials have shed yet further light on the pathogenesis of MS through their sometimes unexpected effects and by their differential effects in terms of impact on relapses, progression of the disease, paraclinical parameters (MRI) and the adverse events that are experienced. Here we review the currently approved medications for the commonest form of multiple sclerosis (relapsing-remitting) and the emerging therapies for which preliminary results from phase II/III clinical trials are available. A detailed analysis of the molecular mechanisms responsible for the efficacy of these medications in multiple sclerosis indicates that blockade or modulation of both T- and B-cell activation and migration pathways in the periphery or CNS can lead to amelioration of the disease. It is hoped that further therapeutic trials will better delineate the pathogenesis of MS, ultimately leading to even better treatments with fewer adverse effects. PMID:23202920

  11. Reachable Workspace in Facioscapulohumeral muscular dystrophy (FSHD) by Kinect

    PubMed Central

    Han, Jay J.; Kurillo, Gregorij; Abresch, Richard T.; de Bie, Evan; Nicorici, Alina; Bajcsy, Ruzena

    2014-01-01

    Introduction A depth-ranging sensor (Kinect) based upper extremity motion analysis system was applied to determine the spectrum of reachable workspace encountered in facioscapulohumeral muscular dystrophy (FSHD). Methods Reachable workspaces were obtained from 22 individuals with FSHD and 24 age- and height-matched healthy controls. To allow comparison, total and quadrant reachable workspace relative surface areas (RSA) were obtained by normalizing the acquired reachable workspace by each individual’s arm length. Results Significantly contracted reachable workspace and reduced RSAs were noted for the FSHD cohort compared to controls (0.473±0.188 vs. 0.747±0.082; P<0.0001). With worsening upper extremity function as categorized by the FSHD evaluation subscale II+III, the upper quadrant RSAs decreased progressively, while the lower quadrant RSAs were relatively preserved. There were no side-to-side differences in reachable workspace based on hand-dominance. Discussion This study demonstrates the feasibility and potential of using an innovative Kinect-based reachable workspace outcome measure in FSHD. PMID:24828906

  12. Elevated HMGA2 expression is associated with cancer aggressiveness and predicts poor outcome in breast cancer.

    PubMed

    Wu, Jingjing; Zhang, Shizhen; Shan, Jinlan; Hu, Zujian; Liu, Xiyong; Chen, Lirong; Ren, Xingchang; Yao, Lifang; Sheng, Hongqiang; Li, Ling; Ann, David; Yen, Yun; Wang, Jian; Wang, Xiaochen

    2016-07-01

    High mobility group AT-hook 2 (HMGA2) is involved in a wide spectrum of biological processes and is upregulated in several tumors. Here, we collected 273 breast cancer (BC) specimens as a training set and 310 specimens as a validation set to examine the expression of HMGA2 by immunohistochemical staining. It was found that HMGA2 expression was significantly positively correlated with advanced tumor grade and poor survival. Subgroup analysis indicated that high level of HMGA2 was significantly correlated with poor prognosis, especially in the subgroups of stage II-III, low pathological grade and non-triple negative breast cancer cases. Gene set enrichment analysis (GSEA) demonstrated a significant positive correlation between HMGA2 level and the gene expression signature of metaplastic and mesenchymal phenotype. Importantly, we also observed that ectopic expression of HMGA2 promoted the migration and invasion of breast cancer cells, and protected cancer cells against genotoxic stress from agents stimulating P53 (Ser15) phosphorylation. As a conclusion, expression of HMGA2 might indicate more advanced malignancy of breast cancer. Thus we believe HMGA2 could serve as a biomarker of poor prognosis and a novel target in treating BC tumors. PMID:27063096

  13. Neuroprotective and neurorestorative effects of thymosin β4 treatment following experimental traumatic brain injury.

    PubMed

    Xiong, Ye; Mahmood, Asim; Meng, Yuling; Zhang, Yanlu; Zhang, Zheng Gang; Morris, Daniel C; Chopp, Michael

    2012-10-01

    Traumatic brain injury (TBI) remains a leading cause of mortality and morbidity worldwide. No effective pharmacological treatments are available for TBI because all phase II/III TBI clinical trials have failed. This highlights a compelling need to develop effective treatments for TBI. Endogenous neurorestoration occurs in the brain after TBI, including angiogenesis, neurogenesis, synaptogenesis, oligodendrogenesis, and axonal remodeling, which may be associated with spontaneous functional recovery after TBI. However, the endogenous neurorestoration following TBI is limited. Treatments amplifying these neurorestorative processes may promote functional recovery after TBI. Thymosin beta 4 (Tβ4) is the major G-actin-sequestering molecule in eukaryotic cells. In addition, Tβ4 has other properties including antiapoptosis and anti-inflammation, promotion of angiogenesis, wound healing, stem/progenitor cell differentiation, and cell migration and survival, which provide the scientific foundation for the corneal, dermal, and cardiac wound repair multicenter clinical trials. Here, we describe Tβ4 as a neuroprotective and neurorestorative candidate for treatment of TBI. PMID:23050817

  14. Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival.

    PubMed

    Fink, Stephen P; Myeroff, Lois L; Kariv, Revital; Platzer, Petra; Xin, Baozhong; Mikkola, Debra; Lawrence, Earl; Morris, Nathan; Nosrati, Arman; Willson, James K V; Willis, Joseph; Veigl, Martina; Barnholtz-Sloan, Jill S; Wang, Zhenghe; Markowitz, Sanford D

    2015-10-13

    Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target. PMID:26437221

  15. Clinical profile and natural history of Ebstein's anomaly of tricuspid valve.

    PubMed

    Jaiswal, P K; Balakrishnan, K G; Saha, A; Venkitachalam, C G; Tharakan, J; Titus, T

    1994-09-01

    There were 63 patients of Ebstein's anomaly of tricuspid valve encountered from 1976 to 1991; 28 (44.4%) were male and 35 (55.6%) female. Their age at presentation ranged from 3 months to 51 years. Five (7.9%) patients were asymptomatic, 48 (76.2%) had class II-III exertional dyspnoea, palpitation or both. Thirty patients (47.6%) had cyanosis. Electrocardiogram showed paroxysmal atrial fibrillation in two, chronic atrial fibrillation in four (6.3%), paroxysmal supraventricular tachycardia in seven, atrial or ventricular ectopic beats in five (7.9%), 2:1 atrioventricular block in one (1.6%), complete atrioventricular block in two (3.2%) and type B WPW syndrome in nine patients (14.3%). Chest X-ray showed diminished vascularity in 22 (34.9%). Diagnosis was established by cardiac catheterization and or echocardiography. Atrialized right ventricular chamber was demonstrated in 51 (80.9%) by angiography and in 40 (63.5%) by electrophysiology. Patients were followed up for 1-172 months. Seventeen patients (26.9%) required surgery. Three patients (4.8%) died during medical follow-up, and five (7.9%) died following surgery. Survival probability for 46 medical patients was 88.9% at 172 months. Factors affecting survival were pulmonary blood flow, cyanosis, clubbing and systemic arterial oxygen saturation. PMID:7814159

  16. Patient-specific quantification of respiratory motion-induced dose uncertainty for step-and-shoot IMRT of lung cancer

    SciTech Connect

    Li, Heng; Park, Peter; Liu, Wei; Matney, Jason; Balter, Peter; Zhang, Xiaodong; Li, Xiaoqiang; Zhu, X. Ronald; Liao, Zhongxing; Li, Yupeng

    2013-12-15

    Purpose: The objective of this study was to quantify respiratory motion-induced dose uncertainty at the planning stage for step-and-shoot intensity-modulated radiation therapy (IMRT) using an analytical technique.Methods: Ten patients with stage II/III lung cancer who had undergone a planning four-dimensional (4D) computed tomographic scan and step-and-shoot IMRT planning were selected with a mix of motion and tumor size for this retrospective study. A step-and-shoot IMRT plan was generated for each patient. The maximum and minimum doses with respiratory motion were calculated for each plan, and the mean deviation from the 4D dose was calculated, taking delivery time, fractionation, and patient breathing cycle into consideration.Results: For all patients evaluated in this study, the mean deviation from the 4D dose in the planning target volume (PTV) was <2.5%, with a standard deviation <1.2%, and maximum point dose variation from the 4D dose was <6.2% in the PTV assuming delivery dose rate of 200 MU/min and patient breathing cycle of 8 s. The motion-induced dose uncertainty is a function of motion, fractionation, MU (plan modulation), dose rate, and patient breathing cycle.Conclusions: Respiratory motion-induced dose uncertainty varies from patient to patient. Therefore, it is important to evaluate the dose uncertainty on a patient-specific basis, which could be useful for plan evaluation and treatment strategy determination for selected patients.

  17. Mitochondrial dysfunction in rabies virus infection of neurons.

    PubMed

    Alandijany, Thamir; Kammouni, Wafa; Roy Chowdhury, Subir K; Fernyhough, Paul; Jackson, Alan C

    2013-12-01

    Infection with the challenge virus standard-11 (CVS) strain of fixed rabies virus induces neuronal process degeneration in adult mice after hindlimb footpad inoculation. CVS-induced axonal swellings of primary rodent dorsal root ganglion neurons are associated with 4-hydroxy-2-nonenal protein adduct staining, indicating a critical role of oxidative stress. Mitochondrial dysfunction is the major cause of oxidative stress. We hypothesized that CVS infection induces mitochondrial dysfunction leading to oxidative stress. We investigated the effects of CVS infection on several mitochondrial parameters in different cell types. CVS infection significantly increased maximal uncoupled respiration and complex IV respiration and complex I and complex IV activities, but did not affect complex II-III or citrate synthase activities. Increases in complex I activity, but not complex IV activity, correlated with susceptibility of the cells to CVS infection. CVS infection maintained coupled respiration and rate of proton leak, indicating a tight mitochondrial coupling. Possibly as a result of enhanced complex activity and efficient coupling, a high mitochondrial membrane potential was generated. CVS infection reduced the intracellular ATP level and altered the cellular redox state as indicated by a high NADH/NAD+ ratio. The basal production of reactive oxygen species (ROS) was not affected in CVS-infected neurons. However, a higher rate of ROS generation occurred in CVS-infected neurons in the presence of mitochondrial substrates and inhibitors. We conclude that CVS infection induces mitochondrial dysfunction leading to ROS overgeneration and oxidative stress. PMID:24277436

  18. Management of neuroblastoma: a study of first- and second-line chemotherapy responses, a single institution experience

    PubMed Central

    Habib, Emmad E.; El-Kashef, Amr T.; Fahmy, Ezzat S.

    2012-01-01

    Neuroblastoma is a high-grade malignancy of childhood. It is chemo- and radio-sensitive but prone to relapse after initial remission. The aim of the current study was to study the results of the first- and second-line chemotherapy on the short-term response and long-term survival of children, and to further describe the side effects of treatment. Ninety-five children with advanced neuroblastoma were included in the study, divided into two groups according to the treatment strategy: 65 were treated by first-line chemotherapy alone, and 30 children who were not responding or relapsed after first-line chemotherapy were treated by second-line chemotherapy. External beam radiotherapy was given to bone and brain secondary cancers when detected. Staging workup was performed before, during and after management. Response was documented after surgery for the primary tumor. Median follow up was 32 months (range 24–60 months). Chemothe rapy was continued until toxicity or disease progression occurred, indicating interruption of chemotherapy. Patients received a maximum of 8 cycles. Toxicity was mainly myelo-suppression, with grade II-III severity in 60% of the firstline and 70% of the second-line chemotherapy patients. Median total actuarial survival was nearly 51 months for the first-line chemotherapy group and 30 months for the second-line line group, with a statistically significant difference between the two groups (P<0.01). PMID:25992205

  19. Present and future treatment possibilities in macular degeneration

    NASA Astrophysics Data System (ADS)

    Fisher, E.; Wegner, A.; Pfeiler, T.; Mertz, M.

    2005-11-01

    Purpose: To discuss present and future treatment possibilities in different types of choroidal neovascularisation. Methods: Presented are angiographic- and OCT-findings in patients with macular degeneration of different origin. Choroidal neovascularisations, which are not likely to respond positively to established procedures like thermal laser coagulation or photodynamic therapy will be discussed. Results and conclusions: Present study-guidelines and new methods of pharmacological intervention are analysed in different patterns of macular degeneration. Conventional laser coagulation in the treatment of classic, extrafoveal CNV and photodynamic therapy of predominantly classic subfoveal CNV still represent a gold standard. There are new recommendations, loosening the tight criteria of the TAP and VIP-guidelines, which cover, for instance, wider visual acuity ranges and the treatment of juxtafoveally located choroidal neovascularisations. Positive findings in literature confirm the role of PDT in pathologic myopia and other non-AMD CNV. Studies about surgical procedures, like macula- or RPE-translocation after surgical removal or thermal laser destruction of the CNV are in progress and are expected to show promising results. Phase II/III studies will soon point out the effect of anti-VEGF agents. The application of intravitreal (triamcinolone) or peribulbar (anecortave acetat) steroids could be useful. The combination with surgical or laser techniques could bring further benefit to the patient.

  20. Molecular characterization and expression profile of the estrogen receptor α gene during different reproductive phases in Monopterus albus

    PubMed Central

    Ding, Weidong; Cao, Liping; Cao, Zheming; Bing, Xuwen; Zhao, Fazhen

    2016-01-01

    To understand the molecular mechanism of estrogen and to evaluate the role of the estrogen receptor in mediating estrogen action, the full-length cDNA of estrogen receptor α (ERα) was cloned from Monopterus albus, and its expression pattern and distribution were investigated. The ERα cDNA of M. albus includes an open reading frame of 1863 bp, a 140-bp 5’-untranslated region and a 797-bp 3’-untranslated region. Amino acid sequence homology analysis showed that the Monopterus albus ERα has a moderate degree of similarity with Sebastes schlegelii, Zoarces viviparus and Haplochromis burtoni (81.1%, 80.7% and 80.4%, respectively). Quantitative PCR results showed that the highest level of ERα expression was in the liver; the next highest level of expression was observed in the gonads, where it was expressed at high levels particularly in the ovary in developmental stages IV and V and in the testis in developmental stage II/III. Immunohistochemistry analysis showed that ERα was present as slender particles distributed mainly in the membranes of spermatocytes and oocytes in the testis and ovary, whereas no positive signal was observed in the cytoplasm of sperm cells. This report describes the first molecular characterization of full-length ERα and its tissue-specific distribution in M. albus. PMID:27295422

  1. Stability hierarchy between Piracetam forms I, II, and III from experimental pressure-temperature diagrams and topological inferences.

    PubMed

    Toscani, Siro; Céolin, René; Minassian, Léon Ter; Barrio, Maria; Veglio, Nestor; Tamarit, Josep-Lluis; Louër, Daniel; Rietveld, Ivo B

    2016-01-30

    The trimorphism of the active pharmaceutical ingredient piracetam is a famous case of polymorphism that has been frequently revisited by many researchers. The phase relationships between forms I, II, and III were ambiguous because they seemed to depend on the heating rate of the DSC and on the history of the samples or they have not been observed at all (equilibrium II-III). In the present paper, piezo-thermal analysis and high-pressure differential thermal analysis have been used to elucidate the positions of the different solid-solid and solid-liquid equilibria. The phase diagram, involving the three solid phases, the liquid phase and the vapor phase, has been constructed. It has been shown that form III is the high-pressure, low-temperature form and the stable form at room temperature. Form II is stable under intermediary conditions and form I is the low pressure, high temperature form, which possesses a stable melting point. The present paper demonstrates the strength of the topological approach based on the Clapeyron equation and the alternation rule when combined with high-pressure measurements. PMID:26617316

  2. Adoptive Cell Therapies for Glioblastoma

    PubMed Central

    Bielamowicz, Kevin; Khawja, Shumaila; Ahmed, Nabil

    2013-01-01

    Glioblastoma (GBM) is the most common and most aggressive primary brain malignancy and, as it stands, is virtually incurable. With the current standard of care, maximum feasible surgical resection followed by radical radiotherapy and adjuvant temozolomide, survival rates are at a median of 14.6 months from diagnosis in molecularly unselected patients (1). Collectively, the current knowledge suggests that the continued tumor growth and survival is in part due to failure to mount an effective immune response. While this tolerance is subtended by the tumor being utterly “self,” it is to a great extent due to local and systemic immune compromise mediated by the tumor. Different cell modalities including lymphokine-activated killer cells, natural killer cells, cytotoxic T lymphocytes, and transgenic chimeric antigen receptor or αβ T cell receptor grafted T cells are being explored to recover and or redirect the specificity of the cellular arm of the immune system toward the tumor complex. Promising phase I/II trials of such modalities have shown early indications of potential efficacy while maintaining a favorable toxicity profile. Efficacy will need to be formally tested in phase II/III clinical trials. Given the high morbidity and mortality of GBM, it is imperative to further investigate and possibly integrate such novel cell-based therapies into the current standards-of-care and herein we collectively assess and critique the state-of-the-knowledge pertaining to these efforts. PMID:24273748

  3. Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice.

    PubMed

    Darvish-Ghane, Soroush; Yamanaka, Manabu; Zhuo, Min

    2016-01-01

    Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA. PMID:27317578

  4. A role for heparan sulfate 3-O-sulfotransferase isoform 2 in herpes simplex virus type 1 entry and spread

    SciTech Connect

    O'Donnell, Christopher D.; Tiwari, Vaibhav; Oh, Myung-Jin; Shukla, Deepak . E-mail: dshukla@uic.edu

    2006-03-15

    Heparan sulfate (HS) 3-O-sulfotransferase isoform-2 (3-OST-2), which belongs to a family of enzymes capable of generating herpes simplex virus type-1 (HSV-1) entry and spread receptors, is predominantly expressed in human brain. Despite its unique expression pattern, the ability of 3-OST-2 to mediate HSV-1 entry and cell-to-cell fusion is not known. Our results demonstrate that expression of 3-OST-2 can render Chinese hamster ovary K1 (CHO-K1) cells susceptible to entry of wild-type and mutant strains of HSV-1. Evidence for generation of gD receptors by 3-OST-2 were suggested by gD-mediated interference assay and the ability of 3-OST-2-expressing CHO-K1 cells to preferentially bind HSV-1 gD, which could be reversed by prior treatment of cells with HS lyases (heparinases II/III). In addition, 3-OST-2-expressing CHO-K1 cells acquired the ability to fuse with cells-expressing HSV-1 glycoproteins, a phenomenon that mimics a way of viral spread in vivo. Demonstrating specificity, the cell fusion was inhibited by soluble 3-O-sulfated forms of HS, but not unmodified HS. Taken together, our results raise the possibility of a role of 3-OST-2 in the spread of HSV-1 infection in the brain.

  5. [TECOS: confirmation of the cardiovascular safety of sitaliptin].

    PubMed

    Scheen, A J; Paquot, N

    2015-10-01

    The cardiovascular safety of sitagliptin has been evaluated in TECOS ("Trial Evaluating Cardiovascular Outcomes with Sitagliptin"). TECOS recruited patients with type 2 diabetes and a history of cardiovascular disease who received, as add-on to their usual therapy, either sitagliptin (n = 7.257) or placebo (n = 7.266), with a median follow-up of 3 years. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% confidence interval, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). The cardiovascular safety of sitagliptin, which was already shown in meta-analyses of phase II-III randomised controlled trials and in observational cohort studies in real life, is now confirmed in the landmark prospective cardiovascular outcome study TECOS. PMID:26727841

  6. HSV Recombinant Vectors for Gene Therapy

    PubMed Central

    Manservigi, Roberto; Argnani, Rafaela; Marconi, Peggy

    2010-01-01

    The very deep knowledge acquired on the genetics and molecular biology of herpes simplex virus (HSV), has allowed the development of potential replication-competent and replication-defective vectors for several applications in human healthcare. These include delivery and expression of human genes to cells of the nervous systems, selective destruction of cancer cells, prophylaxis against infection with HSV or other infectious diseases, and targeted infection to specific tissues or organs. Replication-defective recombinant vectors are non-toxic gene transfer tools that preserve most of the neurotropic features of wild type HSV-1, particularly the ability to express genes after having established latent infections, and are thus proficient candidates for therapeutic gene transfer settings in neurons. A replication-defective HSV vector for the treatment of pain has recently entered in phase 1 clinical trial. Replication-competent (oncolytic) vectors are becoming a suitable and powerful tool to eradicate brain tumours due to their ability to replicate and spread only within the tumour mass, and have reached phase II/III clinical trials in some cases. The progress in understanding the host immune response induced by the vector is also improving the use of HSV as a vaccine vector against both HSV infection and other pathogens. This review briefly summarizes the obstacle encountered in the delivery of HSV vectors and examines the various strategies developed or proposed to overcome such challenges. PMID:20835362

  7. Severe encephalopathy associated to pyruvate dehydrogenase mutations and unbalanced coenzyme Q10 content.

    PubMed

    Asencio, Claudio; Rodríguez-Hernandez, María A; Briones, Paz; Montoya, Julio; Cortés, Ana; Emperador, Sonia; Gavilán, Angela; Ruiz-Pesini, Eduardo; Yubero, Dèlia; Montero, Raquel; Pineda, Mercedes; O'Callaghan, María M; Alcázar-Fabra, María; Salviati, Leonardo; Artuch, Rafael; Navas, Plácido

    2016-03-01

    Coenzyme Q10 (CoQ10) deficiency is associated to a variety of clinical phenotypes including neuromuscular and nephrotic disorders. We report two unrelated boys presenting encephalopathy, ataxia, and lactic acidosis, who died with necrotic lesions in different areas of brain. Levels of CoQ10 and complex II+III activity were increased in both skeletal muscle and fibroblasts, but it was a consequence of higher mitochondria mass measured as citrate synthase. In fibroblasts, oxygen consumption was also increased, whereas steady state ATP levels were decreased. Antioxidant enzymes such as NQO1 and MnSOD and mitochondrial marker VDAC were overexpressed. Mitochondria recycling markers Fis1 and mitofusin, and mtDNA regulatory Tfam were reduced. Exome sequencing showed mutations in PDHA1 in the first patient and in PDHB in the second. These genes encode subunits of pyruvate dehydrogenase complex (PDH) that could explain the compensatory increase of CoQ10 and a defect of mitochondrial homeostasis. These two cases describe, for the first time, a mitochondrial disease caused by PDH defects associated with unbalanced of both CoQ10 content and mitochondria homeostasis, which severely affects the brain. Both CoQ10 and mitochondria homeostasis appears as new markers for PDH associated mitochondrial disorders. PMID:26014431

  8. Characterization of the ionization degree evolution of the PF-400J plasma sheath by means of time resolved optical spectroscopy

    NASA Astrophysics Data System (ADS)

    Avaria, G.; Cuadrado, O.; Moreno, J.; Pavez, C.; Soto, L.

    2016-05-01

    Spectral measurements in the visible range of the plasma sheath ionization degree evolution on the plasma focus device PF-400J are presented. The measurements were done with temporal and spatial resolution in a plasma focus device of low stored energy: PF-400J (176-539 J, 880 nF, 20-35 kV, quarter period ∼ 300ns) [1]. An ICCD was attached to a 0.5 m focal length visible spectrometer, which enabled the acquisition of time resolved spectrum with 20 ns integration time throughout the whole current pulse evolution. The spatial resolution was attained using a set of lenses which allowed the focusing of a small volume of the plasma sheath in different positions of the inter-electrode space. Discharges were carried out in mixtures of Hydrogen with gases in different proportions: 5% Neon, 5% Krypton and 2% Nitrogen. Discharges using Neon as an impurity showed no ionization of the gas, just a very low intensity emission of Ne I at times much larger than the maximum current. Nitrogen, on the other hand, showed a high ionization reaching N V (N 4+) at the end of the axial phase, with a distinctive evolution of the ionization degree as the plasma sheath moved towards the end of the electrodes. A mixed result was found when using Krypton, since the ionization degree only reached levels around Kr II/III, even though it has an ionization potential lower than Neon.

  9. Stimulus-specific defect in the phagocytic pathways of annexin 1 null macrophages

    PubMed Central

    Yona, Simon; Buckingham, Julia C; Perretti, Mauro; Flower, Roderick J

    2004-01-01

    The role of the glucocorticoid-regulated protein annexin 1 during the process of phagocytosis has been studied using annexin 1 null peritoneal macrophages. Wild type and annexin 1 null macrophages were incubated with several distinct phagocytic targets. No differences were observed in rate or the maximal response with respect to IgG complexes or opsonised zymosan phagocytosis, as assessed by monitoring the production of reactive oxygen species. When annexin 1 null macrophages were incubated with non-opsonised zymosan particles, they exhibited impaired generation of reactive oxygen species, which was linked to a defect in binding of cells to the particles, as determined with fluorescent zymosan. This phenomenon was further confirmed by electron microscopy analysis, where annexin 1 null macrophages internalised fewer non-opsonised zymosan particles. Specific alterations in macrophage plasma membrane markers were observed in the annexin 1 null cells. Whereas no differences in dectin-1 and FcγR II/III expression were measured between the two genotypes, decreased membrane CD11b and F4/80 levels were measured selectively in macrophages lacking annexin 1. These cells also responded with an enhanced release of PGE2 and COX-2 protein expression following addition of the soluble stimulants, LPS and heat-activated IgG. In conclusion, these results suggest that participation of endogenous annexin 1 during zymosan phagocytosis is critical and that this protein plays a tonic inhibitory role during macrophage activation. PMID:15197108

  10. Principles Governing Metal Ion Selectivity in Ion Channel Proteins

    NASA Astrophysics Data System (ADS)

    Lim, Carmay

    2014-03-01

    Our research interests are to (i) unravel the principles governing biological processes and use them to identify novel drug targets and guide drug design, and (ii) develop new methods for studying macromolecular interactions. This talk will provide an overview of our work in these two areas and an example of how our studies have helped to unravel the principles underlying the conversion of Ca2+-selective to Na+-selective channels. Ion selectivity of four-domain voltage-gated Ca2+(Cav) and sodium (Nav) channels, which is controlled by the selectivity filter (SF, the narrowest region of an open pore), is crucial for electrical signaling. Over billions of years of evolution, mutation of the Glu from domain II/III in the EEEE/DEEA SF of Ca2+-selective Cav channels to Lys made these channels Na+-selective. This talk will delineate the physical principles why Lys is sufficient for Na+/Ca2+selectivity and why the DEKA SF is more Na+-selective than the DKEA one.

  11. Mitochondrial Oxidative Phosphorylation Compensation May Preserve Vision in Patients with OPA1-Linked Autosomal Dominant Optic Atrophy

    PubMed Central

    Van Bergen, Nicole J.; Crowston, Jonathan G.; Kearns, Lisa S.; Staffieri, Sandra E.; Hewitt, Alex W.; Cohn, Amy C.; Mackey, David A.; Trounce, Ian A.

    2011-01-01

    Autosomal Dominant Optic Atrophy (ADOA) is the most common inherited optic atrophy where vision impairment results from specific loss of retinal ganglion cells of the optic nerve. Around 60% of ADOA cases are linked to mutations in the OPA1 gene. OPA1 is a fission-fusion protein involved in mitochondrial inner membrane remodelling. ADOA presents with marked variation in clinical phenotype and varying degrees of vision loss, even among siblings carrying identical mutations in OPA1. To determine whether the degree of vision loss is associated with the level of mitochondrial impairment, we examined mitochondrial function in lymphoblast cell lines obtained from six large Australian OPA1-linked ADOA pedigrees. Comparing patients with severe vision loss (visual acuity [VA]<6/36) and patients with relatively preserved vision (VA>6/9) a clear defect in mitochondrial ATP synthesis and reduced respiration rates were observed in patients with poor vision. In addition, oxidative phosphorylation (OXPHOS) enzymology in ADOA patients with normal vision revealed increased complex II+III activity and levels of complex IV protein. These data suggest that OPA1 deficiency impairs OXPHOS efficiency, but compensation through increases in the distal complexes of the respiratory chain may preserve mitochondrial ATP production in patients who maintain normal vision. Identification of genetic variants that enable this response may provide novel therapeutic insights into OXPHOS compensation for preventing vision loss in optic neuropathies. PMID:21731710

  12. Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa.

    PubMed

    Taub, Pam R; Ramirez-Sanchez, Israel; Ciaraldi, Theodore P; Perkins, Guy; Murphy, Anne N; Naviaux, Robert; Hogan, Michael; Maisel, Alan S; Henry, Robert R; Ceballos, Guillermo; Villarreal, Francisco

    2012-02-01

    (-)-Epicatechin (Epi), a flavanol in cacao stimulates mitochondrial volume and cristae density and protein markers of skeletal muscle (SkM) mitochondrial biogenesis in mice. Type 2 diabetes mellitus (DM2) and heart failure (HF) are diseases associated with defects in SkM mitochondrial structure/function. A study was implemented to assess perturbations and to determine the effects of Epi-rich cocoa in SkM mitochondrial structure and mediators of biogenesis. Five patients with DM2 and stage II/III HF consumed dark chocolate and a beverage containing approximately 100 mg of Epi per day for 3 months. We assessed changes in protein and/or activity levels of oxidative phosphorylation proteins, porin, mitofilin, nNOS, nitric oxide, cGMP, SIRT1, PGC1α, Tfam, and mitochondria volume and cristae abundance by electron microscopy from SkM. Apparent major losses in normal mitochondria structure were observed before treatment. Epi-rich cocoa increased protein and/or activity of mediators of biogenesis and cristae abundance while not changing mitochondrial volume density. Epi-rich cocoa treatment improves SkM mitochondrial structure and in an orchestrated manner, increases molecular markers of mitochondrial biogenesis resulting in enhanced cristae density. Future controlled studies are warranted using Epi-rich cocoa (or pure Epi) to translate improved mitochondrial structure into enhanced cardiac and/or SkM muscle function. PMID:22376256

  13. Clinical trials update from the American Heart Association meeting 2010: EMPHASIS-HF, RAFT, TIM-HF, Tele-HF, ASCEND-HF, ROCKET-AF, and PROTECT.

    PubMed

    Cleland, John G F; Coletta, Alison P; Buga, Laszlo; Antony, Renjith; Pellicori, Pierpaolo; Freemantle, Nick; Clark, Andrew L

    2011-04-01

    This article provides information and a commentary on key trials relevant to the pathophysiology, prevention, and treatment of heart failure presented at the annual meeting of the American Heart Association held in Chicago in 2010. Unpublished reports should be considered as preliminary, since analyses may change in the final publication. In patients with mild heart failure (HF), EMPHASIS-HF showed that the addition of eplerenone to standard therapy was well tolerated and reduced both the risk of death and hospitalization. The addition of cardiac resynchronization therapy to implantable cardioverter defibrillator (ICD) therapy reduced the incidence of all-cause mortality and HF hospitalizations in patients with NYHA class II-III HF compared with ICD alone in RAFT. Telemonitoring failed to improve outcome compared with a high standard of conventional care in patients with chronic HF (TIM-HF study) and a telephone-based interactive voice response system failed to improve outcome in patients recently hospitalized for HF (Tele-HF study). ASCEND-HF suggested that nesiritide was ineffective but safe in patients with acute decompensated HF. ROCKET-AF suggests that the factor-Xa inhibitor rivaroxaban may be as effective as warfarin in patients with atrial fibrillation. The PROTECT study provided more data to suggest that amino-terminal B-type natriuretic peptide guided therapy may be beneficial in patients with left ventricular systolic dysfunction. PMID:21436363

  14. Effects of neonatal inflammation on the inflammatory and oxidative profile during experimental sepsis in adult life.

    PubMed

    Lunardelli, Adroaldo; Luft, Carolina; Pedrazza, Leonardo; Martha, Bianca Andrade; de Oliveira, Jarbas Rodrigues; Donadio, Márcio Vinícius Fagundes

    2015-11-01

    The present study aimed to evaluate the long-term effects of neonatal inflammation on the inflammatory and oxidative profile during experimental sepsis in adult life. Neonatal Balb/c mice received different treatments on day 10: LPS i.p. injection (100g/kg) (nLPS) or saline i.p. injection (nSal). As adults, fear/anxiety behavior was evaluated in the elevated plus maze. The following week, saline solution or LPS was administered and, after 12h, serum (inflammatory cytokines), liver (mitochondrial complexes and oxidative stress) and adrenal gland samples (angiotensin II type 1 and 2 receptors) were collected. There was an increase in the fear/anxiety behavior in the nLPS group. Neonatal administration of LPS increased the mRNA expression of the AT1 receptor and decreased the mRNA expression of the AT2 receptor in the adrenal glands of males. The complexes II and II-III increased in the nLPS saline male group when compared to control. The LPS administration in adult females, regardless of the neonatal treatment, induced a decrease of the glutathione enzyme activity. There were no differences in the inflammatory cytokines. The results showed that neonatal inflammation influenced mitochondrial respiratory chain metabolism and angiotensin II receptors in a sex-dependent manner. Balb/c mice fear and anxiety behaviors in adulthood were programmed by early life inflammatory stress. PMID:26314499

  15. Paleocene-Eocene potential source rocks in the Avengco Basin, Tibet: Organic geochemical characteristics and their implication for the paleoenvironment

    NASA Astrophysics Data System (ADS)

    Han, Zhongpeng; Xu, Ming; Li, Yalin; Wei, Yushuai; Wang, Chengshan

    2014-10-01

    The Avengco Basin is located in the western part of the Tibetan Plateau and is similar to the Nima Basin in the central part of the plateau and the Lunpola Basin in the eastern part in terms of sedimentary characteristics and tectonic settings, which are well known to provide a good source rock potential. However, the organic geochemical characteristics of the Paleocene-Eocene potential source rocks in the Avengco Basin have been under debate. Thirty-four marl and mudstone outcrop samples of the Niubao Formation in the Avengco Basin were collected and subjected to the following analyses: total organic carbon (TOC), Rock-Eval pyrolysis, stable carbon isotopes of kerogen, gas chromatography (GC) and gas chromatography-mass spectrometry (GC-MS). Here, we present the results indicating the organic matter of the upper Niubao Formation is mainly composed of Type II kerogen with a mixed source, which is dominated by algae. However, the lower Niubao Formation has the less oil-prone Type II-III kerogen, and the sources of the organic matter are mainly terrestrial plants with less plankton. In addition, the samples are thermally immature to marginally mature. The Niubao Formation was deposited in an anoxic-oxic environment which was brackish with an imperceptible stratified water column. The upper Niubao Formation has a medium to good hydrocarbon-generating potential. However, the lower Niubao Formation has a zero to poor hydrocarbon-generating potential.

  16. Selexipag: First Global Approval.

    PubMed

    Scott, Lesley J

    2016-03-01

    Selexipag (Uptravi(®)) is a highly selective, long-acting, nonprostanoid, prostacyclin receptor agonist that is being developed by Actelion Pharmaceuticals Ltd and Nippon Shinyaku. Oral selexipag is approved in the USA for the treatment of pulmonary arterial hypertension (PAH; WHO Group I) to delay disease progression and reduce the risk of hospitalization for PAH. It has subsequently been approved in Canada for the long-term treatment of PAH, and received a positive opinion in the EU for the treatment of PAH in adult patients with WHO functional class II-III. Selexipag received orphan drug designation for the treatment of PAH in Japan in 2014 and is in undergoing regulatory review in several countries for use in this indication. In the large, event-driven, phase III GRIPHON trial, selexipag reduced the risk of the primary composite endpoint of death or a complication related to PAH (whichever occurred first) by 40 % compared with placebo in patients with PAH (80 % were also receiving stable dosages of an endothelin receptor antagonist and/or a phosphodiesterase 5 inhibitor). This article summarizes the milestones in the development of selexipag leading to this first approval for PAH. PMID:26846322

  17. [Recent Status of Postoperative Adjuvant Chemotherapy after Completely Resected Lung Cancer].

    PubMed

    Naito, Masahito; Tsuboi, Masahiro

    2016-02-01

    Several landmark study elucidated that adjuvant cisplatin-based chemotherapy for stage II-IIIA non-small cell lung cancer (NSCLC)patients after appropriate surgical resection can significantly improve 5-year survival rate. Meta-analysis of modern cisplatin based adjuvant chemotherapy trial confirmed this benefit. Furthermore, in Japan, large randomized trial and metaanalysis assessing the efficacy of uracil-tegafur(UFT)for stage I patients with completely resected NSCLC reported that UFT can significantly improve 5-year survival rate. Meta-analysis of subgroup assessed that effectiveness of UFT for stage I NSCLC patients with a tumor lager than 2 cm. According to these evidence, cisplatin-based adjuvant chemotherapy for stage II-III A NSCLC and UFT for stage I NSCLC patients with a tumor lager than 2 cm are used standard postoperative adjuvant chemotherapy in Japan. In recent year, it is presumed that personalized care will be necessary to re-evaluate strategies for postoperative adjuvant chemotherapy of lung cancer. Considering histological subtype of lung cancer, several randomize trial for postoperative adjuvant chemotherapy with non-squamous NSCLC or high neuroendocrine tumor of lung are ongoing. In addition, recent studies of biological research indicate that some tumor marker such as ERCC1 may had a predictive value for selecting patients who will derive the benefit from adjuvant chemotherapy. PMID:27067681

  18. Decline in Age-dependent, MK801-induced Injury Coincides With Developmental Switch in Parvalbumin Expression: Somatosensory and Motor Cortex

    PubMed Central

    Tomé, Carla M Lema; Miller, Ryan; Bauer, Clayton; Smith, Chelsey; Blackstone, Kaitlin; Leigh, Adam; Busch, Jamie; Turner, Christopher P

    2009-01-01

    MK801-induced activation of caspase-3 is developmentally regulated, peaking at postnatal day (P) 7 and decreasing with increasing postnatal age thereafter. Further, at P7, cells displaying activation of caspase-3 lack expression of calcium binding proteins (CaBPs). To further explore this relationship, we investigated postnatal expression of calbindin (CB), calretinin (CR) and parvalbumin (PV) in two brain regions susceptible to MK801-induced injury, the somatosensory cortex (S1) and layer II/III of motor cortex (M1/M2). Expression of CB and especially PV was low to absent prior to P7 but substantially increased from P7 through to P21 and adulthood. In contrast, CR expression was more variable at early developmental ages, stabilized to lower levels after P7 and showed a marked decline by P21. The results suggest that not only does calcium buffering capacity increase developmentally but acquisition of enhanced buffering may be one mechanism by which neurons survive agent-induced alterations in calcium homeostasis. PMID:18688810

  19. Target hepatic artery regional chemotherapy and bevacizumab perfusion in liver metastatic colorectal cancer after failure of first-line or second-line systemic chemotherapy.

    PubMed

    Chen, Hui; Zhang, Ji; Cao, Guang; Liu, Peng; Xu, Haifeng; Wang, Xiaodong; Zhu, Xu; Gao, Song; Guo, Jianhai; Zhu, Linzhong; Zhang, Pengjun

    2016-02-01

    Colorectal cancer liver metastasis (CRLM) is a refractory disease after failure of first-line or second-line chemotherapy. Bevacizumab is recommended as first-line therapy for advanced colorectal cancer, but is unproven in CRLM through the hepatic artery. We report favorable outcomes with targeted vessel regional chemotherapy (TVRC) for liver metastatic gastric cancer. TVRC with FOLFOX and bevacizumab perfusion through the hepatic artery was attempted for CRLM for efficacy and safety evaluation. In a single-institution retrospective observational study, 246 patients with CRLM after at least first-line or second-line failure of systemic chemotherapy received TVRC with FOLFOX (i.e. oxaliplatin, leucovorin, and 5-fluorouracil). Of 246 patients, 63 were enrolled into two groups: group 1 (n=30) received bevacizumab and TVRC following tumor progression during previous TVRC treatments; group 2 (n=33) received TVRC plus bevacizumab for CRLM on initiating TVRC. There were no significant differences in the median survival time (14.7 vs. 13.2 months, P=0.367), although the median time to progression was significant (3.3 vs. 5.5 months, P=0.026) between groups. No severe adverse events related to TVRC plus bevacizumab perfusion occurred. Target vessel regional chemotherapy with FOLFOX plus bevacizumab perfusion through the hepatic artery was effective and safe in CRLM. The optimal combination of TVRC and bevacizumab needs further confirmation in future phase II-III clinical trials. PMID:26566233

  20. [Effect of hypoxia in early perinatal ontogenesis on behavior and structural characteristics of the rat brain].

    PubMed

    Otellin, V A; Khozhaĭ, L I; Vataeva, L A

    2012-01-01

    The study has shown the acute hypoxia in newborn rat pups to lead to disturbances of processes of formation of brain structures, behavior reactions, and learning in the subsequent ontogenesis. The single normobaric hypoxia at the 2nd day of life causes retardation of such integrative parameter or genera development and growth as body mass at the period of feeding. In such animals, essential disturbances of the sensorimotor development were revealed in forms of delay of reflex reactions of turning on a plane, negative geotaxis, and avoidance of edge. Also detected was action of hypoxia on hanging on a rope by using front legs (a symptom of muscle weakness). Morphological study has shown stereotypic reaction to the early postnatal action of hypoxia in all studies of all studied functional zones of neocortex - motor, sensomotor, auditory, visual. The death of nerve cells is predominant in the II-III associative layers, the sizes and number of pyramidal neurons are sharply decreased. Different hippocampus fields maturing in mammals show a characteristic response to hypoxia. In individual hippocampus fields there was detected different degree of death of neurons, predominant in the CA3 and CA4 fields. A possibility of modeling of perinatal encephalopathy with minimal brain dysfunctions in children is discussed. PMID:23136755

  1. Toward Head-Up and Head-Worn Displays for Equivalent Visual Operations

    NASA Technical Reports Server (NTRS)

    Prinzel, Lawrence J., III; Arthur, Jarvis J.; Bailey, Randall E.; Shelton, Kevin J.; Kramer, Lynda J.; Jones, Denise R.; Williams, Steven P.; Harrison, Stephanie J.; Ellis, Kyle K.

    2015-01-01

    A key capability envisioned for the future air transportation system is the concept of equivalent visual operations (EVO). EVO is the capability to achieve the safety of current-day Visual Flight Rules (VFR) operations and maintain the operational tempos of VFR irrespective of the weather and visibility conditions. Enhanced Flight Vision Systems (EFVS) offer a path to achieve EVO. NASA has successfully tested EFVS for commercial flight operations that has helped establish the technical merits of EFVS, without reliance on natural vision, to runways without category II/III ground-based navigation and lighting requirements. The research has tested EFVS for operations with both Head-Up Displays (HUDs) and "HUD equivalent" Head-Worn Displays (HWDs). The paper describes the EVO concept and representative NASA EFVS research that demonstrate the potential of these technologies to safely conduct operations in visibilities as low as 1000 feet Runway Visual Range (RVR). Future directions are described including efforts to enable low-visibility approach, landing, and roll-outs using EFVS under conditions as low as 300 feet RVR.

  2. Utility of adjuvant systemic therapy in melanoma

    PubMed Central

    Eggermont, A. M. M.; Testori, A.; Marsden, J.; Hersey, P.; Quirt, I.; Petrella, T.; Gogas, H.; MacKie, R. M.; Hauschild, A.

    2009-01-01

    The lack of effective drugs in stage IV melanoma has impacted the effectiveness of adjuvant therapies in stage II/III disease. To date, chemotherapy, immunostimulants and vaccines have been used with minimal success. Interferon (IFN) has shown an effect on relapse-free survival (RFS) in several clinical trials; however, without a clinically significant effect on overall survival (OS). A recently conducted meta-analysis demonstrated prolongation of disease-free survival (DFS) in 7% and OS benefit in 3% of IFN-treated patients when compared with observation-only patients. There were no clear differences for the dose and duration of treatment observed. Observation is still an appropriate control arm in adjuvant clinical trials. Regional differences exist in Europe in the adjuvant use of IFN. In Northwest Europe, IFN is infrequently prescribed. In Central and Mediterranean Europe, dermatologists commonly prescribe low-dose IFN therapy for AJCC stage II and III disease. High-dose IFN regimens are not commonly used. The population of patients that may benefit from IFN needs to be further characterised, potentially by finding biomarkers that can predict response. Such studies are ongoing. PMID:19617295

  3. Plitidepsin (Aplidin) is a potent inhibitor of diffuse large cell and Burkitt lymphoma and is synergistic with rituximab.

    PubMed

    Barboza, Nora M; Medina, Daniel J; Budak-Alpdogan, Tulin; Aracil, Miguel; Jimeno, José M; Bertino, Joseph R; Banerjee, Debabrata

    2012-01-15

    Plitidepsin (Aplidin), an antitumor agent of marine origin, presently is undergoing phase II/III clinical trials, and has shown promise for the treatment of lymphoma. Here, we describe the antitumor effects of plitidepsin alone and in combination with rituximab and investigated the effects of each drug and the combination on the cell cycle and mechanism of cell death. Several Diffuse Large Cell Lymphoma (DLCL) lines and Burkitt cell lines were tested for sensitivity to plitidepsin and rituximab. All DLCL and Burkitt lymphoma cell lines were inhibited by plitidepsin in nanomolar concentrations, while rituximab sensitivity varied among different cell lines. Ramos and the RL cell lines proved sensitive to rituximab and were used to test the effects of each of the two drugs. The two agents exhibited synergism at all tested concentrations. For in vivo studies, irradiated athymic nude mice were engrafted with the Ramos lymphoma. Treatment was initiated when the tumors were ~0.5 cm in diameter, and toxic and therapeutic effects were monitored. In the in vivo study, additive effects of the combined two drugs, was demonstrated without an increase in host toxicity. The in vitro synergy and the in vivo additive antitumor effects without an increase in host toxicity with two relatively non-marrow suppressive agents encourages further development of this combination for treatment of aggressive B-cell lymphomas. PMID:22336911

  4. Sulfate radical-induced degradation of Acid Orange 7 by a new magnetic composite catalyzed peroxymonosulfate oxidation process.

    PubMed

    Chen, Dan; Ma, Xiaolong; Zhou, Jizhi; Chen, Xi; Qian, Guangren

    2014-08-30

    We synthesized a novel magnetic composite, Fe3O4/Cu(Ni)Cr-LDH, as a heterogeneous catalyst for the degradation of organic dyes in the solution using sulfate radical-based advanced oxidation processes. The physicochemical properties of the composite synthesized via two-step microwave hydrothermal method were characterized by several techniques, such as X-ray diffraction (XRD), inductively coupled plasma (ICP), transmission electron microscopy (TEM) and vibrating sample magnetometer (VSM). The degradation tests were performed at 25°C with Acid Orange 7 (AO7) initial concentration of 25mg/L and AO7/peroxymonosulfate (PMS) molar ratio of 1:10, which showed that the complete degradation by Fe3O4/Cu1.5Ni0.5Cr-LDH could be achieved and the mineralization rate could reach 46%. PMS was activated by Cu (II) and Fe (II/III) of Fe3O4/Cu(Ni)Cr-LDH to generate sulfate radicals (SO4(-)). Subsequently, the organic functional groups of AO7 molecules were destroyed by sulfate radicals (SO4(-)), inducing the degradation of AO7. Moreover, the catalytic behavior of the catalysts could be reused five times. Therefore, our work suggested that the Fe3O4/Cu(Ni)Cr-LDH composite could be applied widely for the treatment of organic dyes in wastewater. PMID:25103453

  5. Homocysteine Levels in Parkinson's Disease: Is Entacapone Effective?

    PubMed Central

    Guven, Hayat; Comoglu, Selim Selcuk

    2016-01-01

    Plasma homocysteine (Hcy) levels may increase in levodopa-treated patients with Parkinson's disease (PD) as a consequence of levodopa methylation via catechol-O-methyltransferase (COMT). Results from previous studies that assessed the effect of COMT inhibitors on levodopa-induced hyperhomocysteinemia are conflicting. We aimed to evaluate the effects of levodopa and entacapone on plasma Hcy levels. A hundred PD patients were enrolled to the study and divided into three treatment groups (group I: levodopa and/or dopamine agonists; group II: levodopa, entacapone, and/or a dopamine agonist; and group III: dopamine agonist alone). We measured the serum B12, folic acid, and Hcy levels in all patients. There were no statistically significant differences between groups in terms of modified Hoehn and Yahr stages, Unified Parkinson's Disease Rating Scale II/III, Standardized Mini-Mental Test scores, and serum vitamin B12 and folic acid levels. Plasma median Hcy levels were found above the normal laboratory values in groups I and II, but they were normal in group III. However, there was no statistically significant difference in plasma Hcy levels between groups. Our results showed that levodopa treatment may cause a slight increase in the Hcy levels in PD compared with dopamine agonists and that COMT inhibitors may not have a significant effect on preventing hyperhomocysteinemia. PMID:27493964

  6. Raman spectroscopic study of cation disorder in poly- and single crystals of the nickel aluminate spinel

    NASA Astrophysics Data System (ADS)

    Laguna-Bercero, M. A.; Sanjuán, M. L.; Merino, R. I.

    2007-05-01

    The Raman spectrum of NiAl2O4 inverse spinel has been studied in quenched polycrystalline pellets produced by solid-state reaction and in single crystals grown by the floating zone method. The lattice parameters and inversion degrees were determined by x-ray diffraction. Polarization measurements in single crystals allow mode symmetry assignment. Then, a correlation is established between the bands observed in polycrystalline samples and those of single crystals. Both kinds of sample present more bands than the five expected (A1g+Eg+3T2g) in a cubic Fd3m spinel. This multiplicity is attributed to the almost fully inverted cation distribution in NiAl2O4, with inversion parameter xap0.9. The multiplicity of the high-frequency A1g band, in particular, is attributed to the different possible configurations of Ni2+ and Al3+ cations occupying the three octahedral sites close to a given oxygen ion. A strong downshift of the Eg mode frequency, as compared to the normal spinel MgAl2O4, is attributed to the longer bonding distance between oxygen and octahedral cations in inverse II-III spinels. Due to the small range of variation of x upon thermal treatment in NiAl2O4, no significant differences were found between the spectra of samples quenched at different temperatures, from 800 to 1200 °C.

  7. Late Corrective Arthrodesis in Nonplantigrade Diabetic Charcot Midfoot Disease Is Associated with High Complication and Reoperation Rates

    PubMed Central

    Wussow, Annekatrin

    2015-01-01

    Introduction. Charcot arthropathy may lead to a loss of osteoligamentous foot architecture and consequently loss of the plantigrade alignment. In this series of patients a technique of internal corrective arthrodesis with maximum fixation strength was provided in order to lower complication rates. Materials/Methods. 21 feet with severe nonplantigrade diabetic Charcot deformity Eichenholtz stages II/III (Sanders/Frykberg II/III/IV) and reconstructive arthrodesis with medial and additional lateral column support were retrospectively enrolled. Follow-up averaged 4.0 years and included a clinical (AOFAS score/PSS), radiological, and complication analysis. Results. A mean of 2.4 complications/foot occurred, of which 1.5/foot had to be solved surgically. 76% of feet suffered from soft tissue complications; 43% suffered hardware-associated complications. Feet with only 2 out of 5 high risk criteria according to Pinzur showed significantly lower complication counts. Radiographs revealed a correct restoration of all foot axes postoperatively with superior fixation strength medially. Conclusion. Late corrective arthrodesis with medial and lateral column stabilization in the nonplantigrade stages of neuroosteoarthropathy can provide reasonable reconstruction of the foot alignment. Nonetheless, overall complication/reoperation rates were high. With separation into low/high risk criteria a helpful guide in treatment choice is provided. This trial is registered with German Clinical Trials Register (DRKS) under number DRKS00007537. PMID:26000309

  8. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade.

    PubMed

    Bulawa, Christine E; Connelly, Stephen; Devit, Michael; Wang, Lan; Weigel, Charlotte; Fleming, James A; Packman, Jeff; Powers, Evan T; Wiseman, R Luke; Foss, Theodore R; Wilson, Ian A; Kelly, Jeffery W; Labaudinière, Richard

    2012-06-12

    The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A-retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (K(d)s ~2 nM and ~200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis. PMID:22645360

  9. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade

    PubMed Central

    Bulawa, Christine E.; Connelly, Stephen; DeVit, Michael; Wang, Lan; Weigel, Charlotte; Fleming, James A.; Packman, Jeff; Powers, Evan T.; Wiseman, R. Luke; Foss, Theodore R.; Wilson, Ian A.; Kelly, Jeffery W.; Labaudinière, Richard

    2012-01-01

    The transthyretin amyloidoses (ATTR) are invariably fatal diseases characterized by progressive neuropathy and/or cardiomyopathy. ATTR are caused by aggregation of transthyretin (TTR), a natively tetrameric protein involved in the transport of thyroxine and the vitamin A–retinol-binding protein complex. Mutations within TTR that cause autosomal dominant forms of disease facilitate tetramer dissociation, monomer misfolding, and aggregation, although wild-type TTR can also form amyloid fibrils in elderly patients. Because tetramer dissociation is the rate-limiting step in TTR amyloidogenesis, targeted therapies have focused on small molecules that kinetically stabilize the tetramer, inhibiting TTR amyloid fibril formation. One such compound, tafamidis meglumine (Fx-1006A), has recently completed Phase II/III trials for the treatment of Transthyretin Type Familial Amyloid Polyneuropathy (TTR-FAP) and demonstrated a slowing of disease progression in patients heterozygous for the V30M TTR mutation. Herein we describe the molecular and structural basis of TTR tetramer stabilization by tafamidis. Tafamidis binds selectively and with negative cooperativity (Kds ∼2 nM and ∼200 nM) to the two normally unoccupied thyroxine-binding sites of the tetramer, and kinetically stabilizes TTR. Patient-derived amyloidogenic variants of TTR, including kinetically and thermodynamically less stable mutants, are also stabilized by tafamidis binding. The crystal structure of tafamidis-bound TTR suggests that binding stabilizes the weaker dimer-dimer interface against dissociation, the rate-limiting step of amyloidogenesis. PMID:22645360

  10. Larval stages of the deep-sea lobster Polycheles typhlops (Decapoda, Polychelida) identified by DNA analysis: morphology, systematic, distribution and ecology

    NASA Astrophysics Data System (ADS)

    Torres, Asvin P.; Palero, Ferran; Dos Santos, Antonina; Abelló, Pere; Blanco, Edurne; Boné, Alexandra; Guerao, Guillermo

    2014-09-01

    A total of 25 specimens of Eryoneicus larvae were collected near the Balearic Archipelago (Western Mediterranean Sea) in 2009 and 2010. Detailed morphological examination indicated that the smallest individual corresponded with the first zoea (ZI) stage of Polycheles typhlops hatched from a berried female by Guerao and Abelló (J Nat Hist 30(8):1179-1184, 1996). Only two species of deep-sea polychelid lobster, namely P. typhlops and Stereomastis sculpta, are known to occur in the Mediterranean. Genetic distance comparisons and phylogenetic analysis of the mitochondrial 16S rDNA and Cox I genes of this early larva together with adults from several Polycheles and Stereomastis species allowed us to assign it to P. typhlops. This is the first wild-caught larval stage of a polychelid lobster being identified using molecular techniques. The remaining specimens were attributed to zoeal stages II-III and decapodid stage based on morphological comparison. The arrangement of spines along the anterior part of the middorsal line (R, 1, 1, 1, 2, C1), characteristic of the former species E. puritanii, discriminates these larvae from other Eryoneicus found in the Mediterranean. The clear presence of epipods on the third maxilliped and pereiopods of the decapodid stage gives further support to the identification of E. puritanii as the larval stages of P. typhlops. Additionally, information on the ecology of these larvae, their abundances during different seasons, as well as their bathymetric distribution is reported.

  11. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients.

    PubMed

    Kinker, Gabriela Sarti; Thomas, Andrew Maltez; Carvalho, Vinicius Jardim; Lima, Felipe Prata; Fujita, André

    2016-01-01

    Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas. PMID:27052952

  12. Phase II trial of biweekly docetaxel, cisplatin, and 5-fluorouracil chemotherapy for advanced esophageal squamous cell carcinoma.

    PubMed

    Tanaka, Yoshihiro; Yoshida, Kazuhiro; Yamada, Atsuko; Tanahashi, Toshiyuki; Okumura, Naoki; Matsuhashi, Nobuhisa; Yamaguchi, Kazuya; Miyazaki, Tatsuhiko

    2016-06-01

    The prognosis of esophageal cancer patients is still unsatisfactory. Although a docetaxel, cisplatin, and 5-Fu (DCF) regimen has been reported, it is often difficult to accomplish because of severe toxicity. Therefore, we developed a new biweekly DCF (Bi-DCF) regimen and previously reported the recommended dose in a phase I dose-escalation study. We then performed a phase II study of Bi-DCF for advanced esophageal squamous cell carcinoma (SCC). Patients with clinical stage II/III were eligible. Patients received 2 courses of chemotherapy: docetaxel 35 mg/m(2) with cisplatin 40 mg/m(2) on days 1 and 15 and 400 mg/m(2) 5-fluorouracil on days 1-5 and 15-19 every 4 weeks. After completion of the chemotherapy, patients received esophagectomy. The primary endpoint was the completion rate of protocol treatment. Thirty-two patients were enrolled. The completion rate of protocol treatment (completion of two courses of preoperative chemotherapy and R0 surgery) was 100 %. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (31.3 %). No treatment-related death was observed, and the incidence of operative morbidity was tolerable. The overall response rate after the chemotherapy was 90.3 %. This Bi-DCF regimen was well tolerated and highly active. This trial was registered with the University Hospital Medical Information Network (No. UMIN 000014625). PMID:26896963

  13. Tri-State Synfuels Project Review: Volume 8. Commercial status of licensed process units. [Proposed Henderson, Kentucky coal to gasoline plant; licensed commercial processes

    SciTech Connect

    Not Available

    1982-06-01

    This document demonstrates the commercial status of the process units to be used in the Tri-State Synfuels Project at Henderson, Kentucky. The basic design philosophy as established in October, 1979, was to use the commercial SASOL II/III plants as a basis. This was changed in January 1982 to a plant configuration to produce gasoline via a methanol and methanol to gasoline process. To accomplish this change the Synthol, Oil workup and Chemical Workup Units were eliminated and replaced by Methanol Synthesis and Methanol to Gasoline Units. Certain other changes to optimize the Lurgi liquids processing eliminated the Tar Distillation and Naphtha Hydrotreater Units which were replaced by the Partial Oxidation Unit. The coals to be gasified are moderately caking which necessitates the installation of stirring mechanism in the Lurgi Dry Bottom gasifier. This work is in the demonstration phase. Process licenses either have been obtained or must be obtained for a number of processes to be used in the plant. The commercial nature of these processes is discussed in detail in the tabbed sections of this document. In many cases there is a list of commercial installations at which the licensed equipment is used.

  14. Fatal neonatal encephalopathy and lactic acidosis caused by a homozygous loss-of-function variant in COQ9.

    PubMed

    Danhauser, Katharina; Herebian, Diran; Haack, Tobias B; Rodenburg, Richard J; Strom, Tim M; Meitinger, Thomas; Klee, Dirk; Mayatepek, Ertan; Prokisch, Holger; Distelmaier, Felix

    2016-03-01

    Coenzyme Q10 (CoQ10) has an important role in mitochondrial energy metabolism by way of its functioning as an electron carrier in the respiratory chain. Genetic defects disrupting the endogenous biosynthesis pathway of CoQ10 may lead to severe metabolic disorders with onset in early childhood. Using exome sequencing in a child with fatal neonatal lactic acidosis and encephalopathy, we identified a homozygous loss-of-function variant in COQ9. Functional studies in patient fibroblasts showed that the absence of the COQ9 protein was concomitant with a strong reduction of COQ7, leading to a significant accumulation of the substrate of COQ7, 6-demethoxy ubiquinone10. At the same time, the total amount of CoQ10 was severely reduced, which was reflected in a significant decrease of mitochondrial respiratory chain succinate-cytochrome c oxidoreductase (complex II/III) activity. Lentiviral expression of COQ9 restored all these parameters, confirming the causal role of the variant. Our report on the second COQ9 patient expands the clinical spectrum associated with COQ9 variants, indicating the importance of COQ9 already during prenatal development. Moreover, the rescue of cellular CoQ10 levels and respiratory chain complex activities by CoQ10 supplementation points to the importance of an early diagnosis and immediate treatment. PMID:26081641

  15. Two-photon excited fluorescence emission from hemoglobin

    NASA Astrophysics Data System (ADS)

    Sun, Qiqi; Zeng, Yan; Zhang, Wei; Zheng, Wei; Luo, Yi; Qu, Jianan Y.

    2015-03-01

    Hemoglobin, one of the most important proteins in blood, is responsible for oxygen transportation in almost all vertebrates. Recently, we discovered two-photon excited hemoglobin fluorescence and achieved label-free microvascular imaging based on the hemoglobin fluorescence. However, the mechanism of its fluorescence emission still remains unknown. In this work, we studied the two-photon excited fluorescence properties of the hemoglobin subunits, heme/hemin (iron (II)/(III) protoporphyrin IX) and globin. We first studied the properties of heme and the similar spectral and temporal characteristics of heme and hemoglobin fluorescence provide strong evidence that heme is the fluorophore in hemoglobin. Then we studied the fluorescence properties of hemin, globin and methemoglobin, and found that the hemin may have the main effect on the methemoglobin fluorescence and that globin has tryptophan fluorescence like other proteins. Finally, since heme is a centrosymmetric molecule, that the Soret band fluorescence of heme and hemoglobin was not observed in the single photon process in the previous study may be due to the parity selection rule. The discovery of heme two-photon excited fluorescence may open a new window for heme biology research, since heme as a cofactor of hemoprotein has many functions, including chemical catalysis, electron transfer and diatomic gases transportation.

  16. Laminar and regional distribution of galanin binding sites in cat and monkey visual cortex determined by in vitro receptor autoradiography

    SciTech Connect

    Rosier, A.M.; Vandesande, F.; Orban, G.A. )

    1991-03-08

    The distribution of galanin (GAL) binding sites in the visual cortex of cat and monkey was determined by autoradiographic visualization of ({sup 125}I)-GAL binding to tissue sections. Binding conditions were optimized and, as a result, the binding was saturable and specific. In cat visual cortex, GAL binding sites were concentrated in layers I, IVc, V, and VI. Areas 17, 18, and 19 exhibited a similar distribution pattern. In monkey primary visual cortex, the highest density of GAL binding sites was observed in layers II/III, lower IVc, and upper V. Layers IVA and VI contained moderate numbers of GAL binding sites, while layer I and the remaining parts of layer IV displayed the lowest density. In monkey secondary visual cortex, GAL binding sites were mainly concentrated in layers V-VI. Layer IV exhibited a moderate density, while the supragranular layers contained the lowest proportion of GAL binding sites. In both cat and monkey, we found little difference between regions subserving central and those subserving peripheral vision. Similarities in the distribution of GAL and acetylcholine binding sites are discussed.

  17. A forward genetic screen in mice identifies mutants with abnormal cortical patterning.

    PubMed

    Ha, Seungshin; Stottmann, Rolf W; Furley, Andrew J; Beier, David R

    2015-01-01

    Formation of a 6-layered cortical plate and axon tract patterning are key features of cerebral cortex development. Abnormalities of these processes may be the underlying cause for a range of functional disabilities seen in human neurodevelopmental disorders. To identify mouse mutants with defects in cortical lamination or corticofugal axon guidance, N-ethyl-N-nitrosourea (ENU) mutagenesis was performed using mice expressing LacZ reporter genes in layers II/III and V of the cortex (Rgs4-lacZ) or in corticofugal axons (TAG1-tau-lacZ). Four lines with abnormal cortical lamination have been identified. One of these was a splice site mutation in reelin (Reln) that results in a premature stop codon and the truncation of the C-terminal region (CTR) domain of reelin. Interestingly, this novel allele of Reln did not display cerebellar malformation or ataxia, and this is the first report of a Reln mutant without a cerebellar defect. Four lines with abnormal cortical axon development were also identified, one of which was found by whole-genome resequencing to carry a mutation in Lrp2. These findings demonstrated that the application of ENU mutagenesis to mice carrying transgenic reporters marking cortical anatomy is a sensitive and specific method to identify mutations that disrupt patterning of the developing brain. PMID:23968836

  18. Genomic signatures in B-cell lymphoma: How can these improve precision in diagnosis and inform prognosis?

    PubMed

    Iqbal, Javeed; Naushad, Hina; Bi, Chengfeng; Yu, Jiayu; Bouska, Alyssa; Rohr, Joseph; Chao, Wang; Fu, Kai; Chan, Wing C; Vose, Julie M

    2016-03-01

    Current genomic technologies have immensely improved disease classification and prognostication of major subtypes of B-cell lymphomas. This novel genetic information has not only aided in diagnosis, but has also revealed a landscape of critical molecular events that determine the biological and clinical behavior of a lymphoma. In this review, we summarized the genetic characteristics of major subtypes of B-cell lymphomas, including diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), Burkitt lymphoma (BL), and mantle cell lymphoma (MCL). We illustrated how genomic profiling had identified molecular subgroups in DLBCL with varied clinical outcomes, and how a subset of genes defined prognosis in MCL and aided in BL diagnoses. We also highlighted some Phase II/III clinical trials using new therapeutic agents to determine clinical efficacy in novel molecular subgroups with distinct gene expression patterns. We believe that refinement of genomic signatures will require more intensive efforts from the biomedical research community to improve targeted therapy designs and bring a substantial change in the treatment decisions. In the next era of genomic medicine, we anticipate that a clinically and biologically relevant molecular profile of each tumor will be obtained at diagnosis to guide therapy. PMID:26432520

  19. Paired-like Homeodomain Transcription factor 2 expression by breast cancer bone marrow disseminated tumor cells is associated with early recurrent disease development.

    PubMed

    Pillai, Sreeraj G; Dasgupta, Nupur; Siddappa, Chidananda M; Watson, Mark A; Fleming, Timothy; Trinkaus, Kathryn; Aft, Rebecca

    2015-10-01

    The presence of disseminated tumor cells (DTCs) in the bone marrow (BM) of breast cancer patients is prognostic for early relapse. In the present study, we analyzed the gene expression profiles from BM cells of breast cancer patients to identify molecular signatures associated with DTCs and their relevance to metastatic outcome. We analyzed BM from 30 patients with stage II/III breast cancer by gene expression profiling and correlated expression with metastatic disease development. A candidate gene, PITX2, was analyzed for expression and phenotype in breast cancer cell lines. PITX2 was knocked down in the MDAMB231 cell lines for gene expression analysis and cell invasiveness. Expression of various signaling pathway molecules was confirmed by RT-PCR. We found that the expression of Paired-like Homeobox Transcription factor-2 (PITX2) is absent in the BM of normal healthy volunteers and, when detected in the BM of breast cancer patients, is significantly correlated with early metastatic disease development (p = 0.0062). Suppression of PITX2 expression significantly reduced invasiveness in MDAMB231 cells. Three genes-NKD1, LEF1, and DKK4-were significantly downregulated in response to PITX2 suppression. Expression of PITX2 in BM of early-stage breast cancer patients is associated with risk for early disease recurrence. Furthermore, PITX2 likely plays a role in the metastatic process through its effect on the expression of genes associated with the Wnt/beta-Catenin signaling pathway. PMID:26400846

  20. The effects of (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), a potent and selective metabotropic glutamate receptor antagonist.

    PubMed Central

    Toms, N. J.; Jane, D. E.; Kemp, M. C.; Bedingfield, J. S.; Roberts, P. J.

    1996-01-01

    1. In this study we describe the potent antagonist activity of a novel metabotropic glutamate (mGlu) receptor antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG) which exhibits selectivity for mGlu receptors (group II and III) negatively coupled to adenylyl cyclase in the adult rat cortex. 2. Both the L-2-amino-4-phosphonobutyrate (L-AP4) and (2S, 1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-1) inhibition of forskolin-stimulated cyclic AMP accumulation were potently reversed by (RS)-CPPG (IC50 values: 2.2 +/- 0.6 nM and 46.2 +/- 18.2 nM, respectively). 3. In contrast, (RS)-CPPG acted as a weak antagonist against group I mGlu receptors. In neonatal rat cortical slices, (RS)-CPPG antagonized (KB = 0.65 +/- 0.07 mM) (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD)-stimulated phosphoinositide hydrolysis. (RS)-CPPG (100 microM) failed to influence L-quisqualate-stimulated phosphoinositide hydrolysis in cultured cerebellar granule cells. 4. In the rat cerebral cortex, (RS)-CPPG is the most potent antagonist of group II/III mGlu receptors yet described (with 20 fold selectivity for group III mGlu receptors), having negligible activity at group I mGlu receptors. PMID:8922731

  1. Future singularities and teleparallelism in loop quantum cosmology

    SciTech Connect

    Bamba, Kazuharu; Haro, Jaume de; Odintsov, Sergei D. E-mail: jaime.haro@upc.edu

    2013-02-01

    We demonstrate how holonomy corrections in loop quantum cosmology (LQC) prevent the Big Rip singularity by introducing a quadratic modification in terms of the energy density ρ in the Friedmann equation in the Friedmann-Lemaître-Robertson-Walker (FLRW) space-time in a consistent and useful way. In addition, we investigate whether other kind of singularities like Type II,III and IV singularities survive or are avoided in LQC when the universe is filled by a barotropic fluid with the state equation P = −ρ−f(ρ), where P is the pressure and f(ρ) a function of ρ. It is shown that the Little Rip cosmology does not happen in LQC. Nevertheless, the occurrence of the Pseudo-Rip cosmology, in which the phantom universe approaches the de Sitter one asymptotically, is established, and the corresponding example is presented. It is interesting that the disintegration of bound structures in the Pseudo-Rip cosmology in LQC always takes more time than that in Einstein cosmology. Our investigation on future singularities is generalized to that in modified teleparallel gravity, where LQC and Brane Cosmology in the Randall-Sundrum scenario are the best examples. It is remarkable that F(T) gravity may lead to all the kinds of future singularities including Little Rip.

  2. Rapid X-ray Photoreduction of Dimetal-Oxygen Cofactors in Ribonucleotide Reductase

    PubMed Central

    Sigfridsson, Kajsa G. V.; Chernev, Petko; Leidel, Nils; Popović-Bijelić, Ana; Gräslund, Astrid; Haumann, Michael

    2013-01-01

    Prototypic dinuclear metal cofactors with varying metallation constitute a class of O2-activating catalysts in numerous enzymes such as ribonucleotide reductase. Reliable structures are required to unravel the reaction mechanisms. However, protein crystallography data may be compromised by x-ray photoreduction (XRP). We studied XPR of Fe(III)Fe(III) and Mn(III)Fe(III) sites in the R2 subunit of Chlamydia trachomatis ribonucleotide reductase using x-ray absorption spectroscopy. Rapid and biphasic x-ray photoreduction kinetics at 20 and 80 K for both cofactor types suggested sequential formation of (III,II) and (II,II) species and similar redox potentials of iron and manganese sites. Comparing with typical x-ray doses in crystallography implies that (II,II) states are reached in <1 s in such studies. First-sphere metal coordination and metal-metal distances differed after chemical reduction at room temperature and after XPR at cryogenic temperatures, as corroborated by model structures from density functional theory calculations. The inter-metal distances in the XPR-induced (II,II) states, however, are similar to R2 crystal structures. Therefore, crystal data of initially oxidized R2-type proteins mostly contain photoreduced (II,II) cofactors, which deviate from the native structures functional in O2 activation, explaining observed variable metal ligation motifs. This situation may be remedied by novel femtosecond free electron-laser protein crystallography techniques. PMID:23400774

  3. Molecular investigation of isocitrate dehydrogenase gene (IDH) mutations in gliomas: first report of IDH2 mutations in Indian patients.

    PubMed

    Das, Bibhu Ranjan; Tangri, Rajiv; Ahmad, Firoz; Roy, Arnab; Patole, Kamlakar

    2013-01-01

    Recent genome wide sequencing has identified mutations in IDH1/IDH2 predominantly in grade II-III gliomas and secondary glioblastomas which are associated with favorable clinical outcome. These mutations have become molecular markers of significant diagnostic and prognostic relevance in the assessment of human gliomas. In the current study we evaluated IDH1 (R132) and IDH2 (R172) in 32 gliomas of various grades and tumor subtypes. Sequencing analysis revealed R132H mutations in 18.7% tumors, while none of the cases showed IDH2 (R172) mutations. The frequency of IDH1 mutations was higher in females (21.4%) than males (11.1%), and it was significantly higher in younger patients. Histological analyses demonstrated presence of necrosis and micro vascular proliferation in 69% and 75% respectively. Interestingly, IDH1 mutations were predominantly present in non-necrotic tumors as well as in cases showing microvascular proliferation. Of the six IDH1 positive cases, three were glioblastomas (IV), and one each were anaplastic oligoastrocytoma (III), anaplastic oligodendroglioma III (n=1) and diffuse astrocytoma. In conclusion, IDH1 mutations are quite frequent in Indian glioma patients while IDH2 mutations are not observed. Since IDH mutations are associated with good prognosis, their use in routine clinical practice will enable better risk stratification and management of glioma patients. PMID:24460285

  4. Randomized Controlled Clinical Trial to Access Efficacy and Safety of Miltefosine in the Treatment of Cutaneous Leishmaniasis Caused by Leishmania (Viannia) guyanensis in Manaus, Brazil

    PubMed Central

    Chrusciak-Talhari, Anette; Dietze, Reynaldo; Chrusciak Talhari, Carolina; da Silva, Roberto Moreira; Gadelha Yamashita, Ellen Priscila; de Oliveira Penna, Gerson; Lima Machado, Paulo Roberto; Talhari, Sinésio

    2011-01-01

    Miltefosine has been used in the treatment of several new world cutaneous leishmaniasis (CL) species with variable efficacy. Our study is the first evidence on its clinical efficacy in Leishmania (Viannia) guyanensis. In this phase II/III randomized clinical trial, 90 CL patients were randomly allocated (2:1) to oral miltefosine (2.5 mg/kg/day/28 days) (N = 60) or parenteral antimony (15–20 mg/Sb/kg/day/20 days) (N = 30) according to age groups: 2–12 y/o and 13–65 y/o. Patients were human immunodeficiency virus (HIV) noninfected parasitological proven CL without previous treatment. Definitive cure was accessed at 6 months follow-up visit. No severe adverse events occurred. Vomiting was the most frequent adverse event (48.3%) followed by nausea (8.6%) and diarrhea (6.7%). Cure rates were 71.4% (95% confidence interval [CI] = 57.8–82.7) and 53.6% (95% CI = 33.9–72.5) (P = 0.05) for miltefosine and antimonial, respectively. There were no differences in cure rates between age groups within the same treatment arms. Miltefosine was safe and relatively well tolerated and cure rate was higher than antimony. PMID:21292895

  5. Effects of Exercise Training on Autonomic Function in Chronic Heart Failure: Systematic Review

    PubMed Central

    Hsu, Chung-Yin; Hsieh, Ping-Lun; Hsiao, Shu-Fang; Chien, Meng-Yueh

    2015-01-01

    Objectives. Cardiac autonomic imbalance accompanies the progression of chronic heart failure (CHF). It is unclear whether exercise training could modulate autonomic control in CHF. This study aimed to review systematically the effects of exercise training on heart rate recovery (HRR) and heart rate variability (HRV) in patients with CHF. Methods. Literatures were systematically searched in electronic databases and relevant references. Only published randomized controlled trials (RCTs) focusing on exercise training for CHF were eligible for inclusion. Outcome measurements included HRR and HRV parameters. Results. Eight RCTs were eligible for inclusion and provided data on 280 participants (186 men). The participants were 52–70 years of age with New York Heart Association functional class II-III of CHF. Each study examined either aerobic or resistance exercise. Two trials addressed outcome of HRR and six HRV among these studies. Two RCTs showed that moderate aerobic exercise could improve HRR at 2 minutes after exercise training in CHF. Five of six RCTs demonstrated positive effects of exercise training on HRV which revealed the increments in high frequency (HF) and decrements in LF (low frequency)/HF ratio after training. Conclusion. Participation in an exercise training program has positive effects on cardiac autonomic balance in patients with CHF. PMID:26543861

  6. Significance of microvascular density (MVD) in cervical cancer recurrence.

    PubMed

    Cantu De León, D; Lopez-Graniel, C; Frias Mendivil, M; Chanona Vilchis, G; Gomez, C; De La Garza Salazar, J

    2003-01-01

    The purpose of this retrospective study of 118 patients with squamous cell cervical cancer from January 1990 to December 1993 was to evaluate angiogenesis as predictive factor of recurrence in cervical cancer stages II-III treated with standard radiotherapy. Microvessel density (MVD) was evaluated and correlated with other prognostic factors. MVD was greater than 20 in 67.8% of patients with recurrence (P = 0.002) in comparison to 39% of patients without. Disease-free survival was shorter in stage IIA and MVD >20 (P = 0.0193) as well as for stage IIB (P < 0.05 ), but not for IIIB (P = 0.1613 ). Global survival was significantly shorter when MVD was >20 (P = 0.0316). For stage IIA and MVD >20 survival was shorter (P = 0.0008) for stage IIB (P < 0.05) but not for IIIB (P = 0.14). Patients younger than 40 years and MVD >20 had poorer disease-free interval and survival (P = 0.0029). MVD in patients with squamous cell cervical cancer stage II and age younger than 40 may play a role in predicting recurrence and survival. PMID:14675324

  7. [Biologic and molecular genetic properties of a transplantable human primary gastric cancer in nude mice].

    PubMed

    Chen, S S

    1989-05-01

    A human primary gastric cancer tissue (adenocarcinoma II-III) was transplanted into nude mice (SWISS/DF. nu/nu). It has been transferred for 8 generations at 56 sites in 28 nude mice with transplantable rate of 100%. The transplanted tumor is designated as transplantable human primary gastric cancer-1 in nude mice (THPGC-1). The growth of THPGC-1 is rather rapid and the size of transplanted tumor reaches 1 cm2, 4-5 weeks after transfer. The morphology and histochemistry of the original tumor were retained well in the initial and serial transplanted tumors. THPGC-1 could secret carcinoembryonic antigen (CEA). After intravenous or intraperitoneal injection of 131I-antiCEA monoclonal antibody into the THPGC-1 bearing nude mice, the radiolabeled antibody was concentrated and localized in the tumor as shown by gamma-camera analysis. Similar pattern of lactate dehydrogenase isoenzyme was observed both in primary gastric cancer tissue and THPGC-1 tissue. Chromosomal examination revealed that THPGC-1 was human aneuploid ones. Southern blot analysis showed that the pattern of repetitive DNA bands and the structures of 28s, rDNA, c-H-ras and c-myc genes in THPGC-1 were identical to the original primary gastric cancer DNA. The results suggest that THPGC-1 be a reliable model for the research of the molecular biology of cancer cells and experimental gastric cancer diagnosis and treatment. PMID:2693024

  8. Treatment of pulmonary arterial hypertension in connective tissue disease.

    PubMed

    Grünig, Ekkehard

    2012-05-28

    Pulmonary arterial hypertension (PAH) is a group of distinct disorders that includes idiopathic PAH (IPAH), familial PAH and PAH associated with other conditions (APAH) such as connective tissue disease (CTD-APAH) or congenital heart disease. PAH is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. If left untreated, PAH can lead to right heart failure and premature death. CTD-APAH represents an important clinical subgroup of APAH that has a higher risk of death than IPAH. The European treatment guidelines advocate the use of PAH-targeted therapies including bosentan, ambrisentan, sildenafil, inhaled iloprost, intravenous epoprostenol (I-A recommendations), tadalafil or treprostinil (I-B recommendations) for patients in WHO functional class II-III. Not all randomized clinical studies of the approved PAH-targeted therapies have included patients with CTD-APAH. The purpose of this review is to describe the clinical characteristics of CTD-APAH and discuss the approved pharmacological treatments, with a focus on data specific to this subgroup where possible. PMID:22621693

  9. Surveillance for Toxoplasma gondii in California mussels (Mytilus californianus) reveals transmission of atypical genotypes from land to sea.

    PubMed

    Shapiro, Karen; VanWormer, Elizabeth; Aguilar, Beatriz; Conrad, Patricia A

    2015-11-01

    Coastal habitat contamination with Toxoplasma gondii is a health risk to humans and marine wildlife, with infections documented in both nearshore and pelagic marine mammals. Due to lack of sensitive methods for detection of T. gondii in water, this study utilized an alternative surveillance approach for evaluating marine habitat contamination using wild mussels. The objectives of this study were to (i) validate sensitive molecular tools for T. gondii detection in mussels and (ii) apply optimized methods in a surveillance study to determine the prevalence and genotype(s) of T. gondii in mussels. Simplex polymerase chain reaction screening and multiplex genotyping assays were validated and then applied on 959 wild-caught mussels collected from central California. Thirteen mussels (1.4%) had detectable T. gondii DNA and the presence of T. gondii in mussels was significantly associated with proximity to freshwater run-off and collection during the wet season. Molecular characterization revealed alleles from T. gondii types I, II/III, X at the B1 locus, and a novel atypical B1 allele that was recently documented in T. gondii-infected carnivores from California. Findings demonstrate higher than previously reported T. gondii contamination of California coastlines, and describe novel strains of the parasite that further link terrestrial sources with marine contamination. PMID:25367256

  10. Antenatal Magnesium Sulfate, Necrotizing Enterocolitis, and Death among Neonates < 28 Weeks Gestation

    PubMed Central

    Kamyar, Manijeh; Clark, Erin A. S.; Yoder, Bradley A.; Varner, Michael W.; Manuck, Tracy A.

    2016-01-01

    Objective This study aims to examine the relationship between antenatal magnesium sulfate (MgSO4) and neonatal death and/or severe necrotizing enterocolitis (NEC) among infants < 28 weeks. Methods Secondary analysis of a multicenter randomized trial of antenatal MgSO4 versus placebo administered to women to prevent death and cerebral palsy. Neonates < 28 weeks were included. The primary outcome was neonatal death before NICU discharge, and/or severe NEC (Bell criteria stage II/III). Neonates with and without death/severe NEC were compared. Results A total of 697 neonates met the criteria. Out of which 150 (21.5%) died and/or were diagnosed with severe NEC. Antenatal MgSO4 exposure was not associated with death/severe NEC in infants < 28 weeks. In a subgroup analysis of neonates < 26 weeks, treatment group assignment to antenatal MgSO4 was associated with an increased odds of death/severe NEC (adjusted odds ratio: 1.90, 95% confidence interval: 1.12–3.22, p = 0.017). Conclusions Among neonates < 26 weeks, antenatal MgSO4 was associated with death and severe NEC. Further prospective study in larger populations is needed. PMID:27054046

  11. Induction of KIAA1199/CEMIP is associated with colon cancer phenotype and poor patient survival

    PubMed Central

    Fink, Stephen P.; Myeroff, Lois L.; Kariv, Revital; Platzer, Petra; Xin, Baozhong; Mikkola, Debra; Lawrence, Earl; Morris, Nathan; Nosrati, Arman; Willson, James K. V.; Willis, Joseph; Veigl, Martina; Barnholtz-Sloan, Jill S.; Wang, Zhenghe; Markowitz, Sanford D.

    2015-01-01

    Genes induced in colon cancer provide novel candidate biomarkers of tumor phenotype and aggressiveness. We originally identified KIAA1199 (now officially called CEMIP) as a transcript highly induced in colon cancer: initially designating the transcript as Colon Cancer Secreted Protein 1. We molecularly characterized CEMIP expression both at the mRNA and protein level and found it is a secreted protein induced an average of 54-fold in colon cancer. Knockout of CEMIPreduced the ability of human colon cancer cells to form xenograft tumors in athymic mice. Tumors that did grow had increased deposition of hyaluronan, linking CEMIP participation in hyaluronan degradation to the modulation of tumor phenotype. We find CEMIP mRNA overexpression correlates with poorer patient survival. In stage III only (n = 31) or in combined stage II plus stage III colon cancer cases (n = 73), 5-year overall survival was significantly better (p = 0.004 and p = 0.0003, respectively) among patients with low CEMIP expressing tumors than those with high CEMIP expressing tumors. These results demonstrate that CEMIP directly facilitates colon tumor growth, and high CEMIP expression correlates with poor outcome in stage III and in stages II+III combined cohorts. We present CEMIP as a candidate prognostic marker for colon cancer and a potential therapeutic target. PMID:26437221

  12. Is a Clinical Target Volume (CTV) Necessary in the Treatment of Lung Cancer in the Modern Era Combining 4-D Imaging and Image-guided Radiotherapy (IGRT)?

    PubMed Central

    Kilburn, Jeremy M; Lucas, John T; Soike, Michael H; Ayala-Peacock, Diandra N; Blackstock, Arthur W; Hinson, William H; Munley, Michael T; Petty, William J

    2016-01-01

    Objective: We hypothesized that omission of clinical target volumes (CTV) in lung cancer radiotherapy would not compromise control by determining retrospectively if the addition of a CTV would encompass the site of failure. Methods: Stage II-III patients were treated from 2009-2012 with daily cone-beam imaging and a 5 mm planning target volume (PTV) without a CTV. PTVs were expanded 1 cm and termed CTVretro. Recurrences were scored as 1) within the PTV, 2) within CTVretro, or 3) outside the PTV. Locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated. Result: Among 110 patients, Stage IIIA 57%, IIIB 32%, IIA 4%, and IIB 7%. Eighty-six percent of Stage III patients received chemotherapy. Median dose was 70 Gy (45-74 Gy) and fraction size ranged from 1.5-2.7 Gy. Median follow-up was 12 months, median OS was 22 months (95% CI 19-30 months), and LRC at two years was 69%. Fourteen local and eight regional events were scored with two CTVretro failures equating to a two-year CTV failure-free survival of 98%. Conclusion: Omission of a 1 cm CTV expansion appears feasible based on only two events among 110 patients and should be considered in radiation planning. PMID:26929893

  13. Critical dosimetry measures and surrogate tools that can facilitate clinical success in PDT (Conference Presentation)

    NASA Astrophysics Data System (ADS)

    Pogue, Brian W.; Davis, Scott C.; Kanick, Stephen C.; Maytin, Edward V.; Pereira, Stephen P.; Palanisami, Akilan; Hasan, Tayyaba

    2016-03-01

    Photodynamic therapy can be a highly complex treatment with more than one parameter to control, or in some cases it is easily implemented with little control other than prescribed drug and light values. The role of measured dosimetry as related to clinical adoption has not been as successful as it could have been, and part of this may be from the conflicting goals of advocating for as many measurements as possible for accurate control, versus companies and clinical adopters advocating for as few measurements as possible, to keep it simple. An organized approach to dosimetry selection is required, which shifts from mechanistic measurements in pre-clinical and early phase I trials, towards just those essential dose limiting measurements and a focus on possible surrogate measures in phase II/III trials. This essential and surrogate approach to dosimetry should help successful adoption of clinical PDT if successful. The examples of essential dosimetry points and surrogate dosimetry tools which might be implemented in phase II and higher trials are discussed for solid tissue PDT with verteporfin and skin lesion treatment with aminolevulinc acid.

  14. A Phase I study of concurrent radiotherapy and capecitabine as adjuvant treatment for operable rectal cancer

    SciTech Connect

    Jin Jing

    2006-03-01

    Purpose: To determine the maximum tolerated dose and the dose-limiting toxicity of capecitabine with standard radiotherapy (RT) as adjuvant treatment in patients with rectal cancer. Methods and Materials: Patients with Stage II/III rectal cancer after surgery were eligible. Total RT dose was delivered as DT 50 Gy in fractions of 2.0 Gy/day for 5 weeks to the pelvic area. Capecitabine was administered concurrently with RT in escalating doses, twice daily with a 12-h interval, for two cycles of 14 days separated by a 7-day rest. Dose-limiting toxicity included Grade 3 or Grade 4 hematologic and nonhematologic toxicity. Results: Twenty-four patients were enrolled at the following dose levels: 1,000 (3 patients), 1,200 (3 patients), 1,400 (3 patients), 1,500 (3 patients), 1,600 (6 patients), and 1,700 mg/m{sup 2}/day (6 patients). Dose-limiting toxicity was observed in 1 patient at 1,600 mg/m{sup 2}/day (Grade 3 diarrhea) and in 2 patients at 1,700 mg/m{sup 2}/day (1 patient had Grade 3 and 1 Grade 4 diarrhea). Conclusion: The maximum tolerated dose (MTD) of capecitabine given concurrently with RT was 1,600 mg/m{sup 2}, daily from the 1st to the 14th day, with a 7-day rest, for two cycles.

  15. Orthogonal micro-organization of orientation and spatial frequency in primate primary visual cortex

    PubMed Central

    Nauhaus, Ian; Nielsen, Kristina J.; Disney, Anita A.; Callaway, Edward M.

    2012-01-01

    Orientation and spatial frequency tuning are highly salient properties of neurons in primary visual cortex (V1). The combined organization of these particular tuning properties in the cortical space will strongly shape the V1 population response to different visual inputs, yet it is poorly understood. In this study, we used two-photon imaging in macaque monkey V1 to provide the first data demonstrating the 3D cell-by-cell layout of both spatial frequency and orientation tuning in large mammals. We first show that spatial frequency tuning is organized into highly structured maps that remain consistent across the depth of layer II/III, similar to orientation. Next, we show that orientation and spatial frequency maps are intimately related at the fine spatial scale observed with two-photon imaging. We find that not only do the map gradients have a striking tendency toward orthogonality, but they also co-vary negatively from cell-to-cell at the spatial scale of cortical columns. PMID:23143516

  16. Patient-specific quantification of respiratory motion-induced dose uncertainty for step-and-shoot IMRT of lung cancer

    PubMed Central

    Li, Heng; Park, Peter; Liu, Wei; Matney, Jason; Liao, Zhongxing; Balter, Peter; Li, Yupeng; Zhang, Xiaodong; Li, Xiaoqiang; Zhu, X. Ronald

    2013-01-01

    Purpose: The objective of this study was to quantify respiratory motion-induced dose uncertainty at the planning stage for step-and-shoot intensity-modulated radiation therapy (IMRT) using an analytical technique. Methods: Ten patients with stage II/III lung cancer who had undergone a planning four-dimensional (4D) computed tomographic scan and step-and-shoot IMRT planning were selected with a mix of motion and tumor size for this retrospective study. A step-and-shoot IMRT plan was generated for each patient. The maximum and minimum doses with respiratory motion were calculated for each plan, and the mean deviation from the 4D dose was calculated, taking delivery time, fractionation, and patient breathing cycle into consideration. Results: For all patients evaluated in this study, the mean deviation from the 4D dose in the planning target volume (PTV) was <2.5%, with a standard deviation <1.2%, and maximum point dose variation from the 4D dose was <6.2% in the PTV assuming delivery dose rate of 200 MU/min and patient breathing cycle of 8 s. The motion-induced dose uncertainty is a function of motion, fractionation, MU (plan modulation), dose rate, and patient breathing cycle. Conclusions: Respiratory motion-induced dose uncertainty varies from patient to patient. Therefore, it is important to evaluate the dose uncertainty on a patient-specific basis, which could be useful for plan evaluation and treatment strategy determination for selected patients. PMID:24320498

  17. Dry eye syndrome among computer users

    NASA Astrophysics Data System (ADS)

    Gajta, Aurora; Turkoanje, Daniela; Malaescu, Iosif; Marin, Catalin-Nicolae; Koos, Marie-Jeanne; Jelicic, Biljana; Milutinovic, Vuk

    2015-12-01

    Dry eye syndrome is characterized by eye irritation due to changes of the tear film. Symptoms include itching, foreign body sensations, mucous discharge and transitory vision blurring. Less occurring symptoms include photophobia and eye tiredness. Aim of the work was to determine the quality of the tear film and ocular dryness potential risk in persons who spend more than 8 hours using computers and possible correlations between severity of symptoms (dry eyes symptoms anamnesis) and clinical signs assessed by: Schirmer test I, TBUT (Tears break-up time), TFT (Tear ferning test). The results show that subjects using computer have significantly shorter TBUT (less than 5 s for 56 % of subjects and less than 10 s for 37 % of subjects), TFT type II/III in 50 % of subjects and type III 31% of subjects was found when compared to computer non users (TFT type I and II was present in 85,71% of subjects). Visual display terminal use, more than 8 hours daily, has been identified as a significant risk factor for dry eye. It's been advised to all persons who spend substantial time using computers to use artificial tears drops in order to minimize the symptoms of dry eyes syndrome and prevents serious complications.

  18. Tau-Centric Targets and Drugs in Clinical Development for the Treatment of Alzheimer's Disease.

    PubMed

    Panza, Francesco; Solfrizzi, Vincenzo; Seripa, Davide; Imbimbo, Bruno P; Lozupone, Madia; Santamato, Andrea; Zecca, Chiara; Barulli, Maria Rosaria; Bellomo, Antonello; Pilotto, Alberto; Daniele, Antonio; Greco, Antonio; Logroscino, Giancarlo

    2016-01-01

    The failure of several Phase II/III clinical trials in Alzheimer's disease (AD) with drugs targeting β-amyloid accumulation in the brain fuelled an increasing interest in alternative treatments against tau pathology, including approaches targeting tau phosphatases/kinases, active and passive immunization, and anti-tau aggregation. The most advanced tau aggregation inhibitor (TAI) is methylthioninium (MT), a drug existing in equilibrium between a reduced (leuco-methylthioninium) and oxidized form (MT(+)). MT chloride (methylene blue) was investigated in a 24-week Phase II clinical trial in 321 patients with mild to moderate AD that failed to show significant positive effects in mild AD patients, although long-term observations (50 weeks) and biomarker studies suggested possible benefit. The dose of 138 mg/day showed potential benefits on cognitive performance of moderately affected AD patients and cerebral blood flow in mildly affected patients. Further clinical evidence will come from the large ongoing Phase III trials for the treatment of AD and the behavioral variant of frontotemporal dementia on a new form of this TAI, more bioavailable and less toxic at higher doses, called TRx0237. More recently, inhibitors of tau acetylation are being actively pursued based on impressive results in animal studies obtained by salsalate, a clinically used derivative of salicylic acid. PMID:27429978

  19. Loss of expression of the double strand break repair protein ATM is associated with worse prognosis in colorectal cancer and loss of Ku70 expression is associated with CIN

    PubMed Central

    Beggs, Andrew D; Domingo, Enric; McGregor, Megan; Presz, Mikael; Johnstone, Elaine; Midgley, Rachel; Kerr, David; Oukrif, Dahmane; Novelli, Marco; Abulafi, Muti; Hodgson, Shirley V; Fadhil, Wakkas; Ilyas, Mohammad; Tomlinson, Ian PM

    2012-01-01

    Repair of double strand DNA breaks (DSBs) is pivotal in maintaining normal cell division and disruption of this system has been shown to be a key factor in carcinogenesis. Loss of expression of the DSB repair proteins have previously been shown to be associated with poorer survival in colorectal cancer. We wished to ascertain the relationship of altered expression of the DSB repair proteins γ-H2AX (gamma-H2AX), ATM and Ku70 with biological and clinico-pathological features of colorectal cancer. 908 tumours from the VICTOR clinical trial of stage II/III colorectal cancer were analysed for expression of γ-H2AX, ATM and Ku70 using immunohistochemistry. Expression levels were correlated with CIN and with disease-free survival, correcting for microsatellite instability, BRAF/KRAS mutation status, Dukes stage, chemo/radiotherapy, age, gender and tumour location. Down-regulated Ku70 expression was associated with chromosomal instability (p=0.029) in colorectal cancer. Reduced ATM expression was an independent marker of poor disease-free survival (HR=1.67, 95% CI 1.11-2.50, p=0.015). For Ku70, further studies are required to investigate the potential relationship of non-homologous end joining with chromosomal instability. Loss of ATM expression might serve as a biomarker of poor prognosis in colorectal cancer. PMID:23154512

  20. The Impact of Remote Ischemic Preconditioning on Arterial Stiffness and Heart Rate Variability in Patients with Angina Pectoris.

    PubMed

    Zagidullin, Naufal; Scherbakova, Elena; Safina, Yuliana; Zulkarneev, Rustem; Zagidullin, Shamil

    2016-01-01

    Remote ischemic preconditioning (RIPC) is the set of ischemia episodes that protects against subsequent periods of prolonged ischemia through the cascade of adaptive responses; however, the mechanisms of RIPC are not entirely clear. Here, we aimed to study the impact of RIPC in patients with stable angina pectoris and compare it with healthy individuals with respect to arterial stiffness and heart rate variability. In the randomized, sham-controlled, crossover blind design study, a group of 30 coronary heart disease (CHD) patients (63.9 ± 1.6 years) with stable angina pectoris NYHA II-III and a control group of 20 healthy individuals (58.2 ± 2.49) were both randomly allocated for remote RIPC or sham RIPC. Arterial stiffness, pulse wave velocity (Spygmacor, Australia), and heart rate variability (HRV) were recorded before and after the procedure followed by the crossover examination. In the group of healthy individuals, RIPC showed virtually no impact on the cardiovascular parameters, while, in the CHD group, the systolic and central systolic blood pressure, central pulse pressure, and augmentation decreased, and total power of HRV improved. We conclude that ischemic preconditioning reduces not only systolic blood pressure, but also reduces central systolic blood pressure and improves arterial compliance and heart rate modulation reserve, which may be associated with the antianginal effect of preconditioning. PMID:27348009

  1. Capecitabine Monotherapy: Review of Studies in First-Line HER-2-Negative Metastatic Breast Cancer

    PubMed Central

    Kaufmann, Manfred; Siedentopf, Friederike; Dalivoust, Philippe; Debled, Marc; Robert, Nicholas J.; Harbeck, Nadia

    2012-01-01

    The goals of treatment for metastatic breast cancer (MBC) are to prolong overall survival (OS) while maximizing quality of life, palliating symptoms, and delaying tumor progression. For many years, anthracyclines and taxanes have been the mainstay of treatment for MBC, but these agents are now commonly administered earlier in the course of the disease. A recent meta-analysis revealed adverse effects on OS and overall response rates in patients with MBC receiving first-line anthracycline-based chemotherapy following relapse on adjuvant chemotherapy. Noncrossresistant cytotoxic agents and combinations that combine high clinical activity and acceptable tolerability while being convenient for patients are therefore needed for the first-line treatment of MBC patients. Capecitabine has substantial antitumor activity in the first-line treatment of patients with MBC in prospective, randomized, phase II/III clinical trials as monotherapy and in combination with biologic and novel agents. First-line capecitabine monotherapy has a favorable safety profile, lacking myelosuppression and alopecia, and does not compromise the administration of further lines of chemotherapy. Capecitabine is suitable for long-term administration without the cumulative toxicity that can limit the prolonged use of other chemotherapy agents. Here, we review the available data on capecitabine as a single agent for first-line treatment of patients with human epidermal growth factor receptor 2–negative MBC. PMID:22418569

  2. Influence of variations in the chromophoric ligand on the properties of metal-to-ligand charge-transfer excited states

    SciTech Connect

    Johnson, S.R.; Westmoreland, T.D.; Caspar, J.V.; Barqawi, K.R.; Meyer, T.J.

    1988-09-07

    The effects of variations in the chromophoric ligand on the properties of the metal-to-ligand charge-transfer (MLCT) excited states in the series (Os(PP)/sub 3/)/sup 2+/, ((PP)/sub 2/Os(py)/sub 2/)/sup 2+/, and ((PP)/sub 2/Os(LL))/sup 2+/ (PP = 2,2'-bipyridine, 1,10-phenanthroline, or a substituted derivative; py = pyridine; LL = das, dppm, dppb, dppene) have been investigated. From a series of electrochemical and photophysical measurements it has been determined that (1) substituent variations in the chromophoric ligands have a relatively minor effect on the d/pi/(Os) levels as evidenced by variations in E/sub 1/2/ values for the ground-state Os(III/II) couples, (2) linear correlations exist between metal-to-ligand charge-transfer (MLCT) absorption or emission band energies and the difference in metal-based oxidation and ligand-based reduction potentials, E/sub 1/2/(Os/sup III/II/) - E/sub 1/2/(PP/sup 0//minus//), and (3) a linear relationship between 1n k/sub nr/ and the emission energy, E/sub em/, exists, consistent with the energy gap law. It appears that for nonradiative decay both the pattern of acceptor vibrations and the vibrationally induced electronic coupling term remain relatively constant as the chromophoric ligand is varied. 26 references, 4 figures, 2 tables.

  3. Noise-induced hearing loss (NIHL) as a target of oxidative stress-mediated damage: cochlear and cortical responses after an increase in antioxidant defense.

    PubMed

    Fetoni, Anna Rita; De Bartolo, Paola; Eramo, Sara Letizia Maria; Rolesi, Rolando; Paciello, Fabiola; Bergamini, Christian; Fato, Romana; Paludetti, Gaetano; Petrosini, Laura; Troiani, Diana

    2013-02-27

    This study addresses the relationship between cochlear oxidative damage and auditory cortical injury in a rat model of repeated noise exposure. To test the effect of increased antioxidant defenses, a water-soluble coenzyme Q10 analog (Qter) was used. We analyzed auditory function, cochlear oxidative stress, morphological alterations in auditory cortices and cochlear structures, and levels of coenzymes Q9 and Q10 (CoQ9 and CoQ10, respectively) as indicators of endogenous antioxidant capability. We report three main results. First, hearing loss and damage in hair cells and spiral ganglion was determined by noise-induced oxidative stress. Second, the acoustic trauma altered dendritic morphology and decreased spine number of II-III and V-VI layer pyramidal neurons of auditory cortices. Third, the systemic administration of the water-soluble CoQ10 analog reduced oxidative-induced cochlear damage, hearing loss, and cortical dendritic injury. Furthermore, cochlear levels of CoQ9 and CoQ10 content increased. These findings indicate that antioxidant treatment restores auditory cortical neuronal morphology and hearing function by reducing the noise-induced redox imbalance in the cochlea and the deafferentation effects upstream the acoustic pathway. PMID:23447610

  4. Immortal Time Bias: A Frequently Unrecognized Threat to Validity in the Evaluation of Postoperative Radiotherapy

    SciTech Connect

    Park, Henry S.; Gross, Cary P.; Makarov, Danil V.; Yu, James B.

    2012-08-01

    Purpose: To evaluate the influence of immortal time bias on observational cohort studies of postoperative radiotherapy (PORT) and the effectiveness of sequential landmark analysis to account for this bias. Methods and Materials: First, we reviewed previous studies of the Surveillance, Epidemiology, and End Results (SEER) database to determine how frequently this bias was considered. Second, we used SEER to select three tumor types (glioblastoma multiforme, Stage IA-IVM0 gastric adenocarcinoma, and Stage II-III rectal carcinoma) for which prospective trials demonstrated an improvement in survival associated with PORT. For each tumor type, we calculated conditional survivals and adjusted hazard ratios of PORT vs. postoperative observation cohorts while restricting the sample at sequential monthly landmarks. Results: Sixty-two percent of previous SEER publications evaluating PORT failed to use a landmark analysis. As expected, delivery of PORT for all three tumor types was associated with improved survival, with the largest associated benefit favoring PORT when all patients were included regardless of survival. Preselecting a cohort with a longer minimum survival sequentially diminished the apparent benefit of PORT. Conclusions: Although the majority of previous SEER articles do not correct for it, immortal time bias leads to altered estimates of PORT effectiveness, which are very sensitive to landmark selection. We suggest the routine use of sequential landmark analysis to account for this bias.

  5. Outcomes of ureteroscopy for patients with stones in a solitary kidney: evidence from a systematic review

    PubMed Central

    Rai, Bhavan Prasad; Somani, Bhaskar K.

    2016-01-01

    Introduction Management of urolithiasis in a solitary functioning kidney can be clinically challenging. The aim of this article was to review the outcomes of URS for patients with stone disease in a solitary kidney and critically appraise the existing evidence and outcome reporting standards. Material and methods We conducted a systematic review in line with PRISMA checklist and Cochrane guidelines between January 1980 and February 2015. Our inclusion criteria were all English language articles reporting on a minimum of 10 patients with a solitary kidney undergoing ureteroscopy for stone disease. Results A total of 116 patients (mean age 50 years) underwent URS for stones in solitary kidney. For a mean stone size of 16.8 mm (range: 5–60 mm) and 1.23 procedures/patient, the mean stone free rate was 87%. No significant change in renal function was recorded in any of the studies although a transient elevation in creatinine was reported in 10 (8.6%) patients. A total of 33 (28%) complications were recorded a majority (n = 21) of which were Clavien grade I. The Clavien grade II/III complications as reported by authors were urosepsis, steinstrasse and renal colic. None of the procedures required conversion to open surgery with no cases of renal haematoma or ureteric perforation. Conclusions This contemporary review highlights URS as a viable treatment option for stone disease in patients with a solitary kidney. It is associated with superior clearance rates to SWL and fewer high-risk complications compared to PCNL. PMID:27123332

  6. Irreversible deformation processes in PVC and its short glass fiber reinforced composites

    SciTech Connect

    Yuan, J.Y.

    1985-01-01

    The tensile mechanical behavior of PVC and its short glass fiber reinforced composites under superimposed hydrostatic pressure was studied up to 3 x 10/sup 8/ Pa. For rigid PVC, the brittle-to-ductile transition was observed at a pressure between 1 x 10/sup 7/ Pa and 2 x 10/sup 7/ Pa. This pressure-induced brittle-to-ductile transition was controlled by the competitive microdeformation processes of crazing and shear banding. Deformation in the post-yield region occurred by neck formation and subsequent drawing to produce chain orientation. A strong environmental stress-cracking effect was observed when PVC samples were exposed to the pressure-transmitting fluid, silicone oil. Three types of pressure dependent deformation processes was observed for the short glass fiber reinforced composites of PVC. Type I behavior shows debonding at the interface between fiber and matrix followed by brittle fracture of the matrix. Type II behavior, which was observed for the first time, exhibits a sharp stress drop due to debonding at the interface followed by matrix shear yielding. In Type III behavior, only upper shear yielding of matrix was observed. The transitional behavior from Type I and Type II was controlled by the pressure induced brittle to ductile transition of the matrix, while the Type II-III transition was strongly affected by debonding at the interface.

  7. Methicillin-Resistant Staphylococcus saprophyticus Isolates Carrying Staphylococcal Cassette Chromosome mec Have Emerged in Urogenital Tract Infections▿

    PubMed Central

    Higashide, Masato; Kuroda, Makoto; Omura, Carlos Takashi Neves; Kumano, Miyuki; Ohkawa, Saburo; Ichimura, Sadahiro; Ohta, Toshiko

    2008-01-01

    Staphylococcus saprophyticus is a uropathogenic bacterium that causes acute uncomplicated urinary tract infections, particularly in female outpatients. We investigated the dissemination and antimicrobial susceptibilities of 101 S. saprophyticus isolates from the genitourinary tracts of patients in Japan. Eight of these isolates were mecA positive and showed β-lactam resistance. Pulsed-field gel electrophoresis showed that only some isolates were isogenic, indicating that the mecA gene was apparently acquired independently by mecA-positive isolates through staphylococcal cassette chromosome mec (SCCmec). Type determination of SCCmec by multiplex PCR showed a nontypeable element in the eight mecA-positive isolates. Sequence analysis of the entire SCCmec element from a prototype S. saprophyticus strain revealed that it was nontypeable with the current SCCmec classification due to the novel composition of the class A mec gene complex (IS431-mecA-mecR1-mecI genes) and the ccrA1/ccrB3 gene complex. Intriguingly, the attachment sites of SCCmec are similar to those of type I SCCmec in S. aureus NCTC 10442. Furthermore, the genes around the mec gene complex are similar to those of type II/III SCCmec in S. aureus, while those around the ccr gene complex are similar to those of SCC15305RM found in S. saprophyticus ATCC 15305. In comparison with known SCCmec elements, this S. saprophyticus SCCmec is a novel type. PMID:18362191

  8. A review of hyperthermia combined with radiotherapy/chemotherapy on malignant tumors.

    PubMed

    Rao, Wei; Deng, Zhong-Shan; Liu, Jing

    2010-01-01

    Therapeutic hyperthermia is a procedure that involves heating tissues to a higher temperature level, typically ranging from 41 degrees C to 45 degrees C. Its combination with radiotherapy and/or chemotherapy has been performed for many years, with remarkable success in treating advanced and recurrent cancers. The current hyperthermia strategies generally include local, regional, and whole-body hyperthermia, which can be implemented by many heating methods, such as microwave, radiofrequency, laser, and ultrasound. There are several hyperthermic treatment modalities in conjunction with radiotherapy/chemotherapy. Numerous studies have attempted to explain the mechanisms of thermosensitization from radiation and chemotherapy; however, a generalized standard for determining an optimal hyperthermia modality combined with radiotherapy/chemotherapy has not been established, so more research is needed. Fortunately, phase II/III clinical trials have demonstrated that hyperthermia combination therapy is beneficial for local tumor control and survival in patients with high-risk tumors of different types. The aim of this article is to present a comprehensive review of the latest advances in tumor hyperthermia combined with radiotherapy and/ or chemotherapy. We specifically focus on synergistic cellular and molecular mechanisms, thermal dose, treatment sequence, monitoring and imaging, and clinical outcomes of the combination therapy. The role of nanoparticles in sensitization during radio-/chemotherapy is also evaluated. Finally, research challenges and future trends in the related areas are presented. PMID:21175406

  9. Lipidomic analysis and electron transport chain activities in C57BL/6J mouse brain mitochondria

    PubMed Central

    Kiebish, Michael A.; Han, Xianlin; Cheng, Hua; Lunceford, Adam; Clarke, Catherine F.; Moon, Hwi; Chuang, Jeffrey H.; Seyfried, Thomas N.

    2011-01-01

    The objective of this study was to characterize the lipidome and electron transport chain activities in purified non-synaptic (NS) and synaptic (Syn) mitochondria from C57BL/6J mouse cerebral cortex. Contamination from subcellular membranes, especially myelin, has hindered past attempts to accurately characterize the lipid composition of brain mitochondria. An improved Ficoll and sucrose discontinuous gradient method was employed that yielded highly enriched mitochondrial populations free of myelin contamination. The activities of Complexes I, II, III, and II/III were lower in Syn than in NS mitochondria, while Complexes I/III and IV activities were similar in both populations. Shotgun lipidomics showed that levels of cardiolipin (Ptd2Gro) were lower, whereas levels of ceramide and phosphatidylserine were higher in Syn than in NS mitochondria. Coenzyme Q9 and Q10 was also lower in Syn than in NS mitochondria. Gangliosides, phosphatidic acid, sulfatides, and cerebrosides were undetectable in brain mitochondria. The distribution of Ptd2Gro molecular species was similar in both populations and formed a unique pattern, consisting of seven major molecular species groups, when arranged according to mass to charge ratios. Remodeling involving choline and ethanolamine phosphoglycerides could explain Ptd2Gro heterogeneity. NS and Syn mitochondrial lipidomic heterogeneity could influence energy metabolism, which may contribute to metabolic compartmentation of the brain. PMID:18373617

  10. Comparison of different clinical development plans for confirmatory subpopulation selection.

    PubMed

    Rufibach, Kaspar; Chen, Meng; Nguyen, Hoa

    2016-03-01

    Given ever increasing costs to develop a new drug and intense competition, adaptive enrichment designs are an attractive option for a development program that allows selecting a potential subgroup defined by a binary biomarker. Such designs explicitly factor in the possibility that the new drug might differentially benefit distinct biomarker subgroups. We have compared three clinical development plans for a time-to-event endpoint, such as overall survival, that all lead to a decision in a pivotal trial either in all comers only, in allcomers and biomarker positive, in the biomarker positive only, or to declare the drug futile. The decision about which hypothesis to test at the final analysis is made based on a fast time-to-event endpoint, such as progression-free survival, at an interim analysis. We quantify the time gain when using an adaptive enrichment Phase II/III design versus alternative development approaches and we outline what type of biomarker needs to be available prior to Phase II in each scenario. We conclude with a discussion of further features of each of the considered development plans. PMID:26744231

  11. Metabolic targeting of malignant tumors: small-molecule inhibitors of bioenergetic flux.

    PubMed

    Mathupala, Saroj P

    2011-01-01

    Metabolism in tumors deviates significantly from that of normal tissues. Increasingly, the underlying aberrant metabolic pathways are being considered as novel targets for cancer therapy. Denoted "metabolic targeting", small molecule drugs are under investigation for focused inhibition of key metabolic steps that are utilized by tumors, since such inhibitors should harbor minimal toxicity towards surrounding normal tissues. This review will examine the primary biochemical pathways that tumors harness to enhance their bioenergetic capacity, which in turn, help their rapid proliferation and metastasis within the host. It is hoped that "metabolite-mimetic" drugs can be utilized to interfere with metabolic flux pathways active within the tumor, and across tumor-microenvironment boundary. In fact, the major pathways of mammalian metabolism, i.e., the carbohydrate, amino-acid, and fatty-acid metabolic pathways have been examined as putative targets for drug development, with some drug candidates advancing to phase II/III stages. In this regard, glucose metabolism, i.e., the glycolytic pathway - that predominates the bio-energetic flux in tumors, and the associated mitochondrial metabolism have received the most attention as suitable "druggable" targets, focused either at the pathway enzymes or at the plasma-membrane-bound metabolite transporters. Outlined in this review are pre-clinical studies that have led to the discovery of promising drug candidates to target tumor-metabolic flux, and ensuing patents, with descriptions of the biochemical rationale for the combinatorial strategy of a particular metabolic pathway-drug candidate pair. PMID:21110820

  12. Prediction of Long-Term Benefits of Inhaled Steroids by Phenotypic Markers in Moderate-to-Severe COPD: A Randomized Controlled Trial

    PubMed Central

    Snoeck-Stroband, Jiska B.; Lapperre, Therese S.; Sterk, Peter J.; Hiemstra, Pieter S.; Thiadens, Henk A.; Boezen, H. Marike; ten Hacken, Nick H. T.; Kerstjens, Huib A. M.; Postma, Dirkje S.; Timens, Wim; Sont, Jacob K.

    2015-01-01

    Background The decline in lung function can be reduced by long-term inhaled corticosteroid (ICS) treatment in subsets of patients with chronic obstructive pulmonary disease (COPD). We aimed to identify which clinical, physiological and non-invasive inflammatory characteristics predict the benefits of ICS on lung function decline in COPD. Methods Analysis was performed in 50 steroid-naive compliant patients with moderate to severe COPD (postbronchodilator forced expiratory volume in one second (FEV1), 30–80% of predicted, compatible with GOLD stages II-III), age 45–75 years, >10 packyears smoking and without asthma. Patients were treated with fluticasone propionate (500 μg bid) or placebo for 2.5 years. Postbronchodilator FEV1, dyspnea and health status were measured every 3 months; lung volumes, airway hyperresponsiveness (PC20), and induced sputum at 0, 6 and 30 months. A linear mixed effect model was used for analysis of this hypothesis generating study. Results Significant predictors of attenuated FEV1-decline by fluticasone treatment compared to placebo were: fewer packyears smoking, preserved diffusion capacity, limited hyperinflation and lower inflammatory cell counts in induced sputum (p<0.04). Conclusions Long-term benefits of ICS on lung function decline in patients with moderate-to-severe COPD are most pronounced in patients with fewer packyears, and less severe emphysema and inflammation. These data generate novel hypotheses on phenotype-driven therapy in COPD. Trial Registration ClinicalTrials.gov NCT00158847 PMID:26659582

  13. Chronic cannabinoid exposure during adolescence leads to long-term structural and functional changes in the prefrontal cortex.

    PubMed

    Renard, Justine; Vitalis, Tania; Rame, Marion; Krebs, Marie-Odile; Lenkei, Zsolt; Le Pen, Gwenaëlle; Jay, Thérèse M

    2016-01-01

    In many species, adolescence is a critical phase in which the endocannabinoid system can regulate the maturation of important neuronal networks that underlie cognitive function. Therefore, adolescents may be more susceptible to the neural consequences of chronic cannabis abuse. We reported previously that chronically exposing adolescent rats to the synthetic cannabinoid agonist CP55,940 leads to impaired performances in adulthood i.e. long-lasting deficits in both visual and spatial short-term working memories. Here, we examined the synaptic structure and function in the prefrontal cortex (PFC) of adult rats that were chronically treated with CP55,940 during adolescence. We found that chronic cannabinoid exposure during adolescence induces long-lasting changes, including (1) significantly altered dendritic arborization of pyramidal neurons in layer II/III in the medial PFC (2) impaired hippocampal input-induced synaptic plasticity in the PFC and (3) significant changes in the expression of PSD95 (but not synaptophysin or VGLUT3) in the medial PFC. These changes in synaptic structure and function in the PFC provide key insight into the structural, functional and molecular underpinnings of long-term cognitive deficits induced by adolescent cannabinoid exposure. They suggest that cannabinoids may impede the structural maturation of neuronal circuits in the PFC, thus leading to impaired cognitive function in adulthood. PMID:26689328

  14. Fractionation of outdated freeze-dried plasma: a comparative study of cold- and heat-ethanol fractionation procedures.

    PubMed

    Schneider, W; Wolter, D; Shapiro, M; McCarty, L

    1979-01-01

    In a comparative study a total volume of 1435 kg outdated freeze-dried plasma, equivalent to approx. 200,000 kg liquid plasma, was fractionated into albumin (20%): about 30% of the total plasma volume was fractionated following the cold-ethanol procedure and about 70% following the heat-ethanol method. Average albumin recovery following cold-ethanol preparation was 47% of the albumin originally present in the freeze-dried plasma (= 50% of total protein); following heat-ethanol fractionation, 71%. Gelfiltration of heat-ethanol albumin showed a main peak (= 93%) representing albumin monomers and one slightly faster component (= 7%) representing albumin dimers. Gelfiltration of cold-ethanol isolated albumin on the other hand showed four peaks: albumin monomers (= 60%), albumin dimers (= 15%), and two other peaks representing higher molecular weight molecules (= 25%). Hemoglobin present in the reconstituted plasma was reduced about five-fold in the cold-ethanol product and about ten-fold in the heat-ethanol albumin. Stability tests of both products did not differ from equivalent products isolated from normal human plasma. Besides albumin, immunoglobulins may be isolated as Cohn fraction II-III prior to the heating procedure without significant albumin loss. PMID:88384

  15. Novel and emerging therapies for the treatment of polycythemia vera

    PubMed Central

    Verstovsek, Srdan; Komrokji, Rami S

    2016-01-01

    Polycythemia vera (PV) is a chronic myeloproliferative neoplasm defined by erythrocytosis and often accompanied by leukocytosis and thrombocytosis. Current treatment options, including IFN-α and hydroxyurea, effectively manage PV in many patients. However, some high-risk patients, particularly those who become hydroxyurea-intolerant/resistant, may benefit from IFN-α or new treatment options. A better understanding of PV pathophysiology, including the role of the JAK/STAT pathway, has inspired the development of new therapies. Several JAK inhibitors directly target JAK/STAT pathway activation and have been evaluated in Phase II/III trials with promising results. Pegylated variants of IFN-α, which reduce dosing frequency and toxicity associated with recombinant IFN-α, have yielded favorable efficacy results in Phase II trials. Finally, histone deacetylase inhibitors have been developed to manage PV at the level of chromatin-regulated gene expression. The earliest Phase III results from these next-generation therapies are expected in 2014. PMID:25353086

  16. Amolimogene bepiplasmid, a DNA-based therapeutic encoding the E6 and E7 epitopes from HPV, for cervical and anal dysplasia.

    PubMed

    Alvarez-Salas, Luis M

    2008-12-01

    MGI Pharma Biologics is developing amolimogene bepiplasmid as a potential therapy for HPV-associated diseases, including cervical dysplasia. Amolimogene bepiplasmid is a polymer-encapsulated DNA vaccine consisting of a plasmid expressing a chimeric peptide comprising immunogenic hybrid epitopes from HPV-16 and HPV-18 E6 and E7 proteins and an HLA-DRalpha intracellular trafficking peptide. In phase I and I/II clinical trials of ZYC-101 (the precursor of amolimogene bepiplasmid containing a single epitope from HPV-16 E7) in patients with cervical dysplasia and patients with anal dysplasia, ZYC-101 produced significant histological regression and was safe and well tolerated. Results from this trial led to a phase II clinical trial of amolimogene bepiplasmid in patients with cervical dysplasia. This phase II trial demonstrated that treatment with amolimogene bepiplasmid resolution of disease was not significantly superior to placebo except in the predefined group of women who were less than 25 years of age. A phase II/III clinical trial was ongoing at the time of publication examining amolimogene bepiplasmid in this patient population. PMID:19051140

  17. Damus-Kaye-Stansel Procedure with Extracardiac Fontan: Successful Recruitment of Previously Ligated Pulmonary Valve.

    PubMed

    Paczkowski, Konrad; Haponiuk, Ireneusz; Chojnicki, Maciej; Jaworski, Radosław

    2016-01-01

    We present a case of a 2.5-year-old-girl with complex congenital heart disease: tricuspid atresia (TA), bulboventricular septal defect (VSD), hypoplastic right ventricle, d-transposition of the great arteries (d-TGA) with aortic outflow from redundant RV. Due to II/III degree atrioventricular block induced after diagnostic cardiac catheterization, an epicardial pacemaker was implanted during the Glenn procedure. Because of severe left ventricle outflow tract obstruction, she was finally referred for extracardiac TCPC (extracardiac Fontan type) with recruitment of PV and Damus-Kaye-Stansel anastomosis. Intraoperatively, the pulmonary trunk stump was opened and a competent pulmonary valve with flaccid leaflets was found. Simple ligation of the pulmonary trunk with a preserved pulmonary valve enabled an effective aorto-pulmonary bridging of systemic outflow tract with the use of natural fully competent ventricle-arterial valves. The relief of single ventricle outflow tract obstruction led to final stabilization of spontaneous sinus rhythm recovery after 2 years of pacemaker stimulation. PMID:27585204

  18. Dynamics of Femtosecond Laser Ablation Plume Studied With Ultrafast X-ray Absorption Fine Structure Imaging

    SciTech Connect

    Oguri, Katsuya; Okano, Yasuaki; Nishikawa, Tadashi; Nakano, Hidetoshi

    2010-10-08

    We investigated the dynamic process of an expanding femtosecond laser ablation plume of aluminum generated in an irradiation intensity range of 10{sup 13}-10{sup 15} W/cm{sup 2} with the ultrafast x-ray absorption fine structure (XAFS) imaging technique. The XAFS spectra of the aluminum L{sub II,III} edge of the plume revealed that the plume consists of doubly and singly charged ions, neutral atoms, liquid particles, and possible atomic clusters. Scanning electron microscopy of deposited ablation particles confirmed that the liquid particles corresponds to the spherical nanoparticles with a size ranging from several tens nanometers to approximately 200 nm. The spatiotemporal evolution of the XAFS image of the plume shows the sequential appearance of each ablation particle from aluminum surface according to its ejection velocity. The result suggests that the photomechanical fragmentation process, which was theoretically proposed, is dominant mechanism for the nanoparticle ejection under the irradiation intensity far from the ablation threshold of aluminum. This study clearly demonstrates the potential of our technique for measuring the ultrafast dynamics of femtosecond laser ablation process.

  19. Deletion and low expression of NFKBIA are associated with poor prognosis in lower-grade glioma patients

    PubMed Central

    Kinker, Gabriela Sarti; Thomas, Andrew Maltez; Carvalho, Vinicius Jardim; Lima, Felipe Prata; Fujita, André

    2016-01-01

    Lower-grade gliomas (LGGs), which are uniformly fatal in young adults, are classified as grades II-III tumors according to their histological features. The NFκB transcription factor, a crucial player in cancer initiation and progression, is inactivated in the cytoplasm by inhibitory proteins (IκBs) that have been shown to exert tumor-suppressor activity. Therefore, using The Cancer Genome Atlas copy number alteration and RNA-Seq data from 398 patients, we evaluated the association between the expression and dosage of NFKBIA, which encodes IκBα, and the overall malignancy of LGGs. Deletion and low expression of NFKBIA were associated with enhanced tumor aggressiveness and poor prognosis in LGGs. Accordingly, the dosage and expression of NFKBIA were independent prognostic factors for 5-year survival (dosage: P = 0.016; expression: P = 0.002) and 5-year recurrence-free survival (dosage: P = 0.009; expression: P = 0.005). Moreover, gene set enrichment analyses and co-expression network analyses indicated a role for NFKBIA in the negative regulation of cell proliferation, possibly through the modulation of downstream NFκB activation. Overall, the present findings reveal the prognostic value of NFKBIA in LGGs, reinforcing the relevance of NFκB signaling in the development and progression of gliomas. PMID:27052952

  20. Petroleum systems of the northwestern Tachira Depression, Venezuelan Andes

    SciTech Connect

    Ostos, M.; Callejon, A.; Vivan, M.A.

    1996-08-01

    The tectonic evolution and sedimentation of the Tachira Depression was controlled by Paleozoic crustal scale discontinuities, partly or fully inverted during the pre-Andean (Paleocene) and Andean (Neogene) deformations. Outcrop samples were analyzed for source rock evaluation. La Luna, Los Cuervos and Carbonera formations are excellent potential oil sources. However, La Luna and Los Cuervos were the oil-generating units according to ID-modelling (BasinMod), defining La Luna-K/T(!) and Los Cuervos-K/T(!) systems. La Luna contains good to excellent oil prone kerogen type I-II, while Los Cuervos contains gas-oil prone type II-III. Oil seeps, expelled at the peak of oil generation stage (0.85-0.90 %R{sub o}), were derived from marine sources and genetically correlated to La Luna. No correlation of seeps with Los Cuervos was found. Although it exists to the southeast (Burgua depression). Potential clastic and carbonatic Cretaceous (K) and Tertiary (T) reservoirs and regional seals of the Colon and Leon Formations are widespread in the depression. Modelling results indicate that migration started during the Middle Miocene, related to the Andean tectonic loading. The subsequent migration took place northward, to be finally stopped against the Capacho and Bocono fault systems.

  1. Petroleum systems of the Burgua Depression, Tachira and Apure states, Venezuelan Andes

    SciTech Connect

    Ostos, M.; Yoris, F.; Callejon, A.

    1996-08-01

    The Burgua Depression (southeast extension of the Tachira Depression) underwent a severe subsidence during the Andean orogeny. Its tectonosedimentary evolution was controlled by Paleozoic discontinuities. The sedimentary sequence contains Jurassic/Lower Cretaceous syn-rifting transgressive rocks, synDeformational Paleocene/Eocene and Neogene rocks. Deformation is diachronic from SE (Oligocene) to NW (Pleistocene). From oil-rock correlation data, Navay and Los Cuervos samples render excellent potential source rocks. The analyses indicate a marine algal-bacterial organic matter source for Navay and higher plants for Los Cuervos, which plot as moderate yield type II kerogen and low yield type II-III, respectively. Although, the samples are immature (0.50-0.55% R6), ID modelling (BasinMod) suggests that they reached maturation during the Andean orogeny. Oil seeps correlate with Navay and Los Cuervos and were expelled at the peak of oil generation (0.85-0.90% R{sub o}). These source rocks define the Navay-K/T(!) and Los Cuervos-K/T(!) petroleum systems. Potential clastic and carbonatic reservoirs were identified in surface and wells. The Guafita Formation is the regional seal, never extending northward of the Brujas High. Modelling indicates that migration started during late Pliocene and took place northward and south/southeastward of the Andean foredeep.

  2. Survival outcomes after stereotactic body radiotherapy for 79 Japanese patients with hepatocellular carcinoma.

    PubMed

    Yamashita, Hideomi; Onishi, Hiroshi; Murakami, Naoya; Matsumoto, Yasuo; Matsuo, Yukinori; Nomiya, Takuma; Nakagawa, Keiichi

    2015-05-01

    Stereotactic body radiotherapy (SBRT) is a relatively new treatment for liver tumor. Outcomes of SBRT for liver tumors unsuitable for ablation or surgical resection were evaluated. A total of 79 patients treated with SBRT for primary hepatocellular carcinoma (HCC) between 2004 and 2012 in six Japanese institutions were studied retrospectively. Patients treated with SBRT preceded by trans-arterial chemoembolization were eligible. Their median age was 73 years, 76% were males, and their Child-Pugh scores were Grades A (85%) and B (11%) before SBRT. The median biologically effective dose (α/β = 10 Gy) was 96.3 Gy. The median follow-up time was 21.0 months for surviving patients. The 2-year overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival were 53%, 40% and 76%, respectively. Sex and serum PIVKA-II values were significant predictive factors for OS. Hypovascular or hypervascular types of HCC, sex and clinical stage were significant predictive factors for PFS. The 2-year PFS was 66% in Stage I vs 18% in Stages II-III. Multivariate analysis indicated that clinical stage was the only significant predictive factor for PFS. No Grade 3 laboratory toxicities in the acute, sub-acute, and chronic phases were observed. PFS after SBRT for liver tumor was satisfactory, especially for Stage I HCC, even though these patients were unsuitable for resection and ablation. SBRT is safe and might be an alternative to resection and ablation. PMID:25691453

  3. Molecular characterization and expression profile of the estrogen receptor α gene during different reproductive phases in Monopterus albus.

    PubMed

    Ding, Weidong; Cao, Liping; Cao, Zheming; Bing, Xuwen; Zhao, Fazhen

    2016-01-01

    To understand the molecular mechanism of estrogen and to evaluate the role of the estrogen receptor in mediating estrogen action, the full-length cDNA of estrogen receptor α (ERα) was cloned from Monopterus albus, and its expression pattern and distribution were investigated. The ERα cDNA of M. albus includes an open reading frame of 1863 bp, a 140-bp 5'-untranslated region and a 797-bp 3'-untranslated region. Amino acid sequence homology analysis showed that the Monopterus albus ERα has a moderate degree of similarity with Sebastes schlegelii, Zoarces viviparus and Haplochromis burtoni (81.1%, 80.7% and 80.4%, respectively). Quantitative PCR results showed that the highest level of ERα expression was in the liver; the next highest level of expression was observed in the gonads, where it was expressed at high levels particularly in the ovary in developmental stages IV and V and in the testis in developmental stage II/III. Immunohistochemistry analysis showed that ERα was present as slender particles distributed mainly in the membranes of spermatocytes and oocytes in the testis and ovary, whereas no positive signal was observed in the cytoplasm of sperm cells. This report describes the first molecular characterization of full-length ERα and its tissue-specific distribution in M. albus. PMID:27295422

  4. Mitochondrial Disorders May Mimic Amyotrophic Lateral Sclerosis at Onset.

    PubMed

    Finsterer, Josef; Zarrouk-Mahjoub, Sinda

    2016-02-01

    Similarities between a mitochondrial disorder (MID) and amyotrophic lateral sclerosis (ALS) fade with disease progression and the development of mitochondrial multiple organ dysfunction syndrome (MIMODS). However, with mild MIMODS, a MID may still be misinterpreted as ALS. We report a 48-year-old male who presented to the Neurological Hospital Rosenhügel, Vienna, Austria, in February 2001 with slowly progressive weakness, wasting and left upper limb fasciculations which spread to the shoulder girdle and lower limbs. Additionally, he developed tetraspasticity and bulbar involvement. He had been diagnosed with ALS a year previously due to electrophysiological investigations indicative of a chronic neurogenic lesion. However, a muscle biopsy revealed morphological features of a MID and a combined complex-II/III defect. Nerve conduction studies were performed over subsequent years until February 2011. This case demonstrates that MIDs may mimic ALS at onset and begin as a mono-organ disorder but develop into a multi-organ disease with long-term progression. A combined complex II/III defect may manifest with bulbar involvement. PMID:26909222

  5. Complexity of Compensatory Effects in Nrf1 Knockdown: Linking Undeveloped Anxiety-Like Behavior to Prevented Mitochondrial Dysfunction and Oxidative Stress.

    PubMed

    Khalifeh, Solmaz; Oryan, Shahrbanoo; Khodagholi, Fariba; Digaleh, Hadi; Shaerzadeh, Fatemeh; Maghsoudi, Nader; Zarrindast, Mohammad-Reza

    2016-05-01

    Anxiety-related disorders are complex illnesses that underlying molecular mechanisms need to be understood. Mitochondria stand as an important link between energy metabolism, oxidative stress, and anxiety. The nuclear factor, erythroid-derived 2,-like 1(Nrf1) is a member of the cap "n" collar subfamily of basic region leucine zipper transcription factors and plays the major role in regulating the adaptive response to oxidants and electrophiles within the cell. Here, we injected small interfering RNA (siRNA) targeting Nrf1 in dorsal third ventricle of adult male albino Wistar rats and subsequently examined the effect of this silencing on anxiety-related behavior. We also evaluated apoptotic markers and mitochondrial biogenesis factors, along with electron transport chain activity in three brain regions: hippocampus, amygdala, and prefrontal cortex. Our data revealed that in the group that received Nrf1-siRNA, anxiety-related behavior did not show any significant changes compared to the control group. Caspase-3 did not increase in Nrf1-siRNA-injected rats even though Bax/Bcl2 ratio markedly elevated in Nrf1-knockdown rats in all three mentioned regions compared to control rats. Also, Nrf1 silencing of complex I and II-III did not alter, generally. In addition, Nrf1-knockdown affected mitochondrial biogenesis markers. The level of peroxisome proliferator-activated receptor gamma coactivator-1α and cytochrome-c increased, which indicates a possible role for mitochondrial biogenesis in anxiety. PMID:26202310

  6. Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization.

    PubMed

    Achenbach, Peter; Barker, Jennifer; Bonifacio, Ezio

    2008-04-01

    Mucosal administration of insulin represents an attractive antigen-specific therapeutic approach to preventing type 1 diabetes. It can prevent autoimmune diabetes in animal models, but although it has been shown to be safe, it has not yet been proven effective in human studies. Efficacy may depend on the dose and route at which insulin is administered, the stage in type 1 diabetes pathogenesis at which treatment is initiated, and the study cohort that is treated. We have proposed Pre-POINT (Primary Oral/intranasal INsulin Trial), a dose-finding safety and immune efficacy pilot study for primary mucosal insulin therapy in islet autoantibody-negative children at high genetic risk for type 1 diabetes who naturally first develop autoimmunity to insulin. Pre-POINT aims to identify an optimal insulin dose and route of application (orally or intranasally) that is well tolerated and can induce an immune response to insulin for additional use in a phase II/III primary prevention trial in children at risk. PMID:18445349

  7. Exposure to the Synthetic Progestin, 17α-Hydroxyprogesterone Caproate During Development Impairs Cognitive Flexibility in Adulthood.

    PubMed

    Willing, Jari; Wagner, Christine K

    2016-01-01

    The synthetic progestin, 17α-hydroxyprogesterone caproate, is increasingly used for the prevention of premature birth in at-risk women, despite little understanding of the potential effects on the developing brain. Rodent models suggest that many regions of the developing brain are sensitive to progestins, including the mesocortical dopamine pathway, a neural circuit important for complex cognitive behaviors later in life. Nuclear progesterone receptor is expressed during perinatal development in dopaminergic cells of the ventral tegmental area that project to the medial prefrontal cortex. Progesterone receptor is also expressed in the subplate and in pyramidal cell layers II/III of medial prefrontal cortex during periods of dopaminergic synaptogenesis. In the present study, exposure to 17α-hydroxyprogesterone caproate during development of the mesocortical dopamine pathway in rats altered dopaminergic innervation of the prelimbic prefrontal cortex and impaired cognitive flexibility with increased perseveration later in life, perhaps to a greater extent in males. These studies provide evidence for developmental neurobehavioral effects of a drug in widespread clinical use and highlight the need for a reevaluation of the benefits and potential outcomes of prophylactic progestin administration for the prevention of premature delivery. PMID:26556535

  8. MRI parcellation of ex vivo medial temporal lobe.

    PubMed

    Augustinack, Jean C; Magnain, Caroline; Reuter, Martin; van der Kouwe, André J W; Boas, David; Fischl, Bruce

    2014-06-01

    Recent advancements in radio frequency coils, field strength and sophisticated pulse sequences have propelled modern brain mapping and have made validation to biological standards - histology and pathology - possible. The medial temporal lobe has long been established as a pivotal brain region for connectivity, function and unique structure in the human brain, and reveals disconnection in mild Alzheimer's disease. Specific brain mapping of mesocortical areas affected with neurofibrillary tangle pathology early in disease progression provides not only an accurate description for location of these areas but also supplies spherical coordinates that allow comparison between other ex vivo cases and larger in vivo datasets. We have identified several cytoarchitectonic features in the medial temporal lobe with high resolution ex vivo MRI, including gray matter structures such as the entorhinal layer II 'islands', perirhinal layer II-III columns, presubicular 'clouds', granule cell layer of the dentate gyrus as well as lamina of the hippocampus. Localization of Brodmann areas 28 and 35 (entorhinal and perirhinal, respectively) demonstrates MRI based area boundaries validated with multiple methods and histological stains. Based on our findings, both myelin and Nissl staining relate to contrast in ex vivo MRI. Precise brain mapping serves to create modern atlases for cortical areas, allowing accurate localization with important applications to detecting early disease processes. PMID:23702414

  9. Dopaminergic Modulation of Excitatory Transmission in the Anterior Cingulate Cortex of Adult Mice

    PubMed Central

    Darvish-Ghane, Soroush; Yamanaka, Manabu

    2016-01-01

    Dopamine (DA) possesses potent neuromodulatory properties in the central nervous system. In the anterior cingulate cortex, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPAR) are key ion channels in mediating nerve injury induced long-term potentiation (LTP) and chronic pain phenotype. In the present study, we reported the effects of DA on glutamate mediated excitatory post-synaptic currents (EPSCs) in pyramidal neurons of layer II/III of the ACC in adult mice. Bath application of DA (50 μM) caused a significant, rapid and reversible inhibition of evoked EPSCs (eEPSC). This inhibitory effect is dose-related and was absent in lower concentration of DA (5 μM). Furthermore, selective postsynaptic application of GDP-β-S (1.6 mM) in the internal solution completely abolished the inhibitory effects of DA (50 μM). We also investigated modulation of spontaneous EPSCs (sEPSCs) and TTX sensitive, miniature EPSCs (mEPSCs) by DA. Our results indicated mixed effects of potentiation and inhibition of frequency and amplitude for sEPSCs and mEPSCs. Furthermore, high doses of SCH23390 (100 μM) and sulpiride (100 μM) revealed that, inhibition of eEPSCs is mediated by postsynaptic D2-receptors (D2R). Our finding posits a pre- and postsynaptic mode of pyramidal neuron EPSC modulation in mice ACC by DA. PMID:27317578

  10. Evaluation of the In Vivo and In Vitro Effects of Fructose on Respiratory Chain Complexes in Tissues of Young Rats.

    PubMed

    Macongonde, Ernesto António; Vilela, Thais Ceresér; Scaini, Giselli; Gonçalves, Cinara Ludvig; Ferreira, Bruna Klippel; Costa, Naithan Ludian Fernandes; de Oliveira, Marcos Roberto; Avila Junior, Silvio; Streck, Emilio Luiz; Ferreira, Gustavo Costa; Schuck, Patrícia Fernanda

    2015-01-01

    Hereditary fructose intolerance (HFI) is an autosomal-recessive disorder characterized by fructose and fructose-1-phosphate accumulation in tissues and biological fluids of patients. This disease results from a deficiency of aldolase B, which metabolizes fructose in the liver, kidney, and small intestine. We here investigated the effect of acute fructose administration on the activities of mitochondrial respiratory chain complexes, succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) in cerebral cortex, liver, kidney, and skeletal muscle of male 30-day-old Wistar rats. The rats received subcutaneous injection of sodium chloride (0.9%; control group) or fructose solution (5 μmol/g; treated group). One hour later, the animals were euthanized and the cerebral cortex, liver, kidney, and skeletal muscle were isolated and homogenized for the investigations. Acute fructose administration increased complex I-III activity in liver. On the other hand, decreased complexes II and II-III activities in skeletal muscle and MDH in kidney were found. Interestingly, none of these parameters were affected in vitro. Our present data indicate that fructose administration elicits impairment of mitochondrial energy metabolism, which may contribute to the pathogenesis of the HFI patients. PMID:26770008

  11. Four-phase or two-phase signal plan? A study on four-leg intersection by cellular automaton simulations

    NASA Astrophysics Data System (ADS)

    Jin, Cheng-Jie; Wang, Wei; Jiang, Rui

    2016-08-01

    The proper setting of traffic signals at signalized intersections is one of the most important tasks in traffic control and management. This paper has evaluated the four-phase traffic signal plans at a four-leg intersection via cellular automaton simulations. Each leg consists of three lanes, an exclusive left-turn lane, a through lane, and a through/right-turn lane. For a comparison, we also evaluate the two-phase signal plan. The diagram of the intersection states in the space of inflow rate versus turning ratio has been presented, which exhibits four regions: In region I/II/III, congestion will propagate upstream and laterally and result in queue spillover with both signal plans/two-phase signal plan/four-phase signal plan, respectively. Therefore, neither signal plan works in region I, and only the four-phase signal plan/two-phase signal plan works in region II/III. In region IV, both signal plans work, but two-phase signal plan performs better in terms of average delays of vehicles. Finally, we study the diagram of the intersection states and average delays in the asymmetrical configurations.

  12. German Translation and Validation of the “Freezing of Gait Questionnaire” in Patients with Parkinson's Disease

    PubMed Central

    Vogler, Anina; Janssens, Jorina; Nyffeler, Thomas; Bohlhalter, Stephan; Vanbellingen, Tim

    2015-01-01

    Background. Freezing of Gait (FOG) is a disabling parkinsonian symptom. The Freezing of Gait Questionnaire (FOG-Q) reliably detects FOG in patients with Parkinson's disease (PD). Objectives. The aim of this study was to develop a German translated version of the FOG-Q and to assess its validity. Methods. The translation was accomplished using forward-backward-translation. The construct validity of the FOG-Q was examined in twenty-seven German native speaking PD patients. Convergent validity was assessed by correlating the FOG-Q with the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) II-III, the Parkinson Disease Questionnaire 39 (PDQ-39), and the Timed Up and Go Test (TUG). Divergent validity was assessed by correlating the FOG-Q with the MDS-UPDRS I. The internal consistency was measured using Cronbach's alpha (Cα). Results. A good internal structure of the FOG-Q was found (Cα = 0.83). Significant moderate correlations between the FOG-Q and the MDS-UPDRS item 2.13 (freezing) (rs = 0.568, P = 0.002) and between the FOG-Q and the PDQ-39 subscale mobility (rs = 0.516, P = 0.006) were found. The lack of correlation with the MDS-UPDRS I demonstrated good divergent validity. Conclusion. The German FOG-Q is a valid tool to assess FOG in German native speaking PD patients. PMID:25705546

  13. Evaluation of the In Vivo and In Vitro Effects of Fructose on Respiratory Chain Complexes in Tissues of Young Rats

    PubMed Central

    Macongonde, Ernesto António; Vilela, Thais Ceresér; Scaini, Giselli; Gonçalves, Cinara Ludvig; Ferreira, Bruna Klippel; Costa, Naithan Ludian Fernandes; de Oliveira, Marcos Roberto; Avila, Silvio; Streck, Emilio Luiz; Ferreira, Gustavo Costa; Schuck, Patrícia Fernanda

    2015-01-01

    Hereditary fructose intolerance (HFI) is an autosomal-recessive disorder characterized by fructose and fructose-1-phosphate accumulation in tissues and biological fluids of patients. This disease results from a deficiency of aldolase B, which metabolizes fructose in the liver, kidney, and small intestine. We here investigated the effect of acute fructose administration on the activities of mitochondrial respiratory chain complexes, succinate dehydrogenase (SDH), and malate dehydrogenase (MDH) in cerebral cortex, liver, kidney, and skeletal muscle of male 30-day-old Wistar rats. The rats received subcutaneous injection of sodium chloride (0.9%; control group) or fructose solution (5 μmol/g; treated group). One hour later, the animals were euthanized and the cerebral cortex, liver, kidney, and skeletal muscle were isolated and homogenized for the investigations. Acute fructose administration increased complex I-III activity in liver. On the other hand, decreased complexes II and II-III activities in skeletal muscle and MDH in kidney were found. Interestingly, none of these parameters were affected in vitro. Our present data indicate that fructose administration elicits impairment of mitochondrial energy metabolism, which may contribute to the pathogenesis of the HFI patients. PMID:26770008

  14. TOTALLY LAPAROSCOPIC LIVER RESECTION: NEW BRAZILIAN EXPERIENCE

    PubMed Central

    LACERDA, Croider Franco; BERTULUCCI, Paulo Anderson; de OLIVEIRA, Antônio Talvane Torres

    2014-01-01

    Background Despite the increasing number of laparoscopic hepatectomy, there is little published experience. Aim To evaluate the results of a series of hepatectomy completely done with laparoscopic approach. Methods This is a retrospective study of 61 laparoscopic liver resections. Were studied conversion to open technique; mean age; gender, mortality; complications; type of hepatectomy; surgical techniques applied; and simultaneous operations. Results The conversion to open technique was necessary in one case (1.6%). The mean age was 54.7 years (17-84), 34 were men. Three patients (4.9%) had complications. One died postoperatively (mortality 1.6%) and no deaths occurred intraoperatively. The most frequent type was right hepatectomy (37.7%), followed by bisegmentectomy (segments II-III and VI-VII). Were not used hemi-Pringle maneuvers or assisted technic. Six patients (8.1%) underwent simultaneous procedures (hepatectomy and colectomy). Conclusion Laparoscopic hepatectomy is feasible procedure and can be considered the gold standard for various conditions requiring liver resections for both benign to malignant diseases. PMID:25184770

  15. [Combination therapy with S-1 and CDDP for head and neck cancer].

    PubMed

    Fujii, Masato

    2006-06-01

    The combination with cisplatin (CDDP) and 5-FU is considered the first choice chemotherapy for squamous cell carcinoma of the head and neck (HNSCC). S-1, a modulation of tegafur developed in Japan, is an active agent for HNSCC. Some clinical phase I/II studies about the combination with CDDP and S-1 have been reported. The combination showed a good response rate of 67.6% for advanced and recurrent HNSCC in our clinical phase I/II study. The regimens of S-1 combined with carboplatin or nedaplatin have also been reported. Regimens containing S-1 appear to have been effective for HNSCC. Multi-institutional phase II studies with a large sample size are needed in the future. The compliance for patients is better than a 5-FU injection because S-1 is orally administrated. The adverse effect, especially for bone mallow toxicity, is equal or upgraded compared with a 5-FU injection. The efficacy and adverse effects of CDDP plus S-1 should be studied in carefully designed phase II/III trials. S-1 will be one of the key drugs for HNSCC in the future. PMID:16897992

  16. Validation of an ELISA for the quantitation of lanoteplase, a novel plasminogen activator.

    PubMed

    Stouffer, B; Habte, S; Vachharajani, N; Tay, L

    1999-11-01

    An ELISA was developed and validated for the quantitation of lanoteplase in human citrated plasma. The ELISA employed a monoclonal anti-lanoteplase antibody absorbed onto 96-well microtiter plates to capture lanoteplase in citrated human plasma samples containing PPACK, a protease inhibitor. The captured lanoteplase was detected using a biotinylated rabbit anti-lanoteplase polyclonal antibody. The standard curve range in human plasma for the ELISA was 7-100 ng/ml. Assessment of individual standard curve variability indicated reproducible responses with r2 values of > or = 0.985. The accuracy (% DEV) and precision (%RSD) estimates for the ELISA based on the predicted values from quality control (QC) samples were within 7.3% and 11%, respectively. Cross-reactivity with t-PA was determined to be less than 11% by ELISA. The stability of lanoteplase was established in human citrated PPACK plasma for 24 hours at 4 degrees C, for 2 months at -20 degrees C, for 22 months at -70 degrees C, three weeks at room temperature, and through four freeze/thaw cycles. To quantify lanoteplase plasminogen activator (PA) activity, a commercially available chromogenic activity assay was also validated. This method and its application is described briefly here. The lanoteplase ELISA as well as the commercial activity method were successfully employed to evaluate the pharmacokinetic parameters of lanoteplase in support of clinical Phase II/III studies. PMID:10595857

  17. FRETsg: Biomolecular structure model building from multiple FRET experiments

    NASA Astrophysics Data System (ADS)

    Schröder, G. F.; Grubmüller, H.

    2004-04-01

    Fluorescence energy transfer (FRET) experiments of site-specifically labelled proteins allow one to determine distances between residues at the single molecule level, which provide information on the three-dimensional structural dynamics of the biomolecule. To systematically extract this information from the experimental data, we describe a program that generates an ensemble of configurations of residues in space that agree with the experimental distances between these positions. Furthermore, a fluctuation analysis allows to determine the structural accuracy from the experimental error. Program summaryTitle of program: FRETsg Catalogue identifier: ADTU Program obtainable from: CPC Program Library, Queen's University of Belfast, N. Ireland Program summary URL:http://cpc.cs.qub.ac.uk/summaries/ADTU Computer: SGI Octane, Pentium II/III, Athlon MP, DEC Alpha Operating system: Unix, Linux, Windows98/NT/XP Programming language used: ANSI C No. of bits in a word: 32 or 64 No. of processors used: 1 No. of bytes in distributed program, including test data, etc.: 11407 No. of lines in distributed program, including test data, etc.: 1647 Distribution format: gzipped tar file Nature of the physical problem: Given an arbitrary number of distance distributions between an arbitrary number of points in three-dimensional space, find all configurations (set of coordinates) that obey the given distances. Method of solution: Each distance is described by a harmonic potential. Starting from random initial configurations, their total energy is minimized by steepest descent. Fluctuations of positions are chosen to generate distance distribution widths that best fit the given values.

  18. [THE CONTENT OF ELECTROLYTES IN DIFFERENT BIOLOGICAL MEDIUMS UNDER ACUTE CORONARY SYNDROME].

    PubMed

    Shalenkova, M A; Mikhailova, Z D; Maniukova, E T; Klimkin, P F; Korkotashvili, L V; Klemin, V A; Klemina, A V; Dolgov, V V

    2016-01-01

    The sampling of study included 172 patients with ischemic heart disease: 146 with acute coronary syndrome, including myocardial infarction (88 patients) and unstable stenocardia (58 patients); 26 patients with stable stenocardia functional class II-III. At the 1-3 day of hospitalization blood was taken of cubital vein. The mixed unstimulated saliva was selected. In both of them conte of calcium, sodium and potassium was tested (mmol/l). Under acute coronary syndrome, in blood content of calcium was 2. sodium--139.6 and potassium--4.5 i.e. the content was lower than in case of stable stenocardia (2.4; 139.8; 4.7 correspondingl In saliva under acute coronary syndrome higher content of calcium (1.05) and potassium (34.66) and lower content of sodiu (25.42) was established in comparison with stable stenocardia (0.81; 33.7; 28.08 correspondingly). The distribution coefficien (blood/saliva) of calcium, sodium and potassium were higher under myocardium infarction than under unstable stenocardia at uncomplicated course of acute coronary syndrome. PMID:27183724

  19. Early prediction of the response of breast tumors to neoadjuvant chemotherapy using quantitative MRI and machine learning.

    PubMed

    Mani, Subramani; Chen, Yukun; Arlinghaus, Lori R; Li, Xia; Chakravarthy, A Bapsi; Bhave, Sandeep R; Welch, E Brian; Levy, Mia A; Yankeelov, Thomas E

    2011-01-01

    The ability to predict early in the course of treatment the response of breast tumors to neoadjuvant chemotherapy can stratify patients based on response for patient-specific treatment strategies. Currently response to neoadjuvant chemotherapy is evaluated based on physical exam or breast imaging (mammogram, ultrasound or conventional breast MRI). There is a poor correlation among these measurements and with the actual tumor size when measured by the pathologist during definitive surgery. We tested the feasibility of using quantitative MRI as a tool for early prediction of tumor response. Between 2007 and 2010 twenty consecutive patients diagnosed with Stage II/III breast cancer and receiving neoadjuvant chemotherapy were enrolled on a prospective imaging study. Our study showed that quantitative MRI parameters along with routine clinical measures can predict responders from non-responders to neoadjuvant chemotherapy. The best predictive model had an accuracy of 0.9, a positive predictive value of 0.91 and an AUC of 0.96. PMID:22195145

  20. Impact of gasless laparoscopy on circulation, respiration, stress response, and other complications in gynecological geriatrics

    PubMed Central

    Li, Sheng-Hua; Deng, Juan; Huang, Fa-Tian; Gan, Xiao-We; Cao, Yun-Gui

    2014-01-01

    This study aimed to explore the impact of gasless laparoscopy on circulation, respiration, stress response and other complications in gynecological surgery for old female patients. 40 patients (American Society of Anesthesiologists II-III, 60-70y) scheduled for elective gynecological laparoscopy were divided into non-pneumoperitoneum group (NP) and pneumoperitoneum group (P). All patients included were monitored for Compliance, Ppeak, Ppalt, MAP, CVP, HR, SpO2, blood gas analysis (pH, PaCO2, and PaO2), serum cortisol, TNF-α, and IL-6. There were significant differences in bowel tones recovery, postoperative shoulder pain, nausea, and vomiting between two groups (P < 0.05). In the P group, the levels of CVP, and Ppeak and Ppalt at both 10 minutes and 30 minutes after suspension/pneumoperitoneum were significantly higher than those in NP group (P < 0.05). When it came to Compliance, this trend was reversed (P < 0.05). As surgery was conducted, the plasma concentrations of cortisol, IL-6 and TNF-α in the P group were higher than those in the NP group (P < 0.05). Thus, for gynecological diseases of geriatrics, the effect on respiratory and circulatory function is less significant of gasless laparoscopy than in pneumoperitoneum. The stress response, recovery of bowl tone, should pain, nausea, and vomiting after surgery in gasless laparoscopy is improved than in pneumoperitoneum. PMID:25356152

  1. Favorable long-term outcome of patients with multiple myeloma using a frontline tandem approach with autologous and non-myeloablative allogeneic transplantation.

    PubMed

    Ahmad, I; LeBlanc, R; Cohen, S; Lachance, S; Kiss, T; Sauvageau, G; Roy, D C; Busque, L; Delisle, J-S; Bambace, N; Bernard, L; Sabry, W; Roy, J

    2016-04-01

    Despite survival improvement with novel agents and use of autologous hematopoietic stem cell transplantation (HSCT), cure of patients with multiple myeloma (MM) remains anecdotal. Initial observations suggested that chronic GvHD was accompanied by an anti-myeloma effect after myeloablative HSCT, but unfortunately this procedure was hampered by high non-relapse mortality (NRM). To maximize the anti-myeloma effect and minimize NRM, we developed a non-myeloablative (NMA) regimen associated with a high incidence of chronic GvHD and tested its efficacy on patient survival and disease eradication. From 2001 to 2010, 92 patients aged⩽65 years with a compatible sibling donor received autologous HSCT followed by an outpatient NMA allogeneic HSCT using a conditioning of fludarabine and cyclophosphamide. Patient median age was 52 years and 97% presented Durie-Salmon stages II-III disease. After a median follow-up of 8.8 years, probability of 10-year progression free and overall survival were 41% and 62%, respectively. Although the cumulative incidence of extensive chronic GvHD was high (at 79%), the majority of long-term survivors were off immunosuppressive drugs by year 5 and NRM was low (at 10%). Together, our results suggest that potential MM cure can be achieved with NMA transplantation regimens that maximize graft-versus-myeloma effect and minimize NRM. PMID:26691426

  2. Onset of complications following cervical manipulation due to malpractice in osteopathic treatment: a case report.

    PubMed

    Cicconi, Michela; Mangiulli, Tatiana; Bolino, Giorgio

    2014-10-01

    The aim of this study is to correlate cervical disc herniation with manipulation performed by a non-physician osteopath on a patient complaining of neck pain. The authors report a case in which a woman - treated with osteopathic spinal manipulation - developed cervical-brachial neuralgia following the cervical disc herniation. The patient then underwent surgery and was followed by physiotherapists. A clinical condition characterized by limitation of neck mobility, with pain and sensory deficit in the right arm and II-III fingers, still persists. The patient consulted the authors to establish whether cervical disc herniation could be attributed to manipulation. Adverse events or side effects of spinal manipulative therapy are relatively common and usually benign. Most of these side effects are mild or moderate, but sometimes they can be severe. Cervical manipulation can provoke complications less often than thoracic or lumbar manipulation. Furthermore, many diseases can be absolutely and relatively contraindicated to osteopathic treatment. Therefore, the knowledge of a patient's clinical conditions is essential before starting a manipulative treatment; otherwise the osteopath could be accused of malpractice. It is the authors' opinion that a cause-effect relationship exists between the manipulative treatment and the development of disc herniation. PMID:24402084

  3. Recent advances in the mangement of multiple myeloma.

    PubMed

    Kumar, Lalit; Vikram, P; Kochupillai, V

    2006-01-01

    The management of multiple myeloma has undergone a major change during the past decade. Currently, patients < 65 years of age with advanced disease (stage II-III) are best treated with initial chemotherapy (3-4 cycles of vincristine, adriamycin and dexamethasone, or vincristine, adriamycin and methyl prednisolone, or thalidomide and dexamethasone followed by high dose chemotherapy with autologous peripheral blood stem cell transplantation. More than 50% of patients achieve complete response following this approach. The results of a number of nonrandomized and randomized studies indicate that treatment with high dose chemotherapy followed by autologous peripheral blood stem cell transplantation is associated with improved overall and event-free survival compared with conventional chemotherapy. The absence of chromosome 13 abnormalities, serum albumin levels > 3.5 g/dl and low serum b-2 microglobulin are associated with a better outcome. Almost all patients with significant bone disease or osteoporosis are candidates for therapy with bisphosphonates. About one-third of patients with relapsed or refractory myeloma benefit from therapy with thalidomide or bortezomib (a proteosome inhibitor). Recent work in the immunotherapy of myeloma suggests that some novel immune-based approaches might be useful in the management. The application of cytogenetics and molecular genetics, especially gene expression profiling, are likely to be areas of active research in future studies. PMID:16756196

  4. Stage migration vs immunology: The lymph node count story in colon cancer

    PubMed Central

    Märkl, Bruno

    2015-01-01

    Lymph node staging is of crucial importance for the therapy stratification and prognosis estimation in colon cancer. Beside the detection of metastases, the number of harvested lymph nodes itself has prognostic relevance in stage II/III cancers. A stage migration effect caused by missed lymph node metastases has been postulated as most likely explanation for that. In order to avoid false negative node staging reporting of at least 12 lymph nodes is recommended. However, this threshold is met only in a minority of cases in daily practice. Due to quality initiatives the situation has improved in the past. This, however, had no influence on staging in several studies. While the numbers of evaluated lymph nodes increased continuously during the last decades the rate of node positive cases remained relatively constant. This fact together with other indications raised doubts that understaging is indeed the correct explanation for the prognostic impact of lymph node harvest. Several authors assume that immune response could play a major role in this context influencing both the lymph node detectability and the tumor’s behavior. Further studies addressing this issue are need. Based on the findings the recommendations concerning minimal lymph node numbers and adjuvant chemotherapy should be reconsidered. PMID:26604632

  5. Metallography and microstructure interpretation of some archaeological tin bronze vessels from Iran

    SciTech Connect

    Oudbashi, Omid; Davami, Parviz

    2014-11-15

    Archaeological excavations in western Iran have recently revealed a significant Luristan Bronzes collection from Sangtarashan archaeological site. The site and its bronze collection are dated to Iron Age II/III of western Iran (10th–7th century BC) according to archaeological research. Alloy composition, microstructure and manufacturing technique of some sheet metal vessels are determined to reveal metallurgical processes in western Iran in the first millennium BC. Experimental analyses were carried out using Scanning Electron Microscopy–Energy Dispersive X-ray Spectroscopy and Optical Microscopy/Metallography methods. The results allowed reconstructing the manufacturing process of bronze vessels in Luristan. It proved that the samples have been manufactured with a binary copper–tin alloy with a variable tin content that may relates to the application of an uncontrolled procedure to make bronze alloy (e.g. co-smelting or cementation). The presence of elongated copper sulphide inclusions showed probable use of copper sulphide ores for metal production and smelting. Based on metallographic studies, a cycle of cold working and annealing was used to shape the bronze vessels. - Highlights: • Sangtarashan vessels are made by variable Cu-Sn alloys with some impurities. • Various compositions occurred due to applying uncontrolled smelting methods. • The microstructure represents thermo-mechanical process to shape bronze vessels. • In one case, the annealing didn’t remove the eutectoid remaining from casting. • The characteristics of the bronzes are similar to other Iron Age Luristan Bronzes.

  6. Temporal Lobe Sclerosis Associated with Hippocampal Sclerosis in Temporal Lobe Epilepsy: Neuropathological Features

    PubMed Central

    Thom, Maria; Eriksson, Sofia; Martinian, Lillian; Caboclo, Luis O.; McEvoy, Andrew W.; Duncan, John S.; Sisodiya, Sanjay M.

    2009-01-01

    Widespread changes involving neocortical as well as mesial temporal lobe structures can be present in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS). The incidence, pathology and clinical significance of neocortical temporal lobe sclerosis (TLS) are not well characterized. We identified TLS in 30 out of 272 surgically treated cases of HS. TLS was defined by variable reduction of neurons from cortical layers II/III and laminar gliosis; it was typically accompanied by additional architectural abnormalities of layer II, i.e. abnormal neuronal orientation and aggregation. Quantitative analysis including tessellation methods for the distribution of layer II neurons supported these observations. In 40% of cases there was a gradient of TLS with more severe involvement towards the temporal pole, possibly signifying involvement of hippocampal projection pathways. There was a history of a febrile seizure as an initial precipitating injury in 73% of patients with TLS compared to 36% without TLS; no other clinical differences TLS and non-TLS cases were identified. TLS was not evident pre-operatively by neuroimaging. No obvious effect of TLS on seizure outcome was noted after temporal lobe resection; 73% became seizure-free at 2 year follow up. In conclusion, approximately 11% of surgically treated HS is accompanied by TLS. TLS is likely an acquired process with accompanying re-organizational dysplasia and an extension of mesial temporal sclerosis rather than a separate pathological entity. PMID:19606061

  7. Glucitol-specific enzymes of the phosphotransferase system in Escherichia coli. Nucleotide sequence of the gut operon.

    PubMed

    Yamada, M; Saier, M H

    1987-04-25

    The complete nucleotide sequence of the glucitol (gut) operon in Escherichia coli has been determined. The glucitol-specific Enzyme II and Enzyme III of the phosphoenolpyruvate:sugar phosphotransferase system as well as glucitol-6-phosphate dehydrogenase which are encoded by the gutA, gutB, and gutD genes of the gut operon, respectively, are predicted to consist of 506 (Mr = 54,018), 123 (Mr = 13,306), and 259 (Mr = 27,866) amino acyl residues, respectively. The hydropathic profile of the Enzyme IIgut revealed 7 or 8 long hydrophobic segments which may traverse the cell membrane as alpha-helices as well as 2 or 4 short strongly hydrophobic stretches which may traverse the membrane as beta-structure. The number of amino acyl residues in the sum of the molecular weights of the glucitol Enzyme II-III pair are nearly the same as those of the mannitol Enzyme II. The ratio of hydrophobic to hydrophilic amino acyl residues and the numbers of the hydrophobic segments are also nearly the same for both transport systems. However, no significant homology was found in the nucleotide or amino acyl sequences of the two systems. Glucitol-6-phosphate dehydrogenase was found to exhibit sequence homology with ribitol dehydrogenase. A repetitive extragenic palindromic sequence was found in the 3'-flanking region of the gutD gene, suggesting the presence of a gene downstream from the gutD gene. PMID:3553176

  8. Human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine for the prevention of cervical cancer and HPV-related diseases.

    PubMed

    Skinner, S Rachel; Apter, Dan; De Carvalho, Newton; Harper, Diane M; Konno, Ryo; Paavonen, Jorma; Romanowski, Barbara; Roteli-Martins, Cecilia; Burlet, Nansa; Mihalyi, Attila; Struyf, Frank

    2016-01-01

    Vaccines are available against human papillomavirus (HPV), the causal agent of cervical and other cancers. Efficacy data from the HPV-16/18 AS04-adjuvanted vaccine clinical trial program were reviewed. Six randomized, controlled phase II/III trials evaluating cervical endpoints enrolled women from diverse populations and geographical locations. The program analyzed extensively the cohorts most relevant from a public health perspective: the total vaccinated cohort (TVC), approximating a general population including those with existing or previous HPV infection, and TVC-naïve, approximating a population of young women before sexual debut. Results show that the vaccine reduces HPV-16/18 infection and associated cervical endpoints in women regardless of age, location, or sexual experience. It provides cross-protection against some non-vaccine oncogenic HPV types and types causing genital warts, and may be effective against vulvar, oral, and anal HPV infection. Early epidemiology data following its introduction suggest a decline in the prevalence of vaccine and some non-vaccine HPV types. PMID:26902666

  9. Mechanical properties of organic matter in shales mapped at the nanometer scale

    NASA Astrophysics Data System (ADS)

    Eliyahu, M.; Emmanuel, S.; Day-Stirrat, R. J.; Macaulay, C.

    2014-12-01

    The mechanical properties of organic matter strongly influence the way in which shales deform and fracture. However, the response of organic matter to mechanical stresses is not well understood, representing a critical obstacle to assessing oil and gas production in shale formations. Little is known about the mechanical properties of organic matter in fine grained rocks primarily because it often occupies tiny nanometer-scale voids between the mineral grains which cannot be accessed using standard mechanical testing techniques. Here, we report on the use of a new atomic force microscopy technique (PeakForce QNM) to map the mechanical properties of organic and inorganic components at the nanometer scale. We find that the method can identify different phases such as pyrite, quartz, clays, and organic matter. Furthermore, within the organic component Young's modulus values ranged from 0 - 25 GPa; in 3 different samples - all of which come from thermally mature Type II/III source rocks in the dry gas window - a modal value of 15-16 GPa was measured, with additional peaks measured at ≤ 10 GPa. In addition, the maps suggest that some porous organic macerals possess a soft core surrounded by a harder outer shell 50 - 100 nm thick. Our results demonstrate that the method represents a powerful new petrographic tool with which to characterize the mechanical properties of organic-rich sedimentary rocks.

  10. Branching Ratios for The Radiometric Calibration of EUNIS-2012

    NASA Technical Reports Server (NTRS)

    Daw, Adrian N.; Bhatia, A. K.; Rabin, Douglas M.

    2012-01-01

    The Extreme Ultraviolet Normal Incidence Spectrograph (EUNIS) sounding rocket instrument is a two-channel imaging spectrograph that observes the solar corona and transition region with high spectral resolution and a rapid cadence made possible by unprecedented sensitivity. The upcoming flight will incorporate a new wavelength channel covering the range 524-630 Angstroms, the previously-flown 300-370 Angstroms channel, and the first flight demonstration of cooled active pixel sensor (APS) arrays. The new 524-630 Angstrom channel incorporates a Toroidal Varied Line Space (TVLS) grating coated with B4C/Ir, providing broad spectral coverage and a wide temperature range of 0.025 to 10 MK. Absolute radiometric calibration of the two channels is being performed using a hollow cathode discharge lamp and NIST-calibrated AXUV-100G photodiode. Laboratory observations of He I 584 Angstroms and He II 304 Angstroms provide absolute radiometric calibrations of the two channels at those two respective wavelengths by using the AXUV photodiode as a transfer standard. The spectral responsivity is being determined by observing line pairs with a common upper state in the spectra of Ne I-III and Ar II-III. Calculations of A-values for the observed branching ratios are in progress.

  11. Low Level of Microsatellite Instability Correlates with Poor Clinical Prognosis in Stage II Colorectal Cancer Patients

    PubMed Central

    Mojarad, Ehsan Nazemalhosseini; Kashfi, Seyed Mohammad Hossein; Mirtalebi, Hanieh; Taleghani, Mohammad Yaghoob; Azimzadeh, Pedram; Savabkar, Sanaz; Pourhoseingholi, Mohammad Amin; Jalaeikhoo, Hasan; Asadzadeh Aghdaei, Hamid; Kuppen, Peter J. K.; Zali, Mohammad Reza

    2016-01-01

    The influence of microsatellite instability (MSI) on the prognosis of colorectal cancer (CRC) requires more investigation. We assessed the role of MSI status in survival of individuals diagnosed with primary colorectal cancer. In this retrospective cross-sectional study the MSI status was determined in 158 formalin-fixed paraffin-embedded tumors and their matched normal tissues from patients who underwent curative surgery. Cox proportional hazard modeling was performed to assess the clinical prognostic significance. In this study we found that MSI-H tumors were predominantly located in the colon versus rectum (p = 0.03), associated with poorer differentiation (p = 0.003) and TNM stage II/III of tumors (p = 0.02). In CRC patients with stage II, MSI-L cases showed significantly poorer survival compared with patients who had MSI-H or MSS tumors (p = 0.04). This study indicates that MSI-L tumors correlate with poorer clinical outcome in patients with stage II tumors (p = 0.04) or in tumors located in the colon (p = 0.02). MSI-L characterizes a distinct subgroup of CRC patients who have a poorer outcome. This study suggests that MSI status in CRC, as a clinical prognostic marker, is dependent on other factors, such as tumor stage and location. PMID:27429617

  12. Single Cell Functional Proteomics for Assessing Immune Response in Cancer Therapy: Technology, Methods, and Applications

    PubMed Central

    Ma, Chao; Fan, Rong; Elitas, Meltem

    2013-01-01

    In the past decade, significant progresses have taken place in the field of cancer immunotherapeutics, which are being developed for most human cancers. New immunotherapeutics, such as Ipilimumab (anti-CTLA-4), have been approved for clinical treatment; cell-based immunotherapies such as adoptive cell transfer (ACT) have either passed the final stage of human studies (e.g., Sipuleucel-T) for the treatment of selected neoplastic malignancies or reached the stage of phase II/III clinical trials. Immunotherapetics has become a sophisticated field. Multimodal therapeutic regimens comprising several functional modules (up to five in the case of ACT) have been developed to provide focused therapeutic responses with improved efficacy and reduced side-effects. However, a major challenge remains: the lack of effective and clinically applicable immune assessment methods. Due to the complexity of antitumor immune responses within patients, it is difficult to provide comprehensive assessment of therapeutic efficacy and mechanism. To address this challenge, new technologies have been developed to directly profile the cellular immune functions and the functional heterogeneity. With the goal to measure the functional proteomics of single immune cells, these technologies are informative, sensitive, high-throughput, and highly multiplex. They have been used to uncover new knowledge of cellular immune functions and have been utilized for rapid, informative, and longitudinal monitoring of immune response in clinical anti-cancer treatment. In addition, new computational tools are required to integrate high-dimensional data sets generated from the comprehensive, single cell level measurements of patient’s immune responses to guide accurate and definitive diagnostic decision. These single cell immune function assessment tools will likely contribute to new understanding of therapy mechanism, pre-treatment stratification of patients, and ongoing therapeutic monitoring and assessment

  13. An antimicrobial peptide essential for bacterial survival in the nitrogen-fixing symbiosis.

    PubMed

    Kim, Minsoo; Chen, Yuhui; Xi, Jiejun; Waters, Christopher; Chen, Rujin; Wang, Dong

    2015-12-01

    In the nitrogen-fixing symbiosis between legume hosts and rhizobia, the bacteria are engulfed by a plant cell membrane to become intracellular organelles. In the model legume Medicago truncatula, internalization and differentiation of Sinorhizobium (also known as Ensifer) meliloti is a prerequisite for nitrogen fixation. The host mechanisms that ensure the long-term survival of differentiating intracellular bacteria (bacteroids) in this unusual association are unclear. The M. truncatula defective nitrogen fixation4 (dnf4) mutant is unable to form a productive symbiosis, even though late symbiotic marker genes are expressed in mutant nodules. We discovered that in the dnf4 mutant, bacteroids can apparently differentiate, but they fail to persist within host cells in the process. We found that the DNF4 gene encodes NCR211, a member of the family of nodule-specific cysteine-rich (NCR) peptides. The phenotype of dnf4 suggests that NCR211 acts to promote the intracellular survival of differentiating bacteroids. The greatest expression of DNF4 was observed in the nodule interzone II-III, where bacteroids undergo differentiation. A translational fusion of DNF4 with GFP localizes to the peribacteroid space, and synthetic NCR211 prevents free-living S. meliloti from forming colonies, in contrast to mock controls, suggesting that DNF4 may interact with bacteroids directly or indirectly for its function. Our findings indicate that a successful symbiosis requires host effectors that not only induce bacterial differentiation, but also that maintain intracellular bacteroids during the host-symbiont interaction. The discovery of NCR211 peptides that maintain bacterial survival inside host cells has important implications for improving legume crops. PMID:26598690

  14. Disturbance of energy and redox homeostasis and reduction of Na+,K+-ATPase activity provoked by in vivo intracerebral administration of ethylmalonic acid to young rats.

    PubMed

    Ritter, Luciana; Kleemann, Daniele; Hickmann, Fernanda Hermes; Amaral, Alexandre Umpierrez; Sitta, Ângela; Wajner, Moacir; Ribeiro, César Augusto João

    2015-05-01

    Ethylmalonic acid (EMA) accumulation occurs in various metabolic diseases with neurological manifestation, including short acyl-CoA dehydrogenase deficiency (SCADD) and ethylmalonic encephalopathy (EE). Since pathophysiological mechanisms responsible for brain damage in these disorders are still poorly understood, we investigated the ex vivo effects of acute intrastriatal administration of EMA on important parameters of energy and redox homeostasis in striatum from young rats. We evaluated CO(2) production from glucose, glucose utilization and lactate production, as well as the activities of the citric acid cycle (CAC) enzymes, the electron transfer chain (ETC) complexes II-IV (oxidative phosphorylation, OXPHOS) and synaptic Na(+),K(+)-ATPase. We also tested the effect of EMA on malondialdehyde (MDA) levels (marker of lipid oxidation) and reduced glutathione (GSH) levels. EMA significantly reduced CO(2) production, increased glucose utilization and lactate production, and reduced the activities of citrate synthase and of complexes II and II-III of the ETC, suggesting an impairment of CAC and OXPHOS. EMA injection also reduced Na(+),K(+)-ATPase activity and GSH concentrations, whereas MDA levels were increased. Furthermore, EMA-induced diminution of Na(+),K(+)-ATPase activity and reduction of GSH levels were prevented, respectively, by the antioxidants melatonin and N-acetylcysteine, indicating that reactive species were involved in these effects. Considering the importance of CAC and ETC for energy production and Na(+),K(+)-ATPase for the maintenance of the cell membrane potential, the present data indicate that EMA compromises mitochondrial homeostasis and neurotransmission in striatum. We presume that these pathomechanisms may be involved to a certain extent in the neurological damage found in patients affected by SCADD and EE. PMID:25583115

  15. Moderate Prenatal Alcohol Exposure Enhances GluN2B Containing NMDA Receptor Binding and Ifenprodil Sensitivity in Rat Agranular Insular Cortex

    PubMed Central

    Bird, Clark W.; Candelaria-Cook, Felicha T.; Magcalas, Christy M.; Davies, Suzy; Valenzuela, C. Fernando; Savage, Daniel D.; Hamilton, Derek A.

    2015-01-01

    Prenatal exposure to alcohol affects the expression and function of glutamatergic neurotransmitter receptors in diverse brain regions. The present study was undertaken to fill a current gap in knowledge regarding the regional specificity of ethanol-related alterations in glutamatergic receptors in the frontal cortex. We quantified subregional expression and function of glutamatergic neurotransmitter receptors (AMPARs, NMDARs, GluN2B-containing NMDARs, mGluR1s, and mGluR5s) by radioligand binding in the agranular insular cortex (AID), lateral orbital area (LO), prelimbic cortex (PrL) and primary motor cortex (M1) of adult rats exposed to moderate levels of ethanol during prenatal development. Increased expression of GluN2B-containing NMDARs was observed in AID of ethanol-exposed rats compared to modest reductions in other regions. We subsequently performed slice electrophysiology measurements in a whole-cell patch-clamp preparation to quantify the sensitivity of evoked NMDAR-mediated excitatory postsynaptic currents (EPSCs) in layer II/III pyramidal neurons of AID to the GluN2B negative allosteric modulator ifenprodil. Consistent with increased GluN2B expression, ifenprodil caused a greater reduction in NMDAR-mediated EPSCs from prenatal alcohol-exposed rats than saccharin-exposed control animals. No alterations in AMPAR-mediated EPSCs or the ratio of AMPARs/NMDARs were observed. Together, these data indicate that moderate prenatal alcohol exposure has a significant and lasting impact on GluN2B-containing receptors in AID, which could help to explain ethanol-related alterations in learning and behaviors that depend on this region. PMID:25747876

  16. Concurrent weekly cisplatin plus external beam radiotherapy and high-dose rate brachytherapy for advanced cervical cancer: A control cohort comparison with radiation alone on treatment outcome and complications

    SciTech Connect

    Chen, S.-W. . E-mail: vincent1680616@yahoo.com.tw; Liang, J.-A.; Hung, Y.-C.; Yeh, L.-S.; Chang, W.-C.; Lin, W.-C.; Yang, S.-N.; Lin, F.-J.

    2006-12-01

    Purpose: To test, though a control-cohort study, the hypothesis that concurrent chemoradiotherapy (CCRT) using weekly cisplatin, plus high-dose rate intracavitary brachytherapy (HDRICB) is superior to radiation (RT) alone in patients with advanced cervical cancer. Methods and Materials: A total of 171 patients with Stage IIB-III cervical cancer were enrolled in this study. Seventy patients were treated with CCRT and the results were compared with those of 101 patients who had been treated with RT using the same protocol at an early period. RT consisted of 45 Gy in 25 fractions to the whole pelvis, followed by a 12.6-Gy boost to the parametrium. Four courses of HDRICB using 6.0 Gy to Point A were performed. Chemotherapy consisted of weekly cisplatin at a dose of 40 mg/m{sup 2} for 5-6 cycles. Results: The 4-year actuarial survival was 74% for the CCRT group and 68% for the RT group (p = 0.60). The 4-year pelvic relapse-free survival was 87% for the CCRT group and 85% for the RT group (p = 0.37). The 4-year distant metastases-free survival was 75% for the CCRT group and 76% for the RT group (p = 0.44). The cumulative incidence of gastrointestinal and genitourinary injuries of grade 3 or above was 14.3% for the CCRT group and 7.9% for the RT group (p = 0.19). Conclusion: This study did not show a survival benefit of CCRT with weekly cisplatin and HDRICB for Stage II-III cervical cancer, nor did it demonstrate a significant increase of late complications when comparing with RT alone.

  17. Oligosaccharide Composition of Breast Milk Influences Survival of Uninfected Children Born to HIV-Infected Mothers in Lusaka, Zambia12

    PubMed Central

    Kuhn, Louise; Kim, Hae-Young; Hsiao, Lauren; Nissan, Caroline; Kankasa, Chipepo; Mwiya, Mwiya; Thea, Donald M; Aldrovandi, Grace M; Bode, Lars

    2015-01-01

    Background: Human milk oligosaccharides (HMOs) have multiple immunomodulatory functions that influence child health. Objective: In this study we investigated whether HMO composition influences survival to 2 y of age in HIV-infected and HIV-exposed, uninfected (HEU) children during and after breastfeeding. Methods: In the context of an early weaning trial in 958 HIV-infected women in Lusaka, Zambia, we conducted a nested case-cohort analysis of mortality to 2 y of age among 103 HIV-infected and 143 HEU children. Breast-milk samples collected at 1 mo postpartum were analyzed for HMO content. Samples were selected to include mothers of all HIV-infected children detected by 6 wk of age, of whom 63 died at <2 y of age; mothers of all HEU children who died at <2 y of age (n = 66); and a random sample of 77 HEU survivors. Associations before and after weaning in HIV-infected and HEU infants separately were investigated by using Cox models. Results: Among HEU children, higher maternal breast-milk concentrations of 2-linked fucosylated HMOs [2′-fucosyllactose and lacto-N-fucopentaose (LNFP) I] (HR: 0.33; 95% CI: 0.14, 0.74) as well as non–2-linked fucosylated HMOs (3-fucosyllactose and LNFP II/III; HR: 0.28; 95% CI: 0.13, 0.67) were significantly associated with reduced mortality during, but not after, breastfeeding after adjustment for confounders. Breastfeeding was protective against mortality only in HEU children with high concentrations of fucosylated HMOs. Among HIV-infected children, no consistent associations between HMOs and mortality were observed, but breastfeeding was protective against mortality. Conclusions: The oligosaccharide composition of breast milk may explain some of the benefits of breastfeeding in HEU children. HIV infection may modulate some of the consequences of HMOs on child survival. PMID:25527660

  18. Toward Semi-automated Assessment of Target Volume Delineation in Radiotherapy Trials: The SCOPE 1 Pretrial Test Case

    SciTech Connect

    Gwynne, Sarah; Spezi, Emiliano; Wills, Lucy; Nixon, Lisette; Hurt, Chris; Joseph, George; Evans, Mererid; Griffiths, Gareth; Crosby, Tom; Staffurth, John

    2012-11-15

    Purpose: To evaluate different conformity indices (CIs) for use in the analysis of outlining consistency within the pretrial quality assurance (Radiotherapy Trials Quality Assurance [RTTQA]) program of a multicenter chemoradiation trial of esophageal cancer and to make recommendations for their use in future trials. Methods and Materials: The National Cancer Research Institute SCOPE 1 trial is an ongoing Cancer Research UK-funded phase II/III randomized controlled trial of chemoradiation with capecitabine and cisplatin with or without cetuximab for esophageal cancer. The pretrial RTTQA program included a detailed radiotherapy protocol, an educational package, and a single mid-esophageal tumor test case that were sent to each investigator to outline. Investigator gross tumor volumes (GTVs) were received from 50 investigators in 34 UK centers, and CERR (Computational Environment for Radiotherapy Research) was used to perform an assessment of each investigator GTV against a predefined gold-standard GTV using different CIs. A new metric, the local conformity index (l-CI), that can localize areas of maximal discordance was developed. Results: The median Jaccard conformity index (JCI) was 0.69 (interquartile range, 0.62-0.70), with 14 of 50 investigators (28%) achieving a JCI of 0.7 or greater. The median geographical miss index was 0.09 (interquartile range, 0.06-0.16), and the mean discordance index was 0.27 (95% confidence interval, 0.25-0.30). The l-CI was highest in the middle section of the volume, where the tumor was bulky and more easily definable, and identified 4 slices where fewer than 20% of investigators achieved an l-CI of 0.7 or greater. Conclusions: The available CIs analyze different aspects of a gold standard-observer variation, with JCI being the most useful as a single metric. Additional information is provided by the l-CI and can focus the efforts of the RTTQA team in these areas, possibly leading to semi-automated outlining assessment.

  19. Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab).

    PubMed

    Miroddi, Marco; Sterrantino, Carmelo; Simmonds, Mark; Caridi, Luigi; Calapai, Gioacchino; Phillips, Robert S; Stewart, Lesley A

    2016-11-15

    Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165. PMID:27450994

  20. Preoperative Radiotherapy of Advanced Rectal Cancer With Capecitabine and Oxaliplatin With or Without Cetuximab: A Pooled Analysis of Three Prospective Phase I-II Trials

    SciTech Connect

    Weiss, Christian; Arnold, Dirk; Dellas, Kathrin; Liersch, Torsten; Hipp, Matthias; Fietkau, Rainer; Sauer, Rolf; Hinke, Axel; Roedel, Claus

    2010-10-01

    Purpose: A pooled analysis of three prospective trials of preoperative radiochemotherapy (RCT) for rectal cancer by using oxaliplatin and capecitabine with or without cetuximab was performed to evaluate the impact of additional cetuximab on pathologic complete response (pCR) rates and tumor regression (TRG) grades. Methods and Materials: Of 202 patients, 172 patients met the inclusion criteria (primary tumor stage II/III, M0). All patients received concurrent RCT, and 46 patients received additional cetuximab therapy. A correlation of pretreatment clinicopathologic factors and cetuximab treatment with early pCR rates (TRG > 50%) was performed with univariate and multivariate analyses. Toxicity data were recorded for all patients. Results: Of 172 patients, 24 (14%) patients achieved a pCR, and 84 of 172 (71%) patients showed a TRG of >50% in the surgical specimen assessment after preoperative treatment. Age, gender, and T/N stages, as well as localization of the tumor, were not associated with pCR or good TRG. The pCR rate was 16% after preoperative RCT alone and 9% with concurrent cetuximab therapy (p = 0.32). A significantly reduced TRG of >50% was found after RCT with cetuximab compared to RCT alone (p = 0.0035). This was validated by a multivariate analysis with all available clinical factors (p = 0.0037). Acute toxicity and surgical complications were not increased with additional cetuximab. Conclusions: Triple therapy with RCT and cetuximab seems to be feasible, with no unexpected toxicity. Early response assessment (TRG), however, suggests subadditive interaction. A longer follow-up (and finally randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates.

  1. Acquired resistance to 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) in glioblastoma cells

    PubMed Central

    Gaspar, Nathalie; Sharp, Swee Y; Pacey, Simon; Jones, Chris; Walton, Michael; Vassal, Gilles; Eccles, Suzanne; Pearson, Andrew; Workman, Paul

    2009-01-01

    HSP90 inhibitors, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG, tanespimycin) which is currently in phase II/III clinical trials, are promising new anticancer agents. Here, we explored acquired resistance to HSP90 inhibitors in glioblastoma, a primary brain tumor with poor prognosis. Glioblastoma cells were exposed continuously to increased 17-AAG concentrations. Four 17-AAG-resistant glioblastoma cell lines were generated. High resistance levels with resistance indices (RI=resistant line IC50/parental line IC50) of 20-137 were obtained rapidly (2-8 weeks). After cessation of 17-AAG exposure, RI decreased and then stabilised. Cross-resistance was found with other ansamycin benzoquinones but not with the structurally unrelated HSP90 inhibitors, radicicol, the purine BIIB021 and the resorcinylic pyrazole/isoxazole amide compounds VER-49009, VER-50589, and NVP-AUY922. An inverse correlation between NQO1 expression/activity and 17-AAG IC50 was observed in the resistant lines. The NQO1 inhibitor ES936 abrogated the differential effects of 17-AAG sensitivity between the parental and resistant lines. NQO1 mRNA levels and NQO1 DNA polymorphism analysis indicated different underlying mechanisms: reduced expression and selection of the inactive NQO1*2 polymorphism. Decreased NQO1 expression was also observed in a melanoma line with acquired resistance to 17-AAG. No resistance was generated with VER-50589 and NVP-AUY922. In conclusion, low NQO1 activity is a likely mechanism of acquired resistance to 17-AAG in glioblastoma, melanoma and possibly other tumor types. Such resistance can be overcome with novel HSP90 inhibitors. PMID:19244114

  2. Controlled cortical impact results in an extensive loss of dendritic spines that is not mediated by injury-induced amyloid-beta accumulation.

    PubMed

    Winston, Charisse N; Chellappa, Deepa; Wilkins, Tiffany; Barton, David J; Washington, Patricia M; Loane, David J; Zapple, David N; Burns, Mark P

    2013-12-01

    The clinical manifestations that occur after traumatic brain injury (TBI) include a wide range of cognitive, emotional, and behavioral deficits. The loss of excitatory synapses could potentially explain why such diverse symptoms occur after TBI, and a recent preclinical study has demonstrated a loss of dendritic spines, the postsynaptic site of the excitatory synapse, after fluid percussion injury. The objective of this study was to determine if controlled cortical impact (CCI) also resulted in dendritic spine retraction and to probe the underlying mechanisms of this spine loss. We used a unilateral CCI and visualized neurons and dendtritic spines at 24 h post-injury using Golgi stain. We found that TBI caused a 32% reduction of dendritic spines in layer II/III of the ipsilateral cortex and a 20% reduction in the dendritic spines of the ipsilateral dentate gyrus. Spine loss was not restricted to the ipsilateral hemisphere, however, with similar reductions in spine numbers recorded in the contralateral cortex (25% reduction) and hippocampus (23% reduction). Amyloid-β (Aβ), a neurotoxic peptide commonly associated with Alzheimer disease, accumulates rapidly after TBI and is also known to cause synaptic loss. To determine if Aβ contributes to spine loss after brain injury, we administered a γ-secretase inhibitor LY450139 after TBI. We found that while LY450139 administration could attenuate the TBI-induced increase in Aβ, it had no effect on dendritic spine loss after TBI. We conclude that the acute, global loss of dendritic spines after TBI is independent of γ-secretase activity or TBI-induced Aβ accumulation. PMID:23879560

  3. β-secretase inhibitor; a promising novel therapeutic drug in Alzheimer's disease.

    PubMed

    Menting, Kelly Willemijn; Claassen, Jurgen A H R

    2014-01-01

    Alzheimer's disease (AD) and vascular dementia are responsible for up to 90% of dementia cases. According to the World Health Organization (WHO), a staggering number of 35.6 million people are currently diagnosed with dementia. Blocking disease progression or preventing AD altogether is desirable for both social and economic reasons and recently focus has shifted to a new and promising drug: the β-secretase inhibitor. Much of AD research has investigated the amyloid cascade hypothesis, which postulates that AD is caused by changes in amyloid beta (Aβ) stability and aggregation. Blocking Aβ production by inhibiting the first protease required for its generation, β-secretase/BACE1, may be the next step in blocking AD progression. In April 2012, promising phase I data on inhibitor MK-8931 was presented. This drug reduced Aβ cerebral spinal fluids (CSF) levels up to 92% and was well tolerated by patients. In March 2013 data was added from a one week trial in 32 mild to moderate AD patients, showing CSF Aβ levels decreased up to 84%. However, β-site APP cleaving enzyme 1 (BACE1) inhibitors require further research. First, greatly reducing Aβ levels through BACE1 inhibition may have harmful side effects. Second, BACE1 inhibitors have yet to pass clinical trial phase II/III and no data on possible side effects on AD patients are available. And third, there remains doubt about the clinical efficacy of BACE1 inhibitors. In moderate AD patients, Aβ plaques have already been formed. BACE1 inhibitors prevent production of new Aβ plaques, but hypothetically do not influence already existing Aβ peptides. Therefore, BACE1 inhibitors are potentially better at preventing AD instead of having therapeutic use. PMID:25100992

  4. Laser Doppler vibrometry for assessment of arteriosclerosis: A first step towards validation

    SciTech Connect

    Campo, Adriaan; Dirckx, Joris

    2014-05-27

    It has been shown that in cardiovascular risk management, stiffness of large arteries has a very good predictive value for cardiovascular disease and mortality. This parameter can be estimated from the pulse wave velocity (PWV) measured between the common carotid artery (CCA) in the neck and femoral artery (FA) in the groin. However PWV can also be measured locally in the CCA, using non-invasive methods such as ultrasound (US) or laser Doppler vibrometry (LDV). Potential of the latter approach was already explored in previous research, and in this work a first step towards clinical validation is made. 50 hypertension II/III patients aged between 30 and 65 participate in the study. Patients were asked to remain sober for 4 hours prior to the measurements. The trajectory of the CCA in the neck was determined by a trained clinician guided by an US probe. 3 laser Doppler vibrometer (LDV) systems were aimed along the CCA. PWV was then calculated from the distance between beams and the time-shift between waveforms. Immediately after LDV measurements, PWV was measured with US. Additionally, carotid-femoral PWV was measured. As a validation, PWV results of the different techniques were compared with each other, and with medical background of the test subjects. Since data acquisition is still ongoing, data from only 20 patients will be discussed. No trends between measurement methods for PWV are apparent. However, a positive trend was detected between PWV as measured with LDV and blood pressure. More data, including additional experiments will be needed to verify this observation.

  5. A neural network approach for enhancing information extraction from multispectral image data

    USGS Publications Warehouse

    Liu, J.; Shao, G.; Zhu, H.; Liu, S.

    2005-01-01

    A back-propagation artificial neural network (ANN) was applied to classify multispectral remote sensing imagery data. The classification procedure included four steps: (i) noisy training that adds minor random variations to the sampling data to make the data more representative and to reduce the training sample size; (ii) iterative or multi-tier classification that reclassifies the unclassified pixels by making a subset of training samples from the original training set, which means the neural model can focus on fewer classes; (iii) spectral channel selection based on neural network weights that can distinguish the relative importance of each channel in the classification process to simplify the ANN model; and (iv) voting rules that adjust the accuracy of classification and produce outputs of different confidence levels. The Purdue Forest, located west of Purdue University, West Lafayette, Indiana, was chosen as the test site. The 1992 Landsat thematic mapper imagery was used as the input data. High-quality airborne photographs of the same Lime period were used for the ground truth. A total of 11 land use and land cover classes were defined, including water, broadleaved forest, coniferous forest, young forest, urban and road, and six types of cropland-grassland. The experiment, indicated that the back-propagation neural network application was satisfactory in distinguishing different land cover types at US Geological Survey levels II-III. The single-tier classification reached an overall accuracy of 85%. and the multi-tier classification an overall accuracy of 95%. For the whole test, region, the final output of this study reached an overall accuracy of 87%. ?? 2005 CASI.

  6. Mucin 1-specific active cancer immunotherapy with tecemotide (L-BLP25) in patients with multiple myeloma: An exploratory study

    PubMed Central

    Rossmann, Eva; Österborg, Anders; Löfvenberg, Eva; Choudhury, Aniruddha; Forssmann, Ulf; von Heydebreck, Anja; Schröder, Andreas; Mellstedt, Håkan

    2014-01-01

    Patients (n = 34) with previously untreated, slowly progressive asymptomatic stage I/II multiple myeloma or with stage II/III multiple myeloma in stable response/plateau phase following conventional anti-tumor therapy were immunized repeatedly with the antigen-specific cancer immunotherapeutic agent tecemotide (L-BLP25). Additionally, patients were randomly allocated to either single or multiple low doses of cyclophosphamide to inhibit regulatory T cells (Treg). Immunization with tecemotide resulted in the induction/augmentation of a mucin 1-specific immune response in 47% of patients. The immune responses appeared to involve a Th1-like cellular immune response involving CD4 and CD8 T cells. The rate of immune responses was similar with single versus multiple dosing of cyclophosphamide and in patients with vs. without pre-existing mucin 1 immunity. On-treatment reductions in the slope of M-protein concentration over time (but not fulfilling clinical criteria for responses with conventional anti-tumor agents) were observed in 45% of evaluable patients, predominantly in those without versus with pre-existing mucin 1 immunity and in patients with early stage disease. No differences were seen in patients receiving single or multiple cyclophosphamide dosing. Treatment with tecemotide was generally well tolerated. Repeated vs. single dosing of cyclophosphamide had no impact on Treg numbers and was stopped after a case of fatal encephalitis that was assessed as possibly study-related. Tecemotide immunotherapy induces mucin 1-specific cellular immune responses in a substantial proportion of patients, with preliminary evidence of changes in the M-protein concentration time curve in a subset of patients. PMID:25483677

  7. Suicidal ideation, suicide attempts, and HIV infection.

    PubMed

    Kelly, B; Raphael, B; Judd, F; Perdices, M; Kernutt, G; Burnett, P; Dunne, M; Burrows, G

    1998-01-01

    A cross-sectional study was performed to investigate the prevalence and predictors of suicidal ideation and past suicide attempt in an Australian sample of human immunodeficiency virus (HIV)-positive and HIV-negative homosexual and bisexual men. Sixty-five HIV-negative and 164 HIV-positive men participated. A suicidal ideation score was derived from using five items selected from the Beck Depression Inventory and the General Health Questionnaire (28-item version). Lifetime and current prevalence rates of psychiatric disorder were evaluated with the Diagnostic Interview Schedule Version-III-R. The HIV-positive (Centers for Disease Control and Prevention [CDC] Stage IV) men (n = 85) had significantly higher total suicidal ideation scores than the asymptomatic HIV-positive men (CDC Stage II/III) (n = 79) and the HIV-negative men. High rates of past suicide attempt were detected in the HIV-negative (29%) and HIV-positive men (21%). Factors associated with suicidal ideation included being HIV-positive, the presence of current psychiatric disorder, higher neuroticism scores, external locus of control, and current unemployment. In the HIV-positive group analyzed separately, higher suicidal ideation was discriminated by the adjustment to HIV diagnosis (greater hopelessness and lower fighting spirit), disease factors (greater number of current acquired immunodeficiency syndrome [AIDS]-related conditions), and background variables (neuroticism). Significant predictors of a past attempted suicide were a positive lifetime history of psychiatric disorder (particularly depression diagnoses), a lifetime history of infection drug use, and a family history of suicide attempts. The findings indicate increased levels of suicidal ideation in symptomatic HIV-positive men and highlight the role that multiple psychosocial factors associated with suicidal ideation and attempted suicide play in this population. PMID:9775697

  8. Effects of Gamma Hydroxybutyric Acid on Inhibition and Excitation in Rat Neocortex

    PubMed Central

    Li, Qiang; Kuhn, Cynthia M.; Wilson, Wilkie A.; Lewis, Darrell V.

    2008-01-01

    The mechanism by which the sedative and amnestic recreational drug gamma hydroxybutyric acid (GHB) acts is controversial. Some studies indicate that it acts at its unique receptor, while others demonstrate effects mediated through the GABAB receptor. We examined the effect of GHB on evoked GABAA receptor mediated mono- and polysynaptic IPSCs as well as on NMDA and AMPA mediated EPSCs in layers II/III pyramidal cells of the frontal cortex of rat brain. One millimolar (mM) GHB suppressed monosynaptic IPSCs by 20%, whereas polysynaptic IPSCs were reduced by 56%. GHB (1mM) also produced a significant suppression of NMDA-mediated EPSCs by 53% compared to 27% suppression of AMPA-mediated EPSCs. All effects of GHB on IPSCs and EPSCs were reversed by the specific GABAB antagonist CGP62349, but not by the GHB receptor antagonist NCS 382. Consistent with a presynaptic site of action, GHB reduced the frequency but not the amplitude of AMPA receptor mediated mEPSCs and had no effect on postsynaptic currents evoked by direct application of NMDA. Finally, even though GHB appeared to be acting at presynaptic GABAB receptors, GHB and the GABAB agonist baclofen appeared to have opposite potencies for depression of NMDA vs AMPA mediated EPSCs. GHB showed a preference for depressing NMDA responses while baclofen more potently suppressed AMPA responses. The suppression of NMDA more than AMPA responses by GHB at intoxicating doses may make it attractive as a recreational drug and may explain why GHB is abused and baclofen is not. PMID:17904295

  9. Laminar Diversity of Dynamic Sound Processing in Cat Primary Auditory Cortex

    PubMed Central

    Schreiner, Christoph E.

    2010-01-01

    For primary auditory cortex (AI) laminae, there is little evidence of functional specificity despite clearly expressed cellular and connectional differences. Natural sounds are dominated by dynamic temporal and spectral modulations and we used these properties to evaluate local functional differences or constancies across laminae. To examine the layer-specific processing of acoustic modulation information, we simultaneously recorded from multiple AI laminae in the anesthetized cat. Neurons were challenged with dynamic moving ripple stimuli and we subsequently computed spectrotemporal receptive fields (STRFs). From the STRFs, temporal and spectral modulation transfer functions (tMTFs, sMTFs) were calculated and compared across layers. Temporal and spectral modulation properties often differed between layers. On average, layer II/III and VI neurons responded to lower temporal modulations than those in layer IV. tMTFs were mainly band-pass in granular layer IV and became more low-pass in infragranular layers. Compared with layer IV, spectral MTFs were broader and their upper cutoff frequencies higher in layers V and VI. In individual penetrations, temporal modulation preference was similar across layers for roughly 70% of the penetrations, suggesting a common, columnar functional characteristic. By contrast, only about 30% of penetrations showed consistent spectral modulation preferences across layers, indicative of functional laminar diversity or specialization. Since local laminar differences in stimulus preference do not always parallel the main flow of information in the columnar cortical microcircuit, this indicates the influence of additional horizontal or thalamocortical inputs. AI layers that express differing modulation properties may serve distinct roles in the extraction of dynamic sound information, with the differing information specific to the targeted stations of each layer. PMID:19864440

  10. Antimicrobial Peptides in Human Sepsis.

    PubMed

    Martin, Lukas; van Meegern, Anne; Doemming, Sabine; Schuerholz, Tobias

    2015-01-01

    Nearly 100 years ago, antimicrobial peptides (AMPs) were identified as an important part of innate immunity. They exist in species from bacteria to mammals and can be isolated in body fluids and on surfaces constitutively or induced by inflammation. Defensins have anti-bacterial effects against Gram-positive and Gram-negative bacteria as well as anti-viral and anti-yeast effects. Human neutrophil peptides (HNP) 1-3 and human beta-defensins (HBDs) 1-3 are some of the most important defensins in humans. Recent studies have demonstrated higher levels of HNP 1-3 and HBD-2 in sepsis. The bactericidal/permeability-increasing protein (BPI) attenuates local inflammatory response and decreases systemic toxicity of endotoxins. Moreover, BPI might reflect the severity of organ dysfunction in sepsis. Elevated plasma lactoferrin is detected in patients with organ failure. HNP 1-3, lactoferrin, BPI, and heparin-binding protein are increased in sepsis. Human lactoferrin peptide 1-11 (hLF 1-11) possesses antimicrobial activity and modulates inflammation. The recombinant form of lactoferrin [talactoferrin alpha (TLF)] has been shown to decrease mortality in critically ill patients. A phase II/III study with TLF in sepsis did not confirm this result. The growing number of multiresistant bacteria is an ongoing problem in sepsis therapy. Furthermore, antibiotics are known to promote the liberation of pro-inflammatory cell components and thus augment the severity of sepsis. Compared to antibiotics, AMPs kill bacteria but also neutralize pathogenic factors such as lipopolysaccharide. The obstacle to applying naturally occurring AMPs is their high nephro- and neurotoxicity. Therefore, the challenge is to develop peptides to treat septic patients effectively without causing harm. This overview focuses on natural and synthetic AMPs in human and experimental sepsis and their potential to provide significant improvements in the treatment of critically ill with severe infections. PMID

  11. Risk Factors for Esophageal Fistula Associated With Chemoradiotherapy for Locally Advanced Unresectable Esophageal Cancer: A Supplementary Analysis of JCOG0303.

    PubMed

    Tsushima, Takahiro; Mizusawa, Junki; Sudo, Kazuki; Honma, Yoshitaka; Kato, Ken; Igaki, Hiroyasu; Tsubosa, Yasuhiro; Shinoda, Masayuki; Nakamura, Kenichi; Fukuda, Haruhiko; Kitagawa, Yuko

    2016-05-01

    Esophageal fistula is a critical adverse event in patients treated with chemoradiotherapy (CRT) for locally advanced esophageal cancer. However, risk factors associated with esophageal fistula formation in patients receiving CRT have not yet been elucidated.We retrospectively analyzed data obtained from 140 patients who were enrolled in a phase II/III trial comparing low-dose cisplatin with standard-dose cisplatin administered in combination with 5-flurouracil and concomitant radiotherapy. Inclusion criteria were performance status (PS) 0 to 2 and histologically proven thoracic esophageal cancer clinically diagnosed as T4 and/or unresectable lymph node metastasis for which definitive CRT was applicable. Risk factors for esophageal fistula were examined with univariate analysis using Fisher exact test and multivariate analysis using logistic regression models.Esophageal fistula was observed in 31 patients (22%). Of these, 6 patients developed fistula during CRT. Median time interval between the date of CRT initiation and that of fistula diagnosis was 100 days (inter quartile range, 45-171). Esophageal stenosis was the only significant risk factor for esophageal fistula formation both in univariate (P = 0.026) and in multivariate analyses (odds ratio, 2.59; 95% confidence interval, 1.13-5.92, P = 0.025). Other clinicopathological factors, namely treatment arm, age, sex, PS, primary tumor location, T stage, lymph node invasion to adjacent organs, blood cell count, albumin level, and body mass index, were not risk factors fistula formation.Esophageal stenosis was a significant risk factor for esophageal fistula formation in patients treated with CRT for unresectable locally advanced thoracic esophageal squamous cell carcinoma. PMID:27196482

  12. Multi-Targeted Antiangiogenic Tyrosine Kinase Inhibitors in Advanced Non-Small Cell Lung Cancer: Meta-Analyses of 20 Randomized Controlled Trials and Subgroup Analyses

    PubMed Central

    Zhang, Yaxiong; Kang, Shiyang; Fang, Wenfeng; Qin, Tao; Huang, Yan; Zhao, Hongyun; Zhang, Li

    2014-01-01

    Background Multi-targeted antiangiogenic tyrosine kinase inhibitors (MATKIs) have been studied in many randomized controlled trials (RCTs) for treatment of advanced non-small cell lung cancer (NSCLC). We seek to summarize the most up-to-date evidences and perform a timely meta-analysis. Methods Electronic databases were searched for eligible studies. We defined the experimental arm as MATKI-containing group and the control arm as MATKI-free group. The extracted data on objective response rates (ORR), disease control rates (DCR), progression-free survival (PFS) and overall survival (OS) were pooled. Subgroup and sensitivity analyses were conducted. Results Twenty phase II/III RCTs that involved a total of 10834 participants were included. Overall, MATKI-containing group was associated with significant superior ORR (OR 1.29, 95% CI 1.08 to 1.55, P = 0.006) and prolonged PFS (HR 0.83, 0.78 to 0.90, P = 0.005) compared to the MATKI-free group. However, no significant improvements in DCR (OR 1.08, 1.00 to 1.17, P = 0.054) or OS (HR 0.97, 0.93 to 1.01, P = 0.106) were observed. Subgroup analyses showed that the benefits were predominantly presented in pooled results of studies enrolling previously-treated patients, studies not limiting to enroll non-squamous NSCLC, and studies using MATKIs in combination with the control regimens as experimental therapies. Conclusions This up-to-date meta-analysis showed that MATKIs did increase ORR and prolong PFS, with no significant improvement in DCR and OS. The advantages of MATKIs were most prominent in patients who received a MATKI in combination with standard treatments and in patients who had previously experienced chemotherapy. We suggest further discussion as to the inclusion criteria of future studies on MATKIs regarding histology. PMID:25329056

  13. GBAS GAST D availability analysis for business aircraft

    NASA Astrophysics Data System (ADS)

    Dvorska, J.; Lipp, A.; Podivin, L.; Duchet, D.

    This paper analyzes Initial GBAS GAST D availability at a set of current ILS CAT III airports. Eurocontrol Pegasus Availability Tool, designed for SESAR projects is used for the assessment. Overall availability of the GBAS GAST D system is considered, focusing on business aircraft specifics where applicable. Nominal as well as adverse scenarios are presented in order to determine whether GAST D can reach the required availability for business aircraft at CAT III airport locations and under which conditions. The availability target was set at 99.9% availability when considering satellite outages in a given constellation and 99.997% when no outages are included. Sensitivity simulations were run for different scenarios and impacts of geometry screening thresholds, scale heights, aircraft mask, ground mask, sigma pseudorange ground, sigma ionospheric gradient, simulated year and different approach point (decision height) were analyzed. Some were run for a limited set of ILS CAT III airports and most of them for an almost complete set of nominal airports. Business aircraft specific assumptions, as well as aircraft type independent parameters (constellations, satellite outages, etc.) are examined in the paper. Conclusion summarizes the overall outcome of the simulations, showing that Initial GBAS CAT II/III can provide sufficient availability for all or almost all ILS CAT III capable airports considered in this study; and under which conditions. Recommendations for parameters that can be influenced (e.g. antenna location) if necessary are provided. It can also be expected that the availability will increase with the increasing amount of GNSS satellites. The work shows how different parameters impact availability of initial GBAS GAST D service for business aircraft, and that sufficient availability of GAST D service can be expected at most airports.

  14. Occurrence and Molecular Characteristics of Methicillin-Resistant Staphylococcus aureus and Methicillin-Resistant Staphylococcus pseudintermedius in an Academic Veterinary Hospital▿

    PubMed Central

    Ishihara, Kanako; Shimokubo, Natsumi; Sakagami, Akie; Ueno, Hiroshi; Muramatsu, Yasukazu; Kadosawa, Tsuyoshi; Yanagisawa, Chie; Hanaki, Hideaki; Nakajima, Chie; Suzuki, Yasuhiko; Tamura, Yutaka

    2010-01-01

    Recently, methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus pseudintermedius (MRSP) have been increasingly isolated from veterinarians and companion animals. With a view to preventing the spread of MRSA and MRSP, we evaluated the occurrence and molecular characteristics of each in a veterinary college. MRSA and MRSP were isolated from nasal samples from veterinarians, staff members, and veterinary students affiliated with a veterinary hospital. Using stepwise logistic regression, we identified two factors associated with MRSA carriage: (i) contact with an identified animal MRSA case (odds ratio [OR], 6.9; 95% confidence interval [95% CI], 2.2 to 21.6) and (ii) being an employee (OR, 6.2; 95% CI, 2.0 to 19.4). The majority of MRSA isolates obtained from individuals affiliated with the veterinary hospital and dog patients harbored spa type t002 and a type II staphylococcal cassette chromosome mec (SCCmec), similar to the hospital-acquired MRSA isolates in Japan. MRSA isolates harboring spa type t008 and a type IV SCCmec were obtained from one veterinarian on three different sampling occasions and also from dog patients. MRSA carriers can also be a source of MRSA infection in animals. The majority of MRSP isolates (85.2%) carried hybrid SCCmec type II-III, and almost all the remaining MRSP isolates (11.1%) carried SCCmec type V. MRSA and MRSP were also isolated from environmental samples collected from the veterinary hospital (5.1% and 6.4%, respectively). The application of certain disinfection procedures is important for the prevention of nosocomial infection, and MRSA and MRSP infection control strategies should be adopted in veterinary medical practice. PMID:20543040

  15. Effect of L-tyrosine in vitro and in vivo on energy metabolism parameters in brain and liver of young rats.

    PubMed

    Ferreira, Gabriela K; Scaini, Giselli; Carvalho-Silva, Milena; Gomes, Lara M; Borges, Lislaine S; Vieira, Júlia S; Constantino, Larissa S; Ferreira, Gustavo C; Schuck, Patrícia F; Streck, Emilio L

    2013-05-01

    Tyrosinemia is a rare disease caused by a single mutation to the gene that code for the enzyme responsible for tyrosine catabolism. Because the mechanisms underlying the neurological dysfunction in hypertyrosinemic patients are poorly understood, we evaluated the in vitro and in vivo effect of L-tyrosine on the activities of the enzymes citrate synthase, malate dehydrogenase, succinate dehydrogenase and complexes of the mitochondrial respiratory chain in the brains and livers of young rats. Thirty-day-old Wistar rats were killed by decapitation, and the brains and livers were harvested. L-Tyrosine (0.1, 1.0, 2.0 or 4.0 mM) was added to the reaction medium. For in vivo studies, Wistar rats were killed 1 h after a single intraperitoneal injection of either tyrosine (500 mg/kg) or saline. The activities of energy metabolism enzymes were evaluated. In this research, we demonstrated in vitro that L-tyrosine inhibited citrate synthase activity in the posterior cortex and that succinate dehydrogenase was increased in the posterior cortex, hippocampus, striatum and liver. The complex I activity was only inhibited in the hippocampus, whereas complex II activity was inhibited in the hippocampus, cortex and liver. Complex IV activity decreased in the posterior cortex. The acute administration of L-tyrosine inhibited enzyme malate dehydrogenase, citrate synthase and complexes II, II-III and IV in the posterior cortex and liver. The enzyme succinate dehydrogenase and complex I activity were inhibited in the posterior cortex and increased in the striatum. These results suggest impairment in energy metabolism that is likely mediated by oxidative stress. PMID:22847184

  16. Transarterial radioembolization using yttrium-90 microspheres in the treatment of hepatocellular carcinoma: a review on clinical utility and developments

    PubMed Central

    Cappelli, Alberta; Pettinato, Cinzia; Golfieri, Rita

    2014-01-01

    A selective intra-arterial liver injection using yttrium-90-loaded microspheres as sources for internal radiation therapy is a form of transarterial radioembolization (TARE). Current data from the literature suggest that TARE is effective in hepatocellular carcinoma (HCC) and is associated with a low rate of adverse events; however, they are all based on retrospective series or non-controlled prospective studies, since randomized controlled trials comparing the other liver-directed therapies for intermediate and locally advanced stages HCC are still ongoing. The available data show that TARE provides similar or even better survival rates. TARE is very well tolerated and has a low rate of complications; these complications do not result from the embolic effects but mainly from the unintended irradiation to non-target tissue, including the liver parenchyma. The complications can be further reduced by accurate patient selection and a strict pre-treatment evaluation, including dosimetry and assessment of the vascular anatomy. First-line TARE is best indicated for intermediate-stage patients (according to the Barcelona Clinic Liver Cancer [BCLC] staging classification) who are poor candidates for transarterial chemoembolization or patients having locally advanced disease with segmental or lobar branch portal vein thrombosis. Moreover, data are emerging regarding the use of TARE in patients classified slightly above the criteria for liver transplantation with the purpose of downstaging them. TARE can also be applied as a second-line treatment in patients progressing to transarterial chemoembolization or sorafenib; a large number of Phase II/III trials are in progress in order to evaluate the best association with systemic therapies. Given the complexity of a correct treatment algorithm for potential TARE candidates and the need for clinical guidance, a comprehensive review was carried out analyzing both the best selection criteria of patients who really benefit from TARE

  17. Transarterial radioembolization using yttrium-90 microspheres in the treatment of hepatocellular carcinoma: a review on clinical utility and developments.

    PubMed

    Cappelli, Alberta; Pettinato, Cinzia; Golfieri, Rita

    2014-01-01

    A selective intra-arterial liver injection using yttrium-90-loaded microspheres as sources for internal radiation therapy is a form of transarterial radioembolization (TARE). Current data from the literature suggest that TARE is effective in hepatocellular carcinoma (HCC) and is associated with a low rate of adverse events; however, they are all based on retrospective series or non-controlled prospective studies, since randomized controlled trials comparing the other liver-directed therapies for intermediate and locally advanced stages HCC are still ongoing. The available data show that TARE provides similar or even better survival rates. TARE is very well tolerated and has a low rate of complications; these complications do not result from the embolic effects but mainly from the unintended irradiation to non-target tissue, including the liver parenchyma. The complications can be further reduced by accurate patient selection and a strict pre-treatment evaluation, including dosimetry and assessment of the vascular anatomy. First-line TARE is best indicated for intermediate-stage patients (according to the Barcelona Clinic Liver Cancer [BCLC] staging classification) who are poor candidates for transarterial chemoembolization or patients having locally advanced disease with segmental or lobar branch portal vein thrombosis. Moreover, data are emerging regarding the use of TARE in patients classified slightly above the criteria for liver transplantation with the purpose of downstaging them. TARE can also be applied as a second-line treatment in patients progressing to transarterial chemoembolization or sorafenib; a large number of Phase II/III trials are in progress in order to evaluate the best association with systemic therapies. Given the complexity of a correct treatment algorithm for potential TARE candidates and the need for clinical guidance, a comprehensive review was carried out analyzing both the best selection criteria of patients who really benefit from TARE

  18. Effects of whole-body vibration training on physical function, bone and muscle mass in adolescents and young adults with cerebral palsy.

    PubMed

    Gusso, Silmara; Munns, Craig F; Colle, Patrícia; Derraik, José G B; Biggs, Janene B; Cutfield, Wayne S; Hofman, Paul L

    2016-01-01

    We performed a clinical trial on the effects of whole-body vibration training (WBVT) on muscle function and bone health of adolescents and young adults with cerebral palsy. Forty participants (11.3-20.8 years) with mild to moderate cerebral palsy (GMFCS II-III) underwent 20-week WBVT on a vibration plate for 9 minutes/day 4 times/week at 20 Hz (without controls). Assessments included 6-minute walk test, whole-body DXA, lower leg pQCT scans, and muscle function (force plate). Twenty weeks of WBVT were associated with increased lean mass in the total body (+770 g; p = 0.0003), trunk (+410 g; p = 0.004), and lower limbs (+240 g; p = 0.012). Bone mineral content increased in total body (+48 g; p = 0.0001), lumbar spine (+2.7 g; p = 0.0003), and lower limbs (+13 g; p < 0.0001). Similarly, bone mineral density increased in total body (+0.008 g/cm(2); p = 0.013), lumbar spine (+0.014 g/cm(2); p = 0.003), and lower limbs (+0.023 g/cm(2); p < 0.0001). Participants reduced the time taken to perform the chair test, and improved the distance walked in the 6-minute walk test by 11% and 35% for those with GMFCS II and III, respectively. WBVT was associated with increases in muscle mass and bone mass and density, and improved mobility of adolescents and young adults with cerebral palsy. PMID:26936535

  19. Treatment and survival of supratentorial and posterior fossa ependymomas in adults.

    PubMed

    Nuño, Miriam; Yu, Jeffrey J; Varshneya, Kunal; Alexander, Julia; Mukherjee, Debraj; Black, Keith L; Patil, Chirag G

    2016-06-01

    Ependymoma is a rare primary brain or spinal cord tumor that arises from the ependyma, a tissue of the central nervous system. This study analyzed a large cohort of adult supratentorial and posterior fossa ependymoma tumors in order to elucidate factors associated with overall survival. We utilized the USA National Cancer Database to study adult World Health Organization grade II/III supratentorial and posterior fossa ependymoma patients treated between 1998 and 2011. Overall survival was estimated by the Kaplan-Meier method and factors associated with survival were determined using a multivariate Cox proportional hazards model. Among 1318 patients, 1055 (80.0%) had grade II and 263 (20.0%) anaplastic tumors located in the posterior fossa (64.3%) and supratentorial region (35.7%). Overall average age was 44.3years, 48.0% of patients were female, 86.5% were Caucasian, and 36.8% underwent near/gross total surgical resection. Radiotherapy was given to 662 patients (50.8%) and 75 (5.9%) received chemotherapy. Older age at diagnosis (hazard ratio [HR] 1.51, p<0.0001), high tumor grade (HR 1.82, p=0.005), and large tumor size (HR 1.66, p=0.008) were associated with poor survival. Females compared to males (HR 0.67, p=0.03) and patients with posterior fossa tumors versus supratentorial (HR 0.64, p=0.04) had a survival advantage. Our study showed that older patients, with supratentorial tumors, and high histological grade had an increased risk of mortality. A survival benefit was captured in females and patients with posterior fossa tumors. Adjuvant radiotherapy and chemotherapy did not confer a survival benefit among all patients, even after stratification by tumor grade or anatomical location. PMID:26810473

  20. Novel immunological and nutritional-based prognostic index for gastric cancer

    PubMed Central

    Sun, Kai-Yu; Xu, Jian-Bo; Chen, Shu-Ling; Yuan, Yu-Jie; Wu, Hui; Peng, Jian-Jun; Chen, Chuang-Qi; Guo, Pi; Hao, Yuan-Tao; He, Yu-Long

    2015-01-01

    AIM: To assess the prognostic significance of immunological and nutritional-based indices, including the prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), and platelet-lymphocyte ratio in gastric cancer. METHODS: We retrospectively reviewed 632 gastric cancer patients who underwent gastrectomy between 1998 and 2008. Areas under the receiver operating characteristic curve were calculated to compare the predictive ability of the indices, together with estimating the sensitivity, specificity and agreement rate. Univariate and multivariate analyses were performed to identify risk factors for overall survival (OS). Propensity score analysis was performed to adjust variables to control for selection bias. RESULTS: Each index could predict OS in gastric cancer patients in univariate analysis, but only PNI had independent prognostic significance in multivariate analysis before and after adjustment with propensity scoring (hazard ratio, 1.668; 95% confidence interval: 1.368-2.035). In subgroup analysis, a low PNI predicted a significantly shorter OS in patients with stage II-III disease (P = 0.019, P < 0.001), T3-T4 tumors (P < 0.001), or lymph node metastasis (P < 0.001). Canton score, a combination of PNI, NLR, and platelet, was a better indicator for OS than PNI, with the largest area under the curve for 12-, 36-, 60-mo OS and overall OS (P = 0.022, P = 0.030, P < 0.001, and P = 0.024, respectively). The maximum sensitivity, specificity, and agreement rate of Canton score for predicting prognosis were 84.6%, 34.9%, and 70.1%, respectively. CONCLUSION: PNI is an independent prognostic factor for OS in gastric cancer. Canton score can be a novel preoperative prognostic index in gastric cancer. PMID:26019461

  1. Clinical trial opportunities in hemostasis and thrombosis: NHBLI State-of-the-Science symposium.

    PubMed

    Cines, Douglas B; Blajchman, Morris A; High, Katherine A; Bussel, James B

    2012-02-01

    Clinical trials in hemostasis and thrombosis (HT) are needed to guide medical practice and future research. Providing public support for trials that could have the greatest impact on clinical care has been a major challenge. The National Heart, Lung and Blood Institute (NHLBI) convened a State-of-the-Science meeting in Bethesda on September 14th and 15th, 2009 to identify Phase II and III clinical trials in HT that could have critical impact on healthcare. An oversight committee composed of representatives of the NHLBI and three experienced extramural investigators chose chairs of subcommittees representing six broad areas of investigation in adult and pediatric HT. Chairs were charged with identifying important, feasible proposals. Nineteen trial concepts were presented at this public meeting, followed by open commentary from members of an independent external panel chosen to evaluate the trials and from symposium participants from the wider scientific community. Descriptions of two important clinical trial concepts from each of the six subcommittees are provided in the Supporting Information. Phase II-III clinical trials that could have high impact include studies for treatment of venous thromboembolism (TE) in children and in adults, the potential utility of statins in prophylaxis of TE, prophylaxis of adults with severe hemophilia, management of heparin-induced thrombocytopenia (HIT) and of primary immune thrombocytopenia (ITP). The external panel also provided recommendations concerning infrastructure and approach that could improve the conduct of studies including: development of core organizations with expertise in design of clinical trials, biostatistics, and contract development; funding based on output and milestones; and enhanced investment in coordinating centers. PMID:22120890

  2. Phase II trial of weekly Docetaxel, Zoledronic acid, and Celecoxib for castration-resistant prostate cancer.

    PubMed

    Kattan, Joseph; Bachour, Marwan; Farhat, Fadi; El Rassy, Elie; Assi, Tarek; Ghosn, Marwan

    2016-08-01

    Background Treatment options for patients with metastatic castration-resistance prostate cancer are unsatisfactory. Docetaxel monotherapy offers promising results with a tolerable toxicity profile. However, enhancing the clinical index of Docetaxel-based therapy remains the ultimate goal. Methods We conducted a phase II, open label, multinational prospective trial to evaluate the efficacy of weekly Docetaxel combined with Zoledronic acid and Celecoxib. Eligible patients received 25 mg/m(2) Docetaxel weekly for 3 consecutive weeks every 4 weeks, 4 mg Zoledronic acid every 4 weeks, and 200 mg oral Celecoxib twice daily. Enrollment was terminated prematurely upon the publication of reports of cardiac toxicity associated with cyclooxygenase (COX) 2 inhibitors. Results Our study enrolled 22 patients with a median of 4.7 cycles per patient. The median overall survival (OS) was 9.8 months (range 0.7 to 24.1 months) with 36 % and 4.5 % survival rates at 1 and 2 years, respectively. Our patients had a biologic response in 40.1 % of cases and a palliative response in 72.7 %. Among the eight patients with measurable disease, three had partial responses, two had stable disease, and three had progressive disease, leading to a response rate (RR) of 62.5 %. The observed toxicities were mild and limited to grade 3 events. Nine patients had anemia (40.1 %), 5 had sensory neuropathy (22.7 %) and 2 had stomatitis (9.1 %). Conclusion The combination of Docetaxel, Celecoxib, and Zoledronic acid failed to improve OS or to offer an acceptable biologic response. We do not believe that there is compelling evidence to include either Celecoxib or Zoledronic acid in further phase II/III trials. PMID:27159981

  3. Skeletal muscle metabolism during exercise in patients with chronic heart failure.

    PubMed Central

    Schaufelberger, M.; Eriksson, B. O.; Held, P.; Swedberg, K.

    1996-01-01

    OBJECTIVE: To investigate the metabolic response of skeletal muscle to exercise in patients with chronic heart failure and determine its relation to central haemodynamic variables. SETTING: University hospital in Sweden. PARTICIPANTS: 16 patients in New York Heart Association class II-III and 10 healthy controls. MAIN OUTCOME MEASURES: Skeletal muscle biopsies were obtained from the quadriceps muscle at rest and at submaximal and maximal exercise. Right sided heart catheterisation was performed in eight patients. RESULTS: The patients had lower maximal oxygen consumption than the control group (13.2 (2.9) v 26.8 (4.4) ml/kg/min, P < 0.001). They had reduced activities of citrate synthetase (P < 0.05) and 3-hydroxyacyl-CoA dehydrogenase (P < 0.05) compared with the controls. At maximal exercise adenosine triphosphate (P < 0.05), creatine phosphate (P < 0.01), and glycogen (P < 0.01) were higher whereas glucose (P < 0.001) and lactate (P < 0.06) were lower in the patients than in the controls. Citrate synthetase correlated inversely with skeletal muscle lactate at submaximal exercise (r = -0.90, P < 0.003). No correlations between haemodynamic variables and skeletal muscle glycogen, glycolytic intermediates, and adenosine nucleotides during exercise were found. CONCLUSION: Neither skeletal muscle energy compounds nor lactate accumulation were limiting factors for exercise capacity in patients with chronic heart failure. The decreased activity of oxidative enzymes may have contributed to the earlier onset of anaerobic metabolism, but haemodynamic variables seemed to be of lesser importance for skeletal muscle metabolism during exercise. PMID:8774324

  4. Two-photon excited fluorescence spectroscopy and imaging of melanin in vitro and in vivo

    NASA Astrophysics Data System (ADS)

    Krasieva, Tatiana B.; Liu, Feng; Sun, Chung-Ho; Kong, Yu; Balu, Mihaela; Meyskens, Frank L.; Tromberg, Bruce J.

    2012-03-01

    The ability to detect early melanoma non-invasively would improve clinical outcome and reduce mortality. Recent advances in two-photon excited fluorescence (TPEF) in vivo microscopy offer a powerful tool in early malignant melanoma diagnostics. The goal of this work was to develop a TPEF optical index for measuring relative concentrations of eumelanin and pheomelanin since ex vivo studies show that changes in this ratio have been associated with malignant transformation. We acquired TPEF emission spectra (λex=1000 nm) of melanin from several specimens, including human hair, malignant melanoma cell lines, and normal melanocytes and keratinocytes in different skin layers (epidermis, papillary dermis) in five healthy volunteers in vivo. We found that the pheomelanin emission peaks at around 620 nm and is blue-shifted from the eumelanin with broad maximum at 640-680nm. We defined "optical melanin index" (OMI) as a ratio of fluorescence signal intensities measured at 645 nm and 615nm. The measured OMI for a melanoma cell line MNT-1 was 1.6+/-0.2. The MNT-46 and MNT-62 lines (Mc1R gene knockdown) showed an anticipated change in melanins production ratio and had OMI of 0.55+/-0.05 and 0.17+/-0.02, respectively, which strongly correlated with HPLC data obtained for these lines. Average OMI measured for basal cells layers (melanocytes and keratinocytes) in normal human skin type I, II-III (not tanned and tanned) in vivo was 0.5, 1.05 and 1.16 respectively. We could not dependably detect the presence of pheomelanin in highly pigmented skin type V-VI. These data suggest that a non-invasive TPEF index could potentially be used for rapid melanin ratio characterization both in vitro and in vivo, including pigmented lesions.

  5. Adjuvant Chemoradiotherapy After Pancreatic Resection for Invasive Carcinoma Associated With Intraductal Papillary Mucinous Neoplasm of the Pancreas

    SciTech Connect

    Swartz, Michael J.; Hsu, Charles C.; Pawlik, Timothy M.; Winter, Jordan; Hruban, Ralph H.; Guler, Mehmet; Schulick, Richard D.; Cameron, John L.; Laheru, Daniel A.; Wolfgang, Christopher L.; Herman, Joseph M.

    2010-03-01

    Purpose: Intraductal papillary mucinous neoplasms are mucin-producing cystic neoplasms of the pancreas. One-third are associated with invasive carcinoma. We examined the benefit of adjuvant chemoradiotherapy (CRT) for this cohort. Methods and Materials: Patients who had undergone pancreatic resection at Johns Hopkins Hospital between 1999 and 2004 were reviewed. Of these patients, 83 with a resected pancreatic mass were found to have an intraductal papillary mucinous neoplasm with invasive carcinoma, 70 of whom met inclusion criteria for the present analysis. Results: The median age at surgery was 68 years. The median tumor size was 3.3 cm, and invasive carcinoma was present at the margin in 16% of the patients. Of the 70 patients, 50% had metastases to the lymph nodes and 64% had Stage II disease. The median survival was 28.0 months, and 2- and 5-year survival rate was 57% and 45%, respectively. Of the 70 patients, 40 had undergone adjuvant CRT. Those receiving CRT were more likely to have lymph node metastases, perineural invasion, and Stage II-III disease. The 2-year survival rate after surgery with vs. without CRT was 55.8% vs. 59.3%, respectively (p = NS). Patients with lymph node metastases or positive surgical margins benefited significantly from CRT (p = .047 and p = .042, respectively). On multivariate analysis, adjuvant CRT was associated with improved survival, with a relative risk of 0.43 (95% confidence interval, 0.19-0.95; p = .044) after adjusting for major confounders. Conclusion: Adjuvant CRT conferred a 57% decrease in the relative risk of mortality after pancreaticoduodenectomy for intraductal papillary mucinous neoplasms with an associated invasive component after adjusting for major confounders. Patients with lymph node metastases or positive margins appeared to particularly benefit from CRT after definitive surgery.

  6. Postoperative Radiotherapy After Surgical Resection of Thymoma: Differing Roles in Localized and Regional Disease

    SciTech Connect

    Forquer, Jeffrey A.; Rong Nan; Fakiris, Achilles J.; Loehrer, Patrick J.; Johnstone, Peter

    2010-02-01

    Purpose: To analyze the Surveillance, Epidemiology and End Results (SEER) registry data to determine the impact of postoperative radiotherapy (PORT) for thymoma and thymic carcinoma (T/TC). Methods and Materials: Patients with surgically resected localized (LOC) or regional (REG) malignant T/TC with or without PORT were analyzed for overall survival (OS) and cause-specific survival (CSS) by querying the SEER database from 1973-2005. Patients dying within the first 3 months after surgery were excluded. Kaplan-Meier and multivariate analyses with Cox proportional hazards were performed. Results: A total of 901 T/TC patients were identified (275 with LOC disease and 626 with REG disease). For all patients with LOC disease, PORT had no benefit and may adversely impact the 5-year CSS rate (91% vs. 98%, p = 0.03). For patients with REG disease, the 5-year OS rate was significantly improved by adding PORT (76% vs. 66% for surgery alone, p = 0.01), but the 5-year CSS rate was no better (91% vs. 86%, p = 0.12). No benefit was noted for PORT in REG disease after extirpative surgery (defined as radical or total thymectomy). On multivariate OS and CSS analysis, stage and age were independently correlated with survival. For multivariate CSS analysis, the outcome of PORT is significantly better for REG disease than for LOC disease (hazard ratio, 0.167; p = 0.001). Conclusions: Our results from SEER show that PORT for T/TC had no advantage in patients with LOC disease (Masaoka Stage I), but a possible OS benefit of PORT in patients with REG disease (Masaoka Stage II-III) was found, especially after non-extirpative surgery. The role of PORT in T/TC needs further evaluation.

  7. Novel Monoclonal Antibodies for Cancer Treatment: The Trifunctional Antibody Catumaxomab (Removab®)

    PubMed Central

    Seimetz, Diane

    2011-01-01

    The trifunctional antibody (trAb) catumaxomab is characterized by a unique ability to bind three different cell types: tumor cells; T-cells; and accessory cells. It binds to epithelial cell adhesion molecule (EpCAM) on tumor cells, the CD3 antigen on T-cells, and to type I, IIa, and III Fcγ receptors (FcγRs) on accessory cells (e.g. natural killer cells, dendritic cells, and macrophages). Catumaxomab exerts its anti-tumor effects via T-cell-mediated lysis, antibody-dependent, cell-mediated cytotoxicity, and phagocytosis via activation of FcγR-positive accessory cells. Catumaxomab represents a self-supporting system, as no additional immune cell activation is required for tumor eradication. The efficacy and safety of catumaxomab have been demonstrated in a pivotal phase II/III study in malignant ascites (MA) and supporting phase I/II studies. It is administered as four intraperitoneal (i.p.) infusions of 10, 20, 50, and 150 µg on days 0, 3, 7, and 10, respectively. Catumaxomab was approved for the i.p. treatment of MA in patients with EpCAM-positive carcinomas where standard therapy is not available or no longer feasible in the European Union in April 2009. It is the first trAb and the first drug in the world approved specifically for the treatment of MA. Catumaxomab was awarded the Galen of Pergamon Prize, which recognizes pharmacological research for developing new and innovative drugs and diagnostics, in the specialist care category in 2010. The use of catumaxomab in other indications and additional routes of administration are currently being investigated to further exploit its therapeutic potential in EpCAM-positive carcinomas. PMID:21716847

  8. The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy.

    PubMed

    McKee, Ann C; Cairns, Nigel J; Dickson, Dennis W; Folkerth, Rebecca D; Keene, C Dirk; Litvan, Irene; Perl, Daniel P; Stein, Thor D; Vonsattel, Jean-Paul; Stewart, William; Tripodis, Yorghos; Crary, John F; Bieniek, Kevin F; Dams-O'Connor, Kristen; Alvarez, Victor E; Gordon, Wayne A

    2016-01-01

    Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer's disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen's kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen's kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II-III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation

  9. Successful Multidisciplinary Treatment with Secondary Metastatic Liver Resection after Downsizing by Palliative Second-Line Treatment of Colorectal Cancer: A Curative Option

    PubMed Central

    Wein, Axel; Siebler, Jürgen; Goertz, Ruediger; Wolff, Kerstin; Ostermeier, Nicola; Busse, Dagmar; Kremer, Andreas E.; Koch, Franz; Hagel, Alexander; Farnbacher, Michael; Kammerer, Ferdinand J.; Neurath, Markus F.; Gruetzmann, Robert

    2016-01-01

    Introduction The prognostic outcome following progression after palliative first-line treatment for patients suffering from metastatic colorectal adenocarcinoma is generally poor. Long-term relapse-free survival with palliative second-line treatment may be achieved in only a limited number of individual cases. Case Report A 37-year-old patient presented with bilobar liver metastases of colon cancer confirmed by histology with wild-type K-RAS (exon 2). Due to progressive disease after eight cycles of first-line therapy with FOLFIRI plus cetuximab, second-line chemotherapy with modified FOLFOX4 (mFOLFOX4) plus bevacizumab was initiated. During four cycles of mFOLFOX4 plus bevacizumab (2 months), no higher-grade toxicity occurred. Liver MRI with contrast medium revealed downsizing of the segment II/III metastases, as well as regressive, small, faint, hardly definable lesions in segments VI and IVb. The interdisciplinary tumor board of the University of Erlangen thus decided to perform resection of the liver metastases. Segments II and III were resected, and the liver metastases in segments IVa and VI were excised (R0). Histopathology confirmed three of the R0-resected metastases to be completely necrotic, with residual scarring. As perioperative therapy, four additional cycles of mFOLFOX4 plus bevacizumab were administered postoperatively. No higher-grade toxicity was observed. Three years after the initial diagnosis, the patient is relapse free, professionally fully reintegrated, and has an excellent performance status. Conclusion Patients suffering from metastatic colorectal cancer may benefit from multidisciplinary treatment with secondary metastatic liver resection after downsizing by palliative second-line treatment. In individual cases, patients may even have a curative treatment option, provided that close interdisciplinary collaboration exists. PMID:27489542

  10. A non-randomized dose-escalation Phase I trial of a protein-based immunotherapeutic for the treatment of breast cancer patients with HER2-overexpressing tumors.

    PubMed

    Limentani, Steven A; Campone, Mario; Dorval, Thierry; Curigliano, Giuseppe; de Boer, Richard; Vogel, Charles; White, Shane; Bachelot, Thomas; Canon, Jean-Luc; Disis, Mary; Awada, Ahmad; Berlière, Martine; Amant, Frédéric; Levine, Ellis; Burny, Wivine; Callegaro, Andrea; de Sousa Alves, Pedro Miguel; Louahed, Jamila; Brichard, Vincent; Lehmann, Frédéric F

    2016-04-01

    This Phase I dose-escalation study (NCT00058526) assessed the safety and immunogenicity of an anti-cancer immunotherapeutic (recombinant HER2 protein (dHER2) combined with the immunostimulant AS15) in patients with early-stage HER2-overexpressing breast cancer (BC). Sixty-one trastuzumab-naive patients with stage II-III HER2-positive BC received the dHER2 immunotherapeutic after surgical resection and adjuvant therapy. They were allocated into four cohorts receiving different doses of dHER2 (20, 100, 500 µg) combined with a fixed AS15 dose. Safety and immunogenicity (dHER2-specific antibody responses) were assessed. After completing the immunization schedule (three or six doses over 14 weeks) and a six-month follow-up, the patients were followed for 5 years for late toxicity, long-term immunogenicity, and clinical status. The immunizations were well tolerated, and increasing doses of dHER2 had no impact on the frequency or severity of adverse events. Few late toxicities were reported, and after 5 years 45/54 patients (83.3 %) were still alive, while 28/45 (62 %) with known disease status were disease free. Regarding the immunogenicity of the compound, a positive association was found between the dHER2 dose, the immunization schedule, and the prevalence of dHER2-specific humoral responses. Among the patients receiving the most intense immunization schedule with the highest dHER2 dose, 6/8 maintained their dHER2-specific antibody response 5 years after immunization. The dHER2 immunotherapeutic had an acceptable safety profile in early HER2-positive BC patients. dHER2-specific antibody responses were induced, with the rate of responders increasing with the dHER2 dose and the number and frequency of immunizations. PMID:26993131

  11. Spot Scanning-Based Proton Therapy for Intracranial Meningioma: Long-Term Results From the Paul Scherrer Institute

    SciTech Connect

    Weber, Damien C.; Schneider, Ralf; Goitein, Gudrun; Koch, Tamara; Ares, Carmen; Geismar, Jan H.; Schertler, Andreas; Bolsi, Alessandra; Hug, Eugen B.

    2012-07-01

    Background: To assess the long-term clinical results of spot scanning proton therapy (PT) in the treatment of intracranial meningiomas. Patients and Methods: Thirty-nine patients with meningioma (histologically proven 34/39) were treated with PT between July 1997 and January 2010. Thirty-two (82.1%) patients were treated as primary treatment (exclusive PT, n = 8; postoperative PT, n = 24). Mean age was 48.3 {+-} 17.9 years and 32 (82.1%) patients had skull base lesions. For patients undergoing surgery, 24 patients had a diagnosis of World Health Organization (WHO) Grade I and 10 of a WHO Grade II/III meningioma, respectively. The female-to-male ratio was 3.3. The median administered dose was 56.0 Gy (relative biologic effectiveness [RBE]) (range, 52.2-66.6) at 1.8-2.0 Gy (RBE) per fraction. Gross tumor volume (GTV) ranged from 0.76 to 546.5 cm{sup 3} (median, 21.5). Late toxicity was assessed according to Common Terminology Criteria for Adverse Events version 3.0. Mean follow-up time was 62.0 months and all patients were followed for >6 months. Results: Six patients presented with tumor recurrence and 6 patients died during follow-up, of which 4 of tumor progression. Five-year actuarial local control and overall survival rates were 84.8% and 81.8%, respectively, for the entire cohort and 100% for benign histology. Cumulative 5-year Grade {>=}3 late toxicity-free survival was 84.5%. On univariate analysis, LC was negatively influenced by WHO grade (p = 0.001), GTV (p = 0.013), and male gender (p = 0.058). Conclusions: PT is a safe and effective treatment for patients with untreated, recurrent, or incompletely resected intracranial meningiomas. WHO grade and tumor volume was an adverse prognostic factor for local control.

  12. Increased brain uptake of gamma-aminobutyric acid in a rabbit model of hepatic encephalopathy

    SciTech Connect

    Bassett, M.L.; Mullen, K.D.; Scholz, B.; Fenstermacher, J.D.; Jones, E.A. )

    1990-03-01

    Transfer of the inhibitory neurotransmitter gamma-aminobutyric acid across the normal blood-brain barrier is minimal. One prerequisite for gamma-aminobutyric acid in plasma contributing to the neural inhibition of hepatic encephalopathy would be that increased transfer of gamma-aminobutyric acid across the blood-brain barrier occurs in liver failure. The aim of the present study was to determine if brain gamma-aminobutyric acid uptake is increased in rabbits with stage II-III (precoma) hepatic encephalopathy due to galactosamine-induced fulminant hepatic failure. A modification of the Oldendorf intracarotid artery-injection technique was applied. (3H) gamma-aminobutyric acid, (14C) butanol, and 113mIn-labeled serum protein (transferrin) were injected simultaneously 4 s before decapitation. The ipsilateral brain uptake index of gamma-aminobutyric acid was determined from measurements of the 3 isotopes in 5 brain regions. Uncorrected or simple brain uptake indices of (3H) gamma-aminobutyric acid and (113mIn) transferrin were calculated using (14C) butanol as the highly extracted reference compound. The (113mIn) transferrin data were also used to correct the brain uptake index of (3H) gamma-aminobutyric acid for intravascular retention of (3H) gamma-aminobutyric acid. The methodology adopted minimized problems attributable to rapid (3H) gamma-aminobutyric acid metabolism, and slow brain washout and recirculation of the radiolabeled tracers. Both the uncorrected and corrected brain uptake indices of gamma-aminobutyric acid as well as the simple brain uptake index of transferrin were significantly increased in both stage II and III hepatic encephalopathy in all brain regions studied. Moreover, these brain uptake indices were significantly greater in stage III hepatic encephalopathy than in stage II hepatic encephalopathy.

  13. Metastasis suppressor proteins in cutaneous squamous cell carcinoma.

    PubMed

    Bozdogan, Onder; Vargel, Ibrahim; Cavusoglu, Tarik; Karabulut, Ayse A; Karahan, Gurbet; Sayar, Nilufer; Atasoy, Pınar; Yulug, Isik G

    2016-07-01

    Cutaneous squamous cell carcinomas (cSCCs) are common human carcinomas. Despite having metastasizing capacities, they usually show less aggressive progression compared to squamous cell carcinoma (SCC) of other organs. Metastasis suppressor proteins (MSPs) are a group of proteins that control and slow-down the metastatic process. In this study, we established the importance of seven well-defined MSPs including NDRG1, NM23-H1, RhoGDI2, E-cadherin, CD82/KAI1, MKK4, and AKAP12 in cSCCs. Protein expression levels of the selected MSPs were detected in 32 cSCCs, 6 in situ SCCs, and two skin cell lines (HaCaT, A-431) by immunohistochemistry. The results were evaluated semi-quantitatively using the HSCORE system. In addition, mRNA expression levels were detected by qRT-PCR in the cell lines. The HSCOREs of NM23-H1 were similar in cSCCs and normal skin tissues, while RGHOGDI2, E-cadherin and AKAP12 were significantly downregulated in cSCCs compared to normal skin. The levels of MKK4, NDRG1 and CD82 were partially conserved in cSCCs. In stage I SCCs, nuclear staining of NM23-H1 (NM23-H1nuc) was significantly lower than in stage II/III SCCs. Only nuclear staining of MKK4 (MKK4nuc) showed significantly higher scores in in situ carcinomas compared to invasive SCCs. In conclusion, similar to other human tumors, we have demonstrated complex differential expression patterns for the MSPs in in-situ and invasive cSCCs. This complex MSP signature warrants further biological and experimental pathway research. PMID:27215390

  14. Detection of mammaglobin mRNA in peripheral blood is associated with high grade breast cancer: Interim results of a prospective cohort study

    PubMed Central

    Mikhitarian, Kaidi; Martin, Renee Hebert; Ruppel, Megan Baker; Gillanders, William E; Hoda, Rana; Schutte, Del H; Callahan, Kathi; Mitas, Michael; Cole, David J

    2008-01-01

    Background We sought to examine the detection rate of cancer cells in peripheral blood (PBL) and in bone marrow (BM) using an established 7-gene marker panel and evaluated whether there were any definable associations of any individual gene with traditional predictors of prognosis. Methods Patients with T1-T3 primary breast cancer were enrolled into a prospective, multi-institutional cohort study. In this interim analysis 215 PBL and 177 BM samples were analyzed by multimarker, real-time RT-PCR analysis designed to detect circulating and disseminated breast cancer cells. Results At a threshold of three standard deviations from the mean expression level of normal controls, 63% (136/215) of PBL and 11% (19/177) of BM samples were positive for at least one cancer-associated marker. Marker positivity in PBL demonstrated a statistically significant association with grade II-III (vs. grade I; p = 0.0083). Overexpression of the mammaglobin (mam) gene alone had a statistically significant association with high tumor grade (p = 0.0315), and showed a trend towards ER-negative tumors and a high risk category. There was no association between marker positivity in PBL and the pathologic (H&E) and/or molecular (RT-PCR) status of the axillary lymph nodes (ALN). Conclusion This study suggests that molecular detection of circulating cancer cells in PBL detected by RT-PCR is associated with high tumor grade and specifically that overexpression of the mam gene in PBL may be a poor prognostic indicator. There was no statistically significant association between overexpression of cancer-associated genes in PBL and ALN status, supporting the concept of two potentially separate metastatic pathways. PMID:18289390

  15. Helical Tomotherapy of Nasopharyngeal Carcinoma-Any Advantages Over Conventional Intensity-Modulated Radiotherapy?

    SciTech Connect

    Wu, W.C. Vincent Mui, Wing-lun A.; Fung, Wing-ki W.

    2010-07-01

    Helical tomotherapy uses different planning algorithm and dose delivery method from the linear accelerator (linac)-based intensity-modulated radiotherapy (IMRT). This study compared the dosimetric outcomes between the tomotherapy plans and conventional linac-based IMRT plans in the treatment of nasopharyngeal carcinoma (NPC). Fifteen stage II-III cancer (American Joint Committee on Cancer) NPC patients treated by tomotherapy were conveniently recruited. Apart from the tomotherapy plans, a 7-field 6-MV photon conventional IMRT plan was computed for each patient with the same CT dataset and reference from the dose constraints and target dose prescriptions of the tomotherapy plans using the XiO treatment planning system. Average values of the dose parameters including the conformity index (CI), homogeneity index (HI), maximum and minimum doses of the target volumes, and the maximum and mean doses of the organs at risk (OAR) were compared between the two treatment methods. Better dose coverage of the planning target volume (PTV) was demonstrated in the tomotherapy plans, in which the differences in the maximum and mean doses reached statistical significance (p < 0.05). Besides, the CI of the tomotherapy plans were significantly higher than the conventional linac-based plans for the nasopharynx PTV (NP-PTV) and neck lymphatics PTV (LN-PTV) (p = 0.017 and 0.010, respectively). The HI was significantly smaller in both NP-PTV and LN-PTV (p = 0.024 and < 0.001, respectively). Among the OAR, the brain stem and spinal cord doses in the tomotherapy plans were lower than that of the conventional IMRT plans. However, the doses to the other OAR did not show significant dosimetric differences. In the treatment of nasopharyngeal carcinoma, tomotherapy plans were superior to the 7-field conventional IMRT plans in PTV dose conformity and homogeneity and the sparing of the brain stem and spinal cord. However, no significant advantages were observed for the rest of the OAR.

  16. Lung tissue proteomics identifies elevated transglutaminase 2 levels in stable chronic obstructive pulmonary disease.

    PubMed

    Ohlmeier, Steffen; Nieminen, Pentti; Gao, Jing; Kanerva, Tinja; Rönty, Mikko; Toljamo, Tuula; Bergmann, Ulrich; Mazur, Witold; Pulkkinen, Ville

    2016-06-01

    Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by irreversible airflow limitation. Cigarette smoking represents the main risk factor, but the specific mechanisms of COPD are not completely understood. Our aim was to identify COPD-specific proteomic changes involved in disease onset and severity. A comparative proteomic analysis of 51 lung tissues from nonsmokers, smokers, smokers with mild to moderate (stage I-II) COPD, severe to very severe COPD (stage III-IV), and patients with α-1-antitrypsin deficiency (AATD) and idiopathic pulmonary fibrosis (IPF) was performed by cysteine-specific two-dimensional difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry. Selected COPD-specific changes were validated by immunoblotting and further by ELISA in 120 induced sputum and plasma samples from nonsmokers, smokers, and patients with COPD (stage I-III). Altogether 82 altered proteins were identified comprising COPD-, AATD-, and IPF-specific, overlapping, and unspecific changes. Cathepsin D (CTSD), dihydropyrimidinase-related protein 2 (DPYSL2), transglutaminase 2 (TGM2), and tripeptidyl-peptidase 1 (TPP1) were validated as COPD-specific. TGM2 was not associated with smoking and correlated with COPD severity in lung tissue. TGM2 levels in sputum and plasma were elevated in patients with COPD (stage II-III) and correlated with lung function. In conclusion, new proteins related to COPD onset and severity could be identified with TGM2 being a novel potential diagnostic and therapeutic target for COPD. Further studies in carefully characterized cohorts are required to validate the identified changes. PMID:27084846

  17. Influence of Triply-Charged Ions and Ionization Cross-Sections in a Hybrid-PIC Model of a Hall Thruster Discharge

    NASA Technical Reports Server (NTRS)

    Smith, Brandon D.; Boyd, Iain D.; Kamhawi, Hani

    2014-01-01

    The sensitivity of xenon ionization rates to collision cross-sections is studied within the framework of a hybrid-PIC model of a Hall thruster discharge. A revised curve fit based on the Drawin form is proposed and is shown to better reproduce the measured crosssections at high electron energies, with differences in the integrated rate coefficients being on the order of 10% for electron temperatures between 20 eV and 30 eV. The revised fit is implemented into HPHall and the updated model is used to simulate NASA's HiVHAc EDU2 Hall thruster at discharge voltages of 300, 400, and 500 V. For all three operating points, the revised cross-sections result in an increase in the predicted thrust and anode efficiency, reducing the error relative to experimental performance measurements. Electron temperature and ionization reaction rates are shown to follow the trends expected based on the integrated rate coefficients. The effects of triply-charged xenon are also assessed. The predicted thruster performance is found to have little or no dependence on the presence of triply-charged ions. The fraction of ion current carried by triply-charged ions is found to be on the order of 1% and increases slightly with increasing discharge voltage. The reaction rates for the 0?III, I?III, and II?III ionization reactions are found to be of similar order of magnitude and are about one order of magnitude smaller than the rate of 0?II ionization in the discharge channel.

  18. Clark Level Risk Stratifies Patients with Mitogenic Thin Melanomas for Sentinel Lymph Node Biopsy

    PubMed Central

    Bartlett, Edmund K.; Gimotty, Phyllis A.; Sinnamon, Andrew J.; Wachtel, Heather; Roses, Robert E.; Schuchter, Lynn; Xu, Xiaowei; Elder, David E.; Ming, Michael; Elenitsas, Rosalie; Guerry, DuPont; Kelz, Rachel R.; Czerniecki, Brian J.; Fraker, Douglas L.; Karakousis, Giorgos C.

    2014-01-01

    Background The role for sentinel lymph node biopsy (SLNB) in patients with thin melanoma (≤1mm) remains controversial. We examined a large cohort of patients with thin melanoma to better define predictors of SLN positivity. Methods Between 1995-2011, 781 patients with thin primary melanoma and evaluable clinicopathologic data underwent SLNB at our institution. Predictors of SLN positivity were determined using univariate and multivariate regression analyses, and patients were risk-stratified using a classification and regression tree (CART) analysis. Results In the study cohort (n=781), 29 patients (3.7%) had nodal metastases. In the univariate analysis, mitotic rate (OR=8.11, p=0.005), Clark level (OR=4.04, p=0.003), and thickness (OR=3.33, p=0.011) were significantly associated with SLN positivity. In the multivariate analysis, MR (OR=7.01) and level IV-V (OR=3.45) remained significant predictors of SLN positivity. CART analysis initially stratified lesions by mitotic rate; non-mitogenic lesions (n=273) had a 0.7% SLN positivity rate versus 5.6% in mitogenic lesions (n=425). Mitogenic lesions were further stratified by Clark level; patients with level II-III had a 2.9% SLN positivity rate (n=205) versus 8.2% with level IV-V (n=220). With median follow up of 6.3 years, 5 SLN negative patients developed nodal recurrence and 4 SLN positive patients died of disease. Conclusion SLN positivity is low in patients with thin melanoma (3.7%) and exceedingly so in non-mitogenic lesions (0.7%). Appreciable rates of SLN positivity can be identified in patients with mitogenic lesions, particularly with concurrent level IV-V regardless of thickness. These factors may guide appropriate selection of patients with thin melanoma for SLNB. PMID:24121883

  19. VHZ is a novel centrosomal phosphatase associated with cell growth and human primary cancers

    PubMed Central

    2010-01-01

    Background VHZ is a VH1-like (member Z) dual specific protein phosphatase encoded by DUSP23 gene. Some of the dual specific protein phosphatases (DSPs) play an important role in cell cycle control and have shown to be associated with carcinogenesis. Here, the expression of VHZ associated with cell growth and human cancers was investigated. Results We generated a mouse monoclonal antibody (mAb clone#209) and rabbit polyclonal antibodies (rAb) against VHZ. We performed cell proliferation assay to learn how VHZ is associated with cell cycle by retroviral transduction to express VHZ, VHZ(C95S), and control vector in MCF-7 cells. Overexpression of VHZ [but not VHZ(C95S)] in MCF-7 cells promoted cell proliferation compared to control cells. shRNA-mediated knockdown of VHZ in MCF-7 cells showed that reduction of VHZ resulted in increased G1 but decreased S phase cell populations. Using indirect immunofluorescence, we showed that both exogenous and endogenous VHZ protein was localized at the centrosome in addition to its cytoplasmic distribution. Furthermore, using immunohistochemistry, we revealed that VHZ protein was overexpressed either in enlarged centrosomes (VHZ-centrosomal-stain) of some invasive ductal carcinomas (IDC) Stage I (8/65 cases) or in entire cytoplasm (VHZ-cytosol-stain) of invasive epithelia of some IDC Stage II/III (11/47 cases) of breast cancers examined. More importantly, upregulation of VHZ protein is also associated with numerous types of human cancer, in particular breast cancer. VHZ mAb may be useful as a reagent in clinical diagnosis for assessing VHZ positive tumors. Conclusions We generated a VHZ-specific mAb to reveal that VHZ has a novel subcellular localization, namely the centrosome. VHZ is able to facilitate G1/S cell cycle transition in a PTP activity-dependent manner. The upregulation of its protein levels in primary human cancers supports the clinical relevance of the protein in cancers. PMID:20509867

  20. Differential cortical laminar structure revealed by NeuN immunostaining and myeloarchitecture between sulcal and gyral regions independent of sexual dimorphisms in the ferret cerebrum.

    PubMed

    Horiuchi-Hirose, Miwa; Sawada, Kazuhiko

    2016-08-01

    The purpose of this study was to quantitatively clarify differences in laminar structure and myeloarchitecture of sulcal and gyral regions of the cerebral cortex of ferrets. Histological sections of cerebrum from male and female ferrets at postnatal day 90 were made at the coronal plane, and were immunostained with anti-NeuN or anti-myelin basic protein (MBP). Thickness was estimated in the entire depth or three strata, that is, layer I, outer (layers II-III) and inner (layers IV-VI) strata of the neocortex in representative five sulcal and seven gyral regions. As with the entire cortical depth, outer and inner strata were significantly thinner in the sulcal bottoms than in the gyral crowns, whereas layer I had about twofold greater thickness in the sulcal bottoms. However, thicknesses of the entire cortical depth and each cortical stratum were not statistically different among five sulcal regions or seven gyral regions examined. By MBP immunostaining, myelin fibers ran tangentially through the superficial regions of layer I in gyral crowns. Those fibers were relatively denser in gyri of frontal and temporal regions, and relatively sparse in gyri of parietal and occipital regions, although their density in any gyri was not different between sexes. These results show a differential laminar structure and myeloarchitecture between the sulcal and gyral regions of the ferret cerebral cortex present in both sexes. Myelination of layer I tangential fibers varied among primary gyri and was weaker in phylogenetically higher-order cortical gyri. Anat Rec, 299:1003-1011, 2016. © 2016 Wiley Periodicals, Inc. PMID:27144367