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Sample records for accelerated phase chronic

  1. 3-AP and Fludarabine in Treating Patients With Myeloproliferative Disorders, Chronic Myelomonocytic Leukemia, or Accelerated Phase or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-16

    Accelerated Phase Chronic Myelogenous Leukemia; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Blastic Phase Chronic Myelogenous Leukemia; Chronic Eosinophilic Leukemia; Chronic Myelomonocytic Leukemia; Essential Thrombocythemia; Philadelphia Chromosome Negative Chronic Myelogenous Leukemia; Polycythemia Vera; Primary Myelofibrosis; Relapsing Chronic Myelogenous Leukemia

  2. Pregnancy and Accelerated Phase of Myeloid Chronic Leukemia Treated with Imatinib: A Case Report from a Developing Country

    PubMed Central

    Ngolet, Lydie Ocini; Kocko, Innocent; Elira Dokekias, Alexis

    2016-01-01

    Background. Chronic myeloid leukemia is a hematological malignancy caused by expression of BCR-ABL tyrosine kinase oncogene, product of the t(9;22) Philadelphia translocation. Accelerated phase of this disease marks the onset of advanced rapidly progressive disease unresponsive to many therapies. Pregnancy limits broad number of therapies on patients because of their potential teratogenic effects. We report the case of a pregnant 34-year-old patient on accelerated phase successively managed by imatinib. She achieved a safe pregnancy and delivered at 39 weeks a healthy baby without congenital abnormalities. Our case is unusual because of the accelerated phase of the disease. Case Presentation. A 34-year-old African female with history of chronic phase of myeloid leukemia on imatinib, lost to follow-up for 4 months, presented to the hematological department for abdominal discomfort. Accelerated phase of chronic myeloid leukemia was diagnosed. Complete hematological response was achieved on high doses of imatinib. At the completion of 39 weeks, she delivered a healthy child without congenital anomalies. Conclusion. Despite its teratogenic and embryotoxic effects, front line imatinib is the only effective, well-tolerated treatment for patient on accelerated phase that can be offered to patients in sub-Saharan countries. PMID:27123350

  3. Secondary pulmonary alveolar proteinosis in a patient with chronic myeloid leukemia in the accelerated phase.

    PubMed

    Ohmachi, Ken; Ogiya, Daisuke; Morita, Fujiko; Kojima, Minoru; Tsuboi, Kosuke; Tazume, Kei; Komatsu, Masamichi; Hayama, Naoki; Kumaki, Nobue; Ogawa, Yoshiaki; Ando, Kiyoshi

    2008-12-01

    Pulmonary alveolar proteinosis (PAP) is a rare respiratory disease the character of which is accumulation of protein consisting of surfactant in alveolar spaces. PAP sometimes complicates with hematological malignancies, especially myeloid leukemia. As one of the cause of PAP, impairment of alveolar macrophage is considered. We experienced a case of PAP with chronic myeloid leukemia (CML). 41 years old woman having CML for nine years developed PAP, and was treated by bronchoalveolar lavage and imatinib. She died of respiratory failure in the end, but BAL fluid had been becoming gradually crystalline after induction of imatinib. We consider that we should try to treat to improve respiratory status not only PAP but also hematological disease. PMID:21318986

  4. Dasatinib in the Treatment of Chronic Myeloid Leukemia in Accelerated Phase After Imatinib Failure: The START A Trial

    PubMed Central

    Apperley, Jane F.; Cortes, Jorge E.; Kim, Dong-Wook; Roy, Lydia; Roboz, Gail J.; Rosti, Gianantonio; Bullorsky, Eduardo O.; Abruzzese, Elisabetta; Hochhaus, Andreas; Heim, Dominik; de Souza, Carmino A.; Larson, Richard A.; Lipton, Jeffrey H.; Khoury, H. Jean; Kim, Hyeoung-Joon; Sillaber, Christian; Hughes, Timothy P.; Erben, Philipp; Van Tornout, Jan; Stone, Richard M.

    2009-01-01

    Purpose Patients with chronic myelogenous leukemia in accelerated phase (CML-AP) that is resistant or intolerant to imatinib have limited therapeutic options. Dasatinib, a potent inhibitor of BCR-ABL and SRC-family kinases, has efficacy in patients with CML-AP who have experienced treatment failure with imatinib. We now report follow-up data from the full patient cohort of 174 patients enrolled onto a phase II trial to provide a more complete assessment of the efficacy and safety of dasatinib in this population. Patients and Methods Patients with imatinib-resistant (n = 161) or -intolerant (n = 13) CML-AP received dasatinib 70 mg orally twice daily. Results At a median follow-up of 14.1 months (treatment duration, 0.1 to 21.7 months), major and complete hematologic responses were attained by 64% and 45% of patients, respectively, and major and complete cytogenetic responses were achieved in 39% and 32% of patients, respectively. Responses were achieved irrespective of imatinib status (resistant or intolerant), prior stem-cell transplantation, or the presence of prior BCR-ABL mutation. The 12-month progression-free survival and overall survival rates were 66% and 82%, respectively. Dasatinib was generally well tolerated; the most frequent nonhematologic severe treatment-related adverse event was diarrhea (52%; grade 3 to 4, 8%). Cytopenias were common, including grade 3 to 4 neutropenia (76%) and thrombocytopenia (82%). Pleural effusion occurred in 27% of patients (grade 3 to 4, 5%). Conclusion Dasatinib is effective in patients with CML-AP after imatinib treatment failure. PMID:19487385

  5. Chronic acceleration and brain density

    NASA Technical Reports Server (NTRS)

    Hoffman, L. F.; Smith, A. H.

    1982-01-01

    Tests carried out on rabbits show that the effect of chronic acceleration is not uniform among the various tissues studied. Although body mass is reduced by the treatment, as expected, no change is apparent in brain mass or in the density of cerebrospinal fluid. Acceleration-induced changes are encountered in tissue density, the myocardium exhibiting a transient increase followed by an exponential decrease toward a limit and the brain showing an arithmetic increase in density with continued exposure to 2.5 G. The data are seen as suggesting that a specific brain load is not a regulated phenomenon and that no physiological processes occur to attenuate the increased load imposed by the hyperdynamic environment. An equation is derived indicating that the stimulus potential per unit of brain load increases with body size, even though brain density decreases and cerebrospinal fluid density increases.

  6. Embryonic development during chronic acceleration

    NASA Technical Reports Server (NTRS)

    Smith, A. H.; Abbott, U. K.

    1982-01-01

    Experiments carried out on chicken eggs indicate that the embryo is affected during very early development, especially over the first four days, and during hatching. In the first four days, the brain develops as well as the anlage for all other organs. In addition, the heart commences to function and the extraembryonic membranes that compartmentalize the egg contents form. The latter require an appreciable extension and folding of tissue which may be disrupted by the mechanical load. Observations of embryonic abnormalities that occur during chronic acceleration suggest an inhibition of development of the axial skeleton, which is rarely seen otherwise, a general retardation of embryonic growth, and circulatory problems. The final stages of development (after 18 days) involve the uptake of fluids, the transition to aerial respiration, and the reorientation of the embryo into a normal hatching position. At 4 G mortality is very high during this period, with a majority of embryos failing to reorient into the normal hatching position.

  7. Superiority of allogeneic hematopoietic stem cell transplantation to nilotinib and dasatinib for adult patients with chronic myelogenous leukemia in the accelerated phase.

    PubMed

    Xu, Lanping; Zhu, Huanling; Hu, Jianda; Wu, Depei; Jiang, Hao; Jiang, Qian; Huang, Xiaojun

    2015-09-01

    In the tyrosine kinase inhibitor (TKI) era, imatinib is the first-line therapy for patients with chronic myeloid leukemia (CML) in chronic or accelerated phase. Although second-generation TKIs (TKI2), including dasatinib and nilotinib, are appropriate treatment regimens for patients with disease that progressed to accelerated phase following imatinib therapy, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy. This study retrospectively analyzed the efficacy of TKI2 and HSCT for treatment of CML in accelerated phase. Ninety-three patients with CML registered in the Chinese CML alliance database from February 2001 to February 2014 were enrolled and divided into the TKI2 (n = 33) and allo-HSCT (n = 60) groups. In the TKI2 group, 26 and 7 patients received nilotinib and dasatinib, respectively, as initial TKI2 and 11 patients transferred to the alternative TKI2 after failure to one TKI2. In the allo-HSCT group, 22 (36.7%), 35 (58.3%), and 3 (10%) patients underwent allo-HSCT from an HLA-matched sibling donor, HLA mismatched/haploidentical donor, and unrelated donor, respectively. All patients in the HSCT group were engrafted. Overall, 69.7%, 48.5%, and 45.5% of patients presented hematological, cytogenetic, and major molecular responses, respectively, to at least one of TKI2. All 60 patients (100%) achieved CHR and cytogenetic response in the HSCT group. Patients in the TKI2 group exhibited lower 5-year overall survival rate (42.9% vs. 86.4%, P = 0.002), 5-year event-free survival rate (14.3% vs. 76.1%, P < 0.001), and 5-year progression-free survival (28.6% vs. 78.1%, P < 0.001) than those in the allo-HSCT group. Multivariate analysis showed that male sex and TKI2 therapy were predictors of poor overall survival, whereas hemoglobin < 100 g/L and TKI2 therapy were predictors of poor event-free survival and progression-free survival. These results indicated that allo-HSCT may be superior to nilotinib and dasatinib for adult

  8. Phase 3 study of dasatinib 140 mg once daily versus 70 mg twice daily in patients with chronic myeloid leukemia in accelerated phase resistant or intolerant to imatinib: 15-month median follow-up

    PubMed Central

    Cortes, Jorge; Kim, Dong-Wook; Dorlhiac-Llacer, Pedro; Pasquini, Ricardo; DiPersio, John; Müller, Martin C.; Radich, Jerald P.; Khoury, H. Jean; Khoroshko, Nina; Bradley-Garelik, M. Brigid; Zhu, Chao; Tallman, Martin S.

    2009-01-01

    Dasatinib is the most potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Studies have demonstrated the benefits of dasatinib 70 mg twice daily in patients with accelerated-phase chronic myeloid leukemia intolerant or resistant to imatinib. A phase 3 study compared the efficacy and safety of dasatinib 140 mg once daily with the current twice-daily regimen. Here, results from the subgroup with accelerated-phase chronic myeloid leukemia (n = 317) with a median follow-up of 15 months (treatment duration, 0.03-31.15 months) are reported. Among patients randomized to once-daily (n = 158) or twice-daily (n = 159) treatment, rates of major hematologic and cytogenetic responses were comparable (major hematologic response, 66% vs 68%; major cytogenetic response, 39% vs 43%, respectively). Estimated progression-free survival rates at 24 months were 51% and 55%, whereas overall survival rates were 63% versus 72%. Once-daily treatment was associated with an improved safety profile. In particular, significantly fewer patients in the once-daily group experienced a pleural effusion (all grades, 20% vs 39% P < .001). These results demonstrate that dasatinib 140 mg once daily has similar efficacy to dasatinib 70 mg twice daily but with an improved safety profile. This trial is registered at www.clinicaltrials.gov as #CA180-035. PMID:19369231

  9. Body size and chronic acceleration

    NASA Technical Reports Server (NTRS)

    Pitts, G. C.

    1976-01-01

    Experiments were conducted to study body composition as a function of acceleration (1-4.7 G) in mice and rats. It is shown that fat-free body mass is a predictable function of acceleration, and that of nine components of the fat-free body mass only skeletal muscle, liver and heart contributed to observed changes induced by delta G. Fat-free body mass was found to pass through a maximum at 1 G when it was plotted vs G for mice, rats and monkeys (1-4.7 G) and men (0-1 G).

  10. Temsirolimus and Imatinib Mesylate in Treating Patients With Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2013-01-11

    Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Relapsing Chronic Myelogenous Leukemia

  11. Accelerated Adaptive MGS Phase Retrieval

    NASA Technical Reports Server (NTRS)

    Lam, Raymond K.; Ohara, Catherine M.; Green, Joseph J.; Bikkannavar, Siddarayappa A.; Basinger, Scott A.; Redding, David C.; Shi, Fang

    2011-01-01

    The Modified Gerchberg-Saxton (MGS) algorithm is an image-based wavefront-sensing method that can turn any science instrument focal plane into a wavefront sensor. MGS characterizes optical systems by estimating the wavefront errors in the exit pupil using only intensity images of a star or other point source of light. This innovative implementation of MGS significantly accelerates the MGS phase retrieval algorithm by using stream-processing hardware on conventional graphics cards. Stream processing is a relatively new, yet powerful, paradigm to allow parallel processing of certain applications that apply single instructions to multiple data (SIMD). These stream processors are designed specifically to support large-scale parallel computing on a single graphics chip. Computationally intensive algorithms, such as the Fast Fourier Transform (FFT), are particularly well suited for this computing environment. This high-speed version of MGS exploits commercially available hardware to accomplish the same objective in a fraction of the original time. The exploit involves performing matrix calculations in nVidia graphic cards. The graphical processor unit (GPU) is hardware that is specialized for computationally intensive, highly parallel computation. From the software perspective, a parallel programming model is used, called CUDA, to transparently scale multicore parallelism in hardware. This technology gives computationally intensive applications access to the processing power of the nVidia GPUs through a C/C++ programming interface. The AAMGS (Accelerated Adaptive MGS) software takes advantage of these advanced technologies, to accelerate the optical phase error characterization. With a single PC that contains four nVidia GTX-280 graphic cards, the new implementation can process four images simultaneously to produce a JWST (James Webb Space Telescope) wavefront measurement 60 times faster than the previous code.

  12. Quasi-phase-matched laser wakefield acceleration.

    PubMed

    Yoon, S J; Palastro, J P; Milchberg, H M

    2014-04-01

    The energy gain in laser wakefield acceleration is ultimately limited by dephasing, occurring when accelerated electrons outrun the accelerating phase of the wakefield. We apply quasi-phase-matching, enabled by axially modulated plasma channels, to overcome this limitation. Theory and simulations are presented showing that weakly relativistic laser intensities can drive significant electron energy gains. PMID:24745430

  13. Phase motion of accelerated electrons in vacuum laser acceleration

    SciTech Connect

    Hua, J. F.; Lin, Y. Z.; Tang, Ch. X.; Ho, Y. K.; Kong, Q.

    2007-01-15

    The phase stability in the capture and acceleration scenario (CAS) is studied and compared with that of conventional linear electron accelerators (CLEAs). For the CAS case, it has been found that a slow phase slippage occurs due to the difference between the electron velocity and the phase velocity of the longitudinal accelerating electric field. Thus, CAS electrons cannot remain in a fixed small phase region of the accelerating field to obtain a quasimonoenergy gain in contrast to the stability of phase oscillation in CLEAs. Also, the energy spread of the output electron beam for the CAS case cannot be kept as small as the CLEA because there is no good phase bunching phenomenon generated by phase oscillation.

  14. Phase Stable Net Acceleration of Electrons From a Two-Stage Optical Accelerator

    SciTech Connect

    Sears, Christopher M.S.; Colby, Eric; England, R.J.; Ischebeck, Rasmus; McGuinness, Christopher; Nelson, Janice; Noble, Robert; Siemann, Robert H.; Spencer, James; Walz, Dieter; Plettner, Tomas; Byer, Robert L.; /Stanford U., Phys. Dept.

    2011-11-11

    In this article we demonstrate the net acceleration of relativistic electrons using a direct, in-vacuum interaction with a laser. In the experiment, an electron beam from a conventional accelerator is first energy modulated at optical frequencies in an inverse-free-electron-laser and bunched in a chicane. This is followed by a second stage optical accelerator to obtain net acceleration. The optical phase between accelerator stages is monitored and controlled in order to scan the accelerating phase and observe net acceleration and deceleration. Phase jitter measurements indicate control of the phase to {approx}13{sup o} allowing for stable net acceleration of electrons with lasers.

  15. Squirrel Monkey Requirements for Chronic Acceleration

    NASA Technical Reports Server (NTRS)

    Fuller, Charles A.

    1996-01-01

    This study examined: (1) the ability of a small non-human primate to tolerate chronic centrifugation on a centrifuge with a radius of 0.9 m, and (2) the influence of centrifuge radius on the response of primates to hyperdynamic fields. Eight adult male squirrel monkeys were exposed to 1.5 g via centrifugation at two different radii (0.9 m and 3.0 m). Body temperature, activity, feeding and drinking were monitored. These primates did tolerate and adapt to 1.5G via centrifugation on either radius centrifuge. The results show, however, that centrifuge radius does have an effect on the responses of the primate to the hyperdynamic environment. Adaptation to the hyperdynamic environment occurred more quickly on the larger centrifuge. This study demonstrates that a small, non-human primate model, such as the squirrel monkey, could be used on a 0.9 m radius centrifuge such as is being considered by the NASA Space Station Program.

  16. Phase I/II Study of Nilotinib/Ruxolitinb Therapy for TKI Resistant Ph-Leukemia

    ClinicalTrials.gov

    2016-03-04

    Chronic Phase Chronic Myeloid Leukemia; Accelerated Phase Chronic Myeloid Leukemia; Blastic Phase Chronic Myeloid Leukemia; Philadelphia Positive Acute Lymphoblastic Leukemia; Resistant to Tyrosine Kinase Inhibitor Therapy

  17. NeutroPhase® in chronic non-healing wounds

    PubMed Central

    Crew, John; Varilla, Randell; Rocas, Thomas Allandale; Debabov, Dmitri; Wang, Lu; Najafi, Azar; Rani, Suriani Abdul; Najafi, Ramin (Ron); Anderson, Mark

    2012-01-01

    Chronic non-healing wounds, such as venous stasis ulcers, diabetic ulcers, and pressure ulcers are serious unmet medical needs that affect a patient’s morbidity and mortality. Common pathogens observed in chronic non-healing wounds are Staphylococcus including MRSA, Pseudomonas, Enterobacter, Stenotrophomonas, and Serratia spp. Topical and systemically administered antibiotics do not adequately decrease the level of bacteria or the associated biofilm in chronic granulating wounds and the use of sub-lethal concentrations of antibiotics can lead to resistant phenotypes. Furthermore, topical antiseptics may not be fully effective and can actually impede wound healing. We show 5 representative examples from our more than 30 clinical case studies using NeutroPhase® as an irrigation solution with chronic non-healing wounds with and without the technique of negative pressure wound therapy (NPWT). NeutroPhase® is pure 0.01% hypochlorous acid (i.e. >97% relative molar distribution of active chlorine species as HOCl) in a 0.9% saline solution at pH 4-5 and is stored in glass containers. NovaBay has three FDA cleared 510(k)s. Patients showed a profound improvement and marked accelerated rates of wound healing using NeutroPhase® with and without NPWT. NeutroPhase® was non-toxic to living tissues. PMID:23272294

  18. NeutroPhase(®) in chronic non-healing wounds.

    PubMed

    Crew, John; Varilla, Randell; Rocas, Thomas Allandale; Debabov, Dmitri; Wang, Lu; Najafi, Azar; Rani, Suriani Abdul; Najafi, Ramin Ron; Anderson, Mark

    2012-01-01

    Chronic non-healing wounds, such as venous stasis ulcers, diabetic ulcers, and pressure ulcers are serious unmet medical needs that affect a patient's morbidity and mortality. Common pathogens observed in chronic non-healing wounds are Staphylococcus including MRSA, Pseudomonas, Enterobacter, Stenotrophomonas, and Serratia spp. Topical and systemically administered antibiotics do not adequately decrease the level of bacteria or the associated biofilm in chronic granulating wounds and the use of sub-lethal concentrations of antibiotics can lead to resistant phenotypes. Furthermore, topical antiseptics may not be fully effective and can actually impede wound healing. We show 5 representative examples from our more than 30 clinical case studies using NeutroPhase(®) as an irrigation solution with chronic non-healing wounds with and without the technique of negative pressure wound therapy (NPWT). NeutroPhase(®) is pure 0.01% hypochlorous acid (i.e. >97% relative molar distribution of active chlorine species as HOCl) in a 0.9% saline solution at pH 4-5 and is stored in glass containers. NovaBay has three FDA cleared 510(k)s. Patients showed a profound improvement and marked accelerated rates of wound healing using NeutroPhase(®) with and without NPWT. NeutroPhase(®) was non-toxic to living tissues. PMID:23272294

  19. Chronic acceleration and egg production in domestic fowl

    NASA Technical Reports Server (NTRS)

    Smith, A. H.; Besch, E. L.; Burton, R. R.

    1985-01-01

    A study of the influence of chronic acceleration on egg production of commercially raised hens placed on a large animal centrifuge at 90 days of age, was performed. S8 generation hens were stepped up from 1.25 G to 2 G, which was maintained for 30 days. Fifty percent ceased to be in the laying condition at 1.5 G, and 10.8 percent suffered oviduct prolapse above 1.8 G. S21 generation hens had no incidents of oviduct prolapse despite 170-day retention at 2 G, and, assuming a 30 percent population not in the laying condition, approximated the commercial production rate. Chronic acceleration did not appear to affect the relative sizes of albumen or yolk, but it did appear to reduce the relative shell size, consistent with a decrease in plasma calcium. Dry matter content was not affected.

  20. [Tolerance of +Gz accelerations in chronic compensated cardiac muscle disease].

    PubMed

    Suvorov, P M; Bykova, Iu I

    1975-01-01

    The functional potentialities of the cardiovascular system were investigated during an exposure of people with compensated chronic diseases of the cardiac muscle to acceleration (+Gz). The test subjects were exposed to acceleration of 3 and 5 g for 30 sec with an interval of 5 min. The parameters of hemodynamics, ECG and visual perception were recorded. The systolic blood volume, cardiac output and specific peripheral resistance were derived from the Bremser-Ranke formula. Seventy one subjects with heart diseases and 23 healthy subjects were examined. The subjects with myocardiodystrophy and myocarditic cardiosclerosis (12+/-16) showed a reduced tolerance to accelerations. During an exposure the subjects with atherosclerotic cardiosclerosis showed a higher pressure in vessels of ear conch than the healthy subjects. The myocardiodystrophic subjects frequently (20%) exhibited an inversion of electrocardiographic T2. The subjects with heart diseases (27-33%) showed extrasystolic disturbances. The results may be used in medical expertise of pilots. PMID:1214489

  1. A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy

    PubMed Central

    Borthakur, Gautam; Dombret, Herve; Schafhausen, Philippe; Brummendorf, Tim Henrik; Boissel, Nicolas; Jabbour, Elias; Mariani, Mariangela; Capolongo, Laura; Carpinelli, Patrizia; Davite, Cristina; Kantarjian, Hagop; Cortes, Jorge E.

    2015-01-01

    Danusertib is a pan-aurora kinase inhibitor with potent activity against Abl kinase including the gatekeeper T315I mutant. A phase 1 dose escalation study of danusertib was conducted in patients with accelerated or blastic phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Two dosing schedules were studied: schedule A, in which danusertib was given by 3-hour intravenous infusion daily for 7 consecutive days (days 1–7) in a 14-day cycle, and schedule B, in which the danusertib was given by 3-hour intravenous infusion daily for 14 consecutive days (days 1–14) in a 21-day cycle. A total of 37 patients were treated, 29 with schedule A and eight with schedule B. The recommended phase 2 dose for schedule A was 180 mg/m2. Enrollment to schedule B was stopped early because of logistical problems with the frequency of infusions. Febrile neutropenia and mucositis were dose-limiting toxicities in schedule A. Four patients with T315I ABL kinase mutation, all treated with schedule A, responded. Danusertib has an acceptable toxicity profile and is active in patients with Bcr-Abl-associated advanced hematologic malignancies. This study was registered with the European Clinical Trails Data Base (EudraCT number 2007-004070-18). PMID:25887498

  2. Regulation of body mass in rats exposed to chronic acceleration

    NASA Technical Reports Server (NTRS)

    Pitts, G. C.; Bull, L. S.; Oyama, J.

    1975-01-01

    Female rats approximately 6 mo old were chronically centrifuged for up to 30 days at 2.76 G or 3.18 G and sacrificed at intervals for body-composition study. Both fat and the fat-free body mass (FFBM) were reduced during the 1st wk of centrifugation, with the fat showing considerably more variation both within and between groups. The FFBM was reduced below control level to the same extent in rats fed commercial chow, a high-fat diet, or a high-protein diet or in rats prefasted to produce a body-mass deficit at the start of centrifugation. There were no centrifugation-associated changes in body water content. It was concluded that body fat showed no evidence of regulation, FFBM is regulated at any constant level of acceleration between 1 and 4.15 G, and the change in FFBM induced by a change in acceleration is probably not regulated.

  3. Optical Phase Locking of Modelocked Lasers for Particle Accelerators

    SciTech Connect

    Plettner, T.; Sinha, S.; Wisdom, J.; Colby, E.R.; /SLAC

    2006-02-17

    Particle accelerators require precise phase control of the electric field through the entire accelerator structure. Thus a future laser driven particle accelerator will require optical synchronism between the high-peak power laser sources that power the accelerator. The precise laser architecture for a laser driven particle accelerator is not determined yet, however it is clear that the ability to phase-lock independent modelocked oscillators will be of crucial importance. We report the present status on our work to demonstrate long term phaselocking between two modelocked lasers to within one degree of optical phase and describe the optical synchronization techniques that we employ.

  4. Chronic inflammation induces telomere dysfunction and accelerates ageing in mice

    PubMed Central

    Jurk, Diana; Wilson, Caroline; Passos, João F.; Oakley, Fiona; Correia-Melo, Clara; Greaves, Laura; Saretzki, Gabriele; Fox, Chris; Lawless, Conor; Anderson, Rhys; Hewitt, Graeme; Pender, Sylvia LF; Fullard, Nicola; Nelson, Glyn; Mann, Jelena; van de Sluis, Bart; Mann, Derek A.; von Zglinicki, Thomas

    2014-01-01

    Chronic inflammation is associated with normal and pathological ageing. Here we show that chronic, progressive low-grade inflammation induced by knockout of the nfkb1 subunit of the transcription factor NF-κB induces premature ageing in mice. We also show that these mice have reduced regeneration in liver and gut. nfkb1−/− fibroblasts exhibit aggravated cell senescence because of an enhanced autocrine and paracrine feedback through NF-κB, COX-2 and ROS, which stabilizes DNA damage. Preferential accumulation of telomere-dysfunctional senescent cells in nfkb1−/− tissues is blocked by anti-inflammatory or antioxidant treatment of mice, and this rescues tissue regenerative potential. Frequencies of senescent cells in liver and intestinal crypts quantitatively predict mean and maximum lifespan in both short- and long-lived mice cohorts. These data indicate that systemic chronic inflammation can accelerate ageing via ROS-mediated exacerbation of telomere dysfunction and cell senescence in the absence of any other genetic or environmental factor. PMID:24960204

  5. Accelerated atherosclerosis in patients with chronic inflammatory rheumatologic conditions

    PubMed Central

    Hong, Jison; Maron, David J; Shirai, Tsuyoshi; Weyand, Cornelia M

    2015-01-01

    Atherosclerosis is a complex inflammatory disease involving aberrant immune and tissue healing responses, which begins with endothelial dysfunction and ends with plaque development, instability and rupture. The increased risk for coronary artery disease in patients with rheumatologic diseases highlights how aberrancy in the innate and adaptive immune system may be central to development of both disease states and that atherosclerosis may be on a spectrum of immune-mediated conditions. Recognition of the tight association between chronic inflammatory disease and complications of atherosclerosis will impact the understanding of underlying pathogenic mechanisms and change diagnostic and therapeutic approaches in patients with rheumatologic syndromes as well as patients with coronary artery disease. In this review, we provide a summary of the role of the immune system in atherosclerosis, discuss the proposed mechanisms of accelerated atherosclerosis seen in association with rheumatologic diseases, evaluate the effect of immunosuppression on atherosclerosis and provide updates on available risk assessment tools, biomarkers and imaging modalities. PMID:27042216

  6. Induction accelerators for the phase rotator system

    SciTech Connect

    Reginato, Lou; Yu, Simon; Vanecek, Dave

    2001-07-30

    The principle of magnetic induction has been applied to the acceleration of high current beams in betatrons and a variety of induction accelerators. The linear induction accelerator (LIA) consists of a simple nonresonant structure where the drive voltage is applied to an axially symmetric gap that encloses a toroidal ferromagnetic material. The change in flux in the magnetic core induces an axial electric field that provides particle acceleration. This simple nonresonant (low Q) structure acts as a single turn transformer that can accelerate from hundreds of amperes to tens of kiloamperes, basically only limited by the drive impedance. The LIA is typically a low gradient structure that can provide acceleration fields of varying shapes and time durations from tens of nanoseconds to several microseconds. The efficiency of the LIA depends on the beam current and can exceed 50% if the beam current exceeds the magnetization current required by the ferromagnetic material. The acceleration voltage available is simply given by the expression V=A dB/dt. Hence, for a given cross section of material, the beam pulse duration influences the energy gain. Furthermore, a premium is put on minimizing the diameter, which impacts the total weight or cost of the magnetic material. The diameter doubly impacts the cost of the LIA since the power (cost) to drive the cores is proportional to the volume as well. The waveform requirements during the beam pulse makes it necessary to make provisions in the pulsing system to maintain the desired dB/dt during the useful part of the acceleration cycle. This is typically done two ways, by using the final stage of the pulse forming network (PFN) and by the pulse compensation network usually in close proximity of the acceleration cell. The choice of magnetic materials will be made by testing various materials both ferromagnetic and ferrimagnetic. These materials will include the nickel-iron, silicon steel amorphous and various types of ferrites not

  7. Tipifarnib in Treating Patients With Chronic Myeloid Leukemia, Chronic Myelomonocytic Leukemia, or Undifferentiated Myeloproliferative Disorders

    ClinicalTrials.gov

    2016-07-20

    Accelerated Phase of Disease; Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Myelomonocytic Leukemia; Chronic Phase of Disease; Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable; Recurrent Disease

  8. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina

    PubMed Central

    Wang, Jianxiang; Shen, Zhi-Xiang; Saglio, Giuseppe; Jin, Jie; Huang, He; Hu, Yu; Du, Xin; Li, Jianyong; Meng, Fanyi; Zhu, Huanling; Hu, Jianda; Wang, Jianmin; Hou, Ming; Hertle, Sabine; Menssen, Hans D.; Ortmann, Christine-Elke; Tribouley, Catherine; Yuan, Ye; Baccarani, Michele

    2015-01-01

    Treatment with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 is currently the standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP). In this study, we present results of the ENESTchina (Evaluating Nilotinib Efficacy and Safety in Clinical Trials–China) that was conducted to investigate nilotinib 300 mg twice daily vs imatinib 400 mg once daily in a Chinese population. ENESTchina met its primary end point with a statistically significant higher rate of major molecular response (MMR; BCR-ABL1 ≤0.1% on the International Scale) at 12 months in the nilotinib arm vs the imatinib arm (52.2% vs 27.8%; P < .0001), and MMR rates remained higher with nilotinib vs imatinib throughout the follow-up period. Rates of complete cytogenetic response (0% Philadelphia chromosome–positive [Ph+] metaphases by standard cytogenetics) were comparable and ≥80% by 24 months in both arms. The estimated rate of freedom from progression to accelerated phase/blast crisis at 24 months was 95.4% in each arm. The safety profiles of both drugs were similar to those from previous studies. In conclusion, rates of MMR at 12 months were superior with nilotinib vs imatinib in Chinese patients with newly diagnosed Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01275196. PMID:25766724

  9. Phase 3 study of nilotinib vs imatinib in Chinese patients with newly diagnosed chronic myeloid leukemia in chronic phase: ENESTchina.

    PubMed

    Wang, Jianxiang; Shen, Zhi-Xiang; Saglio, Giuseppe; Jin, Jie; Huang, He; Hu, Yu; Du, Xin; Li, Jianyong; Meng, Fanyi; Zhu, Huanling; Hu, Jianda; Wang, Jianmin; Hou, Ming; Hertle, Sabine; Menssen, Hans D; Ortmann, Christine-Elke; Tribouley, Catherine; Yuan, Ye; Baccarani, Michele; Huang, Xiaojun

    2015-04-30

    Treatment with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 is currently the standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP). In this study, we present results of the ENESTchina (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-China) that was conducted to investigate nilotinib 300 mg twice daily vs imatinib 400 mg once daily in a Chinese population. ENESTchina met its primary end point with a statistically significant higher rate of major molecular response (MMR; BCR-ABL1 ≤0.1% on the International Scale) at 12 months in the nilotinib arm vs the imatinib arm (52.2% vs 27.8%; P < .0001), and MMR rates remained higher with nilotinib vs imatinib throughout the follow-up period. Rates of complete cytogenetic response (0% Philadelphia chromosome-positive [Ph+] metaphases by standard cytogenetics) were comparable and ≥80% by 24 months in both arms. The estimated rate of freedom from progression to accelerated phase/blast crisis at 24 months was 95.4% in each arm. The safety profiles of both drugs were similar to those from previous studies. In conclusion, rates of MMR at 12 months were superior with nilotinib vs imatinib in Chinese patients with newly diagnosed Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01275196. PMID:25766724

  10. BCL11A expression in acute phase chronic myeloid leukemia.

    PubMed

    Yin, Jiawei; Zhang, Fan; Tao, Huiquan; Ma, Xiao; Su, Guangsong; Xie, Xiaoli; Xu, Zhongjuan; Zheng, Yanwen; Liu, Hong; He, Chao; Mao, Zhengwei Jenny; Wang, Zhiwei; Chang, Weirong; Gale, Robert Peter; Wu, Depei; Yin, Bin

    2016-08-01

    Chronic myeloid leukemia (CML) has chronic and acute phases. In chronic phase myeloid differentiation is preserved whereas in acute phase myeloid differentiation is blocked. Acute phase CML resembles acute myeloid leukemia (AML). Chronic phase CML is caused by BCR-ABL1. What additional mutation(s) cause transition to acute phase is unknown and may differ in different persons with CML. BCL11A encodes a transcription factor and is aberrantly-expressed in several haematological and solid neoplasms. We analyzed BCL11A mRNA levels in subjects with chronic and acute phase CML. BCL11A transcript levels were increased in subjects with CML in acute phase compared with those in normals and in subjects in chronic phase including some subjects studied in both phases. BCL11A mRNA levels were correlated with percent bone marrow blasts and significantly higher in lymphoid versus myeloid blast crisis. Differentiation of K562 with butyric acid, a CML cell line, decreased BCL11A mRNA levels. Cytology and flow cytometry analyses showed that ectopic expression of BCL11A in K562 cells blocked differentiation. These data suggest BCL11A may operate in transformation of CML from chronic to acute phase in some persons. PMID:27285855

  11. Accelerated Superposition State Molecular Dynamics for Condensed Phase Systems.

    PubMed

    Ceotto, Michele; Ayton, Gary S; Voth, Gregory A

    2008-04-01

    An extension of superposition state molecular dynamics (SSMD) [Venkatnathan and Voth J. Chem. Theory Comput. 2005, 1, 36] is presented with the goal to accelerate timescales and enable the study of "long-time" phenomena for condensed phase systems. It does not require any a priori knowledge about final and transition state configurations, or specific topologies. The system is induced to explore new configurations by virtue of a fictitious (free-particle-like) accelerating potential. The acceleration method can be applied to all degrees of freedom in the system and can be applied to condensed phases and fluids. PMID:26620930

  12. Acceleration of electrons during the flash phase of solar flares

    NASA Technical Reports Server (NTRS)

    Kane, S. R.

    1974-01-01

    The characteristics of the electron acceleration process operating during the flash phase of solar flares are deduced from the high time resolution observations of impulsive solar X rays greater than or equal to 10 keV and other flash phase emissions from small solar flares, and the implications of these findings are discussed.

  13. Cytomegalovirus-induced Hemorrhagic Colitis in a Patient with Chronic Myeloid Leukemia (Chronic Phase) on Dasatinib as an Upfront Therapy.

    PubMed

    Yassin, Mohamed A; Nashwan, Abdulqadir J; Soliman, Ashraf T; Yousif, Anil; Moustafa, Afra; AlBattah, Afaf; Mohamed, Shehab F; Mudawi, Deena S; Elkourashy, Sarah; Asaari, Deena-Raiza; Gutierrez, Hope-Love G; Almusharaf, Mohamed; Hussein, Radwa M; Moustafa, Abbas H; Derhoubi, Hatim El; Boukhris, Sarra; Kohla, Samah; AlDewik, Nader

    2015-01-01

    Dasatinib is a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase and accelerated (myeloid or lymphoid blast) phase, and CML with resistance or intolerance to prior therapy including imatinib and in adults with Ph+ acute lymphoblastic leukemia1 The most common adverse reactions (≥15%) in patients with newly diagnosed chronic-phase (CP) CML include myelosuppression, fluid retention, and diarrhea, whereas in patients with resistance or intolerance to prior imatinib therapy, side effects include myelosuppression, fluid retention, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. We report a 39-year-old Ethiopian female patient who received dasatinib as upfront therapy for the treatment of CP-CML who experienced chronic diarrhea for two months, which progressed to hemorrhagic colitis due to cytomegalovirus (CMV) infection of the colon. To our knowledge, this is the first case of CMV colitis in a patient receiving dasatinib as upfront therapy. PMID:26379451

  14. Cytomegalovirus-induced Hemorrhagic Colitis in a Patient with Chronic Myeloid Leukemia (Chronic Phase) on Dasatinib as an Upfront Therapy

    PubMed Central

    Yassin, Mohamed A; Nashwan, Abdulqadir J; Soliman, Ashraf T; Yousif, Anil; Moustafa, Afra; AlBattah, Afaf; Mohamed, Shehab F; Mudawi, Deena S; Elkourashy, Sarah; Asaari, Deena-Raiza; Gutierrez, Hope-Love G; Almusharaf, Mohamed; Hussein, Radwa M; Moustafa, Abbas H; Derhoubi, Hatim El; Boukhris, Sarra; Kohla, Samah; AlDewik, Nader

    2015-01-01

    Dasatinib is a kinase inhibitor indicated for the treatment of newly diagnosed adults with Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) in chronic phase and accelerated (myeloid or lymphoid blast) phase, and CML with resistance or intolerance to prior therapy including imatinib and in adults with Ph+ acute lymphoblastic leukemia1 The most common adverse reactions (≥15%) in patients with newly diagnosed chronic-phase (CP) CML include myelosuppression, fluid retention, and diarrhea, whereas in patients with resistance or intolerance to prior imatinib therapy, side effects include myelosuppression, fluid retention, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage. We report a 39-year-old Ethiopian female patient who received dasatinib as upfront therapy for the treatment of CP-CML who experienced chronic diarrhea for two months, which progressed to hemorrhagic colitis due to cytomegalovirus (CMV) infection of the colon. To our knowledge, this is the first case of CMV colitis in a patient receiving dasatinib as upfront therapy. PMID:26379451

  15. Scalar-field-dominated cosmology with a transient acceleration phase.

    PubMed

    Carvalho, F C; Alcaniz, J S; Lima, J A S; Silva, R

    2006-08-25

    A new cosmological scenario driven by a slow rolling homogeneous scalar field whose exponential potential V(Phi) has a quadratic dependence on the field Phi in addition to the standard linear term is discussed. The derived equation of state for the field predicts a transient accelerating phase, in which the Universe was decelerated in the past, began to accelerate at redshift z approximately 1, is currently accelerated, but, finally, will return to a decelerating phase in the future. This overall dynamic behavior is profoundly different from the standard evolution of the cold dark matter model with a cosmological constant, and may alleviate some conflicts in reconciling the idea of a dark-energy-dominated universe with observables in String or M theory. Some theoretical predictions for the present scalar field plus dark matter dominated stage are confronted with cosmological observations in order to test the viability of the scenario. PMID:17026287

  16. Accelerated Aging during Chronic Oxidative Stress: A Role for PARP-1

    PubMed Central

    Boesten, Daniëlle M. P. H. J.; de Vos-Houben, Joyce M. J.; Timmermans, Leen; den Hartog, Gertjan J. M.; Bast, Aalt; Hageman, Geja J.

    2013-01-01

    Oxidative stress plays a major role in the pathophysiology of chronic inflammatory disease and it has also been linked to accelerated telomere shortening. Telomeres are specialized structures at the ends of linear chromosomes that protect these ends from degradation and fusion. Telomeres shorten with each cell division eventually leading to cellular senescence. Research has shown that poly(ADP-ribose) polymerase-1 (PARP-1) and subtelomeric methylation play a role in telomere stability. We hypothesized that PARP-1 plays a role in accelerated aging in chronic inflammatory diseases due to its role as coactivator of NF-κb and AP-1. Therefore we evaluated the effect of chronic PARP-1 inhibition (by fisetin and minocycline) in human fibroblasts (HF) cultured under normal conditions and under conditions of chronic oxidative stress, induced by tert-butyl hydroperoxide (t-BHP). Results showed that PARP-1 inhibition under normal culturing conditions accelerated the rate of telomere shortening. However, under conditions of chronic oxidative stress, PARP-1 inhibition did not show accelerated telomere shortening. We also observed a strong correlation between telomere length and subtelomeric methylation status of HF cells. We conclude that chronic PARP-1 inhibition appears to be beneficial in conditions of chronic oxidative stress but may be detrimental under relatively normal conditions. PMID:24319532

  17. Tapered plasma channels to phase-lock accelerating and focusing forces in laser-plasma accelerators

    SciTech Connect

    Rittershofer, W.; Schroeder, C.B.; Esarey, E.; Gruner, F.J.; Leemans, W.P.

    2010-05-17

    Tapered plasma channels are considered for controlling dephasing of a beam with respect to a plasma wave driven by a weakly-relativistic, short-pulse laser. Tapering allows for enhanced energy gain in a single laser plasma accelerator stage. Expressions are derived for the taper, or longitudinal plasma density variation, required to maintain a beam at a constant phase in the longitudinal and/or transverse fields of the plasma wave. In a plasma channel, the phase velocities of the longitudinal and transverse fields differ, and, hence, the required tapering differs. The length over which the tapered plasma density becomes singular is calculated. Linear plasma tapering as well as discontinuous plasma tapering, which moves beams to adjacent plasma wave buckets, are also considered. The energy gain of an accelerated electron in a tapered laser-plasma accelerator is calculated and the laser pulse length to optimize the energy gain is determined.

  18. Bosutinib Versus Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: Results From the BELA Trial

    PubMed Central

    Cortes, Jorge E.; Kim, Dong-Wook; Kantarjian, Hagop M.; Brümmendorf, Tim H.; Dyagil, Irina; Griskevicius, Laimonas; Malhotra, Hemant; Powell, Christine; Gogat, Karïn; Countouriotis, Athena M.; Gambacorti-Passerini, Carlo

    2012-01-01

    Purpose Bosutinib is an oral Src/Abl tyrosine kinase inhibitor. The phase III Bosutinib Efficacy and Safety in Newly Diagnosed Chronic Myeloid Leukemia (BELA) trial compared bosutinib with imatinib in newly diagnosed, chronic-phase chronic myeloid leukemia (CML). Patients and Methods A total of 502 patients were randomly assigned 1:1 to bosutinib 500 mg per day or imatinib 400 mg per day. Results The complete cytogenetic response (CCyR) rate at 12 months was not different for bosutinib (70%; 95% CI, 64% to 76%) versus imatinib (68%; 95% CI, 62% to 74%; two-sided P = .601); therefore, the study did not achieve its primary end point. The major molecular response (MMR) rate at 12 months was higher with bosutinib (41%; 95% CI, 35% to 47%) compared with imatinib (27%; 95% CI, 22% to 33%; two-sided P < .001). Time to CCyR and MMR was faster with bosutinib compared with imatinib (two-sided P < .001 for both). On-treatment transformation to accelerated/blast phase occurred in four patients (2%) on bosutinib compared with 10 patients (4%) on imatinib. A total of three CML-related deaths occurred on the bosutinib arm compared with eight on the imatinib arm. The safety profiles of bosutinib and imatinib were distinct; GI and liver-related events were more frequent with bosutinib, whereas neutropenia, musculoskeletal disorders, and edema were more frequent with imatinib. Conclusion This ongoing trial did not meet its primary end point of CCyR at 12 months, despite the observed higher MMR rate at 12 months, faster times to CCyR and MMR, fewer on-treatment transformations to accelerated/blast phase, and fewer CML-related deaths with bosutinib compared with imatinib. Each drug had a distinct safety profile. PMID:22949154

  19. Accelerated sintering in phase-separating nanostructured alloys

    PubMed Central

    Park, Mansoo; Schuh, Christopher A.

    2015-01-01

    Sintering of powders is a common means of producing bulk materials when melt casting is impossible or does not achieve a desired microstructure, and has long been pursued for nanocrystalline materials in particular. Acceleration of sintering is desirable to lower processing temperatures and times, and thus to limit undesirable microstructure evolution. Here we show that markedly enhanced sintering is possible in some nanocrystalline alloys. In a nanostructured W–Cr alloy, sintering sets on at a very low temperature that is commensurate with phase separation to form a Cr-rich phase with a nanoscale arrangement that supports rapid diffusional transport. The method permits bulk full density specimens with nanoscale grains, produced during a sintering cycle involving no applied stress. We further show that such accelerated sintering can be evoked by design in other nanocrystalline alloys, opening the door to a variety of nanostructured bulk materials processed in arbitrary shapes from powder inputs. PMID:25901420

  20. Accelerated sintering in phase-separating nanostructured alloys.

    PubMed

    Park, Mansoo; Schuh, Christopher A

    2015-01-01

    Sintering of powders is a common means of producing bulk materials when melt casting is impossible or does not achieve a desired microstructure, and has long been pursued for nanocrystalline materials in particular. Acceleration of sintering is desirable to lower processing temperatures and times, and thus to limit undesirable microstructure evolution. Here we show that markedly enhanced sintering is possible in some nanocrystalline alloys. In a nanostructured W-Cr alloy, sintering sets on at a very low temperature that is commensurate with phase separation to form a Cr-rich phase with a nanoscale arrangement that supports rapid diffusional transport. The method permits bulk full density specimens with nanoscale grains, produced during a sintering cycle involving no applied stress. We further show that such accelerated sintering can be evoked by design in other nanocrystalline alloys, opening the door to a variety of nanostructured bulk materials processed in arbitrary shapes from powder inputs. PMID:25901420

  1. Accelerated nanoscale magnetic resonance imaging through phase multiplexing

    SciTech Connect

    Moores, B. A.; Eichler, A. Takahashi, H.; Navaretti, P.; Degen, C. L.; Tao, Y.

    2015-05-25

    We report a method for accelerated nanoscale nuclear magnetic resonance imaging by detecting several signals in parallel. Our technique relies on phase multiplexing, where the signals from different nuclear spin ensembles are encoded in the phase of an ultrasensitive magnetic detector. We demonstrate this technique by simultaneously acquiring statistically polarized spin signals from two different nuclear species ({sup 1}H, {sup 19}F) and from up to six spatial locations in a nanowire test sample using a magnetic resonance force microscope. We obtain one-dimensional imaging resolution better than 5 nm, and subnanometer positional accuracy.

  2. Accelerated nanoscale magnetic resonance imaging through phase multiplexing

    NASA Astrophysics Data System (ADS)

    Moores, B. A.; Eichler, A.; Tao, Y.; Takahashi, H.; Navaretti, P.; Degen, C. L.

    2015-05-01

    We report a method for accelerated nanoscale nuclear magnetic resonance imaging by detecting several signals in parallel. Our technique relies on phase multiplexing, where the signals from different nuclear spin ensembles are encoded in the phase of an ultrasensitive magnetic detector. We demonstrate this technique by simultaneously acquiring statistically polarized spin signals from two different nuclear species (1H, 19F) and from up to six spatial locations in a nanowire test sample using a magnetic resonance force microscope. We obtain one-dimensional imaging resolution better than 5 nm, and subnanometer positional accuracy.

  3. Gravity currents down a slope in the acceleration phase

    NASA Astrophysics Data System (ADS)

    Huang, Yu-Lin; Dai, Albert

    2015-11-01

    Gravity currents generated from an instantaneous buoyancy source propagating down a slope in the range of 0° <= θ <90° have been investigated. Front velocity history shows that, after the heavy fluid is released from rest, the flow goes through the acceleration phase, reaching a maximum front velocity Uf ,max, and followed by the deceleration phase. The existence of a maximum of Uf ,max is found near θ =40° , which is supported by the theory. It is identified that the time of acceleration decreases as the slope angle increases, when the slope angle is approximately greater than 10°, and the time of acceleration increases as the slope angle increases for gravity currents on lower slope angles. A fundamental difference in flow patterns, which helps explain the distinct characteristics of gravity currents on high and low slope angles using scaling arguments, is revealed. Energy budgets further show that, as the slope angle increases, the ambient fluid is more easily engaged in the gravitational convection and the potential energy loss is more efficiently converted into the kinetic energy associated with ambient fluid. Supported by Taiwan Ministry of Science and Technology.

  4. Firstline treatment for chronic phase chronic myeloid leukemia patients should be based on a holistic approach.

    PubMed

    Breccia, Massimo; Alimena, Giuliana

    2015-02-01

    New selective and more potent drugs for the cure of chronic phase chronic myeloid leukemia patients are now available: physicians in some countries must decide the best option, selecting one of the drugs available. What the main prognostic factors are in order to make this selection remains a matter of discussion. Introducing a 'holistic approach' for the first time in chronic myeloid leukemia, as practiced in other diseases, and looking at the patient in a complete picture, considering several variables, such as comorbidities, age, concomitant drugs, lifestyle and patient expectations, may be of help to understand, patient by patient, the best therapeutic strategy. PMID:25431965

  5. Phase and Radial Motion in Ion Linear Accelerators

    SciTech Connect

    Takeda, H.; Billen, J. H.

    2007-03-29

    Parmila is an ion-linac particle-dynamics code. The name comes from the phrase, "Phase and Radial Motion in Ion Linear Accelerators." The code generates DTL, CCDTL, and CCL accelerating cells and, using a "drift-kick" method, transforms the beam, represented by a collection of particles, through the linac. The code includes a 2-D and 3-D space-charge calculations. Parmila uses data generated by the Poisson Superfish postprocessor SEC. This version of Parmila was written by Harunori Takeda and was supported through Feb. 2006 by James H. Billen. Setup installs executable programs Parmila.EXE, Lingraf.EXE, and ReadPMI.EXE in the LANL directory. The directory LANL\\Examples\\Parmila contains several subdirectories with sample files for Parmila.

  6. Phase and Radial Motion in Ion Linear Accelerators

    2007-03-29

    Parmila is an ion-linac particle-dynamics code. The name comes from the phrase, "Phase and Radial Motion in Ion Linear Accelerators." The code generates DTL, CCDTL, and CCL accelerating cells and, using a "drift-kick" method, transforms the beam, represented by a collection of particles, through the linac. The code includes a 2-D and 3-D space-charge calculations. Parmila uses data generated by the Poisson Superfish postprocessor SEC. This version of Parmila was written by Harunori Takeda andmore » was supported through Feb. 2006 by James H. Billen. Setup installs executable programs Parmila.EXE, Lingraf.EXE, and ReadPMI.EXE in the LANL directory. The directory LANL\\Examples\\Parmila contains several subdirectories with sample files for Parmila.« less

  7. Sustained acceleration of colonic transit following chronic homotypic stress in oxytocin knockout mice.

    PubMed

    Babygirija, Reji; Bülbül, Mehmet; Cerjak, Diana; Ludwig, Kirk; Takahashi, Toku

    2011-05-01

    Acute restraint stress delays gastric emptying and accelerates colonic transit via central corticotropin releasing factor (CRF) in rats. In contrast, central oxytocin has anxiolytic effects and attenuates the hypothalamus-pituitary-adrenal (HPA) axis in response to stress. Our recent study showed that up regulated oxytocin expression attenuates hypothalamic CRF expression and restores impaired gastric motility following chronic homotypic stress in mice. We studied the effects of acute and chronic homotypic stress on colonic transit and hypothalamic CRF mRNA expression in wild type (WT) and oxytocin knockout (OXT-KO) mice. Colonic transit was measured following acute restraint stress or chronic homotypic stress (repeated restraint stress for 5 consecutive days). (51)Cr was injected via a catheter into the proximal colon. Ninety minutes after restraint stress loading, the entire colon was removed. The geometric center (GC) was calculated to evaluate colonic transit. Expression of CRF mRNA in the supraoptic nucleus (SON) was measured by real time RT-PCR. Colonic transit was significantly accelerated following acute stress in WT (GC=8.1±0.8; n=7) and OXT KO mice (GC=9.4±0.3; n=7). The accelerated colonic transit was significantly attenuated in WT mice (GC=6.6±0.5; n=9) following chronic homotypic stress while it was still accelerated in OXT KO mice (GC=9.3±0.5; n=8). The increase in CRF mRNA expression at the SON was much greater in OXT-KO mice, compared to WT mice following chronic homotypic stress. It is suggested that oxytocin plays a pivotal role in mediating the adaptation mechanism following chronic homotypic stress in mice. PMID:21439349

  8. Vaccine Therapy Plus Immune Adjuvant in Treating Patients With Chronic Myeloid Leukemia, Acute Myeloid Leukemia, or Myelodysplastic Syndrome

    ClinicalTrials.gov

    2013-01-04

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Myeloid Leukemia in Remission; Chronic Phase Chronic Myelogenous Leukemia; Previously Treated Myelodysplastic Syndromes; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia

  9. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION).

    PubMed

    Kantarjian, Hagop M; Shah, Neil P; Cortes, Jorge E; Baccarani, Michele; Agarwal, Mohan B; Undurraga, María Soledad; Wang, Jianxiang; Ipiña, Juan Julio Kassack; Kim, Dong-Wook; Ogura, Michinori; Pavlovsky, Carolina; Junghanss, Christian; Milone, Jorge H; Nicolini, Franck E; Robak, Tadeusz; Van Droogenbroeck, Jan; Vellenga, Edo; Bradley-Garelik, M Brigid; Zhu, Chao; Hochhaus, Andreas

    2012-02-01

    Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247. PMID:22160483

  10. Dasatinib or imatinib in newly diagnosed chronic-phase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION)

    PubMed Central

    Shah, Neil P.; Cortes, Jorge E.; Baccarani, Michele; Agarwal, Mohan B.; Undurraga, María Soledad; Wang, Jianxiang; Kassack Ipiña, Juan Julio; Kim, Dong-Wook; Ogura, Michinori; Pavlovsky, Carolina; Junghanss, Christian; Milone, Jorge H.; Nicolini, Franck E.; Robak, Tadeusz; Van Droogenbroeck, Jan; Vellenga, Edo; Bradley-Garelik, M. Brigid; Zhu, Chao; Hochhaus, Andreas

    2012-01-01

    Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247. PMID:22160483

  11. Acceleration of the initial phase transformation of mineralization by phosvitin

    NASA Astrophysics Data System (ADS)

    Zhang, Xiaowei; Geng, Fang; Huang, Xi; Ma, Meihu

    2015-01-01

    Phosvitin has a similar structure and similar properties to the phosphorylated proteins that play an important role in biomineralization, suggesting that phosvitin may have similar regulation properties. This study investigated the effect of phosvitin on regulating the phase transformation of the mineral calcium phosphate in a biomimetic mineralization solution; the characterization techniques used were Fourier transform infrared spectroscopy, X-ray diffraction, scanning electron microscopy, energy dispersive spectroscopy and fluorescence spectroscopy. The results clearly demonstrated that phosvitin significantly promotes the initiation of phase transformation, accelerated the transformation process and shortened the transformation time from 6 to 0.5 h. Phosvitin was involved in the phase transformation and incorporated into or strongly absorbed on the mineral, as evidenced by the protein peaks observed in the FTIR spectra and XRD patterns. The effects of the substrate-addition sequence on the phase transformation demonstrated that the phosvitin-Ca2+ interaction played a key role in the regulation of mineralization. Compared with those for BSA, the results revealed that the role of phosvitin in mineralization is closely associated with its high level of phosphorylation. This study provides useful information about using phosvitin as a potential candidate for biomaterials.

  12. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study.

    PubMed

    Hochhaus, A; Rosti, G; Cross, N C P; Steegmann, J L; le Coutre, P; Ossenkoppele, G; Petrov, L; Masszi, T; Hellmann, A; Griskevicius, L; Wiktor-Jedrzejczak, W; Rea, D; Coriu, D; Brümmendorf, T H; Porkka, K; Saglio, G; Gastl, G; Müller, M C; Schuld, P; Di Matteo, P; Pellegrino, A; Dezzani, L; Mahon, F-X; Baccarani, M; Giles, F J

    2016-01-01

    The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR(4) (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10,000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR(4) at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal. PMID:26437782

  13. Frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the European ENEST1st study

    PubMed Central

    Hochhaus, A; Rosti, G; Cross, N C P; Steegmann, J L; le Coutre, P; Ossenkoppele, G; Petrov, L; Masszi, T; Hellmann, A; Griskevicius, L; Wiktor-Jedrzejczak, W; Rea, D; Coriu, D; Brümmendorf, T H; Porkka, K; Saglio, G; Gastl, G; Müller, M C; Schuld, P; Di Matteo, P; Pellegrino, A; Dezzani, L; Mahon, F-X; Baccarani, M; Giles, F J

    2016-01-01

    The Evaluating Nilotinib Efficacy and Safety in Clinical Trials as First-Line Treatment (ENEST1st) study included 1089 patients with newly diagnosed chronic myeloid leukemia in chronic phase. The rate of deep molecular response (MR4 (BCR-ABL1⩽0.01% on the International Scale or undetectable BCR-ABL1 with ⩾10 000 ABL1 transcripts)) at 18 months was evaluated as the primary end point, with molecular responses monitored by the European Treatment and Outcome Study network of standardized laboratories. This analysis was conducted after all patients had completed 24 months of study treatment (80.9% of patients) or discontinued early. In patients with typical BCR-ABL1 transcripts and ⩽3 months of prior imatinib therapy, 38.4% (404/1052) achieved MR4 at 18 months. Six patients (0.6%) developed accelerated or blastic phase, and 13 (1.2%) died. The safety profile of nilotinib was consistent with that of previous studies, although the frequencies of some nilotinib-associated adverse events were lower (for example, rash, 21.4%). Ischemic cardiovascular events occurred in 6.0% of patients. Routine monitoring of lipid and glucose levels was not mandated in the protocol. These results support the use of frontline nilotinib, particularly when achievement of a deep molecular response (a prerequisite for attempting treatment-free remission in clinical trials) is a treatment goal. PMID:26437782

  14. Chronic-phase chronic myeloid leukemia: Not always a reassuring diagnosis

    PubMed Central

    Orlandi, Ester M.; Elena, Chiara; Zibellini, Silvia

    2015-01-01

    Primary resistance to tyrosine-kinase inhibitors (TKIs) is quite uncommon in chronic-phase Chronic Myeloid Leukemia (CML) and related to still poorly understood mechanisms, as ABL mutations are rarely detected in primary resistant patients. We report the challenging case of a CML patient who was resistant to multiple TKIs because of different emerging ABL mutations and became pregnant while on Nilotinib therapy despite repeated and clear discouragement to conceive. She decided to continue with her pregnancy, showing an admirable and incredible perseverance in the pursuit of her personal aims. PMID:26266095

  15. Characterising the acceleration phase of blast wave formation

    SciTech Connect

    Fox, T. E. Pasley, J.; Robinson, A. P. L.; Schmitz, H.

    2014-10-15

    Intensely heated, localised regions in uniform fluids will rapidly expand and generate an outwardly propagating blast wave. The Sedov-Taylor self-similar solution for such blast waves has long been studied and applied to a variety of scenarios. A characteristic time for their formation has also long been identified using dimensional analysis, which by its very nature, can offer several interpretations. We propose that, rather than simply being a characteristic time, it may be interpreted as the definitive time taken for a blast wave resulting from an intense explosion in a uniform media to contain its maximum kinetic energy. A scaling relation for this measure of the acceleration phase, preceding the establishment of the blast wave, is presented and confirmed using a 1D planar hydrodynamic model.

  16. Impact of Baseline BCR-ABL Mutations on Response to Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase

    PubMed Central

    Hughes, Timothy; Saglio, Giuseppe; Branford, Susan; Soverini, Simona; Kim, Dong-Wook; Müller, Martin C.; Martinelli, Giovanni; Cortes, Jorge; Beppu, Lan; Gottardi, Enrico; Kim, Dongho; Erben, Philipp; Shou, Yaping; Haque, Ariful; Gallagher, Neil; Radich, Jerald; Hochhaus, Andreas

    2009-01-01

    Purpose Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. Patients and Methods Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. Results Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC50] ≤ 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC50 > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. Conclusion For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib. PMID:19652056

  17. Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia.

    PubMed

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Gozzini, Antonella; Usala, Emilio; Carella, Angelo M; Rege-Cambrin, Giovanna; Martino, Bruno; Abruzzese, Elisabetta; Albano, Francesco; Stagno, Fabio; Luciano, Luigia; D'Adda, Mariella; Bocchia, Monica; Cavazzini, Francesco; Tiribelli, Mario; Lunghi, Monia; Pia Falcone, Antonietta; Musolino, Caterina; Levato, Luciano; Venturi, Claudia; Soverini, Simona; Cavo, Michele; Alimena, Giuliana; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Rosti, Gianantonio; Baccarani, Michele

    2016-06-01

    The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use. Am. J. Hematol. 91:617-622, 2016. © 2016 Wiley Periodicals, Inc. PMID:26971721

  18. Management of Advanced-Phase Chronic Myelogenous Leukemia.

    PubMed

    Radich, Jerald P

    2016-05-01

    Chronic myelogenous leukemia represents the poster child of successful precision medicine in cancer, with amazing survival results achieved with targeted tyrosine kinase inhibitors (TKIs) in many patients with chronic-phase disease. Unfortunately, however, this good news has not extended to patients in blast crisis, for whom survival has not clearly been improved with TKIs. During his presentation at the NCCN 21st Annual Conference, Jerald P. Radich, MD, briefly explored the biology behind advanced-stage disease and several of the molecular findings in disease progression. He also reviewed some of the therapeutic options in advanced disease, emphasizing that transplantation, although fraught with some difficulties, offers the best long-term prognosis for patients in blast crisis. PMID:27226510

  19. Biomechanical Insights Into Differences Between the Mid-Acceleration and Maximum Velocity Phases of Sprinting.

    PubMed

    Yu, Jiabin; Sun, Yuliang; Yang, Chen; Wang, Donghai; Yin, Keyi; Herzog, Walter; Liu, Yu

    2016-07-01

    Yu, J, Sun, Y, Yang, C, Wang, D, Yin, K, Herzog, W, and Liu, Y. Biomechanical insights into differences between the mid-acceleration and maximum velocity phases of sprinting. J Strength Cond Res 30(7): 1906-1916, 2016-Investigating the differences between distinct phases of sprint running may increase the knowledge about the specific physical abilities needed for different phases of sprinting. Differences between the mid-acceleration and maximum velocity phases of sprint running have not yet been adequately investigated. Twenty male sprinters performed maximum-effort sprint runs, and measurements were made at 12 m from start for the mid-acceleration phase and at 40 m from the start for the maximum velocity phase. Kinematic data and ground reaction forces (GRFs) were collected at a rate of 200 and 1000 Hz, respectively. Intersegmental dynamics analysis was performed to investigate the interaction of muscle torque (MUS) with other passive torques. The peak horizontal braking force was significantly lower for the acceleration compared with that for the maximal velocity phase, whereas the peak horizontal propulsive force was similar for both phases. The peak MUS at the hip and knee joints for the braking phase was significantly smaller in the acceleration phase than in the maximum velocity phase. In conclusion, compared with the maximum velocity phase, the lower horizontal braking force was the primary cause for the increase in running velocity during the mid-acceleration phase. The force produced by lower limb muscles required to counteract external torques caused by the horizontal braking force in the braking phase was smaller during the acceleration phase than the maximum velocity phase. Therefore, training aimed at reducing the horizontal braking force might be more important than increasing the force produced by the lower limb muscles for success of the mid-acceleration phase. PMID:27331914

  20. Population pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia: results of a phase III study

    PubMed Central

    Schmidli, H; Peng, B; Riviere, G-J; Capdeville, R; Hensley, M; Gathmann, I; Bolton, A E; Racine-Poon, A

    2005-01-01

    Aims This study was designed to investigate the biochemical and physiological covariates or comedications that affect the pharmacokinetics of imatinib mesylate in patients with chronic-phase chronic myeloid leukaemia (CP CML). Methods Pharmacokinetic data were analyzed in 371 patients receiving 400 mg imatinib once daily during a phase III trial of imatinib vs interferon-alfa plus cytarabine for the treatment of newly diagnosed CP CML. Covariates included age, weight, sex, ethnicity, haemoglobin (Hb) concentration, white blood cell (WBC) count, liver function, and creatinine concentration. Blood samples for imatinib analysis were taken on treatment days 1 and 29. Nonlinear mixed effects modelling was used for the population pharmacokinetic analysis. Results Population mean estimates (95% confidence interval) at day 1 for apparent clearance (CL) and apparent volume of distribution (V) of imatinib were 14 (13–15) l h−1 and 252 (237–267) l, respectively. Modelling suggested that CL decreased by 4 (3-5) l h−1 from day 1 to day 29, whereas V remained unchanged. Interindividual variability in CL and V was 32% and 31%, respectively. Weight, Hb, and WBC count demonstrated small effects on CL and V. Doubling body weight or Hb or halving the WBC count was associated with a 12%, 86% and 8% increase in CL, respectively, and a 32%, 60% and 5% increase in V, respectively. Comedications showed no clear effects on imatinib CL. Conclusions Population covariates and coadministered drugs minimally affected imatinib pharmacokinetics in newly diagnosed CP CML patients. PMID:15963092

  1. Relationship between Acute Phase of Chronic Periodontitis and Meteorological Factors in the Maintenance Phase of Periodontal Treatment: A Pilot Study

    PubMed Central

    Takeuchi, Noriko; Ekuni, Daisuke; Tomofuji, Takaaki; Morita, Manabu

    2015-01-01

    The acute phase of chronic periodontitis may occur even in patients during supportive periodontal therapy. However, the details are not fully understood. Since the natural environment, including meteorology affects human health, we hypothesized that weather conditions may affect occurrence of acute phase of chronic periodontitis. The aim of this study was to investigate the relationship between weather conditions and acute phase of chronic periodontitis in patients under supportive periodontal therapy. Patients who were diagnosed with acute phase of chronic periodontitis under supportive periodontal therapy during 2011–2013 were selected for this study. We performed oral examinations and collected questionnaires and meteorological data. Of 369 patients who experienced acute phase of chronic periodontitis, 153 had acute phase of chronic periodontitis without direct-triggered episodes. When using the autoregressive integrated moving average model of time-series analysis, the independent covariant of maximum hourly range of barometric pressure, maximum hourly range of temperature, and maximum daily wind speed were significantly associated with occurrence of acute phase of chronic periodontitis (p < 0.05), and 3.1% of the variations in these occurrence over the study period were explained by these factors. Meteorological variables may predict occurrence of acute phase of chronic periodontitis. PMID:26251916

  2. Relationship between Acute Phase of Chronic Periodontitis and Meteorological Factors in the Maintenance Phase of Periodontal Treatment: A Pilot Study.

    PubMed

    Takeuchi, Noriko; Ekuni, Daisuke; Tomofuji, Takaaki; Morita, Manabu

    2015-08-01

    The acute phase of chronic periodontitis may occur even in patients during supportive periodontal therapy. However, the details are not fully understood. Since the natural environment, including meteorology affects human health, we hypothesized that weather conditions may affect occurrence of acute phase of chronic periodontitis. The aim of this study was to investigate the relationship between weather conditions and acute phase of chronic periodontitis in patients under supportive periodontal therapy. Patients who were diagnosed with acute phase of chronic periodontitis under supportive periodontal therapy during 2011-2013 were selected for this study. We performed oral examinations and collected questionnaires and meteorological data. Of 369 patients who experienced acute phase of chronic periodontitis, 153 had acute phase of chronic periodontitis without direct-triggered episodes. When using the autoregressive integrated moving average model of time-series analysis, the independent covariant of maximum hourly range of barometric pressure, maximum hourly range of temperature, and maximum daily wind speed were significantly associated with occurrence of acute phase of chronic periodontitis (p < 0.05), and 3.1% of the variations in these occurrence over the study period were explained by these factors. Meteorological variables may predict occurrence of acute phase of chronic periodontitis. PMID:26251916

  3. Prolonged cold ischemia accelerates cellular and humoral chronic rejection in a rat model of kidney allotransplantation.

    PubMed

    Solini, Samantha; Aiello, Sistiana; Cassis, Paola; Scudeletti, Pierangela; Azzollini, Nadia; Mister, Marilena; Rocchetta, Federica; Abbate, Mauro; Pereira, Rafael Luiz; Noris, Marina

    2012-03-01

    One of the leading causes of long-term kidney graft loss is chronic allograft injury (CAI), a pathological process triggered by alloantigen-dependent and alloantigen-independent factors. Alloantigen-independent factors, such as cold ischemia (CI) may amplify the recipient immune response against the graft. We investigated the impact of prolonged cold ischemia and the subsequent delayed graft function on CAI in a fully MHC-mismatched rat model of kidney allotransplantation. Prolonged CI was associated with anticipation of proteinuria onset and graft function deterioration (ischemia: 90d; no ischemia: 150d), more severe tubular atrophy, interstitial fibrosis, and glomerulosclerosis, and increased mortality rate (180d survival, ischemia: 0%; no ischemia: 67%). In ischemic allografts, T and B cells were detected very early and were organized in inflammatory clusters. Higher expression of BAFF-R and TACI within the ischemic allografts indicates that B cells are mature and activated. As a consequence of B cell activity, anti-donor antibodies, glomerular C4d and IgG deposition, important features of chronic humoral rejection, appeared earlier in ischemic than in non-ischemic allograft recipients. Thus, prolonged CI time plays a main role in CAI development by triggering acceleration of cellular and humoral reactions of chronic rejection. Limiting CI time should be considered as a main target in kidney transplantation. PMID:22239163

  4. Control of seeding phase for a cascaded laser wakefield accelerator with gradient injection

    SciTech Connect

    Wang, Wentao; Li, Wentao; Liu, Jiansheng; Wang, Cheng; Chen, Qiang; Zhang, Zhijun; Qi, Rong; Leng, Yuxin; Liang, Xiaoyan; Liu, Yanqi; Lu, Xiaoming; Wang, Cheng; Li, Ruxin; Xu, Zhizhan

    2013-12-09

    We demonstrated experimentally the seeding-phase control for a two-stage laser wakefield accelerator with gradient injection. By optimizing the seeding phase of electrons into the second stage, electron beams beyond 0.5 GeV with a 3% rms energy spread were produced over a short acceleration distance of ∼2 mm. Peak energy of the electron beam was further extended beyond 1 GeV by lengthening the second acceleration stage to 5 mm. Time-resolved magnetic field measurements via magneto-optical Faraday polarimetry allowed us to monitor the processes of electron seeding and acceleration in the second stage.

  5. Accelerating dual cardiac phase images using undersampled radial phase encoding trajectories.

    PubMed

    Letelier, Karis; Urbina, Jesus; Andía, Marcelo; Tejos, Cristián; Irarrazaval, Pablo; Prieto, Claudia; Uribe, Sergio

    2016-09-01

    A three-dimensional dual-cardiac-phase (3D-DCP) scan has been proposed to acquire two data sets of the whole heart and great vessels during the end-diastolic and end-systolic cardiac phases in a single free-breathing scan. This method has shown accurate assessment of cardiac anatomy and function but is limited by long acquisition times. This work proposes to accelerate the acquisition and reconstruction of 3D-DCP scans by exploiting redundant information of the outer k-space regions of both cardiac phases. This is achieved using a modified radial-phase-encoding trajectory and gridding reconstruction with uniform coil combination. The end-diastolic acquisition trajectory was angularly shifted with respect to the end-systolic phase. Initially, a fully-sampled 3D-DCP scan was acquired to determine the optimal percentage of the outer k-space data that can be combined between cardiac phases. Thereafter, prospectively undersampled data were reconstructed based on this percentage. As gold standard images, the undersampled data were also reconstructed using iterative SENSE. To validate the method, image quality assessments and a cardiac volume analysis were performed. The proposed method was tested in thirteen healthy volunteers (mean age, 30years). Prospectively undersampled data (R=4) reconstructed with 50% combination led high quality images. There were no significant differences in the image quality and in the cardiac volume analysis between our method and iterative SENSE. In addition, the proposed approach reduced the reconstruction time from 40min to 1min. In conclusion, the proposed method obtains 3D-DCP scans with an image quality comparable to those reconstructed with iterative SENSE, and within a clinically acceptable reconstruction time. PMID:27067473

  6. Coherent-phase or random-phase acceleration of electron beams in solar flares

    NASA Technical Reports Server (NTRS)

    Aschwanden, Markus J.; Benz, Arnold O.; Montello, Maria L.

    1994-01-01

    Time structures of electron beam signatures at radio wavelengths are investigated to probe correlated versus random behavior in solar flares. In particular we address the issue whether acceleration and injection of electron beams is coherently modulated by a single source, or whether the injection is driven by a stochastic (possibly spatially fragmented) process. We analyze a total of approximately = 6000 type III bursts observed by Ikarus (Zurich) in the frequency range of 100-500 MHz, during 359 solar flares with simultaneous greater than or = 25 keV hard X-ray emission, in the years 1890-1983. In 155 flares we find a total of 260 continuous type III groups, with an average number of 13 +/- 9 bursts per group, a mean duration of D = 12 +/- 14 s, a mean period of P = 2.0 +/- 1.2 s, with the highest burst rate at a frequency of nu = 310 +/- 120 MHz. Pulse periods have been measured between 0.5 and 10 s, and can be described by an exponential distribution, i.e., N(P) varies as e (exp -P/1.0s). The period shows a frequency dependence of P(nu)=46(exp-0.6)(sub MHz)s for different flares, but is invariant during a particular flare. We measure the mean period P and its standard deviation sigma (sub p) in each type III group, and quantify the degree of periodicity (or phase-coherence) by the dimensionless parameter sigma (sub p)P. The representative sample of 260 type III burst groups shows a mean periodicity of sigma (sub p/P) = 0.37 +/- 0.12, while Monte Carlo simulations of an equivalent set of truly random time series show a distinctly different value of sigma (sub p)P = 0.93 +/- 0.26. This result indicates that the injection of electron beams is coherently modulated by a particle acceleration source which is either compact or has a global organization on a timescale of seconds, in contrast to an incoherent acceleration source, which is stochastic either in time or space. We discuss the constraints on the size of the acceleration region resulting from electron beam

  7. Serum Hepcidin Predicts Uremic Accelerated Atherosclerosis in Chronic Hemodialysis Patients with Diabetic Nephropathy

    PubMed Central

    Li, Han; Feng, Su-Juan; Su, Lu-Lu; Wang, Wei; Zhang, Xiao-Dong; Wang, Shi-Xiang

    2015-01-01

    Background: Hepcidin, as a regulator of body iron stores, has been recently discovered to play a critical role in the pathogenesis of anemia of chronic disease. Atherosclerotic cardiovascular disease is the most common complication and the leading cause of death in chronic hemodialysis (CHD) patients. In the current study, we aimed to explore the relationship between serum hepcidin and uremic accelerated atherosclerosis (UAAS) in CHD patients with diabetic nephropathy (CHD/DN). Methods: A total of 78 CHD/DN and 86 chronic hemodialyzed nondiabetic patients with chronic glomerulonephritis (CHD/non-DN) were recruited in this study. The level of serum hepcidin-25 was specifically measured by liquid chromatography-tandem mass spectrometry. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. Results: High serum level of hepcidin-25 was seen in CHD patients. Serum hepcidin-25 in CHD/DN was significantly higher than that in CHD/non-DN patients. Serum hepcidin-25 was positively correlated with ferritin, high-sensitivity C-reactive protein (hs-CRP), TNF-α, and IL-6 in CHD/DN patients. CHD/DN patients exhibited higher common carotid artery intima media thickness (CCA-IMT), hs-CRP, and hepcidin-25 levels than that in CHD/non-DN patients. Moreover, in CHD/DN patients, CCA-IMT was positively correlated with serum hepcidin, hs-CRP, and low-density lipoprotein-cholesterol. On multiple regression analysis, serum hepcidin and hs-CRP level exhibited independent association with IMT in CHD/DN patients. Conclusions: These findings suggest possible linkage between iron metabolism and hepcidin modulation abnormalities that may contribute to the development of UAAS in CHD/DN patients. PMID:25963357

  8. Chediak-Higashi syndrome presenting in accelerated phase: A case report and literature review.

    PubMed

    Maaloul, I; Talmoudi, J; Chabchoub, I; Ayadi, L; Kamoun, T H; Boudawara, T; Kallel, C H; Hachicha, M

    2016-06-01

    Chediak-Higashi syndrome (CHS) is a rare autosomal recessive lysosomal disorder characterized by frequent infections, oculocutaneous albinism, bleeding diathesis, and progressive neurologic deterioration. In 85% of cases, CHS patients develop the accelerated phase characterized by pancytopenia, high fever, and lymphohistiocytic infiltration of liver, spleen, and lymph nodes. Treatment of accelerated-phase CHS is difficult and the prognosis is poor. Here, we report a case of CHS in a 2-year-old boy who presented in the accelerated phase of the disease. CHS diagnosis was made on the basis of clinical characteristics, hair analysis, and identification of pathognomonic giant azurophilic granules in peripheral blood and bone marrow. PMID:26254864

  9. Bcl-2 and c-myc expression, cell cycle kinetics and apoptosis during the progression of chronic myelogenous leukemia from diagnosis to blastic phase.

    PubMed

    Handa, H; Hegde, U P; Kotelnikov, V M; Mundle, S D; Dong, L M; Burke, P; Rose, S; Gaskin, F; Raza, A; Preisler, H D

    1997-06-01

    Chronic myelogenous leukemia (CML) has a progressive course but little is known about the biologic characteristics of disease progression. This study was designed to assess the changes in cell proliferative characteristics, apoptosis, the expression of the bcl-2 and c-myc genes between the time of initial diagnosis and entrance into the blastic phase of the disease. We observed that the rate of cell proliferation decreased and the cell death rate did not significantly change as the disease accelerated. The level of bcl-2 expression was significantly higher in accelerated/blastic phase cells than in the chronic phase cells in the population as a whole, however, the bcl-2 expression level did not change in blast cell subpopulation. c-myc Expression was significantly higher in the blast cell subpopulation of accelerated/blastic phase than in that of earlier phases of the disease. In conclusion, the characteristics of CML cells, namely proliferation rate, c-myc and bcl-2 change during the course of the disease. It is possible that the change in c-myc expression plays a causative role in evolution of the blastic phase from the chronic phase. PMID:9279359

  10. Force-Time Characteristics and Running Velocity of Male Sprinters During the Acceleration Phase of Sprinting.

    ERIC Educational Resources Information Center

    Mero, Antti

    1988-01-01

    Investigation of the force-time characteristics of eight male sprinters during the acceleration phase of the sprint start suggested that the braking and propulsion phases occur immediately after the block phase and that muscle strength strongly affects running velocity in the sprint start. (Author/CB)

  11. Impact of Imatinib Adherence on the Cytogenetic Response in Pediatric Chronic Myeloid Leukemia - Chronic Phase.

    PubMed

    Ganta, Ranga Raman; Nasaka, Srividya; Gundeti, Sadashivudu

    2016-09-01

    The authors aimed to study the impact of adherence to imatinib during initial 6 mo on the cytogenetic response in pediatric chronic myeloid leukemia - chronic phase (CML CP). The hospital records of pediatric CML patients (age ≤18 y) from 2009 through 2012, were analyzed retrospectively for the drug adherence and cytogenetic response (CyR) at 6 mo. Forty eight children were analyzed, with the median age of 13 y (range 5-18) and slight male preponderance (M:F- 1.18:1). Sokal scores were low, intermediate and high in 14 (29.3 %), 26 (54.1 %), 8 (16.6 %) children respectively. Only a little more than half of the children were adherent (58 %). At the end of 6 mo, complete cytogenetic response (CCyR) was achieved by 78.5 % of adherent children as compared to 5 % of non-adherent children. Majority (80 %) of the non-adherent children had only a partial cytogenetic response (PCyR). Therefore, it is concluded that most of the adherent children had optimal cytogenetic response at the end of 6 mo and majority of those in the non-adherent group did not attain it. PMID:26843266

  12. Chronic stress accelerates ligature-induced periodontitis by suppressing glucocorticoid receptor-α signaling.

    PubMed

    Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan; Zhao, Lisheng

    2016-01-01

    Periodontitis is a common chronic inflammatory disease. Recent studies have shown that chronic stress (CS) might modulate periodontal disease, but there are few models of CS-induced periodontitis, and the underlying mechanisms are unclear. The present study established a rat model of periodontitis associated with CS induced by nylon thread ligatures. The severity of periodontitis was evaluated in this model by radiographic and pathological examination. The inflammatory reaction indicated by the elevated serum levels of interleukin (IL)-1β, IL-6 and IL-8 was assessed by enzyme-linked immunosorbent assay. Toll-like receptor-4 (TLR4) and glucocorticoid receptor-α (GR-α) expressions were detected by reverse transcriptase-PCR and western blotting. Open-field tests and serum corticosterone were used to evaluate CS. The results showed that CS induced behavioral changes and increased corticosterone levels of the animals with periodontitis. CS stimulation markedly increased alveolar bone loss, periodontal pocket depth and the number of plaques. It also enhanced the inflammatory reaction. These results suggest that CS accelerated the ligature-induced pathological changes associated with periodontitis. Further analysis of the mechanisms involved showed that GR-α expression was significantly downregulated in periodontal tissues of the animals undergoing CS. Blocking GR-α signaling in lipopolysaccharide and corticosteroid-treated human periodontal ligament fibroblast cells in vitro significantly upregulated the expression of p-Akt (protein kinase B) and TLR4, promoted nuclear factor-κB activity and increased levels of IL-1β, IL-6 and IL-8. This research suggests that CS might accelerate the pathological progression of periodontitis by a GR-α signaling-mediated inflammatory response and that this may be a potential therapeutic target for the treatment of periodontal disease, particularly in patients with CS. PMID:27012709

  13. Chronic stress accelerates ligature-induced periodontitis by suppressing glucocorticoid receptor-α signaling

    PubMed Central

    Lu, Huaixiu; Xu, Minguang; Wang, Feng; Liu, Shisen; Gu, Jing; Lin, Songshan; Zhao, Lisheng

    2016-01-01

    Periodontitis is a common chronic inflammatory disease. Recent studies have shown that chronic stress (CS) might modulate periodontal disease, but there are few models of CS-induced periodontitis, and the underlying mechanisms are unclear. The present study established a rat model of periodontitis associated with CS induced by nylon thread ligatures. The severity of periodontitis was evaluated in this model by radiographic and pathological examination. The inflammatory reaction indicated by the elevated serum levels of interleukin (IL)-1β, IL-6 and IL-8 was assessed by enzyme-linked immunosorbent assay. Toll-like receptor-4 (TLR4) and glucocorticoid receptor-α (GR-α) expressions were detected by reverse transcriptase-PCR and western blotting. Open-field tests and serum corticosterone were used to evaluate CS. The results showed that CS induced behavioral changes and increased corticosterone levels of the animals with periodontitis. CS stimulation markedly increased alveolar bone loss, periodontal pocket depth and the number of plaques. It also enhanced the inflammatory reaction. These results suggest that CS accelerated the ligature-induced pathological changes associated with periodontitis. Further analysis of the mechanisms involved showed that GR-α expression was significantly downregulated in periodontal tissues of the animals undergoing CS. Blocking GR-α signaling in lipopolysaccharide and corticosteroid-treated human periodontal ligament fibroblast cells in vitro significantly upregulated the expression of p-Akt (protein kinase B) and TLR4, promoted nuclear factor-κB activity and increased levels of IL-1β, IL-6 and IL-8. This research suggests that CS might accelerate the pathological progression of periodontitis by a GR-α signaling-mediated inflammatory response and that this may be a potential therapeutic target for the treatment of periodontal disease, particularly in patients with CS. PMID:27012709

  14. Accelerated life testing effects on CMOS microcircuit characteristics, phase 1

    NASA Technical Reports Server (NTRS)

    Maximow, B.

    1976-01-01

    An accelerated life test of sufficient duration to generate a minimum of 50% cumulative failures in lots of CMOS devices was conducted to provide a basis for determining the consistency of activation energy at 250 C. An investigation was made to determine whether any thresholds were exceeded during the high temperature testing, which could trigger failure mechanisms unique to that temperature. The usefulness of the 250 C temperature test as a predictor of long term reliability was evaluated.

  15. How I treat newly diagnosed chronic phase CML

    PubMed Central

    Kantarjian, Hagop

    2012-01-01

    The progress made in the understanding of chronic myeloid leukemia (CML) since the recognition of a common chromosomal abnormality to the introduction of ever more effective tyrosine kinase inhibitors is unprecedented in cancer. The expected survival for patients diagnosed with CML today, if properly managed, is probably similar to that of the general population. When managing patients with CML the goal is to achieve the best long-term outcome and we should base the treatment decisions on the data available. The results from cytogenetic and molecular analyses have to be interpreted judiciously and all available treatment options integrated into the treatment plan properly. The availability of several treatment options in CML is an asset, but the temptation of rapid succession of treatment changes because of perceived suboptimal response or for adverse events that could be managed needs to be avoided. Any decision to change therapy needs to weigh the expected long-term outcome with the current option versus the true expectations with any new option, particularly as it relates to irre-versible outcomes, such as transformation to blast phase and death. In this manuscript, we discuss the treatment approach that has helped us manage successfully a large CML population. PMID:22613793

  16. GTA (ground test accelerator) Phase 1: Baseline design report

    SciTech Connect

    Not Available

    1986-08-01

    The national Neutral Particle Beam (NPB) program has two objectives: to provide the necessary basis for a discriminator/weapon decision by 1992, and to develop the technology in stages that lead ultimately to a neutral particle beam weapon. The ground test accelerator (GTA) is the test bed that permits the advancement of the state-of-the-art under experimental conditions in an integrated automated system mode. An intermediate goal of the GTA program is to support the Integrated Space Experiments, while the ultimate goal is to support the 1992 decision. The GTA system and each of its major subsystems are described, and project schedules and resource requirements are provided. (LEW)

  17. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial.

    PubMed

    Hochhaus, A; Saglio, G; Hughes, T P; Larson, R A; Kim, D-W; Issaragrisil, S; le Coutre, P D; Etienne, G; Dorlhiac-Llacer, P E; Clark, R E; Flinn, I W; Nakamae, H; Donohue, B; Deng, W; Dalal, D; Menssen, H D; Kantarjian, H M

    2016-05-01

    In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54%; 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR(4.5); BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP. PMID:26837842

  18. Long-term benefits and risks of frontline nilotinib vs imatinib for chronic myeloid leukemia in chronic phase: 5-year update of the randomized ENESTnd trial

    PubMed Central

    Hochhaus, A; Saglio, G; Hughes, T P; Larson, R A; Kim, D-W; Issaragrisil, S; le Coutre, P D; Etienne, G; Dorlhiac-Llacer, P E; Clark, R E; Flinn, I W; Nakamae, H; Donohue, B; Deng, W; Dalal, D; Menssen, H D; Kantarjian, H M

    2016-01-01

    In the phase 3 Evaluating Nilotinib Efficacy and Safety in Clinical Trials–Newly Diagnosed Patients (ENESTnd) study, nilotinib resulted in earlier and higher response rates and a lower risk of progression to accelerated phase/blast crisis (AP/BC) than imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Here, patients' long-term outcomes in ENESTnd are evaluated after a minimum follow-up of 5 years. By 5 years, more than half of all patients in each nilotinib arm (300 mg twice daily, 54% 400 mg twice daily, 52%) achieved a molecular response 4.5 (MR4.5; BCR-ABL⩽0.0032% on the International Scale) compared with 31% of patients in the imatinib arm. A benefit of nilotinib was observed across all Sokal risk groups. Overall, safety results remained consistent with those from previous reports. Numerically more cardiovascular events (CVEs) occurred in patients receiving nilotinib vs imatinib, and elevations in blood cholesterol and glucose levels were also more frequent with nilotinib. In contrast to the high mortality rate associated with CML progression, few deaths in any arm were associated with CVEs, infections or pulmonary diseases. These long-term results support the positive benefit-risk profile of frontline nilotinib 300 mg twice daily in patients with CML-CP. PMID:26837842

  19. Deformed phase space Kaluza-Klein cosmology and late time acceleration

    NASA Astrophysics Data System (ADS)

    Sabido, M.; Yee-Romero, C.

    2016-06-01

    The effects of phase space deformations on Kaluza-Klein cosmology are studied. The deformation is introduced by modifying the symplectic structure of the minisuperspace variables. In the deformed model, we find an accelerating scale factor and therefore infer the existence of an effective cosmological constant from the phase space deformation parameter β.

  20. Subluminous phase velocity of a focused laser beam and vacuum laser acceleration.

    PubMed

    Pang, J; Ho, Y K; Yuan, X Q; Cao, N; Kong, Q; Wang, P X; Shao, L; Esarey, E H; Sessler, A M

    2002-12-01

    It has been found that for a focused laser beam propagating in free space, there exists, surrounding the laser beam axis, a subluminous wave phase velocity region. Relativistic electrons injected into this region can be trapped in the acceleration phase and remain in phase with the laser field for sufficiently long times, thereby receiving considerable energy from the field. Optics placed near the laser focus are not necessary, thus allowing high intensities and large energy gains. Important features of this process are examined via test particle simulations. The resulting energy gains are in agreement with theoretical estimates based on acceleration by the axial laser field. PMID:12513421

  1. Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia

    PubMed Central

    Gambacorti-Passerini, Carlo; Cortes, Jorge E; Lipton, Jeff H; Dmoszynska, Anna; Wong, Raymond S; Rossiev, Victor; Pavlov, Dmitri; Gogat Marchant, Karin; Duvillié, Ladan; Khattry, Navin; Kantarjian, Hagop M; Brümmendorf, Tim H

    2014-01-01

    Bosutinib, an orally active, Src/Abl tyrosine kinase inhibitor, has demonstrated clinical activity and acceptable tolerability in chronic phase chronic myeloid leukemia (CP CML). This updated analysis of the BELA trial assessed the safety profile and management of toxicities of bosutinib versus imatinib in adults with newly diagnosed (≤6 months) CP CML after >30 months from accrual completion. Among patients randomized to bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252), 248 and 251, respectively, received ≥1 dose of study treatment. Adverse events (AEs; any grade) with bosutinib versus imatinib were significantly more common for certain gastrointestinal events (diarrhea, 70% vs. 26%; P < 0.001; vomiting, 33% vs. 16%; P < 0.001), alanine aminotransferase (33% vs. 9%; P < 0.001) and aspartate aminotransferase (28% vs. 10%; P < 0.001) elevations, and pyrexia (19% vs. 12%; P = 0.046). AEs significantly less common with bosutinib included edema (periorbital, 2% vs. 14%; P < 0.001; peripheral, 5% vs. 12%; P = 0.006), musculoskeletal (myalgia, 5% vs. 12%; P = 0.010; muscle cramps, 5% vs. 22%; P < 0.001; bone pain, 4% vs. 11%; P = 0.003), increased creatine phosphokinase (8% vs. 20%; P < 0.001), neutropenia (13% vs. 30%; P < 0.001), and leukopenia (9% vs. 22%; P < 0.001). Between-group differences in the incidence of cardiac and vascular AEs were not significant. Diarrhea was typically transient, mostly Grade 1/2, occurring early during treatment, and was manageable with antidiarrheal medication. Despite higher rates of aminotransferase elevation with bosutinib, events were managed in most patients with dose modification and/or concomitant medication. Bosutinib had a manageable safety profile distinct from that of imatinib in patients with newly diagnosed CP CML. Am. J. Hematol. 89:947–953, 2014. © 2014 The Authors. American Journal of Hematology Published by Wiley Periodicals, Inc. PMID

  2. Peculiarities of laser phase behavior associated with the accelerated electron in a chirped laser pulse

    SciTech Connect

    Song, Q.; Wu, X. Y.; Wang, J. X.; Kawata, S.; Wang, P. X.

    2014-05-15

    In this paper, we qualitatively analyzed peculiarities of laser phase behavior associated with the accelerated electron in a chirped laser pulse. We unveiled the relationship between the changes in the orientation of the electron trajectory and the cusps in magnitude of the phase velocity of the optical field along the electron trajectory in a chirped laser pulse. We also explained how the chirp effect induced the singular point of the phase velocity. Finally, we discussed the phase velocity and phase witnessed by the electron in the particle's moving instantaneous frame.

  3. Correlated histogram representation of Monte Carlo derived medical accelerator photon-output phase space

    DOEpatents

    Schach Von Wittenau, Alexis E.

    2003-01-01

    A method is provided to represent the calculated phase space of photons emanating from medical accelerators used in photon teletherapy. The method reproduces the energy distributions and trajectories of the photons originating in the bremsstrahlung target and of photons scattered by components within the accelerator head. The method reproduces the energy and directional information from sources up to several centimeters in radial extent, so it is expected to generalize well to accelerators made by different manufacturers. The method is computationally both fast and efficient overall sampling efficiency of 80% or higher for most field sizes. The computational cost is independent of the number of beams used in the treatment plan.

  4. The Simpsons program 6-D phase space tracking with acceleration

    NASA Astrophysics Data System (ADS)

    Machida, S.

    1993-12-01

    A particle tracking code, Simpsons, in 6-D phase space including energy ramping has been developed to model proton synchrotrons and storage rings. We take time as the independent variable to change machine parameters and diagnose beam quality in a quite similar way as real machines, unlike existing tracking codes for synchrotrons which advance a particle element by element. Arbitrary energy ramping and rf voltage curves as a function of time are read as an input file for defining a machine cycle. The code is used to study beam dynamics with time dependent parameters. Some of the examples from simulations of the Superconducting Super Collider (SSC) boosters are shown.

  5. Prompt particle acceleration around moving X-point magnetic field during impulsive phase of solar flares

    NASA Technical Reports Server (NTRS)

    Sakai, Jun-Ichi

    1992-01-01

    We present a model for high-energy solar flares to explain prompt proton and electron acceleration, which occurs around moving X-point magnetic field during the implosion phase of the current sheet. We derive the electromagnetic fields during the strong implosion phase of the current sheets, which is driven by the converging flow derived from the magnetohydrodynamic equations. It is shown that both protons and electrons can be promptly (within 1 second) accelerated to approximately 70 MeV and approximately 200 MeV, respectively. This acceleration mechanism can be applicable for the impulsive phase of the gradual gamma ray and proton flares (gradual GR/P flare), which have been called two-ribbon flares.

  6. Imatinib mesylate in Philadelphia chromosome-positive, chronic-phase myeloid leukemia after failure of interferon alpha.

    PubMed

    Tóthová, E; Kafková, A; Fricová, M; Benová, B; Kirschnerová, G; Tóthová, A

    2005-01-01

    Imatinib mesylate (STI 571; Glivec) is a potent and selective tyrosine kinase inhibitor. The introduction of imatinib has chanced the philosophy of mechanisms of cancer therapy and already changed current management of patients with chronic myeloid leukemia (CML). A total of 49 patients with later chronic phase CML in whom previous therapy with interferon alpha had failed were treated with 400 mg of oral imatinib daily. Patients were evaluated for hematologic and cytogenetic responses. Time to progression, survival, and toxic effects were also evaluated. Complete hematologic responses were reported for 48 of 49 patients studied (98 percent). The median time to a complete hematologic response was 1.2 month; 89% of patients who had a response did so within 4 months. Imatinib induced major cytogenetic responses in 73%; 62% had a complete responses. After a median follow-up of 18 months, CML had not progressed to the accelerated or blast phases in an estimated 98% of patients, and 100 percent of the patients were alive. Grade 3 or 4 nonhematologic toxic effects were manageable. No one of patients discontinued treatment due to of drug-related adverse events, and no treatment-related deaths occurred. The results of current study indicate that imatinib has a significant therapy benefit in CML patients in whom treatment with IFN alpha had failed. Therefore, has favorably changed the prognosis for patients with chronic myelogenous leukemia. PMID:15739029

  7. Chronic Oral Infection with Porphyromonas gingivalis Accelerates Atheroma Formation by Shifting the Lipid Profile

    PubMed Central

    Tabeta, Koichi; Aoki, Yukari; Miyashita, Hirotaka; Miyauchi, Sayuri; Miyazawa, Haruna; Nakajima, Takako; Yamazaki, Kazuhisa

    2011-01-01

    Background Recent studies have suggested that periodontal disease increases the risk of atherothrombotic disease. Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in the arteries. Although several studies have suggested that certain periodontopathic bacteria accelerate atherogenesis in apolipoprotein E-deficient mice, the mechanistic link between cholesterol accumulation and periodontal infection-induced inflammation is largely unknown. Methodology/Principal Findings We orally infected C57BL/6 and C57BL/6.KOR-Apoeshl (B6.Apoeshl) mice with Porphyromonas gingivalis, which is a representative periodontopathic bacterium, and evaluated atherogenesis, gene expression in the aorta and liver and systemic inflammatory and lipid profiles in the blood. Furthermore, the effect of lipopolysaccharide (LPS) from P. gingivalis on cholesterol transport and the related gene expression was examined in peritoneal macrophages. Alveolar bone resorption and elevation of systemic inflammatory responses were induced in both strains. Despite early changes in the expression of key genes involved in cholesterol turnover, such as liver X receptor and ATP-binding cassette A1, serum lipid profiles did not change with short-term infection. Long-term infection was associated with a reduction in serum high-density lipoprotein (HDL) cholesterol but not with the development of atherosclerotic lesions in wild-type mice. In B6.Apoeshl mice, long-term infection resulted in the elevation of very low-density lipoprotein (VLDL), LDL and total cholesterols in addition to the reduction of HDL cholesterol. This shift in the lipid profile was concomitant with a significant increase in atherosclerotic lesions. Stimulation with P. gingivalis LPS induced the change of cholesterol transport via targeting the expression of LDL receptor-related genes and resulted in the disturbance of regulatory mechanisms of the cholesterol level in macrophages. Conclusions

  8. Measurement of Beryllium in Biological Samples by Accelerator Mass Spectrometry: Applications for Studying Chronic Beryllium Disease

    SciTech Connect

    Chiarappa-Zucca, M L; Finkel, R C; Martinelli, R E; McAninch, J E; Nelson, D O; Turtletaub, K W

    2004-04-15

    A method using accelerator mass spectrometry (AMS) has been developed for quantifying attomoles of beryllium (Be) in biological samples. This method provides the sensitivity to trace Be in biological samples at very low doses with the purpose of identifying the molecular targets involved in chronic beryllium disease. Proof of the method was tested by administering 0.001, 0.05, 0.5 and 5.0 {micro}g {sup 9}Be and {sup 10}Be by intraperitoneal injection to male mice and removing spleen, liver, femurs, blood, lung, and kidneys after 24 h exposure. These samples were prepared for AMS analysis by tissue digestion in nitric acid, followed by further organic oxidation with hydrogen peroxide and ammonium persulfate and lastly, precipitation of Be with ammonium hydroxide, and conversion to beryllium oxide at 800 C. The {sup 10}Be/{sup 9}Be ratio of the extracted beryllium oxide was measured by AMS and Be in the original sample was calculated. Results indicate that Be levels were dose-dependent in all tissues and the highest levels were measured in the spleen and liver. The measured {sup 10}Be/{sup 9}Be ratios spanned 4 orders of magnitude, from 10{sup -10} to 10{sup -14}, with a detection limit of 3.0 x 10{sup -14}, which is equivalent to 0.8 attomoles of {sup 10}Be. These results show that routine quantification of nanogram levels of Be in tissues is possible and that AMS is a sensitive method that can be used in biological studies to understand the molecular dosimetry of Be and mechanisms of toxicity.

  9. Metabolomic Profiling of Arginine Metabolome Links Altered Methylation to Chronic Kidney Disease Accelerated Atherosclerosis

    PubMed Central

    Mathew, Anna V; Zeng, Lixia; Byun, Jaeman; Pennathur, Subramaniam

    2015-01-01

    Atherosclerotic cardiovascular disease is the leading cause of death in patients with chronic kidney disease (CKD), but the mechanisms underlying vascular disease has not been fully understood. As the nitrogen donor in nitric oxide (NO·) synthesis, arginine and its metabolic products are integrally linked to vascular health and information. We hypothesized that derangements in this pathway could explain, in part, increased atherosclerotic risk in CKD. We developed a targeted metabolomic platform to profile quantitatively arginine metabolites in plasma by liquid chromatography tandem mass spectrometry (LC/MS). Male low-density lipoprotein receptor defcient (LDLr−/−) mice at age 6 weeks were subjected to sham or 5/6 nephrectomy surgery to induce CKD. Subsequently, the animals were maintained on high fat diet for 24 weeks. Targeted metabolomic analysis of arginine metabolites in plasma was performed by isotope dilution LC/MS including asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), N-mono-methylarginine (NMMA), arginine and citrulline. Although elevated plasma levels of ADMA and SDMA were found in the CKD mice, only higher ADMA level correlated with degree of atherosclerosis. No significant differences were noted in levels of NMMA between the groups. CKD mice had high levels of citrulline and arginine, but ADMA levels had no correlation with either of these metabolites. These fndings strongly implicate altered arginine methylation and accumulation of ADMA, may in part contribute to CKD accelerated atherosclerosis. It raises the possibility that interrupting pathways that generate ADMA or enhance its metabolism may have therapeutic potential in mitigating atherosclerosis. PMID:26778898

  10. Nilotinib and Imatinib Mesylate After Donor Stem Cell Transplant in Treating Patients With Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2014-12-09

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Lymphoblastic Leukemia in Remission; Blastic Phase Chronic Myelogenous Leukemia; Childhood Acute Lymphoblastic Leukemia in Remission; Childhood Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Chronic Phase Chronic Myelogenous Leukemia; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Philadelphia Chromosome Positive Childhood Precursor Acute Lymphoblastic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Childhood Acute Lymphoblastic Leukemia

  11. Aberrant activation of CaMKIIγ accelerates chronic myeloid leukemia blast crisis.

    PubMed

    Gu, Y; Zheng, W; Zhang, J; Gan, X; Ma, X; Meng, Z; Chen, T; Lu, X; Wu, Z; Huang, W; Xu, R

    2016-06-01

    Blast crisis (BC) is the final deadly phase of chronic myeloid leukemia (CML), but its molecular basis remains poorly understood. Here, we show that CML BC is regulated by calcium-calmodulin-dependent kinase IIγ (CaMKIIγ). Genetic deletion of CaMKIIγ greatly inhibits disease progression via selectively impairing the self-renewal of leukemia stem cells (LSCs) in mouse models, whereas overexpression of CaMKIIγ has the opposite effects. In human CML, phosphorylated CaMKIIγ abundance is significantly associated with BC. Moreover, CaMKIIγ phosphorylates and reduces the nuclear cyclin-dependent kinase inhibitor p27Kip1, a critical brake that maintains LSC quiescence. These findings suggest that CaMKIIγ might be an important switch for the transition of CML BC and identify a unique mechanism by which CaMKIIγ promotes the self-renewal of LSCs by deceasing nuclear p27Kip1 to wake up dormant LSCs. Therefore, CaMKIIγ may provide a new therapeutic target to treat CML BC. PMID:27012864

  12. Phase velocity of the TEM (1,0)+TEM (0,1) mode laser and electron accelerations in vacuum

    SciTech Connect

    Wu, L.; Kong, Q.; Ho, Y. K.; Wang, P. X.; Xu, J. J.; Lin, D.; Kawata, S.

    2007-04-01

    Unlike at any single TEM (n, m) mode laser, there is a subluminous phase velocity region located along the central region of a TEM (1,0)+TEM (0,1) mode laser. In conjunction with the high longitudinal electric field in this region, it forms another acceleration channel, which also locates inside the transverse ponderomotive potential trap. Through simulation, it is found that relativistic electrons injected into this acceleration channel can stand at the acceleration phase for a long time and be synchronously accelerated to high energies. Also, the accelerated electrons can be well confined inside the trap avoiding the transverse scattering problem.

  13. Study of the transverse beam motion in the DARHT Phase II accelerator

    SciTech Connect

    Chen, Yu-Jiuan; Fawley, W M; Houck, T L

    1998-08-20

    The accelerator for the second-axis of the Dual Axis Radiographic Hydrodynamic Test (DARHT) facility will accelerate a 4-kA, 3-MeV, 2--µs long electron current pulse to 20 MeV. The energy variation of the beam within the flat-top portion of the current pulse is (plus or equal to) 0.5%. The performance of the DARHT Phase II radiographic machine requires the transverse beam motion to be much less than the beam spot size which is about 1.5 mm diameter on the x-ray converter. In general, the leading causes of the transverse beam motion in an accelerator are the beam breakup instability (BBU) and the corkscrew motion. We have modeled the transverse beam motion in the DARHT Phase II accelerator with various magnetic tunes and accelerator cell configurations by using the BREAKUP code. The predicted sensitivity of corkscrew motion and BBU growth to different tuning algorithms will be presented.

  14. Direct acceleration of electrons by a circular polarized laser pulse with phase modulation

    SciTech Connect

    Zhu, Lun-Wu; Sheng, Zheng-Mao; Yu, M. Y.

    2013-11-15

    Electron acceleration by transversely echelon phase-modulated (EPM) circularly polarized (CP) intense laser pulse is investigated. Solution of the relativistic electron equations of motion shows that the CP EPM light wave structure can disrupt the harmonic response of a trapped electron not only in the transverse direction but also in the direction of laser propagation. In each laser cycle, there can be a net gain in the electron's transverse momentum, which is promptly converted into the forward direction by the Lorentz force. As a result, the electron can be trapped and accelerated in the favorable phase of the laser for a rather long time. Its momentum gain then accumulates and can eventually reach high levels. It is also found that with the CP EPM laser, the net acceleration of the electron is not sensitive to its initial position and velocity relative to the phase of the laser fields, so that such a laser can also be useful for accelerating thermal electron bunches to high energies.

  15. Pion-decay radiation and two-phase acceleration in the June 3, 1982 solar flare

    NASA Technical Reports Server (NTRS)

    Ramaty, R.; Dermer, C. D.; Murphy, R. J.

    1986-01-01

    The June 3, 1982 flare is unique in the wealth of observed neutron, gamma-ray and energetic-particle emission that it produced. Using calculations of high-energy emissions to fit the various time-dependent gamma-ray fluxes, a self-consistent interaction model for the June 3 flare is constructed in which the observed fluxes are produced by two distinct particle populations with different acceleration and interaction time histories as well as different but time-independent energy spectra. The two populations are associated with first- and second-phase particle acceleration, respectively.

  16. Mixing, staging, and phasing for a proton-driven wake field accelerator

    SciTech Connect

    Gai, W.; Ruggiero, A.G.; Simpson, J.D.

    1987-01-01

    This paper expands on a few important details of the Wakeatron concept. This is a device where electrons can be accelerated by the wake field of short intense proton bunches travelling along the axis of an rf structure. Specifically, we have examined the consequences of the longitudinal dynamics of both the electron and the proton bunches. Included were ''mixing'' in the proton bunches (crucial to the overall concept) and phase shifts (electron bunches relative to proton bunches) in the acceleration process. Because of the deterioration of the proton bunches, due to the ''mixing'' process, it is required that the Wakeatron is indeed staged in a number of consecutive sections.

  17. Dasatinib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Chronic Myelogenous Leukemia That Did Not Respond to Imatinib Mesylate

    ClinicalTrials.gov

    2013-02-04

    Accelerated Phase Chronic Myelogenous Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Childhood Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Meningeal Chronic Myelogenous Leukemia; Recurrent Childhood Acute Lymphoblastic Leukemia; Relapsing Chronic Myelogenous Leukemia; Unspecified Childhood Solid Tumor, Protocol Specific

  18. Compact laser accelerators for X-ray phase-contrast imaging.

    PubMed

    Najmudin, Z; Kneip, S; Bloom, M S; Mangles, S P D; Chekhlov, O; Dangor, A E; Döpp, A; Ertel, K; Hawkes, S J; Holloway, J; Hooker, C J; Jiang, J; Lopes, N C; Nakamura, H; Norreys, P A; Rajeev, P P; Russo, C; Streeter, M J V; Symes, D R; Wing, M

    2014-03-01

    Advances in X-ray imaging techniques have been driven by advances in novel X-ray sources. The latest fourth-generation X-ray sources can boast large photon fluxes at unprecedented brightness. However, the large size of these facilities means that these sources are not available for everyday applications. With advances in laser plasma acceleration, electron beams can now be generated at energies comparable to those used in light sources, but in university-sized laboratories. By making use of the strong transverse focusing of plasma accelerators, bright sources of betatron radiation have been produced. Here, we demonstrate phase-contrast imaging of a biological sample for the first time by radiation generated by GeV electron beams produced by a laser accelerator. The work was performed using a greater than 300 TW laser, which allowed the energy of the synchrotron source to be extended to the 10-100 keV range. PMID:24470414

  19. Compact laser accelerators for X-ray phase-contrast imaging

    PubMed Central

    Najmudin, Z.; Kneip, S.; Bloom, M. S.; Mangles, S. P. D.; Chekhlov, O.; Dangor, A. E.; Döpp, A.; Ertel, K.; Hawkes, S. J.; Holloway, J.; Hooker, C. J.; Jiang, J.; Lopes, N. C.; Nakamura, H.; Norreys, P. A.; Rajeev, P. P.; Russo, C.; Streeter, M. J. V.; Symes, D. R.; Wing, M.

    2014-01-01

    Advances in X-ray imaging techniques have been driven by advances in novel X-ray sources. The latest fourth-generation X-ray sources can boast large photon fluxes at unprecedented brightness. However, the large size of these facilities means that these sources are not available for everyday applications. With advances in laser plasma acceleration, electron beams can now be generated at energies comparable to those used in light sources, but in university-sized laboratories. By making use of the strong transverse focusing of plasma accelerators, bright sources of betatron radiation have been produced. Here, we demonstrate phase-contrast imaging of a biological sample for the first time by radiation generated by GeV electron beams produced by a laser accelerator. The work was performed using a greater than 300 TW laser, which allowed the energy of the synchrotron source to be extended to the 10–100 keV range. PMID:24470414

  20. Chronic myelogenous leukemia in chronic phase transforming into acute leukemia under treatment with dasatinib 4 months after diagnosis.

    PubMed

    Nakamura, Yukitsugu; Tokita, Katsuya; Nagasawa, Fusako; Takahashi, Wataru; Nakamura, Yuko; Sasaki, Ko; Ichikawa, Motoshi; Mitani, Kinuko

    2016-03-01

    We report a 64-year-old woman morphologically diagnosed with chronic myelogenous leukemia in the chronic phase. Despite having achieved a complete hematological response following treatment with dasatinib, she developed lymphoblastic crisis 4 months later. Blastic cells were in a CD45-negative and SSC-low fraction, and positive for CD10, CD19, CD34, and HLA-DR expression and rearrangement in the immunoglobulin heavy chain gene. Chemotherapy using the HyperCVAD/MA regimen led to a complete cytogenetic response, and after cord blood transplantation, she obtained a complete molecular remission. However, the crisis recurred 6 months later. Another salvage therapy using L-AdVP regimen followed by nilotinib led to a complete molecular remission. Retrospective analyses using flow cytometry and polymerase chain reaction revealed a minimal blastic crisis clone present in the initial marrow in chronic phase. This case is informative as it suggests that sudden blastic crisis may occur from an undetectable blastic clone present at initial diagnosis and that leukemic stem cells may survive cytotoxic chemotherapy that eliminates most of the blastic cells. PMID:26662559

  1. IDH1 and IDH2 mutation analysis in chronic- and blast-phase myeloproliferative neoplasms.

    PubMed

    Pardanani, A; Lasho, T L; Finke, C M; Mai, M; McClure, R F; Tefferi, A

    2010-06-01

    Bone marrow DNA was screened for isocitrate dehydrogenase (IDH) mutations in 200 patients with chronic (n=166) or blast (n=34) phase myeloproliferative neoplasms (MPN). Included among the former were 77 patients with primary myelofibrosis (PMF), 47 essential thrombocythemia and 38 polycythemia vera (PV). Nine IDH mutations (5 IDH1 and 4 IDH2) were detected; mutational frequencies were approximately 21% (7 of 34) for blast-phase MPN and approximately 4% (3 of 77) for PMF. IDH mutations were seen in only 1 of 12 paired chronic-blast-phase samples and in none of 27 concurrently studied acute myeloid leukemia (AML) patients without antecedent MPN. IDH1 mutations included R132C (n=4; two post-PMF AML, one post-PV AML and one PMF) and R132S (n=1; post-PMF AML). IDH2 mutations included R140Q (n=3; one post-PMF AML, one post-PV AML and one PMF) and a novel R140W (n=1; mutation found in both chronic- and blast-phase samples). The entire study cohort was also screened for JAK2 and MPL mutations and JAK2V617F was found in three IDH-mutated cases (two PMF and one PV). This study shows a relatively high incidence of IDH mutations in blast-phase MPN, regardless of JAK2 mutational status, and the occurrence of similar mutations in chronic-phase PMF. PMID:20410924

  2. Imaging of early acceleration phase of the 2013-2014 Boso slow slip event

    NASA Astrophysics Data System (ADS)

    Fukuda, J.; Kato, A.; Obara, K.; Miura, S.; Kato, T.

    2014-12-01

    Based on GPS and seismic data, we examine the spatiotemporal evolution of a slow slip event (SSE) and associated seismic activity that occurred off the Boso peninsula, central Japan, from December 2013 to January 2014. We use GPS data from 71 stations of the GEONET and 6 stations operated by Earthquake Research Institute of the University of Tokyo and Tohoku University around the Boso peninsula. We apply a modified version of the Network Inversion Filter to the GPS time series at the 77 stations to estimate the spatiotemporal evolution of daily cumulative slip and slip rate on the subducting Philippine Sea plate. In addition, we create an improved earthquake catalog by applying a matched filter technique to continuous seismograms and examine the spatiotemporal relations between slow slip and seismicity. We find that the SSE started in early December 2013. The spatiotemporal evolution of slow slip and seismicity is divided into two distinct phases, an earlier slow phase from early to 30 December 2013 (Phase I) and a subsequent faster phase from 30 December 2013 to 9 January 2014 (Phase II). During Phase I, slip accelerated slowly up to a maximum rate of 1.6 m/yr with potentially accelerating along-strike propagation at speeds on the order of 1 km/day or less and no accompanying seismicity. On the other hand, during Phase II, slip accelerated rapidly up to a maximum rate of 4.5 m/yr and then rapidly decelerated. The slip front propagated along strike at a constant speed of ~10 km/day. During the Phase II, slow slip was accompanied by seismic swarm activity that was highly correlated in space and time with slip rate, suggesting that the swarm activity was triggered by stress loading due to slow slip. Early slow acceleration of slip has not been identified in the past Boso SSEs in 1996, 2002, 2007, and 2011. It is not clear at this point whether the past Boso SSEs started with slow acceleration similarly to the 2013-2014 SSE. The transition from the slow to the

  3. Laser-wakefield accelerators for medical phase contrast imaging: Monte Carlo simulations and experimental studies

    NASA Astrophysics Data System (ADS)

    Cipiccia, S.; Reboredo, D.; Vittoria, Fabio A.; Welsh, G. H.; Grant, P.; Grant, D. W.; Brunetti, E.; Wiggins, S. M.; Olivo, A.; Jaroszynski, D. A.

    2015-05-01

    X-ray phase contrast imaging (X-PCi) is a very promising method of dramatically enhancing the contrast of X-ray images of microscopic weakly absorbing objects and soft tissue, which may lead to significant advancement in medical imaging with high-resolution and low-dose. The interest in X-PCi is giving rise to a demand for effective simulation methods. Monte Carlo codes have been proved a valuable tool for studying X-PCi including coherent effects. The laser-plasma wakefield accelerators (LWFA) is a very compact particle accelerator that uses plasma as an accelerating medium. Accelerating gradient in excess of 1 GV/cm can be obtained, which makes them over a thousand times more compact than conventional accelerators. LWFA are also sources of brilliant betatron radiation, which are promising for applications including medical imaging. We present a study that explores the potential of LWFA-based betatron sources for medical X-PCi and investigate its resolution limit using numerical simulations based on the FLUKA Monte Carlo code, and present preliminary experimental results.

  4. Proposal for a study of laser acceleration of electrons using micrograting structures at ATF (Phase 1)

    SciTech Connect

    Chen, W.; Claus, J.; Fernow, R.C.; Fischer, J.; Gallardo, J.C.; Kirk, H.G.; Kramer, H.; Li, Z.; Palmer, R.B.; Rogers, J.; Shrinvasan-Rao, T.; Tsang, T.; Ulc, S.; Veligdan, J.; Warren, J.; Bigio, I.; Kurnit, N.; Shimada, T.; Wang, X.; McDonald, K.T.; Russell, D.P.; Los Alamos National Lab., NM; Princeton Univ., NJ; California Univ., Los Angeles, CA )

    1989-10-29

    We propose to investigate new methods of particle acceleration using a short-pulse CO{sub 2} laser as the power source and grating-like structures as accelerator cavities''. Phase I of this program is intended to demonstrate the principle of the method. We will focus the laser light to a 3 mm line on the surface of the microstructure. The structure is used to transform the electric field pattern of the incoming transversely polarized laser beam to a mode which has a component along the electron beam direction in the vicinity of the surface. With 6 mJ of laser energy and a 6 ps pulse length, the electric field in the spot will be around 1 GV/m. The electron beam from the Brookhaven Accelerator Test Facility (ATF) will be focused transversely within the few micron transverse dimension of the microstructure. The maximum expected acceleration for a 1 GV/m field and a 3 mm acceleration length is 3 MeV. 17 refs., 11 figs., 2 tabs.

  5. Phase-space dynamics of ionization injection in plasma-based accelerators.

    PubMed

    Xu, X L; Hua, J F; Li, F; Zhang, C J; Yan, L X; Du, Y C; Huang, W H; Chen, H B; Tang, C X; Lu, W; Yu, P; An, W; Joshi, C; Mori, W B

    2014-01-24

    The evolution of beam phase space in ionization injection into plasma wakefields is studied using theory and particle-in-cell simulations. The injection process involves both longitudinal and transverse phase mixing, leading initially to a rapid emittance growth followed by oscillation, decay, and a slow growth to saturation. An analytic theory for this evolution is presented and verified through particle-in-cell simulations. This theory includes the effects of injection distance (time), acceleration distance, wakefield structure, and nonlinear space charge forces, and it also shows how ultralow emittance beams can be produced using ionization injection methods. PMID:24484147

  6. Relationship between Lower Limb Angular Kinematic Variables and the Effectiveness of Sprinting during the Acceleration Phase

    PubMed Central

    Konieczny, Grzegorz; Winiarski, Sławomir; Rokita, Andrzej

    2016-01-01

    The ability to reach a high running velocity over a short distance is essential to a high playing performance in team games. The aim of this study was to determine the relationship between running time over a 10-meter section of a 30-meter sprint along a straight line and changes in the angle and angular velocity that were observed in the ankle, knee, and hip joints. The possible presence may help to optimize motion efficiency during acceleration sprint phase. Eighteen girls involved in team sports were examined in the study. The Fusion Smart Speed System was employed for running time measurements. The kinematic data were recorded using the Noraxon MyoMotion system. Statistically significant relationships were found between running time over a 10-meter section and the kinematic variables of hip and ankle joints. An excessively large flexion in hip joints might have an unfavorable effect on running time during the acceleration phase. Furthermore, in order to minimize running time during the acceleration phase, stride should be maintained along a line (a straight line) rather than from side to side. It is also necessary to ensure an adequate range of motion in the hip and ankle joints with respect to the sagittal axis. PMID:27516724

  7. Relationship between Lower Limb Angular Kinematic Variables and the Effectiveness of Sprinting during the Acceleration Phase.

    PubMed

    Struzik, Artur; Konieczny, Grzegorz; Stawarz, Mateusz; Grzesik, Kamila; Winiarski, Sławomir; Rokita, Andrzej

    2016-01-01

    The ability to reach a high running velocity over a short distance is essential to a high playing performance in team games. The aim of this study was to determine the relationship between running time over a 10-meter section of a 30-meter sprint along a straight line and changes in the angle and angular velocity that were observed in the ankle, knee, and hip joints. The possible presence may help to optimize motion efficiency during acceleration sprint phase. Eighteen girls involved in team sports were examined in the study. The Fusion Smart Speed System was employed for running time measurements. The kinematic data were recorded using the Noraxon MyoMotion system. Statistically significant relationships were found between running time over a 10-meter section and the kinematic variables of hip and ankle joints. An excessively large flexion in hip joints might have an unfavorable effect on running time during the acceleration phase. Furthermore, in order to minimize running time during the acceleration phase, stride should be maintained along a line (a straight line) rather than from side to side. It is also necessary to ensure an adequate range of motion in the hip and ankle joints with respect to the sagittal axis. PMID:27516724

  8. Behavior of a new type quantum accelerator mode in phase-modulated optical potential

    NASA Astrophysics Data System (ADS)

    Lam, Wakun; Wimberger, Sandro; Dadras, Siamak; Ni, Jiating; Summy, Gil

    2015-05-01

    It has been shown that the delta-kicked rotor (DKR) with a Bose-Einstein Condensate is a powerful model for studying the dynamics of many-body systems. Many efforts based on this model have been made in study of dynamical localization, quantum accelerator mode (QAM), to name but a few. QAM is a dynamical phenomenon in which the momentum of atoms exposed to a pulsed accelerating optical standing wave manifest linear growth. In many applications, we expect high transport rate to suppress localization. A recent technique utilizing the phase modulation on the optical potential to produce transport islands has been discussed. In this presentation we study the stability of such islands in classical phase space of a modified DKR system in which the phase of the optical potential is modulated by a certain phase on each kick. Numerical simulations testify the existence of QAM even in small phase perturbation. We also investigate the momentum distribution numerically and report a new type of QAM which exposed in stationary optical potential instead. The interesting structure of the area of the transport islands against wide range of dynamical parameters is observed to be quite distinct to the regular one.

  9. Two-phase turbine engines. [using gas-liquid mixture accelerated in nozzles

    NASA Technical Reports Server (NTRS)

    Elliott, D. G.; Hays, L. G.

    1976-01-01

    A description is given of a two-phase turbine which utilizes a uniform mixture of gas and liquid accelerated in nozzles of the types reported by Elliott and Weinberg (1968). The mixture acts directly on an axial flow or tangential impulse turbine or is separated into gas and liquid streams which operate separately on a gas turbine and a hydraulic turbine. The basic two-phase cycles are examined, taking into account working fluids, aspects of nozzle expansion, details of turbine cycle operation, and the effect of mixture ratio variation. Attention is also given to two-phase nozzle efficiency, two-phase turbine operating characteristics and efficiencies, separator turbines, and impulse turbine experiments.

  10. Accelerating Energy Efficiency in Indian Data Centers. Final Report for Phase I Activities

    SciTech Connect

    Ganguly, Suprotim; Raje, Sanyukta; Kumar, Satish; Sartor, Dale; Greenberg, Steve

    2016-01-01

    This report documents Phase 1 of the “Accelerating Energy Efficiency in Indian Data Centers” initiative to support the development of an energy efficiency policy framework for Indian data centers. The initiative is being led by the Confederation of Indian Industry (CII), in collaboration with Lawrence Berkeley National Laboratory (LBNL)-U.S. Department of Energy’s Office of Energy Efficiency and Renewable Energy, and under the guidance of Bureau of Energy Efficiency (BEE). It is also part of the larger Power and Energy Efficiency Working Group of the US-India Bilateral Energy Dialogue. The initiative consists of two phases: Phase 1 (November 2014 – September 2015) and Phase 2 (October 2015 – September 2016).

  11. A deficiency in cold-inducible RNA-binding protein accelerates the inflammation phase and improves wound healing.

    PubMed

    Idrovo, Juan Pablo; Jacob, Asha; Yang, Weng Lang; Wang, Zhimin; Yen, Hao Ting; Nicastro, Jeffrey; Coppa, Gene F; Wang, Ping

    2016-02-01

    Chronic or non-healing wounds are a major concern in clinical practice and these wounds are mostly associated with diabetes, and venous and pressure ulcers. Wound healing is a complex process involving overlapping phases and the primary phase in this complex cascade is the inflammatory state. While inflammation is necessary for wound healing, a prolonged inflammatory phase leads to impaired healing. Cold-inducible RNA-binding protein (CIRP) belongs to a family of cold-shock proteins that are expressed in high levels under stress conditions. Recently, we demonstrated that a deficiency in CIRP led to decreased inflammation and mortality in an experimental model of hemorrhagic shock. Thus, we hypothesized that a deficiency in CIRP would accelerate the inflammatory phase and lead to an improvement in cutaneous wound healing. In this study, to examine this hypothesis, a full-thickness wound was created on the dorsum of wild-type (WT) and CIRP-/- mice. The wound size was measured every other day for 14 days. The wound area was significantly decreased in the CIRP-/- mice by day 9 and continued to decrease until day 14 compared to the WT mice. In a separate cohort, mice were sacrificed on days 3 and 7 after wounding and the skin tissues were harvested for histological analysis and RNA measurements. On day 3, the mRNA expression of tumor necrossis factor (TNF)-α in the skin tissues was increased by 16-fold in the WT mice, whereas these levels were increased by 65-fold in the CIRP-/- mice. Of note on day 7, while the levels of TNF-α remained high in the WT mice, these levels were significantly decreased in the CIRP-/- mice. The histological analysis of the wounded skin tissue indicated an improvement as early as day 3 in the CIRP-/- mice, whereas in the WT mice, infiltrated immune cells were still present on day 7. On day 7 in the CIRP-/- mice, Gr-1 expression was low and CD31 expression was high, whereas in the WT mice, Gr-1 expression was high and CD31 expression was low

  12. Is there a best TKI for chronic phase CML?

    PubMed

    Larson, Richard A

    2015-11-19

    The development of BCR/ABL1 tyrosine kinase inhibitors (TKIs) over the past 20 years has dramatically improved the outcomes for patients with every stage of Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). Clinicians now have access to 5 oral, generally well-tolerated, and highly effective TKIs. How should these agents be used for an individual patient to ensure the best possible duration and quality-of-life, to avoid treatment-related complications, and potentially to achieve a cure at an affordable cost? Because CML patients may need to continue TKI therapy indefinitely, the long-term safety of each treatment option must be considered. Evidence-based care requires an understanding of the optimal use of these drugs, their specific early and late toxicities, the prognostic significance of achieving treatment milestones, and the critical importance of molecular monitoring. Efficacy is important, but treatment choice does not depend only on efficacy. Choosing among various treatment options is informed by understanding the distinct benefits and risks of each agent, along with careful consideration of patient-specific factors, such as risk status, age, and comorbidities. PMID:26585806

  13. High-resolution simulations of downslope gravity currents in the acceleration phase

    NASA Astrophysics Data System (ADS)

    Dai, Albert

    2015-07-01

    Gravity currents generated from an instantaneous buoyancy source propagating down a slope in the range of 0∘ ≤ θ < 90∘ have been investigated in the acceleration phase by means of high-resolution two-dimensional simulations of the incompressible Navier-Stokes equations with the Boussinesq approximation. Front velocity history shows that, after the heavy fluid is released from rest, the flow goes through the acceleration phase, reaching a maximum front velocity Uf,max, and followed by the deceleration phase. The existence of a maximum of Uf,max is found near θ = 40∘, which is supported by the improved theory. It is identified for the first time that the time of acceleration decreases as the slope angle increases, when the slope angle is approximately greater than 10∘, and the time of acceleration increases as the slope angle increases for gravity currents on lower slope angles. A fundamental difference in flow patterns, which helps explain the distinct characteristics of gravity currents on high and low slope angles using scaling arguments, is revealed. Energy budgets further show that, as the slope angle increases, the ambient fluid is more easily engaged in the gravitational convection and the potential energy loss is more efficiently converted into the kinetic energy associated with ambient fluid. The propagation of gravity currents on a slope is found to be qualitatively modified as the depth ratio, i.e., the lock height to channel height ratio, approaches unity. As the depth ratio increases, the conversion of potential energy loss into the kinetic energy associated with heavy fluid is inhibited and the conversion into the kinetic energy associated with ambient fluid is enhanced by the confinement of the top wall.

  14. Rat Cytomegalovirus Vaccine Prevents Accelerated Chronic Rejection in CMV-Naïve Recipients of Infected Donor Allograft Hearts.

    PubMed

    Streblow, D N; Hwee, Y K; Kreklywich, C N; Andoh, T; Denton, M; Smith, P; Hart, E; Broekel, R; Pallett, C; Rogers, K; Streblow, A D; Chuop, M; Perry, A; Slifka, M; Messaoudi, I; Orloff, S L

    2015-07-01

    Cytomegalovirus accelerates transplant vascular sclerosis (TVS) and chronic rejection (CR) in solid organ transplants; however, the mechanisms involved are unclear. We determined the efficacy of a CMV vaccine in preventing CMV-accelerated rat cardiac allograft rejection in naïve recipients of CMV+ donor hearts. F344 donor rats were infected with RCMV 5 days prior to heterotopic cardiac transplantation into CMV-naïve or H2 O2 -inactivated RCMV-vaccinated Lewis recipients. Recipients of RCMV-infected donor hearts rejected at POD59, whereas vaccinated recipients exhibited a significantly prolonged time to rejection-POD97, similar to recipients of uninfected donor hearts (POD108). Although all of the donor hearts were preinfected, the vaccinated recipients had lower graft and PBMC viral loads at POD 7 compared to unvaccinated controls. Adoptive T cell and passive antibody transfers from vaccinated Lewis rats into naïve recipients demonstrate that both T-cell and B-cell arms of the adaptive immune response provide protection against CMV-accelerated rejection. Similar findings were obtained when testing three different adjuvants in passive transfer experiments. We have determined that the timing of the vaccine prior to transplantation and the specific adjuvant play critical roles in mediating anti-viral responses and promoting graft survival. CMV vaccination prior to transplantation may effectively increase graft survival. PMID:25766876

  15. Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations

    PubMed Central

    Müller, Martin C.; Cortes, Jorge E.; Kim, Dong-Wook; Druker, Brian J.; Erben, Philipp; Pasquini, Ricardo; Branford, Susan; Hughes, Timothy P.; Radich, Jerald P.; Ploughman, Lynn; Mukhopadhyay, Jaydip

    2009-01-01

    Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR-ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR-ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC50) greater than 3nM; among patients with mutations with lower or unknown IC50, efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844. PMID:19779040

  16. Chronic exogenous kisspeptin administration accelerates gonadal development in basses of the genus Morone

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The present study assesses the effects of chronic administration of peptides to fish, termed kisspeptins, which are the products of the KISS1 and KISS2 genes, and have been shown to control the development of puberty in animals. Using ecologically and commercially important species (white bass, Mor...

  17. Rayleigh-Taylor Growth Measurements in the Acceleration Phase of Spherical Implosions on OMEGA

    SciTech Connect

    Smalyuk, V. A.; Hu, S. X.; Hager, J. D.; Delettrez, J. A.; Meyerhofer, D. D.; Sangster, T. C.; Shvarts, D.

    2009-09-04

    The Rayleigh-Taylor (RT) growth of 3D broadband nonuniformities was measured using x-ray radiography in spherical plastic shells accelerated by laser light at an intensity of approx2x10{sup 14} W/cm{sup 2}. The 20- and 24-mum-thick spherical shells were imploded with 54 beams on the OMEGA laser system. The shells contained diagnostic openings for backlighter x rays used to image shell modulations. The measured shell trajectories and modulation RT growth were in fair agreement with 2D hydro simulations during the acceleration phase of the implosions with convergence ratios of up to approx2.2. Since the ignition designs rely on these simulations, improvements in the numerical codes will be implemented to achieve better agreement with experiments.

  18. Rayleigh-Taylor Growth Measurements in the Acceleration Phase of Spherical Implosions on OMEGA

    SciTech Connect

    Smalyuk, V.A.; Hu, S.X.; Hager, J.D.; Delettrez, J.A.; Meyerhofer, D.D.; Sangster, T.C.; Shvarts, D.

    2009-09-10

    The Rayleigh-Taylor (RT) growth of 3D broadband nonuniformities was measured using x-ray radiography in spherical plastic shells accelerated by laser light at an intensity of ~2 x 10^14 W/cm^2. The 20- and 24-um-thick spherical shells were imploded with 54 beams on the OMEGA laser system. The shells contained diagnostic openings for backlighter x rays used to image shell modulations. The measured shell trajectories and modulation RT growth were in fair agreement with 2D hydro simulations during the acceleration phase of the implosions with convergence ratios of up to ~2:2. Since the ignition designs rely on these simulations, improvements in the numerical codes will be implemented to achieve better agreement with experiments.

  19. Graphics processing unit-accelerated double random phase encoding for fast image encryption

    NASA Astrophysics Data System (ADS)

    Lee, Jieun; Yi, Faliu; Saifullah, Rao; Moon, Inkyu

    2014-11-01

    We propose a fast double random phase encoding (DRPE) algorithm using a graphics processing unit (GPU)-based stream-processing model. A performance analysis of the accelerated DRPE implementation that employs the Compute Unified Device Architecture programming environment is presented. We show that the proposed methodology executed on a GPU can dramatically increase encryption speed compared with central processing unit sequential computing. Our experimental results demonstrate that in encryption data of an image with a pixel size of 1000×1000, where one pixel has a 32-bit depth, our GPU version of the DRPE scheme can be approximately two times faster than the advanced encryption standard algorithm implemented on a GPU. In addition, the quality of parallel processing on the presented DRPE acceleration method is evaluated with performance parameters, such as speedup, efficiency, and redundancy.

  20. Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks.

    PubMed

    Wolff, Gretchen; Duncan, Marilyn J; Esser, Karyn A

    2013-08-01

    Shifting the onset of light, acutely or chronically, can profoundly affect responses to infection, tumor progression, development of metabolic disease, and mortality in mammals. To date, the majority of phase-shifting studies have focused on acute exposure to a shift in the timing of the light cycle, whereas the consequences of chronic phase shifts alone on molecular rhythms in peripheral tissues such as skeletal muscle have not been studied. In this study, we tested the effect of chronic phase advance on the molecular clock mechanism in two phenotypically different skeletal muscles. The phase advance protocol (CPA) involved 6-h phase advances (earlier light onset) every 4 days for 8 wk. Analysis of the molecular clock, via bioluminescence recording, in the soleus and flexor digitorum brevis (FDB) muscles and lung demonstrated that CPA advanced the phase of the rhythm when studied immediately after CPA. However, if the mice were placed into free-running conditions (DD) for 2 wk after CPA, the molecular clock was not phase shifted in the two muscles but was still shifted in the lung. Wheel running behavior remained rhythmic in CPA mice; however, the endogenous period length of the free-running rhythm was significantly shorter than that of control mice. Core body temperature, cage activity, and heart rate remained rhythmic throughout the experiment, although the onset of the rhythms was significantly delayed with CPA. These results provide clues that lifestyles associated with chronic environmental desynchrony, such as shift work, can have disruptive effects on the molecular clock mechanism in peripheral tissues, including both types of skeletal muscle. Whether this can contribute, long term, to increased incidence of insulin resistance/metabolic disease requires further study. PMID:23703115

  1. Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks

    PubMed Central

    Wolff, Gretchen; Duncan, Marilyn J.

    2013-01-01

    Shifting the onset of light, acutely or chronically, can profoundly affect responses to infection, tumor progression, development of metabolic disease, and mortality in mammals. To date, the majority of phase-shifting studies have focused on acute exposure to a shift in the timing of the light cycle, whereas the consequences of chronic phase shifts alone on molecular rhythms in peripheral tissues such as skeletal muscle have not been studied. In this study, we tested the effect of chronic phase advance on the molecular clock mechanism in two phenotypically different skeletal muscles. The phase advance protocol (CPA) involved 6-h phase advances (earlier light onset) every 4 days for 8 wk. Analysis of the molecular clock, via bioluminescence recording, in the soleus and flexor digitorum brevis (FDB) muscles and lung demonstrated that CPA advanced the phase of the rhythm when studied immediately after CPA. However, if the mice were placed into free-running conditions (DD) for 2 wk after CPA, the molecular clock was not phase shifted in the two muscles but was still shifted in the lung. Wheel running behavior remained rhythmic in CPA mice; however, the endogenous period length of the free-running rhythm was significantly shorter than that of control mice. Core body temperature, cage activity, and heart rate remained rhythmic throughout the experiment, although the onset of the rhythms was significantly delayed with CPA. These results provide clues that lifestyles associated with chronic environmental desynchrony, such as shift work, can have disruptive effects on the molecular clock mechanism in peripheral tissues, including both types of skeletal muscle. Whether this can contribute, long term, to increased incidence of insulin resistance/metabolic disease requires further study. PMID:23703115

  2. High-resolution simulations of non-Boussinesq downslope gravity currents in the acceleration phase

    NASA Astrophysics Data System (ADS)

    Dai, Albert; Huang, Yu-lin

    2016-02-01

    Gravity currents generated from an instantaneous buoyancy source of density contrast in the density ratio range of 0.3 ≤ γ ≤ 0.998 propagating downslope in the slope angle range of 0° ≤ θ < 90° have been investigated in the acceleration phase by means of high-resolution two-dimensional simulations of the incompressible variable-density Navier-Stokes equations. For all density contrasts considered in this study, front velocity history shows that, after the heavy fluid is released from rest, the gravity currents go through the acceleration phase, reaching a maximum front velocity Uf,max, followed by the deceleration phase. It is found that Uf,max increases as the density contrast increases and such a relationship is, for the first time, quantitatively described by the improved thermal theory considering the non-Boussinesq effects. Energy budgets show that, as the density contrast increases, the heavy fluid retains more fraction of potential energy loss while the ambient fluid receives less fraction of potential energy loss in the process of energy transfer during the propagation of downslope gravity currents. Previously, it was reported that for the Boussinesq case, the downslope gravity currents have a maximum of Uf,max at θ ≈ 40°. It is found, as is also confirmed by the energy budgets in this study, that the slope angle at which the downslope gravity currents have a maximum of Uf,max may increase beyond 40° as the density contrast increases.

  3. Treatment with Benznidazole during the Chronic Phase of Experimental Chagas' Disease Decreases Cardiac Alterations

    PubMed Central

    Garcia, Simone; Ramos, Carolina O.; Senra, Juliana F. V.; Vilas-Boas, Fabio; Rodrigues, Maurício M.; Campos-de-Carvalho, Antonio C.; Ribeiro-dos-Santos, Ricardo; Soares, Milena B. P.

    2005-01-01

    Chagas' disease, caused by Trypanosoma cruzi infection, is one of the main causes of death due to heart failure in Latin American countries. Benznidazole, the chemotherapeutic agent most often used for the treatment of chagasic patients, is highly toxic and has limited efficacy, especially in the chronic phase of the disease. In the present study we used a mouse model of chronic Chagas' disease to investigate the effects of benznidazole treatment during the chronic phase on disease progression. The hearts of benznidazole-treated mice had decreased parasitism and myocarditis compared to the hearts of untreated chagasic mice. Both groups of Trypanosoma cruzi-infected mice had significant alterations in their electrocardiograms compared to those of the healthy mice. However, untreated mice had significantly higher cardiac conduction disturbances than benznidazole-treated mice, including intraventricular conduction disturbances, atrioventricular blocks, and extrasystoles. The levels of antibodies against T. cruzi antigens (epimastigote extract, P2β, and trans-sialidase) as well as antibodies against peptides of the second extracellular loops of β1-adrenergic and M2-muscarinic cardiac receptors were also lower in the sera from benznidazole-treated mice than in the sera from untreated mice. These results demonstrate that treatment with benznidazole in the chronic phase of infection prevents the development of severe chronic cardiomyopathy, despite the lack of complete parasite eradication. In addition, our data highlight the role of parasite persistence in the development of chronic Chagas' disease and reinforce the importance of T. cruzi elimination in order to decrease or prevent the development of severe chagasic cardiomyopathy. PMID:15793134

  4. Acceleration- and deceleration-phase nonlinear Rayleigh-Taylor growth at spherical interfaces

    NASA Astrophysics Data System (ADS)

    Clark, Daniel S.; Tabak, Max

    2005-11-01

    The Layzer model for the nonlinear evolution of bubbles in the Rayleigh-Taylor instability has recently been generalized to the case of spherically imploding interfaces [D. S. Clark and M. Tabak, Phys. Rev. E 71, 055302(R) (2005)]. The spherical case is more relevant to, e.g., inertial confinement fusion or various astrophysical phenomena when the convergence is strong or the perturbation wavelength is comparable to the interface curvature. Here, the model is further extended to the case of bubble growth during the deceleration (stagnation) phase of a spherical implosion and to the growth of spikes during both the acceleration and deceleration phases. Differences in the nonlinear growth rates for both bubbles and spikes are found when compared with planar results. The model predictions are verified by comparison with numerical hydrodynamics simulations.

  5. Considering baseline factors and early response rates to optimize therapy for chronic myeloid leukemia in chronic phase.

    PubMed

    Akard, Luke P; Bixby, Dale

    2016-05-01

    Multiple BCR-ABL tyrosine kinase inhibitors (TKIs) are available for the treatment of chronic myeloid leukemia in chronic phase (CML-CP), and several baseline and on-treatment predictive factors have been identified that can be used to help guide TKI selection for individual patients. In particular, early molecular response (EMR; BCR-ABL ≤10% on the International Scale at 3 months) has become an accepted benchmark for evaluating whether patients with CML-CP are responding optimally to frontline TKI therapy. Failure to achieve EMR is considered an inadequate initial response according to the National Comprehensive Cancer Network guidelines and a warning response according to the European LeukemiaNet recommendations. Here we review data supporting the importance of achieving EMR for improving patients' long-term outcomes and discuss key considerations for selecting a frontline TKI in light of these data. Because a higher proportion of patients achieve EMR with second-generation TKIs such as nilotinib and dasatinib than with imatinib, these TKIs may be preferable for many patients, particularly those with known negative prognostic factors at baseline. We also discuss other considerations for frontline TKI choice, including toxicities, cost-effectiveness, and the emerging goals of deep molecular response and treatment-free remission. PMID:26726949

  6. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia

    PubMed Central

    Irvine, David A.; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L.; Moka, Hothri A.; Ho, Yinwei; Nixon, Colin; Manley, Paul W.; Wheadon, Helen; Goodlad, John R.; Holyoake, Tessa L.; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34+ CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34+ CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34+ CP-CML cell engraftment in NSG mice and, upon administration to EGFP+ /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  7. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.

    PubMed

    Irvine, David A; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L; Moka, Hothri A; Ho, Yinwei; Nixon, Colin; Manley, Paul W; Wheadon, Helen; Goodlad, John R; Holyoake, Tessa L; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34(+) CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34(+) CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34(+) CP-CML cell engraftment in NSG mice and, upon administration to EGFP(+) /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  8. Endogenous Delta/Theta Sound-Brain Phase Entrainment Accelerates the Buildup of Auditory Streaming.

    PubMed

    Riecke, Lars; Sack, Alexander T; Schroeder, Charles E

    2015-12-21

    In many natural listening situations, meaningful sounds (e.g., speech) fluctuate in slow rhythms among other sounds. When a slow rhythmic auditory stream is selectively attended, endogenous delta (1‒4 Hz) oscillations in auditory cortex may shift their timing so that higher-excitability neuronal phases become aligned with salient events in that stream [1, 2]. As a consequence of this stream-brain phase entrainment [3], these events are processed and perceived more readily than temporally non-overlapping events [4-11], essentially enhancing the neural segregation between the attended stream and temporally noncoherent streams [12]. Stream-brain phase entrainment is robust to acoustic interference [13-20] provided that target stream-evoked rhythmic activity can be segregated from noncoherent activity evoked by other sounds [21], a process that usually builds up over time [22-27]. However, it has remained unclear whether stream-brain phase entrainment functionally contributes to this buildup of rhythmic streams or whether it is merely an epiphenomenon of it. Here, we addressed this issue directly by experimentally manipulating endogenous stream-brain phase entrainment in human auditory cortex with non-invasive transcranial alternating current stimulation (TACS) [28-30]. We assessed the consequences of these manipulations on the perceptual buildup of the target stream (the time required to recognize its presence in a noisy background), using behavioral measures in 20 healthy listeners performing a naturalistic listening task. Experimentally induced cyclic 4-Hz variations in stream-brain phase entrainment reliably caused a cyclic 4-Hz pattern in perceptual buildup time. Our findings demonstrate that strong endogenous delta/theta stream-brain phase entrainment accelerates the perceptual emergence of task-relevant rhythmic streams in noisy environments. PMID:26628008

  9. Tables of phase functions, opacities, albedos, equilibrium temperatures, and radiative accelerations of dust grains in exoplanets

    NASA Astrophysics Data System (ADS)

    Budaj, J.; Kocifaj, M.; Salmeron, R.; Hubeny, I.

    2015-11-01

    There has been growing observational evidence for the presence of condensates in the atmospheres and/or comet-like tails of extrasolar planets. As a result, systematic and homogeneous tables of dust properties are useful in order to facilitate further observational and theoretical studies. In this paper we present calculations and analysis of non-isotropic phase functions, asymmetry parameter (mean cosine of the scattering angle), absorption and scattering opacities, single scattering albedos, equilibrium temperatures, and radiative accelerations of dust grains relevant for extrasolar planets. Our assumptions include spherical grain shape, Deirmendjian particle size distribution, and Mie theory. We consider several species: corundum/alumina, perovskite, olivines with 0 and 50 per cent iron content, pyroxenes with 0, 20, and 60 per cent iron content, pure iron, carbon at two different temperatures, water ice, liquid water, and ammonia. The presented tables cover the wavelength range of 0.2-500 μm and modal particle radii from 0.01 to 100 μm. Equilibrium temperatures and radiative accelerations assume irradiation by a non-blackbody source of light with temperatures from 7000 to 700 K seen at solid angles from 2π to 10-6 sr. The tables are provided to the community together with a simple code which allows for an optional, finite, angular dimension of the source of light (star) in the phase function.

  10. Fifty communities putting prevention to work: accelerating chronic disease prevention through policy, systems and environmental change.

    PubMed

    Bunnell, Rebecca; O'Neil, Dara; Soler, Robin; Payne, Rebecca; Giles, Wayne H; Collins, Janet; Bauer, Ursula

    2012-10-01

    The burden of preventable chronic diseases is straining our nation's health and economy. Diseases caused by obesity and tobacco use account for the largest portions of this preventable burden. CDC funded 50 communities in 2010 to implement policy, systems, and environmental (PSE) interventions in a 2-year initiative. Funded communities developed PSE plans to reduce obesity, tobacco use, and second-hand smoke exposure for their combined 55 million residents. Community outcome objectives and milestones were categorized by PSE interventions as they related to media, access, promotion, pricing, and social support. Communities estimated population reach based on their jurisdiction's census data and target populations. The average proportion of each community's population that was reached was calculated for each intervention category. Outcome objectives that were achieved within 12 months of program initiation were identified from routine program records. The average proportion of a community's jurisdictional population reached by a specific intervention varied across interventions. Mean population reach for obesity-prevention interventions was estimated at 35%, with 14 (26%) interventions covering over 50% of the jurisdictional populations. For tobacco prevention, mean population reach was estimated at 67%, with 16 (84%) interventions covering more than 50% of the jurisdictional populations. Within 12 months, communities advanced over one-third of their obesity and tobacco-use prevention strategies. Tobacco interventions appeared to have higher potential population reach than obesity interventions within this initiative. Findings on the progress and potential reach of this major initiative may help inform future chronic disease prevention efforts. PMID:22323099

  11. Chronic ethanol intake alters circadian phase shifting and free-running period in mice.

    PubMed

    Seggio, Joseph A; Fixaris, Michael C; Reed, Jeffrey D; Logan, Ryan W; Rosenwasser, Alan M

    2009-08-01

    Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker--including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli--in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes. PMID:19625732

  12. The Kynurenine Pathway in the Acute and Chronic Phases of Cerebral Ischemia

    PubMed Central

    Cuartero, María Isabel; de la Parra, Juan; García-Culebras, Alicia; Ballesteros, Iván; Lizasoain, Ignacio; Moro, María Ángeles

    2016-01-01

    Kynurenines are a wide range of catabolites which derive from tryptophan through the “Kynurenine Pathway” (KP). In addition to its peripheral role, increasing evidence shows a role of the KP in the central nervous system (CNS), mediating both physiological and pathological functions. Indeed, an imbalance in this route has been associated with several neurodegenerative disorders such as Alzheimer’s and Huntington’s diseases. Altered KP catabolism has also been described during both acute and chronic phases of stroke; however the contribution of the KP to the pathophysiology of acute ischemic damage and of post-stroke disorders during the chronic phase including depression and vascular dementia, and the exact mechanisms implicated in the regulation of the KP after stroke are not well established yet. A better understanding of the regulation and activity of the KP after stroke could provide new pharmacological tools in both acute and chronic phases of stroke. In this review, we will make an overview of CNS modulation by the KP. We will detail the KP contribution in the ischemic damage, how the unbalance of the KP might trigger an alteration of the cognitive function after stroke as well as potential targets for the development of new drugs. PMID:25248805

  13. Chronic Ethanol Intake Alters Circadian Phase Shifting and Free-Running Period in Mice

    PubMed Central

    Seggio, Joseph A.; Fixaris, Michael C.; Reed, Jeffrey D.; Logan, Ryan W.; Rosenwasser, Alan M.

    2011-01-01

    Chronic alcohol intake is associated with widespread disruptions in sleep and circadian rhythms in both human alcoholics and in experimental animals. Recent studies have demonstrated that chronic and acute ethanol treatments alter fundamental properties of the circadian pacemaker—including free-running period and responsiveness to photic and nonphotic phase-shifting stimuli—in rats and hamsters. In the present work, the authors extend these observations to the C57BL/6J mouse, an inbred strain characterized by very high levels of voluntary ethanol intake and by reliable and stable free-running circadian activity rhythms. Mice were housed individually in running-wheel cages under conditions of either voluntary or forced ethanol intake, whereas controls were maintained on plain water. Forced ethanol intake significantly attenuated photic phase delays (but not phase advances) and shortened free-running period in constant darkness, but voluntary ethanol intake failed to affect either of these parameters. Thus, high levels of chronic ethanol intake, beyond those normally achieved under voluntary drinking conditions, are required to alter fundamental circadian pacemaker properties in C57BL/6J mice. These observations may be related to the relative ethanol insensitivity displayed by this strain in several other phenotypic domains, including ethanol-induced sedation, ataxia, and withdrawal. Additional experiments will investigate chronobiological sensitivity to ethanol in a range of inbred strains showing diverse ethanol-related phenotypes. PMID:19625732

  14. Accelerated safety analyses - structural analyses Phase I - structural sensitivity evaluation of single- and double-shell waste storage tanks

    SciTech Connect

    Becker, D.L.

    1994-11-01

    Accelerated Safety Analyses - Phase I (ASA-Phase I) have been conducted to assess the appropriateness of existing tank farm operational controls and/or limits as now stipulated in the Operational Safety Requirements (OSRs) and Operating Specification Documents, and to establish a technical basis for the waste tank operating safety envelope. Structural sensitivity analyses were performed to assess the response of the different waste tank configurations to variations in loading conditions, uncertainties in loading parameters, and uncertainties in material characteristics. Extensive documentation of the sensitivity analyses conducted and results obtained are provided in the detailed ASA-Phase I report, Structural Sensitivity Evaluation of Single- and Double-Shell Waste Tanks for Accelerated Safety Analysis - Phase I. This document provides a summary of the accelerated safety analyses sensitivity evaluations and the resulting findings.

  15. BCR-ABL transcript variations in chronic phase chronic myelogenous leukemia patients on imatinib first-line: Possible role of the autologous immune system.

    PubMed

    Clapp, Geoffrey D; Lepoutre, Thomas; Nicolini, Franck E; Levy, Doron

    2016-05-01

    Many chronic myelogenous leukemia (CML) patients in chronic phase who respond well to imatinib therapy show fluctuations in their leukemic loads in the long-term. We developed a mathematical model of CML that incorporates the intervention of an autologous immune response. Our results suggest that the patient's immune system plays a crucial role in imatinib therapy in maintaining disease control over time. The observed BCR-ABL/ABL oscillations in such patients provide a signature of the autologous immune response. PMID:27467931

  16. Omacetaxine Mepesuccinate for Chronic Myeloid Leukemia.

    PubMed

    Rosshandler, Yasmin; Shen, Ann Q; Cortes, Jorge; Khoury, Hanna Jean

    2016-05-01

    Omacetaxine mepesuccinate is approved by the Food and Drug Administration in the United States for the treatment of chronic myeloid leukemia in chronic or accelerated phase resistant to two or more tyrosine kinase inhibitors. This review summarizes the mode of action, pharmacokinetics, efficacy and safety of omacetaxine mepesuccinate. Omacetaxine mepesuccinate has activity in chronic myeloid leukemia, especially in the chronic phase, regardless of the presence of ABL1 kinase domain mutations. Omacetaxine mepesuccinate has distinct but manageable adverse events profile. Omacetaxine mepesuccinate is a treatment option for a subset of patients with refractory chronic myeloid leukemia. PMID:26853281

  17. Long-term outcome with dasatinib after imatinib failure in chronic-phase chronic myeloid leukemia: follow-up of a phase 3 study

    PubMed Central

    Guilhot, François; Cortes, Jorge E.; Schiffer, Charles A.; le Coutre, Philipp; Brümmendorf, Tim H.; Kantarjian, Hagop M.; Hochhaus, Andreas; Rousselot, Philippe; Mohamed, Hesham; Healey, Diane; Cunningham, Michael; Saglio, Giuseppe

    2014-01-01

    We present long-term follow-up of a dasatinib phase 3 study of patients with imatinib-resistant/-intolerant chronic myeloid leukemia (CML). In the CA180-034 study, 670 patients with imatinib-resistant/-intolerant CML in chronic phase (CML-CP) received dasatinib 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. At 6 years, 188 (28%) of 670 patients remained on study treatment. Estimated 6-year protocol-defined progression-free survival (PFS) rates were 49%, 51%, 40%, and 47%, respectively, and estimated 6-year overall survival (OS) rates were 71%, 74%, 77%, and 70%, respectively (intent-to-treat population, including protocol-defined progression or death after discontinuation). Estimated 6-year rates of survival without transformation on study treatment were 76%, 80%, 83%, and 74%, respectively. Major molecular response was achieved in 43% (100 mg once daily) and 40% (all other arms) of patients by 6 years. Molecular and cytogenetic responses at 3 and 6 months were highly predictive of PFS and OS. Notably, estimated 6-year PFS rates based on ≤1%, >1% to 10%, and >10% BCR-ABL transcripts at 3 months were 68%, 58%, and 26%, respectively. Most adverse events occurred by 2 years. Imatinib-resistant/-intolerant patients with CML-CP can experience long-term benefit with dasatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 months. This study was registered at ClinicalTrials.gov: NCT00123474. PMID:24569263

  18. Magnetic Shielding Accelerates the Proliferation of Human Neuroblastoma Cell by Promoting G1-Phase Progression

    PubMed Central

    Liu, Ying; Bartlett, Perry F.; He, Rong-qiao

    2013-01-01

    Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID:23355897

  19. Magnetic shielding accelerates the proliferation of human neuroblastoma cell by promoting G1-phase progression.

    PubMed

    Mo, Wei-chuan; Zhang, Zi-jian; Liu, Ying; Bartlett, Perry F; He, Rong-qiao

    2013-01-01

    Organisms have been exposed to the geomagnetic field (GMF) throughout evolutionary history. Exposure to the hypomagnetic field (HMF) by deep magnetic shielding has recently been suggested to have a negative effect on the structure and function of the central nervous system, particularly during early development. Although changes in cell growth and differentiation have been observed in the HMF, the effects of the HMF on cell cycle progression still remain unclear. Here we show that continuous HMF exposure significantly increases the proliferation of human neuroblastoma (SH-SY5Y) cells. The acceleration of proliferation results from a forward shift of the cell cycle in G1-phase. The G2/M-phase progression is not affected in the HMF. Our data is the first to demonstrate that the HMF can stimulate the proliferation of SH-SY5Y cells by promoting cell cycle progression in the G1-phase. This provides a novel way to study the mechanism of cells in response to changes of environmental magnetic field including the GMF. PMID:23355897

  20. Two-axis acceleration of functional connectivity magnetic resonance imaging by parallel excitation of phase-tagged slices and half k-space acceleration.

    PubMed

    Jesmanowicz, Andrzej; Nencka, Andrew S; Li, Shi-Jiang; Hyde, James S

    2011-01-01

    Whole brain functional connectivity magnetic resonance imaging requires acquisition of a time course of gradient-recalled (GR) volumetric images. A method is developed to accelerate this acquisition using GR echo-planar imaging and radio frequency (RF) slice phase tagging. For N-fold acceleration, a tailored RF pulse excites N slices using a uniform-field transmit coil. This pulse is the Fourier transform of the profile for the N slices with a predetermined RF phase tag on each slice. A multichannel RF receive coil is used for detection. For n slices, there are n/N groups of slices. Signal-averaged reference images are created for each slice within each slice group for each member of the coil array and used to separate overlapping images that are simultaneously received. The time-overhead for collection of reference images is small relative to the acquisition time of a complete volumetric time course. A least-squares singular value decomposition method allows image separation on a pixel-by-pixel basis. Twofold slice acceleration is demonstrated using an eight-channel RF receive coil, with application to resting-state functional magnetic resonance imaging in the human brain. Data from six subjects at 3 T are reported. The method has been extended to half k-space acquisition, which not only provides additional acceleration, but also facilitates slice separation because of increased signal intensity of the central lines of k-space coupled with reduced susceptibility effects. PMID:22432957

  1. Informed Practice: Students' Clinical Experiences in the Undergraduate Phase of an Accelerated Physician Assistant Program.

    PubMed

    Dereczyk, Amy; DeWitt, Rachel

    2016-06-01

    This qualitative study explored the clinical experiences of students in an accelerated physician assistant (PA) program. The participants were either certified nursing assistants (CNAs) or emergency medical technicians-basic (EMTs-B). The study was designed to elicit (1) how the participants perceived their older patients and (2) how the participants' experiences might affect their own future communications, bedside manner, and clinical preparedness as PAs. This study used a focus group to explore students' clinical experiences before the graduate phase of their accelerated PA program. Five female and 2 male PA students (N = 7) participated in the study. All participants were 23 years old and worked as either a CNA or an EMT-B. Results fell into 2 basic themes: informing practice and forming relationships. Regarding the first theme, participants felt that their experience as entry-level health care providers allowed them to improve their communication skills and bedside manner and to provide greater comfort to patients. Regarding the second theme, participants gained appreciation for older people and began to recognize the knowledge deficits and learning needs of their patients. The results suggested that a student's clinical experience as a CNA or an EMT-B before entering a PA program has a positive effect on the student's personal and professional development. The participants acquired greater appreciation and respect for older patients and members of the health care team. PMID:27123599

  2. A GPU-accelerated flow solver for incompressible two-phase fluid flows

    NASA Astrophysics Data System (ADS)

    Codyer, Stephen; Raessi, Mehdi; Khanna, Gaurav

    2011-11-01

    We present a numerical solver for incompressible, immiscible, two-phase fluid flows that is accelerated by using Graphics Processing Units (GPUs). The Navier-Stokes equations are solved by the projection method, which involves solving a pressure Poisson problem at each time step. A second-order discretization of the Poisson problem leads to a sparse matrix with five and seven diagonals for two- and three-dimensional simulations, respectively. Running a serial linear algebra solver on a single CPU can take 50-99.9% of the total simulation time to solve the above system for pressure. To remove this bottleneck, we utilized the large parallelization capabilities of GPUs; we developed a linear algebra solver based on the conjugate gradient iterative method (CGIM) by using CUDA 4.0 libraries and compared its performance with CUSP, an open-source, GPU library for linear algebra. Compared to running the CGIM solver on a single CPU core, for a 2D case, our GPU solver yields speedups of up to 88x in solver time and 81x overall time on a single GPU card. In 3D cases, the speedups are up to 81x (solver) and 15x (overall). Speedup is faster at higher grid resolutions and our GPU solver outperforms CUSP. Current work examines the acceleration versus a parallel CGIM CPU solver.

  3. γδ T Cell Immune Manipulation during Chronic Phase of Simian HIV Infection Confers Immunological Benefits1

    PubMed Central

    Ali, Zahida; Yan, Lin; Plagman, Nicholas; Reichenberg, Armin; Hintz, Martin; Jomaa, Hassan; Villinger, Francois; Chen, Zheng W.

    2010-01-01

    Vγ2Vδ2 T cells, a major human γδ T cell subset, recognize the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by mycobacteria and some opportunistic pathogens, and they contribute to innate/adaptive/homeostatic and anticancer immunity. As initial efforts to explore Vγ2Vδ2 T cell-based therapeutics against HIV/AIDS-associated bacterial/protozoal infections and neoplasms, we investigated whether a well-defined HMBPP/IL-2 therapeutic regimen could overcome HIV-mediated immune suppression to massively expand polyfunctional Vγ2Vδ2 T cells, and whether such activation/expansion could impact AIDS pathogenesis in simian HIV (SHIV)-infected Chinese rhesus macaques. While HMBPP/IL-2 coadministration during acute or chronic phase of SHIV infection induced massive activation/expansion of Vγ2Vδ2 T cells, the consequences of such activation/expansions were different between these two treatment settings. HMBPP/IL-2 cotreatment during acute SHIV infection did not prevent the increases in peak and set-point viral loads or the accelerated disease progression seen with IL-2 treatment alone. In contrast, HMBPP/IL-2 cotreatment during chronic infection did not exacerbate disease, and more importantly it could confer immunological benefits. Surprisingly, although viral antigenic loads were not increased upon HMBPP/IL-2 cotreatment during chronic SHIV infection, HMBPP activation of Vγ2Vδ2 T cells boosted HIV Env-specific Ab titers. Such increases in Abs were sustained for >170 days and were immediately preceded by increased production of IFN-γ, TNF-α, IL-4, and IL-10 during peak expansion of Vγ2Vδ2 T cells displaying memory phenotypes, as well as the short-term increased effector function of Vγ2Vδ2 T cells and CD4+ and CD8+ αβ T cells producing antimicrobial cytokines. Thus, HMBPP/Vγ2Vδ2 T cell-based intervention may potentially be useful for combating neoplasms and HMBPP-producing opportunistic pathogens in chronically HIV

  4. The surface quasiliquid melt acceleration and the role of thermodynamic phase in the thermal decomposition of crystalline organic explosives

    SciTech Connect

    Henson, Bryan F

    2010-01-01

    We show that melt acceleration in the thermal decomposition of crystalline organic solids is a manifestation of the surface quasiliquid phase. We derive a single universal rate law for melt acceleration that is a simple function of the metastable liquid activity below the melting point, and has a zero order term proportional to the quasiliquid thickness. We argue that the underlying mechanisms of this model will provide a molecular definition for the stability of the class of secondary explosives.

  5. Key Techniques of Flat-Earth Phase Removal by Acceleration on the GPU

    NASA Astrophysics Data System (ADS)

    Gao, Zeng; Zeng, Qiming; Jiao, Jian; Cui, Xiai; Liang, Cunren

    2013-01-01

    Because InSAR processing is complex and time-consuming, parallel computing has been drawing more and more attention from researchers. GPUs (Graphics Processing Units) have become an increasingly important parallel platform for image processing in recent years. They are cheap and convenient, compared with large-scale, expensive high performance computing clusters, which have a small marketplace presence. In this paper, a valid parallelism implemented on the GPU is introduced. Taking the flat-earth phase removal for example, we introduced two different techniques that can accelerate applications dramatically on a GPU. From the experiment results, we can see that the result accomplished on the GPU is the same as on the CPU; the two techniques used really work in performance improvement.

  6. A Liquid-to-Solid Phase Transition of the ALS Protein FUS Accelerated by Disease Mutation.

    PubMed

    Patel, Avinash; Lee, Hyun O; Jawerth, Louise; Maharana, Shovamayee; Jahnel, Marcus; Hein, Marco Y; Stoynov, Stoyno; Mahamid, Julia; Saha, Shambaditya; Franzmann, Titus M; Pozniakovski, Andrej; Poser, Ina; Maghelli, Nicola; Royer, Loic A; Weigert, Martin; Myers, Eugene W; Grill, Stephan; Drechsel, David; Hyman, Anthony A; Alberti, Simon

    2015-08-27

    Many proteins contain disordered regions of low-sequence complexity, which cause aging-associated diseases because they are prone to aggregate. Here, we study FUS, a prion-like protein containing intrinsically disordered domains associated with the neurodegenerative disease ALS. We show that, in cells, FUS forms liquid compartments at sites of DNA damage and in the cytoplasm upon stress. We confirm this by reconstituting liquid FUS compartments in vitro. Using an in vitro "aging" experiment, we demonstrate that liquid droplets of FUS protein convert with time from a liquid to an aggregated state, and this conversion is accelerated by patient-derived mutations. We conclude that the physiological role of FUS requires forming dynamic liquid-like compartments. We propose that liquid-like compartments carry the trade-off between functionality and risk of aggregation and that aberrant phase transitions within liquid-like compartments lie at the heart of ALS and, presumably, other age-related diseases. PMID:26317470

  7. Chronic NOS inhibition accelerates NAFLD progression in an obese rat model.

    PubMed

    Sheldon, Ryan D; Padilla, Jaume; Jenkins, Nathan T; Laughlin, M Harold; Rector, R Scott

    2015-03-15

    The progression in nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis is a serious health concern, but the underlying mechanisms remain unclear. We hypothesized that chronic inhibition of nitric oxide (NO) synthase (NOS) via N(ω)-nitro-L-arginine methyl ester (L-NAME) would intensify liver injury in a rat model of obesity, insulin resistance, and NAFLD. Obese Otsuka Long-Evans Tokushima fatty (OLETF) and lean Long-Evans Tokushima Otsuka (LETO) rats received control or L-NAME (65-70 mg·kg(-1)·day(-1))-containing drinking water for 4 wk. L-NAME treatment significantly (P < 0.05) reduced serum NO metabolites and food intake in both groups. Remarkably, despite no increase in body weight, L-NAME treatment increased hepatic triacylglycerol content (+40%, P < 0.05) vs. control OLETF rats. This increase was associated with impaired (P < 0.05) hepatic mitochondrial state 3 respiration. Interestingly, the opposite effect was found in LETO rats, where L-NAME increased (P < 0.05) hepatic mitochondrial state 3 respiration. In addition, L-NAME induced a shift toward proinflammatory M1 macrophage polarity, as indicated by elevated hepatic CD11c (P < 0.05) and IL-1β (P = 0.07) mRNA in OLETF rats and reduced expression of the anti-inflammatory M2 markers CD163 and CD206 (P < 0.05) in LETO rats. Markers of total macrophage content (CD68 and F4/80) mRNA were unaffected by L-NAME in either group. In conclusion, systemic NOS inhibition in the obese OLETF rats reduced hepatic mitochondrial respiration, increased hepatic triacylglycerol accumulation, and increased hepatic inflammation. These findings suggest an important role for proper NO metabolism in the hepatic adaptation to obesity. PMID:25573175

  8. Chronic lead treatment accelerates photochemically induced platelet aggregation in cerebral microvessels of mice, in vivo

    SciTech Connect

    Al Dhaheri, A.H.; El-Sabban, F.; Fahim, M.A.

    1995-04-01

    Effects of two chronic treatment levels with lead on platelet aggregation in cerebral (pial) microcirculation of the mouse were investigated. Exposure to lead was made by subcutaneous injections for 7 days of lead acetate dissolved in 5% glucose solution, vehicle. Two doses of lead were used, a low dose of 0.1 mg/kg and a high dose of 1.0 mg/kg. Adult male mice were divided into three groups, 10 each; one group was injected with vehicle (control), another was injected with the low dose, and the third was injected with the high dose. Additional mice were used for the determination of hematological parameters and for the lead level in serum of the three groups. On the eighth day, platelet aggregation in pial microvessels of these groups of mice was carried out in vivo. Animals were anesthetized (urethane, 1-2 mg/g, ip), the trachea was intubated, and a craniotomy was performed. Platelet aggregation in pial microvessels was induced photochemically, by activation of circulating sodium fluorescein (0.1 mg/25 g, iv) with an intense mercury light. The time required for the first platelet aggregate to appear in pial arterioles was significantly shorter in the lead-treated mice than in control. This effect was in a dose-dependent manner; 113 {+-} 44 sec for low dose and 71 {+-} 18 sec for high dose vs 155 {+-} 25 sec for control, P < 0.02 and P < 0.001, respectively. Between the two lead-treated groups, the high dose significantly (P < 0.05) shortened the time to first aggregate. These data evidenced an increased susceptibility to cerebrovascular thrombosis as a result of exposure to lead. 26 refs., 4 figs., 2 tabs.

  9. Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth.

    PubMed

    Blum-Johnston, Carla; Thorpe, Richard B; Wee, Chelsea; Romero, Monica; Brunelle, Alexander; Blood, Quintin; Wilson, Rachael; Blood, Arlin B; Francis, Michael; Taylor, Mark S; Longo, Lawrence D; Pearce, William J; Wilson, Sean M

    2016-02-01

    Bradykinin-induced activation of the pulmonary endothelium triggers nitric oxide production and other signals that cause vasorelaxation, including stimulation of large-conductance Ca(2+)-activated K(+) (BKCa) channels in myocytes that hyperpolarize the plasma membrane and decrease intracellular Ca(2+). Intrauterine chronic hypoxia (CH) may reduce vasorelaxation in the fetal-to-newborn transition and contribute to pulmonary hypertension of the newborn. Thus we examined the effects of maturation and CH on the role of BKCa channels during bradykinin-induced vasorelaxation by examining endothelial Ca(2+) signals, wire myography, and Western immunoblots on pulmonary arteries isolated from near-term fetal (∼ 140 days gestation) and newborn, 10- to 20-day-old, sheep that lived in normoxia at 700 m or in CH at high altitude (3,801 m) for >100 days. CH enhanced bradykinin-induced relaxation of fetal vessels but decreased relaxation in newborns. Endothelial Ca(2+) responses decreased with maturation but increased with CH. Bradykinin-dependent relaxation was sensitive to 100 μM nitro-L-arginine methyl ester or 10 μM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, supporting roles for endothelial nitric oxide synthase and soluble guanylate cyclase activation. Indomethacin blocked relaxation in CH vessels, suggesting upregulation of PLA2 pathways. BKCa channel inhibition with 1 mM tetraethylammonium reduced bradykinin-induced vasorelaxation in the normoxic newborn and fetal CH vessels. Maturation reduced whole cell BKCa channel α1-subunit expression but increased β1-subunit expression. These results suggest that CH amplifies the contribution of BKCa channels to bradykinin-induced vasorelaxation in fetal sheep but stunts further development of this vasodilatory pathway in newborns. This involves complex changes in multiple components of the bradykinin-signaling axes. PMID:26637638

  10. Geometric phase of an accelerated two-level atom in the presence of a perfectly reflecting plane boundary

    NASA Astrophysics Data System (ADS)

    Zhai, Hua; Zhang, Jialin; Yu, Hongwei

    2016-08-01

    We study the geometric phase of a uniformly accelerated two-level atom coupled with vacuum fluctuations of electromagnetic fields in the presence of a perfectly reflecting plane. We find that the geometric phase difference between the accelerated and inertial atoms which can be observed by atom interferometry crucially depends on the polarizability of the atom and the distance to the boundary and it can be dramatically manipulated with anisotropically polarizable atoms. In particular, extremely close to the boundary, the phase difference can be increased by two times as compared to the case without any boundary. So, the detectability of the effects associated with acceleration using an atom interferometer can be significantly increased by the presence of a boundary using atoms with anisotropic polarizability.

  11. Phase Recovery Acceleration of Quantum-Dot Semiconductor Optical Amplifiers by Optical Pumping to Quantum-Well Wetting Layer

    NASA Astrophysics Data System (ADS)

    Kim, Jungho

    2013-11-01

    We theoretically investigate the phase recovery acceleration of quantum-dot (QD) semiconductor optical amplifiers (SOAs) by means of the optical pump injection to the quantum-well (QW) wetting layer (WL). We compare the ultrafast gain and phase recovery responses of QD SOAs in either the electrical or the optical pumping scheme by numerically solving 1088 coupled rate equations. The ultrafast gain recovery responses on the order of sub-picosecond are nearly the same for the two pumping schemes. The ultrafast phase recovery is not significantly accelerated by increasing the electrical current density, but greatly improved by increasing the optical pumping power to the QW WL. Because the phase recovery time of QD SOAs with the optical pumping scheme can be reduced down to several picoseconds, the complete phase recovery can be achieved when consecutive pulse signals with a repetition rate of 100 GHz is injected.

  12. CML in Chronic Phase with Novel Secondary Cytogenetic Abnormalities: A Case Report.

    PubMed

    Patel, Hiral S; Brahmbhatt, Manisha M; Trivedi, Pina J; Patel, Dharmesh M; Sugandhi, Ankita A; Patel, Binita V; Patel, Prabhudas S

    2016-01-01

    The clonal evolution in t(9;22)-positive Chronic Myelocytic Leukemia (CML) patients is well established. Four major changes occur in more than 70% of patients: +8, i(17q), +19, and an extra Philadelphia chromosome. Here, we present a case with CML-Chronic phase (CML-CP) and novel t(9;13)(q34;q12~13) in addition to t(9;22)(q34;q11.2). Fluorescence in situ hybridization (FISH) using dual color dual fusion probe analysis on interphase and metaphase cells confirmed the t(9;13)(q34;q12~13) as clonal evolution and secondary event to Philadelphia chromosome. This suggests minor route additional chromosomal aberrations which might affect prognosis. Further studies are required to ascertain the expression of genes that play a role in CML-blast crisis in order to to explore its therapeutic significance and prognostic value. PMID:27584557

  13. Acceleration and Deceleration Phase Nonlinear Rayleigh-Taylor Growth at Spherical Interfaces

    NASA Astrophysics Data System (ADS)

    Clark, Daniel

    2005-10-01

    The Layzer model for the nonlinear evolution of bubbles in the Rayleigh-Taylor instability has recently been generalized to the case of spherically imploding interfaces [D. S. Clark and M. Tabak, Phys. Rev. E 71, 055302(R) (2005).]. The spherical case is more relevant to, e.g., Inertial Confinement Fusion (ICF) or various astrophysical phenomena when the convergence is strong or the perturbation wavelength is comparable to the interface curvature. Here, the model is further extended to the case of bubble growth during the deceleration (stagnation) phase of a spherical implosion and to the growth of spikes during both the acceleration and deceleration phases. Differences in the nonlinear growth rates for both bubbles and spikes are found when compared with planar results, and the model predictions are verified by comparison with numerical hydrodynamics simulations. The new nonlinear growth rates are also incorporated into a Haan-type saturation model to give improved predictions of multi-mode saturated growth for ICF capsules.

  14. Interferometric determination of broadband ELF wave phase velocity within a region of transverse auroral ion acceleration

    NASA Astrophysics Data System (ADS)

    Bonnell, J.; Kintner, P.; Wahlund, J.-E.; Lynch, K.; Arnoldy, R.

    Broadband electric field fluctuations with typical amplitudes of 10-20 mV/m peak-to-peak and frequencies from 0 Hz to 3 kHz (BB-ELF) were observed coincident with a region of ≤200 eV transverse H+ acceleration (TAI) near the poleward edge of the pre-midnight aurora. The coherence and phase velocity of the electric fields were measured using a interferometric antenna array over the frequency range of ≈ 100 Hz to 3 kHz. These electric field fluctuations were found to have the following characteristics: 1) incoherence perpendicular to the geomagnetic field, 2) coherence parallel to the the geomagnetic field, 3) parallel phase velocity (ω/k∥) of 30-35 km/s upwards, 4) 0 < |k∥/k⊥| < 0.22. We show that these properties are compatible with the emission being electrostatic H+ cyclotron (EHC) waves. We also discuss possible generation mechanisms for the waves, and their relationship to the TAI.

  15. Chronic lymphocytic leukemia disease progression is accelerated by APRIL-TACI interaction in the TCL1 transgenic mouse model

    PubMed Central

    Lascano, Valeria; Guadagnoli, Marco; Schot, Jan G.; Luijks, Dieuwertje M.; Guikema, Jeroen E. J.; Cameron, Katherine; Hahne, Michael; Pals, Steven; Slinger, Erik; Kipps, Thomas J.; van Oers, Marinus H. J.; Eldering, Eric; Medema, Jan Paul

    2013-01-01

    Although in vitro studies pointed to the tumor necrosis factor family member APRIL (a proliferation-inducing ligand) in mediating survival of chronic lymphocytic leukemia (CLL) cells, clear evidence for a role in leukemogenesis and progression in CLL is lacking. APRIL significantly prolonged in vitro survival of CD5+B220dull leukemic cells derived from the murine Eμ-TCL1-Tg (TCL1-Tg [transgenic]) model for CLL. APRIL-TCL1 double-Tg mice showed a significantly earlier onset of leukemia and disruption of splenic architecture, and survival was significantly reduced. Interestingly, clonal evolution of CD5+B220dull cells (judged by BCR clonality) did not seem to be accelerated by APRIL; both mouse strains were oligoclonal at 4 months. Although APRIL binds different receptors, APRIL-mediated leukemic cell survival depended on tumor necrosis factor receptor superfamily member 13B (TACI) ligation. These findings indicate that APRIL has an important role in CLL and that the APRIL-TACI interaction might be a selective novel therapeutic target for human CLL. PMID:24100449

  16. Trajectories of electrons with large longitudinal momenta in the phase plane during surfatron acceleration by an electromagnetic wave

    SciTech Connect

    Mkrtichyan, G. S.

    2015-07-15

    The trajectories of electrons with large longitudinal momenta in the phase plane in the course of their surfatron acceleration by an electromagnetic wave propagating in space plasma across the external magnetic field are analyzed. Electrons with large longitudinal momenta are trapped immediately if the initial wave phase Ψ(0) on the particle trajectory is positive. For negative values of Ψ(0), no electrons trapping by the wave is observed over the available computational times. According to numerical calculations, the trajectories of trapped particles in the phase plane have a singular point of the stable focus type and the behavior of the trajectory corresponds to the motion in a complex nonstationary effective potential well. For some initial phases, electrons are confined in the region of the accelerating electric field for relatively short time, the energy gain being about 50–130% and more.

  17. A phase 2 study of MK-0457 in patients with BCR-ABL T315I mutant chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia.

    PubMed

    Seymour, J F; Kim, D W; Rubin, E; Haregewoin, A; Clark, J; Watson, P; Hughes, T; Dufva, I; Jimenez, J L; Mahon, F-X; Rousselot, P; Cortes, J; Martinelli, G; Papayannidis, C; Nagler, A; Giles, F J

    2014-01-01

    Aurora kinase overexpression has been observed in patients with hematologic malignancies. MK-0457, a pan-aurora kinase inhibitor that also inhibits the ABL T315I mutant, was evaluated to treat patients with chronic myelogenous leukemia (CML) or Philadelphia chromosome (Ph+) acute lymphoblastic leukemia (ALL) with the T315I mutation. Adults with Ph+ chronic phase (CP)-, accelerated phase (AP)- or blast phase (BP)-CML, or ALL and documented BCR-ABL T315I mutation were treated with a 5-day continuous infusion of MK-0457 administered every 14 days at 40 mg/m(2)/h, 32 mg/m(2)/h or 24 mg/m(2)/h. Fifty-two patients (CP, n=15; AP, n=14; BP, n=11; Ph+ ALL, n=12) were treated. Overall, 8% of patients achieved major cytogenetic response; 6% achieved unconfirmed complete or partial response; 39% had no response. Two patients (CP CML) achieved complete hematologic response. No patients with advanced CML or Ph+ ALL achieved major hematologic response. The most common adverse event (AE) was neutropenia (50%). The most common grade 3/4 AEs were neutropenia (46%) and febrile neutropenia (35%). MK-0457 demonstrated minimal efficacy and only at higher, intolerable doses; lower doses were tolerated and no unexpected toxicities were observed. These data will assist in the development of future aurora kinase inhibitors and in the selection of appropriate target patient populations. PMID:25127392

  18. Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration.

    PubMed

    Xiang, Wei; Cheong, Jit Kong; Ang, Shi Hui; Teo, Bryan; Xu, Peng; Asari, Kartini; Sun, Wen Tian; Than, Hein; Bunte, Ralph M; Virshup, David M; Chuah, Charles

    2015-10-20

    The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). We show that pyrvinium, a FDA-approved anthelminthic drug, selectively targets BP-CML CD34+ progenitor cells. Pyrvinium is effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34+ cells from TKI-resistant BP-CML patients, while cord blood CD34+ are largely unaffected. The effects of pyrvinium are further enhanced upon combination with dasatinib, a second generation BCR-ABL1 TKI. In a CML xenograft model pyrvinium significantly inhibits tumor growth as a single agent, with complete inhibition in combination with dasatinib. While pyrvinium has been shown to inhibit the Wnt/β-catenin signalling pathway via activation of casein kinase 1α , we find its activity in CML is not dependent on this pathway. Instead, we show that pyrvinium localizes to mitochondria and induces apoptosis by inhibiting mitochondrial respiration. Our study suggests that pyrvinium is a useful addition to the treatment armamentarium for BP-CML and that targeting mitochondrial respiration may be a potential therapeutic strategy in aggressive leukemia. PMID:26378050

  19. Pyrvinium selectively targets blast phase-chronic myeloid leukemia through inhibition of mitochondrial respiration

    PubMed Central

    Ang, Shi Hui; Teo, Bryan; Xu, Peng; Asari, Kartini; Sun, Wen Tian; Than, Hein; Bunte, Ralph M.; Virshup, David M.; Chuah, Charles

    2015-01-01

    The use of BCR-ABL1 tyrosine kinase inhibitors (TKI) has led to excellent clinical responses in patients with chronic phase chronic myeloid leukemia (CML). However these inhibitors have been less effective as single agents in the terminal blast phase (BP). We show that pyrvinium, a FDA-approved anthelminthic drug, selectively targets BP-CML CD34+ progenitor cells. Pyrvinium is effective in inducing apoptosis, inhibiting colony formation and self-renewal capacity of CD34+ cells from TKI-resistant BP-CML patients, while cord blood CD34+ are largely unaffected. The effects of pyrvinium are further enhanced upon combination with dasatinib, a second generation BCR-ABL1 TKI. In a CML xenograft model pyrvinium significantly inhibits tumor growth as a single agent, with complete inhibition in combination with dasatinib. While pyrvinium has been shown to inhibit the Wnt/β-catenin signalling pathway via activation of casein kinase 1α, we find its activity in CML is not dependent on this pathway. Instead, we show that pyrvinium localizes to mitochondria and induces apoptosis by inhibiting mitochondrial respiration. Our study suggests that pyrvinium is a useful addition to the treatment armamentarium for BP-CML and that targeting mitochondrial respiration may be a potential therapeutic strategy in aggressive leukemia. PMID:26378050

  20. Natural history of chronic hepatitis B: Phases in a complex relationship

    PubMed Central

    Croagh, Catherine MN; Lubel, John S

    2014-01-01

    Chronic hepatitis B (CHB) is a condition of global prevalence and its sequelae include cirrhosis and hepatocellular carcinoma. The natural history of CHB is a complex interplay of virological, environmental and host factors. The dynamic relationship between the virus and host evolves over the duration of the infection and different phases of the disease have been observed and described. These have been conceptualized in terms of the state of balance between the host immune system and the hepatitis B virus and have been given the labels immune tolerant, immune clearance, immune control and immune escape although other nomenclature is also used. Host factors, such as age at infection, determine progression to chronicity. Virological factors including hepatitis B viral load, mutations and genotype also have an impact on the adverse outcomes of the infection, as do hepatotoxic cofactors such as alcohol. Our understanding of the natural history of CHB has evolved significantly over the past few decades and characterizing the phase of disease of CHB remains an integral part of managing this virus in the clinic. PMID:25132755

  1. Anti-phase action between the angular accelerations of trunk and leg is reduced in the elderly.

    PubMed

    Kato, Tomohisa; Yamamoto, Shin-ichiro; Miyoshi, Tasuku; Nakazawa, Kimitaka; Masani, Kei; Nozaki, Daichi

    2014-01-01

    Quiet standing posture in humans has often been modeled as a single inverted pendulum pivoting around the ankle joint. However, recent studies have suggested that anti-phase action between leg and trunk segments plays a significant role in stabilizing posture by reducing the acceleration of the center of mass (COM) of the body. The aim of this study is to test the hypothesis that anti-phase action is attenuated in the elderly compared to the young. The anterior-posterior movements of leg and trunk segments were measured using 4 laser displacement sensors from 22 healthy young subjects (age range, 20-35 years) and 38 healthy elderly subjects (age range, 57-80 years) standing quietly for 30s twice. To focus on the segmental action between trunk and legs, we applied constraints (i.e., wooden splints) on each segment. We found that the velocity and acceleration of the COM (standard deviation of the time series was evaluated) were significantly higher for the elderly subjects than for young subjects. The increase in the acceleration of the COM resulted not only from an increase in the angular acceleration of the segments but also from the reduction of their anti-phase relationship, as demonstrated by an index that quantifies the degree of cancelation between both segments. We conclude that the degree of anti-phase action between trunk and leg segments during quiet standing is smaller for elderly subjects than for young subjects, and that this change of the anti-phase action due to aging resulted in increased COM acceleration in the elderly subjects. PMID:24708906

  2. Numerical study of liquid phase diffusion growth of SiGe subjected to accelerated crucible rotation

    NASA Astrophysics Data System (ADS)

    Sekhon, M.; Lent, B.; Dost, S.

    2016-03-01

    The effect of accelerated crucible rotation technique (ACRT) on liquid phase diffusion (LPD) growth of SixGe1-x crystal has been investigated numerically. Transient, axisymmetric simulations have been carried out for triangular and trapezoidal ACRT cycles. Natural convection driven flow in the early growth hours is found to be modified by the ACRT induced Ekman flow. Results also reveal that a substantial mixing in the solution can be induced by the application of ACRT in the later hours of growth which is otherwise a diffusion dominated growth period for LPD growth technique. A comparison is drawn to the cases of stationary crucible and crucible rotating at a constant speed examined previously for this growth system by Sekhon and Dost (J. Cryst. Growth 430 (2015) 63). It is found that a superior interface flattening effect and radial compositional uniformity along the growth interface can be accomplished by employing ACRT at 12 rpm than that which could be achieved by using steady crucible rotation at 25 rpm, owing to the higher time averaged growth velocity achieved in the former case. Furthermore, minor differences are also predicted in the results obtained for trapezoidal and triangular ACRT cycles.

  3. Swimming Exercise in the Acute or Late Phase after Sciatic Nerve Crush Accelerates Nerve Regeneration

    PubMed Central

    Teodori, Rosana Macher; Betini, Joice; de Oliveira, Larissa Salgado; Sobral, Luciane Lobato; Takeda, Sibele Yoko Mattozo; Montebelo, Maria Imaculada de Lima

    2011-01-01

    There is no consensus about the best time to start exercise after peripheral nerve injury. We evaluated the morphological and functional characteristics of the sciatic nerves of rats that began to swim immediately after crush nerve injury (CS1), those that began to swim 14 days after injury (CS14), injured rats not submitted to swimming (C), and uninjured rats submitted to swimming (S). After 30 days the number of axons in CS1 and CS14 was lower than in C (P < 0.01). The diameter of axons and nerve fibers was larger in CS1 (P < 0.01) and CS14 (P < 0.05) than in C, and myelin sheath thickness was lower in all crushed groups (P < 0.05). There was no functional difference between CS1 and CS14 (P > 0.05). Swimming exercise applied during the acute or late phase of nerve injury accelerated nerve regeneration and synaptic elimination after axonotmesis, suggesting that exercise may be initiated immediately after injury. PMID:21876821

  4. Nilotinib and Combination Chemotherapy in Treating Patients With Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-10-29

    B-cell Adult Acute Lymphoblastic Leukemia; Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Philadelphia Chromosome Positive Adult Precursor Acute Lymphoblastic Leukemia; Untreated Adult Acute Lymphoblastic Leukemia

  5. Obesity-induced chronic inflammation in high fat diet challenged C57BL/6J mice is associated with acceleration of age-dependent renal amyloidosis

    PubMed Central

    van der Heijden, Roel A.; Bijzet, Johan; Meijers, Wouter C.; Yakala, Gopala K.; Kleemann, Robert; Nguyen, Tri Q.; de Boer, Rudolf A.; Schalkwijk, Casper G.; Hazenberg, Bouke P. C.; Tietge, Uwe J. F.; Heeringa, Peter

    2015-01-01

    Obesity-induced inflammation presumably accelerates the development of chronic kidney diseases. However, little is known about the sequence of these inflammatory events and their contribution to renal pathology. We investigated the effects of obesity on the evolution of age-dependent renal complications in mice in conjunction with the development of renal and systemic low-grade inflammation (LGI). C57BL/6J mice susceptible to develop age-dependent sclerotic pathologies with amyloid features in the kidney, were fed low (10% lard) or high-fat diets (45% lard) for 24, 40 and 52 weeks. HFD-feeding induced overt adiposity, altered lipid and insulin homeostasis, increased systemic LGI and adipokine release. HFD-feeding also caused renal upregulation of pro-inflammatory genes, infiltrating macrophages, collagen I protein, increased urinary albumin and NGAL levels. HFD-feeding severely aggravated age-dependent structural changes in the kidney. Remarkably, enhanced amyloid deposition rather than sclerosis was observed. The degree of amyloidosis correlated significantly with body weight. Amyloid deposits stained positive for serum amyloid A (SAA) whose plasma levels were chronically elevated in HFD mice. Our data indicate obesity-induced chronic inflammation as a risk factor for the acceleration of age-dependent renal amyloidosis and functional impairment in mice, and suggest that obesity-enhanced chronic secretion of SAA may be the driving factor behind this process. PMID:26563579

  6. Acceleration amplitude-phase regulation for electro-hydraulic servo shaking table based on LMS adaptive filtering algorithm

    NASA Astrophysics Data System (ADS)

    Yao, Jianjun; Di, Duotao; Jiang, Guilin; Gao, Shuang

    2012-10-01

    Electro-hydraulic servo shaking table usually requires good control performance for acceleration replication. The poles of the electro-hydraulic servo shaking table are placed by three-variable control method using pole placement theory. The system frequency band is thus extended and the system stability is also enhanced. The phase delay and amplitude attenuation phenomenon occurs in electro-hydraulic servo shaking table corresponding to an acceleration sinusoidal input. The method for phase delay and amplitude attenuation elimination based on LMS adaptive filtering algorithm is proposed here. The task is accomplished by adjusting the weights using LMS adaptive filtering algorithm when there exits phase delay and amplitude attenuation between the input and its corresponding acceleration response. The reference input is weighted in such a way that it makes the system output track the input efficiently. The weighted input signal is inputted to the control system such that the output phase delay and amplitude attenuation are all cancelled. The above concept is used as a basis for the development of amplitude-phase regulation (APR) algorithm. The method does not need to estimate the system model and has good real-time performance. Experimental results demonstrate the efficiency and validity of the proposed APR control scheme.

  7. DC-like Phase Space Manipulation and Particle Acceleration Using Chirped AC Fields

    SciTech Connect

    P.F. Schmit and N.J. Fisch

    2009-06-17

    Waves in plasmas can accelerate particles that are resonant with the wave. A DC electric field also accelerates particles, but without a resonance discrimination, which makes the acceleration mechanism profoundly different. We investigate the effect on a Hamiltonian distribution of an accelerating potential waveform, which could, for example, represent the average ponderomotive effect of two counterpropagating electromagnetic waves. In particular, we examine the apparent DC-like time-asymptotic response of the distribution in regimes where the potential structure is accelerated adiabatically. A highly resonant population within the distribution is always present, and we characterize its nonadiabatic response during wave-particle resonance using an integral method in the noninertial reference frame moving with the wave. Finally, we show that in the limit of infinitely slow acceleration of the wave, these highly resonant particles disappear and the response

  8. Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.

    ClinicalTrials.gov

    2016-08-05

    Leukemia; Leukemia,Pediatric; Leukemia, Myleiod; Leukemia, Mylegenous, Chronic; Leukemia, Mylegenous, Accelerated; BCR-ABL Positive; Myeloproliferative Disorder; Bone Marrow Disease; Hematologic Diseases; Neoplastic Processes; Imatinib; Dasatinib; Enzyme Inhibitor; Protein Kinase Inhibitor

  9. Sepsis chronically in MARS: systemic cytokine responses are always mixed regardless of the outcome, magnitude, or phase of sepsis.

    PubMed

    Osuchowski, Marcin F; Craciun, Florin; Weixelbaumer, Katrin M; Duffy, Elizabeth R; Remick, Daniel G

    2012-11-01

    The paradigm of systemic inflammatory response syndrome-to-compensatory anti-inflammatory response syndrome transition implies that hyperinflammation triggers acute sepsis mortality, whereas hypoinflammation (release of anti-inflammatory cytokines) in late sepsis induces chronic deaths. However, the exact humoral inflammatory mechanisms attributable to sepsis outcomes remain elusive. In the first part of this study, we characterized the systemic dynamics of the chronic inflammation in dying (DIE) and surviving (SUR) mice suffering from cecal ligation and puncture sepsis (days 6-28). In the second part, we combined the current chronic and previous acute/chronic sepsis data to compare the outcome-dependent inflammatory signatures between these two phases. A composite cytokine score (CCS) was calculated to compare global inflammatory responses. Mice were never sacrificed but were sampled daily (20 μl) for blood. In the first part of the study, parameters from chronic DIE mice were clustered into the 72, 48, and 24 h before death time points and compared with SUR of the same post-cecal ligation and puncture day. Cytokine increases were mixed and never preceded chronic deaths earlier than 48 h (3- to 180-fold increase). CCS demonstrated simultaneous and similar upregulation of proinflammatory and anti-inflammatory compartments at 24 h before chronic death (DIE 80- and 50-fold higher versus SUR). In the second part of the study, cytokine ratios across sepsis phases/outcomes indicated steady proinflammatory versus anti-inflammatory balance. CCS showed the inflammatory response in chronic DIE was 5-fold lower than acute DIE mice, but identical to acute SUR. The systemic mixed anti-inflammatory response syndrome-like pattern (concurrent release of proinflammatory and anti-inflammatory cytokines) occurs irrespective of the sepsis phase, response magnitude, and/or outcome. Although different in magnitude, neither acute nor chronic septic mortality is associated with a

  10. A Framework for a General Purpose Intelligent Control System for Particle Accelerators. Phase II Final Report

    SciTech Connect

    Dr. Robert Westervelt; Dr. William Klein; Dr. Michael Kroupa; Eric Olsson; Rick Rothrock

    1999-06-28

    Vista Control Systems, Inc. has developed a portable system for intelligent accelerator control. The design is general in scope and is thus configurable to a wide range of accelerator facilities and control problems. The control system employs a multi-layer organization in which knowledge-based decision making is used to dynamically configure lower level optimization and control algorithms.

  11. Electron acceleration in solar flares and the transition from nonthermal to thermal hard X-ray phases

    NASA Technical Reports Server (NTRS)

    Smith, D. F.

    1985-01-01

    Observations are reviewed which indicate that hard X-rays during the impulsive phase of a flare typically start with a primarily nonthermal phase which undergoes a transition to a primarily thermal phase as the flare progresses. Recent theoretical work on the modified two-stream instability as an efficient electron accelerator and modeling of thermal hard X-ray sources is considered. A scenario which is termed the dissipative thermal model is proposed to explain the observations. Fast tearing modes occurring in a loop give rise to cross-field ion motion. This in turn excites the modified two-stream instability which converts about 50 percent of the ion energy into accelerated electrons along the loop as long as the plasma beta is less than 0.3. These electrons impact the chromosphere and boil off a part of it which rises up the loop. This density increase coupled with the temperature increase due to tearing causes the beta to increase beyond 0.3 and efficient electron acceleration ceases. This leads to the primarily thermal phase.

  12. Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase

    PubMed Central

    Goldman, John M.; Majhail, Navneet S.; Klein, John P.; Wang, Zhiwei; Sobocinski, Kathleen A.; Arora, Mukta; Horowitz, Mary M.; Rizzo, J. Douglas

    2010-01-01

    Purpose Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. Patients and Methods Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen–matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. Results Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). Conclusion Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population. PMID:20212247

  13. Acceleration and deceleration of neutrons: From the phase modulation of a neutron wave to a neutron turbine with refracting prisms

    SciTech Connect

    Frank, A. I.

    2013-05-15

    The possibility of the acceleration and deceleration of neutrons undergoing diffraction at a moving grating is discussed. It is shown that, in contrast to phase {pi} gratings used at the present time, which form a discrete spectrum featuring a large number of lines, a grating that has a special profile may shift, under certain conditions, the entire spectrum of diffracted neutrons. A blazing grating of this type may be used in efficiently accelerating and decelerating neutrons. As the scale of the structure becomes larger, a description based on the idea of neutron-wave refraction at its elements becomes valid, a system of moving prims forming a 'neutron turbine,' which is also able to accelerate or decelerate neutrons, being a classical limit of this enlargement.

  14. Generating high-current monoenergetic proton beams by a circularly polarized laser pulse in the phase-stable acceleration regime.

    PubMed

    Yan, X Q; Lin, C; Sheng, Z M; Guo, Z Y; Liu, B C; Lu, Y R; Fang, J X; Chen, J E

    2008-04-01

    A new ion acceleration method, namely, phase-stable acceleration, using circularly-polarized laser pulses is proposed. When the initial target density n(0) and thickness D satisfy a(L) approximately (n(0)/n(c))D/lambda(L) and D>l(s) with a(L), lambda(L), l(s), and n(c) the normalized laser amplitude, the laser wavelength in vacuum, the plasma skin depth, and the critical density of the incident laser pulse, respectively, a quasiequilibrium for the electrons is established by the light pressure and the space charge electrostatic field at the interacting front of the laser pulse. The ions within the skin depth of the laser pulse are synchronously accelerated and bunched by the electrostatic field, and thereby a high-intensity monoenergetic proton beam can be generated. The proton dynamics is investigated analytically and the results are verified by one- and two-dimensional particle-in-cell simulations. PMID:18517963

  15. Short-Course Accelerated Radiotherapy in Palliative Treatment of Advanced Pelvic Malignancies: A Phase I Study

    SciTech Connect

    Caravatta, Luciana; Padula, Gilbert D.A.; Macchia, Gabriella; Ferrandina, Gabriella; Bonomo, Pierluigi; Deodato, Francesco; Massaccesi, Mariangela; Mignogna, Samantha; Tambaro, Rosa; Rossi, Marco; Flocco, Mariano; Scapati, Andrea; and others

    2012-08-01

    Purpose: To define the maximum tolerated dose of a conformal short-course accelerated radiotherapy in patients with symptomatic advanced pelvic cancer. Methods and Materials: A phase I trial in 3 dose-escalation steps was designed: 14 Gy (3.5-Gy fractions), 16 Gy (4-Gy fractions), and 18 Gy (4.5-Gy fractions). The eligibility criteria included locally advanced and/or metastatic pelvic cancer and Eastern Cooperative Oncology Group performance status of {<=}3. Treatment was delivered in 2 days with twice-daily fractionation and at least an 8-hour interval. Patients were treated in cohorts of 6-12 to define the maximum tolerated dose. The dose-limiting toxicity was defined as any acute toxicity of grade 3 or greater, using the Radiation Therapy Oncology Group scale. Pain was recorded using a visual analog scale. The effect on quality of life was evaluated according to Cancer Linear Analog Scale (CLAS). Results: Of the 27 enrolled patients, 11 were male and 16 were female, with a median age of 72 years (range 47-86). The primary tumor sites were gynecologic (48%), colorectal (33.5%), and genitourinary (18.5%). The most frequent baseline symptoms were bleeding (48%) and pain (33%). Only grade 1-2 acute toxicities were recorded. No patients experienced dose-limiting toxicity. With a median follow-up time of 6 months (range 3-28), no late toxicities were observed. The overall (complete plus partial) symptom remission was 88.9% (95% confidence interval 66.0%-97.8%). Five patients (41.7%) had complete pain relief, and six (50%) showed >30% visual analog scale reduction. The overall response rate for pain was 91.67% (95% confidence interval 52.4%-99.9%). Conclusions: Conformal short course radiotherapy in twice-daily fractions for 2 consecutive days was well tolerated up to a total dose of 18 Gy. A phase II study is ongoing to confirm the efficacy on symptom control and quality of life indexes.

  16. Chronic phase CML patients possess T cells capable of recognising autologous tumour cells.

    PubMed

    Müller, Ludmila; Pawelec, Graham

    2002-05-01

    Much circumstantial evidence points to the immunogenicity of chronic myloid leukemia (CML) cells, most impressively the well-established T cell-dependent GvL effect seen in bone marrow transplantation. However, only a small number of shared antigens expressed by CML cells have been identified as potential targets for T cell-mediated immune responses which might be exploited for immunotherapy. It may be that unique antigens expressed by individual tumours are more potent rejection antigens if the patient's own T cells could be encouraged to react against them. Work is reviewed here which documents that in vitro mixed cultures between autologous T cells and dendritic cells of chronic-phase CML patients can give rise to sensitised T cells capable of recognising the patient's tumour cells. Additionally, mixed autologous tumour cell/lymphocyte cultures, modified by the addition of cytokine cocktails, may also result in the generation of similarly sensitised T cells. These results could be exploited for adoptive immunotherapy, and possibly, after identification of the antigens recognised, also for active immunotherapy, i.e. including therapeutic vaccination. PMID:12148904

  17. Effect of corticosteroids on sputum sol-phase protease inhibitors in chronic obstructive pulmonary disease.

    PubMed Central

    Wiggins, J; Elliott, J A; Stevenson, R D; Stockley, R A

    1982-01-01

    Corticosteroids caused a reduction in the ratio of sol-phase sputum concentration to serum concentration of albumin in 12 patients with chronic obstructive bronchitis, suggesting a reduction in protein transudation. Alpha-1-antitrypsin values followed the same pattern as those of albumin in both the control and treatment periods, confirming the similar behaviour of the two proteins. The alpha 1-antichymotrypsin ratios were on average three times higher than those of albumin in the control period, confirming the presence of local mechanisms in the lung for preferentially concentrating this protein. The sputum-to-serum ratio of alpha 1-antichymotrypsin, however, rose during steroid treatment with the result that there was a selective increase in this protease inhibitor, which may be of potential benefit to such patients. PMID:6984237

  18. Dasatinib in imatinib-resistant or -intolerant chronic-phase, chronic myeloid leukemia patients: 7-year follow-up of study CA180-034.

    PubMed

    Shah, Neil P; Rousselot, Philippe; Schiffer, Charles; Rea, Delphine; Cortes, Jorge E; Milone, Jorge; Mohamed, Hesham; Healey, Diane; Kantarjian, Hagop; Hochhaus, Andreas; Saglio, Giuseppe

    2016-09-01

    Dasatinib was approved at 100 mg once daily for imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase, based on results of the phase 3 CA180-034 (NCT00123474) study. Here we present the final 7-year analysis of this pivotal study, the longest follow-up to date of any second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI). Patients (n = 670) with imatinib-resistant or -intolerant CML in chronic phase received dasatinib. Nineteen percent of patients continued on study treatment, with a greater proportion in the 100 mg once daily arm remaining on therapy. Seven-year rates for major molecular response (MMR), progression-free survival (PFS), and overall survival (OS) were similar across doses; MMR, PFS, and OS results were 46, 42, and 65% at 100 mg once daily, respectively. Improved PFS and OS rates were reported in patients who achieved BCR-ABL1 ≤10% at 3 and 6 months. No new safety signals were identified. The incidence of drug-related pleural effusion was 28% at 100 mg once daily and 35% at the other three dose groups. Incidence of drug-related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3% across all doses). Arterial ischemic events occurred in ≤4% of patients across all doses. These data support the long-term efficacy and well-established safety profile of dasatinib for patients with imatinib-resistant or -intolerant CML in chronic phase. Am. J. Hematol. 91:869-874, 2016. © 2016 Wiley Periodicals, Inc. PMID:27192969

  19. Physics of Phase Space Matching for Staging Plasma and Traditional Accelerator Components Using Longitudinally Tailored Plasma Profiles.

    PubMed

    Xu, X L; Hua, J F; Wu, Y P; Zhang, C J; Li, F; Wan, Y; Pai, C-H; Lu, W; An, W; Yu, P; Hogan, M J; Joshi, C; Mori, W B

    2016-03-25

    Phase space matching between two plasma-based accelerator (PBA) stages and between a PBA and a traditional accelerator component is a critical issue for emittance preservation. The drastic differences of the transverse focusing strengths as the beam propagates between stages and components may lead to a catastrophic emittance growth even when there is a small energy spread. We propose using the linear focusing forces from nonlinear wakes in longitudinally tailored plasma density profiles to control phase space matching between sections with negligible emittance growth. Several profiles are considered and theoretical analysis and particle-in-cell simulations show how these structures may work in four different scenarios. Good agreement between theory and simulation is obtained, and it is found that the adiabatic approximation misses important physics even for long profiles. PMID:27058082

  20. Physics of Phase Space Matching for Staging Plasma and Traditional Accelerator Components Using Longitudinally Tailored Plasma Profiles

    NASA Astrophysics Data System (ADS)

    Xu, X. L.; Hua, J. F.; Wu, Y. P.; Zhang, C. J.; Li, F.; Wan, Y.; Pai, C.-H.; Lu, W.; An, W.; Yu, P.; Hogan, M. J.; Joshi, C.; Mori, W. B.

    2016-03-01

    Phase space matching between two plasma-based accelerator (PBA) stages and between a PBA and a traditional accelerator component is a critical issue for emittance preservation. The drastic differences of the transverse focusing strengths as the beam propagates between stages and components may lead to a catastrophic emittance growth even when there is a small energy spread. We propose using the linear focusing forces from nonlinear wakes in longitudinally tailored plasma density profiles to control phase space matching between sections with negligible emittance growth. Several profiles are considered and theoretical analysis and particle-in-cell simulations show how these structures may work in four different scenarios. Good agreement between theory and simulation is obtained, and it is found that the adiabatic approximation misses important physics even for long profiles.

  1. Mechanism of mark deformation in phase-change media tested in an accelerated environment

    NASA Astrophysics Data System (ADS)

    Hirotsune, Akemi; Terao, Motoyasu; Miyauchi, Yasushi; Tokushuku, Nobuhiro; Tamura, Reiji

    2007-04-01

    Increased jitter caused by recording marks becoming deformed in an accelerated environmental test was investigated and a model where the change in the speed of crystallization is affected by passive oxidation on the amorphous surface of the recording layer was devised. The model clarified the mechanism by which deformation in the marks caused increased jitter in the accelerated environmental test. Adding nitrogen into the gas when sputtering the protective layer adjacent to the recording film was investigated. It was confirmed that a prototype disk with this protective layer has decreased jitter after a 500 h accelerated test and superior power margins.

  2. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib

    PubMed Central

    Kantarjian, Hagop M.; Brümmendorf, Tim H.; Kim, Dong-Wook; Turkina, Anna G.; Shen, Zhi-Xiang; Pasquini, Ricardo; Khoury, H. Jean; Arkin, Steven; Volkert, Angela; Besson, Nadine; Abbas, Richat; Wang, Junyuan; Leip, Eric; Gambacorti-Passerini, Carlo

    2011-01-01

    Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846. PMID:21865346

  3. Relationship between myocardial flow reserve by oxygen-15 water positron emission tomography in the subacute phase of myocardial infarction and left ventricular remodeling in the chronic phase.

    PubMed

    Ohara, Minako; Yukiiri, Kazushi; Masugata, Hisashi; Iwado, Yasuyoshi; Takinami, Hiroyuki; Nishiyama, Yoshihiro; Ohkawa, Motoomi; Senda, Shoichi; Ohmori, Koji; Kohno, Masakazu

    2008-07-01

    The purposes of this study were to examine the effects of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) on myocardial flow reserve in patients with acute myocardial infarction (AMI) in the subacute phase using oxygen-15 positron emission tomography (PET) and to elucidate the relationship between the myocardial flow reserve and remodeling in the chronic phase. Sixty patients who had been treated with coronary angioplasty within 12 h after the onset of AMI were enrolled. Patients were divided into an enalapril (ACEI) group and a candesartan (ARB) group. The myocardial flow reserve was measured by oxygen-15 water PET in the subacute phase from the 20th to the 30th day after the onset of AMI. Left ventriculography was performed to measure the left ventricular ejection fraction in the chronic phase about 6 months after the onset. Ten patients (33%) in the enalapril group and 4 patients (13%) in the candesartan group stopped taking their respective medications within a few days of starting, because of side effects such as cough or hypotension. Thus, the prevalence of medication intolerance was higher in the enalapril group. The myocardial flow reserve in the subacute phase and the left ventricular ejection fraction in the chronic phase were lower in the enalapril group (2.08 +/- 0.30 and 42 +/- 6%) than in the candesartan group (2.25 +/- 0.20 and 49 +/- 5%) (p < 0.05). The myocardial flow reserve significantly correlated with the left ventricular ejection fraction in all patients (r = 0.45, p < 0.01). The myocardial flow reserve assessed by PET in the subacute phase after AMI was found to be related to left ventricular remodeling in the chronic phase. PMID:18957800

  4. Screened selection design for randomised phase II oncology trials: an example in chronic lymphocytic leukaemia

    PubMed Central

    2013-01-01

    Background As there are limited patients for chronic lymphocytic leukaemia trials, it is important that statistical methodologies in Phase II efficiently select regimens for subsequent evaluation in larger-scale Phase III trials. Methods We propose the screened selection design (SSD), which is a practical multi-stage, randomised Phase II design for two experimental arms. Activity is first evaluated by applying Simon’s two-stage design (1989) on each arm. If both are active, the play-the-winner selection strategy proposed by Simon, Wittes and Ellenberg (SWE) (1985) is applied to select the superior arm. A variant of the design, Modified SSD, also allows the arm with the higher response rates to be recommended only if its activity rate is greater by a clinically-relevant value. The operating characteristics are explored via a simulation study and compared to a Bayesian Selection approach. Results Simulations showed that with the proposed SSD, it is possible to retain the sample size as required in SWE and obtain similar probabilities of selecting the correct superior arm of at least 90%; with the additional attractive benefit of reducing the probability of selecting ineffective arms. This approach is comparable to a Bayesian Selection Strategy. The Modified SSD performs substantially better than the other designs in selecting neither arm if the underlying rates for both arms are desirable but equivalent, allowing for other factors to be considered in the decision making process. Though its probability of correctly selecting a superior arm might be reduced, it still performs reasonably well. It also reduces the probability of selecting an inferior arm. Conclusions SSD provides an easy to implement randomised Phase II design that selects the most promising treatment that has shown sufficient evidence of activity, with available R codes to evaluate its operating characteristics. PMID:23819695

  5. The phase-lock dynamics of the laser wakefield acceleration with an intensity-decaying laser pulse

    SciTech Connect

    Li, Wentao; Liu, Jiansheng Wang, Wentao; Zhang, Zhijun; Chen, Qiang; Tian, Ye; Qi, Rong; Yu, Changhai; Wang, Cheng; Li, Ruxin Xu, Zhizhan; Tajima, T.

    2014-03-03

    An electron beam with the maximum energy extending up to 1.8 GeV, much higher than the dephasing limit, is experimentally obtained in the laser wakefield acceleration with the plasma density of 3.5 × 10{sup 18} cm{sup −3}. With particle in cell simulations and theoretical analysis, we find that the laser intensity evolution plays a major role in the enhancement of the electron energy gain. While the bubble length decreases due to the intensity-decay of the laser pulse, the phase of the electron beam in the wakefield can be locked, which contributes to the overcoming of the dephasing. Moreover, the laser intensity evolution is described for the phase-lock acceleration of electrons in the uniform plasma, confirmed with our own simulation. Since the decaying of the intensity is unavoidable in the long distance propagation due to the pump depletion, the energy gain of the high energy laser wakefield accelerator can be greatly enhanced if the current process is exploited.

  6. Influence of optical pumping wavelength on the ultrafast gain and phase recovery acceleration of quantum-dot semiconductor optical amplifiers

    NASA Astrophysics Data System (ADS)

    Kim, Jungho

    2013-10-01

    We numerically investigate the influence of the optical pumping wavelength on the ultrafast gain and phase recovery acceleration of quantum-dot (QD) semiconductor optical amplifiers (SOAs) by solving 1088 coupled rate equations. The temporal variations of the gain and phase recovery response at the ground state (GS) of QDs are calculated at various signal wavelengths when the optical pumping wavelengths at the excited state (ES) of QDs are varied. The phase recovery response is fastest when the wavelength of the signal and pumping beams corresponds to the respective emission wavelength of the GS and the ES in the same size of QDs. The absorption efficiency of the optical pumping beam at the ES is determined by the Lorentzian line shape function of the homogeneous broadening.

  7. Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms.

    PubMed

    Klafke, J Z; da Silva, M A; Rossato, M F; de Prá, S Dal Toé; Rigo, F K; Walker, C I B; Bochi, G V; Moresco, R N; Ferreira, J; Trevisan, G

    2016-02-01

    Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain. PMID:26490459

  8. Accelerated Reader as a Literacy Catch-Up Intervention during Primary to Secondary School Transition Phase

    ERIC Educational Resources Information Center

    Siddiqui, Nadia; Gorard, Stephen; See, Beng Huat

    2016-01-01

    This paper describes an evaluation of an internet-based reading programme called Accelerated Reader (AR), which is widely used in UK schools and worldwide. AR is a whole-group reading management and monitoring programme that aims to stimulate the habit of independent reading among primary and secondary age pupils. The evaluation involved 349…

  9. Quantitative immunoelectrophoretic analysis of the plasma proteins in the sol phase of sputum from patients with chronic bronchitis

    PubMed Central

    Ryley, H. C.; Brogan, T. D.

    1973-01-01

    An analysis of the plasma proteins in the sol phase of sputum was carried out using quantitative cross immunoelectrophoresis. The average concentrations of nine plasma proteins were estimated in the sol phase of sputum specimens from 30 patients with chronic bronchitis and the values were compared with the concentrations of these proteins in saliva and serum specimens from the same group of patients. The results showed that alpha1 antichymotrypsin and IgA concentrations were higher in the sol phase of sputum than would be expected if their presence were due entirely to passive transudation. Images PMID:4128930

  10. Alterations of voltage-dependent K(+) channels in the mesenteric artery during the early and chronic phases of diabetes.

    PubMed

    Hong, Da Hye; Li, Hongliang; Kim, Hye Won; Kim, Han Sol; Son, Youn Kyoung; Yang, Se-Ran; Park, Jeong-Ran; Ha, Kwon-Soo; Han, Eun-Taek; Hong, Seok-Ho; Firth, Amy L; Na, Sung Hun; Park, Won Sun

    2016-09-01

    This study investigated the alteration of voltage-dependent K(+) (Kv) channels in mesenteric arterial smooth muscle cells from control (Long-Evans Tokushima Otsuka [LETO]) and diabetic (Otsuka Long-Evans Tokushima Fatty [OLETF]) rats during the early and chronic phases of diabetes. We demonstrated alterations in the mesenteric Kv channels during the early and chronic phase of diabetes using the patch-clamp technique, the arterial tone measurement system, and RT-PCR in Long-Evans Tokushima (LETO; for control) and Otsuka Long-Evans Tokushima Fatty (OLETF; for diabetes) type 2 diabetic model rats. In the early phase of diabetes, the amplitude of mesenteric Kv currents induced by depolarizing pulses was greater in OLETF rats than in LETO rats. The contractile response of the mesenteric artery induced by the Kv inhibitor, 4-aminopyridine (4-AP), was also greater in OLETF rats. The expression of most Kv subtypes- including Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv1.6, Kv2.1, Kv3.2, Kv4.1, Kv4.3, Kv5.1, Kv6.2, Kv8.1, Kv9.3, and Kv10.1-were increased in mesenteric arterial smooth muscle from OLETF rats compared with LETO rats. However, in the chronic phase of diabetes, the Kv current amplitude did not differ between LETO and OLETF rats. In addition, the 4-AP-induced contractile response of the mesenteric artery and the expression of Kv subtypes did not differ between the two groups. The increased Kv current amplitude and Kv channel-related contractile response were attributable to the increase in Kv channel expression during the early phase of diabetes. The increased Kv current amplitude and Kv channel-related contractile response were reversed during the chronic phase of diabetes. PMID:27218229

  11. Caspr3-Deficient Mice Exhibit Low Motor Learning during the Early Phase of the Accelerated Rotarod Task

    PubMed Central

    Hirata, Haruna; Takahashi, Aki; Shimoda, Yasushi; Koide, Tsuyoshi

    2016-01-01

    Caspr3 (Contactin-associated protein-like 3, Cntnap3) is a neural cell adhesion molecule belonging to the Caspr family. We have recently shown that Caspr3 is expressed abundantly between the first and second postnatal weeks in the mouse basal ganglia, including the striatum, external segment of the globus pallidus, subthalamic nucleus, and substantia nigra. However, its physiological role remains largely unknown. In this study, we conducted a series of behavioral analyses on Capsr3-knockout (KO) mice and equivalent wild-type (WT) mice to investigate the role of Caspr3 in brain function. No significant differences were observed in most behavioral traits between Caspr3-KO and WT mice, but we found that Caspr3-KO mice performed poorly during the early phase of the accelerated rotarod task in which latency to falling off a rod rotating with increasing velocity was examined. In the late phase, the performance of the Caspr3-KO mice caught up to the level of WT mice, suggesting that the deletion of Caspr3 caused a delay in motor learning. We then examined changes in neural activity after training on the accelerated rotarod by conducting immunohistochemistry using antibody to c-Fos, an indirect marker for neuronal activity. Experience of the accelerated rotarod task caused increases in the number of c-Fos-positive cells in the dorsal striatum, cerebellum, and motor cortex in both Caspr3-KO and WT mice, but the number of c-Fos-positive cells was significantly lower in the dorsal striatum of Caspr3-KO mice than in that of WT mice. The expression of c-Fos in the ventral striatum of Caspr3-KO and WT mice was not altered by the training. Our findings suggest that reduced activation of neural cells in the dorsal striatum in Caspr3-KO mice leads to a decline in motor learning in the accelerated rotarod task. PMID:26807827

  12. Caspr3-Deficient Mice Exhibit Low Motor Learning during the Early Phase of the Accelerated Rotarod Task.

    PubMed

    Hirata, Haruna; Takahashi, Aki; Shimoda, Yasushi; Koide, Tsuyoshi

    2016-01-01

    Caspr3 (Contactin-associated protein-like 3, Cntnap3) is a neural cell adhesion molecule belonging to the Caspr family. We have recently shown that Caspr3 is expressed abundantly between the first and second postnatal weeks in the mouse basal ganglia, including the striatum, external segment of the globus pallidus, subthalamic nucleus, and substantia nigra. However, its physiological role remains largely unknown. In this study, we conducted a series of behavioral analyses on Capsr3-knockout (KO) mice and equivalent wild-type (WT) mice to investigate the role of Caspr3 in brain function. No significant differences were observed in most behavioral traits between Caspr3-KO and WT mice, but we found that Caspr3-KO mice performed poorly during the early phase of the accelerated rotarod task in which latency to falling off a rod rotating with increasing velocity was examined. In the late phase, the performance of the Caspr3-KO mice caught up to the level of WT mice, suggesting that the deletion of Caspr3 caused a delay in motor learning. We then examined changes in neural activity after training on the accelerated rotarod by conducting immunohistochemistry using antibody to c-Fos, an indirect marker for neuronal activity. Experience of the accelerated rotarod task caused increases in the number of c-Fos-positive cells in the dorsal striatum, cerebellum, and motor cortex in both Caspr3-KO and WT mice, but the number of c-Fos-positive cells was significantly lower in the dorsal striatum of Caspr3-KO mice than in that of WT mice. The expression of c-Fos in the ventral striatum of Caspr3-KO and WT mice was not altered by the training. Our findings suggest that reduced activation of neural cells in the dorsal striatum in Caspr3-KO mice leads to a decline in motor learning in the accelerated rotarod task. PMID:26807827

  13. Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome-positive chronic myeloid leukemia patients with resistance or intolerance to imatinib.

    PubMed

    Cortes, Jorge E; Kantarjian, Hagop M; Brümmendorf, Tim H; Kim, Dong-Wook; Turkina, Anna G; Shen, Zhi-Xiang; Pasquini, Ricardo; Khoury, H Jean; Arkin, Steven; Volkert, Angela; Besson, Nadine; Abbas, Richat; Wang, Junyuan; Leip, Eric; Gambacorti-Passerini, Carlo

    2011-10-27

    Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinib-intolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846. PMID:21865346

  14. Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase

    PubMed Central

    Mughal, Tariq I; Schrieber, Andrew

    2010-01-01

    Imatinib mesylate (IM), an original Abl tyrosine kinase inhibitor, entered the clinics in 1998 for the treatment of patients with chronic myeloid leukemia (CML). The drug is universally considered the treatment of choice for most, if not all, patients with CML. Importantly, lessons learned from patients with CML have been applied successfully for the treatment of patients with other disorders where IM has since been found to be active by virtue of its ability to target other kinases, such as c-kit in patients with gastrointestinal stromal tumors. IM is associated with mild to moderate toxicity, mostly reversible by dose reduction or discontinuation of the drug. Most adverse effects occur within the first 2 years of starting therapy; however, late effects, many being unique, are now being recognized. In this report, we assess the toxicity associated with IM, with an emphasis on the long-term adverse effects. PMID:21209726

  15. New half-voltage and double phase operation of the Hermes III linear induction accelerator

    SciTech Connect

    Mikkelson, K.A.; Westfall, R.L.; Harper-Slaboszewicz, V.J. ); Neely, S.M. )

    1991-01-01

    The standard operating mode produces bremsstrahlung with an endpoint energy of about 18 MeV. This paper describes a new mode with a 8.5 MeV endpoint energy and the same standard mode pulse characteristics achieved by operating only half of the accelerator at full charge with the advantage of minimal setup time. An extension of the new half-voltage mode is to use the other half of the accelerator for delivering a second pulse at a later time with the same technique. The double pulse mode is ideal for beam generation which requires a long interpulse time in the millisecond regime. The beam characteristics of the two half-voltage pulses are nearly identical with the nominal radiation pulse full width at half maximum of 21 ns and 10--90 risetime of 11 ns recorded by the same Compton diode radiation monitors on instruments triggered 30 ms apart.

  16. Studies of Particle Acceleration, Transport and Radiation in Impulsive Phase of Solar Flares

    NASA Technical Reports Server (NTRS)

    Petrosian, Vahe

    2005-01-01

    Solar activity and its most prominent aspect, the solar flares, have considerable influence on terrestrial and space weather. Solar flares also provide a suitable laboratory for the investigation of many plasma and high energy processes important in the magnetosphere of the Earth and many other space and astrophysical situations. Hence, progress in understanding of flares will have considerable scientific and societal impact. The primary goal of this grant is the understanding of two of the most important problems of solar flare physics, namely the determination of the energy release mechanism and how this energy accelerates particles. This is done through comparison of the observations with theoretical models, starting from observations and gradually proceeding to theoretically more complex situations as the lower foundations of our understanding are secured. It is generally agreed that the source of the flare energy is the annihilation of magnetic fields by the reconnection process. Exactly how this energy is released or how it is dissipated remains controversial. Moreover, the exact mechanism of the acceleration of the particles is still a matter of debate. Data from many spacecrafts and ground based instruments obtained over the past decades have given us some clues. Theoretical analyses of these data have led to the standard thick target model (STT) where most of the released energy goes into an (assumed) power law spectrum of accelerated particles, and where all the observed radiations are the consequence of the interaction of these particles with the flare plasma. However, some theoretical arguments, and more importantly some new observations, have led us to believe that the above picture is not complete. It appears that plasma turbulence plays a more prominent role than suspected previously, and that it is the most likely agent for accelerating particles. The model we have developed is based on production of a high level of plasma waves and turbulence in

  17. Cytophotometry of granulocytes in chronic granulocytic leukemia patients. Part I. Cell cycle distribution, S-phase transition and quantitative cytochemistry.

    PubMed

    Kotelnikov, V M; Lishmanova, N G; Khoroshko, N D; Dultsyna, S M; Alieva, T M; Khrust YuR; Kozinets, G I

    1987-01-01

    In the chronic phase of CGL the proportion of granulocytes in S + G2 was lower (18.7 +/- 1.3% in marrow and 16.7 +/- 2.4% in blood) than in normal bone marrow (42.4 +/- 2.9%) as studied by Feulgen-DNA cytophotometry. During the blast crisis the percentage of S + G2 blasts was 39.3 +/- 8.4 in marrow and 38.7 +/- 7.8 in blood which was much higher than in acute myeloblastic leukemia patients (10.8 +/- 1.4 and 5.1 +/- 1.0). Thymidine labelling index values were lower than the percentage of cytophotometrically detected S-phase cells: up to 28% of cells with Feulgen-DNA content corresponding to S-phase did not incorporate 3H-thymidine. The rate of DNA synthesis remained constant during the S-phase but 3H-thymidine uptake increases towards the end of the S-phase. Morphometric parameters and quantitative cytochemical (PAS, Sudan, myeloperoxidase activity) characteristics of polymorphonuclear neutrophils were altered during the chronic phase of the disease but remained in the normal range during the blast crisis. Mature neutrophils in the blast crisis are assumed to originate from normal granulocyte progenitors. PMID:2448196

  18. Accelerated solvent extraction of vitamin K1 in medical foods in conjunction with matrix solid-phase dispersion.

    PubMed

    Chase, G W; Thompson, B

    2000-01-01

    An extraction technique is described for vitamin K1 in medical foods, using accelerated solvent extraction (ASE) in conjunction with matrix solid-phase dispersion (MSPD). The medical food sample is treated as it would be with MSPD extraction, followed by ASE for a hands-free automated extraction. The vitamin K1 in the ASE extract is then quantitated by reversed-phase liquid chromatography with fluorescence detection. The chromatography specifications are identical to those in previous work that used MSPD only, with a limit of detection of 6.6 pg and a limit of quantitation of 22 pg on column. Recoveries, which were determined for an analyte-fortified zero control reference material for medical foods, averaged 97.6% (n = 25) for vitamin K1. The method provides a rapid, automatic, specific, and easily controlled assay for vitamin K1 in fortified medical foods with minimal solvent usage. PMID:10772179

  19. Ofatumumab in poor-prognosis chronic lymphocytic leukemia: a Phase IV, non-interventional, observational study from the European Research Initiative on Chronic Lymphocytic Leukemia

    PubMed Central

    Moreno, Carol; Montillo, Marco; Panayiotidis, Panayiotis; Dimou, Maria; Bloor, Adrian; Dupuis, Jehan; Schuh, Anna; Norin, Stefan; Geisler, Christian; Hillmen, Peter; Doubek, Michael; Trněný, Marek; Obrtlikova, Petra; Laurenti, Luca; Stilgenbauer, Stephan; Smolej, Lukas; Ghia, Paolo; Cymbalista, Florence; Jaeger, Ulrich; Stamatopoulos, Kostas; Stavroyianni, Niki; Carrington, Patrick; Zouabi, Hamadi; Leblond, Veronique; Gomez-Garcia, Juan C.; Rubio, Martin; Marasca, Roberto; Musuraca, Gerardo; Rigacci, Luigi; Farina, Lucia; Paolini, Rossella; Pospisilova, Sarka; Kimby, Eva; Bradley, Colm; Montserrat, Emili

    2015-01-01

    We report the largest retrospective, phase IV non-interventional, observational study of ofatumumab therapy in heavily pre-treated patients with poor-prognosis chronic lymphocytic leukemia. Total number of patients was 103; median age was 65 years (range 39–85). Median number of prior lines of therapy was 4 (range 1–13), including, in most cases, rituximab-, fludarabine- and alemtuzumab-based regimens; 13 patients had been allografted. Of 113 adverse events, 28 (29%) were considered to be directly related to ofatumumab. Grade 3–4 toxicities included neutropenia (10%), thrombocytopenia (5%), anemia (3%), pneumonia (17%), and fever (3%). Two heavily pre-treated patients developed progressive multifocal leukoencephalopathy. On an intention-to-treat analysis, the overall response rate was 22% (3 complete response, 1 incomplete complete response). Median progression-free and overall survival times were 5 and 11 months, respectively. This study confirms in a daily-life setting the feasibility and acceptable toxicity of ofatumumab treatment in advanced chronic lymphocytic leukemia. The complete response rate, however, was low. Therefore, treatment with ofatumumab should be moved to earlier phases of the disease. Ideally, this should be done in combination with other agents, as recently approved for ofatumumab plus chlorambucil as front-line treatment for patients unfit for fludarabine. This study is registered at clinicaltrials.gov identifier:01453062. PMID:25596264

  20. Nilotinib as frontline therapy for patients with newly diagnosed Ph+ chronic myeloid leukemia in chronic phase: results from the Japanese subgroup of ENESTnd.

    PubMed

    Nakamae, Hirohisa; Shibayama, Hirohiko; Kurokawa, Mineo; Fukuda, Tetsuya; Nakaseko, Chiaki; Kanda, Yoshinobu; Nagai, Tadashi; Ohnishi, Kazunori; Maeda, Yasuhiro; Matsuda, Akira; Amagasaki, Taro; Yanada, Masamitsu

    2011-05-01

    Recent results from the phase 3 ENESTnd (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-Newly Diagnosed Patients) study have demonstrated superiority of nilotinib over imatinib for the treatment of newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (CML-CP). Here, we report results from the Japanese subset of patients in ENESTnd, and assess whether results in this subpopulation are consistent with the overall study population. Seventy-nine Japanese patients with CML-CP were randomized to receive nilotinib 300 mg twice daily (BID) (n = 30), nilotinib 400 mg BID (n = 24) or imatinib 400 mg once daily (QD) (n = 25). Major molecular response rates at 12 months, the primary endpoint, were at least twice as high for nilotinib 300 mg BID (57%) and nilotinib 400 mg BID (50%) compared with imatinib 400 mg QD (24%). No patient on nilotinib progressed, while one patient progressed on imatinib. Both drugs were generally well tolerated and discontinuations due to adverse events were comparable among treatment arms. The results in the subpopulation of Japanese patients from ENESTnd closely mirror the results of the overall population, and support the use of nilotinib at 300 mg BID in Japanese patients with newly diagnosed CML-CP. PMID:21523338

  1. Functional Data Analysis of Spaceflight-Induced Changes in Coordination and Phase in Head Pitch Acceleration During Treadmill Walking

    NASA Technical Reports Server (NTRS)

    Miller, Christopher; Peters, Brian; Feiveson, Alan; Bloomberg, Jacob

    2011-01-01

    Astronauts returning from spaceflight experience neurovestibular disturbances during head movements and attempt to mitigate them by limiting head motion. Analyses to date of the head movements made during walking have concentrated on amplitude and variability measures extracted from ensemble averages of individual gait cycles. Phase shifts within each gait cycle can be determined by functional data analysis through the computation of time-warping functions. Large, localized variations in the timing of peaks in head kinematics may indicate changes in coordination. The purpose of this study was to determine timing changes in head pitch acceleration of astronauts during treadmill walking before and after flight. Six astronauts (5M/1F; age = 43.5+/-6.4yr) participated in the study. Subjects walked at 1.8 m/sec (4 mph) on a motorized treadmill while reading optotypes displayed on a computer screen 4 m in front of their eyes. Three-dimensional motion of the subject s head was recorded with an Inertial Measurement Unit (IMU) device. Data were recorded twice before flight and four times after landing. The head pitch acceleration was calculated by taking the time derivative of the pitch velocity data from the IMU. Data for each session with each subject were time-normalized into gait cycles, then registered to align significant features and create a mean curve. The mean curves of each postflight session for each subject were re-registered based on their preflight mean curve to create time-warping functions. The root mean squares (RMS) of these warping functions were calculated to assess the deviation of head pitch acceleration mean curves in each postflight session from the preflight mean curve. After landing, most crewmembers exhibited localized shifts within their head pitch acceleration regimes, with the greatest deviations in RMS occurring on landing day or 1 day after landing. These results show that the alteration of head pitch coordination due to spaceflight may be

  2. Proposition of a Classification of Adult Patients with Hemiparesis in Chronic Phase

    PubMed Central

    Filipetti, Paul; Remacle, Angélique; Kolanowski, Elisabeth

    2016-01-01

    Background Patients who have developed hemiparesis as a result of a central nervous system lesion, often experience reduced walking capacity and worse gait quality. Although clinically, similar gait patterns have been observed, presently, no clinically driven classification has been validated to group these patients’ gait abnormalities at the level of the hip, knee and ankle joints. This study has thus intended to put forward a new gait classification for adult patients with hemiparesis in chronic phase, and to validate its discriminatory capacity. Methods and Findings Twenty-six patients with hemiparesis were included in this observational study. Following a clinical examination, a clinical gait analysis, complemented by a video analysis, was performed whereby participants were requested to walk spontaneously on a 10m walkway. A patient’s classification was established from clinical examination data and video analysis. This classification was made up of three groups, including two sub-groups, defined with key abnormalities observed whilst walking. Statistical analysis was achieved on the basis of 25 parameters resulting from the clinical gait analysis in order to assess the discriminatory characteristic of the classification as displayed by the walking speed and kinematic parameters. Results revealed that the parameters related to the discriminant criteria of the proposed classification were all significantly different between groups and subgroups. More generally, nearly two thirds of the 25 parameters showed significant differences (p<0.05) between the groups and sub-groups. However, prior to being fully validated, this classification must still be tested on a larger number of patients, and the repeatability of inter-operator measures must be assessed. Conclusions This classification enables patients to be grouped on the basis of key abnormalities observed whilst walking and has the advantage of being able to be used in clinical routines without necessitating

  3. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia

    PubMed Central

    Flynn, Joseph M.; Kipps, Thomas J.; Boxer, Michael; Kolibaba, Kathryn S.; Carlile, David J.; Fingerle-Rowson, Guenter; Tyson, Nicola; Hirata, Jamie; Sharman, Jeff P.

    2016-01-01

    Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205. PMID:26472752

  4. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy.

    PubMed

    Awan, Farrukh T; Jones, Jeffrey A; Maddocks, Kami; Poi, Ming; Grever, Michael R; Johnson, Amy; Byrd, John C; Andritsos, Leslie A

    2016-06-01

    Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m(2) followed by a 4-h infusion of 30 mg/m(2) once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies.Registration number at ClinicalTrials.gov: NCT00377104. PMID:27118540

  5. Randomized phase 2 study of obinutuzumab monotherapy in symptomatic, previously untreated chronic lymphocytic leukemia.

    PubMed

    Byrd, John C; Flynn, Joseph M; Kipps, Thomas J; Boxer, Michael; Kolibaba, Kathryn S; Carlile, David J; Fingerle-Rowson, Guenter; Tyson, Nicola; Hirata, Jamie; Sharman, Jeff P

    2016-01-01

    Obinutuzumab is a glycoengineered, type 2 anti-CD20 humanized antibody with single-agent activity in relapsed chronic lymphocytic leukemia (CLL). With other CD20 antibodies, a dose-response relationship has been shown. We therefore performed a randomized phase 2 study in symptomatic, untreated CLL patients to evaluate if an obinutuzumab dose response exists. Obinutuzumab was given at a dose of 1000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 8 and day 15 of cycle 1; 1000 mg day 1 of cycles 2-8) or 2000 mg (100 mg IV day 1, 900 mg day 2, 1000 mg day 3, 2000 mg day 8 and day 15 of cycle 1; 2000 mg day 1 of cycles 2-8). The primary end point was overall response rate (ORR). Eighty patients were enrolled with similar demographics: median age 67 years, 41% high-risk Rai disease, and 10% del(17p)(13.1). ORR (67% vs 49%, P = .08) and complete response (CR) or CR with incomplete cytopenia response (20% vs 5%) favored 2000 mg obinutuzumab. Overall, therapy was well tolerated, and infusion events were manageable. This study demonstrates significant efficacy of obinutuzumab monotherapy, for 1000 mg as well as for 2000 mg, in untreated CLL patients with acceptable toxicity. Although exploratory, a dose-response relationship may exist, but its relevance to improving progression-free survival is uncertain and will require further follow-up. This trial was registered at www.clinicaltrials.gov as #NCT01414205. PMID:26472752

  6. A phase 1 clinical trial of flavopiridol consolidation in chronic lymphocytic leukemia patients following chemoimmunotherapy

    PubMed Central

    Awan, Farrukh T.; Jones, Jeffrey A.; Maddocks, Kami; Poi, Ming; Grever, Michael R.; Johnson, Amy; Byrd, John C.; Andritsos, Leslie A.

    2016-01-01

    Patients with chronic lymphocytic leukemia (CLL) who receive chemoimmunotherapy and do not achieve complete remission experience significantly shortened progression-free interval (PFS). Additionally, the majority of patients treated for relapsed disease demonstrate evidence of measurable disease. Eradication of minimal residual disease (MRD) results in improved PFS and overall survival. Maintenance therapy might result in eradication of MRD and improve response duration but might be associated with an increase in incidence of infectious complications. Flavopiridol is a broad cyclin-dependent kinase (CDK) inhibitor with established safety and efficacy in patients with relapsed CLL, particularly patients with high-risk cytogenetic features. A pharmacologically derived schedule was utilized as consolidation therapy in this phase I study to assess the safety and feasibility of outpatient therapy with flavopiridol in patients with low tumor burden. Flavopiridol was administered as a 30-min loading dose of 30 mg/m2 followed by a 4-h infusion of 30 mg/ m2 once weekly for 3 weeks every 5 weeks (1 cycle) for planned 2 cycles in ten patients. Therapy was extremely well tolerated and no patient developed acute tumor lysis syndrome. The most common toxicities were gastrointestinal. Of the patients, 22 % improved their response from a PR to CR. Eighty-eight percent experienced a reduction in tumor burden as measured by extent of bone marrow involvement including patients with del17p and complex karyotype. The study establishes the safety and efficacy of flavopiridol as consolidation therapy after chemoimmunotherapy for patients with CLL. Further evaluation is required in larger trials for the utility of CDK inhibitors as consolidation or maintenance strategies. Registration number at ClinicalTrials.gov: NCT00377104. PMID:27118540

  7. Automatic component calibration and error diagnostics for model-based accelerator control. Phase I final report

    SciTech Connect

    Dr. Carl Stern; Dr. Martin Lee

    1999-06-28

    Phase I work studied the feasibility of developing software for automatic component calibration and error correction in beamline optics models. A prototype application was developed that corrects quadrupole field strength errors in beamline models.

  8. Low-complexity feed-forward carrier phase estimation for M-ary QAM based on phase search acceleration by quadratic approximation.

    PubMed

    Xiang, Meng; Fu, Songnian; Deng, Lei; Tang, Ming; Shum, Perry; Liu, Deming

    2015-07-27

    Blind phase search (BPS) algorithm for M-QAM has excellent tolerance to laser linewidth at the expense of rather high computation complexity (CC). Here, we first theoretically obtain the quadratic relationship between the test angle and corresponding distance matric during the BPS implementation. Afterwards, we propose a carrier phase estimation (CPE) based on a two-stage BPS with quadratic approximation (QA). Instead of searching the phase blindly with fixed step-size for the BPS algorithm, QA can significantly accelerate the speed of phase searching. As a result, a group factor of 2.96/3.05, 4.55/4.67 and 2.27/2.3 (in the form of multipliers/adders) reduction of CC is achieved for 16QAM, 64QAM and 256QAM, respectively, in comparison with the traditional BPS scheme. Meanwhile, a guideline for determining the summing filter block length is put forward during performance optimization. Under the condition of optimum filter block length, our proposed scheme shows similar performance as traditional BPS scheme. At 1 dB required E(S)/N(0) penalty @ BER = 10(-2), our proposed CPE scheme can tolerate a times symbol duration productΔf⋅T(S) of 1.7 × 10(-4), 6 × 10(-5) and 1.5 × 10(-5) for 16/64/256-QAM, respectively. PMID:26367577

  9. Enhancement of butanol production in Clostridium acetobutylicum SE25 through accelerating phase shift by different phases pH regulation from cassava flour.

    PubMed

    Li, Han-guang; Zhang, Qing-hua; Yu, Xiao-bin; Wei, Luo; Wang, Qiang

    2016-02-01

    A prominent delay with 12h was encountered in the phase shift from acidogenesis to solventogenesis in butanol production when the substrate-glucose was replaced by cassava flour. To solve this problem, different phase of pH regulation strategies were performed to shorten this delay time. With this effort, the phase shift occurred smoothly and the fermentation time was shortened. Under the optimal conditions, 16.24g/L butanol and 72h fermentation time were achieved, which were 25.3% higher and 14.3% shorter than those in the case of without pH regulation. Additionally, the effect of CaCO3 on "acid crash" and butanol production was also investigated. It was found that organic acids reassimilation would be of benefit to enhance butanol production. These results indicated that the simple but effective approach for acceleration of phase shift is a promising technique for shortening the fermentation time and improvement of butanol production. PMID:26642220

  10. Optical control of electron phase space in plasma accelerators with incoherently stacked laser pulses

    SciTech Connect

    Kalmykov, S. Y. Shadwick, B. A.; Davoine, X.; Lehe, R.; Lifschitz, A. F.

    2015-05-15

    It is demonstrated that synthesizing an ultrahigh-bandwidth, negatively chirped laser pulse by incoherently stacking pulses of different wavelengths makes it possible to optimize the process of electron self-injection in a dense, highly dispersive plasma (n{sub 0}∼10{sup 19} cm{sup −3}). Avoiding transformation of the driving pulse into a relativistic optical shock maintains a quasi-monoenergetic electron spectrum through electron dephasing and boosts electron energy far beyond the limits suggested by existing scaling laws. In addition, evolution of the accelerating bucket in a plasma channel is shown to produce a background-free, tunable train of femtosecond-duration, 35–100 kA, time-synchronized quasi-monoenergetic electron bunches. The combination of the negative chirp and the channel permits acceleration of electrons beyond 1 GeV in a 3 mm plasma with 1.4 J of laser pulse energy, thus offering the opportunity of high-repetition-rate operation at manageable average laser power.

  11. Chronic Psychological Stress Disrupted the Composition of the Murine Colonic Microbiota and Accelerated a Murine Model of Inflammatory Bowel Disease.

    PubMed

    Watanabe, Yohei; Arase, Sohei; Nagaoka, Noriko; Kawai, Mitsuhisa; Matsumoto, Satoshi

    2016-01-01

    The effect of psychological stress on the gastrointestinal microbiota is widely recognized. Chronic psychological stress may be associated with increased disease activity in inflammatory bowel disease, but the relationships among psychological stress, the gastrointestinal microbiota, and the severity of colitis is not yet fully understood. Here, we examined the impact of 12-week repeated water-avoidance stress on the microbiota of two inbred strains of T cell receptor alpha chain gene knockout mouse (background, BALB/c and C57BL/6) by means of next-generation sequencing of bacterial 16S rRNA genes. In both mouse strains, knockout of the T cell receptor alpha chain gene caused a loss of gastrointestinal microbial diversity and stability. Chronic exposure to repeated water-avoidance stress markedly altered the composition of the colonic microbiota of C57BL/6 mice, but not of BALB/c mice. In C57BL/6 mice, the relative abundance of genus Clostridium, some members of which produce the toxin phospholipase C, was increased, which was weakly positively associated with colitis severity, suggesting that expansion of specific populations of indigenous pathogens may be involved in the exacerbation of colitis. However, we also found that colitis was not exacerbated in mice with a relatively diverse microbiota even if their colonic microbiota contained an expanded phospholipase C-producing Clostridium population. Exposure to chronic stress also altered the concentration of free immunoglobulin A in colonic contents, which may be related to both the loss of bacterial diversity in the colonic microbiota and the severity of the colitis exacerbation. Together, these results suggest that long-term exposure to psychological stress induces dysbiosis in the immunodeficient mouse in a strain-specific manner and also that alteration of microbial diversity, which may be related to an altered pattern of immunoglobulin secretion in the gastrointestinal tract, might play a crucial role in the

  12. Chronic Psychological Stress Disrupted the Composition of the Murine Colonic Microbiota and Accelerated a Murine Model of Inflammatory Bowel Disease

    PubMed Central

    Watanabe, Yohei; Arase, Sohei; Nagaoka, Noriko; Kawai, Mitsuhisa; Matsumoto, Satoshi

    2016-01-01

    The effect of psychological stress on the gastrointestinal microbiota is widely recognized. Chronic psychological stress may be associated with increased disease activity in inflammatory bowel disease, but the relationships among psychological stress, the gastrointestinal microbiota, and the severity of colitis is not yet fully understood. Here, we examined the impact of 12-week repeated water-avoidance stress on the microbiota of two inbred strains of T cell receptor alpha chain gene knockout mouse (background, BALB/c and C57BL/6) by means of next-generation sequencing of bacterial 16S rRNA genes. In both mouse strains, knockout of the T cell receptor alpha chain gene caused a loss of gastrointestinal microbial diversity and stability. Chronic exposure to repeated water-avoidance stress markedly altered the composition of the colonic microbiota of C57BL/6 mice, but not of BALB/c mice. In C57BL/6 mice, the relative abundance of genus Clostridium, some members of which produce the toxin phospholipase C, was increased, which was weakly positively associated with colitis severity, suggesting that expansion of specific populations of indigenous pathogens may be involved in the exacerbation of colitis. However, we also found that colitis was not exacerbated in mice with a relatively diverse microbiota even if their colonic microbiota contained an expanded phospholipase C-producing Clostridium population. Exposure to chronic stress also altered the concentration of free immunoglobulin A in colonic contents, which may be related to both the loss of bacterial diversity in the colonic microbiota and the severity of the colitis exacerbation. Together, these results suggest that long-term exposure to psychological stress induces dysbiosis in the immunodeficient mouse in a strain-specific manner and also that alteration of microbial diversity, which may be related to an altered pattern of immunoglobulin secretion in the gastrointestinal tract, might play a crucial role in the

  13. Mass transport perspective on an accelerated exclusion process: Analysis of augmented current and unit-velocity phases

    NASA Astrophysics Data System (ADS)

    Dong, Jiajia; Klumpp, Stefan; Zia, R. K. P.

    2013-02-01

    In an accelerated exclusion process (AEP), each particle can “hop” to its adjacent site if empty as well as “kick” the frontmost particle when joining a cluster of size ℓ⩽ℓmax. With various choices of the interaction range, ℓmax, we find that the steady state of AEP can be found in a homogeneous phase with augmented currents (AC) or a segregated phase with holes moving at unit velocity (UV). Here we present a detailed study on the emergence of the novel phases, from two perspectives: the AEP and a mass transport process (MTP). In the latter picture, the system in the UV phase is composed of a condensate in coexistence with a fluid, while the transition from AC to UV can be regarded as condensation. Using Monte Carlo simulations, exact results for special cases, and analytic methods in a mean field approach (within the MTP), we focus on steady state currents and cluster sizes. Excellent agreement between data and theory is found, providing an insightful picture for understanding this model system.

  14. A low bioimpedance phase angle predicts a higher mortality and lower nutritional status in chronic dialysis patients

    NASA Astrophysics Data System (ADS)

    Dumler Md, Francis

    2010-04-01

    Bioelectrical impedance analysis is an established technique for body composition analysis. The phase angle parameter, an index of body cell mass, tissue hydration, and membrane integrity, makes it suitable for assessing nutritional status and survivability. We evaluated the significance of a low phase angle value on nutritional status and mortality in 285 chronic dialysis patients during a longitudinal prospective observational study. Patients in the lower phase angle tertile had decreased body weight, body mass index, fat free mass, body cell mass, and lower serum albumin concentrations than those in the higher tertile (P<001). In addition, mortality rates were significantly lower (P=0.05) in the highest tertile patients. In conclusion, the phase angle is a useful method for identifying dialysis patients at high risk for malnutrition and increased mortality.

  15. Accelerated exploration of multi-principal element alloys with solid solution phases.

    PubMed

    Senkov, O N; Miller, J D; Miracle, D B; Woodward, C

    2015-01-01

    Recent multi-principal element, high entropy alloy (HEA) development strategies vastly expand the number of candidate alloy systems, but also pose a new challenge--how to rapidly screen thousands of candidate alloy systems for targeted properties. Here we develop a new approach to rapidly assess structural metals by combining calculated phase diagrams with simple rules based on the phases present, their transformation temperatures and useful microstructures. We evaluate over 130,000 alloy systems, identifying promising compositions for more time-intensive experimental studies. We find the surprising result that solid solution alloys become less likely as the number of alloy elements increases. This contradicts the major premise of HEAs--that increased configurational entropy increases the stability of disordered solid solution phases. As the number of elements increases, the configurational entropy rises slowly while the probability of at least one pair of elements favouring formation of intermetallic compounds increases more rapidly, explaining this apparent contradiction. PMID:25739749

  16. Ultra-fast quantum randomness generation by accelerated phase diffusion in a pulsed laser diode.

    PubMed

    Abellán, C; Amaya, W; Jofre, M; Curty, M; Acín, A; Capmany, J; Pruneri, V; Mitchell, M W

    2014-01-27

    We demonstrate a high bit-rate quantum random number generator by interferometric detection of phase diffusion in a gain-switched DFB laser diode. Gain switching at few-GHz frequencies produces a train of bright pulses with nearly equal amplitudes and random phases. An unbalanced Mach-Zehnder interferometer is used to interfere subsequent pulses and thereby generate strong random-amplitude pulses, which are detected and digitized to produce a high-rate random bit string. Using established models of semiconductor laser field dynamics, we predict a regime of high visibility interference and nearly complete vacuum-fluctuation-induced phase diffusion between pulses. These are confirmed by measurement of pulse power statistics at the output of the interferometer. Using a 5.825 GHz excitation rate and 14-bit digitization, we observe 43 Gbps quantum randomness generation. PMID:24515170

  17. Accelerated exploration of multi-principal element alloys with solid solution phases

    PubMed Central

    Senkov, O.N.; Miller, J.D.; Miracle, D.B.; Woodward, C.

    2015-01-01

    Recent multi-principal element, high entropy alloy (HEA) development strategies vastly expand the number of candidate alloy systems, but also pose a new challenge—how to rapidly screen thousands of candidate alloy systems for targeted properties. Here we develop a new approach to rapidly assess structural metals by combining calculated phase diagrams with simple rules based on the phases present, their transformation temperatures and useful microstructures. We evaluate over 130,000 alloy systems, identifying promising compositions for more time-intensive experimental studies. We find the surprising result that solid solution alloys become less likely as the number of alloy elements increases. This contradicts the major premise of HEAs—that increased configurational entropy increases the stability of disordered solid solution phases. As the number of elements increases, the configurational entropy rises slowly while the probability of at least one pair of elements favouring formation of intermetallic compounds increases more rapidly, explaining this apparent contradiction. PMID:25739749

  18. High-Resolution Transcriptomic Analysis of the Adaptive Response of Staphylococcus aureus during Acute and Chronic Phases of Osteomyelitis

    PubMed Central

    Szafranska, Anna K.; Oxley, Andrew P. A.; Chaves-Moreno, Diego; Horst, Sarah A.; Roßlenbroich, Steffen; Peters, Georg; Goldmann, Oliver; Rohde, Manfred; Sinha, Bhanu; Pieper, Dietmar H.; Löffler, Bettina; Jauregui, Ruy; Wos-Oxley, Melissa L.

    2014-01-01

    ABSTRACT Osteomyelitis is a difficult-to-eradicate bone infection typically caused by Staphylococcus aureus. In this study, we investigated the in vivo transcriptional adaptation of S. aureus during bone infection. To this end, we determined the transcriptome of S. aureus during the acute (day 7) and chronic (day 28) phases of experimental murine osteomyelitis using RNA sequencing (RNA-Seq). We identified a total of 180 genes significantly more highly expressed by S. aureus during acute or chronic in vivo infection than under in vitro growth conditions. These genes encoded proteins involved in gluconeogenesis, proteolysis of host proteins, iron acquisition, evasion of host immune defenses, and stress responses. At the regulatory level, sarA and -R and saeR and -S as well as the small RNA RsaC were predominantly expressed by S. aureus during in vivo infection. Only nine genes, including the genes encoding the arginine deiminase (ADI) pathway and those involved in the stringent response, were significantly more highly expressed by S. aureus during the chronic than the acute stage of infection. Analysis by quantitative reverse transcription-PCR (qRT-PCR) of a subset of these in vivo-expressed genes in clinical specimens yielded the same results as those observed in the murine system. Collectively, our results show that during acute osteomyelitis, S. aureus induced the transcription of genes that mediate metabolic adaptation, immune evasion, and replication. During the chronic phase, however, S. aureus switched its transcriptional response from a proliferative to a persistence mode, probably driven by the severe deficiency in nutrient supplies. Interfering with the survival strategies of S. aureus during chronic infection could lead to more effective treatments. PMID:25538190

  19. Simulation Study Using an Injection Phase-locked Magnetron as an Alternative Source for SRF Accelerators

    SciTech Connect

    Wang, Haipeng; Plawski, Tomasz E.; Rimmer, Robert A.

    2015-09-01

    As a drop-in replacement for the CEBAF CW klystron system, a 1497 MHz, CW-type high-efficiency magnetron using injection phase lock and amplitude variation is attractive. Amplitude control using magnetic field trimming and anode voltage modulation has been studied using analytical models and MATLAB/Simulink simulations. Since the 1497 MHz magnetron has not been built yet, previously measured characteristics of a 2.45GHz cooker magnetron are used as reference. The results of linear responses to the amplitude and phase control of a superconducting RF (SRF) cavity, and the expected overall benefit for the current CEBAF and future MEIC RF systems are presented in this paper.

  20. Final safety analysis report for the Ground Test Accelerator (GTA), Phase 2

    SciTech Connect

    1994-10-01

    This document is the first volume of a 3 volume safety analysis report on the Ground Test Accelerator (GTA). The GTA program at the Los Alamos National Laboratory (LANL) is the major element of the national Neutral Particle Beam (NPB) program, which is supported by the Strategic Defense Initiative Office (SDIO). A principal goal of the national NPB program is to assess the feasibility of using hydrogen and deuterium neutral particle beams outside the Earth`s atmosphere. The main effort of the NPB program at Los Alamos concentrates on developing the GTA. The GTA is classified as a low-hazard facility, except for the cryogenic-cooling system, which is classified as a moderate-hazard facility. This volume consists of an introduction, summary/conclusion, site description and assessment, description of facility, and description of operation.

  1. Final safety analysis report for the Ground Test Accelerator (GTA), Phase 2

    SciTech Connect

    1994-10-01

    This document is the third volume of a 3 volume safety analysis report on the Ground Test Accelerator (GTA). The GTA program at the Los Alamos National Laboratory (LANL) is the major element of the national Neutral Particle Beam (NPB) program, which is supported by the Strategic Defense Initiative Office (SDIO). A principal goal of the national NPB program is to assess the feasibility of using hydrogen and deuterium neutral particle beams outside the Earth`s atmosphere. The main effort of the NPB program at Los Alamos concentrates on developing the GTA. The GTA is classified as a low-hazard facility, except for the cryogenic-cooling system, which is classified as a moderate-hazard facility. This volume consists of appendices C through U of the report

  2. Evidence for platelet-activating factor as a late-phase mediator of chronic pancreatitis in the rat.

    PubMed Central

    Zhou, W. G.; Chao, W.; Levine, B. A.; Olson, M. S.

    1990-01-01

    The role of platelet-activating factor (PAF) as a mediator of pancreatic inflammation was examined in the rat pancreatic duct ligation model of obstructive pancreatitis. Pancreatic generation of PAF, as measured by bioassay (ie, platelet [3H]serotonin secretion), was determined at various times after induction of inflammation. Tissue levels of PAF in the normal pancreas averaged 600 +/- 49 pg/g, but PAF was not detectable during the initial 24 hours of pancreatitis, a time when the inflammatory reaction would be considered acute, that is, during the period of maximal serum amylase release and the development of interstitial edema. However a substantial increase in pancreatic PAF levels (12 times control levels) was observed 7 to 14 days after duct ligation during the late-phase response interval similar to the situation characteristic of chronic pancreatitis in which parenchymal atrophy, fibrosis, and pancreatic insufficiency evolve. One week after duct ligation when PAF levels peaked, an evaluation was made of the effects of PAF antagonists (BN52021 and WEB2170) on pancreatic lesions using Evan's blue extravasation, pancreatic myeloperoxidase (MPO) activity, and acid phosphatase activity in peritoneal lavage fluid. BN52021 or WEB2170 treatment was shown to reduce pancreatic damage and inflammation significantly. Long-term in vivo administration of exogenous PAF (20 micrograms/kg/hr for 7 days) exhibited a reduction of [3H]thymidine uptake into and amylase release from pancreatic acini in vitro. Our observations 1) that pancreatic PAF levels increased significantly during the chronic phase of obstructive pancreatitis induced by duct ligation; 2) that inhibition of the action of PAF, through specific receptor antagonism, caused an attenuation of pancreatic lesions; and 3) that chronic administration of PAF resulted in decreased pancreatic regeneration and exocrine function are consistent with a pivotal role for PAF as a late-phase inflammatory mediator in chronic

  3. High-Dose Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: High Rates of Rapid Cytogenetic and Molecular Responses

    PubMed Central

    Cortes, Jorge E.; Kantarjian, Hagop M.; Goldberg, Stuart L.; Powell, Bayard L.; Giles, Francis J.; Wetzler, Meir; Akard, Luke; Burke, John M.; Kerr, Robert; Saleh, Mansoor; Salvado, August; McDougall, Karen; Albitar, Maher; Radich, Jerald

    2009-01-01

    Purpose Long-term clinical outcome data have established imatinib 400 mg/d as standard front-line treatment for newly diagnosed patients with chronic myeloid leukemia (CML). Patients and Methods The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial is a multicenter study of imatinib 400 mg twice a day as initial therapy in 115 patients (70% Sokal low risk) with newly diagnosed CML in chronic phase who were observed for both molecular and cytogenetic responses for up to 18 months. Eighty-three patients (72%) completed the study, 10 patients (9%) discontinued the study because of adverse events, and six patients (5%) discontinued because of unsatisfactory therapeutic effect. Results Polymerase chain reaction analysis demonstrated rapid kinetics of major molecular response (MMR), with 48% of patients achieving MMR by 6 months, 54% by 12 months, and 63% by 18 months. Corresponding complete molecular response rates were 39%, 44%, and 55%, respectively. Median dose-intensity was 98%. Overall, 79% of patients who received at least 90% dose-intensity achieved MMR. The most frequent adverse events included myelosuppression, rash, fatigue, and musculoskeletal symptoms. Conclusion This study suggests that imatinib 400 mg twice a day results in more rapid reduction in tumor burden than imatinib 400 mg/d with minimal added toxicity. PMID:19720924

  4. Effect of additional optical pumping injection into the ground-state ensemble on the gain and the phase recovery acceleration of quantum-dot semiconductor optical amplifiers

    NASA Astrophysics Data System (ADS)

    Kim, Jungho

    2014-02-01

    The effect of additional optical pumping injection into the ground-state ensemble on the ultrafast gain and the phase recovery dynamics of electrically-driven quantum-dot semiconductor optical amplifiers is numerically investigated by solving 1088 coupled rate equations. The ultrafast gain and the phase recovery responses are calculated with respect to the additional optical pumping power. Increasing the additional optical pumping power can significantly accelerate the ultrafast phase recovery, which cannot be done by increasing the injection current density.

  5. Pulse evolution and plasma-wave phase velocity in channel-guided laser-plasma accelerators.

    PubMed

    Benedetti, C; Rossi, F; Schroeder, C B; Esarey, E; Leemans, W P

    2015-08-01

    The self-consistent laser evolution of an intense, short-pulse laser exciting a plasma wave and propagating in a preformed plasma channel is investigated, including the effects of pulse steepening and energy depletion. In the weakly relativistic laser intensity regime, analytical expressions for the laser energy depletion, pulse self-steepening rate, laser intensity centroid velocity, and phase velocity of the plasma wave are derived and validated numerically. PMID:26382537

  6. Phase noise reduction and photoelectron acceleration in a high-Q RF gun

    SciTech Connect

    Landahl, E.C.; Hartemann, F.V.; Baldis, H.A. |; Le Sage, G.P.; White, W.E.; Bennett, C.V.; Heritage, J.P.; Luhmann, N.C. Jr.; Ho, C.H.

    1998-06-01

    The phase noise and jitter characteristics of the laser and RF systems of a high-gradient X-band photoinjector have been measured experimentally. The laser oscillator is a self-mode-locked titanium: sapphire system operating at the 108th subharmonic of the RF gun. The X-band signal is produced from the laser by a phase-locked dielectric resonance oscillator and amplified by a pulsed TWT and klystron. A comparison between the klystron and TWT amplifier phase noise and the fields excited in the RF gun demonstrates the filtering effect of the high-Q structure, thus indicating that the RF gun can be used as a master oscillator and could be energized by either an RF oscillator, such as a magnetron, or a compact source, such as a cross-field amplifier. In particular, the RF gun can play the role of a pulsed RF clock to synchronize the photocathode laser system; direct drive of a synchronously mode-locked AlGaAs quantum well laser has been achieved using the X-band gun RF fields. This novel, gigahertz repetition rate, laser system is being developed to replace the more conventional femtosecond Ti:Al{sub 2}O{sub 3} system. Some advantages include pumping this laser with a stabilized current source instead of a costly, low-efficiency pump laser. Finally, dark current measurements and initial photoelectron measurements are reported.

  7. Accelerated tau aggregation, apoptosis and neurological dysfunction caused by chronic oral administration of aluminum in a mouse model of tauopathies.

    PubMed

    Oshima, Etsuko; Ishihara, Takeshi; Yokota, Osamu; Nakashima-Yasuda, Hanae; Nagao, Shigeto; Ikeda, Chikako; Naohara, Jun; Terada, Seishi; Uchitomi, Yosuke

    2013-11-01

    To clarify whether long-term oral ingestion of aluminum (Al) can increase tau aggregation in mammals, we examined the effects of oral Al administration on tau accumulation, apoptosis in the central nervous system (CNS) and motor function using tau transgenic (Tg) mice that show very slowly progressive tau accumulation. Al-treated tau Tg mice had almost twice as many tau-positive inclusions in the spinal cord as tau Tg mice without Al treatment at 12 months of age, a difference that reached statistical significance, and the development of pretangle-like tau aggregates in the brain was also significantly advanced from 9 months. Al exposure did not induce any tau pathology in wild-type (WT) mice. Apoptosis was observed in the hippocampus in Al-treated tau Tg mice, but was virtually absent in the other experimental groups. Motor function as assessed by the tail suspension test was most severely impaired in Al-treated tau Tg mice. Given our results, chronic oral ingestion of Al may more strongly promote tau aggregation, apoptosis and neurological dysfunction if individuals already had a pathological process causing tau aggregation. These findings may also implicate chronic Al neurotoxicity in humans, who frequently have had mild tau pathology from a young age. PMID:23574527

  8. RBC-/Cr-51/ half-life and albumin turnover in growing Beagle dogs during chronic radial acceleration

    NASA Technical Reports Server (NTRS)

    Beckman, D. A.; Evans, J. W.; Oyama, J.

    1979-01-01

    The effects of chronic centrifugation on growing Beagle dogs exposed to -2 or -2.6 Gx on albumin and RBC turnover rates, albumin concentration and space, and total blood volume were determined and compared with caged and run control of animals. Albumin-(I-125) and autologous RBC-(Cr-51) preparations were injected into all dogs at day 82 of the centrifugation periods, and the disappearance curves were determined by successive bleedings of the animals over the next 35 d, during which the centrifugation was continued. There were no differences in albumin turnover rates or space. Two populations of RBCs were found in both centrifugated groups, one with a normal half-life of 27 + or - 1 S.E.M. d, and one with a significantly (p less than 0.01) shorter half-life of 15 + or - 2 S.E.M. d. An absolute polycythemia was also observed in both centrifuged groups. The results suggest that chronic centrifugation acts through some as-yet unknown mechanism to affect RBC population kinetics.

  9. Electrochemical deposition of platinum within nanopores on silicon: Drastic acceleration originating from surface-induced phase transition

    NASA Astrophysics Data System (ADS)

    Fukami, Kazuhiro; Koda, Ryo; Sakka, Tetsuo; Ogata, Yukio; Kinoshita, Masahiro

    2013-03-01

    An electrochemical reaction within nanopores is remarkably decelerated once a diffusion-limited condition is reached due to the difficulty in supply of reactants from the bulk. Here, we report a powerful method of overcoming this problem for electrochemical deposition of platinum within nanopores formed on silicon. We made the pore wall surface of the silicon electrode hydrophobic by covering it with organic molecules and adopted platinum complex ions with sufficiently large sizes. Such ions, which are only weakly hydrated, are excluded from the bulk aqueous electrolyte solution to the surface and rather hydrophobic in this sense. When the ion concentration in the bulk was gradually increased, at a threshold the deposition behavior exhibited a sudden change, leading to drastic acceleration of the electrochemical deposition. Using our statistical-mechanical theory for confined molecular liquids, we show that this change originates from a surface-induced phase transition: The space within nanopores is abruptly filled with the second phase within which the ion concentration is orders of magnitude higher. When the affinity of the surface with water was gradually reduced with fixing the ion concentration, qualitatively the same transition phenomenon was observed, which can also be elucidated by our theory. The utilization of the surface-induced phase transition sheds new light on the design and control of a chemical reaction in nanospace.

  10. Combination strategies for repair, plasticity, and regeneration using regulation of gene expression during the chronic phase after spinal cord injury.

    PubMed

    Gerin, Christine G; Madueke, Ikenna C; Perkins, Tina; Hill, Seritta; Smith, Kristin; Haley, Benjamin; Allen, Shannon A; Garcia, Richard P; Paunesku, Tanjana; Woloschak, Gayle

    2011-12-01

    Although recovery after spinal cord injury (SCI) is rare in humans, recent literature indicates that some patients do recover sensorimotor function years after the trauma. This study seeks to elucidate the genetic underpinnings of SCI repair through the investigation of neurodegenerative and regenerative associated genes involved in the response to SCI during the chronic phase in adult rats. Intervention on the level of gene regulation focused on enhancing naturally attempting SCI regenerative genes has the potential to promote SCI repair. Our aim was to analyze gene expression characteristics of candidate genes involved in the neuro-degenerative and -regenerative processes following various animal models of SCI. We compiled data showing gene expression changes after SCI in adult rats and created a chronological time-line of candidate genes differentially expressed during the chronic phase of SCI. Compiled data showed that SCI induced a transient upregulation of endogenous neuro-regenerative genes not only within a few hours but also within a few days, weeks, and months after SCI. For example, gene controlling growth-associated protein-43 (GAP-43), brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and others, showed significant changes in mRNA accumulation in SCI animals, from 48 hours to 12 weeks after SCI. Similarly, inhibitory genes, such as RhoA, LINGO-1, and others, were upregulated as late as 4 to 14 days after injury. This indicates that gene specific regulation changes, corresponding to repair and regenerative attempts, are naturally orchestrated over time after injury. These delayed changes after SCI give ample time for therapeutic gene modulation through upregulation or silencing of specific genes responsible for the synthesis of the corresponding biogenic proteins. By following the examination of differential gene regulation during the chronic phase, we have determined times, successions, co

  11. Microbially-accelerated consolidation of oil sands tailings. Pathway II: solid phase biogeochemistry

    PubMed Central

    Siddique, Tariq; Kuznetsov, Petr; Kuznetsova, Alsu; Li, Carmen; Young, Rozlyn; Arocena, Joselito M.; Foght, Julia M.

    2014-01-01

    Consolidation of clay particles in aqueous tailings suspensions is a major obstacle to effective management of oil sands tailings ponds in northern Alberta, Canada. We have observed that microorganisms indigenous to the tailings ponds accelerate consolidation of mature fine tailings (MFT) during active metabolism by using two biogeochemical pathways. In Pathway I, microbes alter porewater chemistry to indirectly increase consolidation of MFT. Here, we describe Pathway II comprising significant, direct and complementary biogeochemical reactions with MFT mineral surfaces. An anaerobic microbial community comprising Bacteria (predominantly Clostridiales, Synergistaceae, and Desulfobulbaceae) and Archaea (Methanolinea/Methanoregula and Methanosaeta) transformed FeIII minerals in MFT to amorphous FeII minerals during methanogenic metabolism of an added organic substrate. Synchrotron analyses suggested that ferrihydrite (5Fe2O3. 9H2O) and goethite (α-FeOOH) were the dominant FeIII minerals in MFT. The formation of amorphous iron sulfide (FeS) and possibly green rust entrapped and masked electronegative clay surfaces in amended MFT. Both Pathways I and II reduced the surface charge potential (repulsive forces) of the clay particles in MFT, which aided aggregation of clays and formation of networks of pores, as visualized using cryo-scanning electron microscopy (SEM). These reactions facilitated the egress of porewater from MFT and increased consolidation of tailings solids. These results have large-scale implications for management and reclamation of oil sands tailings ponds, a burgeoning environmental issue for the public and government regulators. PMID:24711806

  12. Final safety analysis report for the Ground Test Accelerator (GTA), Phase 2

    SciTech Connect

    1994-10-01

    This document is the second volume of a 3 volume safety analysis report on the Ground Test Accelerator (GTA). The GTA program at the Los Alamos National Laboratory (LANL) is the major element of the national Neutral Particle Beam (NPB) program, which is supported by the Strategic Defense Initiative Office (SDIO). A principal goal of the national NPB program is to assess the feasibility of using hydrogen and deuterium neutral particle beams outside the Earth`s atmosphere. The main effort of the NPB program at Los Alamos concentrates on developing the GTA. The GTA is classified as a low-hazard facility, except for the cryogenic-cooling system, which is classified as a moderate-hazard facility. This volume consists of failure modes and effects analysis; accident analysis; operational safety requirements; quality assurance program; ES&H management program; environmental, safety, and health systems critical to safety; summary of waste-management program; environmental monitoring program; facility expansion, decontamination, and decommissioning; summary of emergency response plan; summary plan for employee training; summary plan for operating procedures; glossary; and appendices A and B.

  13. Multi-Directional Sprinting and Acceleration Phase in Basketball and Handball Players Aged 14 and 15 Years.

    PubMed

    Popowczak, Marek; Rokita, Andrzej; Struzik, Artur; Cichy, Ireneusz; Dudkowski, Andrzej; Chmura, Paweł

    2016-10-01

    An important role in handball and basketball is played by ability to accelerate and ability to repeat multiple sprints. The aim of the study was to assess level of ability in multi-directional sprinting and running time over the first 5 m of the 30 m sprint in 93 basketball and handball players (46 boys and 47 girls) aged 14 to 15 years. The attempts were also made to find the relationships between the time of a 5-m run to evaluate initial acceleration phase and multi-directional sprinting evaluated using Five-Time Shuttle Run To Gates Test Statistical analysis revealed no important differences in times of 5-m runs and times of multi-directional sprinting between groups with different ages, genders, and sports specialties. Furthermore, no significant correlations were found based on Spearman's rank correlation coefficient between times of 5-m run and multi-directional sprinting in the most of subgroups studied. PMID:27565172

  14. Evaluation of the Acceleration and Deceleration Phase-Rectified Slope to Detect and Improve IUGR Clinical Management

    PubMed Central

    Tagliaferri, Salvatore; Fanelli, Andrea; Esposito, Giuseppina; Esposito, Francesca Giovanna; Magenes, Giovanni; Signorini, Maria Gabriella; Campanile, Marta; Martinelli, Pasquale

    2015-01-01

    Objective. This study used a new method called Acceleration (or Deceleration) Phase-Rectified Slope, APRS (or DPRS) to analyze computerized Cardiotocographic (cCTG) traces in intrauterine growth restriction (IUGR), in order to calculate acceleration- and deceleration-related fluctuations of the fetal heart rate, and to enhance the prediction of neonatal outcome. Method. Cardiotocograms from a population of 59 healthy and 61 IUGR fetuses from the 30th gestation week matched for gestational age were included. APRS and DPRS analysis was compared to the standard linear and nonlinear cCTG parameters. Statistical analysis was performed through the t-test, ANOVA test, Pearson correlation test and receiver operator characteristic (ROC) curves (p < 0, 05). Results. APRS and DPRS showed high performance to discriminate between Healthy and IUGR fetuses, according to gestational week. A linear correlation with the fetal pH at birth was found in IUGR. The area under the ROC curve was 0.865 for APRS and 0.900 for DPRS before the 34th gestation week. Conclusions. APRS and DPRS could be useful in the identification and management of IUGR fetuses and in the prediction of the neonatal outcome, especially before the 34th week of gestation. PMID:26779279

  15. Preliminary results of a phase I/II study of sodium pentosanpolysulfate in the treatment of chronic radiation-induced proctitis

    SciTech Connect

    Grigsby, P.W.; Pilepich, M.V.; Parsons, C.L. )

    1990-02-01

    This is a report of a phase I/II study of 13 patients treated with sodium pentosanpolysulfate (PPS) for chronic radiation-induced proctitis. A complete response was obtained in 82%, a partial response occurred in 9%, and 9% failed to respond to therapy. No significant toxicity was observed. It is concluded that PPS is an effective treatment for chronic radiation-induced proctitis and a phase III randomized, double-blind study of PPS versus placebo is planned.

  16. Phase-space moment-equation model of highly relativistic electron-beams in plasma-wakefield accelerators

    SciTech Connect

    Robson, R.E.; Mehrling, T.; Osterhoff, J.

    2015-05-15

    We formulate a new procedure for modelling the transverse dynamics of relativistic electron beams with significant energy spread when injected into plasma-based accelerators operated in the blow-out regime. Quantities of physical interest, such as the emittance, are furnished directly from solution of phase space moment equations formed from the relativistic Vlasov equation. The moment equations are closed by an Ansatz, and solved analytically for prescribed wakefields. The accuracy of the analytic formulas is established by benchmarking against the results of a semi-analytic/numerical procedure which is described within the scope of this work, and results from a simulation with the 3D quasi-static PIC code HiPACE.

  17. Acceleration of the matrix multiplication of Radiance three phase daylighting simulations with parallel computing on heterogeneous hardware of personal computer

    SciTech Connect

    Zuo, Wangda; McNeil, Andrew; Wetter, Michael; Lee, Eleanor S.

    2013-05-23

    Building designers are increasingly relying on complex fenestration systems to reduce energy consumed for lighting and HVAC in low energy buildings. Radiance, a lighting simulation program, has been used to conduct daylighting simulations for complex fenestration systems. Depending on the configurations, the simulation can take hours or even days using a personal computer. This paper describes how to accelerate the matrix multiplication portion of a Radiance three-phase daylight simulation by conducting parallel computing on heterogeneous hardware of a personal computer. The algorithm was optimized and the computational part was implemented in parallel using OpenCL. The speed of new approach was evaluated using various daylighting simulation cases on a multicore central processing unit and a graphics processing unit. Based on the measurements and analysis of the time usage for the Radiance daylighting simulation, further speedups can be achieved by using fast I/O devices and storing the data in a binary format.

  18. Effects of Sled Towing on Peak Force, the Rate of Force Development and Sprint Performance During the Acceleration Phase

    PubMed Central

    Martínez-Valencia, María Asunción; Romero-Arenas, Salvador; Elvira, José L.L.; González-Ravé, José María; Navarro-Valdivielso, Fernando; Alcaraz, Pedro E.

    2015-01-01

    Resisted sprint training is believed to increase strength specific to sprinting. Therefore, the knowledge of force output in these tasks is essential. The aim of this study was to analyze the effect of sled towing (10%, 15% and 20% of body mass (Bm)) on sprint performance and force production during the acceleration phase. Twenty-three young experienced sprinters (17 men and 6 women; men = 17.9 ± 3.3 years, 1.79 ± 0.06 m and 69.4 ± 6.1 kg; women = 17.2 ± 1.7 years, 1.65 ± 0.04 m and 56.6 ± 2.3 kg) performed four 30 m sprints from a crouch start. Sprint times in 20 and 30 m sprint, peak force (Fpeak), a peak rate of force development (RFDpeak) and time to RFD (TRFD) in first step were recorded. Repeated-measures ANOVA showed significant increases (p ≤ 0.001) in sprint times (20 and 30 m sprint) for each resisted condition as compared to the unloaded condition. The RFDpeak increased significantly when a load increased (3129.4 ± 894.6 N·s−1, p ≤ 0.05 and 3892.4 ± 1377.9 N·s−1, p ≤ 0.01). Otherwise, no significant increases were found in Fpeak and TRFD. The RFD determines the force that can be generated in the early phase of muscle contraction, and it has been considered a factor that influences performance of force-velocity tasks. The use of a load up to 20% Bm might provide a training stimulus in young sprinters to improve the RFDpeak during the sprint start, and thus, early acceleration. PMID:26240657

  19. Effects of Sled Towing on Peak Force, the Rate of Force Development and Sprint Performance During the Acceleration Phase.

    PubMed

    Martínez-Valencia, María Asunción; Romero-Arenas, Salvador; Elvira, José L L; González-Ravé, José María; Navarro-Valdivielso, Fernando; Alcaraz, Pedro E

    2015-06-27

    Resisted sprint training is believed to increase strength specific to sprinting. Therefore, the knowledge of force output in these tasks is essential. The aim of this study was to analyze the effect of sled towing (10%, 15% and 20% of body mass (Bm)) on sprint performance and force production during the acceleration phase. Twenty-three young experienced sprinters (17 men and 6 women; men = 17.9 ± 3.3 years, 1.79 ± 0.06 m and 69.4 ± 6.1 kg; women = 17.2 ± 1.7 years, 1.65 ± 0.04 m and 56.6 ± 2.3 kg) performed four 30 m sprints from a crouch start. Sprint times in 20 and 30 m sprint, peak force (Fpeak), a peak rate of force development (RFDpeak) and time to RFD (TRFD) in first step were recorded. Repeated-measures ANOVA showed significant increases (p ≤ 0.001) in sprint times (20 and 30 m sprint) for each resisted condition as compared to the unloaded condition. The RFDpeak increased significantly when a load increased (3129.4 ± 894.6 N·s-1, p ≤ 0.05 and 3892.4 ± 1377.9 N·s-1, p ≤ 0.01). Otherwise, no significant increases were found in Fpeak and TRFD. The RFD determines the force that can be generated in the early phase of muscle contraction, and it has been considered a factor that influences performance of force-velocity tasks. The use of a load up to 20% Bm might provide a training stimulus in young sprinters to improve the RFDpeak during the sprint start, and thus, early acceleration. PMID:26240657

  20. Traumatic axonal injury: Relationships between lesions in the early phase and diffusion tensor imaging parameters in the chronic phase of traumatic brain injury.

    PubMed

    Moen, Kent Gøran; Vik, Anne; Olsen, Alexander; Skandsen, Toril; Håberg, Asta Kristine; Evensen, Kari Anne I; Eikenes, Live

    2016-07-01

    This prospective study of traumatic brain injury (TBI) patients investigates fractional anisotropy (FA) from chronic diffusion tensor imaging (DTI) in areas corresponding to persistent and transient traumatic axonal injury (TAI) lesions detected in clinical MRI from the early phase. Thirty-eight patients (mean 24.7 [range 13-63] years of age) with moderate-to-severe TBI and 42 age- and sex-matched healthy controls were included. Patients underwent 1.5-T clinical MRI in the early phase (median 7 days), including fluid-attenuated inversion recovery (FLAIR) and T2* gradient echo (T2*GRE) sequences. TAI lesions from the early phase were characterized as nonhemorrhagic or microhemorrhagic. In the chronic phase (median 3 years), patients and controls were imaged at 3 T with FLAIR, T2*GRE, T1, and DTI sequences. TAI lesions were classified as transient or persistent. The FLAIR/T2*GRE images from the early phase were linearly registered to the FA images from the chronic phase and lesions manually segmented on the FA-registered FLAIR/T2*GRE images. For regions of interest (ROIs) from both nonhemorrhagic and microhemorrhagic lesion, we found a significant linear trend of lower mean FA from ROIs in healthy controls to ROIs in patients without either nonhemorrhagic or microhemorrhagic lesions and further to transient and finally persistent lesion ROIs (P < 0.001). Histogram analyses showed lower FA in persistent compared with transient nonhemorrhagic lesion ROIs (P < 0.001), but this was not found in microhemorrhagic lesion ROIs (P = 0.08-0.55). The demonstrated linear trend of lower FA values from healthy controls to persistent lesion ROIs was found in both nonhemorrhagic and microhemorrhagic lesions and indicates a gradual increasing disruption of the microstructure. Lower FA values in persistent compared with transient lesions were found only in nonhemorrhagic lesions. Thus, clinical MRI techniques are able to depict important aspects of white matter pathology across the

  1. Evaluation of the Safety of Imatinib Mesylate in 200 Iraqi Patients with Chronic Myeloid Leukemia in the Chronic Phase: Single-Center Study

    PubMed Central

    Matti, Bassam Francis; Alwan, Alaa Fadhil; Alwan, Alaa Fadhil

    2013-01-01

    Objective: Imatinib mesylate, a tyrosine kinase inhibitor, is presently the drug of choice for chronic myeloid leukemia (CML). During therapy, a few patients may develop hematological and non-hematological adverse effects. Materials and Methods: The aim of this study was to evaluate the safety of imatinib therapy in patients with CML. Between December 2007 and October 2009 two hundred patients with CML in chronic phase were included in the study. Written informed consent was obtained from all patients prior to the start of the study. Imatinib was started at 400 mg orally daily. Patients were monitored carefully for any adverse effects. Complete blood count, liver, and renal function tests were done once in 2 weeks during the first month and on a monthly basis during follow-up. Toxicities that encountered were graded as per the National Cancer Institute common toxicity criteria version 2. Both hematologic and non-hematologic toxicities were managed with short interruptions of treatment and supportive measures, but the daily dose of imatinib was not reduced below 300 mg/day. Results: Two hundred CML patients in chronic phase were included in this study; the male:female ratio was 0.7:1 with mean age 39.06±13.21 years (ranged from 15-81 years). The study showed that the commonest hematological side effects were grade 2 anemia (12.5%) followed by leukopenia (8%) and thrombocytopenia (4%), while the most common non-hematological adverse effects were superficial edema and weight gain (51.5%), followed by musculoskeletal pain (35.5%), then gastro-intestinal symptoms (vomiting, diarrhea) (19%). Fluid retention was the commonest side effect, which responded to low-dose diuretics. The drug was safe and well tolerated. There were no deaths due to toxicity. Conclusion: Imatinib mesylate a well-tolerated drug, and all undesirable effects could be ameliorated easily. The most common hematological and non-hematological side effects were anemia and fluid retention, respectively

  2. Chronic loss of subcutaneous adipose tissue in HIV-associated lipodystrophy may not be associated with accelerated apoptosis.

    PubMed

    Mynarcik, Dennis; Wei, Lin-Xiang; Komaroff, Eugene; Ferris, Robert; McNurlan, Margaret; Gelato, Marie

    2005-03-01

    HIV-associated lipodystrophy (HIV-LD) is characterized by a loss of adipose tissue from the subcutaneous compartment. Previously reported data suggested that this loss of adipose tissue was the result of an increased rate of apoptosis in subcutaneous adipose tissue (SAT). The present study examined the rate of apoptosis in SAT with a sensitive ligase-mediated polymerase chain reaction technique to amplify DNA ladders. Individuals with HIV-LD were compared with HIV-infected subjects without LD and subjects without HIV disease. Although apoptosis was observed in subjects with HIV-LD, there was no difference in the incidence of individuals with apoptosis among those with HIV-LD (10 of 22 subjects), those with HIV but no LD (13 of 25 subjects), and those without HIV disease (13 of 27 subjects). These data suggest that HIV-related chronic loss of SAT may not always be associated with increased frequency of adipocyte apoptosis. PMID:15776544

  3. Quantification of hepatic blood flow using a high-resolution phase-contrast MRI sequence with compressed sensing acceleration.

    PubMed

    Dyvorne, Hadrien A; Knight-Greenfield, Ashley; Besa, Cecilia; Cooper, Nancy; Garcia-Flores, Julio; Schiano, Thomas D; Markl, Michael; Taouli, Bachir

    2015-03-01

    OBJECTIVE. The objective of our study was to evaluate the performance of a high-spatial-resolution 2D phase-contrast (PC) MRI technique accelerated with compressed sensing for portal vein (PV) and hepatic artery (HA) flow quantification in comparison with a standard PC MRI sequence. SUBJECTS AND METHODS. In this prospective study, two PC MRI sequences were compared, one with parallel imaging acceleration and low spatial resolution (generalized autocalibrating partial parallel acquisition [GRAPPA]) and one with compressed sensing acceleration and high spatial resolution (sparse). Seventy-six patients were assessed, including 37 patients with cirrhosis. Two observers evaluated PC image quality. Quantitative analyses yielded a mean velocity, flow, and vessel area for the PV and HA and an arterial fraction. The PC techniques were compared using the paired Wilcoxon test and Bland-Altman statistics. The sensitivity of the flow parameters to the severity of cirrhosis was also assessed. RESULTS. Vessel delineation was significantly improved using the PC sparse sequence (p < 0.034). For both in vitro and in vivo measurements, PC sparse yielded lower estimates for vessel area and flow, and larger differences between PC GRAPPA and PC sparse were observed in the HA. PV velocity and flow were significantly lower in patients with cirrhosis on both PC sparse (p < 0.001 and p = 0.042, respectively) and PC GRAPPA (p < 0.001 and p = 0.005, respectively). PV velocity correlated negatively with Child-Pugh class (r = -0.50, p < 0.001), whereas the arterial fraction measured with PC sparse was higher in patients with Child-Pugh class B or C disease than in those with Child-Pugh class A disease, with a trend toward significance (p = 0.055). CONCLUSION. A high-spatial-resolution highly accelerated compressed sensing technique (PC sparse) allows total hepatic blood flow measurements obtained in 1 breath-hold, provides improved delineation of the hepatic vessels compared with a standard PC

  4. Accelerated Phase of Chediak-Higashi Syndrome at Initial Presentation: A Case Report of an Uncommon Occurrence in a Rare Disorder.

    PubMed

    Jaiswal, Pooja; Yadav, Yogesh Kumar; Bhasker, Nilam; Kushwaha, Rashmi

    2015-12-01

    Chediak-Higashi syndrome (CHS) is an uncommon and fatal congenital disorder. The characteristic features of CHS are partial oculocutaneous albinism, increased vulnerability to infections, presence of abnormal large granules in leukocytes and an accelerated lymphohistiocytic phase. Accelerated phase at initial presentation is rarely seen as it is usually preceded by repeated episodes of infections. Hence this interesting case of a four-month-old Indian child born to consanguineous parents in accelerated phase at initial presentation is described. The boy presented with fever, hepatosplenomegaly, and cleft lip. Clinical diagnosis was leukemia or a lysosomal storage disorder. Cytopaenias, lymphohistiocytic infiltration in bone marrow, and the characteristic large granules in leucocytes helped in the diagnosis, emphasizing the importance of bone marrow in diagnosis of unusual presentation of this rare disorder. PMID:26816903

  5. Accelerated Phase of Chediak-Higashi Syndrome at Initial Presentation: A Case Report of an Uncommon Occurrence in a Rare Disorder

    PubMed Central

    Jaiswal, Pooja; Bhasker, Nilam; Kushwaha, Rashmi

    2015-01-01

    Chediak-Higashi syndrome (CHS) is an uncommon and fatal congenital disorder. The characteristic features of CHS are partial oculocutaneous albinism, increased vulnerability to infections, presence of abnormal large granules in leukocytes and an accelerated lymphohistiocytic phase. Accelerated phase at initial presentation is rarely seen as it is usually preceded by repeated episodes of infections. Hence this interesting case of a four-month-old Indian child born to consanguineous parents in accelerated phase at initial presentation is described. The boy presented with fever, hepatosplenomegaly, and cleft lip. Clinical diagnosis was leukemia or a lysosomal storage disorder. Cytopaenias, lymphohistiocytic infiltration in bone marrow, and the characteristic large granules in leucocytes helped in the diagnosis, emphasizing the importance of bone marrow in diagnosis of unusual presentation of this rare disorder. PMID:26816903

  6. Studies on solar hard X-Rays and gamma-rays: Compton backscatter, anisotropy, polarization and evidence for two phases of acceleration. Ph.D. Thesis - Maryland Univ.

    NASA Technical Reports Server (NTRS)

    Bai, T.

    1977-01-01

    Observations of solar X-rays and gamma-rays from large flares show that the hard X-ray spectrum extends into the gamma ray region, where a flattening in the spectrum of the continuum emission is observed above about 1 MeV. This emission is believed to be due to bremsstrahlung. In addition to electron-proton collisions, at energies greater than approximately 500 keV, bremsstrahlung due to electron-electron collisions becomes significant. Bremsstrahlung production was calculated for a variety of electron spectra extending from the nonrelativistic region to relativistic energies and electron-electron bremsstrahlung is taken into account. By comparing these calculations with data, it is shown that the flattening in the spectrum of the continuum emission can be best explained by an electron spectrum consisting of two distinctive components. This evidence, together with information on the X-ray and gamma ray time profiles, implied the existence of two phases of acceleration. The first phase accelerates electrons mainly up to about several hundred keV; the second phase accelerates a small fraction of the electrons accelerated in the first phase to relativistic energies and accelerates protons to tens and hundreds of MeV.

  7. Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

    PubMed Central

    Lipton, Jeff H.; Rea, Delphine; Digumarti, Raghunadharao; Chuah, Charles; Nanda, Nisha; Benichou, Annie-Claude; Craig, Adam R.; Michallet, Mauricette; Nicolini, Franck E.; Kantarjian, Hagop

    2012-01-01

    Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n = 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219. PMID:22896000

  8. Cessation of tyrosine kinase inhibitors in patients with chronic-phase chronic myelogenous leukemia following durable complete molecular response: a single center facing the dilemma.

    PubMed

    Iliakis, Theodoros; Papadopoulou, Vasiliki; Diamantopoulos, Panagiotis T; Panayiotidis, Panayiotis; Zervakis, Konstantinos; Giannakopoulou, Nefeli; Tilimidos, Gerassimos; Angelopoulou, Maria; Siakantaris, Marina P; Pangalis, Gerassimos; Mantzourani, Marina; Variami, Eleni; Viniou, Nora Athina

    2013-08-01

    Tyrosine kinase inhibitors (TKIs), namely imatinib mesylate (IM) and recently approved second-generation TKIs dasatinib and nilotinib, are currently considered the treatment of choice for newly-diagnosed chronic phase chronic myelogenous leukemia (CP-CML). Although treatment with TKIs has not yet been proven curative, it certainly accomplishes a sustained control of the disease in the vast majority of patients. More than a decade after the successful launching of IM in first-line treatment of CP-CML and the subsequent introduction of second-generation TKIs in this setting, the question of the possibility of TKI cessation in a specific subset of patients has emerged. Side-effects of TKIs, along with some patients' wish to abandon the drugs and the rising financial burden upon healthcare systems, have led to the dilemma whether IM can be safely withdrawn after achieving deep molecular remissions and which patients are suitable for this discontinuation. We examined the data of our patients with CML in search of potential canditates for cessation of TKI therapy and identified their characteristics. We also performed a thorough review of the relevant literature. Eight out of fifty patients were discriminated on grounds of sustained complete molecular response (CMR) exceeding 12 months, most of them with a low or intermediate Sokal score at diagnosis. The median interval from IM initiation to CMR was almost 2 years and the median duration of detected CMR reached 6.5 years. Based on the promising results of prospective clinical trials reporting successful cessation of treatment with TKIs on selected subgroups of patients, we decided to proceed to interruption of therapy in the specific subset of our patients and closely monitor their response. PMID:23898127

  9. Tyrosine kinase inhibitors as a first-line treatment in patients with newly diagnosed chronic myeloid leukemia in chronic phase: A mixed-treatment comparison.

    PubMed

    Firwana, Belal; Sonbol, Mohamad Bassam; Diab, Maria; Raza, Shahzad; Hasan, Rim; Yousef, Ibrahim; Zarzour, Ahmad; Garipalli, Archana; Doll, Donald; Murad, M Hassan; Al-Kali, Aref

    2016-03-15

    Tyrosine kinase inhibitors (TKI) are the initial treatment for majority of newly diagnosed patients with chronic myelogenous leukemia (CML) in chronic phase (CP) and are associated with marked improvement in hematological, cytogenetic, molecular response and survival rates compared with other therapies. In this review, we summarize the evidence of TKI efficacy for patients with newly diagnosed CP-CML. Six trials at low risk of bias evaluating TKIs as an initial treatment in adults with newly diagnosed CP-CML and enrolling 2,456 patients were included. Follow-up times ranged from a median of 3 months to 5 years. Direct comparison showed statistically higher rates of major molecular response (MMR ≤ 0.1%(IS)) achievement with second-generation TKIs at 12 months which was sustained throughout treatment period. Bayesian mixed-treatment comparison (MTC) analysis demonstrated superiority of both nilotinib and dasatinib over imatinib in terms of efficacy. Nilotinib was associated with higher deeper molecular responses (MR(4.5) ≤ 0.0032%(IS)) at 60 months than dasatinib but no difference in MMR. The differences between nilotinib and dasatinib are likely clinically trivial. Among TKIs, nilotinib was found to have the best survival profile. Both nilotinib and dasatinib are associated with significantly better MMR compared to imatinib that is sustained over 60 months. This analysis shows that new-generation TKIs are not only showing faster response but also maintaining a more potent one through longer follow-up period. It is important to note out that MTC is not a substitute for well-conducted RCTs investigating direct comparisons. PMID:26455714

  10. HLA-Identical Sibling Compared With 8/8 Matched and Mismatched Unrelated Donor Bone Marrow Transplant for Chronic Phase Chronic Myeloid Leukemia

    PubMed Central

    Arora, Mukta; Weisdorf, Daniel J.; Spellman, Stephen R.; Haagenson, Michael D.; Klein, John P.; Hurley, Carolyn K.; Selby, George B.; Antin, Joseph H.; Kernan, Nancy A.; Kollman, Craig; Nademanee, Auayporn; McGlave, Philip; Horowitz, Mary M.; Petersdorf, Effie W.

    2009-01-01

    Purpose Transplantation of hematopoietic stem cells from an unrelated donor (URD) is an option for many patients who do not have an HLA-identical sibling donor (MSD). Current criteria for the selection of URDs include consideration for HLA alleles determined by high resolution typing methods, with preference for allele-matched donors. However, the utility and outcome associated with transplants from URDs compared with those from MSDs remains undefined. Patients and Methods We examined clinical outcome after patients received bone marrow transplants (BMTs) from MSDs; HLA-A, -B, -C, and DRB1 allele-matched URDs (8/8); and HLA-mismatched URDs in a homogeneous population of patients with chronic myeloid leukemia (CML) in first chronic phase (CP1) where a strong allogeneic effect and hence a lower risk of relapse is anticipated. Transplantation outcomes were compared between 1,052 URD and 3,514 MSD BMT recipients with CML in CP1. Results Five-year overall survival and leukemia-free survival (LFS) after receipt of BMTs from 8/8 matched URDs were worse than those after receipt of BMTs from MSDs (5-year survival, 55% v 63%; RR, 1.35; 95% CI, 1.17 to 1.56; P < .001; LFS, 50% v 55%; RR, 1.21; 95% CI, 1.06 to 1.40; P = .006). Survival was progressively worse with greater degrees of mismatch. Similar and low risk of relapse were observed after receipt of transplant from either MSD or URD. Conclusion In this homogeneous cohort of good risk patients with CML in CP1, 5-year overall survival and LFS after receipt of transplant from 8/8 allele-matched donors were modestly though significantly worse than those after receipt of transplant from MSDs. Additive adverse effects of multilocus mismatching are not well tolerated and should be avoided if possible. PMID:19224849

  11. Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States

    PubMed Central

    Padula, William V.; Larson, Richard A.; Dusetzina, Stacie B.; Apperley, Jane F.; Hehlmann, Rudiger; Baccarani, Michele; Eigendorff, Ekkehard; Guilhot, Joelle; Guilhot, Francois; Hehlmann, Rudiger; Mahon, Francois-Xavier; Martinelli, Giovanni; Mayer, Jiri; Müller, Martin C.; Niederwieser, Dietger; Saussele, Susanne; Schiffer, Charles A.; Silver, Richard T.; Simonsson, Bengt

    2016-01-01

    Background: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib’s price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness (“imatinib-first”) would be cost-effective compared with the current standard of care: “physicians’ choice” of initiating treatment with any one of the three TKIs. Methods: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician’s choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models’ clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven’s MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study’s conduct. Results: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician’s choice ($365 744, 3.97 QALYs). The imatinib-first incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. Conclusion: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP. PMID:26944912

  12. Cost-effectiveness of Tyrosine Kinase Inhibitor Treatment Strategies for Chronic Myeloid Leukemia in Chronic Phase After Generic Entry of Imatinib in the United States

    PubMed Central

    Padula, William V.; Larson, Richard A.; Dusetzina, Stacie B.; Apperley, Jane F.; Hehlmann, Rudiger; Baccarani, Michele; Eigendorff, Ekkehard; Guilhot, Joelle; Guilhot, Francois; Hehlmann, Rudiger; Mahon, Francois-Xavier; Martinelli, Giovanni; Mayer, Jiri; Müller, Martin C.; Niederwieser, Dietger; Saussele, Susanne; Schiffer, Charles A.; Silver, Richard T.; Simonsson, Bengt

    2016-01-01

    Background: We analyzed the cost-effectiveness of treating incident chronic myeloid leukemia in chronic phase (CML-CP) with generic imatinib when it becomes available in United States in 2016. In the year following generic entry, imatinib’s price is expected to drop 70% to 90%. We hypothesized that initiating treatment with generic imatinib in these patients and then switching to the other tyrosine-kinase inhibitors (TKIs), dasatinib or nilotinib, because of intolerance or lack of effectiveness (“imatinib-first”) would be cost-effective compared with the current standard of care: “physicians’ choice” of initiating treatment with any one of the three TKIs. Methods: We constructed Markov models to compare the five-year cost-effectiveness of imatinib-first vs physician’s choice from a US commercial payer perspective, assuming 3% annual discounting ($US 2013). The models’ clinical endpoint was five-year overall survival taken from a systematic review of clinical trial results. Per-person spending on incident CML-CP treatment overall care components was estimated using Truven’s MarketScan claims data. The main outcome of the models was cost per quality-adjusted life-year (QALY). We interpreted outcomes based on a willingness-to-pay threshold of $100 000/QALY. A panel of European LeukemiaNet experts oversaw the study’s conduct. Results: Both strategies met the threshold. Imatinib-first ($277 401, 3.87 QALYs) offered patients a 0.10 decrement in QALYs at a savings of $88 343 over five years to payers compared with physician’s choice ($365 744, 3.97 QALYs). The imatinib-first incremental cost-effectiveness ratio was approximately $883 730/QALY. The results were robust to multiple sensitivity analyses. Conclusion: When imatinib loses patent protection and its price declines, its use will be the cost-effective initial treatment strategy for CML-CP.

  13. A phase II trial of accelerated radiotherapy using weekly stereotactic conformal boost for supratentorial glioblastoma multiforme: RTOG 0023

    SciTech Connect

    Cardinale, Robert; Choucair, Ali; Gillin, Michael; Chakravarti, Arnab; Schultz, Christopher; Souhami, Luis; Chen, Allan; Pham, Huong; Mehta, Minesh

    2006-08-01

    Purpose: This phase II trial was performed to assess the feasibility, toxicity, and efficacy of dose-intense accelerated radiation therapy using weekly fractionated stereotactic radiotherapy (FSRT) boost for patients with glioblastoma multiforme (GBM). Methods and Materials: Patients with histologically confirmed GBM with postoperative enhancing tumor plus tumor cavity diameter <60 mm were enrolled. A 50-Gy dose of standard radiation therapy (RT) was given in daily 2-Gy fractions. In addition, patients received four FSRT treatments, once weekly, during Weeks 3 to 6. FSRT dosing of either 5 Gy or 7 Gy per fraction was given for a cumulative dose of 70 or 78 Gy in 29 (25 standard RT + 4 FSRT) treatments over 6 weeks. After the RT course, carmustine (BCNU) at 80 mg/m{sup 2} was given for 3 days, every 8 weeks, for 6 cycles. Results: A total of 76 patients were analyzed. Toxicity included: 3 Grade 4 chemotherapy, 3 acute Grade 4 radiotherapy, and 1 Grade 3 late. The median survival time was 12.5 months. No survival difference is seen when compared with the RTOG historical database. Patients with gross total resection (41%) had a median survival time of 16.6 months vs. 12.0 months for historic controls with gross total resection (p = 0.14). Conclusion: This first, multi-institutional FSRT boost trial for GBM was feasible and well tolerated. There is no significant survival benefit using this dose-intense RT regimen. Subset analysis revealed a trend toward improved outcome for GTR patients suggesting that patients with minimal disease burden may benefit from this form of accelerated RT.

  14. Phase II study of accelerated fractionation radiation therapy with carboplatin followed by vincristine chemotherapy for the treatment of glioblastoma multiforme

    SciTech Connect

    Levin, V.A.; Yung, W.K.A.; Kyritsis, A.P.

    1995-09-30

    The purpose of this investigation was to conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with intravenous carboplatin for patients with previously untreated glioblastoma multiforme tumors. Between 1988 and 1992, 83 patients received 1.9-2.0 Gy radiation three times a day with 2-h infusions of 33 mg/m{sup 2} carboplatin for two 5-day cycles separated by 2 weeks. Seventy-four of the 83 patients (89%) received one or more courses of PCV; their median survival was 55 weeks. Total resection was performed in 20% (15 of 74), subtotal resection in 69% (51 or 74), and biospy in 11% (8 of 74); reoperation (total or subtotal resection) was performed in 28 patients (37%). Survival was worst for those {ge} 61 year old (median 35 weeks). Fits of the Cox proportional hazards regression model showed covariated individually predictive of improved survival were younger age (p <0.01), smaller log of radiation volume (p = 0.008), total or subtotal resection vs. biopsy (p = 0.056), and higher Karnofsky performance status (p = 0.055). A multivariate analysis showed that age (p = 0.013) and extent of initial surgery (p = 0.003) together were predictive of a better survival with no other variables providing additional significance. Only 8.4% (7 of 83) of patients had clinically documented therapy-associated neurotoxicity ({open_quotes}radiation necrosis{close_quotes}). When comparable selection criteria were applied, the survival in this study is similar to the results currently attainable with other chemoradiation approaches. The relative safety of accelerated fractionated radiotherapy, as used in this study with carboplatin, enables concomitant full-dose administration of chemotherapy or radiosensitizing agents in glioblastoma multiforme patients. 42 refs., 3 figs., 5 tabs.

  15. Treatment for sulfur mustard lung injuries; new therapeutic approaches from acute to chronic phase

    PubMed Central

    2012-01-01

    Objective Sulfur mustard (SM) is one of the major potent chemical warfare and attractive weapons for terrorists. It has caused deaths to hundreds of thousands of victims in World War I and more recently during the Iran-Iraq war (1980–1988). It has ability to develop severe acute and chronic damage to the respiratory tract, eyes and skin. Understanding the acute and chronic biologic consequences of SM exposure may be quite essential for developing efficient prophylactic/therapeutic measures. One of the systems majorly affected by SM is the respiratory tract that numerous clinical studies have detailed processes of injury, diagnosis and treatments of lung. The low mortality rate has been contributed to high prevalence of victims and high lifetime morbidity burden. However, there are no curative modalities available in such patients. In this review, we collected and discussed the related articles on the preventive and therapeutic approaches to SM-induced respiratory injury and summarized what is currently known about the management and therapeutic strategies of acute and long-term consequences of SM lung injuries. Method This review was done by reviewing all papers found by searching following key words sulfur mustard; lung; chronic; acute; COPD; treatment. Results Mustard lung has an ongoing pathological process and is active disorder even years after exposure to SM. Different drug classes have been studied, nevertheless there are no curative modalities for mustard lung. Conclusion Complementary studies on one hand regarding pharmacokinetic of drugs and molecular investigations are mandatory to obtain more effective treatments. PMID:23351279

  16. Unpredictable chronic stress decreases inhibitory avoidance learning in Tuebingen long-fin zebrafish: stronger effects in the resting phase than in the active phase.

    PubMed

    Manuel, Remy; Gorissen, Marnix; Zethof, Jan; Ebbesson, Lars O E; van de Vis, Hans; Flik, Gert; van den Bos, Ruud

    2014-11-01

    Zebrafish (Danio rerio Hamilton) are increasingly used as a model to study the effects of chronic stress on brain and behaviour. In rodents, unpredictable chronic stress (UCS) has a stronger effect on physiology and behaviour during the active phase than during the resting phase. Here, we applied UCS during the daytime (active phase) for 7 and 14 days or during the night-time (resting phase) for 7 nights in an in-house-reared Tuebingen long-fin (TLF) zebrafish strain. Following UCS, inhibitory avoidance learning was assessed using a 3 day protocol where fish learn to avoid swimming from a white to a black compartment where they will receive a 3 V shock. Latencies of entering the black compartment were recorded before training (day 1; first shock) and after training on day 2 (second shock) and day 3 (no shock, tissue sampling). Fish whole-body cortisol content and expression levels of genes related to stress, fear and anxiety in the telencephalon were quantified. Following 14 days of UCS during the day, inhibitory avoidance learning decreased (lower latencies on days 2 and 3); minor effects were found following 7 days of UCS. Following 7 nights of UCS, inhibitory avoidance learning decreased (lower latency on day 3). Whole-body cortisol levels showed a steady increase compared with controls (100%) from 7 days of UCS (139%), to 14 days of UCS (174%) to 7 nights of UCS (231%), suggestive of an increasing stress load. Only in the 7 nights of UCS group did expression levels of corticoid receptor genes (mr, grα, grβ) and of bdnf increase. These changes are discussed as adaptive mechanisms to maintain neuronal integrity and prevent overload, and as being indicative of a state of high stress load. Overall, our data suggest that stressors during the resting phase have a stronger impact than during the active phase. Our data warrant further studies on the effect of UCS on stress axis-related genes, especially grβ; in mammals this receptor has been implicated in

  17. Approaches to Improving Cardiac Structure and Function During and After an Acute Myocardial Infarction: Acute and Chronic Phases.

    PubMed

    Kloner, Robert A; Dai, Wangde; Hale, Sharon L; Shi, Jianru

    2016-07-01

    While progress has been made in improving survival following myocardial infarction, this injury remains a major source of mortality and morbidity despite modern reperfusion therapy. While one approach has been to develop therapies to reduce lethal myocardial cell reperfusion injury, this concept has not translated to the clinics, and several recent negative clinical trials raise the question of whether reperfusion injury is important in humans undergoing reperfusion for acute ST segment elevation myocardial infarction. Therapy aimed at reducing myocardial cell death while the myocytes are still ischemic is more likely to further reduce myocardial infarct size. Developing new therapies to further reduce left ventricular remodeling after the acute event is another approach to preserving structure and function of the heart after infarction. Such therapy may include chronic administration of pharmacologic agents and/or therapies developed from the field of regenerative cardiology, including cellular or non-cellular materials such as extracellular matrix. The optimal therapy will be to administer agents that both reduce myocardial infarct size in the acute phase of infarction as well as reduce adverse left ventricular remodeling during the chronic or healing phase of myocardial infarction. Such a dual approach will help optimize the preservation of both cardiac structure and function. PMID:26612091

  18. Sequential combined treatment with allopurinol and benznidazole in the chronic phase of Trypanosoma cruzi infection: a pilot study

    PubMed Central

    Perez-Mazliah, D. E.; Alvarez, M. G.; Cooley, G.; Lococo, B. E.; Bertocchi, G.; Petti, M.; Albareda, M. C.; Armenti, A. H.; Tarleton, R. L.; Laucella, S. A.; Viotti, R.

    2013-01-01

    Objectives Even though the use of combined drugs has been proved to be effective in other chronic infections, assessment of combined treatment of antiparasitic drugs in human Chagas' disease has not been performed. Herein, a pilot study was conducted to evaluate the tolerance and side effects of a sequential combined treatment of two antiparasitic drugs, allopurinol and benznidazole, in the chronic phase of Trypanosoma cruzi infection. Patients and methods Changes in total and T. cruzi-specific T and B cells were monitored during a median follow-up of 36 months. Allopurinol was administered for 3 months (600 mg/day) followed by 30 days of benznidazole (5 mg/kg/day) in 11 T. cruzi-infected subjects. Results The combined sequential treatment of allopurinol and benznidazole was well tolerated. The levels of T. cruzi-specific antibodies significantly decreased after sequential combined treatment, as determined by conventional serology and by a multiplex assay using recombinant proteins. The frequency of T. cruzi-specific interferon-γ-producing T cells significantly increased after allopurinol treatment and decreased to background levels following benznidazole administration in a substantial proportion of subjects evaluated. The levels of total naive (CD45RA + CCR7 + CD62L+) CD4 + and CD8 + T cells were restored after allopurinol administration and maintained after completion of the combined drug protocol, along with a decrease in T cell activation in total peripheral CD4 + and CD8 + T cells. Conclusions This pilot study shows that the combination of allopurinol and benznidazole induces significant modifications in T and B cell responses indicative of a reduction in parasite burden, and sustains the feasibility of administration of two antiparasitic drugs in the chronic phase of Chagas' disease. PMID:23104493

  19. Dasatinib in Imatinib-Resistant or Imatinib-Intolerant Chronic Myeloid Leukemia in Blast Phase After 2 Years of Follow-Up in a Phase 3 Study

    PubMed Central

    Saglio, Giuseppe; Hochhaus, Andreas; Goh, Yeow Tee; Masszi, Tamas; Pasquini, Ricardo; Maloisel, Frederic; Erben, Philipp; Cortes, Jorge; Paquette, Ronald; Bradley-Garelik, M. Brigid; Zhu, Chao; Dombret, Herve

    2016-01-01

    BACKGROUND In a phase 3 study, the authors assessed the effects of dasatinib at doses of 140 mg once daily and 70 mg twice daily in patients who had either chronic myeloid leukemia (CML) in advanced phases or Philadelphia chromosome-positive acute lymphoblastic leukemia and were resistant or intolerant to imatinib. In the current report, the results for patients with CML in blast phase after 2 years of follow-up are reported. METHODS Patients were stratified according to whether they had CML in myeloid blast phase (MBP-CML) or in lymphoid blast phase (LBP-CML) and were randomized (1:1) within each stratum to receive either oral dasatinib 140 mg once daily or 70 mg twice daily. RESULTS In patients with MBP-CML, the major hematologic response rate was 28% for both regimens; and, in patients with LBP-CML, the major hematologic response rate was 42% for once-daily dasatinib and 32% for twice-daily dasatinib. The major cytogenetic response rates were 25% for once-daily dasatinib and 28% for twice-daily dasatinib in patients with MBP-CML, and the respective rates in patients with LBP-CML were 50% and 40%. The overall survival rate at 24 months was 24% for once-daily dasatinib and 28% for twice-daily dasatinib in patients with MBP-CML, and the respective values in patients with LBP-CML were 21% and 16%. Adverse events indicated a trend toward improved tolerability for the once-daily regimen. CONCLUSIONS The current results suggested that dasatinib 140 mg once daily had similar efficacy and improved tolerability relative to the 70-mg twice-daily regimen in patients with imatinib-resistant, blast phase CML. PMID:20564086

  20. A Phase I Study of Short-Course Accelerated Whole Brain Radiation Therapy for Multiple Brain Metastases

    SciTech Connect

    Caravatta, Luciana; Deodato, Francesco; Ferro, Marica; Macchia, Gabriella; Massaccesi, Mariangela; Cilla, Savino; Padula, Gilbert D.A.; Mignogna, Samantha; Tambaro, Rosa; Carrozza, Francesco; Flocco, Mariano; Cantore, Giampaolo; Scapati, Andrea; Buwenge, Milly; and others

    2012-11-15

    Purpose: To define the maximum tolerated dose (MTD) of a SHort-course Accelerated whole brain RadiatiON therapy (SHARON) in the treatment of patients with multiple brain metastases. Methods and Materials: A phase 1 trial in 4 dose-escalation steps was designed: 12 Gy (3 Gy per fraction), 14 Gy (3.5 Gy per fraction), 16 Gy (4 Gy per fraction), and 18 Gy (4.5 Gy per fraction). Eligibility criteria included patients with unfavorable recursive partitioning analysis (RPA) class > or =2 with at least 3 brain metastases or metastatic disease in more than 3 organ systems, and Eastern Cooperative Oncology Group (ECOG) performance status {<=}3. Treatment was delivered in 2 days with twice-daily fractionation. Patients were treated in cohorts of 6-12 to define the MTD. The dose-limiting toxicity (DLT) was defined as any acute toxicity {>=}grade 3, according to the Radiation Therapy Oncology Group scale. Information on the status of the main neurologic symptoms and quality of life were recorded. Results: Characteristics of the 49 enrolled patients were as follows: male/female, 30/19; median age, 66 years (range, 23-83 years). ECOG performance status was <3 in 46 patients (94%). Fourteen patients (29%) were considered to be in recursive partitioning analysis (RPA) class 3. Grade 1-2 acute neurologic (26.4%) and skin (18.3%) toxicities were recorded. Only 1 patient experienced DLT (neurologic grade 3 acute toxicity). With a median follow-up time of 5 months (range, 1-23 months), no late toxicities have been observed. Three weeks after treatment, 16 of 21 symptomatic patients showed an improvement or resolution of presenting symptoms (overall symptom response rate, 76.2%; confidence interval 0.95: 60.3-95.9%). Conclusions: Short-course accelerated radiation therapy in twice-daily fractions for 2 consecutive days is tolerated up to a total dose of 18 Gy. A phase 2 study has been planned to evaluate the efficacy on overall survival, symptom control, and quality of life indices.

  1. Evaluation of acceleration and deceleration cardiac processes using phase-rectified signal averaging in healthy and idiopathic dilated cardiomyopathy subjects.

    PubMed

    Bas, Rosana; Vallverdú, Montserrat; Valencia, Jose F; Voss, Andreas; de Luna, Antonio Bayés; Caminal, Pere

    2015-02-01

    The aim of the present study was to investigate the suitability of the Phase-Rectified Signal Averaging (PRSA) method for improved risk prediction in cardiac patients. Moreover, this technique, which separately evaluates acceleration and deceleration processes of cardiac rhythm, allows the effect of sympathetic and vagal modulations of beat-to-beat intervals to be characterized. Holter recordings of idiopathic dilated cardiomyopathy (IDC) patients were analyzed: high-risk (HR), who suffered sudden cardiac death (SCD) during the follow-up; and low-risk (LR), without any kind of cardiac-related death. Moreover, a control group of healthy subjects was analyzed. PRSA indexes were analyzed, for different time scales T and wavelet scales s, from RR series of 24 h-ECG recordings, awake periods and sleep periods. Also, the behavior of these indexes from simulated data was analyzed and compared with real data results. Outcomes demonstrated the PRSA capacity to significantly discriminate healthy subjects from IDC patients and HR from LR patients on a higher level than traditional temporal and spectral measures. The behavior of PRSA indexes agrees with experimental evidences related to cardiac autonomic modulations. Also, these parameters reflect more regularity of the autonomic nervous system (ANS) in HR patients. PMID:25585858

  2. Quantifying factors determining the rate of CTL escape and reversion during acute and chronic phases of HIV infection

    SciTech Connect

    Ganusov, Vitaly V; Korber, Bette M; Perelson, Alan S

    2009-01-01

    Human immunodeficiency virus (HIV) often evades cytotoxic T cell (CTL) responses by generating variants that are not recognized by CTLs. However, the importance and quantitative details of CTL escape in humans are poorly understood. In part, this is because most studies looking at escape of HIV from CTL responses are cross-sectional and are limited to early or chronic phases of the infection. We use a novel technique of single genome amplification (SGA) to identify longitudinal changes in the transmitted/founder virus from the establishment of infection to the viral set point at 1 year after the infection. We find that HIV escapes from virus-specific CTL responses as early as 30-50 days since the infection, and the rates of viral escapes during acute phase of the infection are much higher than was estimated in previous studies. However, even though with time virus acquires additional escape mutations, these late mutations accumulate at a slower rate. A poor correlation between the rate of CTL escape in a particular epitope and the magnitude of the epitope-specific CTL response suggests that the lower rate of late escapes is unlikely due to a low efficacy of the HIV-specific CTL responses in the chronic phase of the infection. Instead, our results suggest that late and slow escapes are likely to arise because of high fitness cost to the viral replication associated with such CTL escapes. Targeting epitopes in which virus escapes slowly or does not escape at all by CTL responses may, therefore, be a promising direction for the development of T cell based HIV vaccines.

  3. Promoting state health department evidence-based cancer and chronic disease prevention: a multi-phase dissemination study with a cluster randomized trial component

    PubMed Central

    2013-01-01

    Background Cancer and other chronic diseases reduce quality and length of life and productivity, and represent a significant financial burden to society. Evidence-based public health approaches to prevent cancer and other chronic diseases have been identified in recent decades and have the potential for high impact. Yet, barriers to implement prevention approaches persist as a result of multiple factors including lack of organizational support, limited resources, competing emerging priorities and crises, and limited skill among the public health workforce. The purpose of this study is to learn how best to promote the adoption of evidence based public health practice related to chronic disease prevention. Methods/design This paper describes the methods for a multi-phase dissemination study with a cluster randomized trial component that will evaluate the dissemination of public health knowledge about evidence-based prevention of cancer and other chronic diseases. Phase one involves development of measures of practitioner views on and organizational supports for evidence-based public health and data collection using a national online survey involving state health department chronic disease practitioners. In phase two, a cluster randomized trial design will be conducted to test receptivity and usefulness of dissemination strategies directed toward state health department chronic disease practitioners to enhance capacity and organizational support for evidence-based chronic disease prevention. Twelve state health department chronic disease units will be randomly selected and assigned to intervention or control. State health department staff and the university-based study team will jointly identify, refine, and select dissemination strategies within intervention units. Intervention (dissemination) strategies may include multi-day in-person training workshops, electronic information exchange modalities, and remote technical assistance. Evaluation methods include pre

  4. CCI-779 in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndromes, or Chronic Myelogenous Leukemia in Blastic Phase

    ClinicalTrials.gov

    2013-01-22

    Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Myelodysplastic Syndromes

  5. X-ray phase contrast imaging of biological specimens with femtosecond pulses of betatron radiation from a compact laser plasma wakefield accelerator

    SciTech Connect

    Kneip, S.; McGuffey, C.; Dollar, F.; Chvykov, V.; Kalintchenko, G.; Krushelnick, K.; Maksimchuk, A.; Mangles, S. P. D.; Matsuoka, T.; Schumaker, W.; Thomas, A. G. R.; Yanovsky, V.; Bloom, M. S.; Najmudin, Z.; Palmer, C. A. J.; Schreiber, J.

    2011-08-29

    We show that x-rays from a recently demonstrated table top source of bright, ultrafast, coherent synchrotron radiation [Kneip et al., Nat. Phys. 6, 980 (2010)] can be applied to phase contrast imaging of biological specimens. Our scheme is based on focusing a high power short pulse laser in a tenuous gas jet, setting up a plasma wakefield accelerator that accelerates and wiggles electrons analogously to a conventional synchrotron, but on the centimeter rather than tens of meter scale. We use the scheme to record absorption and phase contrast images of a tetra fish, damselfly and yellow jacket, in particular highlighting the contrast enhancement achievable with the simple propagation technique of phase contrast imaging. Coherence and ultrafast pulse duration will allow for the study of various aspects of biomechanics.

  6. In Vivo Antiprotozoal Activity of the Chloroform Extract from Carica papaya Seeds against Amastigote Stage of Trypanosoma cruzi during Indeterminate and Chronic Phase of Infection.

    PubMed

    Jimenez-Coello, Matilde; Acosta-Viana, Karla Y; Ortega-Pacheco, Antonio; Perez-Gutierrez, Salud; Guzman-Marin, Eugenia

    2014-01-01

    In order to evaluate the antiprotozoal activity of the chloroform extract of Carica papaya seeds during the subacute and chronic phase of infection of Trypanosoma cruzi, doses of 50 and 75 mg/kg were evaluated during the subacute phase, including a mixture of their main components (oleic, palmitic, and stearic acids). Subsequently, doses of 50 and 75 mg/kg in mice during the chronic phase of infection (100 dpi) were also evaluated. It was found that chloroform extract was able to reduce the amastigote nests numbers during the subacute phase in 55.5 and 69.7% (P > 0.05) as well as in 56.45% in animals treated with the mixture of fatty acids. Moreover, the experimental groups treated with 50 and 75 mg/kg during the chronic phase of the infection showed a significant reduction of 46.8 and 53.13% respectively (P < 0.05). It is recommended to carry out more studies to determine if higher doses of chloroformic extract or its administration in combination with other antichagasic drugs allows a better response over the intracellular stage of T. cruzi in infected animal models and determine if the chloroform extract of C. papaya could be considered as an alternative for treatment during the indeterminate and chronic phase of the infection. PMID:25276216

  7. In Vivo Antiprotozoal Activity of the Chloroform Extract from Carica papaya Seeds against Amastigote Stage of Trypanosoma cruzi during Indeterminate and Chronic Phase of Infection

    PubMed Central

    Ortega-Pacheco, Antonio; Perez-Gutierrez, Salud; Guzman-Marin, Eugenia

    2014-01-01

    In order to evaluate the antiprotozoal activity of the chloroform extract of Carica papaya seeds during the subacute and chronic phase of infection of Trypanosoma cruzi, doses of 50 and 75 mg/kg were evaluated during the subacute phase, including a mixture of their main components (oleic, palmitic, and stearic acids). Subsequently, doses of 50 and 75 mg/kg in mice during the chronic phase of infection (100 dpi) were also evaluated. It was found that chloroform extract was able to reduce the amastigote nests numbers during the subacute phase in 55.5 and 69.7% (P > 0.05) as well as in 56.45% in animals treated with the mixture of fatty acids. Moreover, the experimental groups treated with 50 and 75 mg/kg during the chronic phase of the infection showed a significant reduction of 46.8 and 53.13% respectively (P < 0.05). It is recommended to carry out more studies to determine if higher doses of chloroformic extract or its administration in combination with other antichagasic drugs allows a better response over the intracellular stage of T. cruzi in infected animal models and determine if the chloroform extract of C. papaya could be considered as an alternative for treatment during the indeterminate and chronic phase of the infection. PMID:25276216

  8. Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia.

    PubMed

    Wendtner, Clemens-Martin; Hillmen, Peter; Mahadevan, Daruka; Bühler, Andreas; Uharek, Lutz; Coutré, Steven; Frankfurt, Olga; Bloor, Adrian; Bosch, Francesc; Furman, Richard R; Kimby, Eva; Gribben, John G; Gobbi, Marco; Dreisbach, Luke; Hurd, David D; Sekeres, Mikkael A; Ferrajoli, Alessandra; Shah, Sheetal; Zhang, Jennie; Moutouh-de Parseval, Laure; Hallek, Michael; Heerema, Nyla A; Stilgenbauer, Stephan; Chanan-Khan, Asher A

    2012-03-01

    Based on clinical activity in phase 2 studies, lenalidomide was evaluated in a phase 2/3 study in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). Following tumor lysis syndrome (TLS) complications, the protocol was amended to a phase 1 study to identify the maximum tolerated dose-escalation level (MTDEL). Fifty-two heavily pretreated patients, 69% with bulky disease and 48% with high-risk genomic abnormalities, initiated lenalidomide at 2.5 mg/day, with dose escalation until the MTDEL or the maximum assigned dose was attained. Lenalidomide was safely titrated to 20 mg/day; the MTDEL was not reached. Most common grade 3-4 adverse events were neutropenia and thrombocytopenia; TLS was mild and rare. The low starting dose and conservative dose escalation strategy resulted in six partial responders and 30 patients obtaining stable disease. In summary, lenalidomide 2.5 mg/day is a safe starting dose that can be titrated up to 20 mg/day in patients with CLL. PMID:21879809

  9. Phase II study of dasatinib in Philadelphia chromosome-negative acute and chronic myeloid diseases, including systemic mastocytosis

    PubMed Central

    Verstovsek, Srdan; Tefferi, Ayalew; Cortes, Jorge; O’Brien, Susan; Garcia-Manero, Guillermo; Pardanani, Animesh; Akin, Cem; Faderl, Stefan; Manshouri, Taghi; Thomas, Deborah; Kantarjian, Hagop

    2016-01-01

    Molecular characterization of Philadelphia chromosome-negative (Ph−) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and PDGFR-B TKs, and is active against cells carrying the mutant KIT-D816V gene. In this phase 2, open-label study, the efficacy of dasatinib (140 mg/day) was investigated in 67 patients with various Ph− myeloid disorders, including SM (N=33; 28 KIT-D816V positive). The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional 9 SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia, hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2. These data show that dasatinib may benefit a selected group of SM patients, primarily by improving their symptoms. PMID:18559612

  10. The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

    PubMed Central

    van Dorp, Suzanne; Resemann, Henrike; te Boome, Liane; Pietersma, Floor; van Baarle, Debbie; Gmelig-Meyling, Frits; de Weger, Roel; Petersen, Eefke; Minnema, Monique; Lokhorst, Henk; Ebeling, Saskia; Beijn, Scott J.P.; Knol, Edward F.; van Dijk, Marijke; Meijer, Ellen; Kuball, Jürgen

    2011-01-01

    Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versus-host disease. Overall response rate was 61%. Only responding patients were found to have increased B-cell numbers prior to treatment. B cells had a naïve-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression. Normal B-cell homeostasis was reestablished in responding patients one year after ritxumab treatment and associated with a significant decline in skin-infiltrating CD8+ T cells, suggesting that host B cells play a role in maintaining pathological CD8+ T-cell responses. Imbalances in B-cell homeostasis could be used to identify patients a priori with a higher chance of response to rituximab treatment (Eudra-CT 2008-004125-42). PMID:21546493

  11. Order-parameter-aided temperature-accelerated sampling for the exploration of crystal polymorphism and solid-liquid phase transitions

    PubMed Central

    Yu, Tang-Qing; Chen, Pei-Yang; Chen, Ming; Samanta, Amit; Vanden-Eijnden, Eric; Tuckerman, Mark

    2014-01-01

    The problem of predicting polymorphism in atomic and molecular crystals constitutes a significant challenge both experimentally and theoretically. From the theoretical viewpoint, polymorphism prediction falls into the general class of problems characterized by an underlying rough energy landscape, and consequently, free energy based enhanced sampling approaches can be brought to bear on the problem. In this paper, we build on a scheme previously introduced by two of the authors in which the lengths and angles of the supercell are targeted for enhanced sampling via temperature accelerated adiabatic free energy dynamics [T. Q. Yu and M. E. Tuckerman, Phys. Rev. Lett. 107, 015701 (2011)]. Here, that framework is expanded to include general order parameters that distinguish different crystalline arrangements as target collective variables for enhanced sampling. The resulting free energy surface, being of quite high dimension, is nontrivial to reconstruct, and we discuss one particular strategy for performing the free energy analysis. The method is applied to the study of polymorphism in xenon crystals at high pressure and temperature using the Steinhardt order parameters without and with the supercell included in the set of collective variables. The expected fcc and bcc structures are obtained, and when the supercell parameters are included as collective variables, we also find several new structures, including fcc states with hcp stacking faults. We also apply the new method to the solid-liquid phase transition in copper at 1300 K using the same Steinhardt order parameters. Our method is able to melt and refreeze the system repeatedly, and the free energy profile can be obtained with high efficiency. PMID:24907992

  12. A Phase I Dose-Escalation Study (ISIDE-BT-1) of Accelerated IMRT With Temozolomide in Patients With Glioblastoma

    SciTech Connect

    Morganti, Alessio G.; Balducci, Mario; Salvati, Maurizio; Esposito, Vincenzo; Romanelli, Pantaleo; Ferro, Marica; Calista, Franco; Digesu, Cinzia; Macchia, Gabriella; Ianiri, Massimo; Deodato, Francesco; Cilla, Savino; Piermattei, Angelo M.P.; Valentini, Vincenzo; Cellini, Numa; Cantore, Gian Paolo

    2010-05-01

    Purpose: To determine the maximum tolerated dose (MTD) of fractionated intensity-modulated radiotherapy (IMRT) with temozolomide (TMZ) in patients with glioblastoma. Methods and Materials: A Phase I clinical trial was performed. Eligible patients had surgically resected or biopsy-proven glioblastoma. Patients started TMZ (75 mg/day) during IMRT and continued for 1 year (150-200 mg/day, Days 1-5 every 28 days) or until disease progression. Clinical target volume 1 (CTV1) was the tumor bed +- enhancing lesion with a 10-mm margin; CTV2 was the area of perifocal edema with a 20-mm margin. Planning target volume 1 (PTV1) and PTV2 were defined as the corresponding CTV plus a 5-mm margin. IMRT was delivered in 25 fractions over 5 weeks. Only the dose for PTV1 was escalated (planned dose escalation: 60 Gy, 62.5 Gy, 65 Gy) while maintaining the dose for PTV2 (45 Gy, 1.8 Gy/fraction). Dose limiting toxicities (DLT) were defined as any treatment-related nonhematological adverse effects rated as Grade >=3 or any hematological toxicity rated as >=4 by Radiation Therapy Oncology Group (RTOG) criteria. Results: Nineteen consecutive glioblastoma were treated with step-and-shoot IMRT, planned with the inverse approach (dose to the PTV1: 7 patients, 60 Gy; 6 patients, 62.5 Gy; 6 patients, 65 Gy). Five coplanar beams were used to cover at least 95% of the target volume with the 95% isodose line. Median follow-up time was 23 months (range, 8-40 months). No patient experienced DLT. Grade 1-2 treatment-related neurologic and skin toxicity were common (11 and 19 patients, respectively). No Grade >2 late neurologic toxicities were noted. Conclusion: Accelerated IMRT to a dose of 65 Gy in 25 fractions is well tolerated with TMZ at a daily dose of 75 mg.

  13. Radiation dose escalation by simultaneous modulated accelerated radiotherapy combined with chemotherapy for esophageal cancer: a phase II study

    PubMed Central

    Zhai, Tiantian; Chang, Daniel; Chen, Zhijian; Huang, Ruihong; Zhang, Wuzhe; Lin, Kun; Guo, Longjia; Zhou, Mingzhen; Li, Dongsheng; Li, Derui; Chen, Chuangzhen

    2016-01-01

    The outcomes for patients with esophageal cancer (EC) underwent standard-dose radical radiotherapy were still disappointing. This phase II study investigated the feasibility, safety and efficacy of radiation dose escalation using simultaneous modulated accelerated radiotherapy (SMART) combined with chemotherapy in 60 EC patients. Radiotherapy consisted of 66Gy at 2.2 Gy/fraction to the gross tumor and 54Gy at 1.8 Gy/fraction to subclinical diseases simultaneously. Chemotherapy including cisplatin and 5fluorouracil were administered to all patients during and after radiotherapy. The data showed that the majority of patients (98.3%) completed the whole course of radiotherapy and concurrent chemotherapy. The most common ≥ grade 3 acute toxicities were neutropenia (16.7%), followed by esophagitis (6.7%) and thrombopenia (5.0%). With a median follow-up of 24 months (5-38) for all patients and 30 months (18-38) for those still alive, 11 patients (18.3%) developed ≥ Grade 3 late toxicities and 2 (3.3%) of them died subsequently due to esophageal hemorrhage. The 1- and 2-year local-regional control, distant metastasis-free survival, disease-free survival and overall survival rates were 87.6% and 78.6%, 86.0% and 80.5%, 75.6% and 64.4%, 86.7% and 72.7%, respectively. SMART combined with concurrent chemotherapy is feasible in EC patients with tolerable acute toxicities. They showed a trend of significant improvements in local-regional control and overall survival. Further follow-up is needed to evaluate the late toxicities. PMID:26992206

  14. Order-parameter-aided temperature-accelerated sampling for the exploration of crystal polymorphism and solid-liquid phase transitions

    SciTech Connect

    Yu, Tang-Qing Vanden-Eijnden, Eric; Chen, Pei-Yang; Chen, Ming; Samanta, Amit; Tuckerman, Mark

    2014-06-07

    The problem of predicting polymorphism in atomic and molecular crystals constitutes a significant challenge both experimentally and theoretically. From the theoretical viewpoint, polymorphism prediction falls into the general class of problems characterized by an underlying rough energy landscape, and consequently, free energy based enhanced sampling approaches can be brought to bear on the problem. In this paper, we build on a scheme previously introduced by two of the authors in which the lengths and angles of the supercell are targeted for enhanced sampling via temperature accelerated adiabatic free energy dynamics [T. Q. Yu and M. E. Tuckerman, Phys. Rev. Lett. 107, 015701 (2011)]. Here, that framework is expanded to include general order parameters that distinguish different crystalline arrangements as target collective variables for enhanced sampling. The resulting free energy surface, being of quite high dimension, is nontrivial to reconstruct, and we discuss one particular strategy for performing the free energy analysis. The method is applied to the study of polymorphism in xenon crystals at high pressure and temperature using the Steinhardt order parameters without and with the supercell included in the set of collective variables. The expected fcc and bcc structures are obtained, and when the supercell parameters are included as collective variables, we also find several new structures, including fcc states with hcp stacking faults. We also apply the new method to the solid-liquid phase transition in copper at 1300 K using the same Steinhardt order parameters. Our method is able to melt and refreeze the system repeatedly, and the free energy profile can be obtained with high efficiency.

  15. Treatment of nasopharyngeal carcinoma using simultaneous modulated accelerated radiation therapy via helical tomotherapy: a phase II study

    PubMed Central

    Du, Lei; Zhang, Xin Xin; Feng, Lin Chun; Chen, Jing; Yang, Jun; Liu, Hai Xia; Xu, Shou Ping; Xie, Chuan Bin

    2016-01-01

    Abstract Background The aim of the study was to evaluate short-term safety and efficacy of simultaneous modulated accelerated radiation therapy (SMART) delivered via helical tomotherapy in patients with nasopharyngeal carcinoma (NPC). Methods Between August 2011 and September 2013, 132 newly diagnosed NPC patients were enrolled for a prospective phase II study. The prescription doses delivered to the gross tumor volume (pGTVnx) and positive lymph nodes (pGTVnd), the high risk planning target volume (PTV1), and the low risk planning target volume (PTV2), were 67.5 Gy (2.25 Gy/F), 60 Gy (2.0 Gy/F), and 54 Gy (1.8 Gy/F), in 30 fractions, respectively. Acute toxicities were evaluated according to the established RTOG/EORTC criteria. This group of patients was compared with the 190 patients in the retrospective P70 study, who were treated between September 2004 and August 2009 with helical tomotherapy, with a dose of 70-74 Gy/33F/6.5W delivered to pGTVnx and pGTVnd. Results The median follow-up was 23.7 (12–38) months. Acute radiation related side-effects were mainly problems graded as 1 or 2. Only a small number of patients suffered from grade 4 leucopenia (4.5%) or thrombocytopenia (2.3%). The local relapse-free survival (LRFS), nodal relapse-free survival (NRFS), local-nodal relapse-free survival (LNRFS), distant metastasis-free survival (DMFS) and overall survival (OS) were 96.7%, 95.5%, 92.2%, 92.7% and 93.2%, at 2 years, respectively, with no significant difference compared with the P70 study. Conclusions Smart delivered via the helical tomotherapy technique appears to be associated with an acceptable acute toxicity profile and favorable short-term outcomes for patients with NPC. Long-term toxicities and patient outcomes are under investigation. PMID:27247555

  16. Cannabidiol Post-Treatment Alleviates Rat Epileptic-Related Behaviors and Activates Hippocampal Cell Autophagy Pathway Along with Antioxidant Defense in Chronic Phase of Pilocarpine-Induced Seizure.

    PubMed

    Hosseinzadeh, Mahshid; Nikseresht, Sara; Khodagholi, Fariba; Naderi, Nima; Maghsoudi, Nader

    2016-04-01

    Abnormal and sometimes severe behavioral and molecular symptoms are usually observed in epileptic humans and animals. To address this issue, we examined the behavioral and molecular aspects of seizure evoked by pilocarpine. Autophagy can promote both cell survival and death, but there are controversial reports about the neuroprotective or neurodegenerative effects of autophagy in seizure. Cannabidiol has anticonvulsant properties in some animal models when used as a pretreatment. In this study, we investigated alteration of seizure scores, autophagy pathway proteins, and antioxidant status in hippocampal cells during the chronic phase of pilocarpine-induced epilepsy after treatment with cannabidiol. Cannabidiol (100 ng, intracerebroventricular injection) delayed the chronic phase of epilepsy. Single administration of cannabidiol during the chronic phase of seizure significantly diminished seizure scores such as mouth clonus, head nodding, monolateral and bilateral forelimb clonus and increased the activity of catalase enzyme and reduced glutathione content. Such a protective effect in the behavioral scores of epileptic rats was also observed after repeated administrations of cannabidiol at the onset of the silent phase. Moreover, the amount of Atg7, conjugation of Atg5/12, Atg12, and LC3II/LC3I ratio increased significantly in epileptic rats treated with repeated injections of cannabidiol. In short, our results suggest that post-treatment of Cannabidiol could enhance the induction of autophagy pathway and antioxidant defense in the chronic phase of epilepsy, which could be considered as the protective mechanisms of cannabidiol in a temporal lobe epilepsy model. PMID:26738731

  17. The effect of phase-I periodontal therapy on pregnancy outcome in chronic periodontitis patients.

    PubMed

    Reddy, B V Ramesh; Tanneeru, S; Chava, V K

    2014-01-01

    Recent studies have shown periodontal diseases (gum diseases) as risk factors for adverse pregnancy outcomes, such as prematurity and low birth weight. Objectives of the present study were to determine the effect of non-surgical periodontal therapy on pregnancy outcomes in women with periodontitis and to detect IgM and IgG status in cord blood during delivery. A total of 20 pregnant women in their 2nd trimester and associated with chronic generalised periodontitis were selected and recruited for the study. They were grouped into two: Group 1 (treatment group) and Group 2 (control). Periodontal parameters of all the subjects were recorded at baseline and after delivery. Data related to weight of the infant and type of delivery was recorded. During the delivery, cord blood was collected for the estimation of IgM and IgG antibodies. All the recordings were subjected for statistical analysis. The study concluded that maternal periodontitis was associated with adverse pregnancy outcomes. PMID:24359045

  18. Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study

    PubMed Central

    Cortes, Jorge E.; Baccarani, Michele; Guilhot, François; Druker, Brian J.; Branford, Susan; Kim, Dong-Wook; Pane, Fabrizio; Pasquini, Ricardo; Goldberg, Stuart L.; Kalaycio, Matt; Moiraghi, Beatriz; Rowe, Jacob M.; Tothova, Elena; De Souza, Carmino; Rudoltz, Marc; Yu, Richard; Krahnke, Tillmann; Kantarjian, Hagop M.; Radich, Jerald P.; Hughes, Timothy P.

    2010-01-01

    Purpose To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Patients and Methods A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. Results At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. Conclusion MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib. PMID:20008622

  19. Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

    PubMed Central

    Garcia-Manero, Guillermo; Gore, Steven D.; Cogle, Christopher; Ward, Renee; Shi, Tao; MacBeth, Kyle J.; Laille, Eric; Giordano, Heidi; Sakoian, Sarah; Jabbour, Elias; Kantarjian, Hagop; Skikne, Barry

    2011-01-01

    Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML. PMID:21576646

  20. Integrity of emotional and motivational states during the prodromal, first-episode, and chronic phases of schizophrenia.

    PubMed

    Yee, Cindy M; Mathis, Kristopher Ian; Sun, Jane C; Sholty, Gretchen L; Lang, Peter J; Bachman, Peter; Williams, Terrance J; Bearden, Carrie E; Cannon, Tyrone D; Green, Michael F; Subotnik, Kenneth L; Ventura, Joseph; Nuechterlein, Keith H

    2010-02-01

    Emotional and motivational dysfunction is fundamental to schizophrenia, and yet, the nature and scope of associated deficits are not well understood. This study assessed the integrity of emotional responding from the perspective of its underlying motivational systems during different phases of schizophrenia. Evaluative, somatic, and autonomic responses were measured during viewing of pictures categorized by emotional content, including threat, mutilation, contamination, illness, pollution, mild erotica, families, food, and nature. Participants were 13 patients at ultra high risk or prodromal for psychosis, 40 first-episode schizophrenia patients, 37 chronic schizophrenia patients, and 74 healthy comparison subjects. Irrespective of phase of illness, schizophrenia patients showed a robust and normal pattern of response across multiple systems, with differential engagement of the defensive and appetitive systems as a function of the motivational significance assigned to specific emotional contexts. Although the integrity of core motivational states also appeared to be intact in prodromal patients, a less consistent pattern of response was observed. As continuing efforts are made to identify emotional and motivational abnormalities in schizophrenia, identified deficits will likely be independent of a fundamental dysfunction in basic emotion and motivation response systems and involve integration with higher order processes. PMID:20141244

  1. Phase I/II Study Evaluating Early Tolerance in Breast Cancer Patients Undergoing Accelerated Partial Breast Irradiation Treated With the MammoSite Balloon Breast Brachytherapy Catheter Using a 2-Day Dose Schedule

    SciTech Connect

    Wallace, Michelle; Martinez, Alvaro; Mitchell, Christina; Chen, Peter Y.; Ghilezan, Mihai; Benitez, Pamela; Brown, Eric; Vicini, Frank

    2010-06-01

    Purpose: Initial Phase I/II results using balloon brachytherapy to deliver accelerated partial breast irradiation (APBI) in 2 days in patients with early-stage breast cancer are presented. Materials and Methods: Between March 2004 and August 2007, 45 patients received adjuvant radiation therapy after lumpectomy with balloon brachytherapy in a Phase I/II trial delivering 2800 cGy in four fractions of 700 cGy. Toxicities were evaluated using the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0 scale and cosmesis was documented at >=6 months. Results: The median age was 66 years (range, 48-83) and median skin spacing was 12 mm (range, 8-24). The median follow-up was 11.4 months (5.4-48 months) with 21 patients (47%) followed >=1 year, 11 (24%) >=2 years, and 7 (16%) >=3 years. At <6 months (n = 45), Grade II toxicity rates were 9% radiation dermatitis, 13% breast pain, 2% edema, and 2% hyperpigmentation. Grade III breast pain was reported in 13% (n = 6). At >=6 months (n = 43), Grade II toxicity rates were: 2% radiation dermatitis, 2% induration, and 2% hypopigmentation. Grade III breast pain was reported in 2%. Infection was 13% (n = 6) at <6 months and 5% (n = 2) at >=6 months. Persistent seroma >=6 months was 30% (n = 13). Fat necrosis developed in 4 cases (2 symptomatic). Rib fractures were seen in 4% (n = 2). Cosmesis was good/excellent in 96% of cases. Conclusions: Treatment with balloon brachytherapy using a 2-day dose schedule resulted acceptable rates of Grade II/III chronic toxicity rates and similar cosmetic results observed with a standard 5-day accelerated partial breast irradiation schedule.

  2. GPU-Accelerated Molecular Dynamics Simulation to Study Liquid Crystal Phase Transition Using Coarse-Grained Gay-Berne Anisotropic Potential.

    PubMed

    Chen, Wenduo; Zhu, Youliang; Cui, Fengchao; Liu, Lunyang; Sun, Zhaoyan; Chen, Jizhong; Li, Yunqi

    2016-01-01

    Gay-Berne (GB) potential is regarded as an accurate model in the simulation of anisotropic particles, especially for liquid crystal (LC) mesogens. However, its computational complexity leads to an extremely time-consuming process for large systems. Here, we developed a GPU-accelerated molecular dynamics (MD) simulation with coarse-grained GB potential implemented in GALAMOST package to investigate the LC phase transitions for mesogens in small molecules, main-chain or side-chain polymers. For identical mesogens in three different molecules, on cooling from fully isotropic melts, the small molecules form a single-domain smectic-B phase, while the main-chain LC polymers prefer a single-domain nematic phase as a result of connective restraints in neighboring mesogens. The phase transition of side-chain LC polymers undergoes a two-step process: nucleation of nematic islands and formation of multi-domain nematic texture. The particular behavior originates in the fact that the rotational orientation of the mesogenes is hindered by the polymer backbones. Both the global distribution and the local orientation of mesogens are critical for the phase transition of anisotropic particles. Furthermore, compared with the MD simulation in LAMMPS, our GPU-accelerated code is about 4 times faster than the GPU version of LAMMPS and at least 200 times faster than the CPU version of LAMMPS. This study clearly shows that GPU-accelerated MD simulation with GB potential in GALAMOST can efficiently handle systems with anisotropic particles and interactions, and accurately explore phase differences originated from molecular structures. PMID:26986851

  3. GPU-Accelerated Molecular Dynamics Simulation to Study Liquid Crystal Phase Transition Using Coarse-Grained Gay-Berne Anisotropic Potential

    PubMed Central

    Cui, Fengchao; Liu, Lunyang; Sun, Zhaoyan; Chen, Jizhong; Li, Yunqi

    2016-01-01

    Gay-Berne (GB) potential is regarded as an accurate model in the simulation of anisotropic particles, especially for liquid crystal (LC) mesogens. However, its computational complexity leads to an extremely time-consuming process for large systems. Here, we developed a GPU-accelerated molecular dynamics (MD) simulation with coarse-grained GB potential implemented in GALAMOST package to investigate the LC phase transitions for mesogens in small molecules, main-chain or side-chain polymers. For identical mesogens in three different molecules, on cooling from fully isotropic melts, the small molecules form a single-domain smectic-B phase, while the main-chain LC polymers prefer a single-domain nematic phase as a result of connective restraints in neighboring mesogens. The phase transition of side-chain LC polymers undergoes a two-step process: nucleation of nematic islands and formation of multi-domain nematic texture. The particular behavior originates in the fact that the rotational orientation of the mesogenes is hindered by the polymer backbones. Both the global distribution and the local orientation of mesogens are critical for the phase transition of anisotropic particles. Furthermore, compared with the MD simulation in LAMMPS, our GPU-accelerated code is about 4 times faster than the GPU version of LAMMPS and at least 200 times faster than the CPU version of LAMMPS. This study clearly shows that GPU-accelerated MD simulation with GB potential in GALAMOST can efficiently handle systems with anisotropic particles and interactions, and accurately explore phase differences originated from molecular structures. PMID:26986851

  4. Accelerated test methods for life prediction of hermetic motor insulation systems exposed to alternative refrigerant/lubricant mixtures. Phase 3: Reproducibility and discrimination testing. Final report

    SciTech Connect

    Ellis, P.F. II; Ferguson, A.F.; Fuentes, K.T.

    1996-05-06

    In 1992, the Air-Conditioning and Refrigeration Technology Institute, Inc. (ARTI) contracted Radian Corporation to ascertain whether an improved accelerated test method or procedure could be developed that would allow prediction of the life of motor insulation materials used in hermetic motors for air-conditioning and refrigeration equipment operated with alternative refrigerant/lubricant mixtures. This report presents the results of phase three concerning the reproducibility and discrimination testing.

  5. Interleukin-1β and Interleukin-6 in Arthritis Animal Models: Roles in the Early Phase of Transition from Acute to Chronic Inflammation and Relevance for Human Rheumatoid Arthritis

    PubMed Central

    Ferraccioli, Gianfranco; Bracci-Laudiero, Luisa; Alivernini, Stefano; Gremese, Elisa; Tolusso, Barbara; De Benedetti, Fabrizio

    2010-01-01

    Tumor necrosis factor-α (TNF-α) is the major target of the therapeutic approach in rheumatoid arthritis. A key issue in the approach to chronic arthritis is the understanding of the crucial molecules driving the transition from the acute phase to the chronic irreversible phase of the disease. In this review we analyzed five experimental arthritis animal models (antigen-induced arthritis, adjuvant-induced arthritis, streptococcal cell wall arthritis, collagen-induced arthritis and SKG) considered as possible scenarios to facilitate interpretation of the biology of human rheumatoid arthritis. The SKG model is strictly dependent on interleukin (IL)-6. In the other models, IL-1β and IL-6, more than TNF-α, appear to be relevant in driving the transition, which suggests that these should be the targets of an early intervention to stop the course toward the chronic form of the disease. PMID:20683549

  6. Tipifarnib and Bortezomib in Treating Patients With Acute Leukemia or Chronic Myelogenous Leukemia in Blast Phase

    ClinicalTrials.gov

    2015-04-14

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Blastic Phase; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Disease; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  7. Stochastic shock response spectrum decomposition method based on probabilistic definitions of temporal peak acceleration, spectral energy, and phase lag distributions of mechanical impact pyrotechnic shock test data

    NASA Astrophysics Data System (ADS)

    Hwang, James Ho-Jin; Duran, Adam

    2016-08-01

    Most of the times pyrotechnic shock design and test requirements for space systems are provided in Shock Response Spectrum (SRS) without the input time history. Since the SRS does not describe the input or the environment, a decomposition method is used to obtain the source time history. The main objective of this paper is to develop a decomposition method producing input time histories that can satisfy the SRS requirement based on the pyrotechnic shock test data measured from a mechanical impact test apparatus. At the heart of this decomposition method is the statistical representation of the pyrotechnic shock test data measured from the MIT Lincoln Laboratory (LL) designed Universal Pyrotechnic Shock Simulator (UPSS). Each pyrotechnic shock test data measured at the interface of a test unit has been analyzed to produce the temporal peak acceleration, Root Mean Square (RMS) acceleration, and the phase lag at each band center frequency. Maximum SRS of each filtered time history has been calculated to produce a relationship between the input and the response. Two new definitions are proposed as a result. The Peak Ratio (PR) is defined as the ratio between the maximum SRS and the temporal peak acceleration at each band center frequency. The ratio between the maximum SRS and the RMS acceleration is defined as the Energy Ratio (ER) at each band center frequency. Phase lag is estimated based on the time delay between the temporal peak acceleration at each band center frequency and the peak acceleration at the lowest band center frequency. This stochastic process has been applied to more than one hundred pyrotechnic shock test data to produce probabilistic definitions of the PR, ER, and the phase lag. The SRS is decomposed at each band center frequency using damped sinusoids with the PR and the decays obtained by matching the ER of the damped sinusoids to the ER of the test data. The final step in this stochastic SRS decomposition process is the Monte Carlo (MC

  8. Chronic Artificial Blue-Enriched White Light Is an Effective Countermeasure to Delayed Circadian Phase and Neurobehavioral Decrements

    PubMed Central

    Najjar, Raymond P.; Wolf, Luzian; Taillard, Jacques; Schlangen, Luc J. M.; Salam, Alex

    2014-01-01

    Studies in Polar Base stations, where personnel have no access to sunlight during winter, have reported circadian misalignment, free-running of the sleep-wake rhythm, and sleep problems. Here we tested light as a countermeasure to circadian misalignment in personnel of the Concordia Polar Base station during the polar winter. We hypothesized that entrainment of the circadian pacemaker to a 24-h light-dark schedule would not occur in all crew members (n = 10) exposed to 100–300 lux of standard fluorescent white (SW) light during the daytime, and that chronic non-time restricted daytime exposure to melanopsin-optimized blue-enriched white (BE) light would establish an a stable circadian phase, in participants, together with increased cognitive performance and mood levels. The lighting schedule consisted of an alternation between SW lighting (2 weeks), followed by a BE lighting (2 weeks) for a total of 9 weeks. Rest-activity cycles assessed by actigraphy showed a stable rest-activity pattern under both SW and BE light. No difference was found between light conditions on the intra-daily stability, variability and amplitude of activity, as assessed by non-parametric circadian analysis. As hypothesized, a significant delay of about 30 minutes in the onset of melatonin secretion occurred with SW, but not with BE light. BE light significantly enhanced well being and alertness compared to SW light. We propose that the superior efficacy of blue-enriched white light versus standard white light involves melanopsin-based mechanisms in the activation of the non-visual functions studied, and that their responses do not dampen with time (over 9-weeks). This work could lead to practical applications of light exposure in working environment where background light intensity is chronically low to moderate (polar base stations, power plants, space missions, etc.), and may help design lighting strategies to maintain health, productivity, and personnel safety. PMID:25072880

  9. A phase II study of bortezomib plus prednisone for initial therapy of chronic graft-versus-host disease.

    PubMed

    Herrera, Alex F; Kim, Haesook T; Bindra, Bhavjot; Jones, Kyle T; Alyea, Edwin P; Armand, Philippe; Cutler, Corey S; Ho, Vincent T; Nikiforow, Sarah; Blazar, Bruce R; Ritz, Jerome; Antin, Joseph H; Soiffer, Robert J; Koreth, John

    2014-11-01

    Chronic graft-versus-host disease (GVHD) induces significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Corticosteroids are standard initial therapy, despite limited efficacy and long-term toxicity. Based on our experience using bortezomib as effective acute GVHD prophylaxis, we hypothesized that proteasome-inhibition would complement the immunomodulatory effects of corticosteroids to improve outcomes in chronic GVHD (cGVHD). We undertook a single-arm phase II trial of bortezomib plus prednisone for initial therapy of cGVHD. Bortezomib was administered at 1.3 mg/m(2) i.v. on days 1, 8, 15, and 22 of each 35-day cycle for 3 cycles (15 weeks). Prednisone was dosed at .5 to 1 mg/kg/day, with a suggested taper after cycle 1. All 22 enrolled participants were evaluable for toxicity; 20 were evaluable for response. Bortezomib plus prednisone therapy was well tolerated, with 1 occurrence of grade 3 sensory peripheral neuropathy possibly related to bortezomib. The overall response rate at week 15 in evaluable participants was 80%, including 2 (10%) complete and 14 (70%) partial responses. The organ-specific complete response rate was 73% for skin, 53% for liver, 75% for gastrointestinal tract, and 33% for joint, muscle, or fascia involvement. The median prednisone dose decreased from 50 mg/day to 20 mg/day at week 15 (P < .001). The combination of bortezomib and prednisone for initial treatment of cGVHD is feasible and well tolerated. We observed a high response rate to combined bortezomib and prednisone therapy; however, in this single-arm study, we could not directly measure the impact of bortezomib. Proteasome inhibition may offer benefit in the treatment of cGVHD and should be further evaluated. PMID:25017765

  10. In Situ Characterization of Splenic Brucella melitensis Reservoir Cells during the Chronic Phase of Infection in Susceptible Mice

    PubMed Central

    Hanot Mambres, Delphine; Machelart, Arnaud; Vanderwinden, Jean-Marie; De Trez, Carl; Ryffel, Bernhard

    2015-01-01

    Brucella are facultative intracellular Gram-negative coccobacilli that chronically infect humans as well as domestic and wild-type mammals, and cause brucellosis. Alternatively activated macrophages (M2a) induced by IL-4/IL-13 via STAT6 signaling pathways have been frequently described as a favorable niche for long-term persistence of intracellular pathogens. Based on the observation that M2a-like macrophages are induced in the spleen during the chronic phase of B. abortus infection in mice and are strongly infected in vitro, it has been suggested that M2a macrophages could be a potential in vivo niche for Brucella. In order to test this hypothesis, we used a model in which infected cells can be observed directly in situ and where the differentiation of M2a macrophages is favored by the absence of an IL-12-dependent Th1 response. We performed an in situ analysis by fluorescent microscopy of the phenotype of B. melitensis infected spleen cells from intranasally infected IL-12p40-/- BALB/c mice and the impact of STAT6 deficiency on this phenotype. Most of the infected spleen cells contained high levels of lipids and expressed CD11c and CD205 dendritic cell markers and Arginase1, but were negative for the M2a markers Fizz1 or CD301. Furthermore, STAT6 deficiency had no effect on bacterial growth or the reservoir cell phenotype in vivo, leading us to conclude that, in our model, the infected cells were not Th2-induced M2a macrophages. This characterization of B. melitensis reservoir cells could provide a better understanding of Brucella persistence in the host and lead to the design of more efficient therapeutic strategies. PMID:26376185

  11. Chronic artificial blue-enriched white light is an effective countermeasure to delayed circadian phase and neurobehavioral decrements.

    PubMed

    Najjar, Raymond P; Wolf, Luzian; Taillard, Jacques; Schlangen, Luc J M; Salam, Alex; Cajochen, Christian; Gronfier, Claude

    2014-01-01

    Studies in Polar Base stations, where personnel have no access to sunlight during winter, have reported circadian misalignment, free-running of the sleep-wake rhythm, and sleep problems. Here we tested light as a countermeasure to circadian misalignment in personnel of the Concordia Polar Base station during the polar winter. We hypothesized that entrainment of the circadian pacemaker to a 24-h light-dark schedule would not occur in all crew members (n = 10) exposed to 100-300 lux of standard fluorescent white (SW) light during the daytime, and that chronic non-time restricted daytime exposure to melanopsin-optimized blue-enriched white (BE) light would establish an a stable circadian phase, in participants, together with increased cognitive performance and mood levels. The lighting schedule consisted of an alternation between SW lighting (2 weeks), followed by a BE lighting (2 weeks) for a total of 9 weeks. Rest-activity cycles assessed by actigraphy showed a stable rest-activity pattern under both SW and BE light. No difference was found between light conditions on the intra-daily stability, variability and amplitude of activity, as assessed by non-parametric circadian analysis. As hypothesized, a significant delay of about 30 minutes in the onset of melatonin secretion occurred with SW, but not with BE light. BE light significantly enhanced well being and alertness compared to SW light. We propose that the superior efficacy of blue-enriched white light versus standard white light involves melanopsin-based mechanisms in the activation of the non-visual functions studied, and that their responses do not dampen with time (over 9-weeks). This work could lead to practical applications of light exposure in working environment where background light intensity is chronically low to moderate (polar base stations, power plants, space missions, etc.), and may help design lighting strategies to maintain health, productivity, and personnel safety. PMID:25072880

  12. Intra-cyclic distance per stroke phase, velocity fluctuations and acceleration time ratio of a breaststroker's hip: a comparison between elite and nonelite swimmers at different race paces.

    PubMed

    Leblanc, H; Seifert, L; Tourny-Chollet, C; Chollet, D

    2007-02-01

    The aim of this study was to compare the intra-cyclic velocity graphs of breaststroke swimmers at two skill levels in relation to their movement phases. Two groups of nine male swimmers were videotaped underwater at three swimming race paces corresponding to their actual competitive times for the 200-m, 100-m and 50-m breaststroke. Their forward intra-cyclic hip velocity was recorded with a velocity-meter. The breaststroke cycle was divided into four phases: leg propulsion, leg-arm lag phase, arm propulsion, and arm and leg recovery. From the velocity-time data, the following parameters were computed: an index of velocity fluctuations (IVF), the distance covered during each stroke phase, and an acceleration-deceleration time ratio (ADTR). The main results showed that in both groups of swimmers, when the race pace increased, the distance covered during the leg-arm lag phase decreased, while the other swimming phases remained stable. When expressed in relative values, the percentage of distance covered during the leg-arm lag phase decreased. In nonelite swimmers, the percentage of distance covered in the other stroke phases increased significantly, while only a tendency was noted in the elite group. Elite swimmers demonstrated a higher ADTR at the 50-m pace than at their 100-m and 200-m paces. An inter-group comparison showed that elite swimmers had higher values for the IVF and ADTR, which indicated their capacity to accelerate to boost the swim and highlighted the relevancy of these factors to discriminate skill level. PMID:16835822

  13. Telemetry system for the transmission of data from projectiles during the acceleration phase in the gun barrel

    NASA Astrophysics Data System (ADS)

    Wegner, V.

    1984-05-01

    A ballistic telemetry system reliable for accelerations up 100,00 g was developed. It consist of industrially produced thick layer 10 mm x 10 mm components which can be assembled to a telemetry system according to the unit box principle depending on user requirements. The electronic circuits are fixed in the gun barrel with epoxy resin. The short time phenomena and the limited space require analog data transmission. The 30 mm barrels used for interior ballistics tests and the block diagram of the measuring system are described. The results of the axial acceleration measurements show very clearly the effect of the injection resistance at the beginning of the projectile motion, and by integration provide the temporal evolution of the projectile velocity in the barrel. The measurements of the transverse acceleration clearly show the effect of the barrel curvature and the gravitational force. A wire and an optoelectronic transmission system were developed.

  14. GTI-2040 in Treating Patients With Relapsed, Refractory, or High-Risk Acute Leukemia, High-Grade Myelodysplastic Syndromes, or Refractory or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-12-03

    Acute Undifferentiated Leukemia; Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(15;17)(q22;q12); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Blastic Phase Chronic Myelogenous Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes; Untreated Adult Acute Lymphoblastic Leukemia; Untreated Adult Acute Myeloid Leukemia

  15. Novel drug candidates for blast phase chronic myeloid leukemia from high-throughput drug sensitivity and resistance testing

    PubMed Central

    Pietarinen, P O; Pemovska, T; Kontro, M; Yadav, B; Mpindi, J P; Andersson, E I; Majumder, M M; Kuusanmäki, H; Koskenvesa, P; Kallioniemi, O; Wennerberg, K; Heckman, C A; Mustjoki, S; Porkka, K

    2015-01-01

    Chronic myeloid leukemia in blast crisis (CML BC) remains a challenging disease to treat despite the introduction and advances in tyrosine kinase inhibitor (TKI) therapy. In this study we set out to identify novel candidate drugs for CML BC by using an unbiased high-throughput drug testing platform. We used three CML cell lines representing different types of CML blast phases (K562, EM-2 and MOLM-1) and primary leukemic cells from three CML BC patients. Profiling of drug responses was performed with a drug sensitivity and resistance testing platform comprising 295 anticancer agents. Overall, drug sensitivity scores and the drug response profiles of cell line and primary cell samples correlated well and were distinct from other types of leukemia samples. The cell lines were highly sensitive to TKIs and the clinically TKI-resistant patient samples were also resistant ex vivo. Comparison of cell line and patient sample data identified new candidate drugs for CML BC, such as vascular endothelial growth factor receptor and nicotinamide phosphoribosyltransferase inhibitors. Our results indicate that these drugs in particular warrant further evaluation by analyzing a larger set of primary patient samples. The results also pave way for designing rational combination therapies. PMID:25933373

  16. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wen, Sijin; Wierda, William G.; O'Brien, Susan M.; Faderl, Stefan; Sargent, Rachel; Burger, Jan A.; Ferrajoli, Alessandra

    2013-01-01

    Purpose Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL. Patients and Methods Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m2 intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically. Results The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study. Conclusion The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation. PMID:23270003

  17. Array comparative genomic hybridization and sequencing of 23 genes in 80 patients with myelofibrosis at chronic or acute phase.

    PubMed

    Brecqueville, Mandy; Rey, Jérôme; Devillier, Raynier; Guille, Arnaud; Gillet, Rémi; Adélaide, José; Gelsi-Boyer, Véronique; Arnoulet, Christine; Chaffanet, Max; Mozziconacci, Marie-Joelle; Vey, Norbert; Birnbaum, Daniel; Murati, Anne

    2014-01-01

    Myelofibrosis is a myeloproliferative neoplasm that occurs de novo (primary myelofibrosis) or results from the progression of polycythemia vera or essential thrombocytemia (hereafter designated as secondary myelofibrosis or post-polycythemia vera/ essential thrombocythemia myelofibrosis). To progress in the understanding of myelofibrosis and to find molecular prognostic markers we studied 104 samples of primary and secondary myelofibrosis at chronic (n=68) and acute phases (n=12) from 80 patients, by using array-comparative genomic hybridization and sequencing of 23 genes (ASXL1, BMI1, CBL, DNMT3A, EZH2, IDH1/2, JAK2, K/NRAS, LNK, MPL, NF1, PPP1R16B, PTPN11, RCOR1, SF3B1, SOCS2, SRSF2, SUZ12, TET2, TP53, TRPS1). We found copy number aberrations in 54% of samples, often involving genes with a known or potential role in leukemogenesis. We show that cases carrying a del(20q), del(17) or del(12p) evolve in acute myeloid leukemia (P=0.03). We found that 88% of the cases were mutated, mainly in signaling pathway (JAK2 69%, NF1 6%) and epigenetic genes (ASXL1 26%, TET2 14%, EZH2 8%). Overall survival was poor in patients with more than one mutation (P=0.001) and in patients with JAK2/ASXL1 mutations (P=0.02). Our study highlights the heterogeneity of myelofibrosis, and points to several interesting copy number aberrations and genes with diagnostic and prognostic impact. PMID:23996481

  18. NOTE: A software tool for 2D/3D visualization and analysis of phase-space data generated by Monte Carlo modelling of medical linear accelerators

    NASA Astrophysics Data System (ADS)

    Neicu, Toni; Aljarrah, Khaled M.; Jiang, Steve B.

    2005-10-01

    A computer program has been developed for novel 2D/3D visualization and analysis of the phase-space parameters of Monte Carlo simulations of medical accelerator radiation beams. The software is written in the IDL language and reads the phase-space data generated in the BEAMnrc/BEAM Monte Carlo code format. Contour and colour-wash plots of the fluence, mean energy, energy fluence, mean angle, spectra distribution, energy fluence distribution, angular distribution, and slices and projections of the 3D ZLAST distribution can be calculated and displayed. Based on our experience of using it at Massachusetts General Hospital, the software has proven to be a useful tool for analysis and verification of the Monte Carlo generated phase-space files. The software is in the public domain.

  19. GPU-accelerated 3D phase-field simulations of dendrite competitive growth during directional solidification of binary alloy

    NASA Astrophysics Data System (ADS)

    Sakane, S.; Takaki, T.; Ohno, M.; Shimokawabe, T.; Aoki, T.

    2015-06-01

    Phase-field method has emerged as the most powerful numerical scheme to simulate dendrite growth. However, most phase-field simulations of dendrite growth performed so far are limited to two-dimension or single dendrite in three-dimension because of the large computational cost involved. To express actual solidification microstructures, multiple dendrites with different preferred growth directions should be computed at the same time. In this study, in order to enable large-scale phase-field dendrite growth simulations, we developed a phase-field code using multiple graphics processing units in which a quantitative phase-field method for binary alloy solidification and moving frame algorithm for directional solidification were employed. First, we performed strong and weak scaling tests for the developed parallel code. Then, dendrite competitive growth simulations in three-dimensional binary alloy bicrystal were performed and the dendrite interactions in three-dimensional space were investigated.

  20. Epidemiologic investigation to identify chronic health effects of ambient air pollutants in Southern California. Phase 2. Final report

    SciTech Connect

    Peters, J.M.

    1997-09-01

    The Phase II cross-sectional study was conducted to provide early information on the possible chronic effects of air pollution in Southern California children and to determine, if effects are found, which pollutant (or pollutants) is responsible. Annual questionnaires were completed on these children which covered health history (including history of wheezing, asthma, bronchitis, pneumonia and other respiratory conditions), residential history, housing characteristics (such as heating and air conditioning practices), and history of exposure to other possibly harmful agents, such as tobacco smoke (both active and passive smoking). In addition, the usual physical and outdoor/indoor activity of each subject was ascertained. The lung function of each subject was assessed annually to determine ventilatory capacity. School absenses were recorded to determine frequency and severity of respiratory illnesses. After the development and deployment of the instrumentation, monitoring for air pollutants was conducted for the twelve communities, the schools and a sample of the subject`s residences. Ozone, PM{sub 10}, PM{sub 2.5}, NO{sub 2}, and acid vapor concentrations were determined at the community level, and indoor ozone concentrations were measured at schools. A sample of homes was measured for indoor ozone, PM{sub 10}, PM{sub 2.5}, acid and formaldehyde. The information from the questionnaire on residential history allowed for the construction of an estimated life-time exposure level for the different pollutants based on existing data. The information collected at schools and homes allowed for adjustments for exposures based on whether the subjects were indoors or outdoors.

  1. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia

    PubMed Central

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Levato, Luciano; D’Adda, Mariella; Stagno, Fabio; Tiribelli, Mario; Salvucci, Marzia; Fava, Carmen; Martino, Bruno; Cedrone, Michele; Bocchia, Monica; Trabacchi, Elena; Cavazzini, Francesco; Usala, Emilio; Rossi, Antonella Russo; Bochicchio, Maria Teresa; Soverini, Simona; Alimena, Giuliana; Cavo, Michele; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

    2015-01-01

    Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052). PMID:26113419

  2. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia.

    PubMed

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Levato, Luciano; D'Adda, Mariella; Stagno, Fabio; Tiribelli, Mario; Salvucci, Marzia; Fava, Carmen; Martino, Bruno; Cedrone, Michele; Bocchia, Monica; Trabacchi, Elena; Cavazzini, Francesco; Usala, Emilio; Russo Rossi, Antonella; Bochicchio, Maria Teresa; Soverini, Simona; Alimena, Giuliana; Cavo, Michele; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

    2015-09-01

    Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052). PMID:26113419

  3. Engineering deceleration and acceleration of soliton emitted from Airy pulse with quadratic phase modulation in optical fibers without high-order effects

    NASA Astrophysics Data System (ADS)

    Zhang, Lifu; Liu, Kun; Zhong, Haizhe; Zhang, Jinggui; Deng, Jianqin; Li, Ying; Fan, Dianyuan

    2015-07-01

    Soliton propagation direction can be engineered in optical fibers in the presence of high-order effects (HOEs). It is well known that Raman effects can decelerate the soliton. Here we investigate the manipulation of the deceleration or acceleration of soliton emitted from Airy pulse whose spectrum is imposed an initial quadratic phase modulation (QPM) in optical fibers in the absence of HOEs. We show that, under the action of the anomalous second-order dispersion (SOD) and Kerr nonlinearity, Airy pulse with QPM is able to emit soliton with acceleration or deceleration depending on whether the QPM is negative or positive, and at a rate that is determined by the magnitude of QPM. The reason is that the acceleration behaviors of incident Airy pulse is altered depending on whether SOD and QPM have the same or opposite signs. Our study shows the possibility of controlling and manipulating the soliton propagation and interaction in optical fibers without HOEs, by purposely choosing appropriate QPM parameter of an Airy pulse.

  4. Engineering deceleration and acceleration of soliton emitted from Airy pulse with quadratic phase modulation in optical fibers without high-order effects.

    PubMed

    Zhang, Lifu; Liu, Kun; Zhong, Haizhe; Zhang, Jinggui; Deng, Jianqin; Li, Ying; Fan, Dianyuan

    2015-01-01

    Soliton propagation direction can be engineered in optical fibers in the presence of high-order effects (HOEs). It is well known that Raman effects can decelerate the soliton. Here we investigate the manipulation of the deceleration or acceleration of soliton emitted from Airy pulse whose spectrum is imposed an initial quadratic phase modulation (QPM) in optical fibers in the absence of HOEs. We show that, under the action of the anomalous second-order dispersion (SOD) and Kerr nonlinearity, Airy pulse with QPM is able to emit soliton with acceleration or deceleration depending on whether the QPM is negative or positive, and at a rate that is determined by the magnitude of QPM. The reason is that the acceleration behaviors of incident Airy pulse is altered depending on whether SOD and QPM have the same or opposite signs. Our study shows the possibility of controlling and manipulating the soliton propagation and interaction in optical fibers without HOEs, by purposely choosing appropriate QPM parameter of an Airy pulse. PMID:26173387

  5. Immunodominance: a new hypothesis to explain parasite escape and host/parasite equilibrium leading to the chronic phase of Chagas' disease?

    PubMed

    Rodrigues, M M; Alencar, B C G de; Claser, C; Tzelepis, F

    2009-03-01

    Intense immune responses are observed during human or experimental infection with the digenetic protozoan parasite Trypanosoma cruzi. The reasons why such immune responses are unable to completely eliminate the parasites are unknown. The survival of the parasite leads to a parasite-host equilibrium found during the chronic phase of chagasic infection in most individuals. Parasite persistence is recognized as the most likely cause of the chagasic chronic pathologies. Therefore, a key question in Chagas' disease is to understand how this equilibrium is established and maintained for a long period. Understanding the basis for this equilibrium may lead to new approaches to interventions that could help millions of individuals at risk for infection or who are already infected with T. cruzi. Here, we propose that the phenomenon of immunodominance may be significant in terms of regulating the host-parasite equilibrium observed in Chagas' disease. T. cruzi infection restricts the repertoire of specific T cells generating, in some cases, an intense immunodominant phenotype and in others causing a dramatic interference in the response to distinct epitopes. This immune response is sufficiently strong to maintain the host alive during the acute phase carrying them to the chronic phase where transmission usually occurs. At the same time, immunodominance interferes with the development of a higher and broader immune response that could be able to completely eliminate the parasite. Based on this, we discuss how we can interfere with or take advantage of immunodominance in order to provide an immunotherapeutic alternative for chagasic individuals. PMID:19287899

  6. Geometrically undistorted MRI in the presence of field inhomogeneities using compressed sensing accelerated broadband 3D phase encoded turbo spin-echo imaging

    NASA Astrophysics Data System (ADS)

    van Gorp, Jetse S.; Bakker, Chris J. G.; Bouwman, Job G.; Smink, Jouke; Zijlstra, Frank; Seevinck, Peter R.

    2015-01-01

    In this study, we explore the potential of compressed sensing (CS) accelerated broadband 3D phase-encoded turbo spin-echo (3D-PE-TSE) for the purpose of geometrically undistorted imaging in the presence of field inhomogeneities. To achieve this goal 3D-PE-SE and 3D-PE-TSE sequences with broadband rf pulses and dedicated undersampling patterns were implemented on a clinical scanner. Additionally, a 3D multi-spectral spin-echo (ms3D-SE) sequence was implemented for reference purposes. First, we demonstrated the influence of susceptibility induced off-resonance effects on the spatial encoding of broadband 3D-SE, ms3D-SE, 3D-PE-SE and 3D-PE-TSE using a grid phantom containing a titanium implant (Δχ = 182 ppm) with x-ray CT as a gold standard. These experiments showed that the spatial encoding of 3D-PE-(T)SE was unaffected by susceptibility induced off-resonance effects, which caused geometrical distortions and/or signal hyper-intensities in broadband 3D-SE and, to a lesser extent, in ms3D-SE frequency encoded methods. Additionally, an SNR analysis was performed and the temporally resolved signal of 3D-PE-(T)SE sequences was exploited to retrospectively decrease the acquisition bandwidth and obtain field offset maps. The feasibility of CS acceleration was studied retrospectively and prospectively for the 3D-PE-SE sequence using an existing CS algorithm adapted for the reconstruction of 3D data with undersampling in all three phase encoded dimensions. CS was combined with turbo-acceleration by variable density undersampling and spherical stepwise T2 weighting by randomly sorting consecutive echoes in predefined spherical k-space layers. The CS-TSE combination resulted in an overall acceleration factor of 60, decreasing the original 3D-PE-SE scan time from 7 h to 7 min. Finally, CS accelerated 3D-PE-TSE in vivo images of a titanium screw were obtained within 10 min using a micro-coil demonstrating the feasibility of geometrically undistorted MRI near severe

  7. Geometrically undistorted MRI in the presence of field inhomogeneities using compressed sensing accelerated broadband 3D phase encoded turbo spin-echo imaging.

    PubMed

    van Gorp, Jetse S; Bakker, Chris J G; Bouwman, Job G; Smink, Jouke; Zijlstra, Frank; Seevinck, Peter R

    2015-01-21

    In this study, we explore the potential of compressed sensing (CS) accelerated broadband 3D phase-encoded turbo spin-echo (3D-PE-TSE) for the purpose of geometrically undistorted imaging in the presence of field inhomogeneities. To achieve this goal 3D-PE-SE and 3D-PE-TSE sequences with broadband rf pulses and dedicated undersampling patterns were implemented on a clinical scanner. Additionally, a 3D multi-spectral spin-echo (ms3D-SE) sequence was implemented for reference purposes. First, we demonstrated the influence of susceptibility induced off-resonance effects on the spatial encoding of broadband 3D-SE, ms3D-SE, 3D-PE-SE and 3D-PE-TSE using a grid phantom containing a titanium implant (Δχ = 182 ppm) with x-ray CT as a gold standard. These experiments showed that the spatial encoding of 3D-PE-(T)SE was unaffected by susceptibility induced off-resonance effects, which caused geometrical distortions and/or signal hyper-intensities in broadband 3D-SE and, to a lesser extent, in ms3D-SE frequency encoded methods. Additionally, an SNR analysis was performed and the temporally resolved signal of 3D-PE-(T)SE sequences was exploited to retrospectively decrease the acquisition bandwidth and obtain field offset maps. The feasibility of CS acceleration was studied retrospectively and prospectively for the 3D-PE-SE sequence using an existing CS algorithm adapted for the reconstruction of 3D data with undersampling in all three phase encoded dimensions. CS was combined with turbo-acceleration by variable density undersampling and spherical stepwise T2 weighting by randomly sorting consecutive echoes in predefined spherical k-space layers. The CS-TSE combination resulted in an overall acceleration factor of 60, decreasing the original 3D-PE-SE scan time from 7 h to 7 min. Finally, CS accelerated 3D-PE-TSE in vivo images of a titanium screw were obtained within 10 min using a micro-coil demonstrating the feasibility of geometrically undistorted MRI near severe

  8. A three-dimensional phase field model coupled with lattice kinetics solver for modeling crystal growth in furnaces with accelerated crucible rotation and traveling magnetic field

    SciTech Connect

    Lin, Guang; Bao, Jie; Xu, Zhijie

    2014-11-01

    In this study, which builds on other related work, we present a new three-dimensional numerical model for crystal growth in a vertical solidification system. This model accounts for buoyancy, accelerated crucible rotation technique (ACRT), and traveling magnetic field (TMF) induced convective flow and their effect on crystal growth and the chemical component's transport process. The evolution of the crystal growth interface is simulated using the phase field method. A semi-implicit lattice kinetics solver based on the Boltzmann equation is employed to model the unsteady incompressible flow. A one-way coupled concentration transport model is used to simulate the component fraction variation in both the liquid and solid phases, which can be used to check the quality of the crystal growth.

  9. Linear Accelerators

    NASA Astrophysics Data System (ADS)

    Sidorin, Anatoly

    2010-01-01

    In linear accelerators the particles are accelerated by either electrostatic fields or oscillating Radio Frequency (RF) fields. Accordingly the linear accelerators are divided in three large groups: electrostatic, induction and RF accelerators. Overview of the different types of accelerators is given. Stability of longitudinal and transverse motion in the RF linear accelerators is briefly discussed. The methods of beam focusing in linacs are described.

  10. Linear Accelerators

    SciTech Connect

    Sidorin, Anatoly

    2010-01-05

    In linear accelerators the particles are accelerated by either electrostatic fields or oscillating Radio Frequency (RF) fields. Accordingly the linear accelerators are divided in three large groups: electrostatic, induction and RF accelerators. Overview of the different types of accelerators is given. Stability of longitudinal and transverse motion in the RF linear accelerators is briefly discussed. The methods of beam focusing in linacs are described.

  11. Twisted waveguide accelerating structure.

    SciTech Connect

    Kang, Y. W.

    2000-08-15

    A hollow waveguide with a uniform cross section may be used for accelerating charged particles if the phase velocity of an accelerating mode is equal to or less than the free space speed of light. Regular straight hollow waveguides have phase velocities of propagating electromagnetic waves greater than the free-space speed of light. if the waveguide is twisted, the phase velocities of the waveguide modes become slower. The twisted waveguide structure has been modeled and computer simulated in 3-D electromagnetic solvers to show the slow-wave properties for the accelerating mode.

  12. Accelerated versus conventional fractionated postoperative radiotherapy for advanced head and neck cancer: Results of a multicenter Phase III study

    SciTech Connect

    Sanguineti, Giuseppe . E-mail: gisangui@utmb.edu; Richetti, Antonella; Bignardi, Mario; Corvo, Renzo; Gabriele, Pietro; Sormani, Maria Pia; Antognoni, Paolo

    2005-03-01

    Purpose: To determine whether, in the postoperative setting, accelerated fractionation (AF) radiotherapy (RT) yields a superior locoregional control rate compared with conventional fractionation (CF) RT in locally advanced squamous cell carcinomas of the oral cavity, oropharynx, larynx, or hypopharynx. Methods and materials: Patients from four institutions with one or more high-risk features (pT4, positive resection margins, pN >1, perineural/lymphovascular invasion, extracapsular extension, subglottic extension) after surgery were randomly assigned to either RT with one daily session of 2 Gy up to 60 Gy in 6 weeks or AF. Accelerated fractionation consisted of a 'biphasic concomitant boost' schedule, with the boost delivered during the first and last weeks of treatment, to deliver 64 Gy in 5 weeks. Informed consent was obtained. The primary endpoint of the study was locoregional control. Analysis was on an intention-to-treat basis. Results: From March 1994 to August 2000, 226 patients were randomized. At a median follow-up of 30.6 months (range, 0-110 months), 2-year locoregional control estimates were 80% {+-} 4% for CF and 78% {+-} 5% for AF (p = 0.52), and 2-year overall survival estimates were 67% {+-} 5% for CF and 64% {+-} 5% for AF (p = 0.84). The lack of difference in outcome between the two treatment arms was confirmed by multivariate analysis. However, interaction analysis with median values as cut-offs showed a trend for improved locoregional control for those patients who had a delay in starting RT and who were treated with AF compared with those with a similar delay but who were treated with CF (hazard ratio = 0.5, 95% confidence interval 0.2-1.1). Fifty percent of patients treated with AF developed confluent mucositis, compared with only 27% of those treated with CF (p = 0.006). However, mucositis duration was not different between arms. Although preliminary, actuarial Grade 3+ late toxicity estimates at 2 years were 18% {+-} 4% and 27% {+-} 6% for CF

  13. Late course accelerated hyperfractionated radiotherapy plus concurrent chemotherapy for squamous cell carcinoma of the esophagus: A phase III randomized study

    SciTech Connect

    Zhao Kuaile; Shi Xuehui; Jiang Guoliang . E-mail: jianggl@21cn.com; Yao Weiqiang; Guo Xiaomao; Wu Gendi; Zhu Longxiang

    2005-07-15

    Purpose: Late course accelerated hyperfractionated (LCAF) radiotherapy (RT) is as effective as standard chemoradiotherapy for nonsurgical management of locally advanced esophageal squamous cell carcinoma (SCC). We have evaluated further the efficacy of concurrent LCAF RT and chemotherapy. Methods and Materials: In all, 111 eligible patients with esophageal SCC were randomized to receive LCAF alone (LCAF) or concurrent LCAF and chemotherapy (LCAT+CT) between March 1998 and July 2000. All patients received conventional fractionation irradiation of 1.8 Gy per day, to a dose of 41.4 Gy/23 fractions in 4-5 weeks, followed by accelerated hyperfractionated irradiation using reduced fields, 1.5 Gy/fractions twice a day, to a dose of 27 Gy in 18 days. Thus, the total dose was 68.4 Gy/41 fractions in 44 days. Fifty-four patients in the LCAF+CT arm had an additional four cycles of chemotherapy using cisplatin 25 mg/m{sup 2} daily and fluorouracil (5-FU) 600 mg/m{sup 2} daily on Days 1-3 every 4 weeks starting on the same day that LCAF was delivered. Results: The median survival was 23.9 months (95% confidence [CI], 20.1-27.7) for the LCAF arm and 30.8 months (95% CI, 17.6-44.1) for the LCAF+CT arm, respectively. Survival rates at 1, 3, and 5 years of the LCAF arm were 77%, 39%, and 28%, respectively, while those of the LCAF+CT arm were 67%, 44%, and 40%, respectively (p = 0.310). Grades 3 and 4 acute toxicities occurred in 46% and 25% of the patients in the LCAF arm and the LCAF+CT arm, respectively; 6% of the patients in the combined arm had Grade 5 acute toxicities, whereas none was noted in the LCAF alone arm. Conclusions: Late course accelerated hyperfractionation was effective for locally advanced esophageal SCC. There was a trend toward better survival among patients who received intensified treatment with concurrent chemotherapy. Further randomized studies with a larger number of patients should be carried out, but additional measures must be taken to reduce the higher

  14. High-affinity NGF receptor in the rat spinal cord during acute and chronic phases of experimental autoimmune encephalomyelitis: a possible functional significance.

    PubMed

    Oderfeld-Nowak, B; Zaremba, M; Lipkowski, A W; Kwiatkowska-Patzer, B; Triaca, V; Aloe, L

    2003-03-01

    The biological effects of Nerve Growth Factor (NGF) are primarily mediated via its high affinity receptor-TrkA. In the present study, we examined the effect of experimental autoimmune encephalomyelitis (EAE) upon the expression of TrkA in neuronal and non-neuronal cells of the spinal cord of Lewis rats during the acute (14 days postimmunization) and chronic (12 months postimmunization) phases of the disease. In the normal spinal cord, both of mature and aged rats, we found TrkA immunoreaction (TrkA-IR) in the motoneurons of the Rexed lamina IX and in both oligo- and astroglia cells. In the acute phase of the disease, we found a reduction of TrkA immunoreactivity in motoneurons and its up-regulation in oligodendroglia, mainly in the white matter. We also confirmed our previous findings concerning the up-regulation of TrkA-IR in astroglia. Both neuronal and non-neuronal changes of TrkA immunoreactivity had a transient character: they were not seen in the chronic phase of the disease. Our results suggest that both neuronal and glial TrkA expression changes depend on inflammation. Moreover, our data indicate that, during the acute phase of EAE, the glial cells become more receptive to NGF, pointing to glia as an important target for pharmacological manipulations, particularly for exogenously administered NGF. PMID:12825322

  15. Chronic pancreatitis

    MedlinePlus

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  16. MRI-based brain atrophy rates in ADNI phase 2: acceleration and enrichment considerations for clinical trials.

    PubMed

    Hua, Xue; Ching, Christopher R K; Mezher, Adam; Gutman, Boris A; Hibar, Derrek P; Bhatt, Priya; Leow, Alex D; Jack, Clifford R; Bernstein, Matt A; Weiner, Michael W; Thompson, Paul M

    2016-01-01

    The goal of this work was to assess statistical power to detect treatment effects in Alzheimer's disease (AD) clinical trials using magnetic resonance imaging (MRI)-derived brain biomarkers. We used unbiased tensor-based morphometry (TBM) to analyze n = 5,738 scans, from Alzheimer's Disease Neuroimaging Initiative 2 participants scanned with both accelerated and nonaccelerated T1-weighted MRI at 3T. The study cohort included 198 healthy controls, 111 participants with significant memory complaint, 182 with early mild cognitive impairment (EMCI) and 177 late mild cognitive impairment (LMCI), and 155 AD patients, scanned at screening and 3, 6, 12, and 24 months. The statistical power to track brain change in TBM-based imaging biomarkers depends on the interscan interval, disease stage, and methods used to extract numerical summaries. To achieve reasonable sample size estimates for potential clinical trials, the minimal scan interval was 6 months for LMCI and AD and 12 months for EMCI. TBM-based imaging biomarkers were not sensitive to MRI scan acceleration, which gave results comparable with nonaccelerated sequences. ApoE status and baseline amyloid-beta positron emission tomography data improved statistical power. Among healthy, EMCI, and LMCI participants, sample size requirements were significantly lower in the amyloid+/ApoE4+ group than for the amyloid-/ApoE4- group. ApoE4 strongly predicted atrophy rates across brain regions most affected by AD, but the remaining 9 of the top 10 AD risk genes offered no added predictive value in this cohort. PMID:26545631

  17. A Radio Frequency Quadrupole Instrument for use with Accelerator Mass Spectrometry: Application to Low Kinetic Energy Reactive Isobar Suppression and Gas--Phase Anion Reaction Studies

    NASA Astrophysics Data System (ADS)

    Eliades, John Alexander

    A radio frequency (rf) quadrupole instrument, currently known as an Isobar Separator for Anions (ISA), has been integrated into an Accelerator Mass Spectrometry (AMS) system to facilitate anion--gas reactions before the tandem accelerator. An AMS Cs+ sputter source provided ≥ 15 keV ions that were decelerated in the prototype ISA to < 20 eV for reaction in a single collision cell and re-accelerated for AMS analysis. Reaction based isobar suppression capabilities were assessed for smaller AMS systems and a new technique for gas--phase reaction studies was developed. Isobar suppression of 36S-- and 12C3-- for 36Cl analysis, and YF3-- and ZrF3-- for 90Sr analysis were studied in NO2 with deceleration to ≤ 12 eV. Observed attenuation cross sections, sigma [x 10--15 cm2], were sigma(S-- + NO2) = 6.6, sigma(C3-- + NO2) = 4.2, sigma(YF3-- + NO 2) = 7.6, sigma(ZrF3-- + NO2) = 19. With 8 mTorr NO2, relative attenuations of S-- /Cl-- ˜ 10--6, C 3--/Cl-- ˜ 10--7 , YF3--/SrF3-- ˜ 5 x 10--5 and ZrF3-- /SrF3-- ˜ 4 x 10--6 were observed with Cl-- ˜ 30% and SrF 3-- > 90% transmission. Current isobar attenuation limits with ≤ 1.75 MV accelerator terminal voltage and ppm impurity levels were calculated to be 36S--/Cl-- ˜ 4 x 10--16, 12C3 --/Cl-- ˜ 1.2 x 10--16, 90YF3--/SrF3-- ˜ 10--15 and 90ZrF3 --/SrF3-- ˜ 10--16 . Using 1.75 MV, four 36Cl reference standards in the range 4 x 10--13 ≤ 36Cl/Cl ≤ 4 x 10 --11 were analyzed with 8 mTorr NO2. The measured 36Cl/Cl ratios plotted very well against the accepted values. A sample impurity content S/Cl ≤ 6 x 10--5 was measured and a background level of 36S--/Cl ≤ 9 x 10--15 was determined. Useful currents of a wide variety of anions are produced in AMS sputter sources and molecules can be identified relatively unambiguously by stripping fragments from tandem accelerators. Reactions involving YF3 --, ZrF3--, S-- and SO-- + NO2 in the ISA analyzed by AMS are described, and some interesting reactants are identified.

  18. The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia.

    PubMed

    Hallek, Michael; Kay, Neil E; Osterborg, Anders; Chanan-Khan, Asher A; Mahler, Michelle; Salman, Mariya; Wan, Ying; Sun, Steven; Zhuang, Sen Hong; Howes, Angela

    2015-01-01

    Ibrutinib is an orally administered, covalent inhibitor of Bruton's tyrosine kinase with activity in B-cell malignancies based on Phase I/II studies. We describe the design and rationale for the Phase III HELIOS trial (trial registration: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745) investigating whether ibrutinib added to bendamustine and rituximab (BR) provides benefits over BR alone in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible patients must have relapsed/refractory disease measurable on CT scan and meet ≥ 1 International Workshop on Chronic Lymphocytic Leukemia criterion for requiring treatment; patients with del(17p) are excluded. All patients receive BR (maximum six cycles) as background therapy and are randomized 1:1 to placebo or ibrutinib 420 mg/day. Treatment with ibrutinib or placebo will start concomitantly with BR and continue until disease progression or unacceptable toxicity. The primary end point is progression-free survival. Secondary end points include safety, objective response rate, overall survival, rate of minimal residual disease-negative remissions, and patient-reported outcomes. Tumor response will be assessed using the International Workshop on Chronic Lymphocytic Leukemia guidelines. PMID:24901734

  19. Effects of sensorimotor foot training on the symmetry of weight distribution on the lower extremities of patients in the chronic phase after stroke

    PubMed Central

    Goliwas, Magdalena; Kocur, Piotr; Furmaniuk, Lech; Majchrzycki, Marian; Wiernicka, Marzena; Lewandowski, Jacek

    2015-01-01

    [Purpose] To assess the effects of sensorimotor foot stimulation on the symmetry of weight distribution on the feet of patients in the chronic post-stroke phase. [Subjects and Methods] This study was a prospective, single blind, randomized controlled trial. In the study we examined patients with chronic stroke (post-stroke duration > 1 year). They were randomly allocated to the study group (n=8) or to the control group (n=12). Both groups completed a standard six-week rehabilitation programme. In the study group, the standard rehabilitation programme was supplemented with sensorimotor foot stimulation training. Each patient underwent two assessments of symmetry of weight distribution on the lower extremities with and without visual control, on a treadmill, with stabilometry measurements, and under static conditions. [Results] Only the study group demonstrated a significant increase in the weight placed on the leg directly affected by stroke, and a reduction in asymmetry of weight-bearing on the lower extremities. [Conclusion] Sensorimotor stimulation of the feet enhanced of weight bearing on the foot on the side of the body directly affected by stroke, and a decreased asymmetry of weight distribution on the lower extremities of patients in the chronic post-stroke phase. PMID:26504326

  20. Accelerated long-term assessment of thermal and chemical stability of bio-based phase change materials

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Thermal energy storage (TES) systems incorporated with phase change materials (PCMs) have potential applications to control energy use by building envelopes. However, it is essential to evaluate long term performance of the PCMs and cost effectiveness prior to full scale implementation. For this rea...

  1. High brightness electron accelerator

    DOEpatents

    Sheffield, Richard L.; Carlsten, Bruce E.; Young, Lloyd M.

    1994-01-01

    A compact high brightness linear accelerator is provided for use, e.g., in a free electron laser. The accelerator has a first plurality of acclerating cavities having end walls with four coupling slots for accelerating electrons to high velocities in the absence of quadrupole fields. A second plurality of cavities receives the high velocity electrons for further acceleration, where each of the second cavities has end walls with two coupling slots for acceleration in the absence of dipole fields. The accelerator also includes a first cavity with an extended length to provide for phase matching the electron beam along the accelerating cavities. A solenoid is provided about the photocathode that emits the electons, where the solenoid is configured to provide a substantially uniform magnetic field over the photocathode surface to minimize emittance of the electons as the electrons enter the first cavity.

  2. Can Accelerators Accelerate Learning?

    NASA Astrophysics Data System (ADS)

    Santos, A. C. F.; Fonseca, P.; Coelho, L. F. S.

    2009-03-01

    The 'Young Talented' education program developed by the Brazilian State Funding Agency (FAPERJ) [1] makes it possible for high-schools students from public high schools to perform activities in scientific laboratories. In the Atomic and Molecular Physics Laboratory at Federal University of Rio de Janeiro (UFRJ), the students are confronted with modern research tools like the 1.7 MV ion accelerator. Being a user-friendly machine, the accelerator is easily manageable by the students, who can perform simple hands-on activities, stimulating interest in physics, and getting the students close to modern laboratory techniques.

  3. PARTICLE ACCELERATOR

    DOEpatents

    Teng, L.C.

    1960-01-19

    ABS>A combination of two accelerators, a cyclotron and a ring-shaped accelerator which has a portion disposed tangentially to the cyclotron, is described. Means are provided to transfer particles from the cyclotron to the ring accelerator including a magnetic deflector within the cyclotron, a magnetic shield between the ring accelerator and the cyclotron, and a magnetic inflector within the ring accelerator.

  4. Modelling multi-phase liquid-sediment scour and resuspension induced by rapid flows using Smoothed Particle Hydrodynamics (SPH) accelerated with a Graphics Processing Unit (GPU)

    NASA Astrophysics Data System (ADS)

    Fourtakas, G.; Rogers, B. D.

    2016-06-01

    A two-phase numerical model using Smoothed Particle Hydrodynamics (SPH) is applied to two-phase liquid-sediments flows. The absence of a mesh in SPH is ideal for interfacial and highly non-linear flows with changing fragmentation of the interface, mixing and resuspension. The rheology of sediment induced under rapid flows undergoes several states which are only partially described by previous research in SPH. This paper attempts to bridge the gap between the geotechnics, non-Newtonian and Newtonian flows by proposing a model that combines the yielding, shear and suspension layer which are needed to predict accurately the global erosion phenomena, from a hydrodynamics prospective. The numerical SPH scheme is based on the explicit treatment of both phases using Newtonian and the non-Newtonian Bingham-type Herschel-Bulkley-Papanastasiou constitutive model. This is supplemented by the Drucker-Prager yield criterion to predict the onset of yielding of the sediment surface and a concentration suspension model. The multi-phase model has been compared with experimental and 2-D reference numerical models for scour following a dry-bed dam break yielding satisfactory results and improvements over well-known SPH multi-phase models. With 3-D simulations requiring a large number of particles, the code is accelerated with a graphics processing unit (GPU) in the open-source DualSPHysics code. The implementation and optimisation of the code achieved a speed up of x58 over an optimised single thread serial code. A 3-D dam break over a non-cohesive erodible bed simulation with over 4 million particles yields close agreement with experimental scour and water surface profiles.

  5. k-t acceleration in pure phase encode MRI to monitor dynamic flooding processes in rock core plugs.

    PubMed

    Xiao, Dan; Balcom, Bruce J

    2014-06-01

    Monitoring the pore system in sedimentary rocks with MRI when fluids are introduced is very important in the study of petroleum reservoirs and enhanced oil recovery. However, the lengthy acquisition time of each image, with pure phase encode MRI, limits the temporal resolution. Spatiotemporal correlations can be exploited to undersample the k-t space data. The stacked frames/profiles can be well approximated by an image matrix with rank deficiency, which can be recovered by nonlinear nuclear norm minimization. Sparsity of the x-t image can also be exploited for nonlinear reconstruction. In this work the results of a low rank matrix completion technique were compared with k-t sparse compressed sensing. These methods are demonstrated with one dimensional SPRITE imaging of a Bentheimer rock core plug and SESPI imaging of a Berea rock core plug, but can be easily extended to higher dimensionality and/or other pure phase encode measurements. These ideas will enable higher dimensionality pure phase encode MRI studies of dynamic flooding processes in low magnetic field systems. PMID:24809307

  6. k-t Acceleration in pure phase encode MRI to monitor dynamic flooding processes in rock core plugs

    NASA Astrophysics Data System (ADS)

    Xiao, Dan; Balcom, Bruce J.

    2014-06-01

    Monitoring the pore system in sedimentary rocks with MRI when fluids are introduced is very important in the study of petroleum reservoirs and enhanced oil recovery. However, the lengthy acquisition time of each image, with pure phase encode MRI, limits the temporal resolution. Spatiotemporal correlations can be exploited to undersample the k-t space data. The stacked frames/profiles can be well approximated by an image matrix with rank deficiency, which can be recovered by nonlinear nuclear norm minimization. Sparsity of the x-t image can also be exploited for nonlinear reconstruction. In this work the results of a low rank matrix completion technique were compared with k-t sparse compressed sensing. These methods are demonstrated with one dimensional SPRITE imaging of a Bentheimer rock core plug and SESPI imaging of a Berea rock core plug, but can be easily extended to higher dimensionality and/or other pure phase encode measurements. These ideas will enable higher dimensionality pure phase encode MRI studies of dynamic flooding processes in low magnetic field systems.

  7. Direct observation of the phase space footprint of a painting injection in the Rapid Cycling Synchrotron at the Japan Proton Accelerator Research Complex

    NASA Astrophysics Data System (ADS)

    Saha, P. K.; Shobuda, Y.; Hotchi, H.; Hayashi, N.; Takayanagi, T.; Harada, H.; Irie, Y.

    2009-04-01

    The 3 GeV Rapid Cycling Synchrotron (RCS) at Japan Proton Accelerator Research Complex is nearly at the operational stage with regard to the beam commissioning aspects. Recently, the design painting injection study has been commenced with the aim of high output beam power at the extraction. In order to observe the phase space footprint of the painting injection, a method was developed utilizing a beam position monitor (BPM) in the so-called single pass mode. The turn-by-turn phase space coordinates of the circulating beam directly measured using a pair of BPMs entirely positioned in drift space, and the calculated transfer matrices from the injection point to the pair of BPMs with several successive turns were used together in order to obtain the phase space footprint of the painting injection. There are two such pairs of BPMs placed in two different locations in the RCS, the results from which both agreed and were quite consistent with what was expected.

  8. Laser acceleration with open waveguides

    SciTech Connect

    Xie, Ming

    1999-03-01

    A unified framework based on solid-state open waveguides is developed to overcome all three major limitations on acceleration distance and hence on the feasibility of two classes of laser acceleration. The three limitations are due to laser diffraction, acceleration phase slippage, and damage of waveguide structure by high power laser. The two classes of laser acceleration are direct-field acceleration and ponderomotive-driven acceleration. Thus the solutions provided here encompass all mainstream approaches for laser acceleration, either in vacuum, gases or plasmas.

  9. Acceleration of the loss of the first-phase insulin response during the progression to type 1 diabetes in diabetes prevention trial-type 1 participants.

    PubMed

    Sosenko, Jay M; Skyler, Jay S; Beam, Craig A; Krischer, Jeffrey P; Greenbaum, Carla J; Mahon, Jeffrey; Rafkin, Lisa E; Matheson, Della; Herold, Kevan C; Palmer, Jerry P

    2013-12-01

    We studied the change in the first-phase insulin response (FPIR) during the progression to type 1 diabetes (T1D). Seventy-four oral insulin trial progressors to T1D from the Diabetes Prevention Trial-Type 1 with at least one FPIR measurement after baseline and before diagnosis were studied. The FPIR was examined longitudinally in 26 progressors who had FPIR measurements during each of the 3 years before diagnosis. The association between the change from the baseline FPIR to the last FPIR and time to diagnosis was studied in the remainder (n = 48). The 74 progressors had lower baseline FPIR values than nonprogressors (n = 270), with adjustments made for age and BMI. In the longitudinal analysis of the 26 progressors, there was a greater decline in the FPIR from 1.5 to 0.5 years before diagnosis than from 2.5 to 1.5 years before diagnosis. This accelerated decline was also evident in a regression analysis of the 48 remaining progressors in whom the rate of decline became more marked with the approaching diagnosis. The patterns of decline were similar between the longitudinal and regression analyses. There is an acceleration of decline in the FPIR during the progression to T1D, which becomes especially marked between 1.5 and 0.5 years before diagnosis. PMID:23863814

  10. Doppler-derived acceleration rate of right ventricular early filling as a measurement of right atrial pressure in chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

    PubMed

    Scapellato, F; Eleuteri, E; Temporelli, P L; Imparato, A; Corrà, U; Giannuzzi, P

    1998-02-15

    This study demonstrates that a Doppler-derived tricuspid flow velocity pattern provides an accurate, feasible, and noninvasive method of estimating and monitoring mean right atrial pressure in patients with heart failure due to left ventricular systolic dysfunction, and who are both in sinus rhythm and atrial fibrillation. In particular, the acceleration rate of early right ventricular filling is a powerful and independent predictor of mean right atrial pressure. PMID:9485149

  11. [One of the Mechanisms in Blastic Transformation of Chronic Myeloid Leukemia: Epigenetics Abnormality--Review].

    PubMed

    Meng, Zhen; Li, Ying-Hua

    2016-02-01

    Chronic myeloid leukemia is a myeloproliferative disorder characterized by excessive cloning of bone marrow multipotent stem cells. According to the disease course, the CML may be divided into chronic phase (CP), accelerated phase (AP) and blastic phase (BP). At present, the molecular mechanisms of acute transformation of CML has not been fully understood. The recent studies have shown that the epigenetics is one of mechanisms in blastic transformation of CML, including three molecular mechanisms such as DNA modification, histone modifications and RNA-related dysregulation. The molecular mechanisms for epigenetics leading to the transformation of CML are discussed in this review. PMID:26913431

  12. Acceleration gradient of a plasma wakefield accelerator

    SciTech Connect

    Uhm, Han S.

    2008-02-25

    The phase velocity of the wakefield waves is identical to the electron beam velocity. A theoretical analysis indicates that the acceleration gradient of the wakefield accelerator normalized by the wave breaking amplitude is K{sub 0}({xi})/K{sub 1}({xi}), where K{sub 0}({xi}) and K{sub 1}({xi}) are the modified Bessel functions of the second kind of order zero and one, respectively and {xi} is the beam parameter representing the beam intensity. It is also shown that the beam density must be considerably higher than the diffuse plasma density for the large radial velocity of plasma electrons that are required for a high acceleration gradient.

  13. Near infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute vs. chronic phases of arthritis in mice

    PubMed Central

    Zhou, Quan; Wood, Ronald; Schwarz, Edward M.; Wang, Yong-Jun; Xing, Lianping

    2010-01-01

    Objective Development of an in vivo imaging method to assess lymphatic draining function in the K/B×N mouse model of inflammatory arthritis. Methods Indocyanine green (ICG), a near-infrared (NIR) fluorescent dye, was injected intradermally into the footpad of wild-type mice, the limb was illuminated with an 806 nm NIR laser, and the movement of ICG from the injection site to the draining popliteal lymph node (PLN) was recorded with a CCD camera. ICG-NIR images were analyzed to obtain 5 measures of lymphatic function across time. K/B×N arthritic mice and control non-arthritic littermates were imaged at one-month of age when acute joint inflammation commenced, and repeated at 3 months when joint inflammation became chronic. Lymphangiogenesis in PLNs was assessed by immunochemistry. Results ICG and its transport within lymphatic vessels were readily visualized and quantitative measures derived. During the acute phase of arthritis, the lymphatic vessels were dilated with increased ICG signal intensity and lymphatic pulses, and PLNs became fluorescent quickly. During the chronic phase, new lymphatic vessels were present near the foot. However, ICG appearance in lymphatic vessels was delayed. The size and area of PLN lymphatic sinuses progressively increased in the K/B×N mice. Conclusion ICG-NIR lymphatic imaging is a valuable method to assess the lymphatic draining function in mice with inflammatory arthritis. ICG-NIR imaging of K/B×N mice identified two distinct lymphatic phenotypes during the acute and chronic phase of inflammation. This technique can be used to assess new therapies for lymphatic disorders. PMID:20309866

  14. Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients.

    PubMed

    Breccia, Massimo; Efficace, Fabio; Sica, Simona; Abruzzese, Elisabetta; Cedrone, Michele; Turri, Diamante; Gobbi, Marco; Carella, Angelo Michele; Gozzini, Antonella; Usala, Emilio; Cavazzini, Francesco; Danise, Paolo; Tiribelli, Mario; Binotto, Gianni; Pregno, Patrizia; Bocchia, Monica; Gaidano, Gianluca; Crugnola, Monica; Bonifacio, Massimiliano; Avanzini, Paolo; Celesti, Francesca; Guella, Anna; Martino, Bruno; Annunziata, Mario; Luciano, Luigiana; Stagno, Fabio; Vallisa, Daniele; Pungolino, Esther; Iurlo, Alessandra; Rambaldi, Alessandro; Nardiello, Ida; Orlandi, Esther; Gambacorti-Passerini, Carlo; Alimena, Giuliana

    2015-10-01

    Therapeutic approach for chronic myeloid leukemia (CML) patients has undergone a revolutionary change with the introduction of tyrosine kinase inhibitors, which improved overall survival and quality of life. Optimal therapy adherence has become of paramount importance to maximize the benefits in the long-term outcome. Several evidences have been reported that personal factors, such as social support, psychological and subjective perceptions about the drug used and the future, could influence adherence. We here report the results of a questionnaire specifically designed to evaluate factors influencing adherence and perceptions about the future, distributed to patients during regional Italian meetings. Overall, 1133 patients compiled the questionnaire: median age was 57 years. High rate of adherence was reported, but 42% of interviewed patients admitted that they had occasionally postponed a dose and 58% had discontinued therapy mainly for forgetfulness. The majority of patients discussed with personal physician about the importance of adherence and received sufficient information about illness and treatment, but would like to have discussed more about discomfort, anxiety and fear of the future. Summarizing personal drug compliance and estimating how many days a month, on average, the patients did not take the drug, the majority answered that it was less than 3 days (55%) and only a minority (4%) admitted that it was more than 7 days. Interviewed about discontinuation, 49% of patients answered that wouldn't interrupt because of fear of losing all the results achieved so far. This study suggests a higher level of satisfaction with more information received but the need of improving communication about possible future treatment free remission. PMID:26282944

  15. Early onset hypercholesterolemia induced by the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with chronic phase-chronic myeloid leukemia

    PubMed Central

    Rea, Delphine; Mirault, Tristan; Cluzeau, Thomas; Gautier, Jean-François; Guilhot, François; Dombret, Hervé; Messas, Emmanuel

    2014-01-01

    Despite a well-recognized clinical benefit of the 2nd-generation tyrosine kinase inhibitor nilotinib in patients with imatinib-resistant/-intolerant or newly diagnosed chronic myeloid leukemia, recent evidence suggests that nilotinib has a propensity to increase the risk of occlusive arterial events, especially in patients with pre-existing cardiovascular risk factors. Given the key role of lipids in cardiovascular diseases, we studied the plasma lipid profile and global cardiovascular risk prior to and during nilotinib therapy in a series of 27 patients in the setting of a prospective single center study. Data from a minimum 1-year follow up showed that nilotinib significantly increased total, low- and high-density lipoprotein cholesterol within three months. Consequently, the proportion of patients with non-optimal low-density lipoprotein cholesterol increased from 48.1% to 88.9% by 12 months, leading to cholesterol-lowering drug intervention in 22.2% of patients. The proportion of patients with low levels of high-density lipoprotein cholesterol decreased from 40.7% to 7.4% by 12 months. In contrast, a significant decrease in triglycerides was observed. Global cardiovascular risk worsened in 11.1% of patients due to diabetes or occlusive arterial events. Whether hypercholesterolemia was the main driver of occlusive arterial events was uncertain: a longer follow up is necessary to ask whether nilotinib-induced hypercholesterolemia increases long-term risk of atherosclerotic diseases. Nevertheless, given key atherogenic properties of low-density lipoprotein cholesterol, we conclude that when prescribing nilotinib, commitment to detect lipid disorders at baseline and during follow up is mandatory given their frequency, requirement for changes in lifestyle or drug intervention, and potential for long-term cardiovascular complications. PMID:24658819

  16. Accelerating cosmologies and the phase structure of F (R ) gravity with Lagrange multiplier constraints: A mimetic approach

    NASA Astrophysics Data System (ADS)

    Odintsov, S. D.; Oikonomou, V. K.

    2016-01-01

    We study mimetic F (R ) gravity with a potential and Lagrange multiplier constraint. In the context of these theories, we introduce a reconstruction technique which enables us to realize arbitrary cosmologies, given the Hubble rate and an arbitrarily chosen F (R ) gravity. We exemplify our method by realizing cosmologies that are in concordance with current observations (Planck data) and also well-known bouncing cosmologies. The attribute of our method is that the F (R ) gravity can be arbitrarily chosen, so we can have the appealing features of the mimetic approach combined with the known features of some F (R ) gravities, which unify early-time with late-time acceleration. Moreover, we study the existence and the stability of de Sitter points in the context of mimetic F (R ) gravity. In the case of unstable de Sitter points, it is demonstrated that graceful exit from inflation occurs. We also study the Einstein-frame counterpart theory of the Jordan-frame mimetic F (R ) gravity, and we discuss the general properties of the theory and exemplify our analysis by studying a quite interesting (from a phenomenological point of view) model with two scalar fields. We also calculate the observational indices of the two-scalar-field model, by using the two-scalar-field formalism. Furthermore, we extensively study the dynamical system that corresponds to the mimetic F (R ) gravity, by finding the fixed points and studying their stability. Finally, we modify our reconstruction method to function in the inverse way and thus yield which F (R ) gravity can realize a specific cosmological evolution, given the mimetic potential and the Lagrange multiplier.

  17. Analysis of tetragonal to monoclinic phase transformation caused by accelerated artificial aging and the effects of microstructure in stabilized zirconia

    NASA Astrophysics Data System (ADS)

    Lucas, Thomas J.

    This investigation addresses the issue that yttria stabilized zirconia is being used as a dental biomaterial without substantial evidence of its long-term viability. Furthermore, stabilized zirconia (SZ) undergoes low temperature degradation (LTD), which can lead to roughening of the surface. A rougher exterior can lead to increased wear of the antagonist in the oral environment. Despite the LTD concerns, SZ is now widely used in restorative dentistry, including full contour crowns. A comparison of aging methods to determine the role of artificial aging on inducing the transformation has not been extensively studied. Therefore, simulations of the transformation process were investigated by comparing different methods of accelerated aging. The rejected null hypothesis is that the temperature of aging treatment will not affect the time required to cause measurable monoclinic transformation of yttria stabilized zirconia. The transformation of SZ starts at the surface and progresses inward; however, it is unclear whether the progression is constant for different aging conditions. This investigation analyzed the depth of transformation as a function of aging conditions for stabilized zirconia in the top 5-6 mum from the surface. The rejected null hypothesis is that the transformation amount is constant throughout the first six micrometers from the surface. The effects of grain size on the amount of monoclinic transformation were also investigated. This study aimed to determine if the grain size of partially stabilized zirconia affects the amount of monoclinic transformation, surface roughness, and property degradation due to aging. The rejected null hypothesis is that the grain size will not affect the amount of monoclinic transformation, thus have no effect on surface roughening or property degradation. The final part of this study addresses the wear of enamel when opposing zirconia by observing how grain size and aging affected the wear rate of an enamel antagonist

  18. Bevacizumab, Capecitabine, Amifostine, and Preoperative Hypofractionated Accelerated Radiotherapy (HypoArc) for Rectal Cancer: A Phase II Study

    SciTech Connect

    Koukourakis, Michael I.; Tsoutsou, Pelagia; Chloropoulou, Pelagia A.; Manolas, Kostantinos; Sivridis, Efthimios

    2011-06-01

    Purpose: Bevacizumab has established therapeutic activity in patients with metastatic colorectal cancer, and anti-vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models. We assessed the feasibility and efficacy of preoperative radiochemotherapy combined with bevacizumab in patients with rectal cancer. Methods and Materials: Nineteen patients with radiologic T3 and/or N+ rectal carcinoma were treated with preoperative conformal hypofractionated accelerated radiotherapy (3.4 Gy in 10 consecutive fractions) supported with amifostine (500-1,000 mg daily), capecitabine (600 mg/m{sup 2} twice daily, 5 days per week), and bevacizumab (5 mg/kg every 2 weeks for 2 cycles). Surgery followed 6 weeks after the end of radiotherapy. A cohort of 14 sequential patients treated with the same regimen without bevacizumab was available for comparison. Results: Grade 2 or 3 diarrhea was noted in 7 of 19 patients (36.8%), which was statistically worse than patients receiving the same regimen without bevacizumab (p = 0.01). A higher incidence of Grade 2 or 3 proctalgia was also noted (21.1%) (p = 0.03). Bladder and skin toxicity was negligible. All toxicities regressed completely within 2 weeks after the end of therapy. Pathologic complete and partial response was noted in 7 of 19 cases (36.8%) and 8 of 19 cases (42.1%). Within a median follow-up of 21 months, none of the patients has had late complications develop and only 1 of 18 evaluable cases (5.5%) has had locoregional relapse. Conclusions: Bevacizumab can be safely combined with hypofractionated radiotherapy and capecitabine as a preoperative radiochemotherapy regimen for patients with rectal cancer. The high pathologic complete response rates urges the testing of bevacizumab in randomized studies.

  19. Preliminary results of a phase I/II study of simultaneous modulated accelerated radiotherapy for nondisseminated nasopharyngeal carcinoma

    SciTech Connect

    Lee, Sang-wook . E-mail: lsw@amc.seoul.kr; Back, Geum Mun; Yi, Byong Yong; Choi, Eun Kyung; Ahn, Seung Do; Shin, Seong Soo; Kim, Jung-hun; Kim, Sang Yoon; Lee, Bong-Jae; Nam, Soon Yuhl; Choi, Seung-Ho; Kim, Seung-Bae; Park, Jin-hong; Lee, Kang Kyoo; Park, Sung Ho; Kim, Jong Hoon

    2006-05-01

    Purpose: To present preliminary results of intensity-modulated radiotherapy (IMRT) with the simultaneous modulated accelerated radiotherapy (SMART) boost technique in patients with nasopharyngeal carcinoma (NPC). Methods and Materials: Twenty patients who underwent IMRT for nondisseminated NPC at the Asan Medical Center between September 2001 and December 2003 were prospectively evaluated. Intensity-modulated radiotherapy was delivered with the 'step and shoot' SMART technique at prescribed doses of 72 Gy (2.4 Gy/day) to the gross tumor volume, 60 Gy (2 Gy/day) to the clinical target volume and metastatic nodal station, and 46 Gy (2 Gy/day) to the clinically negative neck region. Eighteen patients also received cisplatin once per week. Results: The median follow-up period was 27 months. Nineteen patients completed the treatment without interruption; the remaining patient interrupted treatment for 2 weeks owing to severe pharyngitis and malnutrition. Five patients (25%) had Radiation Therapy Oncology Group Grade 3 mucositis, whereas 9 (45%) had Grade 3 pharyngitis. Seven patients (35%) lost more than 10% of their pretreatment weight, whereas 11 (55%) required intravenous fluids and/or tube feeding. There was no Grade 3 or 4 xerostomia. All patients showed complete response. Two patients had distant metastases and locoregional recurrence, respectively. Conclusion: Intensity-modulated radiotherapy with the SMART boost technique allows parotid sparing, as shown clinically and by dosimetry, and might also be more effective biologically. A larger population of patients and a longer follow-up period are needed to evaluate ultimate tumor control and late toxicity.

  20. Particle acceleration in flares

    NASA Technical Reports Server (NTRS)

    Benz, Arnold O.; Kosugi, Takeo; Aschwanden, Markus J.; Benka, Steve G.; Chupp, Edward L.; Enome, Shinzo; Garcia, Howard; Holman, Gordon D.; Kurt, Victoria G.; Sakao, Taro

    1994-01-01

    Particle acceleration is intrinsic to the primary energy release in the impulsive phase of solar flares, and we cannot understand flares without understanding acceleration. New observations in soft and hard X-rays, gamma-rays and coherent radio emissions are presented, suggesting flare fragmentation in time and space. X-ray and radio measurements exhibit at least five different time scales in flares. In addition, some new observations of delayed acceleration signatures are also presented. The theory of acceleration by parallel electric fields is used to model the spectral shape and evolution of hard X-rays. The possibility of the appearance of double layers is further investigated.

  1. Targeting chronic myeloid leukemia stem cells.

    PubMed

    Kinstrie, Ross; Copland, Mhairi

    2013-03-01

    Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder that is characterized by the presence of the fusion oncogene BCR-ABL that encodes the tyrosine kinase BCR-ABL. Constitutive expression of BCR-ABL leads to the unregulated production of mature myeloid cells in the bone marrow and their subsequent release into the blood. Untreated, CML will progress from a chronic to accelerated phase over a number of years before quickly proceeding to a terminal blast crisis phase, reminiscent of acute leukemia. The advent of tyrosine kinase inhibitors has led to much improved management of the disease, but these drugs do not provide a cure as they are unable to eradicate the most primitive, quiescent fraction of CML stem cells. This review looks at recent research into targeting CML stem cells and focuses on major signalling pathways of interest. PMID:23264204

  2. A randomised pilot Phase II study of doxorubicin and cyclophosphamide (AC) or epirubicin and cyclophosphamide (EC) given 2 weekly with pegfilgrastim (accelerated) vs 3 weekly (standard) for women with early breast cancer

    PubMed Central

    Jones, R L; Walsh, G; Ashley, S; Chua, S; Agarwal, R; O'Brien, M; Johnston, S; Smith, I E

    2009-01-01

    Accelerated (dose-dense) chemotherapy, in which the frequency of administration is increased without changing total dose or duration, may increase the efficacy of cancer chemotherapy. We performed a randomised Phase II study to assess the safety and relative toxicity of AC (doxorubicin; cyclophosphamide) vs E(epirubicin)C given by conventional or accelerated schedules as neoadjuvant or adjuvant chemotherapy for early breast cancer. Furthermore, the relative toxicity of doxorubicin and epirubicin remains uncertain. Patients were randomised to one of four arms; four courses of standard 3 weekly cyclophosphamide 600 mg m−2 in combination with doxorubicin 60 mg m−2 (AC) vs epirubicin 90 mg m−2 (EC) 3 weekly vs the same regimens administered every 2 weeks with pegfilgrastim (G-CSF). A total of 126 patients were treated, 42 with standard AC, 42 with accelerated AC, 19 with standard EC and 23 with accelerated EC. Significantly more grade 3/4 day one neutropenia was seen with standard (6/61, 10%) compared to accelerated (0/65,) regimens (P=0.01). A trend towards more neutropenic sepsis was seen in the combined standard and accelerated AC arms (12/84, 14%) compared to the combined EC arms (1/42, 2%), P=0.06. Falls in left ventricular ejection fraction were not increased with accelerated treatment. Accelerated AC and EC with pegfilgrastim are safe and feasible regimens in the treatment of early breast cancer with less neutropenia than conventional 3 weekly schedules. PMID:19165198

  3. Comparison of blood velocity measurements between ultrasound Doppler and accelerated phase-contrast MR angiography in small arteries with disturbed flow

    NASA Astrophysics Data System (ADS)

    Jiang, Jingfeng; Strother, Charles; Johnson, Kevin; Baker, Sara; Consigny, Dan; Wieben, Oliver; Zagzebski, James

    2011-03-01

    Ultrasound Doppler (UD) velocity measurements are commonly used to quantify blood flow velocities in vivo. The aim of our work was to investigate the accuracy of in vivo spectral Doppler measurements of velocity waveforms. Waveforms were derived from spectral Doppler signals and corrected for intrinsic spectral broadening errors by applying a previously published algorithm. The method was tested in a canine aneurysm model by determining velocities in small arteries (3-4 mm diameter) near the aneurysm where there was moderately disturbed flow. Doppler results were compared to velocity measurements in the same arteries acquired with a rapid volumetric phase contrast MR angiography technique named phase contrast vastly undersampled isotropic projection reconstruction magnetic resonance angiography (PC-VIPR MRA). After correcting for intrinsic spectral broadening, there was a high degree of correlation between velocities obtained by the real-time UD and the accelerated PC-MRA technique. The peak systolic velocity yielded a linear correlation coefficient of r = 0.83, end diastolic velocity resulted in r = 0.81, and temporally averaged mean velocity resulted in r = 0.76. The overall velocity waveforms obtained by the two techniques were also highly correlated (r = 0.89 ± 0.06). There were, however, only weak correlations for the pulsatility index (PI: 0.25) and resistive index (RI: 0.14) derived from the two techniques. Results demonstrate that to avoid overestimations of peak systolic velocities, the results for UD must be carefully corrected to compensate for errors caused by intrinsic spectral broadening.

  4. Measurements of the temporal and spatial phase variations of a 33 GHz pulsed free electron laser amplifier and application to high gradient RF acceleration

    SciTech Connect

    Volfbeyn, P.; Bekefi, G.

    1995-12-31

    We report the results of temporal and spatial measurements of phase of a pulsed free electron laser amplifier (FEL) operating in combined wiggler and axial guide magnetic fields. The 33 GHz FEL is driven by a mildly relativistic electron beam (750 kV, 90-300 A, 30 ns) and generates 61 MW of radiation with a high power magnetron as the input source. The phase is measured by an interferometric technique from which frequency shifting is determined. The results are simulated with a computer code. Experimental studies on a CERN-CLIC 32.98 GHz 26-cell high gradient accelerating section (HGA) were carried out for input powers from 0.1 MW to 35 MW. The FEL served as the r.f. power source for the HGA. The maximum power in the transmitted pulse was measured to be 15 MW for an input pulse of 35 MW. The theoretically calculated shunt impedance of 116 M{Omega}/m predicts a field gradient of 65 MeV/m inside the HGA. For power levels >3MW the pulse transmitted through the HGA was observed to be shorter than the input pulse and pulse shortening became more serious with increasing power input. At the highest power levels the output pulse length (about 5 nsec) was about one quarter of the input pulse length. Various tests suggest that these undesirable effects occur in the input coupler to the HGA. Light and X-ray production inside the HGA have been observed.

  5. Treatment of relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma with everolimus (RAD001) and alemtuzumab: a Phase I/II study.

    PubMed

    Zent, Clive S; Bowen, Deborah A; Conte, Michael J; LaPlant, Betsy R; Call, Timothy G

    2016-07-01

    Patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL), and especially those with purine analogue refractory disease or TP53 deletion/mutation, had a poor prognosis prior to the introduction of therapy targeting B cell receptor signaling. The mammalian target of rapamycin (mTOR) inhibitor everolimus has biological activity in CLL and can mobilize CLL cells from the lymphoid tissues into the circulation. In this clinical trial we determined the maximum tolerated dose (MTD) of everolimus together with eight weeks of standard dose subcutaneous alemtuzumab (Phase I) and then evaluated the tolerability and efficacy of therapy of relapsed/refractory CLL with the combination of everolimus and alemtuzumab (Phase II). The maximum tolerated dose of oral everolimus was 2.5 mg three times/week. Therapy with everolimus and alemtuzumab was tolerable, but not sufficiently efficacious (33% partial responses, no complete responses) to recommend further development of the regimen. PMID:26699397

  6. Phase I trial of tirapazamine, cisplatin, and concurrent accelerated boost reirradiation in patients with recurrent head and neck cancer

    SciTech Connect

    Cohen, Ezra E.W.; Haraf, Daniel J.; Loh, Elwyn; Shen, Liji; Lusinchi, Antoine; Vokes, Everett E.; Bourhis, Jean

    2007-03-01

    Purpose: Reirradiation (re-RT) with concurrent chemotherapy offers a therapeutic option in patients who have locoregional recurrence of head and neck cancer (HNC). The hypoxic cell sensitizer, tirapazamine (TPZ), has demonstrated promising results in first-line therapy for HNC. This phase I trial was designed to test the feasibility of giving TPZ in the re-RT setting. Methods and Materials: Patients with recurrent HNC who received prior radiotherapy (RT) were enrolled and received TPZ (260 mg/m{sup 2}) and cisplatin (50 mg/m{sup 2}) Weeks 1, 3, and 5 concurrently with RT (72 Gy, 42 fractions over 6 weeks). TPZ (160 mg/m{sup 2}) alone was added on Days 1, 3, and 5 of Week 2 (cohort 1) or Weeks 2 and 4 (cohort 2). Results: Twenty-five subjects were enrolled, 7 and 18 on cohorts 1 and 2, respectively. Significant toxicities included Grade 3 dermatitis (20%) and Grade 3 mucositis (40%). Dose-limiting toxicity was observed on cohort 2 (1 patient with aspiration pneumonia). Four deaths occurred during treatment. Two fatalities occurred after completing therapy as a result of carotid artery rupture. With a minimum and median follow-up of 14 and 24 months, respectively, median overall survival was 14 months with actuarial 1-year and 2-year survival of 56% and 27%, respectively. Conclusion: Reirradiation with concomitant chemotherapy including TPZ in patients with unresectable recurrent HNC is feasible and results in long-term survival in a significant proportion of patients.

  7. Plasma inverse transition acceleration

    SciTech Connect

    Xie, Ming

    2001-06-18

    It can be proved fundamentally from the reciprocity theorem with which the electromagnetism is endowed that corresponding to each spontaneous process of radiation by a charged particle there is an inverse process which defines a unique acceleration mechanism, from Cherenkov radiation to inverse Cherenkov acceleration (ICA) [1], from Smith-Purcell radiation to inverse Smith-Purcell acceleration (ISPA) [2], and from undulator radiation to inverse undulator acceleration (IUA) [3]. There is no exception. Yet, for nearly 30 years after each of the aforementioned inverse processes has been clarified for laser acceleration, inverse transition acceleration (ITA), despite speculation [4], has remained the least understood, and above all, no practical implementation of ITA has been found, until now. Unlike all its counterparts in which phase synchronism is established one way or the other such that a particle can continuously gain energy from an acceleration wave, the ITA to be discussed here, termed plasma inverse transition acceleration (PITA), operates under fundamentally different principle. As a result, the discovery of PITA has been delayed for decades, waiting for a conceptual breakthrough in accelerator physics: the principle of alternating gradient acceleration [5, 6, 7, 8, 9, 10]. In fact, PITA was invented [7, 8] as one of several realizations of the new principle.

  8. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION).

    PubMed

    Jabbour, Elias; Kantarjian, Hagop M; Saglio, Giuseppe; Steegmann, Juan Luis; Shah, Neil P; Boqué, Concepción; Chuah, Charles; Pavlovsky, Carolina; Mayer, Jirí; Cortes, Jorge; Baccarani, Michele; Kim, Dong-Wook; Bradley-Garelik, M Brigid; Mohamed, Hesham; Wildgust, Mark; Hochhaus, Andreas

    2014-01-23

    This analysis explores the impact of early cytogenetic and molecular responses on the outcomes of patients with chronic myeloid leukemia in chronic phase (CML-CP) in the phase 3 DASatinib versus Imatinib Study In treatment-Naive CML patients trial with a minimum follow-up of 3 years. Patients with newly diagnosed CML-CP were randomized to receive 100 mg dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. The retrospective landmark analysis included patients evaluable at the relevant time point (3, 6, or 12 months). Median time to complete cytogenetic response was 3 vs 6 months with dasatinib vs imatinib. At 3 and 6 months, the proportion of patients with BCR-ABL transcript levels ≤10% was higher in the dasatinib arm. Deeper responses at 3, 6, and 12 months were observed in a higher proportion of patients on dasatinib therapy and were associated with better 3-year progression-free survival and overall survival in both arms. First-line dasatinib resulted in faster and deeper responses compared with imatinib. The achievement of an early molecular response was predictive of improved progression-free survival and overall survival, supporting new milestones for optimal response in patients with early CML-CP treated with tyrosine kinase inhibitors. This study was registered at www.clinicaltrials.gov as NCT00481247. PMID:24311723

  9. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION)

    PubMed Central

    Jabbour, Elias; Saglio, Giuseppe; Steegmann, Juan Luis; Shah, Neil P.; Boqué, Concepción; Chuah, Charles; Pavlovsky, Carolina; Mayer, Jiří; Cortes, Jorge; Baccarani, Michele; Kim, Dong-Wook; Bradley-Garelik, M. Brigid; Mohamed, Hesham; Wildgust, Mark; Hochhaus, Andreas

    2014-01-01

    This analysis explores the impact of early cytogenetic and molecular responses on the outcomes of patients with chronic myeloid leukemia in chronic phase (CML-CP) in the phase 3 DASatinib versus Imatinib Study In treatment-Naive CML patients trial with a minimum follow-up of 3 years. Patients with newly diagnosed CML-CP were randomized to receive 100 mg dasatinib (n = 259) or 400 mg imatinib (n = 260) once daily. The retrospective landmark analysis included patients evaluable at the relevant time point (3, 6, or 12 months). Median time to complete cytogenetic response was 3 vs 6 months with dasatinib vs imatinib. At 3 and 6 months, the proportion of patients with BCR-ABL transcript levels ≤10% was higher in the dasatinib arm. Deeper responses at 3, 6, and 12 months were observed in a higher proportion of patients on dasatinib therapy and were associated with better 3-year progression-free survival and overall survival in both arms. First-line dasatinib resulted in faster and deeper responses compared with imatinib. The achievement of an early molecular response was predictive of improved progression-free survival and overall survival, supporting new milestones for optimal response in patients with early CML-CP treated with tyrosine kinase inhibitors. This study was registered at www.clinicaltrials.gov as NCT00481247. PMID:24311723

  10. Local release of pioglitazone (a peroxisome proliferator-activated receptor γ agonist) accelerates proliferation and remodeling phases of wound healing.

    PubMed

    Sakai, Shigeki; Sato, Keisuke; Tabata, Yasuhiko; Kishi, Kazuo

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily known for its anti-inflammatory and macrophage differentiation effects, as well as its ability to promote fat cell differentiation and reduce insulin resistance. Pioglitazone (Pio) is a PPARγ agonist used clinically as an anti-diabetic agent for improving insulin sensitivity in patients with diabetes. The objective of this study was to develop a drug delivery system (DDS) for the local release of Pio to promote wound healing. Pio of low aqueous solubility was water-solubilized by micelles formed from gelatin grafted with L-lactic acid oligomers, and incorporated into a biodegradable gelatin hydrogel. An 8-mm punch biopsy tool was used to prepare two skin wounds on either side of the midline of 8-week-old mice. Wounds were treated by the hydrogels with (Pio-hydrogel group) or without (control group) Pio, and the wound area were observed 1, 4, 7, and 14 days after treatment. In addition, a protein assay and immunohistological stain were performed to determine the effects of the Pio-hydrogel on inflammation and macrophage differentiation. The Pio-hydrogels promote wound healing. Moreover, Western blotting analysis demonstrated that treatment with Pio-hydrogels resulted in decreased levels of the cytokines MIP-2 and TGF-β, and increased levels of glucose-regulating adiponectin. It is concluded that Pio-incorporated hydrogels promote the proliferation and remodeling phases of wound healing, and may prove to be effective as wound dressings. PMID:26710090

  11. Morphometric age estimate of the last phase of accelerated uplift in the Kazdag area (Biga Peninsula, NW Turkey)

    NASA Astrophysics Data System (ADS)

    Demoulin, A.; Altin, T. Bayer; Beckers, A.

    2013-11-01

    While the Plio-Quaternary uplift of the Kazdag mountain range (Biga Peninsula, NW Turkey) is generally acknowledged, little is known about its detailed timing. Partly because of this lack of data, the cause of this uplift phase is also debated, being associated either to back-arc extension in the rear of the Hellenic subduction zone, to transpression along the northern edge of the west-moving Anatolian microplate, or to extension driven by gravitational collapse. Here, we perform a morphometric study of the fluvial landscape at the scale of the Biga Peninsula, coupling the recently developed R/SR analysis of the drainage network with concavity and steepness measures of a set of 29 rivers of all sizes. While the dependence of profile concavity on basin size confirms that the landscape of the peninsula is still in a transient state, the spatial distribution of profile steepness values characterized by higher values for streams flowing down from the Kazdag massif shows that the latter undergoes higher uplift rates than the rest of the peninsula. We obtain a SR value of 0.324 ± 0.035 that, according to the relation established by Demoulin (2012), yields an age range of 0.5-1.3 Ma and a most probable value of 0.8 Ma for the time of the last tectonic perturbation in the region. In agreement with the analysis of knickpoint migration in a subset of rivers, this suggests that a pulse of uplift occurred at that time and, corroborated by sparse published observations in the Bayramiç and Çanakkale depressions, that the peninsula was uplifted as a whole from that time. This uplift pulse might have been caused by transient compressive conditions in the Anatolian plate when the Eratosthenes seamount came to subduct beneath the Cyprus arc around the early-to-mid Pleistocene transition (Schattner, 2010).

  12. Accuracy of immunohistochemistry and flow cytometry in estimating the proportion of leukemic cells in S phase in chronic myeloid leukemia patients.

    PubMed

    Hegde, U; Kotelnikov, V M; Handa, H; Burke, P; Preisler, H D

    1996-08-01

    We compared the proportion of S phase cells in bone marrow and peripheral blood samples obtained from 17 patients with chronic myeloid leukemia (CML). Before sampling all patients received a one hour i.v. infusion of iododeoxyuridine (IdUrd). The proportion of S phase cells was studied by immunohistochemistry (IHC) in bone marrow biopsies, and by flow cytometry (FCM) in bone marrow aspirates and peripheral blood samples. The IdUrd labelling index (LI) in bone marrow biopsy sections (27.5 +/- 1.8%) was significantly higher than the proportion of IdUrd labelled cells in bone marrow aspirate (15.1 +/- 2.0%). The percentage of S phase cells in peripheral blood was approximately the same as that in the aspirate (12.4 +/- 1.3%) and was correlated with that of bone marrow aspirate indicating a high degree of the aspirate dilution by peripheral blood. It is likely that the differences in % S phase cells in the aspirate and the biopsy result from this dilution. Estimates of the % S phase cells in the peripheral blood study by IHC and FCM were essentially the same. Samples labelled for one hour in vitro resulted in 1.5 fold higher LI than the same samples labelled in vivo. We conclude that estimates of the 8% S phase cells in the bone marrow of patients with CML should be made by infusing patients with IdUrd or BrdUrd with immunohistochemical evaluation of a marrow biopsy. Additionally in vitro labelling is not reflective of the percent S phase cells in vivo in patients. PMID:8882956

  13. Autoxidation and acetylene-accelerated oxidation of NO in a 2-phase system; implications for the expression of denitrification in ex situ experiments

    NASA Astrophysics Data System (ADS)

    Nadeem, Shahid; Dörsch, Peter; Bakken, Lars

    2013-04-01

    Denitrification allows microorganisms to sustain respiration under anoxic conditions. The typical niche for denitrification is an environment with fluctuating oxygen concentrations such as soils and borders between anoxic and oxic zones of biofilms and sediments. In such environments, the organisms need adequate regulation of denitrification in response to changing oxygen availability to tackle both oxic and anoxic spells. The regulation of denitrification in soils has environmental implications, since it affects the proportions of N2, N2O and NO emitted to the atmosphere. The expression of denitrification enzymes is regulated by a complex regulatory network involving one or several positive feedback loops via the intermediate nitrogen oxides. Nitric oxide (NO) is known to induce denitrification in model organisms, but the quantitative effect of NO and its concentration dependency has not been assessed for denitrification in soils. NO is chemically unstable in the presence of oxygen due to autoxidation, and the oxidation of NO is accelerated by acetylene (C2H2) which is commonly used as an inhibitor of N2O reductase in denitrification studies. As a first step to a better understanding of NO's role in soil denitrification, we investigated NO oxidation kinetics for a closed "two phase" system (i.e. liquid phase + headspace) typically used for denitrification experiments with soil slurries, with and without acetylene present. Models were developed to adequately predict autoxidation and acetylene-accelerated oxidation. The minimum oxygen concentration in the headspace ([O2]min, mL L-1) for acetylene-accelerated NO oxidation was found to increase linearly with the NO concentration ([NO], mL L-1); [O2]min= 0.192 + [NO]*0.1 (r2=0.978). The models for NO oxidation were then used to assess NO-oxidation rates in denitrification experiments with batches of bacterial cells extracted from soil. The batches were exposed to low initial oxygen concentrations in gas tight serum

  14. Accelerated Partial Breast Irradiation: 5-Year Results of the German-Austrian Multicenter Phase II Trial Using Interstitial Multicatheter Brachytherapy Alone After Breast-Conserving Surgery

    SciTech Connect

    Strnad, Vratislav; Hildebrandt, Guido; Poetter, Richard; Hammer, Josef; Hindemith, Marion; Resch, Alexandra; Spiegl, Kurt; Lotter, Michael; Uter, Wolfgang; Bani, Mayada; Kortmann, Rolf-Dieter; Beckmann, Matthias W.; Fietkau, Rainer; Ott, Oliver J.

    2011-05-01

    Purpose: To evaluate the impact of accelerated partial breast irradiation on local control, side effects, and cosmesis using multicatheter interstitial brachytherapy as the sole method for the adjuvant local treatment of patients with low-risk breast cancer. Methods and Materials: 274 patients with low-risk breast cancer were treated on protocol. Patients were eligible for the study if the tumor size was < 3 cm, resection margins were clear by at least 2 mm, no lymph node metastases existed, age was >35 years, hormone receptors were positive, and histologic grades were 1 or 2. Of the 274 patients, 175 (64%) received pulse-dose-rate brachytherapy (D{sub ref} = 50 Gy). and 99 (36%) received high-dose-rate brachytherapy (D{sub ref} = 32.0 Gy). Results: Median follow-up was 63 months (range, 9-103). Only 8 of 274 (2.9%) patients developed an ipsilateral in-breast tumor recurrence at the time of analysis. The 5-year actuarial local recurrence-free survival probability was 98%. The 5- year overall and disease-free survival probabilities of all patients were 97% and 96%, respectively. Contralateral in-breast malignancies were detected in 2 of 274 (0.7%) patients, and distant metastases occurred in 6 of 274 (2.2%). Late side effects {>=}Grade 3 (i.e., breast tissue fibrosis and telangiectasia) occurred in 1 patient (0.4%, 95%CI:0.0-2.0%) and 6 patients (2.2%, 95%CI:0.8-4.7%), respectively. Cosmetic results were good to excellent in 245 of 274 patients (90%). Conclusions: The long-term results of this prospective Phase II trial confirm that the efficacy of accelerated partial breast irradiation using multicatheter brachytherapy is comparable with that of whole breast irradiation and that late side effects are negligible.

  15. Accelerated Radiotherapy, Carbogen, and Nicotinamide (ARCON) in the Treatment of Advanced Bladder Cancer: Mature Results of a Phase II Nonrandomized Study

    SciTech Connect

    Hoskin, Peter; Rojas, Ana Ph.D. Saunders, Michele

    2009-04-01

    Purpose: We previously showed that accelerated radiotherapy combined with carbogen and nicotinamide (ARCON) was an effective approach to use in the radical treatment of patients with advanced bladder carcinoma. Interim analysis from this Phase II study showed that it achieved a high level of locoregional control and overall survival (OS) and an acceptable level of adverse events. Methods and Materials: From 1994 to 2000, a total of 105 consecutive patients with high-grade superficial or muscle-invasive bladder carcinoma were given accelerated radiotherapy (50-55 Gy in 4 weeks) with carbogen alone or ARCON. End points of the study were OS, disease-specific, and local regional relapse-free survival, and for late adverse events, urinary (altered urination frequency, incontinence, hematuria, and urgency) and bowel dysfunction (stool frequency and blood loss). Results: At 5 and 10 years, local regional relapse-free survival rates were 44% after ARCON excluding the effect of salvage treatment and 62% after ARCON including the effect of salvage treatment (p = 0.04). Five- and 10-year rates were 35% and 27% for OS and 47% and 46% for disease-specific survival. The highest actuarial rate for Grade 3 or worse late urinary or bowel dysfunction was observed for altered urinary frequency (44% of patients had urinary events every 1 hour or less) and stool frequency of four or more events (26% at 5 years). Conclusions: Historic comparisons with other studies indicate no evidence of an increase in severe or worse adverse events and good permanent control of bladder disease after ARCON radiotherapy.

  16. Acute Toxicity Profile and Compliance to Accelerated Radiotherapy Plus Carbogen and Nicotinamide for Clinical Stage T2-4 Laryngeal Cancer: Results of a Phase III Randomized Trial

    SciTech Connect

    Janssens, Geert O.; Terhaard, Chris H.; Doornaert, Patricia A.; Bijl, Hendrik P.; Ende, Piet van den; Chin, Alim; Pop, Lucas A.; Kaanders, Johannes H.

    2012-02-01

    Purpose: To report the acute toxicity profile and compliance from a randomized Phase III trial comparing accelerated radiotherapy (AR) with accelerated radiotherapy plus carbogen and nicotinamide (ARCON) in laryngeal cancer. Methods and Materials: From April 2001 to February 2008, 345 patients with cT2-4 squamous cell laryngeal cancer were randomized to AR (n = 174) and ARCON (n = 171). Acute toxicity was scored weekly until Week 8 and every 2-4 weeks thereafter. Compliance to carbogen and nicotinamide was reported. Results: Between both treatment arms (AR vs. ARCON) no statistically significant difference was observed for incidence of acute skin reactions (moist desquamation: 56% vs. 58%, p = 0.80), acute mucosal reactions (confluent mucositis: 79% vs. 85%, p = 0.14), and symptoms related to acute mucositis (severe pain on swallowing: 53% vs. 58%, p = 0.37; nasogastric tube feeding: 28% vs. 28%, p = 0.98; narcotic medicines required: 58% vs. 58%, p = 0.97). There was a statistically significant difference in median duration of confluent mucositis in favor of AR (2.0 vs 3.0 weeks, p = 0.01). There was full compliance with carbogen breathing and nicotinamide in 86% and 80% of the patients, with discontinuation in 6% and 12%, respectively. Adjustment of antiemesis prophylaxis was needed in 42% of patients. Conclusion: With the exception of a slight increase in median duration of acute confluent mucositis, the present data reveal a similar acute toxicity profile between both regimens and a good compliance with ARCON for clinical stage T2-4 laryngeal cancers. Treatment outcome and late morbidity will determine the real therapeutic benefit.

  17. Initial Molecular Response at 3 Months May Predict Both Response and Event-Free Survival at 24 Months in Imatinib-Resistant or -Intolerant Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in Chronic Phase Treated With Nilotinib

    PubMed Central

    Branford, Susan; Kim, Dong-Wook; Soverini, Simona; Haque, Ariful; Shou, Yaping; Woodman, Richard C.; Kantarjian, Hagop M.; Martinelli, Giovanni; Radich, Jerald P.; Saglio, Giuseppe; Hochhaus, Andreas; Hughes, Timothy P.; Müller, Martin C.

    2012-01-01

    Purpose The association between initial molecular response and longer-term outcomes with nilotinib was examined. Patients and Methods Patients with imatinib-resistant or -intolerant chronic myeloid leukemia in chronic phase from the phase II nilotinib registration study with available postbaseline BCR-ABL1 transcript assessments were included (N = 237). Results BCR-ABL1 transcript levels (International Scale [IS]) at 3 months correlated with complete cytogenetic response (CCyR) by 24 months. Patients with BCR-ABL1 (IS) of > 1% to ≤ 10% at 3 months with nilotinib had higher cumulative incidence of CCyR by 24 months than patients with BCR-ABL1 (IS) of > 10% (53% v 16%). BCR-ABL1 (IS) at 3 months predicted major molecular response (MMR) by 24 months. Cumulative incidence of MMR by 24 months for patients with BCR-ABL1 (IS) of > 0.1% to ≤ 1%, > 1% to ≤ 10%, and > 10% was 65%, 27%, and 9%, respectively. These differences were observed for patients with or without baseline BCR–ABL1 mutations and for those with imatinib resistance or intolerance. Estimated event-free survival (EFS) rates at 24 months decreased with higher transcript levels at 3 months; patients with BCR-ABL1 (IS) of ≤ 1% had an estimated 24-month EFS rate of 82%, compared with 70% for patients with BCR-ABL1 (IS) of > 1% to ≤ 10% and 48% for patients with BCR-ABL1 (IS) of > 10%. Conclusion Patients with BCR-ABL1 (IS) of > 10% at 3 months had a lower cumulative incidence of CCyR and MMR and lower rates of EFS versus patients with BCR-ABL1 (IS) of ≤ 10%. Prospective studies may determine whether close monitoring or alternative therapies are warranted for patients with minimal initial molecular response. PMID:23109697

  18. Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front-line imatinib or nilotinib 300 mg twice daily

    PubMed Central

    Hughes, Timothy P.; Hochhaus, Andreas; Kantarjian, Hagop M.; Cervantes, Francisco; Guilhot, François; Niederwieser, Dietger; le Coutre, Philipp D.; Rosti, Gianantonio; Ossenkoppele, Gert; Lobo, Clarisse; Shibayama, Hirohiko; Fan, Xiaolin; Menssen, Hans D.; Kemp, Charisse; Larson, Richard A.; Saglio, Giuseppe

    2014-01-01

    In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers:00718263, 00471497 - extension). PMID:24532039

  19. Interferon-alpha suppresses proliferation of chronic myelogenous leukemia cells K562 by extending cell cycle S-phase without inducing apoptosis.

    PubMed

    Grebenová, Dana; Kuzelová, Katerina; Fuchs, Ota; Halada, Petr; Havlícek, Vladimír; Marinov, Iuri; Hrkal, Zbynĕk

    2004-01-01

    We examined the effects of interferon-alpha (IFN-alpha) treatment on the growth, cell cycle, proliferation, and apoptotic parameters as well as adhesive properties and proteome of chronic myelogenous leukemia (CML)-derived K562 cells. IFN-alpha treatment (200 to 600 U/ml, 24 to 72 h) suppressed growth and caused accumulation of K562 cells in the S-phase of cell cycle (increase in S-phase cells by up to 52% in comparison with the untreated controls) at the expenses of cells in G1-phase. No transition of cells to G0-phase occurred as followed from Ki-67 protein determination. Although the level of chimeric gene product, BCR-ABL mRNA coding for BCR-ABL protein with anti-apoptotic properties, decreased by 30%, apoptosis was not triggered as judged from Annexin-V, APO2.7, and TUNEL assays. Adhesion of K562 cells to fibronectin-coated surfaces increased by up to 52% as determined by calcein assay. The proteomic analysis (2-D electrophoresis in combination with mass spectrometry, MALDI-MS) revealed a single protein, ubiquitine cross-reactive protein (UBCR), whose level markedly increased due to IFN-alpha treatment. The ubiquitination-like directed degradation processes may thus play a role in the mechanism of IFN-alpha antiproliferative effects. PMID:14757443

  20. Plasma accelerators

    SciTech Connect

    Ruth, R.D.; Chen, P.

    1986-03-01

    In this paper we discuss plasma accelerators which might provide high gradient accelerating fields suitable for TeV linear colliders. In particular we discuss two types of plasma accelerators which have been proposed, the Plasma Beat Wave Accelerator and the Plasma Wake Field Accelerator. We show that the electric fields in the plasma for both schemes are very similar, and thus the dynamics of the driven beams are very similar. The differences appear in the parameters associated with the driving beams. In particular to obtain a given accelerating gradient, the Plasma Wake Field Accelerator has a higher efficiency and a lower total energy for the driving beam. Finally, we show for the Plasma Wake Field Accelerator that one can accelerate high quality low emittance beams and, in principle, obtain efficiencies and energy spreads comparable to those obtained with conventional techniques.

  1. Rates and risk factors for hepatitis B reactivation in a cohort of persons in the inactive phase of chronic hepatitis B—Alaska, 2001–2010

    PubMed Central

    Tohme, Rania A.; Bulkow, Lisa; Homan, Chriss E.; Negus, Susan; McMahon, Brian J.

    2015-01-01

    Background A high prevalence of reactivation of hepatitis B has been documented among immunosuppressed individuals in the inactive phase of chronic hepatitis B; However, the proportion of and the risk factors for reactivation are largely unknown among non-immunosuppressed persons. Objectives Estimate the incidence rate of and risk factors for hepatitis B reactivation in a population-based cohort of persons in the inactive phase of chronic hepatitis B in Alaska. Study design A cohort of 414 Alaska Native Persons in the inactive phase of hepatitis B (HBV DNA < 2000 IU/mL and normal alanine aminotransferase (ALT) for 12 months) was followed-up for 10 years. Reactivation of hepatitis B was defined as HBV DNA ≥ 2000 IU/mL and ALT ≥ 40 IU/L. Cox-proportional hazards regression models were used to identify factors associated with reactivation. Results A total of 36 (9%) persons had reactivation during 2984 person-years of follow-up, with an annual incidence of 1.2%. Persons aged ≥50 years (1.8%) at study entry had the highest incidence rates of reactivation although incidence rates were not significantly different by age group. Risk factors for hepatitis B reactivation were male sex (Hazard Ratio (HR) = 2.41; 95% Confidence Interval (CI): 1.17–4.96), HBV DNA ≥ 1000 IU/mL at study entry (HR = 7.61; 95% CI: 2.81–20.6), and HBV genotype B (HR = 6.08; 95% CI: 1.32–28.0). Conclusions The incidence of hepatitis B reactivation was low during the 10 years of follow-up. However, given the higher risk of reactivation than their counterparts, males, and those with HBV DNA ≥ 1000 IU/mL need to be followed-up more frequently. PMID:24001884

  2. Determination of acetanilide herbicides in cereal crops using accelerated solvent extraction, solid-phase extraction and gas chromatography-electron capture detector.

    PubMed

    Zhang, Yaping; Yang, Jun; Shi, Ronghua; Su, Qingde; Yao, Li; Li, Panpan

    2011-07-01

    A method was developed to determine eight acetanilide herbicides from cereal crops based on accelerated solvent extraction (ASE) and solid-phase extraction (SPE) followed by gas chromatography-electron capture detector (GC-ECD) analysis. During the ASE process, the effect of four parameters (temperature, static time, static cycles and solvent) on the extraction efficiency was considered and compared with shake-flask extraction method. After extraction with ASE, four SPE tubes (graphitic carbon black/primary secondary amine (GCB/PSA), GCB, Florisil and alumina-N) were assayed for comparison to obtain the best clean-up efficiency. The results show that GCB/PSA cartridge gave the best recoveries and cleanest chromatograms. The analytical process was validated by the analysis of spiked blank samples. Performance characteristics such as linearity, limit of detection (LOD), limit of quantitation (LOQ), precision and recovery were studied. At 0.05 mg/kg spiked level, recoveries and precision values for rice, wheat and maize were 82.3-115.8 and 1.1-13.6%, respectively. For all the herbicides, LOD and LOQ ranged from 0.8 to 1.7 μg/kg and from 2.4 to 5.3 μg/kg, respectively. The proposed analytical methodology was applied for the analysis of the targets in samples; only three herbicides, propyzamid, metolachlor and diflufenican, were detected in two samples. PMID:21656677

  3. Therapeutic benefit of decitabine, a hypomethylating agent, in patients with high-risk primary myelofibrosis and myeloproliferative neoplasm in accelerated or blastic/acute myeloid leukemia phase.

    PubMed

    Badar, Talha; Kantarjian, Hagop M; Ravandi, Farhad; Jabbour, Elias; Borthakur, Gautam; Cortes, Jorge E; Pemmaraju, Naveen; Pierce, Sherry R; Newberry, Kate J; Daver, Naval; Verstovsek, Srdan

    2015-09-01

    Myeloproliferative neoplasm (MPN) transformed to acute myeloid leukemia (MPN-AML), MPN in accelerated phase (MPN-AP), and high-risk primary myelofibrosis (PMF) are associated with a poor response to therapy and very short survival. Several reports have suggested clinical activity of hypomethylating agents in these patients. We conducted a retrospective study of 21 patients with MPN-AML, 13 with MPN-AP and 11 with DIPSS-plus high-risk PMF treated with decitabine at our institution over the last 7 years and evaluated their clinical outcomes. Six patients (29%) with MPN-AML responded to decitabine (3 CR, 2 CRi, and 1 PR); median response duration was 7 months. The median overall survival (OS) was significantly higher in those who responded (10.5 vs 4 months). Among patients with MPN-AP, 8 patients (62%) benefited; the median response duration was 6.5 months. The median OS was 11.8 months in responders vs 4.7 months in non-responders. Among patients with DIPSS-plus high-risk PMF, 9 (82%) benefited; the median response duration was 9 months. The median OS was 32 months in responders vs 16.3 months in non-responders. Decitabine is a viable therapeutic option for patients with MPN-AML, MP-AP and high-risk PMF. Prospective clinical studies combining decitabine with other clinically active agents are needed to improve overall outcome. PMID:26183878

  4. Relative characterization of rosemary samples according to their geographical origins using microwave-accelerated distillation, solid-phase microextraction and Kohonen self-organizing maps.

    PubMed

    Tigrine-Kordjani, N; Chemat, F; Meklati, B Y; Tuduri, L; Giraudel, J L; Montury, M

    2007-09-01

    For centuries, rosemary (Rosmarinus officinalis L.) has been used to prepare essential oils which, even now, are highly valued due to their various biological activities. Nevertheless, it has been noted that these activities often depend on the origin of the rosemary plant and the method of extraction. Since both of these quality parameters can greatly influence the chemical composition of rosemary oil, an original analytical method was developed where "dry distillation" was coupled to headspace solid-phase microextraction (HS-SPME) and then a data mining technique using the Kohonen self-organizing map algorithm was applied to the data obtained. This original approach uses the newly described microwave-accelerated distillation technique (MAD) and HS-SPME; neither of these techniques require external solvent and so this approach provides a novel "green" chemistry sampling method in the field of biological matrix analysis. The large data set obtained was then treated with a rarely used chemometric technique based on nonclassical statistics. Applied to 32 rosemary samples collected at the same time from 12 different sites in the north of Algeria, this method highlighted a strong correlation between the volatile chemical compositions of the samples and their origins, and it therefore allowed the samples to be grouped according to geographical distribution. Moreover, the method allowed us to identify the constituents that exerted the most influence during classification. PMID:17646972

  5. Polarization-phase diagnostics of latent course of cholelithiasis in patients with chronic cholecystitis combined with diabetes mellitus type 2

    NASA Astrophysics Data System (ADS)

    Fediv, O. I.; Ivashchuk, O. I.; Marchuk, Yu. F.; Andriychuk, D. R.

    2012-01-01

    The principles of optical model of human bile polycrystalline structure are described. The three optical levels - isotropic, liquid-crystal and solid-crystal have been proposed. It has been introduced and proposed the scenarios of phase distribution formation in the boundary field of laser radiation, transformed by bile layers. The experimental scheme of direct measurement of coordinate phase distributions has been presented. The results of investigating the interrelation between the values of correlation and fractal parameters are presented. They characterize the coordinate distributions of phase shifts between the orthogonal components of the amplitude in the points of laser images of bile smears of cholelithiasis patients in combination with other pathologies. The diagnostic criteria of the cholelithiasis nascency and its severity degree differentiation are determined.

  6. Polarization-phase diagnostics of latent course of cholelithiasis in patients with chronic cholecystitis combined with diabetes mellitus type 2

    NASA Astrophysics Data System (ADS)

    Fediv, O. I.; Ivashchuk, O. I.; Marchuk, Yu. F.; Andriychuk, D. R.

    2011-09-01

    The principles of optical model of human bile polycrystalline structure are described. The three optical levels - isotropic, liquid-crystal and solid-crystal have been proposed. It has been introduced and proposed the scenarios of phase distribution formation in the boundary field of laser radiation, transformed by bile layers. The experimental scheme of direct measurement of coordinate phase distributions has been presented. The results of investigating the interrelation between the values of correlation and fractal parameters are presented. They characterize the coordinate distributions of phase shifts between the orthogonal components of the amplitude in the points of laser images of bile smears of cholelithiasis patients in combination with other pathologies. The diagnostic criteria of the cholelithiasis nascency and its severity degree differentiation are determined.

  7. Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease

    PubMed Central

    Fuwa, Daisuke; Fukuda, Michio; Ogiyama, Yoshiaki; Sato, Ryo; Mizuno, Masashi; Miura, Toshiyuki; Abe-Dohmae, Sumiko; Michikawa, Makoto; Kobori, Hiroyuki; Ohte, Nobuyuki

    2016-01-01

    Objective Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR). Methods The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease. Results Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (tNa), although 24-hour urinary Na excretion (UNaV) remained constant. Daily urinary angiotensinogen excretion (UAGTV, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r2=0.26) and tNa (r2=0.25) correlated with baseline 24-hour UAGTV. Changes in filtered Na load correlated with changes in nighttime systolic BP (r2=0.17), but not with changes in daytime systolic BP. The change in the tNa to filtered Na load ratio was influenced by the change in daytime UNaV (β=−0.67, F=16.8), rather than the change in nighttime UNaV. Conclusions Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of UAGTV by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events. PMID:27283968

  8. Chronic unpredictable stress (CUS) enhances the carcinogenic potential of 7,12-dimethylbenz(a)anthracene (DMBA) and accelerates the onset of tumor development in Swiss albino mice.

    PubMed

    Suhail, Nida; Bilal, Nayeem; Hasan, Shirin; Ahmad, Ausaf; Ashraf, Ghulam Md; Banu, Naheed

    2015-11-01

    Social stressors evolving from individual and population interactions produce stress reactions in many organisms (including humans), influencing homeostasis, altering the activity of the immunological system, and thus leading to various pathological states including cancer and their progression. The present study sought to validate the effectiveness of chronic unpredictable stress (CUS) in cancer promotion and to assess oxidative stress outcomes in terms of various in vivo biochemical parameters, oxidative stress markers, DNA damage, and the development of skin tumors in Swiss albino mice. Animals were randomized into different groups based on their exposure to CUS alone, 7,12-dimethylbenz(a)anthracene (DMBA) alone (topical), and DMBA-12-O-tetradecanoylphorbol-13-acetate (TPA) (topical) and exposure to CUS prior to DMBA or DMBA-TPA treatments and sacrificed after 16 weeks of treatment. Prior exposure to CUS significantly increased the pro-oxidant effect of carcinogen, depicted by compromised levels of antioxidants in the circulation and skin, accompanied by enhanced lipid peroxidation, plasma corticosterone, and marker enzymes as compared to DMBA-alone or DMBA-TPA treatments. DNA damage results corroborated the above biochemical outcomes. Also, the development of skin tumors (in terms of their incidence, tumor yield, and tumor burden) in mice in the presence and absence of stress further strongly supported our above biochemical measurements. CUS may work as a promoter of carcinogenesis by enhancing the pro-oxidant potential of carcinogens. Further studies may be aimed at the development of interventions for disease prevention by identifying the relations between psychological factors and DNA damage. PMID:26272695

  9. The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century

    PubMed Central

    Ito, Sawa

    2015-01-01

    The introduction of tyrosine kinase inhibitors (TKIs), a treatment of chronic myelogenous leukemia (CML), has largely replaced curative strategies based on allogeneic stem cell transplantation (SCT). Nevertheless, SCT still remains an option for accelerated/blastic-phase and selected chronic-phase CML. Transplant outcomes can be optimized by peritransplant TKIs, conditioning regimen, BCR-ABL monitoring, and relapse management. Controversies exist in transplant timing, pediatric CML, alternative donors, and economics. SCT continues to serve as a platform of “operational cure” for CML with TKIs and immunotherapies. PMID:25852053

  10. Analysis of 2013 European LeukaemiaNet (ELN) responses in chronic phase CML across four frontline TKI modalities and impact on clinical outcomes.

    PubMed

    Jain, Preetesh; Kantarjian, Hagop; Sasaki, Koji; Jabbour, Elias; Dasarathula, Jyothsna; Nogueras Gonzalez, Graciela; Verstovsek, Srdan; Borthakur, Gautam; Wierda, William; Kadia, Tapan; Dellasala, Sara; Pierce, Sherry; Ravandi, Farhad; O'Brien, Susan; Cortes, Jorge

    2016-04-01

    This study assessed the relevance of 2013 European LeukaemiaNet (ELN) response categories on patients treated with common frontline tyrosine kinase inhibitors (TKI) in chronic myeloid leukaemia in chronic phase (CML-CP). Four hundred and eighty-seven patients treated with imatinib (400 mg; IM 400, n = 70; 800 mg; IM800, n = 201), dasatinib (n = 107) or nilotinib (n = 109) were analysed. Intention to treat (ITT) analysis indicated that the proportion of patients falling into optimal, warning and failure ELN categories were 89%, 6%, 6% at 3 months, 78%, 17% and 6% at 6 months, and 75%, 13% and 13% at 12 months, respectively. Rates of optimal response at 3 months were 75% for IM400, 90% for IM800, 89% for dasatinib and 97% for nilotinib; 41%, 80%, 86% and 89% at 6 months; and 47%, 77%, 76% and 87% at 12 months, respectively. Patients achieving optimal response had longer eventfree (EFS), failurefree (FFS), transformationfree (TFS) and overall survival (OS) compared to warning and failure responses at all-time points. Treatment with imatinib 800, dasatinib or nilotinib predicted for achieving an optimal response. Optimal response predicted for significantly longer EFS, FFS, TFS and OS at 3, 6 and 12 months, irrespective of the TKI modality used. ELN response categories reliably predicted outcomes in CML patients receiving commonly used TKIs. PMID:26846160

  11. Confronting Twin Paradox Acceleration

    NASA Astrophysics Data System (ADS)

    Murphy, Thomas W.

    2016-05-01

    The resolution to the classic twin paradox in special relativity rests on the asymmetry of acceleration. Yet most students are not exposed to a satisfactory analysis of what exactly happens during the acceleration phase that results in the nonaccelerated observer's more rapid aging. The simple treatment presented here offers both graphical and quantitative solutions to the problem, leading to the correct result that the acceleration-induced age gap is 2Lβ years when the one-way distance L is expressed in light-years and velocity β ≡v/c .

  12. Chronic stimulation of cultured neuronal networks boosts low-frequency oscillatory activity at theta and gamma with spikes phase-locked to gamma frequencies

    NASA Astrophysics Data System (ADS)

    Leondopulos, Stathis S.; Boehler, Michael D.; Wheeler, Bruce C.; Brewer, Gregory J.

    2012-04-01

    Slow wave oscillations in the brain are essential for coordinated network activity but have not been shown to self-organize in vitro. Here, the development of dissociated hippocampal neurons into an active network with oscillations on multi-electrode arrays was evaluated in the absence and presence of chronic external stimulation. Significant changes in signal power were observed in the range of 1-400 Hz with an increase in amplitude during bursts. Stimulation increased oscillatory activity primarily in the theta (4-11 Hz) and slow gamma (30-55 Hz) bands. Spikes were most prominently phase-locked to the slow gamma waves. Notably, the dissociated network self-organized to exhibit sustained delta, theta, beta and gamma oscillations without input from cortex, thalamus or organized pyramidal cell layers.

  13. METHODS FOR AQUATIC TOXICITY IDENTIFICATION EVALUATIONS: PHASE III TOXICITY CONFIRMATION PROCEDURES FOR SAMPLES EXHIBITING ACUTE AND CHRONIC TOXICITY

    EPA Science Inventory

    In 1989, the guidance document for acutely toxic effluents titled Methods for Aquatic Toxicity Identification Evaluations: Phase III Toxicity Confirmation Procedures was published (EPA, 1989D)This manual and its companion documents (EPA, 1991A; EPA, 1992; EPA, 1993A) are intended...

  14. Neuroplastic Effects of Transcranial Direct Current Stimulation on Painful Symptoms Reduction in Chronic Hepatitis C: A Phase II Randomized, Double Blind, Sham Controlled Trial

    PubMed Central

    Brietzke, Aline P.; Rozisky, Joanna R.; Dussan-Sarria, Jairo A.; Deitos, Alicia; Laste, Gabriela; Hoppe, Priscila F. T.; Muller, Suzana; Torres, Iraci L. S.; Alvares-da-Silva, Mário R.; de Amorim, Rivadavio F. B.; Fregni, Felipe; Caumo, Wolnei

    2016-01-01

    Introduction: Pegylated Interferon Alpha (Peg-IFN) in combination with other drugs is the standard treatment for chronic hepatitis C infection (HCV) and is related to severe painful symptoms. The aim of this study was access the efficacy of transcranial direct current stimulation (tDCS) in controlling the painful symptoms related to Peg-IFN side effects. Materials and Methods: In this phase II double-blind trial, twenty eight (n = 28) HCV subjects were randomized to receive either 5 consecutive days of active tDCS (n = 14) or sham (n = 14) during 5 consecutive days with anodal stimulation over the primary motor cortex region using 2 mA for 20 min. The primary outcomes were visual analogue scale (VAS) pain and brain-derived neurotrophic factor (BDNF) serum levels. Secondary outcomes were the pressure-pain threshold (PPT), the Brazilian Profile of Chronic Pain: Screen (B-PCP:S), and drug analgesics use. Results: tDCS reduced the VAS scores (P < 0.003), with a mean pain drop of 56% (p < 0.001). Furthermore, tDCS was able to enhance BDNF levels (p < 0.01). The mean increase was 37.48% in the active group. Finally, tDCS raised PPT (p < 0.001) and reduced the B-PCP:S scores and analgesic use (p < 0.05). Conclusions: Five sessions of tDCS were effective in reducing the painful symptoms in HCV patients undergoing Peg-IFN treatment. These findings support the efficacy of tDCS as a promising therapeutic tool to improve the tolerance of the side effects related to the use of Peg-IFN. Future larger studies (phase III and IV trials) are needed to confirm the clinical use of the therapeutic effects of tDCS in such condition. Trial registration: Brazilian Human Health Regulator for Research with the approval number CAAE 07802012.0.0000.5327. PMID:26793047

  15. Granulocytic sarcoma with compressive myelopathy: a rare presentation of chronic myelogenous leukemia.

    PubMed

    Ganapule, Abhijeet P; Viswabandya, Auro; Jasper, Anita; Patel, Palak; Kokil, Gautami

    2014-07-01

    Granulocytic sarcoma occurs most commonly in acute myelogenous leukemia. The appearance of granulocytic sarcoma in chronic myelogenous leukemia signals accelerated phase/ blast transformation. This is a rare case of undiagnosed chronic myelogenous leukemia with granulocytic sarcoma causing cord compression, which went into tumour lysis syndrome requiring dialysis after starting of steroids and radiotherapy. A 43-year-old male presented in emergency department with acute onset of flaccid paralysis. On clinical examination, there was hepatosplenomegaly and lower motor neuron paralysis in the lower limbs. The peripheral smear was consistent with chronic myelogenous leukemia in chronic phase. The MRI spine revealed para-spinal and epidural masses causing cord compression and the biopsy from the paraspinal mass was consistent with granulocytic sarcoma. PMID:25177619

  16. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia.

    PubMed

    O'Brien, Susan M; Lamanna, Nicole; Kipps, Thomas J; Flinn, Ian; Zelenetz, Andrew D; Burger, Jan A; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S; Johnson, David M; Miller, Langdon L; Kim, Yeonhee; Dansey, Roger D; Dubowy, Ronald L; Coutre, Steven E

    2015-12-17

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  17. Subcutaneous injections of low doses of humanized anti-CD20 veltuzumab: a phase I study in chronic lymphocytic leukemia.

    PubMed

    Kalaycio, Matt E; George Negrea, O; Allen, Steven L; Rai, Kanti R; Abbasi, Rashid M; Horne, Heather; Wegener, William A; Goldenberg, David M

    2016-01-01

    To evaluate the potential of subcutaneous (SC) injections with anti-CD20 antibody veltuzumab in chronic lymphocytic leukemia (CLL), 21 patients received 80, 160, or 320 mg injections every 2 weeks × 4 doses (n = 11) or 160 or 320 mg twice-weekly × 16 doses (n = 10). Treatment was well tolerated with only occasional, mild-moderate, transient injection reactions. Lymphocytosis decreased in all patients (maximum decrease, 5-91%), with 12 patients obtaining >50% decreases. Of 14 patients with lymphadenopathy on CT imaging, 5 (36%) achieved 14-61% reductions (sum of perpendicular diameters). By NCI-WG criteria, two patients achieved partial responses (10%). SC veltuzumab appeared active in all dose groups, with no obvious exposure-response relationship, despite cumulative doses ranging from 320-5120 mg. Overall median progression-free survival was 7.7 months; three patients remained progression-free >1 year (2 ongoing at 2-year study completion). These data suggest further studies of SC veltuzumab in CLL are warranted. PMID:26389849

  18. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia

    PubMed Central

    Lamanna, Nicole; Kipps, Thomas J.; Flinn, Ian; Zelenetz, Andrew D.; Burger, Jan A.; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S.; Johnson, David M.; Miller, Langdon L.; Kim, Yeonhee; Dansey, Roger D.; Dubowy, Ronald L.; Coutre, Steven E.

    2015-01-01

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m2 weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  19. Impaired Hepatitis C Virus (HCV)-Specific Effector CD8+ T Cells Undergo Massive Apoptosis in the Peripheral Blood during Acute HCV Infection and in the Liver during the Chronic Phase of Infection▿

    PubMed Central

    Radziewicz, Henry; Ibegbu, Chris C.; Hon, Huiming; Osborn, Melissa K.; Obideen, Kamil; Wehbi, Mohammad; Freeman, Gordon J.; Lennox, Jeffrey L.; Workowski, Kimberly A.; Hanson, Holly L.; Grakoui, Arash

    2008-01-01

    A majority of patients infected with hepatitis C virus (HCV) do not sustain an effective T-cell response, and viremia persists. The mechanism leading to failure of the HCV-specific CD8+ T-cell response in patients developing chronic infection is unclear. We investigated apoptosis susceptibility of HCV-specific CD8+ T cells during the acute and chronic stages of infection. Although HCV-specific CD8+ T cells in the blood during the acute phase of infection and in the liver during the chronic phase were highly activated and expressed an effector phenotype, the majority was undergoing apoptosis. In contrast, peripheral blood HCV-specific CD8+ T cells during the chronic phase expressed a resting memory phenotype. Apoptosis susceptibility of HCV-specific CD8+ T cells was associated with very high levels of programmed death-1 (PD-1) and low CD127 expression and with significant functional T-cell deficits. Further evaluation of the “death phase” of HCV-specific CD8+ T cells during acute HCV infection showed that the majority of cells were dying by a process of cytokine withdrawal, mediated by activated caspase 9. Contraction during the acute phase occurred rapidly via this process despite the persistence of the virus. Remarkably, in the chronic phase of HCV infection, at the site of infection in the liver, a substantial frequency of caspase 9-mediated T-cell death was also present. This study highlights the importance of cytokine deprivation-mediated apoptosis with consequent down-modulation of the immune response to HCV during acute and chronic infections. PMID:18667503

  20. A Phase I Study of Chemoradiotherapy With Use of Involved-Field Conformal Radiotherapy and Accelerated Hyperfractionation for Stage III Non-Small Cell Lung Cancer: WJTOG 3305

    SciTech Connect

    Tada, Takuhito; Chiba, Yasutaka; Tsujino, Kayoko; Fukuda, Haruyuki; Nishimura, Yasumasa; Kokubo, Masaki; Negoro, Shunichi; Kudoh, Shinzoh; Fukuoka, Masahiro; Nakagawa, Kazuhiko; Nakanishi, Yoichi

    2012-05-01

    Purpose: A Phase I study to determine a recommended dose of thoracic radiotherapy using accelerated hyperfractionation for unresectable non-small-cell lung cancer was conducted. Methods and Materials: Patients with unresectable Stage III non-small-cell lung cancer were treated intravenously with carboplatin (area under the concentration curve 2) and paclitaxel (40 mg/m{sup 2}) on Days 1, 8, 15, and 22 with concurrent twice-daily thoracic radiotherapy (1.5 Gy per fraction) beginning on Day 1 followed by two cycles of consolidation chemotherapy using carboplatin (area under the concentration curve 5) and paclitaxel (200 mg/m{sup 2}). Total doses were 54 Gy in 36 fractions, 60 Gy in 40 fractions, 66 Gy in 44 fractions, and 72 Gy in 48 fractions at Levels 1 to 4. The dose-limiting toxicity, defined as Grade {>=}4 esophagitis and neutropenic fever and Grade {>=}3 other nonhematologic toxicities, was monitored for 90 days. Results: Of 26 patients enrolled, 22 patients were assessable for response and toxicity. When 4 patients entered Level 4, enrollment was closed to avoid severe late toxicities. Dose-limiting toxicities occurred in 3 patients. They were Grade 3 neuropathy at Level 1 and Level 3 and Grade 3 infection at Level 1. However, the maximum tolerated dose was not reached. The median survival time was 28.6 months for all patients. Conclusions: The maximum tolerated dose was not reached, although the dose of radiation was escalated to 72 Gy in 48 fractions. However, a dose of 66 Gy in 44 fractions was adopted for this study because late toxicity data were insufficient.

  1. Arandomized multicenter Phase II study of perioperative tiotropium intervention in gastric cancer patients with chronic obstructive pulmonary disease

    PubMed Central

    Fushida, Sachio; Oyama, Katsunobu; Kaji, Masahide; Hirono, Yasuo; Kinoshita, Jun; Tsukada, Tomoya; Nezuka, Hideaki; Nakano, Tatsuo; Noto, Masahiro; Nishijima, Koji; Fujimura, Takashi; Ohta, Tetsuo

    2015-01-01

    Background Tiotropium, a long-acting inhaled anticholinergic drug, has been widely used in the treatment of chronic obstructive pulmonary disease (COPD). However, the issue of whether perioperative tiotropium improves postoperative outcomes for gastric cancer patients with COPD remains unclear. Thus, the aim of this study was to determine the efficacy of perioperative tiotropium intervention for gastric cancer patients with COPD. Patients and methods Eighty-four gastric cancer patients with mild-to-moderate COPD were randomly assigned to receive perioperative pulmonary rehabilitation alone (control group) or pulmonary rehabilitation with 18 µg of tiotropium once daily (tiotropium group). The patients in the tiotropium group received tiotropium for more than 1 week before surgery and for 2 weeks after surgery. Spirometry was performed prior to group assignment and at 2 weeks after surgery. Postoperative complications, forced expiratory volume in 1 second, forced vital capacity, and the ratio of forced expiratory volume in second to forced vital capacity (%) were compared between the two groups. Results There were no significant differences between the two groups in terms of age, body mass index, smoking, gastrectomy incision, operation time, and bleeding volume (all P>0.05). Postoperative complications and pulmonary functions did not differ significantly between the control and tiotropium groups. A subgroup analysis of gastric cancer patients with moderate COPD showed that perioperative tiotropium intervention significantly decreased the rate of postoperative complications compared with the control group (P=0.046). However, even after gastrectomy, many patients with mild COPD in both the control and tiotropium groups showed improved pulmonary function. Conclusion Although perioperative tiotropium intervention had no significant effects in gastric cancer patients with mild COPD, it may be beneficial in those with moderate COPD. Therefore, the next prospective study

  2. A phase I trial of the aurora kinase inhibitor, ENMD-2076, in patients with relapsed or refractory acute myeloid leukemia or chronic myelomonocytic leukemia.

    PubMed

    Yee, Karen W L; Chen, Hsiao-Wei T; Hedley, David W; Chow, Sue; Brandwein, Joseph; Schuh, Andre C; Schimmer, Aaron D; Gupta, Vikas; Sanfelice, Deborah; Johnson, Tara; Le, Lisa W; Arnott, Jamie; Bray, Mark R; Sidor, Carolyn; Minden, Mark D

    2016-10-01

    ENMD-2076 is a novel, orally-active molecule that inhibits Aurora A kinase, as well as c-Kit, FLT3 and VEGFR2. A phase I study was conducted to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D) and toxicities of ENMD-2076 in patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Patients received escalating doses of ENMD-2076 administered orally daily [225 mg (n = 7), 375 mg (n = 6), 325 mg (n = 9), or 275 mg (n = 5)]. Twenty-seven patients were treated (26 AML; 1 CMML-2). The most common non-hematological toxicities of any grade, regardless of association with drug, were fatigue, diarrhea, dysphonia, dyspnea, hypertension, constipation, and abdominal pain. Dose-limiting toxicities (DLTs) consisted of grade 3 fatigue, grade 3 typhilitis, grade 3 syncope and grade 3 QTc prolongation). Of the 16 evaluable patients, one patient achieved a complete remission with incomplete count recovery (CRi), three experienced a morphologic leukemia-free state (MLFS) with a major hematologic improvement in platelets (HI-P), and 5 other patients had a reduction in marrow blast percentage (i.e. 11-65 %). The RP2D in this patient population is 225 mg orally once daily. PMID:27406088

  3. Comparison of the effectiveness and safety of cefpodoxime and ciprofloxacin in acute exacerbation of chronic suppurative otitis media: A randomized, open-labeled, phase IV clinical trial

    PubMed Central

    Ghosh, Arijit; Jana, Utpal; Khaowas, Ajoy; Das, Saumik; Mandal, Ananya; Das, Nina

    2012-01-01

    Objective: To compare the effectiveness and safety of cefpodoxime and ciprofloxacin for the treatment of mild to moderate cases of acute exacerbation of chronic suppurative otitis media (AECSOM). Materials and Methods: Adult patients diagnosed with AECSOM were screened and patients fulfilling the inclusion criteria were randomized to receive either cefpodoxime 200 mg twice daily or ciprofloxacin 500 mg twice daily orally for 7 days. The primary outcome of this randomized, open-labeled, phase IV clinical trial (Registration Number - CTRI/2011/10/002079) was clinical success rate at day 14 visit and the secondary outcome was incidence of adverse events (AEs). Forty-six patients were enrolled: 23 in the cefpodoxime group and 23 in the ciprofloxacin group. Results: The clinical success rates were 95.6% in the cefpodoxime group versus 90.9% in the ciprofloxacin group. These rates are comparable, but no statistically significant difference was observed between the groups. Few mild and self-limiting AEs were observed and the tolerability of both the drugs was also good. Conclusion: The results of this randomized, open-labeled phase IV clinical trial showed that a 7-day course of cefpodoxime is therapeutically comparable to ciprofloxacin in terms of both clinical effectiveness and safety for the treatment of patients with AECSOM. PMID:23326103

  4. The expression of IL-2, IL-4 and interferon-gamma (IFN-gamma) mRNA using liver biopsies at different phases of acute exacerbation of chronic hepatitis B.

    PubMed Central

    Fukuda, R; Ishimura, N; Nguyen, T X; Chowdhury, A; Ishihara, S; Kohge, N; Akagi, S; Watanabe, M; Fukumoto, S

    1995-01-01

    To investigate the hypothesis that Th1 phenotype cytokines are associated with the increasing activity of hepatitis and Th2 phenotype cytokines with decreasing activity in the liver of chronic viral hepatitis, expressions of the mRNA of the cytokines IL-2, IFN-gamma and IL-4 in the liver of 23 patients with chronic hepatitis B were investigated by reverse transcription polymerase chain reaction. Patients were divided into three groups according to the phase of acute exacerbation of hepatitis as increasing (n = 9), decreasing (n = 8), and stable phase (n = 6). Both IL-2 and IFN-gamma mRNA were preferentially expressed in increasing phase than in decreasing phase (P < 0.01, P < 0.05, respectively) and associated with the high serum alanine aminotransferase (ALT) level. On the other hand, IL-4 mRNA was detected in decreasing phase with significant frequency compared with increasing phase (P < 0.05). However, expression of IL-4 mRNA was not associated with serum ALT level. Our results suggest that Th1 phenotype cytokines up-regulate and Th2 phenotype cytokines down-regulate the liver inflammation of chronic viral hepatitis. PMID:7774054

  5. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient.

    PubMed

    Ash, Stephen R; Singh, Bhupinder; Lavin, Philip T; Stavros, Fiona; Rasmussen, Henrik S

    2015-08-01

    Hyperkalemia contributes to significant mortality and limits the use of cardioprotective and renoprotective renin-angiotensin-aldosterone blockers. Current therapies are poorly tolerated and not always effective. Here we conducted a phase 2 randomized, double-blind, placebo-controlled dose-escalation study to assess safety and efficacy of ZS-9. This oral selective cation exchanger that preferentially entraps potassium in the gastrointestinal tract was given to patients with stable Stage 3 chronic kidney disease and hyperkalemia (5.0 to 6.0 mEq/l) during a 2-day period. Of 90 eligible patients with mean baseline serum potassium of 5.1 mEq/l, 30 were randomized to placebo, 12-0.3 g, 24-3 g, or 24 to 10 g of ZS-9 three times daily for 2 days with regular meals. None withdrew and ZS-9 dose-dependently reduced serum potassium. The primary efficacy end point (rate of serum potassium decline in the first 48 h) was met with significance in the 3- and 10-g cohorts. From baseline, mean serum potassium was significantly decreased by 0.92±0.52 mEq/l at 38 h. Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/- 21.8 vs. +8.9 +/- 22.9 mEq per 24h) from placebo at day 2. In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment. Thus, ZS-9 was well-tolerated in patients with stable chronic kidney disease and hyperkalemia leading to a rapid, sustained reduction in serum potassium. PMID:25651363

  6. The effects of 4-aminopyridine on neurological deficits in chronic cases of traumatic spinal cord injury in dogs: a phase I clinical trial.

    PubMed

    Blight, A R; Toombs, J P; Bauer, M S; Widmer, W R

    1991-01-01

    A Phase I trial of 4-aminopyridine (4-AP) was carried out in 39 dogs referred to the veterinary teaching hospital with naturally occurring traumatic paraplegia or paraparesis. The rationale for the study was provided by the observation that 4-AP restores conduction in demyelinated nerve fibers in experimental spinal cord injury. Most injuries (77%) resulted from degenerative disk disease, occurring at or near the thoracolumbar junction, and producing chronic, complete paraplegia. Neurological examination of each dog was recorded on videotape before and at intervals after administration of 4-AP. The drug was administered systemically in total doses between 0.5 and 1 mg/kg body weight. Three areas of neurological status changed significantly at 15-45 minutes following administration of 4-AP: (a) striking improvements in hindlimb placing occurred in 18 animals; (b) increased awareness of painful stimuli to the hindlimb in 10 animals; (c) partial recovery of the cutaneus trunci muscle reflex of the back skin in 9 animals. These effects reversed within a few hours of administration. Other animals (36%) showed no change in neurological signs except a slight enhancement of hindlimb reflex tone. Significant side effects were seen in 6 dogs receiving higher intravenous doses, with elevation of body temperature and apparent anxiety, leading to mild seizures in 3 of the animals. These seizures were controlled with diazepam. The results indicate that conduction block may contribute significantly to functional deficits in closed-cord injuries and that potassium channel blockade may prove to be a valid, if limited approach to therapeutic intervention in chronic paraplegia and paraparesis. PMID:1870134

  7. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient

    PubMed Central

    Ash, Stephen R; Singh, Bhupinder; Lavin, Philip T; Stavros, Fiona; Rasmussen, Henrik S

    2015-01-01

    Hyperkalemia contributes to significant mortality and limits the use of cardioprotective and renoprotective renin–angiotensin–aldosterone blockers. Current therapies are poorly tolerated and not always effective. Here we conducted a phase 2 randomized, double-blind, placebo-controlled dose-escalation study to assess safety and efficacy of ZS-9. This oral selective cation exchanger that preferentially entraps potassium in the gastrointestinal tract was given to patients with stable Stage 3 chronic kidney disease and hyperkalemia (5.0 to 6.0 mEq/l) during a 2-day period. Of 90 eligible patients with mean baseline serum potassium of 5.1 mEq/l, 30 were randomized to placebo, 12–0.3 g, 24–3 g, or 24 to 10 g of ZS-9 three times daily for 2 days with regular meals. None withdrew and ZS-9 dose-dependently reduced serum potassium. The primary efficacy end point (rate of serum potassium decline in the first 48 h) was met with significance in the 3- and 10-g cohorts. From baseline, mean serum potassium was significantly decreased by 0.92±0.52 mEq/l at 38 h. Urinary potassium excretion significantly decreased with 10-g ZS-9 as compared to placebo at day 2 (+15.8 +/− 21.8 vs. +8.9 +/− 22.9 mEq per 24h) from placebo at day 2. In this short-term study, no serious adverse events were reported; only mild constipation in the 3-g dose group was possibly related to treatment. Thus, ZS-9 was well-tolerated in patients with stable chronic kidney disease and hyperkalemia leading to a rapid, sustained reduction in serum potassium. PMID:25651363

  8. Accelerated Reader.

    ERIC Educational Resources Information Center

    Education Commission of the States, Denver, CO.

    This paper provides an overview of Accelerated Reader, a system of computerized testing and record-keeping that supplements the regular classroom reading program. Accelerated Reader's primary goal is to increase literature-based reading practice. The program offers a computer-aided reading comprehension and management program intended to motivate…

  9. Particle acceleration in solar flares

    NASA Technical Reports Server (NTRS)

    Ramaty, R.; Forman, M. A.

    1987-01-01

    The most direct signatures of particle acceleration in flares are energetic particles detected in interplanetary space and in the Earth atmosphere, and gamma rays, neutrons, hard X-rays, and radio emissions produced by the energetic particles in the solar atmosphere. The stochastic and shock acceleration theories in flares are reviewed and the implications of observations on particle energy spectra, particle confinement and escape, multiple acceleration phases, particle anistropies, and solar atmospheric abundances are discussed.

  10. Sorafenib in Treating Patients With Refractory or Relapsed Acute Leukemia, Myelodysplastic Syndromes, or Blastic Phase Chronic Myelogenous Leukemia

    ClinicalTrials.gov

    2015-04-27

    Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia; Adult Acute Monoblastic Leukemia; Adult Acute Monocytic Leukemia; Adult Acute Myeloid Leukemia With Inv(16)(p13.1q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With Maturation; Adult Acute Myeloid Leukemia With Minimal Differentiation; Adult Acute Myeloid Leukemia With t(16;16)(p13.1;q22); CBFB-MYH11; Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); RUNX1-RUNX1T1; Adult Acute Myeloid Leukemia With t(9;11)(p22;q23); MLLT3-MLL; Adult Acute Myeloid Leukemia Without Maturation; Adult Acute Myelomonocytic Leukemia; Adult Acute Promyelocytic Leukemia With t(15;17)(q22;q12); PML-RARA; Adult Erythroleukemia; Adult Pure Erythroid Leukemia; Alkylating Agent-Related Acute Myeloid Leukemia; Blastic Phase; de Novo Myelodysplastic Syndrome; Previously Treated Myelodysplastic Syndrome; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndrome

  11. Efficacy and Safety of Artemether in the Treatment of Chronic Fascioliasis in Egypt: Exploratory Phase-2 Trials

    PubMed Central

    Keiser, Jennifer; Sayed, Hanan; El-Ghanam, Maged; Sabry, Hoda; Anani, Saad; El-Wakeel, Aly; Hatz, Christoph; Utzinger, Jürg; el-Din, Sayed Seif; El-Maadawy, Walaa; Botros, Sanaa

    2011-01-01

    Background Fascioliasis is an emerging zoonotic disease of considerable veterinary and public health importance. Triclabendazole is the only available drug for treatment. Laboratory studies have documented promising fasciocidal properties of the artemisinins (e.g., artemether). Methodology We carried out two exploratory phase-2 trials to assess the efficacy and safety of oral artemether administered at (i) 6×80 mg over 3 consecutive days, and (ii) 3×200 mg within 24 h in 36 Fasciola-infected individuals in Egypt. Efficacy was determined by cure rate (CR) and egg reduction rate (ERR) based on multiple Kato-Katz thick smears before and after drug administration. Patients who remained Fasciola-positive following artemether dosing were treated with single 10 mg/kg oral triclabendazole. In case of treatment failure, triclabendazole was re-administered at 20 mg/kg in two divided doses. Principal Findings CRs achieved with 6×80 mg and 3×200 mg artemether were 35% and 6%, respectively. The corresponding ERRs were 63% and nil, respectively. Artemether was well tolerated. A high efficacy was observed with triclabendazole administered at 10 mg/kg (16 patients; CR: 67%, ERR: 94%) and 20 mg/kg (4 patients; CR: 75%, ERR: 96%). Conclusions/Significance Artemether, administered at malaria treatment regimens, shows no or only little effect against fascioliasis, and hence does not represent an alternative to triclabendazole. The role of artemether and other artemisinin derivatives as partner drug in combination chemotherapy remains to be elucidated. PMID:21909440

  12. Research Update: Retardation and acceleration of phase separation evaluated from observation of imbalance between structure and valence in LiFePO{sub 4}/FePO{sub 4} electrode

    SciTech Connect

    Tokuda, Kazuya; Kawaguchi, Tomoya; Ichitsubo, Tetsu; Matsubara, Eiichiro; Fukuda, Katsutoshi

    2014-07-01

    LiFePO{sub 4} is a potential positive electrode material for lithium ion batteries. We have experimentally observed an imbalance between the valence change of Fe ions and the structure change from the LiFePO{sub 4} phase to the FePO{sub 4} phase during delithiation by simultaneous in situ XRD and XANES measurements in an LiFePO{sub 4}/FePO{sub 4} electrode. The ratio of structure change to valence change clearly indicates that the phase separation from LiFePO{sub 4} to FePO{sub 4} is suppressed at the beginning of delithiation, while it is accelerated at the latter stage, which is due to the coherent strain caused by the lattice misfit between the two phases.

  13. Slow release delivery of rioprostil by an osmotic pump inhibits the formation of acute aspirin-induced gastric lesions in dogs and accelerates the healing of chronic lesions without incidence of side effects.

    PubMed

    Katz, L B; Shriver, D A

    1989-10-01

    Rioprostil, a primary alcohol prostaglandin E1 analog, inhibits gastric acid secretion and prevents gastric lesions induced by a variety of irritants in experimental animals. Because rioprostil is relatively short-acting, it would be of significant benefit clinically if its duration of action could be extended to allow once daily dosing. This investigation demonstrates that when administered via an osmotically driven pump (Osmet, Alza Corp.), rioprostil prevents the acute effects of aspirin on the gastric mucosa of dogs, accelerates the healing of aspirin-induced gastric lesions, and heals preexisting aspirin-induced gastric lesions during chronic administration of aspiring. The potency of rioprostil against acute gastric lesion formation was greatest when delivered from a 24-hr release pump (ED50 = 0.77 micrograms/kg/24 hr) and was 37 times greater than when administered as a single oral bolus. In addition, this activity occurred at doses which had little or no gastric antisecretory activity in betazole-stimulated Heidenhain pouch dogs. When delivered from a 24-hr pump, rioprostil (100 micrograms/kg/24 hr) healed preexisting aspirin-induced gastric lesions within 8 days after removal of aspirin, or after 15 days during continued daily aspirin administration. Additional studies determined that administration of rioprostil at doses of 720, 1440, or 2160 micrograms/kg/24 hr (935-2805 times the gastroprotective ED50 in 24 hr pumps) was well tolerated, with only slight, transient increases in body temperature, softening of the stools, and mild sedation at the highest dose. Administration of rioprostil daily for 5 days at 960 micrograms/kg/24 hr from 24-hr release pumps was also well tolerated by all dogs with no evidence of any accumulation of effect of rioprostil. In summary, administration of rioprostil via an osmotic pump increases its potency and duration of action against the gastric lesion-inducing effect of aspirin, and maintains a wide ratio of safety. PMID

  14. Bosutinib in the management of chronic myelogenous leukemia.

    PubMed

    Amsberg, Gunhild Keller-von; Schafhausen, Philippe

    2013-01-01

    Bosutinib (SKI-606) is an orally available, once-daily dual Src and Abl kinase inhibitor, approved by the US Food and Drug Administration for the treatment of adults with chronic, accelerated, or blast-phase Philadelphia chromosome-positive chronic myelogenous leukemia who are intolerant of or resistant to first- or second-generation tyrosine kinase inhibitors. Bosutinib effectively overcomes the majority of imatinib-resistance-conferring BCR-ABL mutations except V299L and T315I. In the Bosutinib Efficacy and Safety in chronic myeloid LeukemiA (BELA) trial, bosutinib attained a faster and deeper molecular response than imatinib in newly diagnosed chronic-phase chronic myelogenous leukemia patients. Treatment-emergent adverse events are usually very manageable. Low grade, mostly self-limiting diarrhea represents the most frequently observed toxicity of bosutinib. Anti-diarrheal drugs, antiemetic agents, and/or fluid replacement should be used to treat these patients. The improved hematological toxicity of bosutinib compared with other tyrosine kinase inhibitors has been ascribed to its minimal activity against platelet-derived growth factor receptor and KIT. In this review, we give an overview on the profile of bosutinib, the clinical potential and treatment-emergent adverse events. PMID:23674887

  15. Adjusting for the acute phase response is essential to interpret iron status indicators among young Zanzibari children prone to chronic malaria and helminth infections.

    PubMed

    Kung'u, Jacqueline K; Wright, Victoria J; Haji, Hamad J; Ramsan, Mahdi; Goodman, David; Tielsch, James M; Bickle, Quentin D; Raynes, John G; Stoltzfus, Rebecca J

    2009-11-01

    The extent to which the acute phase response (APR) influences iron status indicators in chronic infections is not well documented. We investigated this relationship using reported recent fever and 2 acute phase proteins (APP), C-reactive protein (CRP), and alpha-1-acid glycoprotein (AGP). In a sample of 690 children matched on age and helminth infection status at baseline, we measured plasma for AGP, CRP, ferritin, transferrin receptor (TfR), and erythropoietin (EPO) and whole blood for hemoglobin (Hb) concentration, zinc protoporphyrin (ZPP), and malaria parasite density, and we obtained maternal reports of recent fever. We then examined the influence of the APR on each iron status indicator using regression analysis with Hb as the outcome variable. Ferritin was inversely related to Hb in the APR-unadjusted model. Adjusting for the APR using reported recent fever alone was not sufficient to reverse the inverse Hb-ferritin relationship. However, using CRP and/or AGP resulted in the expected positive relationship. The best fit model included reported recent fever, AGP and CRP (R(2) = 0.241; P < 0.001). The best fit Hb-ZPP, Hb-TfR, and Hb-EPO models included reported recent fever and AGP but not CRP (R(2) = 0.253, 0.310, and 0.292, respectively; P < 0.001). ZPP, TfR, and EPO were minimally influenced by the APR, whereas ferritin was immensely affected. Reported recent fever alone cannot be used as a marker for the APR. Either AGP or CRP is useful for adjusting if only 1 APP can be measured. However, AGP best predicted the APR in this population. PMID:19741202

  16. Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease

    PubMed Central

    Roberts, Andrew W.; Seymour, John F.; Brown, Jennifer R.; Wierda, William G.; Kipps, Thomas J.; Khaw, Seong Lin; Carney, Dennis A.; He, Simon Z.; Huang, David C.S.; Xiong, Hao; Cui, Yue; Busman, Todd A.; McKeegan, Evelyn M.; Krivoshik, Andrew P.; Enschede, Sari H.; Humerickhouse, Rod

    2012-01-01

    Purpose BCL2 overexpression is a hallmark of chronic lymphocytic leukemia (CLL). The novel BH3 mimetic navitoclax (ABT-263) specifically inhibits BCL2 and related proteins BCL-xl and BCL-w, potently inducing apoptosis of CLL cells in vitro. A phase I trial in patients with CLL was conducted to evaluate the safety, pharmacokinetics, and biologic activity of oral navitoclax. Patients and Methods Twenty-nine patients with relapsed or refractory CLL received daily navitoclax for 14 days (10, 110, 200, or 250 mg/d; n = 15) or 21 days (125, 200, 250, or 300 mg/d; n = 14) of each 21-day cycle. Dose escalation decisions were informed by continual reassessment methodology. Results Lymphocytosis was reduced by more than 50% in 19 of 21 patients with baseline lymphocytosis. Among 26 patients treated with navitoclax ≥ 110 mg/d, nine (35%) achieved a partial response and seven maintained stable disease for more than 6 months. Median treatment duration was 7 months (range, 1 to ≥ 29 months). Median progression-free survival was 25 months. Activity was observed in patients with fludarabine-refractory disease, bulky adenopathy, and del(17p) CLL. Thrombocytopenia due to BCL-xl inhibition was the major dose-limiting toxicity and was dose-related. Low MCL1 expression and high BIM:MCL1 or BIM:BCL2 ratios in leukemic cells correlated with response. We determined that the navitoclax dose of 250 mg/d in a continuous dosing schedule was optimal for phase II studies. Conclusion BCL2 is a valid therapeutic target in CLL, and its inhibition by navitoclax warrants further evaluation as monotherapy and in combination in this disease. PMID:22184378

  17. LINEAR ACCELERATOR

    DOEpatents

    Colgate, S.A.

    1958-05-27

    An improvement is presented in linear accelerators for charged particles with respect to the stable focusing of the particle beam. The improvement consists of providing a radial electric field transverse to the accelerating electric fields and angularly introducing the beam of particles in the field. The results of the foregoing is to achieve a beam which spirals about the axis of the acceleration path. The combination of the electric fields and angular motion of the particles cooperate to provide a stable and focused particle beam.

  18. Phase III, randomized study of ofatumumab versus physicians' choice of therapy and standard versus extended-length ofatumumab in patients with bulky fludarabine-refractory chronic lymphocytic leukemia.

    PubMed

    Österborg, Anders; Udvardy, Miklós; Zaritskey, Andrey; Andersson, Per-Ola; Grosicki, Sebastian; Mazur, Grzegorz; Kaplan, Polina; Steurer, Michael; Schuh, Anna; Montillo, Marco; Kryachok, Iryna; Middeke, Jan Moritz; Kulyaba, Yaroslav; Rekhtman, Grygoriy; Gorczyca, Michele; Daly, Siobhan; Chang, Chai-Ni; Lisby, Steen; Gupta, Ira

    2016-09-01

    We report results of a randomized, phase III study of ofatumumab versus physicians' choice treatment in patients with bulky fludarabine-refractory chronic lymphocytic leukemia and explore extended versus standard-length ofatumumab treatment. Patients (79 ofatumumab, 43 physicians' choice) completed a median 6 (ofatumumab) or 3 (physicians' choice) months' therapy. Ofatumumab-treated patients with stable disease or better were randomized (2:1) to 6 months' extended ofatumumab treatment or observation. Although the study did not meet the primary endpoint of progression-free survival (PFS) by independent review committee (ofatumumab: 5.4 months, physicians' choice: 3.6 months; p = 0.27), median PFS by investigators was significantly longer for ofatumumab versus physicians' choice (7.0 versus 4.5 months; p = 0.003) as was time to next therapy (median 11.5 versus 6.5 months; p = 0.0004). PFS and time to next therapy were significantly longer with ofatumumab extended treatment than observation (p = 0.026 and p = 0.002, respectively; n = 37). The adverse-event profile of long-term ofatumumab administration showed no unexpected findings (Clinicaltrials.gov identifier: NCT01313689). PMID:26784000

  19. Additive antileukemia effects by GFI1B- and BCR-ABL-specific siRNA in advanced phase chronic myeloid leukemic cells.

    PubMed

    Koldehoff, M; Zakrzewski, J L; Beelen, D W; Elmaagacli, A H

    2013-07-01

    Previous studies demonstrated selective inhibition of the BCR-ABL (breakpoint cluster region-Abelson murine leukemia oncogene) tyrosine kinase by RNA interference in leukemic cells. In this study, we evaluated the effect of BCR-ABL small interfering RNA (siRNA) and GFI1B siRNA silencing on chronic myeloid leukemia (CML) cells in myeloid blast crises. The GFI1B gene was mapped to chromosome 9 and is, therefore, located downstream of the BCR-ABL translocation in CML cells. Co-transfection of BCR-ABL siRNA and GFI1B siRNA dramatically decreased cell viability and significantly induced apoptosis and inhibited proliferation in K562 cells (P<0.0001) and primary advanced phase CML cells (P<0.0001) versus controls. Furthermore, combining of BCR-ABL siRNA and GFI1B siRNA significantly modified the expression of several relevant genes including Myc, MDR1, MRP1 and tyrosyl-phosphoproteins in primary CML cells. Our data suggest that silencing of both BCR-ABL siRNA and GFI1B siRNA is associated with an additive antileukemic effect against K562 cells and primary advanced CML cells, further validating these genes as attractive therapeutic targets. PMID:23788109

  20. A phase 1 study of imatinib for corticosteroid-dependent/refractory chronic graft-versus-host disease: response does not correlate with anti-PDGFRA antibodies

    PubMed Central

    Chen, George L.; Arai, Sally; Flowers, Mary E. D.; Otani, Joanne M.; Qiu, Jingxin; Cheng, Ethan C.; McMillan, Alex; Johnston, Laura J.; Shizuru, Judith A.

    2011-01-01

    Stimulatory antiplatelet derived growth factor receptor α (PDGFRA) antibodies have been associated with extensive chronic graft-versus-host disease (cGVHD). We performed a phase 1 dose escalation trial of imatinib in corticosteroid-dependent/refractory cGVHD to assess the safety of imatinib and test the hypothesis that abrogation of PDGFRA signaling can ameliorate the manifestations of cGVHD. Fifteen patients were enrolled. Mean follow-up time was 56.6 weeks (range, 18-82.4 weeks). Imatinib 400 mg daily was associated with more frequent moderate to life-threatening adverse events than 200 mg daily. The main adverse events were nausea, edema, confusion, diarrhea, liver function test elevation, fatigue, and myalgia. The overall response rate was 40% (6 of 15). The treatment failure rate was 40% (6 of 15). Twenty percent (3 of 15) of subjects had stable disease. Of 4 subjects with phospho-PDGFRA and phospho-PDGFRB immunohistochemistry studies before and after treatment, inhibition of phosphorylation was observed in 3 but correlated with response in one. Anti-PDGFRA antibodies were observed in 7 of 11 evaluable subjects but correlated with clinical activity in 4. We conclude that cGVHD responds to imatinib through multiple pathways that may include PDGFRA signal transduction. This study is registered at www.clinicaltrials.gov as #NCT00760981. PMID:21828142

  1. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia.

    PubMed

    Sharman, Jeff; Hawkins, Michael; Kolibaba, Kathryn; Boxer, Michael; Klein, Leonard; Wu, Meihua; Hu, Jing; Abella, Steve; Yasenchak, Chris

    2015-04-01

    Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889. PMID:25696919

  2. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia

    PubMed Central

    Hawkins, Michael; Kolibaba, Kathryn; Boxer, Michael; Klein, Leonard; Wu, Meihua; Hu, Jing; Abella, Steve; Yasenchak, Chris

    2015-01-01

    Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889. PMID:25696919

  3. Traditional Chinese herbal medicine in the supportive management of patients with chronic cytopaenic marrow diseases -- a phase I/II clinical study.

    PubMed

    Linn, Yeh-Ching; Lu, Jiahui; Lim, Lay-Cheng; Sun, Huili; Sun, Jue; Zhou, Yongming

    2011-08-01

    We report on a phase I/II, single arm clinical trial studying the safety and efficacy of Traditional Chinese Medicine (TCM) in patients with various chronic cytopaenic marrow diseases including myelodysplastic syndrome (MDS), myelofibrosis (MF), aplastic anaemia (AA) and thalassemia intermedia, who either have failed, are unfit for or refused currently available Western medical treatment. Patients took oral herbal concoctions according to their TCM syndromes for 24 weeks while continuing with western medical management. The median age of this group of 31 patients was 61 (26--84) years old and median disease duration was 5 years (0.3--40 years). TCM herbs were well tolerated in these patients with multiple comorbidities and previous disease-related complications. Twenty-three patients completed the study with 5 (2 with MDS, 2 with MF and 1 with SAA) achieving some degree of haematological improvement. EORTC quality of life indicators improved in more than half of patients. This small study offers positive results and provides the basis for future larger studies which should randomize patients with MDS, MF and AA managed with standard Western medical treatment to without and with upfront combinations with TCM herbs. This will conclusively define the role of TCM in the supportive management of these diseases. This study was registered with Clinicaltrial.gov as NCT01224496. PMID:21742281

  4. Intensive care unit nurses' perceptions of patient participation in the acute phase of chronic obstructive pulmonary disease exacerbation: an interview study

    PubMed Central

    Kvangarsnes, Marit; Torheim, Henny; Hole, Torstein; Öhlund, Lennart S

    2013-01-01

    Aim To report a study conducted to explore intensive care unit nurses’ perceptions of patient participation in the acute phase of chronic obstructive pulmonary disease exacerbation. Background An acute exacerbation is a life-threatening situation, which patients often consider to be extremely frightening. Healthcare personnel exercise considerable power in this situation, which challenges general professional notions of patient participation. Design Critical discourse analysis. Methods In the autumn of 2009, three focus group interviews with experienced intensive care nurses were conducted at two hospitals in western Norway. Two groups had six participants each, and one group had five (N = 17). The transcribed interviews were analysed by means of critical discourse analysis. Findings The intensive care nurses said that an exacerbation is often an extreme situation in which healthcare personnel are exercising a high degree of control and power over patients. Patient participation during exacerbation often takes the form of non-involvement. The participating nurses attached great importance to taking a sensitive approach when meeting patients. The nurses experienced challenging ethical dilemmas. Conclusion This study shows that patient participation should not be understood in universal terms, but rather in relation to a specific setting and the interactions that occur in this setting. Healthcare personnel must develop skill, understanding, and competence to meet these challenging ethical dilemmas. A collaborative inter-professional approach between physicians and nurses is needed to meet the patients’ demand for involvement. PMID:22512673

  5. Lenalidomide treatment and prognostic markers in relapsed or refractory chronic lymphocytic leukemia: data from the prospective, multicenter phase-II CLL-009 trial

    PubMed Central

    Bühler, A; Wendtner, C-M; Kipps, T J; Rassenti, L; Fraser, G A M; Michallet, A-S; Hillmen, P; Dürig, J; Gregory, S A; Kalaycio, M; Aurran-Schleinitz, T; Trentin, L; Gribben, J G; Chanan-Khan, A; Purse, B; Zhang, J; De Bedout, S; Mei, J; Hallek, M; Stilgenbauer, S

    2016-01-01

    Efficacy of lenalidomide was investigated in 103 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) treated on the prospective, multicenter randomized phase-II CLL-009 trial. Interphase cytogenetic and mutational analyses identified TP53 mutations, unmutated IGHV, or del(17p) in 36/96 (37.5%), 68/88 (77.3%) or 22/92 (23.9%) patients. The overall response rate (ORR) was 40.4% (42/104). ORRs were similar irrespective of TP53 mutation (36.1% (13/36) vs 43.3% (26/60) for patients with vs without mutation) or IGHV mutation status (45.0% (9/20) vs 39.1% (27/68)); however, patients with del(17p) had lower ORRs than those without del(17p) (21.7% (5/22) vs 47.1% (33/70); P=0.049). No significant differences in progression-free survival and overall survival (OS) were observed when comparing subgroups defined by the presence or absence of high-risk genetic characteristics. In multivariate analyses, only multiple prior therapies (⩾3 lines) significantly impacted outcomes (median OS: 21.2 months vs not reached; P=0.019). This analysis indicates that lenalidomide is active in patients with relapsed/refractory CLL with unfavorable genetic profiles, including TP53 inactivation or unmutated IGHV. (ClinicalTrials.gov identifier: NCT00963105). PMID:26967821

  6. Effects of chronic acceleration on body composition

    NASA Technical Reports Server (NTRS)

    Pitts, G. C.

    1982-01-01

    Studies of the centrifugation of adult rats showed an unexpected decrease in the mass of fat-free muscle and bone, in spite of the added load induced by centrifugation. It is suggested that the lower but constant fat-free body mass was probably regulated during centrifugation. Rats placed in weightless conditions for 18.5 days gave indirect but strong evidence that the muscle had increased in mass. Other changes in the rats placed in weightless conditions included a smaller fraction of skeletal mineral, a smaller fraction of water in the total fat-free body, and a net shift of fluid from skin to viscera. Adult rats centrifuged throughout the post-weaning growth period exhibited smaller masses of bone and central nervous system (probably attributable to slower growth of the total body), and a larger mass of skin than controls at 1 G. Efforts at simulating the effects of weightlessness or centrifugation on the body composition of rats by regimens at terrestrial gravity were inconclusive.

  7. Acceleration switch

    DOEpatents

    Abbin, J.P. Jr.; Devaney, H.F.; Hake, L.W.

    1979-08-29

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  8. Acceleration switch

    DOEpatents

    Abbin, Jr., Joseph P.; Devaney, Howard F.; Hake, Lewis W.

    1982-08-17

    The disclosure relates to an improved integrating acceleration switch of the type having a mass suspended within a fluid filled chamber, with the motion of the mass initially opposed by a spring and subsequently not so opposed.

  9. ION ACCELERATOR

    DOEpatents

    Bell, J.S.

    1959-09-15

    An arrangement for the drift tubes in a linear accelerator is described whereby each drift tube acts to shield the particles from the influence of the accelerating field and focuses the particles passing through the tube. In one embodiment the drift tube is splii longitudinally into quadrants supported along the axis of the accelerator by webs from a yoke, the quadrants. webs, and yoke being of magnetic material. A magnetic focusing action is produced by energizing a winding on each web to set up a magnetic field between adjacent quadrants. In the other embodiment the quadrants are electrically insulated from each other and have opposite polarity voltages on adjacent quadrants to provide an electric focusing fleld for the particles, with the quadrants spaced sufficienily close enough to shield the particles within the tube from the accelerating electric field.

  10. LINEAR ACCELERATOR

    DOEpatents

    Christofilos, N.C.; Polk, I.J.

    1959-02-17

    Improvements in linear particle accelerators are described. A drift tube system for a linear ion accelerator reduces gap capacity between adjacent drift tube ends. This is accomplished by reducing the ratio of the diameter of the drift tube to the diameter of the resonant cavity. Concentration of magnetic field intensity at the longitudinal midpoint of the external sunface of each drift tube is reduced by increasing the external drift tube diameter at the longitudinal center region.

  11. Muon Acceleration - RLA and FFAG

    SciTech Connect

    Bogacz, Alex

    2011-10-01

    Various acceleration schemes for muons are presented. The overall goal of the acceleration systems: large acceptance acceleration to 25 GeV and 'beam shaping' can be accomplished by various fixed field accelerators at different stages. They involve three superconducting linacs: a single pass linear Pre-accelerator followed by a pair of multi-pass Recirculating Linear Accelerators (RLA) and finally a non-scaling FFAG ring. The present baseline acceleration scenario has been optimized to take maximum advantage of appropriate acceleration scheme at a given stage. The solenoid based Pre-accelerator offers very large acceptance and facilitates correction of energy gain across the bunch and significant longitudinal compression trough induced synchrotron motion. However, far off-crest acceleration reduces the effective acceleration gradient and adds complexity through the requirement of individual RF phase control for each cavity. The RLAs offer very efficient usage of high gradient superconducting RF and ability to adjust path-length after each linac pass through individual return arcs with uniformly periodic FODO optics suitable for chromatic compensation of emittance dilution with sextupoles. However, they require spreaders/recombiners switchyards at both linac ends and significant total length of the arcs. The non-scaling Fixed Field Alternating Gradient (FFAG) ring combines compactness with very large chromatic acceptance (twice the injection energy) and it allows for large number of passes through the RF (at least eight, possibly as high as 15).

  12. High field gradient particle accelerator

    DOEpatents

    Nation, John A.; Greenwald, Shlomo

    1989-01-01

    A high electric field gradient electron accelerator utilizing short duration, microwave radiation, and capable of operating at high field gradients for high energy physics applications or at reduced electric field gradients for high average current intermediate energy accelerator applications. Particles are accelerated in a smooth bore, periodic undulating waveguide, wherein the period is so selected that the particles slip an integral number of cycles of the r.f. wave every period of the structure. This phase step of the particles produces substantially continuous acceleration in a traveling wave without transverse magnetic or other guide means for the particle.

  13. High field gradient particle accelerator

    DOEpatents

    Nation, J.A.; Greenwald, S.

    1989-05-30

    A high electric field gradient electron accelerator utilizing short duration, microwave radiation, and capable of operating at high field gradients for high energy physics applications or at reduced electric field gradients for high average current intermediate energy accelerator applications is disclosed. Particles are accelerated in a smooth bore, periodic undulating waveguide, wherein the period is so selected that the particles slip an integral number of cycles of the r.f. wave every period of the structure. This phase step of the particles produces substantially continuous acceleration in a traveling wave without transverse magnetic or other guide means for the particle. 10 figs.

  14. Microwave inverse Cerenkov accelerator

    SciTech Connect

    Zhang, T.B.; Marshall, T.C.; LaPointe, M.A.; Hirshfield, J.L.

    1997-03-01

    A Microwave Inverse Cerenkov Accelerator (MICA) is currently under construction at the Yale Beam Physics Laboratory. The accelerating structure in MICA consists of an axisymmetric dielectrically lined waveguide. For the injection of 6 MeV microbunches from a 2.856 GHz RF gun, and subsequent acceleration by the TM{sub 01} fields, particle simulation studies predict that an acceleration gradient of 6.3 MV/m can be achieved with a traveling-wave power of 15 MW applied to the structure. Synchronous injection into a narrow phase window is shown to allow trapping of all injected particles. The RF fields of the accelerating structure are shown to provide radial focusing, so that longitudinal and transverse emittance growth during acceleration is small, and that no external magnetic fields are required for focusing. For 0.16 nC, 5 psec microbunches, the normalized emittance of the accelerated beam is predicted to be less than 5{pi}mm-mrad. Experiments on sample alumina tubes have been conducted that verify the theoretical dispersion relation for the TM{sub 01} mode over a two-to-one range in frequency. No excitation of axisymmetric or non-axisymmetric competing waveguide modes was observed. High power tests showed that tangential electric fields at the inner surface of an uncoated sample of alumina pipe could be sustained up to at least 8.4 MV/m without breakdown. These considerations suggest that a MICA test accelerator can be built to examine these predictions using an available RF power source, 6 MeV RF gun and associated beam line. {copyright} {ital 1997 American Institute of Physics.}

  15. Accelerator simulation of astrophysical processes

    NASA Technical Reports Server (NTRS)

    Tombrello, T. A.

    1983-01-01

    Phenomena that involve accelerated ions in stellar processes that can be simulated with laboratory accelerators are described. Stellar evolutionary phases, such as the CNO cycle, have been partially explored with accelerators, up to the consumption of He by alpha particle radiative capture reactions. Further experimentation is indicated on reactions featuring N-13(p,gamma)O-14, O-15(alpha, gamma)Ne-19, and O-14(alpha,p)F-17. Accelerated beams interacting with thin foils produce reaction products that permit a determination of possible elemental abundances in stellar objects. Additionally, isotopic ratios observed in chondrites can be duplicated with accelerator beam interactions and thus constraints can be set on the conditions producing the meteorites. Data from isotopic fractionation from sputtering, i.e., blasting surface atoms from a material using a low energy ion beam, leads to possible models for processes occurring in supernova explosions. Finally, molecules can be synthesized with accelerators and compared with spectroscopic observations of stellar winds.

  16. Cosmic Plasma Wakefield Acceleration

    NASA Astrophysics Data System (ADS)

    Chen, Pisin; Tajima, Toshiki; Takahashi, Yoshiyuki

    2002-10-01

    A cosmic acceleration mechanism is introduced which is based on the wakefields excited by the Alfven shocks in a relativistically flowing plasma. We show that there exists a threshold condition for transparency below which the accelerating particle is collision-free and suffers little energy loss in the plasma medium. The stochastic encounters of the random accelerating-decelerating phases results in a power-law energy spectrum: f([epsilon]) [is proportional to] 1/[epsilon]2. As an example, we discuss the possible production of super-GZK ultra high energy cosmic rays (UHECR) in the atmosphere of gamma ray bursts. The estimated event rate in our model agrees with that from UHECR observations. [copyright] 2002 American Institute of Physics

  17. High-Intensity Proton Accelerator

    SciTech Connect

    Jay L. Hirshfield

    2011-12-27

    Analysis is presented for an eight-cavity proton cyclotron accelerator that could have advantages as compared with other accelerators because of its potentially high acceleration gradient. The high gradient is possible since protons orbit in a sequence of TE111 rotating mode cavities of equally diminishing frequencies with path lengths during acceleration that greatly exceed the cavity lengths. As the cavities operate at sequential harmonics of a basic repetition frequency, phase synchronism can be maintained over a relatively wide injection phase window without undue beam emittance growth. It is shown that use of radial vanes can allow cavity designs with significantly smaller radii, as compared with simple cylindrical cavities. Preliminary beam transport studies show that acceptable extraction and focusing of a proton beam after cyclic motion in this accelerator should be possible. Progress is also reported on design and tests of a four-cavity electron counterpart accelerator for experiments to study effects on beam quality arising from variations injection phase window width. This device is powered by four 500-MW pulsed amplifiers at 1500, 1800, 2100, and 2400 MHz that provide phase synchronous outputs, since they are driven from a with harmonics derived from a phase-locked 300 MHz source.

  18. Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

    PubMed Central

    Tong, Wei-Gang; Chen, Rong; Plunkett, William; Siegel, David; Sinha, Rajni; Harvey, R. Donald; Badros, Ashraf Z.; Popplewell, Leslie; Coutre, Steven; Fox, Judith A.; Mahadocon, Kristi; Chen, Tianling; Kegley, Peggy; Hoch, Ute; Wierda, William G.

    2010-01-01

    Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy. PMID:20479412

  19. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment

    PubMed Central

    Fluge, Øystein; Risa, Kristin; Lunde, Sigrid; Alme, Kine; Rekeland, Ingrid Gurvin; Sapkota, Dipak; Kristoffersen, Einar Kleboe; Sørland, Kari; Bruland, Ove; Dahl, Olav; Mella, Olav

    2015-01-01

    Background Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS. Methods In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months. Findings Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8–66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity. Conclusion In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed

  20. Acceleration Studies

    NASA Technical Reports Server (NTRS)

    Rogers, Melissa J. B.

    1993-01-01

    Work to support the NASA MSFC Acceleration Characterization and Analysis Project (ACAP) was performed. Four tasks (analysis development, analysis research, analysis documentation, and acceleration analysis) were addressed by parallel projects. Work concentrated on preparation for and implementation of near real-time SAMS data analysis during the USMP-1 mission. User support documents and case specific software documentation and tutorials were developed. Information and results were presented to microgravity users. ACAP computer facilities need to be fully implemented and networked, data resources must be cataloged and accessible, future microgravity missions must be coordinated, and continued Orbiter characterization is necessary.

  1. Cytogenetic conversion following allogeneic bone marrow transplantation for advanced chronic myelogenous leukemia

    SciTech Connect

    McGlave, P.B.; Miller, W.J.; Hurd, D.D.; Arthur, D.C.; Kim, T.

    1981-11-01

    We performed a pilot study to test the effectiveness of allogeneic bone marrow transplantation in the treatment of chronic myelogenous leukemia. Five patients in the advanced stages of chronic myelogenous leukemia (four in blast crisis, one in accelerated phase) with abnormal chromosomes underwent matched-sibling allogeneic bone marrow transplantation after preparation with busulfan, vincristine, cyclophosphamide, and fractionated total body irradiation. Engraftment and conversion to normal chromosome patterns after transplantation occurred in all five patients. None of the patients reverted to an abnormal chromosome pattern or demonstrated clinical or hematologic evidence of recurrent disease during the course of this study; however, longest survival from transplant was 248 days. Allogeneic bone marrow transplantation can eradicate the abnormal clone even in far advanced chronic myelogenous leukemia and can provide normal hematopoiesis. We suggest that clinical complications of chemotherapeutic toxicity and infection were responsible for the short survival in this group of patients, and that these complications could be decreased by performing transplantation in the chronic phase or early accelerated phase of the disease.

  2. Effect of solution and solid-phase conditions on the Fe(II)-accelerated transformation of ferrihydrite to lepidocrocite and goethite.

    PubMed

    Boland, Daniel D; Collins, Richard N; Miller, Christopher J; Glover, Chris J; Waite, T David

    2014-05-20

    Aqueous ferrous iron (Fe(II)) accelerates the transformation of ferrihydrite into secondary, more crystalline minerals however the factors controlling the rate and, indeed, the underlying mechanism of this transformation process remain unclear. Here, we present the first detailed study of the kinetics of the Fe(II)-accelerated transformation of ferrihydrite to goethite, via lepidocrocite, for a range of pH and Fe(II) concentrations and, from the results obtained, provide insight into the factors controlling the transformation rate and the processes responsible for transformation. A reaction scheme for the Fe(II)-accelerated secondary mineralization of ferrihydrite is developed in which an Fe(II) atom attaches to the ferrihydrite surface where it is immediately oxidized to Fe(III) with the resultant electron transferred, sequentially, to other iron oxyhydroxide Fe(III) atoms before release to solution as Fe(II). This freshly precipitated Fe(III) forms the nuclei for the formation of secondary minerals and also facilitates the ongoing uptake of Fe(II) from solution by creation of fresh surface sites. The concentration of solid-associated Fe(II) and the rate of transport of Fe(II) to the oxyhydroxide surface appear to determine which particular secondary minerals form and their rates of formation. Lepidocrocite growth is enhanced at lower solid-associated Fe(II) concentrations while conditions leading to more rapid uptake of Fe(II) from solution lead to higher goethite growth rates. PMID:24724707

  3. Modulational effects in accelerators

    SciTech Connect

    Satogata, T.

    1997-12-01

    We discuss effects of field modulations in accelerators, specifically those that can be used for operational beam diagnostics and beam halo control. In transverse beam dynamics, combined effects of nonlinear resonances and tune modulations influence diffusion rates with applied tune modulation has been demonstrated. In the longitudinal domain, applied RF phase and voltage modulations provide mechanisms for parasitic halo transport, useful in slow crystal extraction. Experimental experiences with transverse tune and RF modulations are also discussed.

  4. Plasma accelerator

    DOEpatents

    Wang, Zhehui; Barnes, Cris W.

    2002-01-01

    There has been invented an apparatus for acceleration of a plasma having coaxially positioned, constant diameter, cylindrical electrodes which are modified to converge (for a positive polarity inner electrode and a negatively charged outer electrode) at the plasma output end of the annulus between the electrodes to achieve improved particle flux per unit of power.

  5. Accelerated Achievement

    ERIC Educational Resources Information Center

    Ford, William J.

    2010-01-01

    This article focuses on the accelerated associate degree program at Ivy Tech Community College (Indiana) in which low-income students will receive an associate degree in one year. The three-year pilot program is funded by a $2.3 million grant from the Lumina Foundation for Education in Indianapolis and a $270,000 grant from the Indiana Commission…

  6. ACCELERATION INTEGRATOR

    DOEpatents

    Pope, K.E.

    1958-01-01

    This patent relates to an improved acceleration integrator and more particularly to apparatus of this nature which is gyrostabilized. The device may be used to sense the attainment by an airborne vehicle of a predetermined velocitv or distance along a given vector path. In its broad aspects, the acceleration integrator utilizes a magnetized element rotatable driven by a synchronous motor and having a cylin drical flux gap and a restrained eddy- current drag cap deposed to move into the gap. The angular velocity imparted to the rotatable cap shaft is transmitted in a positive manner to the magnetized element through a servo feedback loop. The resultant angular velocity of tae cap is proportional to the acceleration of the housing in this manner and means may be used to measure the velocity and operate switches at a pre-set magnitude. To make the above-described dcvice sensitive to acceleration in only one direction the magnetized element forms the spinning inertia element of a free gyroscope, and the outer housing functions as a gimbal of a gyroscope.

  7. Particle acceleration

    NASA Technical Reports Server (NTRS)

    Vlahos, L.; Machado, M. E.; Ramaty, R.; Murphy, R. J.; Alissandrakis, C.; Bai, T.; Batchelor, D.; Benz, A. O.; Chupp, E.; Ellison, D.

    1986-01-01

    Data is compiled from Solar Maximum Mission and Hinothori satellites, particle detectors in several satellites, ground based instruments, and balloon flights in order to answer fundamental questions relating to: (1) the requirements for the coronal magnetic field structure in the vicinity of the energization source; (2) the height (above the photosphere) of the energization source; (3) the time of energization; (4) transistion between coronal heating and flares; (5) evidence for purely thermal, purely nonthermal and hybrid type flares; (6) the time characteristics of the energization source; (7) whether every flare accelerates protons; (8) the location of the interaction site of the ions and relativistic electrons; (9) the energy spectra for ions and relativistic electrons; (10) the relationship between particles at the Sun and interplanetary space; (11) evidence for more than one acceleration mechanism; (12) whether there is single mechanism that will accelerate particles to all energies and also heat the plasma; and (13) how fast the existing mechanisms accelerate electrons up to several MeV and ions to 1 GeV.

  8. Hyperbaric oxygen for patients with chronic bowel dysfunction after pelvic radiotherapy (HOT2): a randomised, double-blind, sham-controlled phase 3 trial

    PubMed Central

    Glover, Mark; Smerdon, Gary R; Andreyev, H Jervoise; Benton, Barbara E; Bothma, Pieter; Firth, Oliver; Gothard, Lone; Harrison, John; Ignatescu, Mihaela; Laden, Gerard; Martin, Sue; Maynard, Lauren; McCann, Des; Penny, Christine E L; Phillips, Spencer; Sharp, Grace; Yarnold, John

    2016-01-01

    Summary Background Hyperbaric oxygen has been used as a therapy for patients experiencing chronic intestinal syndromes after pelvic radiotherapy for decades, yet the evidence to support the use of this therapy is based almost exclusively on non-randomised studies. We aimed to provide conclusive results for the clinical benefits of hyperbaric oxygen in patients with chronic bowel dysfunction after radiotherapy for pelvic malignancies. Methods HOT2 was a double-blind, sham-controlled, phase 3 randomised study of patients (≥18 years) with chronic gastrointestinal symptoms for 12 months or more after radiotherapy and which persisted despite at least 3 months of optimal medical therapy and no evidence of cancer recurrence. Participants were stratified by participating hyperbaric centre and randomly assigned (2:1) by a computer-generated list (block size nine or 12) to receive treatment with hyperbaric oxygen therapy or sham. Participants in the active treatment group breathed 100% oxygen at 2·4 atmospheres of absolute pressure (ATA) and the control group breathed 21% oxygen at 1·3 ATA; both treatment groups received 90-min air pressure exposures once daily for 5 days per week for a total of 8 weeks (total of 40 exposures). Staff at the participating hyperbaric medicine facilities knew the allocated treatment, but patients, clinicians, nurse practitioners, and other health-care professionals associated with patients' care were masked to treatment allocation. Primary endpoints were changes in the bowel component of the modified Inflammatory Bowel Disease Questionnaire (IBDQ) score and the IBDQ rectal bleeding score 12 months after start of treatment relative to baseline. The primary outcome was analysed in a modified intention-to-treat population, excluding patients who did not provide IBDQ scores within a predetermined time-frame. All patients have completed 12 months of follow-up and the final analysis is complete. The trial is registered with the ISRCTN registry

  9. Chronic cholecystitis

    MedlinePlus

    Cholecystitis - chronic ... Most of the time, chronic cholecystitis is caused by repeated attacks of acute (sudden) cholecystitis. Most of these attacks are caused by gallstones in the gallbladder. These ...

  10. Chronic Bronchitis

    MedlinePlus

    Bronchitis is an inflammation of the bronchial tubes, the airways that carry air to your lungs. It ... chest tightness. There are two main types of bronchitis: acute and chronic. Chronic bronchitis is one type ...

  11. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial

    PubMed Central

    Minniti, Caterina P; Gorbach, Alexander M; Xu, Dihua; Hon, Yuen Yi; Delaney, Kara-Marie; Seidel, Miles; Malik, Nitin; Peters-Lawrence, Marlene; Cantilena, Carly; Nichols, James S; Mendelsohn, Laurel; Conrey, Anna; Grimes, George; Kato, Gregory J

    2015-01-01

    Summary Background Well-tolerated and effective treatments are needed for chronic leg ulcers in sickle cell anaemia. Topical sodium nitrite, a known nitric oxide donor, enhances blood flow in ulcers and has known bacteriostatic effects. We aimed to assess the safety, tolerability, and pharmacokinetics of topical sodium nitrite in patients with sickle cell disease and chronic leg ulcers. Methods We enrolled adult patients from an ambulatory clinic at the National Institutes of Health (Bethesda, MD, USA) with sickle cell anaemia with leg ulcers (with a surface area of 2.5–100 cm2) persisting for at least 4 weeks into a safety and tolerability phase 1 dose-escalation trial of topical sodium nitrite. Increasing concentrations of sodium nitrite cream were applied twice weekly for 4 weeks to one ulcer per patient at five dose levels (0.5%, 1%, 1.5%, 1.8%, and 2%). The primary endpoints were safety and tolerability, with secondary endpoints of pharmacokinetics, blood flow, and wound healing. Pain relief was analysed post hoc. Endpoints were analysed over time for the whole study population and according to dose level. This study is registered with ClinicalTrials.gov, number NCT01316796. Findings Between April 4, 2011, and March 19, 2013, we enrolled 18 adult patients with sickle cell anaemia and leg ulcers into our trial. We assigned three patients into each cohort, and each cohort was treated with a different concentration of sodium nitrite cream (cohort 1: 0.5%, cohort 2: 1.0%, cohort 3: 1.5%, and cohort 4: 2.0%). Patients were not enrolled into the next cohort dose until we were able to establish that no dose-limiting toxicities were observed. An additional six patients were enrolled to cohort 3a: 1.8%, after two patients in cohort 4 had asymptomatic drops in diastolic blood pressure. No grade 3–4 adverse events were observed, and there were no serious adverse events or dose-limiting side-effects. Pharmacokinetic analysis showed that systemic absorption of sodium

  12. Chronic Bronchitis

    MedlinePlus

    ... carry air to your lungs. It causes a cough that often brings up mucus. It can also cause shortness of breath, wheezing, a low fever, and chest tightness. There are two main types of bronchitis: acute and chronic. Chronic bronchitis is one type of COPD (chronic ...

  13. Particle acceleration processes in the solar corona

    NASA Astrophysics Data System (ADS)

    Melrose, D. B.

    A review is presented of some theoretical ideas on particle acceleration associated with solar flares. Various acceleration mechanisms are discussed, including forms of stochastic acceleration, shock drift acceleration, resonant acceleration, diffusive acceleration at shock fronts, acceleration during magnetic reconnection, and acceleration by parallel electric fields in double layers or electrostatic shocks. Particular attention is given to first phase acceleration of electrons in solar flares, which is usually attributed to bulk energization of electrons. It is proposed that the dissipation cannot be due to classical resistivity and entails anomalous resistivity or hyperresistivity, such as in multiple double layers. A model is developed for bulk energization due to the continual formation and decay of weak double layers.

  14. Chronic Hepatitis B Virus Infection: The Relation between Hepatitis B Antigen Expression, Telomere Length, Senescence, Inflammation and Fibrosis

    PubMed Central

    Tachtatzis, Phaedra M.; Marshall, Aileen; Aravinthan, Aloysius; Verma, Suman; Penrhyn-Lowe, Sue; Mela, Marianna; Scarpini, Cinzia; Davies, Susan E.; Coleman, Nicholas; Alexander, Graeme J. M.

    2015-01-01

    Background Chronic Hepatitis B virus (HBV) infection can lead to the development of chronic hepatitis, cirrhosis and hepatocellular carcinoma. We hypothesized that HBV might accelerate hepatocyte ageing and investigated the effect of HBV on hepatocyte cell cycle state and biological age. We also investigated the relation between inflammation, fibrosis and cell cycle phase. Methods Liver samples from patients with chronic HBV (n = 91), normal liver (n = 55) and regenerating liver (n = 15) were studied. Immunohistochemistry for cell cycle phase markers and HBV antigens was used to determine host cell cycle phase. Hepatocyte-specific telomere length was evaluated by quantitative fluorescent in-situ hybridization (Q-FISH) in conjunction with hepatocyte nuclear area and HBV antigen expression. The effects of induced cell cycle arrest and induced cellular senescence on HBV production were assessed in vitro. Results 13.7% hepatocytes in chronic HBV had entered cell cycle, but expression of markers for S, G2 and M phase was low compared with regenerating liver. Hepatocyte p21 expression was increased (10.9%) in chronic HBV and correlated with liver fibrosis. Mean telomere length was reduced in chronic HBV compared to normal. However, within HBV-affected livers, hepatocytes expressing HBV antigens had longer telomeres. Telomere length declined and hepatocyte nuclear size increased as HBV core antigen (HBcAg) expression shifted from the nucleus to cytoplasm. Nuclear co-expression of HBcAg and p21 was not observed. Cell cycle arrest induced in vitro was associated with increased HBV production, in contrast to 
in vitro induction of cellular senescence, which had no effect. Conclusion Chronic HBV infection was associated with hepatocyte G1 cell cycle arrest and accelerated hepatocyte ageing, implying that HBV induced cellular senescence. However, HBV replication was confined to biologically younger hepatocytes. Changes in the cellular location of HBcAg may be related to the

  15. Compact accelerator

    DOEpatents

    Caporaso, George J.; Sampayan, Stephen E.; Kirbie, Hugh C.

    2007-02-06

    A compact linear accelerator having at least one strip-shaped Blumlein module which guides a propagating wavefront between first and second ends and controls the output pulse at the second end. Each Blumlein module has first, second, and third planar conductor strips, with a first dielectric strip between the first and second conductor strips, and a second dielectric strip between the second and third conductor strips. Additionally, the compact linear accelerator includes a high voltage power supply connected to charge the second conductor strip to a high potential, and a switch for switching the high potential in the second conductor strip to at least one of the first and third conductor strips so as to initiate a propagating reverse polarity wavefront(s) in the corresponding dielectric strip(s).

  16. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial

    PubMed Central

    Farooqui, Mohammed Z H; Valdez, Janet; Martyr, Sabrina; Aue, Georg; Saba, Nakhle; Niemann, Carsten U; Herman, Sarah E M; Tian, Xin; Marti, Gerald; Soto, Susan; Hughes, Thomas E; Jones, Jade; Lipsky, Andrew; Pittaluga, Stefania; Stetler-Stevenson, Maryalice; Yuan, Constance; Lee, Yuh Shan; Pedersen, Lone B; Geisler, Christian H; Calvo, Katherine R; Arthur, Diane C; Maric, Irina; Childs, Richard; Young, Neal S; Wiestner, Adrian

    2015-01-01

    Summary Background Patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations respond poorly to first-line chemoimmunotherapy resulting in early relapse and short survival. We investigated the safety and activity of ibrutinib in previously untreated and relapsed or refractory CLL with TP53 aberrations. Methods In this investigator-initiated, single-arm phase 2 study we enrolled eligible adult patients with active CLL with TP53 aberrations at the National Institutes of Health Clinical Center (Bethesda, MD, USA). Patients received 28-day cycles of ibrutinib 420 mg orally once daily until disease progression or the occurrence of limiting toxicities. The primary endpoint was overall response to treatment at 24 weeks in all evaluable patients. This study is registered with ClinicalTrials.gov number NCT01500733, and is fully enrolled. Findings Between Dec 22, 2011 and Jan 2, 2014 we enrolled 51 patients; 47 had CLL with deletion 17p13.1 and four carried a TP53 mutation in the absence of deletion 17p13.1. All patients had active disease requiring therapy. 35 enrolled patients had previously untreated CLL and 16 had relapsed or refractory disease. Median follow-up was 24 months (IQR 12·9-27·0). 33 previously untreated patients and 15 patients with relapsed or refractory CLL were evaluable for response at 24 weeks. 32 (97%; 95% CI 86-100) of 33 previously untreated patients achieved an objective response, including partial response in 18 patients (55%) and partial response with lymphocytosis in 14 (42%). One patient had progressive disease at 0·4 months. 12 (80%; 95% CI 52-96) of the 15 patients with relapsed or refractory CLL had an objective response: six (40%) achieved a partial response and six (40%) a partial response with lymphocytosis; the remaining three (20%) patients had stable disease. Grade 3 or worse treatment-related adverse events were neutropenia in 12 (24%) patients (grade 4 in one [2%] patient), anaemia in seven (14%) patients, and

  17. A phase I/II study examining pentostatin, chlorambucil, and theophylline in patients with relapsed chronic lymphocytic leukemia and non-Hodgkin's lymphoma.

    PubMed

    Willis, Carl R; Goodrich, Amy; Park, Kathy; Waselenko, Jamie K; Lucas, Margaret; Reese, Amy; Diehl, Louis F; Grever, Michael R; Byrd, John C; Flinn, Ian W

    2006-05-01

    In an attempt to exploit bcl-2 overexpression and aberrant p53 function, two frequently encountered aberrations that predict marked treatment resistance and worse prognosis in patients with chronic lymphocytic leukemia (CLL) and non-Hodgkin's lymphoma (NHL), we combined theophylline, pentostatin, and chlorambucil at two dose levels (cohort I: 30 mg/m(2); cohort II: 20 mg/m(2)) on a 21-day cycle for up to six courses. We employed a phase I/II design to determine feasibility, define the maximum tolerated dose (MTD), and explore the impact of biologic modulation on response and time to progression (TTP) in 20 patients with relapsed or refractory CLL and NHL. Eight patients were enrolled in cohort I. They demonstrated a response rate (RR) of 28% and a 16.5-month TTP after receiving a median of two cycles. A 50% RR was observed in this cohort when patients with adverse histologies were excluded. Because of myelotoxicity, this dose level defined the MTD, and de-escalation occurred. All 12 patients in cohort II received 20 mg/m(2) chlorambucil. A 50% RR and an 18-month TTP were observed after a median of 5.5 cycles. An RR of 47% and a complete remission (CR) of 5% were observed for the entire group, although responses and TTP varied greatly by histology. Significant activity was observed in patients with B-cell CLL and follicular lymphoma (FL). RR and TTP for fludarabine-sensitive/naïve and fludarabine-refractory (FR) B-cell CLL patients were 66 vs 25% and 20 vs 8.5 months, respectively. Both FL patients responded (one with partial remission and one with CR), with a 22.5-monthly median TTP. For responding patients, median TTP and overall survival (OS) was 21 and 69 months, respectively, compared to a median TTP of 2 months and an OS of 13.5 months for nonresponders. The combination of pentostatin, chlorambucil, and theophylline is the active regimen in patients with FL and B-cell CLL. PMID:16518606

  18. Hepatitis B Surface Antigen Quantity Positively Correlates with Plasma Levels of microRNAs Differentially Expressed in Immunological Phases of Chronic Hepatitis B in Children

    PubMed Central

    Winther, Thilde Nordmann; Heiberg, Ida Louise; Bang-Berthelsen, Claus Heiner; Pociot, Flemming; Hogh, Birthe

    2013-01-01

    Background and Aim Children with chronic hepatitis B (CHB) are at high risk of progressive liver disease. It is suggested that a newly-identified panel of 16 microRNAs is important in the pathogenesis of CHB in children. Subviral hepatitis B surface antigen (HBsAg) particles are produced in large excess over infectious virions. Interestingly, circulating HBsAg particles have been shown to carry microRNAs. A thorough characterisation of the identified microRNAs and HBsAg over time in plasma from children with CHB may provide useful information about the natural course of childhood CHB. Patients and Methods A cohort of 42 children with CHB was followed over time. Three to five blood samples were obtained from each child at minimum intervals of half a year; in total 180 blood samples. Plasma levels of the 16 microRNAs previously identified were analysed by quantitative real-time polymerase-chain-reaction. Plasma HBsAg was quantified using ARCHITECT® HBsAg assay. Results The presence of 14/16 plasma microRNAs in children with CHB was confirmed. All 14 microRNAs were significantly differentially expressed in different immunological phases of the disease. MicroRNA plasma levels were highest in immune-tolerant children, lower in immune-active children, and reached the lowest values in immune-inactive children, p<0.001. Plasma levels of four microRNAs decreased significantly over time in immune-tolerant and immune-active children whereas the microRNA plasma levels were stable in immune-inactive children, p<0.004. HBsAg quantity was positively correlated with plasma levels of 11/14 microRNAs, p<0.004. Conclusion This is the first study to characterise plasma microRNAs and HBsAg over time in children with CHB. Our data suggest that plasma levels of selected microRNAs and HBsAg are inversely correlated with immunological control of CHB in children. Further studies are, however, needed to advance the understanding of microRNAs and HBsAg in the pathogenesis of CHB in children

  19. Beam acceleration through proton radio frequency quadrupole accelerator in BARC

    NASA Astrophysics Data System (ADS)

    Bhagwat, P. V.; Krishnagopal, S.; Mathew, J. V.; Singh, S. K.; Jain, P.; Rao, S. V. L. S.; Pande, M.; Kumar, R.; Roychowdhury, P.; Kelwani, H.; Rama Rao, B. V.; Gupta, S. K.; Agarwal, A.; Kukreti, B. M.; Singh, P.

    2016-05-01

    A 3 MeV proton Radio Frequency Quadrupole (RFQ) accelerator has been designed at the Bhabha Atomic Research Centre, Mumbai, India, for the Low Energy High Intensity Proton Accelerator (LEHIPA) programme. The 352 MHz RFQ is built in 4 segments and in the first phase two segments of the LEHIPA RFQ were commissioned, accelerating a 50 keV, 1 mA pulsed proton beam from the ion source, to an energy of 1.24 MeV. The successful operation of the RFQ gave confidence in the physics understanding and technology development that have been achieved, and indicate that the road forward can now be traversed rather more quickly.

  20. The energy amplifier: A solid-phase, accelerator driven, sub critical Th/233 U breeder for nuclear energy production with minimal actinide waste

    SciTech Connect

    Rubbia, C.

    1994-12-31

    We describe a hybrid system consisting of a medium current (1-10 mA), medium energy (1 GeV) proton accelerator feeding a subcritical assembly consisting of Thorium (or another fertile element) and a moderator medium (e.g. light water). Under conditions of moderate neutron flux (10{sup 14} ncm{sup -2}), we show by a computer simulation that a stable equilibrium evolves whereby the concentration of fissile {sup 233}U which is bred from Thorium is stable at about 1.3%. The {sup 233}U produces energy by fission and is continuously regenerated in-situ without resorting to any chemical separation. It is shown that the energy produced is several times larger than the energy required to power the proton accelerator, hence the name Energy Amplifier that we have chosen for that system. We have paid particular attention to the question of toxicity and show that this system will result in very small quantities of Plutonium and higher actinide waste. We also show the composition of actinides produced makes this system particularly resistant to nuclear weapons proliferation. This safe subcritical system is based on an abundant and inexpensive resource which is natural Thorium and can be built using present day technology.

  1. BICEP's acceleration

    SciTech Connect

    Contaldi, Carlo R.

    2014-10-01

    The recent Bicep2 [1] detection of, what is claimed to be primordial B-modes, opens up the possibility of constraining not only the energy scale of inflation but also the detailed acceleration history that occurred during inflation. In turn this can be used to determine the shape of the inflaton potential V(φ) for the first time — if a single, scalar inflaton is assumed to be driving the acceleration. We carry out a Monte Carlo exploration of inflationary trajectories given the current data. Using this method we obtain a posterior distribution of possible acceleration profiles ε(N) as a function of e-fold N and derived posterior distributions of the primordial power spectrum P(k) and potential V(φ). We find that the Bicep2 result, in combination with Planck measurements of total intensity Cosmic Microwave Background (CMB) anisotropies, induces a significant feature in the scalar primordial spectrum at scales k∼ 10{sup -3} Mpc {sup -1}. This is in agreement with a previous detection of a suppression in the scalar power [2].

  2. Prospects for Accelerator Technology

    NASA Astrophysics Data System (ADS)

    Todd, Alan

    2011-02-01

    Accelerator technology today is a greater than US$5 billion per annum business. Development of higher-performance technology with improved reliability that delivers reduced system size and life cycle cost is expected to significantly increase the total accelerator technology market and open up new application sales. Potential future directions are identified and pitfalls in new market penetration are considered. Both of the present big market segments, medical radiation therapy units and semiconductor ion implanters, are approaching the "maturity" phase of their product cycles, where incremental development rather than paradigm shifts is the norm, but they should continue to dominate commercial sales for some time. It is anticipated that large discovery-science accelerators will continue to provide a specialty market beset by the unpredictable cycles resulting from the scale of the projects themselves, coupled with external political and economic drivers. Although fraught with differing market entry difficulties, the security and environmental markets, together with new, as yet unrealized, industrial material processing applications, are expected to provide the bulk of future commercial accelerator technology growth.

  3. Advanced concepts for acceleration

    SciTech Connect

    Keefe, D.

    1986-07-01

    Selected examples of advanced accelerator concepts are reviewed. Such plasma accelerators as plasma beat wave accelerator, plasma wake field accelerator, and plasma grating accelerator are discussed particularly as examples of concepts for accelerating relativistic electrons or positrons. Also covered are the pulsed electron-beam, pulsed laser accelerator, inverse Cherenkov accelerator, inverse free-electron laser, switched radial-line accelerators, and two-beam accelerator. Advanced concepts for ion acceleration discussed include the electron ring accelerator, excitation of waves on intense electron beams, and two-wave combinations. (LEW)

  4. Accelerated test methods for predicting the life of motor materials exposed to refrigerant/lubricant mixtures. Phase 1, Conceptual design: Final report

    SciTech Connect

    Ellis, P.F. II; Ferguson, A.

    1993-08-18

    The federally mandated phase-out of chlorofluorocarbon refrigerants requires screening tests for motor materials compatibility with alternative refrigerant/lubricant mixtures. In the current phase of the program, ARTI is supporting tests of promising candidate refrigeration/lubricant systems in key refrigeration component systems such as bearings and hermetic motor insulation systems to screen for more subtle detrimental effects and allow estimates of motor-compressor life. This report covers: mechanisms of failure of hermetic motor insulation, current methods for estimation of life of hermetic motors, and conceptual design of improved stator simulator device for testing of alternative refrigerant/lubricant mixtures.

  5. Tandem betatron accelerator

    NASA Astrophysics Data System (ADS)

    Keinigs, Rhon K.

    1991-04-01

    1407_50The tandem betatron is a compact, high-current induction accelerator that has the capability to accelerate electrons to an energy of order one gigavolt. Based upon the operating principle of a conventional betatron, the tandem betatron employs two synchronized induction cores operating 180 degrees out of phase. Embedded within the cores are the vacuum chambers, and these are connected by linear transport sections to allow for moving the beam back and forth between the two betatrons. The 180 degree phase shift between the core fluxes permits the circumvention of the flux swing constraint that limits the maximum energy gain of a conventional betatron. By transporting the beam between the synchronized cores, an electron can access more than one acceleration cycle, and thereby continue to gain energy. This added degree of freedom also permits a significant decrease in the size of the magnet system. Biasing coils provide independent control of the confining magnetic field. Provided that efficient beam switching can be performed, it appears feasible that a one gigavolt electron beam can be generated and confined. At this energy, a high current electron beam circulating in a one meter radius orbit could provide a very intense source of short wavelength ((lambda) < 10 nm) synchrotron radiation. This has direct application to the emerging field of x-ray lithography. At more modest energies (10 MeV-30 MeV) a compact tandem betatron could be employed in the fields of medical radiation therapy, industrial radiography, and materials processing.

  6. Accelerators and the Accelerator Community

    SciTech Connect

    Malamud, Ernest; Sessler, Andrew

    2008-06-01

    In this paper, standing back--looking from afar--and adopting a historical perspective, the field of accelerator science is examined. How it grew, what are the forces that made it what it is, where it is now, and what it is likely to be in the future are the subjects explored. Clearly, a great deal of personal opinion is invoked in this process.

  7. Continuous accelerated 7-days-a-week radiotherapy for head-and-neck cancer: Long-term results of Phase III clinical trial

    SciTech Connect

    Skladowski, Krzysztof . E-mail: skladowski@io.gliwice.pl; Maciejewski, Boguslaw; Golen, Maria; Tarnawski, Rafal; Slosarek, Krzysztof; Suwinski, Rafal; Sygula, Mariusz; Wygoda, Andrzej

    2006-11-01

    Purpose: To update 5-year results of a previously published study on special 7-days-a-week fractionation continuous accelerated irradiation (CAIR) for head-and-neck cancer patients. Methods and Materials: One hundred patients with squamous cell carcinoma of head and neck in Stage T{sub 2-4}N{sub 0-1}M were randomized between two definitive radiation treatments: accelerated fractionation 7 days a week including weekends (CAIR) and conventional 5 days a week (control). Hence the overall treatment time was 2 weeks shorter in CAIR. Results: Five-year local tumor control was 75% in the CAIR group and 33% in the control arm (p < 0.00004). Tumor-cure benefit corresponded with significant improvement in disease-free survival and overall survival rates. Confluent mucositis was the main acute toxicity, with the incidence significantly higher in CAIR patients than in control (respectively, 94% vs. 53%). When 2.0-Gy fractions were used, radiation necrosis developed in 5 patients (22%) in the CAIR group as a consequential late effect (CLE), but when fraction size was reduced to 1.8 Gy no more CLE occurred. Actuarial 5-year morbidity-free survival rate was similar for both treatments. Conclusions: Selected head-and-neck cancer patients could be treated very effectively with 7-days-a-week radiation schedule with no compromise of total dose and with slight 10% reduction of fraction dose (2 Gy-1.8 Gy), which article gives 1 week reduction of overall treatment time compared with standard 70 Gy in 35 fractions over 47-49 days. Although this report is based on the relatively small group of patients, its results have encouraged us to use CAIR fractionation in a standard radiation treatment for moderately advanced head-and-neck cancer patients.

  8. Flow characteristics in a canine aneurysm model: A comparison of 4D accelerated phase-contrast MR measurements and computational fluid dynamics simulations

    PubMed Central

    Jiang, Jingfeng; Johnson, Kevin; Valen-Sendstad, Kristian; Mardal, Kent-Andre; Wieben, Oliver; Strother, Charles

    2011-01-01

    Purpose: Our purpose was to compare quantitatively velocity fields in and around experimental canine aneurysms as measured using an accelerated 4D PC-MR angiography (MRA) method and calculated based on animal-specific CFD simulations. Methods: Two animals with a surgically created bifurcation aneurysm were imaged using an accelerated 4D PC-MRA method. Meshes were created based on the geometries obtained from the PC-MRA and simulations using “subject-specific” pulsatile velocity waveforms and geometries were then solved using a commercial CFD solver. Qualitative visual assessments and quantitative comparisons of the time-resolved velocity fields obtained from the PC-MRA measurements and the CFD simulations were performed using a defined similarity metric combining both angular and magnitude differences of vector fields. Results: PC-MRA and image-based CFD not only yielded visually consistent representations of 3D streamlines in and around both aneurysms, but also showed good agreement with regard to the spatial velocity distributions. The estimated similarity between time-resolved velocity fields from both techniques was reasonably high (mean value >0.60; one being the highest and zero being the lowest). Relative differences in inflow and outflow zones among selected planes were also reasonable (on the order of 10%–20%). The correlation between CFD-calculated and PC-MRA-measured time-averaged wall shear stresses was low (0.22 and 0.31, p < 0.001). Conclusions: In two experimental canine aneurysms, PC-MRA and image-based CFD showed favorable agreement in intra-aneurismal velocity fields. Combining these two complementary techniques likely will further improve the ability to characterize and interpret the complex flow that occurs in human intracranial aneurysms. PMID:22047395

  9. Chronic migraine.

    PubMed

    Schwedt, Todd J

    2014-01-01

    Chronic migraine is a disabling neurologic condition that affects 2% of the general population. Patients with chronic migraine have headaches on at least 15 days a month, with at least eight days a month on which their headaches and associated symptoms meet diagnostic criteria for migraine. Chronic migraine places an enormous burden on patients owing to frequent headaches; hypersensitivity to visual, auditory, and olfactory stimuli; nausea; and vomiting. It also affects society through direct and indirect medical costs. Chronic migraine typically develops after a slow increase in headache frequency over months to years. Several factors are associated with an increased risk of transforming to chronic migraine. The diagnosis requires a carefully performed patient interview and neurologic examination, sometimes combined with additional diagnostic tests, to differentiate chronic migraine from secondary headache disorders and other primary chronic headaches of long duration. Treatment takes a multifaceted approach that may include risk factor modification, avoidance of migraine triggers, drug and non-drug based prophylaxis, and abortive migraine treatment, the frequency of which is limited to avoid drug overuse. This article provides an overview of current knowledge regarding chronic migraine, including epidemiology, risk factors for its development, pathophysiology, diagnosis, management, and guidelines. The future of chronic migraine treatment and research is also discussed. PMID:24662044

  10. Accelerating PV Cost Effectiveness Through Systems Design, Engineering, and Quality Assurance: Phase I Annual Technical Report, 4 November 2004 - 3 November 2005

    SciTech Connect

    Botkin, J.

    2006-07-01

    During Phase I of this PV Manufacturing R&D subcontract, PowerLight Corporation has made significant progress toward the reduction of installed costs for commercial-scale, rooftop PV systems. PowerLight has worked to reduce operating costs by improving long-term reliability and performance through the development of more sophisticated tools used in system design and monitoring. Additionally, PowerLight has implemented design improvements with the goal of reducing cost while maintaining and/or improving product quality. As part of this effort, PowerLight also modified manufacturing and shipping processes to accommodate these design changes, streamline material flow, reduce cost, and decrease waste streams. During Phase II of this project, PowerLight plans to continue this work with the goal of reducing system cost and improving system performance.

  11. Chronic kidney disease

    MedlinePlus

    Kidney failure - chronic; Renal failure - chronic; Chronic renal insufficiency; Chronic kidney failure; Chronic renal failure ... Chronic kidney disease (CKD) slowly gets worse over months or years. You may not notice any symptoms for some ...

  12. Analyses of critical target cell responses during preclinical phases of evolving chronic radiation-induced myeloproliferative disease-exploitation of a unique canine model

    SciTech Connect

    Seed, T.M.; Kaspar, L.V.; Tolle, D.V.; Fritz, T.E.; Frazier, M.E.

    1988-01-01

    This document briefly summarizes and highlights ongoing studies on the cellular and molecular processes involved in the induction and progression of myeloid leukemia in dogs chronically exposed to low daily doses of wholebody gamma irradiation. Under such conditions, select groups of dogs exhibit extremely high frequencies of myeloproliferative disease (MPD) (i.e., /congruent/50%) of which myeloid leukemia is most prominent. 2 figs.

  13. Ocular safety of sildenafil citrate when administered chronically for pulmonary arterial hypertension: results from phase III, randomised, double masked, placebo controlled trial and open label extension

    PubMed Central

    Tressler, Charles; Hwang, Lie-Ju; Burgess, Gary; Laties, Alan M

    2012-01-01

    Objective To assess the ocular effects and safety profile of chronic sildenafil oral dosing in patients with pulmonary arterial hypertension. Design 12 week, double masked, randomised, placebo controlled, phase III trial with open label extension. Setting 53 institutions worldwide. Participants 277 adults with idiopathic pulmonary arterial hypertension or pulmonary arterial hypertension associated with connective tissue disease or after congenital heart disease repair (mean pulmonary artery pressure ≥25 mm Hg; pulmonary capillary wedge pressure ≤15 mm Hg at rest). Interventions During the double masked study, oral sildenafil 20 mg, 40 mg, or 80 mg or placebo (1:1:1:1) three times daily for 12 weeks was added to baseline drug treatment. In the extension study, the placebo, 20 mg and 40 mg groups received 40 mg three times daily titrated to 80 mg three times daily at week 6. After unmasking, the dose was titrated according to clinical need. Main outcome measure Ocular safety (ocular examinations, visual function tests, participants’ reports of adverse events, and visual disturbance questionnaire completed by investigators) by treatment group at 12 weeks, 24 weeks, 18 months, and yearly. Results Findings of the objective assessments—that is, intraocular pressure and visual function tests (visual acuity, colour vision, and visual field)—were similar across groups (20 mg, n=69; 40 mg, n=67; 80 mg, n=71; placebo, n=70). No clinically significant changes occurred between baseline and 12 weeks, except for an efficacy signal in contrast sensitivity for the sildenafil 40 mg three times daily group. In right eyes, changes in intraocular pressure from baseline to week 12 ranged from a mean of −0.5 (95% confidence interval −1.3 to 0.2) mm Hg with placebo, −0.2 (−0.9 to 0.5) mm Hg with sildenafil 40 mg, and −0.1 (−0.7 to 0.5) mm Hg with 80 mg to 0.3 (−0.4 to 0.9) mm Hg with sildenafil 20 mg (the approved dose for pulmonary arterial hypertension). Mean

  14. Gymnastics in Phase Space

    SciTech Connect

    Chao, Alexander Wu; /SLAC

    2012-03-01

    As accelerator technology advances, the requirements on accelerator beam quality become increasingly demanding. Facing these new demands, the topic of phase space gymnastics is becoming a new focus of accelerator physics R&D. In a phase space gymnastics, the beam's phase space distribution is manipulated and precision tailored to meet the required beam qualities. On the other hand, all realization of such gymnastics will have to obey accelerator physics principles as well as technological limitations. Recent examples of phase space gymnastics include Emittance exchanges, Phase space exchanges, Emittance partitioning, Seeded FELs and Microbunched beams. The emittance related topics of this list are reviewed in this report. The accelerator physics basis, the optics design principles that provide these phase space manipulations, and the possible applications of these gymnastics, are discussed. This fascinating new field promises to be a powerful tool of the future.

  15. Accelerated solvent extraction followed by on-line solid-phase extraction coupled to ion trap LC/MS/MS for analysis of benzalkonium chlorides in sediment samples

    USGS Publications Warehouse

    Ferrer, I.; Furlong, E.T.

    2002-01-01

    Benzalkonium chlorides (BACs) were successfully extracted from sediment samples using a new methodology based on accelerated solvent extraction (ASE) followed by an on-line cleanup step. The BACs were detected by liquid chromatography/ion trap mass spectrometry (LC/MS) or tandem mass spectrometry (MS/MS) using an electrospray interface operated in the positive ion mode. This methodology combines the high efficiency of extraction provided by a pressurized fluid and the high sensitivity offered by the ion trap MS/MS. The effects of solvent type and ASE operational variables, such as temperature and pressure, were evaluated. After optimization, a mixture of acetonitrile/water (6:4 or 7:3) was found to be most efficient for extracting BACs from the sediment samples. Extraction recoveries ranged from 95 to 105% for C12 and C14 homologues, respectively. Total method recoveries from fortified sediment samples, using a cleanup step followed by ASE, were 85% for C12BAC and 79% for C14-BAC. The methodology developed in this work provides detection limits in the subnanogram per gram range. Concentrations of BAC homologues ranged from 22 to 206 ??g/kg in sediment samples from different river sites downstream from wastewater treatment plants. The high affinity of BACs for soil suggests that BACs preferentially concentrate in sediment rather than in water.

  16. Phase III study of cisplatin with pemtrexed or vinorelbine plus concurrent late course accelerated hyperfractionated radiotherapy in patients with unresectable stage III non-small cell lung cancer

    PubMed Central

    Zhao, Qian; Wang, Zhongtang; Huang, Wei; Wang, Qiang; Yu, Shuzeng; Zhou, Tao; Han, Dan; Wu, Zhenying; Gong, Heyi; Sun, Hongfu; Zhang, Jian; Wei, Yumei; Li, Hongsheng; Zhang, Zicheng; Lin, Haiqun; Li, Baosheng

    2016-01-01

    Our aim was to evaluate the efficacy and safety of cisplatin with pemtrexed or vinorelbine and concurrent late course accelerated hyperfractionated radiotherapy (LCAHRT). Patients with unresectable stage III non-small-cell lung cancer (NSCLC) were randomly assigned to two regimens. The experimental (PP) arm included cisplatin, pemtrexed and concurrent LCAHRT based on bilateral lung V20 = 33%. The control (NP) arm used cisplatin, vinorelbine with the same radiotherapy protocol. The primary endpoint was overall survival. Median survival times were 26.0 months (95% CI 23.2 to 28.7 months) and 28.5 months (95% CI 17.1 to 39.9 months) for the NP and PP arms, respectively (P = 0.26). Median progression-free survival was 12.5 months and 17.5 months in the NP and PP arms (P = 0.07). In both arms of the study, there were no differences in overall survival between patients with squamous and nonsquamous NSCLC. The incidences of grade 3 or 4 toxicity were higher in NP than PP arm. With concurrent LCAHRT, pemetrexed/cisplatin was equally as efficacious as vinorelbine/cisplatin, but showed a more favorable toxicity profile. PMID:26761213

  17. Management of chronic immune thrombocytopenic purpura: targeting insufficient megakaryopoiesis as a novel therapeutic principle

    PubMed Central

    Rank, Andreas; Weigert, Oliver; Ostermann, Helmut

    2010-01-01

    Traditionally, anti-platelet autoantibodies accelerating platelet clearance from the peripheral circulation have been recognized as the primary pathopysiological mechanism in chronic immune thrombocytopenia (ITP). Recently, increasing evidence supports the co-existence of insufficient megakaryopoiesis. Inadequate low thrombopoietin (TPO) levels are associated with insufficient proliferation and differentiation of megakaryocytes, decreased proplatelet formation, and subsequent platelet release. Recently two novel activators of TPO receptors have been made available: romiplostim and eltrombopag. In several phase III studies, both agents demonstrated increase of platelet counts in about 80% of chronic ITP patients within 2 to 3 weeks. These agents substantially broaden the therapeutic options for patients with chronic ITP although long-term results are still pending. This review will provide an update on the current conception of underlying mechanisms in ITP and novel, pathophysiologically based treatment options. PMID:20531970

  18. Accelerator system and method of accelerating particles

    NASA Technical Reports Server (NTRS)

    Wirz, Richard E. (Inventor)

    2010-01-01

    An accelerator system and method that utilize dust as the primary mass flux for generating thrust are provided. The accelerator system can include an accelerator capable of operating in a self-neutralizing mode and having a discharge chamber and at least one ionizer capable of charging dust particles. The system can also include a dust particle feeder that is capable of introducing the dust particles into the accelerator. By applying a pulsed positive and negative charge voltage to the accelerator, the charged dust particles can be accelerated thereby generating thrust and neutralizing the accelerator system.

  19. Attention's Accelerator.

    PubMed

    Reinhart, Robert M G; McClenahan, Laura J; Woodman, Geoffrey F

    2016-06-01

    How do people get attention to operate at peak efficiency in high-pressure situations? We tested the hypothesis that the general mechanism that allows this is the maintenance of multiple target representations in working and long-term memory. We recorded subjects' event-related potentials (ERPs) indexing the working memory and long-term memory representations used to control attention while performing visual search. We found that subjects used both types of memories to control attention when they performed the visual search task with a large reward at stake, or when they were cued to respond as fast as possible. However, under normal circumstances, one type of target memory was sufficient for slower task performance. The use of multiple types of memory representations appears to provide converging top-down control of attention, allowing people to step on the attentional accelerator in a variety of high-pressure situations. PMID:27056975

  20. Long-term Cosmetic Outcomes and Toxicities of Proton Beam Therapy Compared With Photon-Based 3-Dimensional Conformal Accelerated Partial-Breast Irradiation: A Phase 1 Trial

    SciTech Connect

    Galland-Girodet, Sigolène; Pashtan, Itai; MacDonald, Shannon M.; Ancukiewicz, Marek; Hirsch, Ariel E.; Kachnic, Lisa A.; Specht, Michelle; Gadd, Michele; Smith, Barbara L.; Powell, Simon N.; Recht, Abram; Taghian, Alphonse G.

    2014-11-01

    Purpose: To present long-term outcomes of a prospective feasibility trial using either protons or 3-dimensional conformal photon-based (accelerated partial-breast irradiation [APBI]) techniques. Methods and Materials: From October 2003 to April 2006, 98 evaluable patients with stage I breast cancer were treated with APBI (32 Gy in 8 fractions given twice daily) on a prospective clinical trial: 19 with proton beam therapy (PBT) and 79 with photons or mixed photons/electrons. Median follow-up was 82.5 months (range, 2-104 months). Toxicity and patient satisfaction evaluations were performed at each visit. Results: At 7 years, the physician rating of overall cosmesis was good or excellent for 62% of PBT patients, compared with 94% for photon patients (P=.03). Skin toxicities were more common for the PBT group: telangiectasia, 69% and 16% (P=.0013); pigmentation changes, 54% and 22% (P=.02); and other late skin toxicities, 62% and 18% (P=.029) for PBT and photons, respectively. There were no significant differences between the groups in the incidences of breast pain, edema, fibrosis, fat necrosis, skin desquamation, and rib pain or fracture. Patient-reported cosmetic outcomes at 7 years were good or excellent for 92% and 96% of PBT and photon patients, respectively (P=.95). Overall patient satisfaction was 93% for the entire cohort. The 7-year local failure rate for all patients was 6%, with 3 local recurrences in the PBT group (7-year rate, 11%) and 2 in photon-treated patients (4%) (P=.22). Conclusions: Local failure rates of 3-dimensional APBI and PBT were similar in this study. However, PBT, as delivered in this study, led to higher rates of long-term telangiectasia, skin color changes, and skin toxicities. We recommend the use of multiple fields and treatment of all fields per treatment session or the use of scanning techniques to minimize skin toxicity.

  1. Chronic pancreatitis.

    PubMed

    Majumder, Shounak; Chari, Suresh T

    2016-05-01

    Chronic pancreatitis describes a wide spectrum of fibro-inflammatory disorders of the exocrine pancreas that includes calcifying, obstructive, and steroid-responsive forms. Use of the term chronic pancreatitis without qualification generally refers to calcifying chronic pancreatitis. Epidemiology is poorly defined, but incidence worldwide seems to be on the rise. Smoking, drinking alcohol, and genetic predisposition are the major risk factors for chronic calcifying pancreatitis. In this Seminar, we discuss the clinical features, diagnosis, and management of chronic calcifying pancreatitis, focusing on pain management, the role of endoscopic and surgical intervention, and the use of pancreatic enzyme-replacement therapy. Management of patients is often challenging and necessitates a multidisciplinary approach. PMID:26948434

  2. Alterations of the renal function and oxidative stress in renal tissue from rats chronically treated with aluminium during the initial phase of hepatic regeneration.

    PubMed

    Mahieu, Stella; Millen, Néstor; González, Marcela; Contini, María del Carmen; Elías, María Mónica

    2005-09-01

    Various indices of renal functions during the early stage of hepatic injury were studied in rats chronically treated with aluminum (Al) lactate. Tubular and hemodynamic parameters were analyzed four days after producing a 65% partial hepatectomy (PH). Water and sodium balances were also studied. Oxidative stress and the activity of Na-K-ATPase were determined in renal tissue. The rats were distributed in four groups: control, Al, PH, Al+PH. Al did not modify the hemodynamic renal functions and the PH-group reduced the glomerular filtrate rate (GFR). The Al + PH group presented a decrease in the renal blood flow and accentuated the GFR fall as compared with PH. The fractional excretion (FE) of water and sodium increased in the PH group. The rats chronically treated with Al and then submitted to the PH protocol developed a further increase in FE of water but a reduction in FE of sodium. Both PH and Al promoted an increase in the aldosterone. PH and Al induced a similar increase of the lipoperoxidation status with reduction of glutathione (GSH) and the activity of glutathione peroxidase (GSH-Px). The data indicated that Al is an inhibitor of catalase. The GSH and GSH-Px activity in the Al + PH group demonstrated a synergic effect of Al and PH. This work demonstrates that rats treated chronically with Al and submitted to another injury (such as hepatic damage) can aggravate renal functions, probably by increasing the oxidative state, at least in kidneys. PMID:16129492

  3. Phase 2 Study of Accelerated Hypofractionated Thoracic Radiation Therapy and Concurrent Chemotherapy in Patients With Limited-Stage Small-Cell Lung Cancer

    SciTech Connect

    Xia, Bing; Hong, Ling-Zhi; Cai, Xu-Wei; Zhu, Zheng-Fei; Liu, Qi; Zhao, Kuai-Le; Fan, Min; Mao, Jing-Fang; Yang, Huan-Jun; Wu, Kai-Liang; Fu, Xiao-Long

    2015-03-01

    Purpose: To prospectively investigate the efficacy and toxicity of accelerated hypofractionated thoracic radiation therapy (HypoTRT) combined with concurrent chemotherapy in the treatment of limited-stage small-cell lung cancer (LS-SCLC), with the hypothesis that both high radiation dose and short radiation time are important in this setting. Methods and Materials: Patients with previously untreated LS-SCLC, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function were eligible. HypoTRT of 55 Gy at 2.5 Gy per fraction over 30 days was given on the first day of the second or third cycle of chemotherapy. An etoposide/cisplatin regimen was given to 4 to 6 cycles. Patients who had a good response to initial treatment were offered prophylactic cranial irradiation. The primary endpoint was the 2-year progression-free survival rate. Results: Fifty-nine patients were enrolled from July 2007 through February 2012 (median age, 58 years; 86% male). The 2-year progression-free survival rate was 49.0% (95% confidence interval [CI] 35.3%-62.7%). Median survival time was 28.5 months (95% CI 9.0-48.0 months); the 2-year overall survival rate was 58.2% (95% CI 44.5%-71.9%). The 2-year local control rate was 76.4% (95% CI 63.7%-89.1%). The severe hematologic toxicities (grade 3 or 4) were leukopenia (32%), neutropenia (25%), and thrombocytopenia (15%). Acute esophagitis and pneumonitis of grade ≥3 occurred in 25% and 10% of the patients, respectively. Thirty-eight patients (64%) received prophylactic cranial irradiation. Conclusion: Our study showed that HypoTRT of 55 Gy at 2.5 Gy per fraction daily concurrently with etoposide/cisplatin chemotherapy has favorable survival and acceptable toxicity. This radiation schedule deserves further investigation in LS-SCLC.

  4. Acceleration modules in linear induction accelerators

    NASA Astrophysics Data System (ADS)

    Wang, Shao-Heng; Deng, Jian-Jun

    2014-05-01

    The Linear Induction Accelerator (LIA) is a unique type of accelerator that is capable of accelerating kilo-Ampere charged particle current to tens of MeV energy. The present development of LIA in MHz bursting mode and the successful application into a synchrotron have broadened LIA's usage scope. Although the transformer model is widely used to explain the acceleration mechanism of LIAs, it is not appropriate to consider the induction electric field as the field which accelerates charged particles for many modern LIAs. We have examined the transition of the magnetic cores' functions during the LIA acceleration modules' evolution, distinguished transformer type and transmission line type LIA acceleration modules, and re-considered several related issues based on transmission line type LIA acceleration module. This clarified understanding should help in the further development and design of LIA acceleration modules.

  5. Diagnosing and managing advanced chronic myeloid leukemia.

    PubMed

    Deininger, Michael W

    2015-01-01

    Clinical staging of chronic myeloid leukemia (CML) distinguishes between chronic phase (CP-CML), accelerated phase (AP-CML), and blastic phase (BP-CML), reflecting its natural history in the absence of effective therapy. Morphologically, transformation from CP-CML to AP/BP-CML is characterized by a progressive or sudden loss of differentiation. Multiple different somatic mutations have been implicated in transformation from CP-CML to AP/BC-CML, but no characteristic mutation or combination of mutations have emerged. Gene expression profiles of AP-CML and BP-CML are similar, consistent with biphasic evolution at the molecular level. Gene expression of tyrosine kinase inhibitor (TKI)-resistant CP-CML and second CP-CML resemble AP/BP-CML, suggesting that morphology alone is a poor predictor of biologic behavior. At the clinical level, progression to AP/BP-CML or resistance to first-line TKI therapy distinguishes a good risk condition with survival close to the general population from a disease likely to reduce survival. Progression while receiving TKI therapy is frequently caused by mutations in the target kinase BCR-ABL1, but progression may occur in the absence of explanatory BCR-ABL1 mutations, suggesting involvement of alternative pathways. Identifying patients in whom milestones of TKI response fail to occur or whose disease progress while receiving therapy requires appropriate molecular monitoring. Selection of salvage TKI depends on prior TKI history, comorbidities, and BCR-ABL1 mutation status. Despite the introduction of novel TKIs, therapy of AP/BP-CML remains challenging and requires accepting modalities with substantial toxicity, such as hematopoietic stem cell transplantation (HSCT). PMID:25993200

  6. Algorithmic-Reducibility = Renormalization-Group Fixed-Points; ``Noise''-Induced Phase-Transitions (NITs) to Accelerate Algorithmics (``NIT-Picking'') Replacing CRUTCHES!!!: Gauss Modular/Clock-Arithmetic Congruences = Signal X Noise PRODUCTS..

    NASA Astrophysics Data System (ADS)

    Siegel, J.; Siegel, Edward Carl-Ludwig

    2011-03-01

    Cook-Levin computational-"complexity"(C-C) algorithmic-equivalence reduction-theorem reducibility equivalence to renormalization-(semi)-group phase-transitions critical-phenomena statistical-physics universality-classes fixed-points, is exploited with Gauss modular/clock-arithmetic/model congruences = signal X noise PRODUCT reinterpretation. Siegel-Baez FUZZYICS=CATEGORYICS(SON of ``TRIZ''): Category-Semantics(C-S) tabular list-format truth-table matrix analytics predicts and implements "noise"-induced phase-transitions (NITs) to accelerate versus to decelerate Harel [Algorithmics(1987)]-Sipser[Intro. Theory Computation(1997) algorithmic C-C: "NIT-picking" to optimize optimization-problems optimally(OOPO). Versus iso-"noise" power-spectrum quantitative-only amplitude/magnitude-only variation stochastic-resonance, this "NIT-picking" is "noise" power-spectrum QUALitative-type variation via quantitative critical-exponents variation. Computer-"science" algorithmic C-C models: Turing-machine, finite-state-models/automata, are identified as early-days once-workable but NOW ONLY LIMITING CRUTCHES IMPEDING latter-days new-insights!!!

  7. Multi-beam linear accelerator EVT

    NASA Astrophysics Data System (ADS)

    Teryaev, Vladimir E.; Kazakov, Sergey Yu.; Hirshfield, Jay L.

    2016-09-01

    A novel electron multi-beam accelerator is presented. The accelerator, short-named EVT (Electron Voltage Transformer) belongs to the class of two-beam accelerators. It combines an RF generator and essentially an accelerator within the same vacuum envelope. Drive beam-lets and an accelerated beam are modulated in RF modulators and then bunches pass into an accelerating structure, comprising uncoupled with each other and inductive tuned cavities, where the energy transfer from the drive beams to the accelerated beam occurs. A phasing of bunches is solved by choice correspond distances between gaps of the adjacent cavities. Preliminary results of numerical simulations and the initial specification of EVT operating in S-band, with a 60 kV gun and generating a 2.7 A, 1.1 MV beam at its output is presented. A relatively high efficiency of 67% and high design average power suggest that EVT can find its use in industrial applications.

  8. Progress on plasma accelerators

    SciTech Connect

    Chen, P.

    1986-05-01

    Several plasma accelerator concepts are reviewed, with emphasis on the Plasma Beat Wave Accelerator (PBWA) and the Plasma Wake Field Accelerator (PWFA). Various accelerator physics issues regarding these schemes are discussed, and numerical examples on laboratory scale experiments are given. The efficiency of plasma accelerators is then revealed with suggestions on improvements. Sources that cause emittance growth are discussed briefly.

  9. Chronic Pain

    MedlinePlus

    ... adults. Common chronic pain complaints include headache, low back pain, cancer pain, arthritis pain, neurogenic pain (pain resulting ... Institute of Neurological Disorders and Stroke (NINDS). Low Back Pain Fact Sheet Back Pain information sheet compiled by ...

  10. Chronic cholecystitis

    MedlinePlus

    ... foods may relieve symptoms in people. However, the benefit of a low-fat diet has not been proven. Alternative Names Cholecystitis - chronic Images Cholecystitis, CT scan Cholecystitis, cholangiogram Cholecystolithiasis Gallstones, cholangiogram Cholecystogram References Wang ...

  11. Chronic Pain

    MedlinePlus

    ... your pain. Medicines used for chronic pain include pain relievers, antidepressants, and anticonvulsants. Different types of medicines help ... If your doctor recommends an over-the-counter pain reliever, read and follow the instructions on the box. ...

  12. GS-9857 in patients with chronic hepatitis C virus genotype 1-4 infection: a randomized, double-blind, dose-ranging phase 1 study.

    PubMed

    Rodriguez-Torres, M; Glass, S; Hill, J; Freilich, B; Hassman, D; Di Bisceglie, A M; Taylor, J G; Kirby, B J; Dvory-Sobol, H; Yang, J C; An, D; Stamm, L M; Brainard, D M; Kim, S; Krefetz, D; Smith, W; Marbury, T; Lawitz, E

    2016-08-01

    GS-9857, an inhibitor of the hepatitis C virus (HCV) nonstructural protein (NS) 3/4A, demonstrates potent activity against HCV genotypes 1-6 and improved coverage against commonly encountered NS3 resistance-associated variants (RAVs). In this study, the safety, tolerability, antiviral activity and pharmacokinetics (PK) of GS-9857 were evaluated in patients with chronic HCV genotype 1-4 infection. Patients with genotype 1-4 infection received placebo or once-daily GS-9857 at doses ranging from 50 to 300 mg for 3 days under fasting conditions. GS-9857 was well tolerated; all reported adverse events (AEs) were mild or moderate in severity. Diarrhoea and headache were the most commonly reported AEs. Grade 3 or 4 laboratory abnormalities were observed in 17% of patients receiving GS-9857; there were no Grade 3 or 4 abnormalities in alanine aminotransferase, aspartate aminotransferase or alkaline phosphatase levels. GS-9857 demonstrated potent antiviral activity in patients with chronic HCV infection, achieving mean and median maximum reductions in HCV RNA of ≥3 log10 IU/mL following administration of a 100-mg dose in patients with HCV genotype 1a, 1b, 2, 3 or 4 infection. The antiviral activity of GS-9857 was unaffected by the presence of pretreatment NS3 RAVs. In patients with genotype 1-4 infection, GS-9857 exhibited linear PK and was associated with a median half-life of 29-42 h, supporting once-daily dosing. Thus, the tolerability, efficacy and pharmacokinetic profile of GS-9857 support its further evaluation for treatment of patients with chronic HCV infection. PMID:26957110

  13. Ear infection - chronic

    MedlinePlus

    Middle ear infection - chronic; Otitis media - chronic; Chronic otitis media; Chronic ear infection ... Chole RA. Chronic otitis media, mastoiditis, and petrositis. In: Flint PW, Haughey BH, Lund LJ, et al, eds. Cummings Otolaryngology: Head & Neck Surgery . 6th ed. ...

  14. Accelerated glass reaction under PCT conditions

    SciTech Connect

    Ebert, W.L.; Bates, J.K.; Buck, E.C.; Bradley, C.R.

    1992-01-01

    Static leach tests similar to PCT (Product Consistency Test) were performed for up to 2 years to assess long-term reaction behavior of high-level nuclear waste glasses similar to those at Defense Waste Processing Facility. These tests show the reaction rate to decrease with the reaction time from an initially high rate to a low rate, but then to accelerate to a higher rate after reaction times of about 1 year, depending on glass surface area/leachant volume ratio used. Solution concentrations of soluble glass components increase as the reaction is accelerated, while release of other glass components into solution is controlled by secondary phases. Net result is that transformation of glass to stable phases is accelerated while the solution becomes enriched in soluble components not effectively contained in secondary phases. Rate becomes linear in time after the acceleration and may be similar to the initial forward rate. A current model of glass reaction predicts that the glass reaction will be accelerated upon the formation of secondary phases which lower the silicic acid solution concentration. These tests show total Si concentration to increase upon reaction acceleration, however, which may be due to the slightly higher pH attained with the acceleration. The sudden change in the reaction rate is likely due to secondary phase formation. 17 refs, 2 tabs, 3 figs.

  15. Accelerated glass reaction under PCT conditions

    SciTech Connect

    Ebert, W.L.; Bates, J.K.; Buck, E.C.; Bradley, C.R.

    1992-12-31

    Static leach tests similar to PCT (Product Consistency Test) were performed for up to 2 years to assess long-term reaction behavior of high-level nuclear waste glasses similar to those at Defense Waste Processing Facility. These tests show the reaction rate to decrease with the reaction time from an initially high rate to a low rate, but then to accelerate to a higher rate after reaction times of about 1 year, depending on glass surface area/leachant volume ratio used. Solution concentrations of soluble glass components increase as the reaction is accelerated, while release of other glass components into solution is controlled by secondary phases. Net result is that transformation of glass to stable phases is accelerated while the solution becomes enriched in soluble components not effectively contained in secondary phases. Rate becomes linear in time after the acceleration and may be similar to the initial forward rate. A current model of glass reaction predicts that the glass reaction will be accelerated upon the formation of secondary phases which lower the silicic acid solution concentration. These tests show total Si concentration to increase upon reaction acceleration, however, which may be due to the slightly higher pH attained with the acceleration. The sudden change in the reaction rate is likely due to secondary phase formation. 17 refs, 2 tabs, 3 figs.

  16. Laser Acceleration in Vacuum and Gases with Capillary Waveguide

    SciTech Connect

    Xie, Ming

    1999-02-01

    A unified framework is developed to overcome all three major limitations on acceleration and distance and hence on the feasibility of two classes of laser acceleration. The three limitations are due to laser diffraction, acceleration phase slippage, and structure damage by high power laser if solid-state optical waveguide is used. The two classes of laser acceleration are direct-field acceleration and ponderomotive-driven acceleration. Thus this letter and its companion [1] provide solutions that are crucial to all mainstream approaches for laser acceleration, either in vacuum, gases or plasmas.

  17. Chronic constant light-induced hippocampal late-phase long-term potentiation impairment in vitro is attenuated by antagonist of D1/D5 receptors.

    PubMed

    Chai, An-Ping; Ma, Wen-Pei; Wang, Li-Ping; Cao, Jun; Xu, Lin; Yang, Yue-Xiong; Mao, Rong-Rong

    2015-10-01

    Previous study reported that chronic constant light exposure caused hippocampus-dependent long-term memory deficit. However, the underlying cellular mechanism of this impairment is still unclear. Multiple lines of evidence indicated that long-term potentiation (LTP) is a cellular model for memory formation. Here we found that, by recording of field excitatory postsynaptic potential (fEPSP) in vitro, chronic constant light (CCL, 3 weeks) exposure impaired the late long-term potentiation (L-LTP), but not early long-term potentiation (E-LTP) and basal transmission in Schaffer collateral (SC)-CA1 synapses of hippocampal slices from rats. Because L-LTP depends on D1/D5 receptors, we examined whether interference of D1/D5 receptors can modulate L-LTP of CCL rats. Bath application of D1/D5 receptors antagonist SCH23390 (1μM) blocked L-LTP in control rats and attenuated the impaired L-LTP in CCL rats. In contrast, pre-incubation of D1/D5 receptors agonist SKF38393 (25μM) occluded further L-LTP in control rats while exacerbated the L-LTP impairment in CCL rats. These results suggested that CCL-induced L-LTP impairment can be modulated by D1/D5 receptors. Our findings may contribute to the further understanding of synaptic plasticity mechanism underlying hippocampal long-term memory impairment induced by circadian rhythm disruption. PMID:26115584

  18. Chronic Bronchitis and Chronic Obstructive Pulmonary Disease

    PubMed Central

    Criner, Gerard J.

    2013-01-01

    Chronic bronchitis (CB) is a common but variable phenomenon in chronic obstructive pulmonary disease (COPD). It has numerous clinical consequences, including an accelerated decline in lung function, greater risk of the development of airflow obstruction in smokers, a predisposition to lower respiratory tract infection, higher exacerbation frequency, and worse overall mortality. CB is caused by overproduction and hypersecretion of mucus by goblet cells, which leads to worsening airflow obstruction by luminal obstruction of small airways, epithelial remodeling, and alteration of airway surface tension predisposing to collapse. Despite its clinical sequelae, little is known about the pathophysiology of CB and goblet cell hyperplasia in COPD, and treatment options are limited. In addition, it is becoming increasingly apparent that in the classic COPD spectrum, with emphysema on one end and CB on the other, most patients lie somewhere in the middle. It is known now that many patients with severe emphysema can develop CB, and small airway pathology has been linked to worse clinical outcomes, such as increased mortality and lesser improvement in lung function after lung volume reduction surgery. However, in recent years, a greater understanding of the importance of CB as a phenotype to identify patients with a beneficial response to therapy has been described. Herein we review the epidemiology of CB, the evidence behind its clinical consequences, the current understanding of the pathophysiology of goblet cell hyperplasia in COPD, and current therapies for CB. PMID:23204254

  19. Wideband induction acceleration and its intrinsic nature in the KEK digital accelerator

    NASA Astrophysics Data System (ADS)

    Yoshimoto, T.; Hirose, M.; Liu, X.; Adachi, T.; Kadokura, E.; Kawakubo, T.; Takano, S.; Takayama, K.

    2015-10-01

    The wideband induction acceleration method makes it possible to accelerate any ion species directly from the low-energy region of several hundred kiloelectron volts in the KEK induction synchrotron. The wideband acceleration method for heavy ions in the KEK digital accelerator (KEK-DA), which is a fast cycling induction synchrotron, is presented and the experimental results are discussed. A macroparticle simulation is described that well reproduces the longitudinal beam motion of the experiment, which is characterized by a non-uniform bunch motion in the longitudinal phase space. This is caused by as an intrinsic characteristic of the current acceleration system of the KEK-DA.

  20. Microcomputer-based Acceleration Sensor Device for Swimming Stroke Monitoring

    NASA Astrophysics Data System (ADS)

    Ohgi, Yuji; Ichikawa, Hiroshi; Miyaji, Chikara

    The purpose of this study was to develop a microcomputer-based acceleration logger device for the swimming stroke monitoring. The authors measured the swimmer's tri-axial wrist acceleration and applied this device for the fatigue evaluation of the swimmers. The experimental protocol led the swimmers exhausted after the crawl stroke interval training. Every single stroke was determined by the impact acceleration peak, which appeared on the x and z-axis acceleration. The change of the underwater stroke phases was identified by the characteristics of the acceleration peaks. In their exhaustion, the y-axis acceleration, which was longitudinal forearm acceleration decreased at the beginning of the upsweep phase. At that time, the swimmer could not extend his elbow joint. Since the developed acceleration data logger could provide us the information about the underwater stroke phases and it would be a helpful tool in the swimming training.

  1. Tanespimycin and Cytarabine in Treating Patients With Relapsed or Refractory Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Chronic Myelogenous Leukemia, Chronic Myelomonocytic Leukemia, or Myelodysplastic Syndromes

    ClinicalTrials.gov

    2013-09-27

    Accelerated Phase Chronic Myelogenous Leukemia; Adult Acute Basophilic Leukemia; Adult Acute Eosinophilic Leukemia; Adult Acute Megakaryoblastic Leukemia (M7); Adult Acute Minimally Differentiated Myeloid Leukemia (M0); Adult Acute Monoblastic Leukemia (M5a); Adult Acute Monocytic Leukemia (M5b); Adult Acute Myeloblastic Leukemia With Maturation (M2); Adult Acute Myeloblastic Leukemia Without Maturation (M1); Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities; Adult Acute Myeloid Leukemia With Inv(16)(p13;q22); Adult Acute Myeloid Leukemia With t(16;16)(p13;q22); Adult Acute Myeloid Leukemia With t(8;21)(q22;q22); Adult Acute Myelomonocytic Leukemia (M4); Adult Erythroleukemia (M6a); Adult Pure Erythroid Leukemia (M6b); Blastic Phase Chronic Myelogenous Leukemia; Chronic Myelomonocytic Leukemia; de Novo Myelodysplastic Syndromes; Previously Treated Myelodysplastic Syndromes; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Refractory Anemia With Excess Blasts in Transformation; Relapsing Chronic Myelogenous Leukemia; Secondary Acute Myeloid Leukemia; Secondary Myelodysplastic Syndromes

  2. Elementary principles of linear accelerators

    NASA Astrophysics Data System (ADS)

    Loew, G. A.; Talman, R.

    1983-09-01

    A short chronology of important milestones in the field of linear accelerators is presented. Proton linacs are first discussed and elementary concepts such as transit time, shunt impedance, and Q are introduced. Critical issues such as phase stability and transverse forces are addressed. An elementary discussion of waveguide acclerating structures is also provided. Finally, electron accelerators addressed. Taking SLAC as an exmple, various topics are discussed such as structure design, choice of parameters, frequency optmization, beam current, emittance, bunch length and beam loading. Recent developments and future challenges are mentioned briefly.

  3. Chronic obstructive pulmonary disease.

    PubMed

    Barnes, Peter J; Burney, Peter G J; Silverman, Edwin K; Celli, Bartolome R; Vestbo, Jørgen; Wedzicha, Jadwiga A; Wouters, Emiel F M

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is a common disease with high global morbidity and mortality. COPD is characterized by poorly reversible airway obstruction, which is confirmed by spirometry, and includes obstruction of the small airways (chronic obstructive bronchiolitis) and emphysema, which lead to air trapping and shortness of breath in response to physical exertion. The most common risk factor for the development of COPD is cigarette smoking, but other environmental factors, such as exposure to indoor air pollutants - especially in developing countries - might influence COPD risk. Not all smokers develop COPD and the reasons for disease susceptibility in these individuals have not been fully elucidated. Although the mechanisms underlying COPD remain poorly understood, the disease is associated with chronic inflammation that is usually corticosteroid resistant. In addition, COPD involves accelerated ageing of the lungs and an abnormal repair mechanism that might be driven by oxidative stress. Acute exacerbations, which are mainly triggered by viral or bacterial infections, are important as they are linked to a poor prognosis. The mainstay of the management of stable disease is the use of inhaled long-acting bronchodilators, whereas corticosteroids are beneficial primarily in patients who have coexisting features of asthma, such as eosinophilic inflammation and more reversibility of airway obstruction. Apart from smoking cessation, no treatments reduce disease progression. More research is needed to better understand disease mechanisms and to develop new treatments that reduce disease activity and progression. PMID:27189863

  4. Enhanced striatial /sup 3/H-spiroperidol binding induced by chronic haloperidol treatment inhibited by peptides administered during the withdrawal phase

    SciTech Connect

    Bhargava, H.N.

    1984-02-27

    Chronic intragastric administration of haloperidol (1.5 mg/kg/day) for 21 days followed by a 3-day withdrawal period resulted in the development of enhanced locomotor activity response to apomorphine, and an increase in the number of binding sites for /sup 3/H-spiroperidol in the striatal membranes of the rat brain. Subcutaneous administration of Pro-Leu-Gly-NH/sub 2/ or cyclo-(Leu-Gly) in doses of 2 mg/kg/day given for 3-days after termination of haloperidol treatment inhibited the enhanced response to apomorphine, as well as the increases in the number of /sup 3/H-spiroperidol binding sites in the striatum. If indeed, the supersensitivity of striatal dopamine receptors is one of the mechanisms in the development of tardive dyskinesia symptoms, the present results suggest that the above peptides may be helpful in ameliorating some of the symptoms of tardive dyskinesia induced by neuroleptic drugs. 31 references, 3 figures.

  5. The prodromal phase of obesity-related chronic kidney disease: early alterations in cardiovascular and renal function in obese children and adolescents.

    PubMed

    Doyon, Anke; Schaefer, Franz

    2013-11-01

    Childhood overweight and obesity is a relevant health condition with multi-organ involvement. Obesity shows significant tracking into adult life and is associated with an increased risk of serious adverse health outcomes both during childhood and later adulthood. The classical sequelae of obesity such as hypertension, metabolic syndrome and inflammation do develop at a paediatric age. Cardiovascular consequences, such as increased carotid intima-media thickness, and left ventricular hypertrophy, as well as functional alterations of the heart and arteries, are commonly traceable at an early age. Renal involvement can occur at a young age and is associated with a high probability of progressive chronic kidney disease. There is solid evidence suggesting that consequent treatment including both lifestyle changes and pharmacological therapy can reduce cardiovascular, metabolic and renal risks in obese children and adolescents. PMID:23975744

  6. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.

    PubMed

    Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo

    2014-09-01

    Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs. PMID:25118789

  7. Acceleration schedules for a recirculating heavy-ion accelerator

    SciTech Connect

    Sharp, W.M.; Grote, D.P.

    2002-05-01

    Recent advances in solid-state switches have made it feasible to design programmable, high-repetition-rate pulsers for induction accelerators. These switches could lower the cost of recirculating induction accelerators, such as the ''small recirculator'' at Lawrence Livermore National Laboratory (LLNL), by substantially reducing the number of induction modules. Numerical work is reported here to determine what effects the use of fewer pulsers at higher voltage would have on the beam quality of the LLNL small recirculator. Lattices with different numbers of pulsers are examined using the fluid/envelope code CIRCE, and several schedules for acceleration and compression are compared for each configuration. For selected schedules, the phase-space dynamics is also studied using the particle-in-cell code WARP3d.

  8. Design of a case management model for people with chronic disease (Heart Failure and COPD). Phase I: modeling and identification of the main components of the intervention through their actors: patients and professionals (DELTA-icE-PRO Study)

    PubMed Central

    2010-01-01

    Background Chronic diseases account for nearly 60% of deaths around the world. The extent of this silent epidemic has not met determined responses in governments, policies or professionals in order to transform old Health Care Systems, configured for acute diseases. There is a large list of research about alternative models for people with chronic conditions, many of them with an advanced practice nurse as a key provider, as case management. But some methodological concerns raise, above all, the design of the intervention (intensity, frequency, components, etc). Methods/Design Objectives: General: To develop the first and second phases (theorization and modeling) for designing a multifaceted case-management intervention in people with chronic conditions (COPD and heart failure) and their caregivers. Specific aims: 1) To identify key events in people living with chronic disease and their relation with the Health Care System, from their point of view. 2) To know the coping mechanisms developed by patients and their caregivers along the story with the disease. 3) To know the information processing and its utilization in their interactions with health care providers. 4) To detect potential unmet needs and the ways deployed by patients and their caregivers to resolve them. 5) To obtain a description from patients and caregivers, about their itineraries along the Health Care System, in terms of continuity, accessibility and comprehensiveness of care. 6) To build up a list of promising case-management interventions in patients with Heart Failure and COPD with this information in order to frame it into theoretical models for its reproducibility and conceptualization. 7) To undergo this list to expert judgment to assess its feasibility and pertinence in the Andalusian Health Care. Design: Qualitative research with two phases: For the first five objectives, a qualitative technique with biographic stories will be developed and, for the remaining objectives, an expert

  9. Chronic Cough.

    PubMed

    Pacheco, Adalberto; de Diego, Alfredo; Domingo, Christian; Lamas, Adelaida; Gutierrez, Raimundo; Naberan, Karlos; Garrigues, Vicente; López Vime, Raquel

    2015-11-01

    Chronic cough (CC), or cough lasting more than 8 weeks, has attracted increased attention in recent years following advances that have changed opinions on the prevailing diagnostic and therapeutic triad in place since the 1970s. Suboptimal treatment results in two thirds of all cases, together with a new notion of CC as a peripheral and central hypersensitivity syndrome similar to chronic pain, have changed the approach to this common complaint in routine clinical practice. The peripheral receptors involved in CC are still a part of the diagnostic triad. However, both convergence of stimuli and central nervous system hypersensitivity are key factors in treatment success. PMID:26165783

  10. Visions for the future of particle accelerators

    NASA Astrophysics Data System (ADS)

    Romaniuk, Ryszard S.

    2013-10-01

    The ambitions of accelerator based science, technology and applications far exceed the present accelerator possibilities. Accelerator science and technology is one of a key enablers of the developments in the particle physic, photon physics and also applications in medicine and industry. The paper presents a digest of the research results and visions for the future in the domain of accelerator science and technology in Europe, shown during the final fourth annual meeting of the EuCARD - European Coordination of Accelerator Research and Development. The conference concerns building of the research infrastructure, including advanced photonic and electronic systems for servicing large high energy physics experiments. There are debated a few basic groups of such systems like: measurement - control networks of large geometrical extent, multichannel systems for large amounts of metrological data acquisition, precision photonic networks of reference time, frequency and phase distribution. The main subject is however the vision for the future of particle accelerators and next generation light sources.

  11. Method and apparatus for varying accelerator beam output energy

    DOEpatents

    Young, Lloyd M.

    1998-01-01

    A coupled cavity accelerator (CCA) accelerates a charged particle beam with rf energy from a rf source. An input accelerating cavity receives the charged particle beam and an output accelerating cavity outputs the charged particle beam at an increased energy. Intermediate accelerating cavities connect the input and the output accelerating cavities to accelerate the charged particle beam. A plurality of tunable coupling cavities are arranged so that each one of the tunable coupling cavities respectively connect an adjacent pair of the input, output, and intermediate accelerating cavities to transfer the rf energy along the accelerating cavities. An output tunable coupling cavity can be detuned to variably change the phase of the rf energy reflected from the output coupling cavity so that regions of the accelerator can be selectively turned off when one of the intermediate tunable coupling cavities is also detuned.

  12. Plasma Anti-Glial Fibrillary Acidic Protein Autoantibody Levels during the Acute and Chronic Phases of Traumatic Brain Injury: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study.

    PubMed

    Wang, Kevin K W; Yang, Zhihui; Yue, John K; Zhang, Zhiqun; Winkler, Ethan A; Puccio, Ava M; Diaz-Arrastia, Ramon; Lingsma, Hester F; Yuh, Esther L; Mukherjee, Pratik; Valadka, Alex B; Gordon, Wayne A; Okonkwo, David O; Manley, Geoffrey T; Cooper, Shelly R; Dams-O'Connor, Kristen; Hricik, Allison J; Inoue, Tomoo; Maas, Andrew I R; Menon, David K; Schnyer, David M; Sinha, Tuhin K; Vassar, Mary J

    2016-07-01

    We described recently a subacute serum autoantibody response toward glial fibrillary acidic protein (GFAP) and its breakdown products 5-10 days after severe traumatic brain injury (TBI). Here, we expanded our anti-GFAP autoantibody (AutoAb[GFAP]) investigation to the multicenter observational study Transforming Research and Clinical Knowledge in TBI Pilot (TRACK-TBI Pilot) to cover the full spectrum of TBI (Glasgow Coma Scale 3-15) by using acute (<24 h) plasma samples from 196 patients with acute TBI admitted to three Level I trauma centers, and a second cohort of 21 participants with chronic TBI admitted to inpatient TBI rehabilitation. We find that acute patients self-reporting previous TBI with loss of consciousness (LOC) (n = 43) had higher day 1 AutoAb[GFAP] (mean ± standard error: 9.11 ± 1.42; n = 43) than healthy controls (2.90 ± 0.92; n = 16; p = 0.032) and acute patients reporting no previous TBI (2.97 ± 0.37; n = 106; p < 0.001), but not acute patients reporting previous TBI without LOC (8.01 ± 1.80; n = 47; p = 0.906). These data suggest that while exposure to TBI may trigger the AutoAb[GFAP] response, circulating antibodies are elevated specifically in acute TBI patients with a history of TBI. AutoAb[GFAP] levels for participants with chronic TBI (average post-TBI time 176 days or 6.21 months) were also significantly higher (15.08 ± 2.82; n = 21) than healthy controls (p < 0.001). These data suggest a persistent upregulation of the autoimmune response to specific brain antigen(s) in the subacute to chronic phase after TBI, as well as after repeated TBI insults. Hence, AutoAb[GFAP] may be a sensitive assay to study the dynamic interactions between post-injury brain and patient-specific autoimmune responses across acute and chronic settings after TBI. PMID:26560343

  13. Chronic myelogenous leukemia (CML)

    MedlinePlus

    CML; Chronic myeloid leukemia; Chronic granulocytic leukemia; Leukemia - chronic granulocytic ... nuclear disaster. It takes many years to develop leukemia from radiation exposure. Most people treated for cancer ...

  14. Laser driven ion accelerator

    DOEpatents

    Tajima, Toshiki

    2006-04-18

    A system and method of accelerating ions in an accelerator to optimize the energy produced by a light source. Several parameters may be controlled in constructing a target used in the accelerator system to adjust performance of the accelerator system. These parameters include the material, thickness, geometry and surface of the target.

  15. Laser driven ion accelerator

    DOEpatents

    Tajima, Toshiki

    2005-06-14

    A system and method of accelerating ions in an accelerator to optimize the energy produced by a light source. Several parameters may be controlled in constructing a target used in the accelerator system to adjust performance of the accelerator system. These parameters include the material, thickness, geometry and surface of the target.

  16. Accelerating Spectrum Sharing Technologies

    SciTech Connect

    Juan D. Deaton; Lynda L. Brighton; Rangam Subramanian; Hussein Moradi; Jose Loera

    2013-09-01

    Spectrum sharing potentially holds the promise of solving the emerging spectrum crisis. However, technology innovators face the conundrum of developing spectrum sharing technologies without th