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Sample records for cediranib recentin azd2171

  1. Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

    Science.gov (United States)

    Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C

    2016-01-01

    An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

  2. A Phase 1 trial of the PARP inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer

    Science.gov (United States)

    Liu, Joyce F.; Tolaney, Sara M.; Birrer, Michael; Fleming, Gini F.; Buss, Mary K.; Dahlberg, Suzanne E.; Lee, Hang; Whalen, Christin; Tyburski, Karin; Winer, Eric; Ivy, Percy; Matulonis, Ursula A.

    2014-01-01

    Background PARP-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of VEGFR-1/2/3, and olaparib, a PARP-inhibitor (NCT01116648). Methods Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by RECIST 1.1 or met GCIG CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. Results 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 DLTs (1 grade 4 neutropenia ≥4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30mg daily; olaparib 400mg BID). The RP2D was cediranib 30mg daily and olaparib 200mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus SD >24 weeks) of 61%. None of the 7 evaluable breast cancer patients achieved clinical response; 2 patients had stable disease for >24 weeks. Interpretation The combination of cediranib and olaparib has hematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients. PMID:23810467

  3. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer.

    Science.gov (United States)

    Liu, Joyce F; Tolaney, Sara M; Birrer, Michael; Fleming, Gini F; Buss, Mary K; Dahlberg, Suzanne E; Lee, Hang; Whalen, Christin; Tyburski, Karin; Winer, Eric; Ivy, Percy; Matulonis, Ursula A

    2013-09-01

    Poly(ADP-ribose) polymerase (PARP)-inhibitors and anti-angiogenics have activity in recurrent ovarian and breast cancer; however, the effect of combined therapy against PARP and angiogenesis in this population has not been reported. We investigated the toxicities and recommended phase 2 dosing (RP2D) of the combination of cediranib, a multitargeted inhibitor of vascular endothelial growth factor receptor (VEGFR)-1/2/3 and olaparib, a PARP-inhibitor (NCT01116648). Cediranib tablets once daily and olaparib capsules twice daily were administered orally in a standard 3+3 dose escalation design. Patients with recurrent ovarian or metastatic triple-negative breast cancer were eligible. Patients had measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or met Gynecologic Cancer InterGroup (GCIG) CA125 criteria. No prior PARP-inhibitors or anti-angiogenics in the recurrent setting were allowed. 28 patients (20 ovarian, 8 breast) enrolled to 4 dose levels. 2 dose limiting toxicities (DLTs) (1 grade 4 neutropenia ≥ 4 days; 1 grade 4 thrombocytopenia) occurred at the highest dose level (cediranib 30 mg daily; olaparib 400 mg twice daily [BID]). The RP2D was cediranib 30 mg daily and olaparib 200 mg BID. Grade 3 or higher toxicities occurred in 75% of patients, and included grade 3 hypertension (25%) and grade 3 fatigue (18%). One grade 3 bowel obstruction occurred. The overall response rate (ORR) in the 18 RECIST-evaluable ovarian cancer patients was 44%, with a clinical benefit rate (ORR plus stable disease (SD) > 24 weeks) of 61%. None of the seven evaluable breast cancer patients achieved clinical response; two patients had stable disease for > 24 weeks. The combination of cediranib and olaparib has haematologic DLTs and anticipated class toxicities, with promising evidence of activity in ovarian cancer patients. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Cediranib for Metastatic Alveolar Soft Part Sarcoma

    Science.gov (United States)

    Kummar, Shivaani; Allen, Deborah; Monks, Anne; Polley, Eric C.; Hose, Curtis D.; Ivy, S. Percy; Turkbey, Ismail B.; Lawrence, Scott; Kinders, Robert J.; Choyke, Peter; Simon, Richard; Steinberg, Seth M.; Doroshow, James H.; Helman, Lee

    2013-01-01

    Purpose Alveolar soft part sarcoma (ASPS) is a rare, highly vascular tumor, for which no effective standard systemic treatment exists for patients with unresectable disease. Cediranib is a potent, oral small-molecule inhibitor of all three vascular endothelial growth factor receptors (VEGFRs). Patients and Methods We conducted a phase II trial of once-daily cediranib (30 mg) given in 28-day cycles for patients with metastatic, unresectable ASPS to determine the objective response rate (ORR). We also compared gene expression profiles in pre- and post-treatment tumor biopsies and evaluated the effect of cediranib on tumor proliferation and angiogenesis using positron emission tomography and dynamic contrast-enhanced magnetic resonance imaging. Results Of 46 patients enrolled, 43 were evaluable for response at the time of analysis. The ORR was 35%, with 15 of 43 patients achieving a partial response. Twenty-six patients (60%) had stable disease as the best response, with a disease control rate (partial response + stable disease) at 24 weeks of 84%. Microarray analysis with validation by quantitative real-time polymerase chain reaction on paired tumor biopsies from eight patients demonstrated downregulation of genes related to vasculogenesis. Conclusion In this largest prospective trial to date of systemic therapy for metastatic ASPS, we observed that cediranib has substantial single-agent activity, producing an ORR of 35% and a disease control rate of 84% at 24 weeks. On the basis of these results, an open-label, multicenter, randomized phase II registration trial is currently being conducted for patients with metastatic ASPS comparing cediranib with another VEGFR inhibitor, sunitinib. PMID:23630200

  5. 22 CFR 217.1 - Purpose.

    Science.gov (United States)

    2010-04-01

    ... RECEIVING FEDERAL FINANCIAL ASSISTANCE General Provisions § 217.1 Purpose. The purpose of this part is to... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Purpose. 217.1 Section 217.1 Foreign Relations... the basis of handicap in any program or activity within the United States receiving Federal financial...

  6. Phase I evaluation of the effects of ketoconazole and rifampicin on cediranib pharmacokinetics in patients with solid tumours

    DEFF Research Database (Denmark)

    Lassen, U; Miller, W H; Hotte, S

    2013-01-01

    PURPOSE: To investigate any effect of a CYP3A4 inhibitor (ketoconazole) or inducer (rifampicin) on cediranib steady-state pharmacokinetics in patients with advanced solid tumours. METHODS: In two Phase I, open-label trials, patients received once-daily oral doses of cediranib alone [20 mg...... (ketoconazole study); 45 mg (rifampicin study)] for 7 days followed by cediranib at the same dose with ketoconazole 400 mg/day for 3 days or once-daily rifampicin 600 mg/day for 7 days, respectively. Patients then continued to receive once-daily cediranib. RESULTS: In the ketoconazole study, 46 patients were...... dosed; 38 were evaluable for C (ss,max), 36 for AUC(ss). gMean AUC(ss) and C (ss,max) for cediranib 20 mg increased by 21 % (94 % CI 9-35 %) and 26 % (94 % CI 10-43 %), respectively, in the presence of ketoconazole. In the rifampicin study, 64 patients were dosed; 44 were evaluable for C (ss,max) and 41...

  7. Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients

    International Nuclear Information System (INIS)

    Forsberg, Anton; Andersson, Jan; Varnaes, Katarina; Halldin, Christer; Jureus, Anders; Swahn, Britt-Marie; Sandell, Johan; Julin, Per; Svensson, Samuel; Cselenyi, Zsolt; Schou, Magnus; Johnstroem, Peter; Farde, Lars; Eriksdotter, Maria; Freund-Levi, Yvonne; Jeppsson, Fredrik

    2013-01-01

    The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [ 11 C]AZD2995 and [ 11 C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [ 3 H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [ 11 C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [ 11 C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [ 11 C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [ 11 C]AZD2995. However, the very low nonspecific binding of [ 11 C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. (orig.)

  8. A randomized phase 2 study of combination cediranib and olaparib versus olaparib alone as recurrence therapy in platinum-sensitive ovarian cancer

    Science.gov (United States)

    Liu, Joyce F.; Barry, William T.; Birrer, Michael; Lee, Jung-Min; Buckanovich, Ronald J.; Fleming, Gini F.; Rimel, BJ; Buss, Mary K.; Nattam, Sreenivasa; Hurteau, Jean; Luo, Weixiu; Quy, Philippa; Whalen, Christin; Obermayer, Lisa; Lee, Hang; Winer, Eric P.; Kohn, Elise C.; Ivy, S. Percy; Matulonis, Ursula A.

    2015-01-01

    Background Olaparib is an oral poly(ADP-ribose) polymerase inhibitor and cediranib is an oral anti-angiogenic with activity against VEGFR-1, 2, and 3. Both agents have antitumor activity in women with recurrent ovarian cancer, and the combination of these agents was active and had manageable toxicities in a Phase 1 trial. We asked whether the combination of cediranib and olaparib could improve progression-free survival compared to olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. Methods We conducted a randomized, open-label, phase 2 study to evaluate the activity of olaparib monotherapy compared with combination cediranib and olaparib in women with ovarian cancer with measurable platinum-sensitive, relapsed, high-grade serous or endometrioid disease or those with deleterious germline BRCA1/2 mutations (gBRCAm). Patients were randomized using permuted blocks within stratum defined by gBRCA status and prior anti-angiogenic therapy to receive olaparib capsules 400mg twice daily or the combination at the recommended phase 2 dose of cediranib 30mg daily and olaparib capsules 200mg twice daily. The primary endpoint was progression-free survival (PFS) analyzed under intention to treat. The trial is registered with ClinicalTrials.gov, NCT01116648. The Phase 2 portion of the trial reported here is no longer accruing patients. Findings Forty-six of 90 randomized patients received olaparib alone, and 44 received cediranib/olaparib. Median PFS was significantly longer with cediranib/olaparib (17.7 vs. 9.0 mos, HR 0.42; p = 0.005). Grade 3 and 4 adverse events were more common with cediranib/olaparib, including fatigue (12 vs. 5), diarrhea (10 vs. 0), and hypertension (18 vs. 0). Subset analysis within stratum defined by BRCA1/2 status demonstrated activity of cediranib/olaparib in both gBRCAm and gBRCAwt/u (wild-type/unknown) patients. Significant improvement in PFS occurred in gBRCAwt/u women receiving cediranib/olaparib (16.5 vs. 5.7 mos, p = 0

  9. Low background and high contrast PET imaging of amyloid-{beta} with [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in Alzheimer's disease patients

    Energy Technology Data Exchange (ETDEWEB)

    Forsberg, Anton; Andersson, Jan; Varnaes, Katarina; Halldin, Christer [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Jureus, Anders; Swahn, Britt-Marie; Sandell, Johan; Julin, Per; Svensson, Samuel [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Cselenyi, Zsolt; Schou, Magnus; Johnstroem, Peter; Farde, Lars [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Karolinska Hospital, AstraZeneca Translational Sciences Centre, PET CoE, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm (Sweden); Eriksdotter, Maria; Freund-Levi, Yvonne [Karolinska Institutet, Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital, Department of Geriatric Medicine, Stockholm (Sweden); Jeppsson, Fredrik [AstraZeneca Research and Development, Neuroscience Research and Therapy Area, Soedertaelje (Sweden); Karolinska Institutet, Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Stockholm (Sweden)

    2013-04-15

    The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-{beta} in Alzheimer's disease (AD). In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-{beta} PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [{sup 11}C]AZD2995 and [{sup 11}C]AZD2184 in three healthy control subjects and seven AD patients. AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-{beta}. [{sup 3}H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [{sup 11}C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [{sup 11}C]AZD2995 was greater in areas with lower amyloid-{beta} load, e.g. the hippocampus. Both AZD2995 and AZD2184 detect amyloid-{beta} with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [{sup 11}C]AZD2184 seems to be an amyloid-{beta} radioligand with higher uptake and better group separation when compared to [{sup 11}C]AZD2995. However, the very low nonspecific binding of [{sup 11}C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-{beta}. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy. (orig.)

  10. Inhibition of Bcl-2 potentiates AZD-2014-induced anti-head and neck squamous cell carcinoma cell activity

    International Nuclear Information System (INIS)

    Li, Yi; Cui, Jiang-Tao

    2016-01-01

    Mammalian target of rapamycin (mTOR) is a therapeutic target for head and neck squamous cell carcinoma (HNSCC). Here, we evaluated the activity of AZD-2014, a potent mTOR complex 1/2 (mTORC1/2) dual inhibitor, against HNSCC cells. We showed that AZD-2014 blocked mTORC1/2 activation in established and primary human HNSCC cells, where it was anti-proliferative and pro-apoptotic. Yet, AZD-2014 was non-cytotoxic to the human oral epithelial cells with low basal mTORC1/2 activation. In an effect to identify possible AZD-2014 resistance factors, we showed that the anti-apoptosis protein Bcl-2 was upregulated in AZD-2014-resistant SQ20B HNSCC cells. Inhibition of Bcl-2 by ABT-737 (a known Bcl-2 inhibitor) or Bcl-2 shRNA dramatically potentiated AZD-2014 lethality against HNSCC cells. On the other hand, exogenous overexpression of Bcl-2 largely attenuated AZD-2014’s activity against HNSCC cells. For the in vivo studies, we showed that oral gavage of AZD-2014 suppressed SQ20B xenograft growth in severe combined immunodeficient (SCID) mice. It also significantly improved mice survival. Importantly, AZD-2014’s anti-HNSCC activity in vivo was potentiated with co-administration of ABT-737. The preclinical results of this study suggest that AZD-2014 could be further tested as a valuable anti-HNSCC agent, either alone or in combination with Bcl-2 inhibitors. - Highlights: • AZD-2014 blocks mTORC1/2 activation in HNSCC cells. • AZD-2014 suppresses HNSCC cell proliferation. • AZD-2014 activates caspase-3 and apoptosis in HNSCC cells. • Bcl-2 is the key resistance factor of AZD-2014 in HNSCC cells. • ABT-737 sensitizes AZD-2014-induced anti-HNSCC activity in vivo.

  11. Inhibition of Bcl-2 potentiates AZD-2014-induced anti-head and neck squamous cell carcinoma cell activity

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yi; Cui, Jiang-Tao, E-mail: cuijingtaopaper@126.com

    2016-09-02

    Mammalian target of rapamycin (mTOR) is a therapeutic target for head and neck squamous cell carcinoma (HNSCC). Here, we evaluated the activity of AZD-2014, a potent mTOR complex 1/2 (mTORC1/2) dual inhibitor, against HNSCC cells. We showed that AZD-2014 blocked mTORC1/2 activation in established and primary human HNSCC cells, where it was anti-proliferative and pro-apoptotic. Yet, AZD-2014 was non-cytotoxic to the human oral epithelial cells with low basal mTORC1/2 activation. In an effect to identify possible AZD-2014 resistance factors, we showed that the anti-apoptosis protein Bcl-2 was upregulated in AZD-2014-resistant SQ20B HNSCC cells. Inhibition of Bcl-2 by ABT-737 (a known Bcl-2 inhibitor) or Bcl-2 shRNA dramatically potentiated AZD-2014 lethality against HNSCC cells. On the other hand, exogenous overexpression of Bcl-2 largely attenuated AZD-2014’s activity against HNSCC cells. For the in vivo studies, we showed that oral gavage of AZD-2014 suppressed SQ20B xenograft growth in severe combined immunodeficient (SCID) mice. It also significantly improved mice survival. Importantly, AZD-2014’s anti-HNSCC activity in vivo was potentiated with co-administration of ABT-737. The preclinical results of this study suggest that AZD-2014 could be further tested as a valuable anti-HNSCC agent, either alone or in combination with Bcl-2 inhibitors. - Highlights: • AZD-2014 blocks mTORC1/2 activation in HNSCC cells. • AZD-2014 suppresses HNSCC cell proliferation. • AZD-2014 activates caspase-3 and apoptosis in HNSCC cells. • Bcl-2 is the key resistance factor of AZD-2014 in HNSCC cells. • ABT-737 sensitizes AZD-2014-induced anti-HNSCC activity in vivo.

  12. 20 CFR 416.2171 - Duration of agreement.

    Science.gov (United States)

    2010-04-01

    ... selected by whoever wants to end the agreement; or (c)(1) The State fails to pay our costs as agreed; (2....2171 Employees' Benefits SOCIAL SECURITY ADMINISTRATION SUPPLEMENTAL SECURITY INCOME FOR THE AGED... and again at the end of each 1-year renewal term, unless— (a) The State and we agree in writing to end...

  13. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer.

    Science.gov (United States)

    Matulonis, Ursula A; Berlin, Suzanne; Ivy, Percy; Tyburski, Karin; Krasner, Carolyn; Zarwan, Corrine; Berkenblit, Anna; Campos, Susana; Horowitz, Neil; Cannistra, Stephen A; Lee, Hang; Lee, Julie; Roche, Maria; Hill, Margaret; Whalen, Christin; Sullivan, Laura; Tran, Chau; Humphreys, Benjamin D; Penson, Richard T

    2009-11-20

    Angiogenesis is important for epithelial ovarian cancer (EOC) growth, and blocking angiogenesis can lead to EOC regression. Cediranib is an oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) -1, VEGFR-2, VEGFR-3, and c-kit. We conducted a phase II study of cediranib for recurrent EOC or peritoneal or fallopian tube cancer; cediranib was administered as a daily oral dose, and the original dose was 45 mg daily. Because of toxicities observed in the first 11 patients, the dose was lowered to 30 mg. Eligibility included 16 weeks, or CA-125 nonprogression > 16 weeks), which was the primary end point, was 30%; eight patients (17%; 95% CI, 7.6% to 30.8%) had a PR, six patients (13%; 95% CI, 4.8% to 25.7%) had SD, and there were no CRs. Eleven patients (23%) were removed from study because of toxicities before two cycles. Grade 3 toxicities (> 20% of patients) included hypertension (46%), fatigue (24%), and diarrhea (13%). Grade 2 hypothyroidism occurred in 43% of patients. Grade 4 toxicities included CNS hemorrhage (n = 1), hypertriglyceridemia/hypercholesterolemia/elevated lipase (n = 1), and dehydration/elevated creatinine (n = 1). No bowel perforations or fistulas occurred. Median PFS was 5.2 months, and median OS has not been reached; median follow-up time is 10.7 months. Cediranib has activity in recurrent EOC, tubal cancer, and peritoneal cancer with predictable toxicities observed with other TKIs.

  14. Combination cediranib and olaparib versus olaparib alone for women with recurrent platinum-sensitive ovarian cancer: a randomised phase 2 study.

    Science.gov (United States)

    Liu, Joyce F; Barry, William T; Birrer, Michael; Lee, Jung-Min; Buckanovich, Ronald J; Fleming, Gini F; Rimel, Bj; Buss, Mary K; Nattam, Sreenivasa; Hurteau, Jean; Luo, Weixiu; Quy, Philippa; Whalen, Christin; Obermayer, Lisa; Lee, Hang; Winer, Eric P; Kohn, Elise C; Ivy, S Percy; Matulonis, Ursula A

    2014-10-01

    Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7-not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7-16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23-0·76; p=0·005). Grade

  15. 12 CFR 217.1 - Authority, purpose, and scope.

    Science.gov (United States)

    2010-01-01

    ...(t) of the Board's Regulation D—Reserve Requirements of Depository Institutions (12 CFR 20.4). [Reg... 217.1 Banks and Banking FEDERAL RESERVE SYSTEM BOARD OF GOVERNORS OF THE FEDERAL RESERVE SYSTEM... Reserve Act (12 U.S.C. 371a, 461, 505), section 7 of the International Banking Act of 1978 (12 U.S.C. 3105...

  16. Development of rapid multistep carbon-11 radiosynthesis of the myeloperoxidase inhibitor AZD3241 to assess brain exposure by PET microdosing

    International Nuclear Information System (INIS)

    Johnström, Peter; Bergman, Linda; Varnäs, Katarina; Malmquist, Jonas; Halldin, Christer; Farde, Lars

    2015-01-01

    Introduction: The myeloperoxidase inhibitor AZD3241 has been selected as a candidate drug currently being developed to delay progression in patients with neurodegenerative brain disorders. Part of the decision tree for translation of AZD3241 into clinical studies included the need for assessment of brain exposure in non-human primates by PET microdosing. For that purpose a rapid multistep method for 11 C-labeling of AZD3241 was developed. Methods: AZD3241 was labeled in the thio-carbonyl position starting from [ 11 C]potassium cyanide in a 4-step procedure using microwave assisted heating. In the first step [ 11 C]potassium cyanide was converted to [ 11 C]potassium thiocyanate followed by reaction with benzoyl chloride to yield benzoyl [ 11 C]isothiocyanate. The benzoyl [ 11 C]isothiocyanate was subsequently reacted with the precursor ethyl 3-(2-isopropoxyethylamino)-1H-pyrrole-2-carboxylate and the formed intermediate underwent a base catalyzed cyclization to obtain [ 11 C]AZD3241 in the final step. To assess [ 11 C]AZD3241 brain exposure PET measurements were performed in three cynomolgus monkeys. Results: [ 11 C]AZD3241 was produced in good and reproducible radiochemical yield 710 ± 294 MBq (mean ± SD, n = 7). Total time of synthesis was 60 min from end of bombardment. The specific radioactivity was 9 ± 4 GBq/μmol and the radiochemical purity was > 98%. Following iv administration of [ 11 C]AZD3241 there was a rapid presence of radioactivity in brain in each of the three monkeys. The distribution of [ 11 C]AZD3241 to brain was fast and a C max of 1.9 to 2.6% of the injected radioactivity was observed within 1.5 min. [ 11 C]AZD3241 was homogeneously distributed in brain. Conclusion: The MPO inhibitor AZD3241 was successfully labeled with carbon-11 in a challenging 4-step procedure in good radiochemical yield allowing PET microdosing studies in cynomolgus monkey. [ 11 C]AZD3241 rapidly entered brain and confirmed adequate brain exposure to support translation

  17. Activation of MAPK signalling results in resistance to saracatinib (AZD0530) in ovarian cancer.

    Science.gov (United States)

    McGivern, Niamh; El-Helali, Aya; Mullan, Paul; McNeish, Iain A; Paul Harkin, D; Kennedy, Richard D; McCabe, Nuala

    2018-01-12

    SRC tyrosine kinase is frequently overexpressed and activated in late-stage, poor prognosis ovarian tumours, and preclinical studies have supported the use of targeted SRC inhibitors in the treatment of this disease. The SAPPROC trial investigated the addition of the SRC inhibitor saracatinib (AZD0530) to weekly paclitaxel for the treatment of platinum resistant ovarian cancer; however, this drug combination did not provide any benefit to progression free survival (PFS) of women with platinum resistant disease. In this study we aimed to identify mechanisms of resistance to SRC inhibitors in ovarian cancer cells. Using two complementary strategies; a targeted tumour suppressor gene siRNA screen, and a phospho-receptor tyrosine kinase array, we demonstrate that activation of MAPK signalling, via a reduction in NF1 (neurofibromin) expression or overexpression of HER2 and the insulin receptor, can drive resistance to AZD0530. Knockdown of NF1 in two ovarian cancer cell lines resulted in resistance to AZD0530, and was accompanied with activated MEK and ERK signalling. We also show that silencing of HER2 and the insulin receptor can partially resensitize AZD0530 resistant cells, which was associated with decreased phosphorylation of MEK and ERK. Furthermore, we demonstrate a synergistic effect of combining SRC and MEK inhibitors in both AZD0530 sensitive and resistant cells, and that MEK inhibition is sufficient to completely resensitize AZD0530 resistant cells. This work provides a preclinical rationale for the combination of SRC and MEK inhibitors in the treatment of ovarian cancer, and also highlights the need for biomarker driven patient selection for clinical trials.

  18. Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting β2-adrenoreceptor agonist (uLABA

    Directory of Open Access Journals (Sweden)

    Bjermer L

    2015-02-01

    Full Text Available Leif Bjermer,1 Piotr Kuna,2 Carin Jorup,3 Thomas Bengtsson,4 Johan Rosenborg4 1Department of Respiratory Medicine and Allergology, University Hospital, Lund, Sweden; 2Department of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Medical University of Lodz, Lodz, Poland; 3AstraZeneca R&D, Mölndal, Sweden; 4StatMind, Lund, Sweden Objective: The clinical pharmacokinetics of AZD3199, an ultra-long-acting β2-agonist, were investigated in healthy volunteers and patients with asthma or chronic obstructive pulmonary disease (COPD. Materials and methods: Five studies are presented: one single ascending dose study in healthy Caucasian males; two multiple ascending dose studies in healthy males, one in Caucasians and one in Japanese; a Phase IIA asthma study; and a Phase IIB COPD study. Subjects received AZD3199 via a Spira nebulizer (Turbuhaler; equivalent delivered doses 5–3200 µg or Turbuhaler (single delivered doses of 120–1920 µg or repeated delivered once-daily doses 240–1,680 µg. AZD3199 pharmacokinetics were assessed using total plasma concentration and urinary excretion, and tolerability using adverse events, clinical laboratory tests, and physical examinations. Results: AZD3199 appeared rapidly in the systemic circulation following single and multiple dosing in healthy volunteers and patients (maximum plasma concentration within 30 minutes, with dose-proportional time-independent pharmacokinetics. Plasma exposure to unmetabolized drug was similar in healthy volunteers and patients with asthma, but relatively lower in patients with COPD. Estimated terminal half-life was up to 142 hours in healthy Caucasian males. AZD3199 was well tolerated and showed no or at most mild systemic effects. Conclusion: AZD3199 plasma exposure in healthy volunteers and patients suggested linear pharmacokinetics and a long half-life. Systemic availability was similar in healthy subjects and patients with asthma, but was lower in patients

  19. The selective Aurora B kinase inhibitor AZD1152 is a potential new treatment for multiple myeloma.

    Science.gov (United States)

    Evans, Robert P; Naber, Claudia; Steffler, Tara; Checkland, Tamara; Maxwell, Christopher A; Keats, Jonathan J; Belch, Andrew R; Pilarski, Linda M; Lai, Raymond; Reiman, Tony

    2008-02-01

    Aurora kinases are potential targets for cancer therapy. Previous studies have validated Aurora kinase A as a therapeutic target in multiple myeloma (MM), and have demonstrated in vitro anti-myeloma effects of small molecule Aurora kinase inhibitors that inhibit both Aurora A and B. This study demonstrated that Aurora B kinase was strongly expressed in myeloma cell lines and primary plasma cells. The selective Aurora B inhibitor AZD1152-induced apoptotic death in myeloma cell lines at nanomolar concentrations, with a cell cycle phenotype consistent with that reported previously for Aurora B inhibition. In some cases, AZD1152 in combination with dexamethasone showed increased anti-myeloma activity compared with the use of either agent alone. AZD1152 was active against sorted CD138(+) BM plasma cells from myeloma patients but also, as expected, was toxic to CD138(-) marrow cells from the same patients. In a murine myeloma xenograft model, AZD1152-inhibited tumour growth at well-tolerated doses and induced cell death in established tumours, with associated mild, transient leucopenia. AZD1152 shows promise in these preclinical studies as a novel treatment for MM.

  20. Evaluation of AZD1446 as a Therapeutic in DYT1 Dystonia

    Directory of Open Access Journals (Sweden)

    Chelsea N. Zimmerman

    2017-06-01

    Full Text Available DYT1 dystonia is an early-onset, hyperkinetic movement disorder caused by a deletion in the gene TOR1A, which encodes the protein torsinA. Several lines of evidence show that in animal models of DTY1 dystonia, there is impaired basal dopamine (DA release and enhanced acetylcholine tone. Clinically, anticholinergic drugs are the most effective pharmacological treatment for DYT1 dystonia, but the currently used agents are non-selective muscarinic antagonists and associated with side effects. We used a DYT1 ∆GAG knock-in mouse model (DYT1 KI to investigate whether nicotine and/or a non-desensitizing nicotinic agonist, AZD1446, would increase DA output in DYT1 dystonia. Using in vivo microdialysis, we found that DYT1 KI mice showed significantly increased DA output and greater sensitivity to nicotine compared to wild type (WT littermate controls. In contrast, neither systemic injection (0.25–0.75 mg/kg or intrastriatal infusion (30 μM–1 mM of AZD1446 had a significant effect on DA efflux in WT or DYT1 KI mice. In vitro, we found that AZD1446 had no effect on the membrane properties of striatal spiny projection neurons (SPNs and did not alter the spontaneous firing of ChI interneurons in either WT or DYT1 KI mice. We did observe that the firing frequency of dopaminergic neurons was significantly increased by AZD1446 (10 μM, an effect blocked by dihydro-beta-erythroidine (DHβE 3 μM, but the effect was similar in WT and DYT1 KI mice. Our results support the view that DYT1 models are associated with abnormal striatal cholinergic transmission, and that the DYT1 KI animals have enhanced sensitivity to nicotine. We found little effect of AZD1446 in this model, suggesting that other approaches to nicotinic modulation should be explored.

  1. A randomized phase II study of gemcitabine and carboplatin with or without cediranib as first-line therapy in advanced non-small-cell lung cancer: North Central Cancer Treatment Group Study N0528.

    Science.gov (United States)

    Dy, Grace K; Mandrekar, Sumithra J; Nelson, Garth D; Meyers, Jeffrey P; Adjei, Araba A; Ross, Helen J; Ansari, Rafat H; Lyss, Alan P; Stella, Philip J; Schild, Steven E; Molina, Julian R; Adjei, Alex A

    2013-01-01

    The purpose of this study was to assess the safety and efficacy of gemcitabine and carboplatin with (arm A) or without (arm B) daily oral cediranib as first-line therapy for advanced non-small-cell lung cancer. A lead-in phase to determine the tolerability of gemcitabine 1000 mg/m on days 1 and 8, and carboplatin on day 1 at area under curve 5 administered every 21 days with cediranib 45 mg once daily was followed by a 2 (A):1 (B) randomized phase II study. The primary end point was confirmed overall response rate (ORR) with 6-month progression-free survival (PFS6) rate in arm A as secondary end point. Polymorphisms in genes encoding cediranib targets and transport were correlated with treatment outcome. On the basis of the safety assessment, cediranib 30 mg daily was used in the phase II portion. A total of 58 and 29 evaluable patients were accrued to arms A and B. Patients in A experienced more grade 3+ nonhematologic adverse events, 71% versus 45% (p = 0.01). The ORR was 19% (A) versus 20% (B) (p = 1.0). PFS6 in A was 48% (95% confidence interval: 35%-62%), thus meeting the protocol-specified threshold of at least 40%. The median overall survival was 12.0 versus 9.9 months (p = 0.10). FGFR1 rs7012413, FGFR2 rs2912791, and VEGFR3 rs11748431 polymorphisms were significantly associated with decreased overall survival (hazard ratio 2.78-5.01, p = 0.0002-0.0095). The trial did not meet its primary end point of ORR but met its secondary end point of PFS6. The combination with cediranib 30 mg daily resulted in increased toxicity. Pharmacogenetic analysis revealed an association of FGFR and VEGFR variants with survival.

  2. Detection of amyloid in Alzheimer's disease with positron emission tomography using [11C]AZD2184

    International Nuclear Information System (INIS)

    Nyberg, Svante; Cselenyi, Zsolt; Julin, Per; Olsson, Hans; Svensson, Samuel; Eriksdotter Joenhagen, Maria; Freund-Levi, Yvonne; Halldin, Christer; Andersson, Jan; Varnaes, Katarina; Farde, Lars

    2009-01-01

    Current positron emission tomography (PET) radioligands for detection of Aβ amyloid in Alzheimer's disease (AD) are not ideal for quantification. To improve the signal to noise ratio we have developed the radioligand [ 11 C]AZD2184 and report here the first clinical evaluation. Eight AD patients and four younger control subjects underwent 93-min PET measurements with [ 11 C]AZD2184. A ratio approach using the cerebellum as reference region was applied to determine binding parameters. Brain uptake of [ 11 C]AZD2184 peaked within 1 min at 3-4% of injected radioactivity. AD patients had high radioactivity in cortical regions while controls had uniformly low radioactivity uptake. Specific binding peaked within 30 min at which time standardized uptake value ratios (SUVR) ranged between 1.19 and 2.57. [ 11 C]AZD2184 is a promising radioligand for detailed mapping of Aβ amyloid depositions in Alzheimer's disease, due to low non-specific binding, high signal to background ratio and reversible binding as evident from early peak equilibrium. (orig.)

  3. The dual mTORC1 and mTORC2 inhibitor AZD8055 inhibits head and neck squamous cell carcinoma cell growth in vivo and in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qiang; Song, Xin-mao; Ji, Yang-yang; Jiang, Hui; Xu, Lin-gen, E-mail: drlingenxu@126.com

    2013-11-01

    Highlights: •AZD8055 induces significant cytotoxic effects in cultured HNSCC cells. •AZD8055 blocks mTORC1 and mTORC2 activation in cultured HNSCC cells. •JNK activation is required for AZD8055-induced HNSCC cell death. •AZD8055 inhibits Hep-2 cell growth in vivo, and was more efficient than rapamycin. -- Abstract: The serine/threonine kinase mammalian target of rapamycin (mTOR) promotes cell survival and proliferation, and is constitutively activated in head and neck squamous cell carcinoma (HNSCC). Thus mTOR is an important target for drug development in this disease. Here we tested the anti-tumor ability of AZD8055, the novel mTOR inhibitor, in HNSCC cells. AZD8055 induced dramatic cell death of HNSCC lines (Hep-2 and SCC-9) through autophagy. AZD8055 blocked both mTOR complex (mTORC) 1 and mTORC2 activation without affecting Erk in cultured HNSCC cells. Meanwhile, AZD8055 induced significant c-Jun N-terminal kinase (JNK) activation, which was also required for cancer cell death. JNK inhibition by its inhibitors (SP 600125 and JNK-IN-8), or by RNA interference (RNAi) alleviated AZD8055-induced cell death. Finally, AZD8055 markedly increased the survival of Hep-2 transplanted mice through a significant reduction of tumor growth, without apparent toxicity, and its anti-tumor ability was more potent than rapamycin. Meanwhile, AZD8055 administration activated JNK while blocking mTORC1/2 in Hep-2 tumor engrafts. Our current results strongly suggest that AZD8055 may be further investigated for HNSCC treatment in clinical trials.

  4. A randomized, comparative study of three doses of AZD0865 and esomeprazole for healing of reflux esophagitis

    DEFF Research Database (Denmark)

    Kahrilas, Peter J; Dent, John; Lauritsen, Karsten

    2007-01-01

    BACKGROUND & AIMS: AZD0865 belongs to a new class of acid-suppressing agents with rapid onset of action and potent acid inhibition. We evaluated its effectiveness for healing reflux esophagitis. METHODS: One thousand five hundred twenty-one patients with Los Angeles A-D esophagitis and heartburn......, especially at the 75-mg dose. CONCLUSIONS: AZD0865 25, 50, and 75 mg provided similar efficacy to esomeprazole 40 mg in terms of esophagitis healing and heartburn control. These findings suggest that increasing the degree of acid inhibition beyond that already achieved by esomeprazole 40 mg (or AZD0865 25 mg...

  5. Molecular Docking and Dynamic Simulation of AZD3293 and Solanezumab Effects Against BACE1 to Treat Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Mubashir Hassan

    2018-06-01

    Full Text Available The design of novel inhibitors to target BACE1 with reduced cytotoxicity effects is a promising approach to treat Alzheimer's disease (AD. Multiple clinical drugs and antibodies such as AZD3293 and Solanezumab are being tested to investigate their therapeutical potential against AD. The current study explores the binding pattern of AZD3293 and Solanezumab against their target proteins such as β-secretase (BACE1 and mid-region amyloid-beta (Aβ (PDBIDs: 2ZHV & 4XXD, respectively using molecular docking and dynamic simulation (MD approaches. The molecular docking results show that AZD3293 binds within the active region of BACE1 by forming hydrogen bonds against Asp32 and Lys107 with distances 2.95 and 2.68 Å, respectively. However, the heavy chain of Solanezumab interacts with Lys16 and Asp23 of amyloid beta having bond length 2.82, 2.78, and 3.00 Å, respectively. The dynamic cross correlations and normal mode analyses show that BACE1 depicted good residual correlated motions and fluctuations, as compared to Solanezumab. Using MD, the Root Mean Square Deviation and Fluctuation (RMSD/F graphs show that AZD3293 residual fluctuations and RMSD value (0.2 nm was much better compared to Solanezumab (0.7 nm. Moreover, the radius of gyration (Rg results also depicts the significance of AZD3293 docked complex compared to Solanezumab through residual compactness. Our comparative results show that AZD3293 is a better therapeutic agent for treating AD than Solanezumab.

  6. Serial MR Spectroscopy Reveals a Direct Metabolic Effect of Cediranib in Glioblastoma

    Science.gov (United States)

    Kim, Heisoog; Catana, Ciprian; Ratai, Eva-Maria; Andronesi, Ovidiu C.; Jennings, D.; Batchelor, Tracy T.; Jain, Rakesh K.; Sorensen, A. Gregory

    2011-01-01

    Proton magnetic resonance spectroscopy (1H-MRS) is increasingly used in clinical studies of brain tumor to provide information about tissue metabolic profiles. In this study, we evaluated changes in the levels of metabolites predominant in recurrent glioblastoma (rGBM), to characterize the response of rGBM to anti-angiogenic therapy. We examined thirty-one rGBM patients treated with daily doses of cediranib, acquiring serial chemical shift imaging data at specific time points during the treatment regimen. We defined spectra from three regions of interest (ROIs)—enhancing tumor (ET), peritumoral tissue (PT), and normal tissue on the contralateral side (cNT)—in post-contrast T1-weighted images, and normalized the concentrations of N-acetylaspartate (NAA) and choline (Cho) in each ROI to the concentration of creatine in cNT (norCre). We analyzed the ratios of these normalized metabolites (i.e., NAA/Cho, NAA/norCre, and Cho/norCre) by averaging all patients and categorizing two different survival groups. Relative to pre-treatment values, NAA/Cho in ET was unchanged through day 28. However, after day 28, NAA/Cho significantly increased in relation to a significant increase in NAA/norCre and a decrease in Cho/norCre; interestingly, the observed trend was reversed after day 56, consistent with the clinical course of GBM recurrence. Notably, ROC analysis indicated that NAA/Cho in tumor shows a high prediction to 6-month overall survival. These metabolic changes in these rGBM patients strongly suggest a direct metabolic effect of cediranib, and might also reflect an anti-tumor response to anti-angiogenic treatment during the first two months of treatment. Further study is needed to confirm these findings. PMID:21507932

  7. Pharmacological cardioversion of atrial fibrillation--a double-blind, randomized, placebo-controlled, multicentre, dose-escalation study of AZD1305 given intravenously

    DEFF Research Database (Denmark)

    Rónaszéki, Aladár; Alings, Marco; Egstrup, Kenneth

    2011-01-01

    AZD1305 is a combined ion channel blocker developed for the treatment of atrial fibrillation (AF). The aim of this study was to determine whether AZD1305 was effective in converting AF to sinus rhythm (SR)....

  8. Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes

    DEFF Research Database (Denmark)

    Storey, Robert F; Husted, Steen; Harrington, Robert A

    2007-01-01

    OBJECTIVES: In a substudy of DISPERSE (Dose confIrmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction)-2, we compared the antiplatelet effects of AZD6140 and clopidogrel and assessed the effects of AZD6140 in clopidogrel...

  9. Cetuximab improves AZD6244 antitumor activity in colorectal cancer HT29 cells in vitro and in nude mice by attenuating HER3/Akt pathway activation.

    Science.gov (United States)

    Zhang, Qin; Xiao, He; Jin, Feng; Li, Mengxia; Luo, Jia; Wang, Ge

    2018-07-01

    The present study investigated the molecular mechanism by which the epidermal growth factor receptor (EGFR) inhibitor cetuximab enhances the antitumor activity of the mitogen-activated protein kinase kinase (MEK) inhibitor AZD6244 in colorectal cancer HT29 cells. HT29 cells were treated with AZD6244 plus cetuximab and then subjected to the following assays: Cell Counting kit-8, BrdU-incorporation, flow cytometric cell cycle distribution and apoptosis analysis, western blot analysis, and nude mouse xenografts. The combination of AZD6244 and cetuximab significantly reduced HT29 cell viability and proliferation compared with AZD6244 alone. The combination treatment reduced the IC 50 value from 108.12±10.05 to 28.45±1.92 nM. AZD6244 and cetuximab also induced cell cycle arrest at G1 phase and reduced S phase (88.53% vs. 93.39%, P=0.080; 8.73% vs. 4.24%, P=0.082, respectively). Combination of AZD6244 with cetuximab significantly induced tumor cells apoptosis (14.61% vs. 8.99%, P=0.046). Inhibition of EGFR activity using cetuximab partially abrogated the feedback-activation of phosphorylated receptor tyrosine-protein kinase erB-3 (p-HER3) and p-AKT serine/threonine kinase (AKT), as well as prevented reactivation of p-extracellular regulated kinase (ERK) conferred by AZD6244 treatment. Combination of AZD6244 and cetuximab also inhibited HT29 cell xenograft growth in nude mice and suppressed HER3 and p-AKT levels in xenografts. The EGFR inhibitor cetuximab enhanced the antitumor activity of the MEK inhibitor AZD6244 in colorectal cells in vitro and in vivo . Co-inhibition of MEK and EGFR may be a promising treatment strategy in colorectal cancers.

  10. Tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in moderate to severe COPD patients

    DEFF Research Database (Denmark)

    Kerstjens, Huib A; Bjermer, Leif; Eriksson, Leif

    2010-01-01

    OBJECTIVE: This study evaluated the tolerability and efficacy of inhaled AZD4818, a CCR1 antagonist, in patients with COPD. METHODS: This double-blind, placebo-controlled study (NCT00629239) randomised patients with moderate to severe COPD to AZD4818 300mug or placebo twice daily via Turbuhaler....... These findings in COPD are in line with other studies reporting a lack of clinical efficacy with CCR1 antagonists in other therapy areas....

  11. Inhibition of fibroblast growth factor receptor with AZD4547 mitigates juvenile nasopharyngeal angiofibroma.

    Science.gov (United States)

    Le, Tran; New, Jacob; Jones, Joel W; Usman, Shireen; Yalamanchali, Sreeya; Tawfik, Ossama; Hoover, Larry; Bruegger, Dan E; Thomas, Sufi Mary

    2017-10-01

    Juvenile nasopharyngeal angiofibroma (JNA) is a benign tumor that presents in adolescent males. Although surgical excision is the mainstay of treatment, recurrences complicate treatment. There is a need to develop less invasive approaches for management. JNA tumors are composed of fibroblasts and vascular endothelial cells. We identified fibroblast growth factor receptor (FGFR) and vascular endothelial growth factor (VEGF) expression in JNA-derived fibroblasts. FGFR influences fibroblast proliferation and VEGF is necessary for angiogenesis. We hypothesized that targeting FGFR would mitigate JNA fibroblast proliferation, invasion, and migration, and that targeting the VEGF receptor would attenuate endothelial tubule formation. After informed consent, fibroblasts from JNA explants of 3 patients were isolated. Fibroblasts were treated with FGFR inhibitor AZD4547, 0 to 25 μg/mL for 72 hours and proliferation was quantified using CyQuant assay. Migration and invasion of JNA were assessed using 24-hour transwell assays with subsequent fixation and quantification. Mitigation of FGFR and downstream signaling was evaluated by immunoblotting. Tubule formation was assessed in human umbilical vein endothelial cells (HUVECs) treated with vehicle control (dimethylsulfoxide [DMSO]) or semaxanib (SU5416) as well as in serum-free media (SFM) or JNA conditioned media (CM). Tubule length was compared between treatment groups. Compared to control, AZD4547 inhibited JNA fibroblast proliferation, migration, and invasion through inhibition of FGFR and downstream signaling, specifically phosphorylation of - p44/42 mitogen activated protein kinase (p44/42 MAPK). JNA fibroblast CM significantly increased HUVEC tubule formation (p = 0.0039). AZD4547 effectively mitigates FGFR signaling and decreases JNA fibroblast proliferation, migration, and invasion. SU5416 attenuated JNA fibroblast-induced tubule formation. AZD4547 may have therapeutic potential in the treatment of JNA. © 2017 ARS

  12. AZD2014 Radiosensitizes Oral Squamous Cell Carcinoma by Inhibiting AKT/mTOR Axis and Inducing G1/G2/M Cell Cycle Arrest.

    Directory of Open Access Journals (Sweden)

    Chih-Chia Yu

    Full Text Available Oral squamous cell carcinoma (OSCC is one of the most common malignant neoplasms in Taiwan. Activation of the mTOR signaling pathway has been linked to decreased radiation responsiveness in human oral cancer, thus it limits efficacy of radiotherapy. To address this question, we investigated the effect of AZD2014, a novel small molecular ATP-competitive inhibitor of mTORC1 and mTORC2 kinase, as a radiosensitizer in primary OSCC and OSCC-derived cell line models.We isolated primary tumor cells from OSCC tissues and cell lines. AZD2014 was administered with and without ionizing radiation. The radiosensitizing effect of AZD2014 were then assessed using cell viability assays, clonogenic survival assays, and cell cycle analyses. Western blotting was used to detect protein expression.Combination treatment with AZD2014 and irradiation resulted in significant reduction in OSCC cell line and primary OSCC cell colony formation due to the enhanced inhibition of AKT and both mTORC1 and mTORC2 activity. Pre-treatment with AZD2014 in irradiated oral cancer cells induced tumor cell cycle arrest at the G1 and G2/M phases, which led to disruption of cyclin D1-CDK4 and cyclin B1-CDC2 complexes. Moreover, AZD2014 synergized with radiation to promote both apoptosis and autophagy by increasing caspase-3 and LC3 in primary OSCC cells.These findings suggest that in irradiated OSCC cells, co-treatment with AZD2014, which targets mTORC1 and mTORC2 blockade, is an effective radiosensitizing strategy for oral squamous cell carcinoma.

  13. Tracking Normalization of Brain Tumor Vasculature by Magnetic Imaging and Proangiogenic Biomarkers

    Science.gov (United States)

    Hormigo, Adília; Gutin, Philip H.; Rafii, Shahin

    2010-01-01

    Clinical assessment of the response to antiangiogenic therapy has been cumbersome. A study in this issue of Cancer Cell demonstrates that a combination of magnetic resonance imaging (MRI) for quantification of normalized vessels with measurements of circulating levels of proangiogenic factors, including FGF2, SDF1, and viable circulating endothelial cells, provides an effective means to evaluate the response of recurrent glioblastoma to a prototypical pan-VEGF receptor tyrosine kinase inhibitor, AZD2171. PMID:17222788

  14. Rapid slowing of the atrial fibrillatory rate after administration of AZD7009 predicts conversion of atrial fibrillation

    DEFF Research Database (Denmark)

    Aunes, Maria; Egstrup, Kenneth; Frison, Lars

    2014-01-01

    to sinus rhythm (SR) and were matched to 35 non-converters. The mean AFR before conversion was 231 fibrillations per minute (fpm), having decreased by 41%; in non-converters, it was 296 fpm at the end of infusion, having decreased by 26%. The rate of decrease was greater in converters at 5 min, -88 vs. -66......BACKGROUND: Effects on the atrial fibrillatory rate (AFR) were studied during infusion with the combined potassium and sodium channel blocker AZD7009. METHODS AND RESULTS: Patients with persistent atrial fibrillation (AF) were randomized to AZD7009 or placebo. Thirty-five patients converted...... fpm (p=0.02), and at 10 min, -133 vs. -111 fpm (p=0.048). The AFR-SD and the exponential decay decreased. A small left atrial area was the only baseline predictor of conversion to SR. CONCLUSIONS: AZD7009 produced a significantly more rapid decrease of the AFR in converters than in non...

  15. A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.

    Science.gov (United States)

    Dean, Emma; Banerji, Udai; Schellens, Jan H M; Krebs, Matthew G; Jimenez, Begona; van Brummelen, Emilie; Bailey, Chris; Casson, Ed; Cripps, Diana; Cullberg, Marie; Evans, Stephen; Foxley, Andrew; Lindemann, Justin; Rugman, Paul; Taylor, Nigel; Turner, Guy; Yates, James; Lawrence, Peter

    2018-05-01

    AZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet. Adults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a '4-days-on/3-days-off' schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and C max ratios of 0.75-1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2). In evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and C max were 0.90 (0.77-1.06) and 1.02 (0.86-1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later t max and lower C max after food versus overnight fast. Fed and fasted AUCτ and C max ratios were 0.89 (0.76-1.05) and 0.67 (0.55-0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states. PK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.

  16. Randomized, double-blind, placebo-controlled trial of the 5-HT1A receptor antagonist AZD7371 tartrate monohydrate (robalzotan tartrate monohydrate) in patients with irritable bowel syndrome.

    Science.gov (United States)

    Drossman, Douglas A; Danilewitz, Mervyn; Naesdal, Jørgen; Hwang, Clara; Adler, John; Silberg, Debra G

    2008-10-01

    To investigate the efficacy and safety of the 5-hydroxytrypamine 1A (5-HT(1A)) receptor antagonist AZD7371 tartrate monohydrate (robalzotan tartrate monohydrate), termed AZD7371 here, in patients with irritable bowel syndrome (IBS). Patients meeting the Rome II criteria for IBS (N = 402) were randomized to treatment with AZD7371 20 mg or 5 mg or matching placebo tablets twice daily for 12 wk. The patients completed daily and weekly diary assessments, reporting abdominal discomfort or pain and description of bowel movements. They also completed validated symptom and quality-of-life questionnaires. Neither AZD7371 regimen was significantly more effective than placebo in providing adequate relief from IBS symptoms in at least 2 out of 4 wk per month over the 12 wk of treatment. There was also no significant difference between the treatment groups and placebo in the change in score in the validated symptom and quality-of-life questionnaires. Overall, 22.1% of patients experienced adverse events (AEs) attributed to the study medication: 44 of 133 (33.1%) in the 20 mg AZD7371 group, 27 of 131 (20.6%) in the 5 mg AZD7371 group, and 17 of 134 (12.7%) in the placebo group. Also, 31 of 57 (54%) of AEs leading to discontinuation were central nervous system-related. Hallucinations or hallucination-like AEs were reported by eight patients taking AZD7371, and by none of the patients in the placebo group. After these events led to discontinuation in six patients, the study was prematurely terminated. In view of the AE profile and lack of efficacy in IBS, the clinical development of AZD7371 has been stopped.

  17. The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Patel NR

    2018-03-01

    Full Text Available Naimish R Patel,1,2 Danen M Cunoosamy,1 Malin Fagerås,1 Ziad Taib,1 Sara Asimus,1 Tove Hegelund-Myrbäck,1 Sofia Lundin,1 Katerina Pardali,1 Nisha Kurian,1 Eva Ersdal,1 Cecilia Kristensson,1 Katarina Korsback,1 Robert Palmér,1 Mary N Brown,3 Steven Greenaway,4 Leonard Siew,4 Graham W Clarke,4,5 Stephen I Rennard,6,7 Barry J Make,8 Robert A Wise,9 Paul Jansson11Innovative Medicines and Early Development, AstraZeneca, Gothenburg, Sweden; 2Division of Pulmonary, Critical Care, and Sleep Medicine, Beth Israel Deaconess Hospital, Boston, MA, 3Innovative Medicines and Early Development, AstraZeneca, Boston, MA, USA; 4Quintiles Drug Research Unit at Guy’s Hospital, London, 5Department of Cardiothoracic Pharmacology, NHLI, Imperial College London, London, UK; 6Division of Pulmonary, Critical Care, Sleep and Allergy, University of Nebraska, Omaha, NE, USA; 7Clinical Discovery Unit, Innovative Medicines and Early Development, AstraZeneca, Cambridge, UK; 8Division of Pulmonary Sciences and Critical Care Medicine, National Jewish Health, University of Colorado, Denver, CO, 9Division of Pulmonary and Critical Care, School of Medicine, Johns Hopkins University, Baltimore, MD, USABackground: p38 mitogen-activated protein kinase (MAPK plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations.Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations.Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls

  18. Synergetic Effects of PARP Inhibitor AZD2281 and Cisplatin in Oral Squamous Cell Carcinoma in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Masaaki Yasukawa

    2016-02-01

    Full Text Available Cisplatin is a commonly used chemotherapeutic drug for treatment of oral carcinoma, and combinatorial effects are expected to exert greater therapeutic efficacy compared with monotherapy. Poly(ADP-ribosylation is reported to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, and genomic stability. Based on these properties, poly(ADP-ribose polymerase (PARP inhibitors are used for treatment of cancers, such as BRCA1/2 mutated breast and ovarian cancers, or certain solid cancers in combination with anti-cancer drugs. However, the effects on oral cancer have not been fully evaluated. In this study, we examined the effects of PARP inhibitor on the survival of human oral cancer cells in vitro and xenografted tumors derived from human oral cancer cells in vivo. In vitro effects were assessed by microculture tetrazolium and survival assays. The PARP inhibitor AZD2281 (olaparib showed synergetic effects with cisplatin in a dose-dependent manner. Combinatorial treatment with cisplatin and AZD2281 significantly inhibited xenografted tumor growth compared with single treatment of cisplatin or AZD2281. Histopathological analysis revealed that cisplatin and AZD2281 increased TUNEL-positive cells and decreased Ki67- and CD31-positive cells. These results suggest that PARP inhibitors have the potential to improve therapeutic strategies for oral cancer.

  19. AZD3480, a novel nicotinic receptor agonist, for the treatment of attention-deficit/hyperactivity disorder in adults.

    Science.gov (United States)

    Potter, Alexandra S; Dunbar, Geoffrey; Mazzulla, Emily; Hosford, David; Newhouse, Paul A

    2014-02-01

    Laboratory studies have found that acute stimulation of nicotinic acetylcholine receptors improves cognition in adult attention-deficit/hyperactivity disorder (ADHD). Clinical trials of nicotinic agonists have been mixed, underscoring the need to understand the mechanisms for individual differences in clinical response. Using cognitive models within a clinical trial framework may provide insight into these differences. This was a within-subjects, randomized, placebo-controlled double-blind trial of the nicotinic agonist AZD3480 (also termed TC-1734) at doses of 5 mg and 50 mg and placebo in adults with ADHD. The order of the 2-week treatment periods was randomized, and a 3-week wash out separated each drug treatment period. Response inhibition (Stop Signal Task [SST]) and clinical efficacy (Investigator Rated Conners Adult ADHD Rating Scale [CAARS-INV]) were the a priori primary outcome measures of cognitive and clinical effects. We hypothesized that AZD3480 treatment would improve SST performance and clinical symptoms (CAARS-INV Total ADHD Symptoms Score). Thirty subjects were randomized, with 24 included in the intent-to-treat analyses. SST performance and total ADHD symptoms were significantly improved with 50 mg of AZD3480. CAARS-INV ratings of inattention, memory problems, and emotional lability/impulsivity were significantly improved with 50 mg of AZD3480. These results support previous work suggesting that nicotinic agonists are viable as treatments for adult ADHD. Measuring cognitive endophenotypes related to both the disorder and mechanism of treatment may help further rational drug development for dimensional features that cross-cut psychiatric disorders. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  20. Effects of PARP-1 inhibitors AG-014699 and AZD2281 on proliferation and apoptosis of human hepatoma cell line HepG2

    Directory of Open Access Journals (Sweden)

    DU Senrong

    2015-06-01

    Full Text Available ObjectiveTo observe the inhibitory and pro-apoptotic effects of two poly(ADP-ribose polymerase (PARP-1 inhibitors, AG-014699 and AZD2281, on human hepatoma HepG2 cells and preliminarily explore the mechanism by which AG-014699 induces HepG2 cell apoptosis, and to provide a new therapeutic target for hepatoma. MethodsThe effects of different concentrations of AG-014699 and AZD2281 on HepG2 cell proliferation were determined by MTT assay. The cell apoptosis rate was measured by flow cytometry. The expression levels of caspase-3 and caspase-8 were measured by Western Blot. Inter-group comparison was made by t test. ResultsBoth AG-014699 and AZD2281 suppressed HepG2 cell proliferation in a time- and dose-dependent manner. However, the sensitivity of HepG2 cells to the two PARP-1 inhibitors was different. The half-maximal inhibitory concentrations of AG-014699 and AZD2281 at 48 h determined by MTT assay were about 20 μmol/L and 400 μmol/L, respectively. Flow cytometry and Western blot were not used to evaluate the apoptosis of HepG2 cells exposed to AZD2281 to which these cells were not sensitive. HepG2 cell apoptosis could be induced by 10, 30, and 50 μmol/L AG-014699, and the highest apoptosis rate at 48 h was significantly higher than that of the control group (3100%±2.13% vs 09%±0013%, P<0.01. Compared with those in the control group, the protein levels of caspase-3 and caspase-8 in HepG2 cells after 48-h exposure to 30, and 50 μmol/L AG-014699 increased. ConclusionThe two PARP-1 inhibitors AG-014699 and AZD2281 can inhibit the proliferation of HepG2 cells, which showed different sensitivities to the two inhibitors. AG-014699 can induce HepG2 cell apoptosis by up-regulating the protein expression of caspase-3 and caspase-8.

  1. Rapid conversion of persistent atrial fibrillation to sinus rhythm by intravenous AZD7009

    DEFF Research Database (Denmark)

    Geller, J Christoph; Egstrup, Kenneth; Kulakowski, Piotr

    2009-01-01

    This randomized, double-blind trial compared cardioversion rates between AZD7009 infusion (15-minute 3.25 mg/min, 15-minute 4.4 mg/min, or 30-minute 3.25 mg/min) and placebo infusion (15 or 30 minutes) in patients with atrial fibrillation (AF) scheduled for DC cardioversion. One hundred sixty...

  2. The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere.

    Science.gov (United States)

    Li, Jing; Davies, Barry R; Han, Sufang; Zhou, Minhua; Bai, Yu; Zhang, Jingchuan; Xu, Yan; Tang, Lily; Wang, Huiying; Liu, Yuan Jie; Yin, Xiaolu; Ji, Qunsheng; Yu, De-Hua

    2013-10-02

    Activation of the PI3K/AKT pathway is a common phenomenon in cancer due to multiple mechanisms, including mutation of PI3KCA, loss or mutation of PTEN, or over-expression of receptor tyrosine kinases. We recently developed a novel AKT kinase inhibitor, AZD5363, and demonstrated that HGC27, a cell line harboring both PI3KCA mutation and PTEN loss, displayed the greatest sensitivity to this AKT inhibitor in vitro and in vivo. To further elucidate the correlation between AZD5363 response and genetic alterations in gastric cancer (GC) and identify GC patients with both PI3KCA mutations and PTEN loss, we investigated the effects of pharmacological inhibition of AKT on a panel of 20 GC cell lines and genetic aberrations in tumor samples from a cohort of Chinese GC patients. We demonstrated that GC cells with PI3KCA mutations were selectively sensitive to AZD5363. Disease linkage studies showed that PI3KCA activating mutations or PTEN loss were found in 2.7% (4/150) and 23% (14/61) of Chinese GC patients respectively. To further dissect the role of PI3KCA mutation and PTEN loss in response to AKT inhibition, we tested the antitumor activity of AZD5363 in two patient-derived GC xenograft (PDGCX) models harboring either PI3KCA mutation or PTEN loss. Our data indicated that AZD5363 monotherapy treatment led to a moderate response in the PI3KCA mutant PDGCX model. Whilst monotherapy AZD5363 or Taxotere were ineffective in the PTEN negative PDGCX model, significant anti-tumor activity was observed when AZD5363 was combined with Taxotere. Our results indicated that PI3KCA mutation is an important determinant of response to AKT inhibition in GC and combination with AZD5363 can overcome innate resistance to Taxotere in a PTEN loss PDGCX model. It is suggested that AKT inhibitor is an attractive option for treatment of a new segment of GC patients with aberrant PI3K/AKT signaling.

  3. The orally active and bioavailable ATR kinase inhibitor AZD6738 potentiates the anti-tumor effects of cisplatin to resolve ATM-deficient non-small cell lung cancer in vivo.

    Science.gov (United States)

    Vendetti, Frank P; Lau, Alan; Schamus, Sandra; Conrads, Thomas P; O'Connor, Mark J; Bakkenist, Christopher J

    2015-12-29

    ATR and ATM are DNA damage signaling kinases that phosphorylate several thousand substrates. ATR kinase activity is increased at damaged replication forks and resected DNA double-strand breaks (DSBs). ATM kinase activity is increased at DSBs. ATM has been widely studied since ataxia telangiectasia individuals who express no ATM protein are the most radiosensitive patients identified. Since ATM is not an essential protein, it is widely believed that ATM kinase inhibitors will be well-tolerated in the clinic. ATR has been widely studied, but advances have been complicated by the finding that ATR is an essential protein and it is widely believed that ATR kinase inhibitors will be toxic in the clinic. We describe AZD6738, an orally active and bioavailable ATR kinase inhibitor. AZD6738 induces cell death and senescence in non-small cell lung cancer (NSCLC) cell lines. AZD6738 potentiates the cytotoxicity of cisplatin and gemcitabine in NSCLC cell lines with intact ATM kinase signaling, and potently synergizes with cisplatin in ATM-deficient NSCLC cells. In contrast to expectations, daily administration of AZD6738 and ATR kinase inhibition for 14 consecutive days is tolerated in mice and enhances the therapeutic efficacy of cisplatin in xenograft models. Remarkably, the combination of cisplatin and AZD6738 resolves ATM-deficient lung cancer xenografts.

  4. High In Vitro Activity of the Novel Spiropyrimidinetrione AZD0914, a DNA Gyrase Inhibitor, against Multidrug-Resistant Neisseria gonorrhoeae Isolates Suggests a New Effective Option for Oral Treatment of Gonorrhea

    Science.gov (United States)

    Jacobsson, Susanne; Golparian, Daniel; Alm, Richard A.; Huband, Michael; Mueller, John; Jensen, Jorgen Skov; Ohnishi, Makoto

    2014-01-01

    We evaluated the activity of the novel spiropyrimidinetrione AZD0914 (DNA gyrase inhibitor) against clinical gonococcal isolates and international reference strains (n = 250), including strains with diverse multidrug resistance and extensive drug resistance. The AZD0914 MICs were substantially lower than those of most other currently or previously recommended antimicrobials. AZD0914 should be further evaluated, including in vitro selection, in vivo emergence and mechanisms of resistance, pharmacokinetics/pharmacodynamics in humans, optimal dosing, and performance, in appropriate randomized and controlled clinical trials. PMID:24982070

  5. Efficacy and safety of the CRTh2 antagonist AZD1981 as add-on therapy to inhaled corticosteroids and long-acting β2-agonists in patients with atopic asthma

    Directory of Open Access Journals (Sweden)

    Bateman ED

    2018-05-01

    Full Text Available Eric D Bateman,1 Christopher O’Brien,2 Paul Rugman,2 Sally Luke,2 Stefan Ivanov,2 Mohib Uddin2,3 1Department of Medicine, University of Cape Town, Cape Town, 7700, South Africa; 2Research and Development, 3Respiratory, Inflammation, and Autoimmunity, IMED Biotech Unit, AstraZeneca, Gothenburg, SE-431 83, Sweden Objectives: To evaluate the efficacy and safety of AZD1981, a potent, specific antagonist of the CRTh2 receptor, as add-on therapy to inhaled corticosteroids (ICS and long-acting β2-agonists (LABA, in patients with persistent asthma with an allergic component.Patients and methods: In this placebo-controlled, parallel-group Phase IIb study, patients with persistent atopic asthma on ICS and LABA were randomized to receive 12 weeks of treatment with placebo or AZD1981 (80 mg daily, 200 mg daily, and 10 mg, 40 mg, 100 mg, or 400 mg twice daily [BID]. The primary end point was the mean change from baseline in predose, prebronchodilator forced expiratory volume in 1 second (FEV1 averaged over weeks 2, 4, 8, and 12 in the AZD1981-treatment group vs the placebo group. Secondary end points included other measures of lung function, symptoms, and asthma control, as well as standard measures of safety.Results: In total, 1,140 patients (99.7% received study treatment. There were improvements in the primary end point across all treatment groups over 12 weeks of treatment. However, the improvement for the highest AZD1981 dose (400 mg BID vs placebo was not statistically significant (0.02 L, P=0.58, preventing interpretation of statistical testing for the lower doses. AZD1981 was well tolerated, and the incidence of adverse events was comparable across placebo and treatment groups.Conclusion: In patients with allergic asthma receiving ICS and LABA therapy, the addition of AZD1981 at doses up to 400 mg BID failed to produce a clinically relevant improvement in lung function or any other measured end point, but appeared to have an acceptable safety

  6. Insight into resistance mechanisms of AZD4547 and E3810 to FGFR1 gatekeeper mutation via theoretical study

    Directory of Open Access Journals (Sweden)

    Liang D

    2017-02-01

    Full Text Available Donglou Liang,1,* Qiaowan Chen,2,* Yujin Guo,1 Ting Zhang,3 Wentao Guo4 1Pharmacy Department, Jining First People’s Hospital, 2Department of Obstetrics, Affiliated Hospital of Jining Medical University, Jining, Shandong, 3Department of Rheumatology, The First Affiliated Hospital of Wenzhou Medical University, 4School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China *These authors contributed equally to this work Abstract: Inhibitors targeting the amplification of the fibroblast growth factor receptor 1 (FGFR1 have found success in the treatment of FGFR1-positive squamous cell lung and breast cancers. A secondary mutation of gatekeeper residue (V561M in the binding site has been linked to the acquired resistance. Recently, two well-known small molecule inhibitors of FGFR1, AZD4547 and E3810, reported that the V561M mutation confers significant resistance to E3810, while retaining affinity for AZD4547. FGFR1 is widely investigated as potential therapeutic target, while there are few computational studies made to understand the resistance mechanisms about FGFR1 V561M gatekeeper mutation. In this study, molecular docking, classical molecular dynamics simulations, molecular mechanics/generalized born surface area (MM/GBSA free energy calculations, and umbrella sampling (US simulations were carried out to make clear the principle of the binding preference of AZD4547 and E3810 toward FGFR1 V561M gatekeeper mutation. The results provided by MM/GBSA reveal that AZD4547 has similar binding affinity to both FGFR1WT and FGFR1V561M, whereas E3810 has much higher binding affinity to FGFR1WT than to FGFR1V561M. Comparison of individual energy terms indicates that the major variation of E3810 between FGFR1WT and FGFR1V561M are van der Waals interactions. In addition, US simulations prove that the potential of mean force (PMF profile of AZD4547 toward FGFR1WT and FGFR1V561M has similar PMF depth. However, the PMF profile

  7. β-Amyloid binding in elderly subjects with declining or stable episodic memory function measured with PET and [11C]AZD2184

    International Nuclear Information System (INIS)

    Mattsson, Patrik; Forsberg, Anton; Halldin, Christer; Persson, Jonas; Nilsson, Lars-Goeran; Nyberg, Lars; Farde, Lars

    2015-01-01

    Cognitive decline has been suggested as an early marker for later onset of Alzheimer's disease. We therefore explored the relationship between decline in episodic memory and β-amyloid using positron emission tomography (PET) and [ 11 C]AZD2184, a radioligand with potential to detect low levels of amyloid deposits. Healthy elderly subjects with declining (n = 10) or stable (n = 10) episodic memory over 15 years were recruited from the population-based Betula study and examined with PET. Brain radioactivity was measured after intravenous administration of [ 11 C]AZD2184. The binding potential BP ND was calculated using linear graphical analysis with the cerebellum as reference region. The binding of [ 11 C]AZD2184 in total grey matter was generally low in the declining group, whereas some binding could be observed in the stable group. Mean BP ND was significantly higher in the stable group compared to the declining group (p = 0.019). An observation was that the three subjects with the highest BP ND were ApoE ε4 allele carriers. We conclude that cognitive decline in the general population does not seem to stand by itself as an early predictor for amyloid deposits. (orig.)

  8. The value of integrating pre-clinical data to predict nausea and vomiting risk in humans as illustrated by AZD3514, a novel androgen receptor modulator

    Energy Technology Data Exchange (ETDEWEB)

    Grant, Claire, E-mail: claire.grant@astrazeneca.com [Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Ewart, Lorna [Drug Safety and Metabolism, AstraZeneca, Da Vinci Building, Melbourn Science Park, Cambridge Road, Melbourn, Royston SG8 6HB (United Kingdom); Muthas, Daniel [Respiratory, Inflammation and Autoimmunity iMED, AstraZeneca, Pepparedsleden 1, 431 83 Mölndal (Sweden); Deavall, Damian [Drug Safety and Metabolism, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Smith, Simon A. [Oncology Translational Medicine Unit, Early Clinical Development, AstraZeneca, Da Vinci Building, Melbourn Science Park, Melbourn, Royston SG8 6HB (United Kingdom); Clack, Glen [Translational Medicine Unit, Early Clinical Development, AstraZeneca, Alderley Park, Macclesfield SK10 4TG (United Kingdom); Newham, Pete [Drug Safety and Metabolism, AstraZeneca, Darwin Building, Cambridge Science Park, Milton Road, Cambridge CB4 0WG (United Kingdom)

    2016-04-01

    Nausea and vomiting are components of a complex mechanism that signals food avoidance and protection of the body against the absorption of ingested toxins. This response can also be triggered by pharmaceuticals. Predicting clinical nausea and vomiting liability for pharmaceutical agents based on pre-clinical data can be problematic as no single animal model is a universal predictor. Moreover, efforts to improve models are hampered by the lack of translational animal and human data in the public domain. AZD3514 is a novel, orally-administered compound that inhibits androgen receptor signaling and down-regulates androgen receptor expression. Here we have explored the utility of integrating data from several pre-clinical models to predict nausea and vomiting in the clinic. Single and repeat doses of AZD3514 resulted in emesis, salivation and gastrointestinal disturbances in the dog, and inhibited gastric emptying in rats after a single dose. AZD3514, at clinically relevant exposures, induced dose-responsive “pica” behaviour in rats after single and multiple daily doses, and induced retching and vomiting behaviour in ferrets after a single dose. We compare these data with the clinical manifestation of nausea and vomiting encountered in patients with castration-resistant prostate cancer receiving AZD3514. Our data reveal a striking relationship between the pre-clinical observations described and the experience of nausea and vomiting in the clinic. In conclusion, the emetic nature of AZD3514 was predicted across a range of pre-clinical models, and the approach presented provides a valuable framework for predicition of clinical nausea and vomiting. - Highlights: • Integrated pre-clinical data can be used to predict clinical nausea and vomiting. • Data integrated from standard toxicology studies is sufficient to make a prediction. • The use of the nausea algorithm developed by Parkinson (2012) aids the prediction. • Additional pre-clinical studies can be used

  9. Wee1 Kinase Inhibitor AZD1775 Radiosensitizes Hepatocellular Carcinoma Regardless of TP53 Mutational Status Through Induction of Replication Stress

    Energy Technology Data Exchange (ETDEWEB)

    Cuneo, Kyle C., E-mail: kcuneo@umich.edu; Morgan, Meredith A.; Davis, Mary A.; Parcels, Leslie A.; Parcels, Joshua; Karnak, David; Ryan, Caila; Liu, Na; Maybaum, Jonathan; Lawrence, Theodore S.

    2016-06-01

    Purpose: Wee1 kinase inhibitors are effective radiosensitizers in cells lacking a G{sub 1} checkpoint. In this study we examined the potential effect of Wee1 kinase inhibition on inducing replication stress in hepatocellular carcinoma (HCC). Methods and Materials: Five independent datasets from the Oncomine database comparing gene expression in HCC compared to normal tissue were combined and specific markers associated with Wee1 sensitivity were analyzed. We then performed a series of in vitro experiments to study the effect of Wee1 inhibition on irradiated HCC cell lines with varying p53 mutational status. Clonogenic survival assays and flow cytometry using anti-γH2AX and phospho-histone H3 antibodies with propidium iodide were performed to study the effect of AZD1775 on survival, cell cycle, and DNA repair. Additionally, nucleoside enriched medium was used to examine the effect of altering nucleotide pools on Wee1 targeted radiation sensitization. Results: Our analysis of the Oncomine database found high levels of CDK1 and other cell cycle regulators indicative of Wee1 sensitivity in HCC. In our in vitro experiments, treatment with AZD1775 radiosensitized and chemosensitized Hep3B, Huh7, and HepG2 cell lines and was associated with delayed resolution of γH2AX foci and the induction of pan-nuclear γH2AX staining. Wee1 inhibition attenuated radiation-induced G{sub 2} arrest in the Hep3B (TP53 null) and Huh7 (TP53 mutant) cell lines but not in the TP53 wild-type cell line HepG2. Supplementation with nucleosides reversed the radiation-sensitizing effect of AZD1775 and reduced the amount of cells with pan-nuclear γH2AX staining after radiation. Conclusions: Radiation sensitization with Wee1 inhibition occurs in cells regardless of their p53 mutational status. In this study we show for the first time that replication stress via the overconsumption of nucleotides plays an important role in AZD1775-induced radiation sensitization.

  10. β-Amyloid binding in elderly subjects with declining or stable episodic memory function measured with PET and [{sup 11}C]AZD2184

    Energy Technology Data Exchange (ETDEWEB)

    Mattsson, Patrik [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Karolinska University Hospital, Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatry Research, Stockholm (Sweden); Forsberg, Anton; Halldin, Christer [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); Persson, Jonas; Nilsson, Lars-Goeran [Karolinska Institute and Stockholm University, Aging Research Center (ARC), Stockholm (Sweden); Nyberg, Lars [Umeaa University, Department of Radiation Sciences (Diagnostic Radiology), Umeaa (Sweden); Farde, Lars [Karolinska Institutet, Centre for Psychiatry Research, Department of Clinical Neuroscience, Stockholm (Sweden); AstraZeneca Translational Science Center at Karolinska Institutet, Stockholm (Sweden)

    2015-09-15

    Cognitive decline has been suggested as an early marker for later onset of Alzheimer's disease. We therefore explored the relationship between decline in episodic memory and β-amyloid using positron emission tomography (PET) and [{sup 11}C]AZD2184, a radioligand with potential to detect low levels of amyloid deposits. Healthy elderly subjects with declining (n = 10) or stable (n = 10) episodic memory over 15 years were recruited from the population-based Betula study and examined with PET. Brain radioactivity was measured after intravenous administration of [{sup 11}C]AZD2184. The binding potential BP{sub ND} was calculated using linear graphical analysis with the cerebellum as reference region. The binding of [{sup 11}C]AZD2184 in total grey matter was generally low in the declining group, whereas some binding could be observed in the stable group. Mean BP{sub ND} was significantly higher in the stable group compared to the declining group (p = 0.019). An observation was that the three subjects with the highest BP{sub ND} were ApoE ε4 allele carriers. We conclude that cognitive decline in the general population does not seem to stand by itself as an early predictor for amyloid deposits. (orig.)

  11. AZD5363 inhibits inflammatory synergy between interleukin-17 and insulin/insulin-like growth factor 1

    Directory of Open Access Journals (Sweden)

    Chong eChen

    2014-12-01

    Full Text Available In the United States, one third of population is affected by obesity and almost 29 million people are suffering from type 2 diabetes. Obese people have elevated serum levels of insulin, insulin-like growth factor 1 (IGF1 and interleukin-17 (IL-17. Insulin and IGF1 are known to enhance IL-17-induced expression of inflammatory cytokines and chemokines, which may contribute to the chronic inflammatory status observed in obese people. We have previously demonstrated that insulin/IGF1 signaling pathway crosstalks with IL-17-activated nuclear factor-kappa B (NF-κB pathway through inhibiting glycogen synthase kinase 3β (GSK3β activity. However, it is unclear whether GSK3α also plays a role and whether this crosstalk can be manipulated by AZD5363, a novel pan-Akt inhibitor that has been shown to increase GSK3 activity through reducing phosphorylation of GSK3α and GSK3β. In this study, we investigated IL-17-induced expression of C-X-C motif ligand 1 (Cxcl1, C-C motif ligand 20 (Ccl20 and interleukin-6 (Il-6 in wild-type, GSK3α-/-, and GSK3β-/- mouse embryonic fibroblast (MEF cells as well as in mouse prostate tissues by real-time quantitative PCR. We examined the proteins involved in the signaling pathways by Western blot analysis. We found that insulin and IGF1 enhanced IL-17- induced expression of Cxcl1, Ccl20 and Il-6, which was associated with increased phosphorylation of GSK3α and GSK3β in the presence of insulin and IGF1. AZD5363 inhibited the synergy between IL-17 and insulin/IGF1 through reducing phosphorylation of GSK3α and GSK3β by inhibiting Akt function. These findings imply that the cooperative crosstalk of IL-17 and insulin/IGF1 in initiating inflammatory responses may be alleviated by AZD5363.

  12. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate

    NARCIS (Netherlands)

    Gerlag, Daniëlle M.; Hollis, Sally; Layton, Mark; Vencovský, Jiří; Szekanecz, Zoltán; Braddock, Martin; Tak, Paul P.; Oparanov, Boycho; Stoilov, Rumen; Yaneva, Tanya; Batalov, Anastas; Arteaga, Edgardo Tobias; Escalante, William Otero; Velez, Patricia; Restrepo, Jose Molina; Augustinova, Sevda; Blahova, Anna; Dvorak, Zdenek; Novosad, Libor; Rosa, Jan; Stehlikova, Helena; Vitek, Petr; Balazs, Tibor; Seregely, Katalin; Szombati, Istvan; Tarjan, Katalin; Csengei, Gabor; Galeazzi, Mauro; Saleniece, Sarmite; Saulite-Kandevica, Daina; Coleiro, Bernard; Badurski, Janusz; Brzosko, Marek; Chudzik, Dariusz; Gruszecka-Marczynska, Katarzyna; Hensel, Joanna; Pokrzywnicka-Gajek, Ines; Korpanty-Danda, Joanna; Sochocka-Bykowska, Malgorzata; Tlustochowicz, Witold; Stopinska-Polaszewska, Maria; Gluszko, Piotr; Nedelcovici, Corina; Radulescu, Florin; Gavrila, Mirea; Tanasescu, Coman; Korshunov, Nikolay; Matsievskaia, Galina; Damjanov, Nemanja; Dimic, Aleksandar

    2010-01-01

    To investigate both the preclinical effects of blocking the chemokine receptor CCR5 and the clinical effects of this approach on the signs and symptoms of rheumatoid arthritis (RA) in patients with active disease. Preclinical evaluations of AZD5672, a small-molecule antagonist of CCR5, were

  13. Antitumor Effect of AZD4547 in a Fibroblast Growth Factor Receptor 2–Amplified Gastric Cancer Patient–Derived Cell Model

    Directory of Open Access Journals (Sweden)

    Jiryeon Jang

    2017-08-01

    Full Text Available BACKGROUND: FGFR2 amplification is associated with aggressive gastric cancer (GC, and targeted drugs have been developed for treatment of GC. We evaluated the antitumor activity of an FGFR inhibitor in FGFR2-amplified GC patients with peritoneal carcinomatosis. METHODS: Two GC patients with FGFR2 amplification confirmed by fluorescence in situ hybridization showed peritoneal seeding and malignant ascites. We used the patient-derived xenograft model; patient-derived cells (PDCs from malignant ascites were used to assess FGFR2 expression and its downstream pathway using immunofluorescence analysis and immunoblot assay in vitro. Apoptosis and cell cycle arrest after treatment of FGFR inhibitor were analyzed by Annexin V-FITC assay and cell cycle analysis. RESULTS: FGFR2 amplification was verified in both PDC lines. AZD4547 as an FGFR inhibitor decreased proliferation of PDCs, and the IC50 value was estimated to be 250 nM in PDC#1 and 210 nM in PDC#2. FGFR inhibitor also significantly decreased levels of phosphorylated FGFR2 and downstream signaling molecules in FGFR2-amplified PDC lines. In cell cycle analysis, apoptosis was significantly increased in AZD4547-treated cells compared with nontreated cells. The proportion of cells in the sub-G1 stage was significantly higher in AZD4547-treated PDCs than in control cells. CONCLUSION: Our findings suggest that FGFR2 amplification is a relevant therapeutic target in GC with peritoneal carcinomatosis.

  14. The use of 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET as a non-invasive pharmacodynamic biomarker to determine the minimally pharmacologically active dose of AZD8835, a novel PI3Kα inhibitor.

    Directory of Open Access Journals (Sweden)

    Juliana Maynard

    Full Text Available The phosphatidyl inositol 3 kinase (PI3K, AKT and mammalian target of rapamycin (mTOR signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development. It has been used widely with PI3K inhibitors both clinically and pre-clinically because of the role of the PI3K pathway in glucose metabolism. In this study we investigated the potential of 18F-FDG PET as a non-invasive pharmacodynamic biomarker for AZD8835. We sought to understand if 18F-FDG PET could determine the minimally effective dose of AZD8835 and correlate with other pharmacodynamic biomarkers for validation of its use in clinical development. 18F-FDG PET scans were performed in nude mice in the BT474C breast xenograft model. Mice were fasted prior to imaging and static 18F-FDG PET was performed. Treatment groups received AZD8835 by oral gavage at a dose volume of 10ml/kg. Treatment groups received either 3, 6, 12.5, 25 or 50mg/kg AZD8835. Tumour growth was monitored throughout the study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis was performed.Results showed that AZD8835 reduced 18F-FDG uptake at a dose of 12.5, 25 and 50mg/kg with no significant reduction at doses of 3 and 6mg/kg. These results were consistent with other pharmacodynamics biomarkers measured and show 18F-FDG PET as a sensitive biomarker with the ability to determine the minimal effective dose of AZD8835.Our pre-clinical studies support the use of 18F-FDG PET imaging as a sensitive and non- invasive pharmacodynamic biomarker (understanding the role of PI3K signalling in glucose uptake for AZD8835 with a decrease in 18

  15. Edema control by cediranib, a vascular endothelial growth factor receptor-targeted kinase inhibitor, prolongs survival despite persistent brain tumor growth in mice

    DEFF Research Database (Denmark)

    Kamoun, Walid S; Ley, Carsten D; Farrar, Christian T

    2009-01-01

    anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. METHODS: We treated...... mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis...... by an increase in plasma collagen IV. These rapid changes in tumor vascular morphology and function led to edema alleviation -- as measured by MRI and by dry/wet weight measurement of water content -- but did not affect tumor growth. By immunohistochemistry, we found a transient decrease in macrophage...

  16. AZD9291 in epidermal growth factor receptor inhibitor-resistant non-small-cell lung cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E

    2016-02-01

    Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in advanced EGFR mutant non-small cell lung cancer have an objective response rate (ORR) of approximately 60-70% and a median progression free-survival (PFS) of approximately 10-13 months. Studies of tumor biopsies performed after progression on EGFR TKI revealed that 50-60% of EGFR mutant NSCLC developed an EGFR exon 20 T790M mutation as a mechanism of acquired resistance. AZD9291 is a third generation irreversible EGFR TKI with activity against the activating EGFR mutation, the T790M acquired resistance mutation, and relative sparing of the wild-type EGFR. AZD9291 was investigated in a phase I trial with expansion cohorts in patients with disease progression after EGFR TKI. Patients with and without detectable T790M mutations were enrolled in the trial. The ORR in patients with centrally confirmed and without detectable T790M mutations was 61% (95% CI, 52-70%) and 21% (95% CI, 12-34%), respectively. The PFS observed in patients with centrally confirmed and without detectable T790M mutations was 9.6 months (95% CI, 8.3 to not reached) and 2.8 months (95% CI, 2.1-4.3 months), respectively. At the dose for further investigation, 80 mg daily, the rate of all grade 3-5 drug related adverse events was 11%, and the rates of grade 3 diarrhea and rash were 1% and 0%, respectively. The identification of the T790M resistance mutation and the subsequent development of an agent against the mechanism of resistance provide a template for future drug development for acquired resistance to targeted therapy.

  17. QT response after a test dose and during maintenance therapy with AZD1305 in patients with atrial fibrillation: a double-blind, randomized, placebo-controlled trial

    DEFF Research Database (Denmark)

    Egstrup, Kenneth; Bergfeldt, Lennart; Duris, Tibor

    2011-01-01

    AZD1305 is an investigational antiarrhythmic agent that prolongs refractoriness through combined potassium and sodium channel inhibition. This study aimed to explore the utility of a test dose in predicting QT interval corrected according to Fridericia's formula (QTcF) during subsequent maintenance...

  18. Sensitivity of MRI tumor biomarkers to VEGFR inhibitor therapy in an orthotopic mouse glioma model.

    Directory of Open Access Journals (Sweden)

    Christian T Farrar

    Full Text Available MRI biomarkers of tumor edema, vascular permeability, blood volume, and average vessel caliber are increasingly being employed to assess the efficacy of tumor therapies. However, the dependence of these biomarkers on a number of physiological factors can compromise their sensitivity and complicate the assessment of therapeutic efficacy. Here we examine the response of these MRI tumor biomarkers to cediranib, a potent vascular endothelial growth factor receptor (VEGFR inhibitor, in an orthotopic mouse glioma model. A significant increase in the tumor volume and relative vessel caliber index (rVCI and a slight decrease in the water apparent diffusion coefficient (ADC were observed for both control and cediranib treated animals. This contrasts with a clinical study that observed a significant decrease in tumor rVCI, ADC and volume with cediranib therapy. While the lack of a difference between control and cediranib treated animals in these biomarker responses might suggest that cediranib has no therapeutic benefit, cediranib treated mice had a significantly increased survival. The increased survival benefit of cediranib treated animals is consistent with the significant decrease observed for cediranib treated animals in the relative cerebral blood volume (rCBV, relative microvascular blood volume (rMBV, transverse relaxation time (T2, blood vessel permeability (K(trans, and extravascular-extracellular space (ν(e. The differential response of pre-clinical and clinical tumors to cediranib therapy, along with the lack of a positive response for some biomarkers, indicates the importance of evaluating the whole spectrum of different tumor biomarkers to properly assess the therapeutic response and identify and interpret the therapy-induced changes in the tumor physiology.

  19. A novel reflux inhibitor lesogaberan (AZD3355) as add-on treatment in patients with GORD with persistent reflux symptoms despite proton pump inhibitor therapy: a randomised placebo-controlled trial

    NARCIS (Netherlands)

    Boeckxstaens, Guy E.; Beaumont, Hanneke; Hatlebakk, Jan G.; Silberg, Debra G.; Björck, Karin; Karlsson, Maria; Denison, Hans

    2011-01-01

    o evaluate the efficacy and tolerability of add-on treatment with lesogaberan (AZD3355), a novel reflux inhibitor, in patients with persistent gastro-oesophageal reflux disease (GORD) symptoms despite proton pump inhibitor (PPI) therapy. double-blind, placebo-controlled, randomised, parallel-group,

  20. Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial

    DEFF Research Database (Denmark)

    Cannon, Christopher P; Husted, Steen; Harrington, Robert A

    2007-01-01

    , or clopidogrel 300-mg loading dose plus 75 mg once daily for up to 12 weeks. RESULTS: The primary end point, the Kaplan-Meier rate of major or minor bleeding through 4 weeks, was 8.1% in the clopidogrel group, 9.8% in the AZD6140 90-mg group, and 8.0% in the AZD6140 180-mg group (p = 0.43 and p = 0.......96, respectively, vs. clopidogrel); the major bleeding rates were 6.9%, 7.1%, and 5.1%, respectively (p = 0.91 and p = 0.35, respectively, vs. clopidogrel). Although not statistically significant, favorable trends were seen in the Kaplan-Meier rates of myocardial infarction (MI) over the entire study period (MI: 5...

  1. Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD

    DEFF Research Database (Denmark)

    Dahl, Ronald; Titlestad, Ingrid Louise; Lindqvist, Ari

    2012-01-01

    Abstract Background There is a pressing need for new forms of treatment for COPD. Based on the known pathophysiology of COPD, inhibition of matrix metalloproteinases is a theoretically promising approach. This Phase IIa study evaluated the effects of AZD1236, a selective MMP-9 and MMP-12 inhibitor......, on the biomarkers of inflammation and emphysematous lung tissue degradation in patients with moderate-to-severe COPD. Methods This was a multinational, randomized, double-blind, placebo-controlled signal-searching study conducted in men and women aged ≥40 years with stable moderate-to-severe COPD. After a 2–6-week......-term signal-searching study, although possible evidence of an impact on desmosine may suggest the potential value of selective inhibitors of MMPs in the treatment of COPD in longer term trials....

  2. A Phase I Clinical Trial of AZD1775 in Combination With Neoadjuvant Weekly Docetaxel and Cisplatin Before Definitive Therapy in Head and Neck Squamous Cell Carcinoma. | Office of Cancer Genomics

    Science.gov (United States)

    Purpose: The WEE1 tyrosine kinase regulates G2/M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. There is a need to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel.

  3. Discovery of (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), a kinesin spindle protein inhibitor and potential anticancer agent.

    Science.gov (United States)

    Theoclitou, Maria-Elena; Aquila, Brian; Block, Michael H; Brassil, Patrick J; Castriotta, Lillian; Code, Erin; Collins, Michael P; Davies, Audrey M; Deegan, Tracy; Ezhuthachan, Jayachandran; Filla, Sandra; Freed, Ellen; Hu, Haiqing; Huszar, Dennis; Jayaraman, Muthusamy; Lawson, Deborah; Lewis, Paula M; Nadella, Murali V P; Oza, Vibha; Padmanilayam, Maniyan; Pontz, Timothy; Ronco, Lucienne; Russell, Daniel; Whitston, David; Zheng, Xiaolan

    2011-10-13

    Structure-activity relationship analysis identified (+)-N-(3-aminopropyl)-N-[1-(5-benzyl-3-methyl-4-oxo-[1,2]thiazolo[5,4-d]pyrimidin-6-yl)-2-methylpropyl]-4-methylbenzamide (AZD4877), from a series of novel kinesin spindle protein (KSP) inhibitors, as exhibiting both excellent biochemical potency and pharmaceutical properties suitable for clinical development. The selected compound arrested cells in mitosis leading to the formation of the monopolar spindle phenotype characteristic of KSP inhibition and induction of cellular death. A favorable pharmacokinetic profile and notable in vivo efficacy supported the selection of this compound as a clinical candidate for the treatment of cancer.

  4. Translational Modeling to Guide Study Design and Dose Choice in Obesity Exemplified by AZD1979, a Melanin-concentrating Hormone Receptor 1 Antagonist.

    Science.gov (United States)

    Gennemark, P; Trägårdh, M; Lindén, D; Ploj, K; Johansson, A; Turnbull, A; Carlsson, B; Antonsson, M

    2017-07-01

    In this study, we present the translational modeling used in the discovery of AZD1979, a melanin-concentrating hormone receptor 1 (MCHr1) antagonist aimed for treatment of obesity. The model quantitatively connects the relevant biomarkers and thereby closes the scaling path from rodent to man, as well as from dose to effect level. The complexity of individual modeling steps depends on the quality and quantity of data as well as the prior information; from semimechanistic body-composition models to standard linear regression. Key predictions are obtained by standard forward simulation (e.g., predicting effect from exposure), as well as non-parametric input estimation (e.g., predicting energy intake from longitudinal body-weight data), across species. The work illustrates how modeling integrates data from several species, fills critical gaps between biomarkers, and supports experimental design and human dose-prediction. We believe this approach can be of general interest for translation in the obesity field, and might inspire translational reasoning more broadly. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  5. Repeated intranasal TLR7 stimulation reduces allergen responsiveness in allergic rhinitis

    Directory of Open Access Journals (Sweden)

    Greiff Lennart

    2012-06-01

    Full Text Available Abstract Background Interactions between Th1 and Th2 immune responses are of importance to the onset and development of allergic disorders. A Toll-like receptor 7 agonist such as AZD8848 may have potential as a treatment for allergic airway disease by skewing the immune system away from a Th2 profile. Objective To evaluate the efficacy and safety of intranasal AZD8848. Methods In a placebo-controlled single ascending dose study, AZD8848 (0.3-600 μg was given intranasally to 48 healthy subjects and 12 patients with allergic rhinitis (NCT00688779. In a placebo-controlled repeat challenge/treatment study, AZD8848 (30 and 60 μg was given once weekly for five weeks to 74 patients with allergic rhinitis out of season: starting 24 hours after the final dose, daily allergen challenges were given for seven days (NCT00770003. Safety, tolerability, pharmacokinetics, and biomarkers were monitored. During the allergen challenge series, nasal symptoms and lavage fluid levels of tryptase and α2-macroglobulin, reflecting mast cell activity and plasma exudation, were monitored. Results AZD8848 produced reversible blood lymphocyte reductions and dose-dependent flu-like symptoms: 30–100 μg produced consistent yet tolerable effects. Plasma interleukin-1 receptor antagonist was elevated after administration of AZD8848, reflecting interferon production secondary to TLR7 stimulation. At repeat challenge/treatment, AZD8848 reduced nasal symptoms recorded ten minutes after allergen challenge up to eight days after the final dose. Tryptase and α2-macroglobulin were also reduced by AZD8848. Conclusions Repeated intranasal stimulation of Toll-like receptor 7 by AZD8848 was safe and produced a sustained reduction in the responsiveness to allergen in allergic rhinitis. Trial registration NCT00688779 and NCT00770003 as indicated above.

  6. MEK inhibitor effective against proliferation in breast cancer cell.

    Science.gov (United States)

    Zhou, Yan; Hu, Hai-Yan; Meng, Wei; Jiang, Ling; Zhang, Xing; Sha, Jing-Jing; Lu, Zhigang; Yao, Yang

    2014-09-01

    The targeted small-molecule drug AZD6244 is an allosteric, ATP-noncompetitive inhibitor of MEK1/2 that has shown activity against several malignant tumors. Here, we report that AZD6244 repressed cell growth and induced apoptosis and G1-phase arrest in the breast cancer cell lines MDA-MB-231 and HCC1937. Using microRNA (miRNA) arrays and quantitative RT-PCR, we found that miR-203 was up-regulated after AZD6244 treatment. In accordance with bioinformatics and luciferase activity analyses, CUL1 was found to be the direct target of miR-203. Furthermore, miR-203 inhibition and CUL1 overexpression reversed the cytotoxicity of AZD6244 on the MDA-MB-231 and HCC1937 cells. Collectively, our data indicate that miR-203 mediates the AZD6244-induced cytotoxicity of breast cancer cells and that the MEK/ERK/miR-203/CUL1 signaling pathway may participate in this process.

  7. Continual reassessment method for dose escalation clinical trials in oncology: a comparison of prior skeleton approaches using AZD3514 data.

    Science.gov (United States)

    James, Gareth D; Symeonides, Stefan N; Marshall, Jayne; Young, Julia; Clack, Glen

    2016-08-31

    The continual reassessment method (CRM) requires an underlying model of the dose-toxicity relationship ("prior skeleton") and there is limited guidance of what this should be when little is known about this association. In this manuscript the impact of applying the CRM with different prior skeleton approaches and the 3 + 3 method are compared in terms of ability to determine the true maximum tolerated dose (MTD) and number of patients allocated to sub-optimal and toxic doses. Post-hoc dose-escalation analyses on real-life clinical trial data on an early oncology compound (AZD3514), using the 3 + 3 method and CRM using six different prior skeleton approaches. All methods correctly identified the true MTD. The 3 + 3 method allocated six patients to both sub-optimal and toxic doses. All CRM approaches allocated four patients to sub-optimal doses. No patients were allocated to toxic doses from sigmoidal, two from conservative and five from other approaches. Prior skeletons for the CRM for phase 1 clinical trials are proposed in this manuscript and applied to a real clinical trial dataset. Highly accurate initial skeleton estimates may not be essential to determine the true MTD, and, as expected, all CRM methods out-performed the 3 + 3 method. There were differences in performance between skeletons. The choice of skeleton should depend on whether minimizing the number of patients allocated to suboptimal or toxic doses is more important. NCT01162395 , Trial date of first registration: July 13, 2010.

  8. Expression profiling and functional analysis reveals that TOR is a key player in regulating photosynthesis and phytohormone signaling pathways in Arabidopsis.

    Science.gov (United States)

    Dong, Pan; Xiong, Fangjie; Que, Yumei; Wang, Kai; Yu, Lihua; Li, Zhengguo; Ren, Maozhi

    2015-01-01

    Target of rapamycin (TOR) acts as a master regulator to control cell growth by integrating nutrient, energy, and growth factors in all eukaryotic species. TOR plays an evolutionarily conserved role in regulating the transcription of genes associated with anabolic and catabolic processes in Arabidopsis, but little is known about the functions of TOR in photosynthesis and phytohormone signaling, which are unique features of plants. In this study, AZD8055 (AZD) was screened as the strongest active-site TOR inhibitor (asTORi) in Arabidopsis compared with TORIN1 and KU63794 (KU). Gene expression profiles were evaluated using RNA-seq after treating Arabidopsis seedlings with AZD. More than three-fold differentially expressed genes (DEGs) were identified in AZD-treated plants relative to rapamycin-treated plants in previous studies. Most of the DEGs and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways involved in cell wall elongation, ribosome biogenesis, and cell autophagy were common to both AZD- and rapamycin-treated samples, but AZD displayed much broader and more efficient inhibition of TOR compared with rapamycin. Importantly, the suppression of TOR by AZD resulted in remodeling of the expression profile of the genes associated with photosynthesis and various phytohormones, indicating that TOR plays a crucial role in modulating photosynthesis and phytohormone signaling in Arabidopsis. These newly identified DEGs expand the understanding of TOR signaling in plants. This study elucidates the novel functions of TOR in photosynthesis and phytohormone signaling and provides a platform to study the downstream targets of TOR in Arabidopsis.

  9. mTOR Inhibition Induces EGFR Feedback Activation in Association with Its Resistance to Human Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Feng Wei

    2015-02-01

    Full Text Available The mammalian target of rapamycin (mTOR is dysregulated in diverse cancers and contributes to tumor progression and drug resistance. The first generation of mTOR inhibitors have failed to show clinical efficiency in treating pancreatic cancers due in part to the feedback relief of the insulin-like growth factor-1 receptor (IGF-1R-AKT signaling pathway. The second generation of mTOR inhibitors, such as AZD8055, could inhibit AKT activation upon mTOR complex 2 (mTORC2 inhibition. However, whether this generation of mTOR inhibitors can obtain satisfactory activities in pancreatic cancer therapy remains unclear. In this study, we found AZD8055 did not show great improvement compared with everolimus, AZD8055 induced a temporal inhibition of AKT kinase activities and AKT was then rephosphorylated. Additionally, we found that AZD8055-induced transient AKT inhibition increased the expression and activation of epidermal growth factor receptor (EGFR by releasing its transcriptional factors Fork-head box O 1/3a (FoxO1/3a, which might contribute to cell resistance to AZD8055. The in vitro and in vivo experiments further indicated the combination of AZD8055 and erlotinib synergistically inhibited the mTORC1/C2 signaling pathway, EGFR/AKT feedback activation, and cell growth, as well as suppressed the progression of pancreatic cancer in a xenograft model. This study provides a rationale and strategy for overcoming AZD8055 resistance by a combined treatment with the EGFR inhibitor erlotinib in pancreatic cancer therapy.

  10. mTOR Inhibition Attenuates Dextran Sulfate Sodium-Induced Colitis by Suppressing T Cell Proliferation and Balancing TH1/TH17/Treg Profile.

    Directory of Open Access Journals (Sweden)

    Shurong Hu

    Full Text Available It has been established that mammalian target of Rapamycin (mTOR inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD. Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL-17A, IL-1β,IL-6 and tumor necrosis factor(TNF-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1 cells and TH17 cells and increases regulatory T (Treg cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.

  11. The APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients. EORTC 1613.

    Science.gov (United States)

    Remon, Jordi; Menis, Jessica; Hasan, Baktiar; Peric, Aleksandra; De Maio, Eleonora; Novello, Silvia; Reck, Martin; Berghmans, Thierry; Wasag, Bartosz; Besse, Benjamin; Dziadziuszko, Rafal

    2017-09-01

    The AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients (APPLE) trial is a randomized, open-label, multicenter, 3-arm, phase II study in advanced, epidermal growth factor receptor (EGFR)-mutant and EGFR tyrosine kinase inhibitor (TKI)-naive non-small-cell lung cancer (NSCLC) patients, to evaluate the best strategy for sequencing gefitinib and osimertinib treatment. Advanced EGFR-mutant NSCLC patients, with World Health Organization performance status 0-2 who are EGFR TKI treatment-naive and eligible to receive first-line treatment with EGFR TKI will be randomized to: In all arms, a plasmatic ctDNA T790M test will be performed by a central laboratory at the Medical University of Gdansk (Poland) but will be applied as a predictive marker for making treatment decisions only in arm B. The primary objective is to evaluate the best strategy for sequencing of treatment with gefitinib and osimertinib in advanced NSCLC patients with common EGFR mutations, and to understand the value of liquid biopsy for the decision-making process. The progression-free survival rate at 18 months is the primary end point of the trial. The activity of osimertinib versus gefitinib to prevent brain metastases will be evaluated. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  12. mTOR inhibition sensitizes human hepatocellular carcinoma cells to resminostat

    Energy Technology Data Exchange (ETDEWEB)

    Peng, Xingang, E-mail: pengxinggang26@sina.com [Department of Emergency General Surgery, The Affiliated Hospital of Qingdao University, Qingdao (China); Zhang, Donghui, E-mail: zhangdonghuiyx@sina.com [Department of Infectious Disease, Linyi People’s Hospital, Linyi (China); Li, Zhengling, E-mail: lizhenglingzz@sina.com [Department of Nursing, Tengzhou Central People’s Hospital, Tengzhou (China); Fu, Meili, E-mail: fumeilidrlinyi@tom.com [Department of Infectious Disease, Linyi People’s Hospital, Linyi (China); Liu, Haiyan, E-mail: liuhaiyanlinyi5@sina.com [Department of Nursing, Linyi People’s Hospital, Linyi (China)

    2016-09-02

    Histone deacetylases (HDACs) hyper-activity in hepatocellular carcinoma (HCC) is often associated with patients’ poor prognosis. Our previous study has shown that resminostat, a novel HDAC inhibitor (HDACi), activated mitochondrial permeability transition pore (mPTP)-dependent apoptosis pathway in HCC cells. Here we explored the potential resminostat resistance factor by focusing on mammalian target of rapamycin (mTOR). We showed that AZD-2014, a novel mTOR kinase inhibitor, potentiated resminostat-induced cytotoxicity and proliferation inhibition in HCC cells. Molecularly, AZD-2014 enhanced resminostat-induced mPTP apoptosis pathway activation in HCC cells. Inhibition of this apoptosis pathway, by the caspase-9 specific inhibitor Ac-LEHD-CHO, the mPTP blockers (sanglifehrin A/cyclosporine A), or by shRNA-mediated knockdown of mPTP component cyclophilin-D (Cyp-D), significantly attenuated resminostat plus AZD-2014-induced cytotoxicity and apoptosis in HCC cells. Significantly, mTOR shRNA knockdown or kinase-dead mutation (Asp-2338-Ala) also sensitized HCC cells to resminostat, causing profound cytotoxicity and apoptosis induction. Together, these results suggest that mTOR could be a primary resistance factor of resminostat. Targeted inhibition of mTOR may thus significantly sensitize HCC cells to resminostat. - Highlights: • AZD-2014 potentiates resminostat’s cytotoxicity against HCC cells. • AZD-2014 facilitates resminostat-induced HCC cell apoptosis. • AZD-2014 augments resminostat-induced mitochondrial apoptosis pathway activation. • mTOR shRNA or kinase-dead mutation significantly sensitizes HCC cells to resminostat.

  13. Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo

    DEFF Research Database (Denmark)

    Kleinert, Maximilian; Sylow, Lykke; Fazakerley, Daniel J

    2014-01-01

    , but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype...... SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose...

  14. Acute mTOR inhibition induces insulin resistance and alters substrate utilization in vivo

    DEFF Research Database (Denmark)

    Kleinert, Maximilian; Sylow, Lykke; Fazakerley, Daniel J.

    2014-01-01

    , but not rapamycin reduced insulin-stimulated glucose uptake into incubated muscles, despite normal GLUT4 translocation in muscle cells. AZD8055 inhibited glycolysis in MEF cells. Abrogation of mTORC2 activity by SIN1 deletion impaired glycolysis and AZD8055 had no effect in SIN1 KO MEFs. Re-expression of wildtype...... SIN1 rescued glycolysis. Glucose intolerance following AZD8055 administration was absent in mice lacking the mTORC2 subunit Rictor in muscle, and in vivo glucose uptake into Rictor-deficient muscle was reduced despite normal Akt activity. Taken together, acute mTOR inhibition is detrimental to glucose...

  15. The novel, peripherally restricted GABAB receptor agonist lesogaberan (AZD3355) inhibits acid reflux and reduces esophageal acid exposure as measured with 24-h pHmetry in dogs.

    Science.gov (United States)

    Brändén, Lena; Fredriksson, Anita; Harring, Emelie; Jensen, Jörgen; Lehmann, Anders

    2010-05-25

    While patients with symptoms of gastroesophageal reflux disease generally respond well to proton pump inhibitors, 20-30% continue to experience troublesome symptoms. In such cases, agents that target transient lower esophageal sphincter (LES) relaxation may be useful as add-on therapy to proton pump inhibitors. The GABAB receptor agonist baclofen inhibits transient LES relaxation but it is not an ideal agent due to central nervous system activity. Lesogaberan (AZD3355) is a peripherally restricted GABAB receptor agonist with limited central nervous system activity that inhibits transient LES relaxation in dogs. In the present study, the comparative effects of lesogaberan (7 micromol/kg) and baclofen (2.8 micromol/kg) on reflux were studied in dogs using 24-h pHmetry. Drugs (or vehicle control) were administered orally prior to the first meal of the day, and the number of reflux episodes (pH or = 5 s) and acid exposure time were computed for the 24-h monitoring period. The mean (S.E.M.) number of reflux episodes/24 h was 4.6 (0.4) and 6.4 (0.6) for lesogaberan and baclofen, respectively, versus 10.7 (0.5) for control (PAcid exposure time was 51.2 (4.5) min for control versus 23.6 (3.8) min for lesogaberan (Pacid reflux in dogs, with comparable efficacy to baclofen. Copyright 2010 Elsevier B.V. All rights reserved.

  16. The crosstalk between Target of Rapamycin (TOR) and Jasmonic Acid (JA) signaling existing in Arabidopsis and cotton.

    Science.gov (United States)

    Song, Yun; Zhao, Ge; Zhang, Xueyan; Li, Linxuan; Xiong, Fangjie; Zhuo, Fengping; Zhang, Chaojun; Yang, Zuoren; Datla, Raju; Ren, Maozhi; Li, Fuguang

    2017-04-04

    Target of rapamycin (TOR) acts as an important regulator of cell growth, development and stress responses in most examined diploid eukaryotes. However, little is known about TOR in tetraploid species such as cotton. Here, we show that TORC1-S6K-RPS6, the major signaling components, are conserved and further expanded in cotton genome. Though the cotton seedlings are insensitive to rapamycin, AZD8055, the second-generation inhibitor of TOR, can significantly suppress the growth in cotton. Global transcriptome analysis revealed that genes associated with jasmonic acid (JA) biosynthesis and transduction were significantly altered in AZD8055 treated cotton seedlings, suggesting the potential crosstalk between TOR and JA signaling. Pharmacological and genetic approaches have been employed to get further insights into the molecular mechanism of the crosstalk between TOR and JA. Combination of AZD8055 with methyl jasmonate can synergistically inhibit cotton growth, and additionally JA levels were significantly increased when cotton seedlings were subjected to AZD8055. JA biosynthetic and signaling mutants including jar1, coi1-2 and myc2-2 displayed TOR inhibitor-resistant phenotypes, whereas COI1 overexpression transgenic lines and jaz10 exhibited sensitivity to AZD8055. Consistently, cotton JAZ can partially rescue TOR-suppressed phenotypes in Arabidopsis. These evidences revealed that the crosstalk between TOR and JA pathway operates in cotton and Arabidopsis.

  17. TOR-inhibitor insensitive-1 (TRIN1) regulates cotyledons greening in Arabidopsis.

    Science.gov (United States)

    Li, Linxuan; Song, Yun; Wang, Kai; Dong, Pan; Zhang, Xueyan; Li, Fuguang; Li, Zhengguo; Ren, Maozhi

    2015-01-01

    Target of Rapamycin (TOR) is an eukaryotic protein kinase and evolutionally conserved from the last eukaryotic common ancestor (LECA) to humans. The growing evidences have shown that TOR signaling acts as a central controller of cell growth and development. The downstream effectors of TOR have been well-identified in yeast and animals by using the immunosuppression agent rapamycin. However, less is known about TOR in plants. This is largely due to the fact that plants are insensitive to rapamycin. In this study, AZD8055 (AZD), the novel ATP-competitive inhibitor of TOR, was employed to decipher the downstream effectors of TOR in Arabidopsis. One AZD insensitive mutant, T O R - i nhibitor i n sensitive- 1 (trin1), was screened from 10,000 EMS-induced mutation seeds. The cotyledons of trin1 can turn green when its seeds were germinated on ½ MS medium supplemented with 2 μM AZD, whereas the cotyledons greening of wild-type (WT) can be completely blocked at this concentration. Through genetic mapping, TRIN1 was mapped onto the long arm of chromosome 2, between markers SGCSNP26 and MI277. Positional cloning revealed that TRIN1 was an allele of ABI4, which encoded an ABA-regulated AP2 domain transcription factor. Plants containing P35S::TRIN1 or P35S::TRIN1-GUS were hypersensitive to AZD treatment and displayed the opposite phenotype observed in trin1. Importantly, GUS signaling was significantly enhanced in P35S::TRIN1-GUS transgenic plants in response to AZD treatment, indicating that suppression of TOR resulted in the accumulation of TRIN1. These observations revealed that TOR controlled seed-to-seedling transition by negatively regulating the stability of TRIN1 in Arabidopsis. For the first time, TRIN1, the downstream effector of TOR signaling, was identified through a chemical genetics approach.

  18. A novel in situ hydrophobic ion paring (HIP) formulation strategy for clinical product selection of a nanoparticle drug delivery system.

    Science.gov (United States)

    Song, Young Ho; Shin, Eyoung; Wang, Hong; Nolan, Jim; Low, Susan; Parsons, Donald; Zale, Stephen; Ashton, Susan; Ashford, Marianne; Ali, Mir; Thrasher, Daniel; Boylan, Nicholas; Troiano, Greg

    2016-05-10

    The present studies were aimed at formulating AZD2811-loaded polylactic acid-polyethylene glycol (PLA-PEG) nanoparticles with adjustable release rates without altering the chemical structures of the polymer or active pharmaceutical ingredient (API). This was accomplished through the use of a hydrophobic ion pairing approach. A series of AZD2811-containing nanoparticles with a variety of hydrophobic counterions including oleic acid, 1-hydroxy-2-naphthoic acid, cholic acid, deoxycholic acid, dioctylsulfosuccinic acid, and pamoic acid is described. The hydrophobicity of AZD2811 was increased through formation of ion pairs with these hydrophobic counterions, producing nanoparticles with exceptionally high drug loading-up to five fold higher encapsulation efficiency and drug loading compared to nanoparticles made without hydrophobic ion pairs. Furthermore, the rate at which the drug was released from the nanoparticles could be controlled by employing counterions with various hydrophobicities and structures, resulting in release half-lives ranging from about 2 to 120h using the same polymer, nanoparticle size, and nanoemulsion process. Process recipe variables affecting drug load and release rate were identified, including pH and molarity of quench buffer. Ion pair formation between AZD2811 and pamoic acid as a model counterion was investigated using solubility enhancement as well as nuclear magnetic resonance spectroscopy to demonstrate solution-state interactions. Further evidence for an ion pairing mechanism of controlled release was provided through the measurement of API and counterion release profiles using high-performance liquid chromatography, which had stoichiometric relationships. Finally, Raman spectra of an AZD2811-pamoate salt compared well with those of the formulated nanoparticles, while single components (AZD2811, pamoic acid) alone did not. A library of AZD2811 batches was created for analytical and preclinical characterization. Dramatically improved

  19. Cyclin-dependent kinases regulate apoptosis of intestinal epithelial cells

    Science.gov (United States)

    Bhattacharya, Sujoy; Ray, Ramesh M.; Johnson, Leonard R.

    2014-01-01

    Homeostasis of the gastrointestinal epithelium is dependent upon a balance between cell proliferation and apoptosis. Cyclin-dependent kinases (Cdks) are well known for their role in cell proliferation. Previous studies from our group have shown that polyamine-depletion of intestinal epithelial cells (IEC-6) decreases cyclin-dependent kinase 2 (Cdk2) activity, increases p53 and p21Cip1 protein levels, induces G1 arrest, and protects cells from camptothecin (CPT)-induced apoptosis. Although emerging evidence suggests that members of the Cdk family are involved in the regulation of apoptosis, their roles directing apoptosis of IEC-6 cells are not known. In this study, we report that inhibition of Cdk1, 2, and 9 (with the broad range Cdk inhibitor, AZD5438) in proliferating IEC-6 cells triggered DNA damage, activated p53 signaling, inhibited proliferation, and induced apoptosis. By contrast, inhibition of Cdk2 (with NU6140) increased p53 protein and activity, inhibited proliferation, but had no effect on apoptosis. Notably, AZD5438 sensitized, whereas, NU6140 rescued proliferating IEC-6 cells from CPT-induced apoptosis. However, in colon carcinoma (Caco2) cells with mutant p53, treatment with either AZD5438 or NU6140 blocked proliferation, albeit more robustly with AZD5438. Both Cdk inhibitors induced apoptosis in Caco2 cells in a p53-independent manner. In serum starved quiescent IEC-6 cells, both AZD5438 and NU6140 decreased TNF- /CPT-induced activation of p53 and, consequently, rescued cells from apoptosis, indicating that sustained Cdk activity is required for apoptosis of quiescent cells. Furthermore, AZD5438 partially reversed the protective effect of polyamine depletion whereas NU6140 had no effect. Together, these results demonstrate that Cdks possess opposing roles in the control of apoptosis in quiescent and proliferating cells. In addition, Cdk inhibitors uncouple proliferation from apoptosis in a p53-dependent manner. PMID:24242917

  20. Assessing the Madigan Effort: Capitation, Purple Suits, CHAMPUS (Civilian Health and Medical Program of the Uniformed Services) and Other Issues.

    Science.gov (United States)

    1980-04-01

    appendicitis, without peritonitis 2 1618 625-993 809 Appendicitis, unqualified 6 3193 163-1230 532 Inguinal hernia , without obstruction 2 180 85-95 90 Umbilical... hernia , without obstruction 1 262 --- 262 Abdominal hernia of other specified site 1 1785 --- 1785 Abdominal hernia with obstruction of other site 1...unspecified parts 1 2171 --- 2171 Injury to nerve in wrist, hand (no open wound) 1 151 --- 151 Cervical spinal cord lesion (no open wound) 4 19027 3373

  1. PKPD modelling of PR and QRS intervals in conscious dogs using standard safety pharmacology data.

    Science.gov (United States)

    Bergenholm, Linnéa; Collins, Teresa; Evans, Neil D; Chappell, Michael J; Parkinson, Joanna

    2016-01-01

    Pharmacokinetic-pharmacodynamic (PKPD) modelling can improve safety assessment, but few PKPD models describing drug-induced QRS and PR prolongations have been published. This investigation aims to develop and evaluate PKPD models for describing QRS and PR effects in routine safety studies. Exposure and telemetry data from safety pharmacology studies in conscious beagle dogs were acquired. Mixed effects baseline and PK-QRS/PR models were developed for the anti-arrhythmic compounds AZD1305, flecainide, quinidine and verapamil and the anti-muscarinic compounds AZD8683 and AZD9164. RR interval correction and circadian rhythms were investigated for predicting baseline variability. Individual PK predictions were used to drive the pharmacological effects evaluating linear and non-linear direct and effect compartment models. Conduction slowing induced by the tested anti-arrhythmics was direct and proportional at low exposures, whilst time delays and non-linear effects were evident for the tested anti-muscarinics. AZD1305, flecainide and quinidine induced QRS widening with 4.2, 10 and 5.6% μM(-1) unbound drug. AZD1305 and flecainide also prolonged PR with 13.5 and 11.5% μM(-1). PR prolongations induced by the anti-muscarinics and verapamil were best described by Emax models with maximal effects ranging from 55 to 95%. RR interval correction and circadian rhythm improved PR but not QRS modelling. However, circadian rhythm had minor impact on estimated drug effects. Baseline and drug-induced effects on QRS and PR intervals can be effectively described with PKPD models using routine data, providing quantitative safety information to support drug discovery and development. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Potyviruses differ in their requirement for TOR signalling.

    Science.gov (United States)

    Ouibrahim, Laurence; Rubio, Ana Giner; Moretti, André; Montané, Marie-Hélène; Menand, Benoît; Meyer, Christian; Robaglia, Christophe; Caranta, Carole

    2015-09-01

    Potyviruses are important plant pathogens that rely on many plant cellular processes for successful infection. TOR (target of rapamycin) signalling is a key eukaryotic energy-signalling pathway controlling many cellular processes such as translation and autophagy. The dependence of potyviruses on active TOR signalling was examined. Arabidopsis lines downregulated for TOR by RNAi were challenged with the potyviruses watermelon mosaic virus (WMV) and turnip mosaic virus (TuMV). WMV accumulation was found to be severely altered while TuMV accumulation was only slightly delayed. In another approach, using AZD-8055, an active site inhibitor of the TOR kinase, WMV infection was found to be strongly affected. Moreover, AZD-8055 application can cure WMV infection. In contrast, TuMV infection was not affected by AZD-8055. This suggests that potyviruses have different cellular requirements for active plant TOR signalling.

  3. 2171-IJBCS-Article -Kougoum Seydou

    African Journals Online (AJOL)

    hp

    L'étude avait pour but d'évaluer les effets de l'incorporation des graines torréfiées de niébé dans l'alimentation de la poule locale en ponte, sur ses performances zootechniques et économique. Six coqs et soixante poules de race locale de 7,5 mois d'âge ont été répartis en six lots, par tirage aléatoire. Deux régimes.

  4. 14 CFR 217.1 - Definitions.

    Science.gov (United States)

    2010-01-01

    ... passengers when traveling free or pursuant to token charges: (1) Directors, officers, employees, and others authorized by the air carrier operating the aircraft; (2) Directors, officers, employees, and others... remuneration. (This definition is for 14 CFR part 217 traffic reporting purposes and may differ from the...

  5. Synthesis and evaluation of fluorine-substituted phenyl acetate derivatives as ultra-short recovery sedative/hypnotic agents.

    Directory of Open Access Journals (Sweden)

    Heng Zhang

    Full Text Available BACKGROUND: Soft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile. In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives. METHODOLOGY/PRINCIPAL FINDINGS: Fluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and γ-aminobutyric acidA (GABAA receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size. CONCLUSIONS/SIGNIFICANCE: The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home

  6. Salt formation improved the properties of a candidate drug during early formulation development.

    Science.gov (United States)

    Sigfridsson, Kalle; Ahlqvist, Matti; Lindsjö, Martin; Paulsson, Stefan

    2018-07-30

    The purpose of this study was to investigate if AZD5329, a dual neurokinin NK1/2 receptor antagonist, is a suitable candidate for further development as an oral immediate release (IR) solid dosage form as a final product. The neutral form of AZD5329 has only been isolated as amorphous material. In order to search for a solid material with improved physical and chemical stability and more suitable solid-state properties, a salt screen was performed. Crystalline material of a maleic acid salt and a fumaric acid salt of AZD5329 were obtained. X-ray powder diffractiometry, thermogravimetric analysis, differential scanning calorimetry and dynamic vapor sorption were used to investigate the physicochemical characteristics of the two salts. The fumarate salt of AZD5329 is anhydrous, the crystallization is reproducible and the hygroscopicity is acceptable. Early polymorphism assessment work using slurry technique did not reveal any better crystal modification or crystallinity for the fumarate salt. For the maleate salt, the form isolated originally was found to be a solvate, but an anhydrous form was found in later experiments; by suspension in water or acetone, by drying of the solvate to 100-120 °C or by subjecting the solvate form to conditions of 40 °C/75%RH for 3 months. The dissolution behavior and the chemical stability (in aqueous solutions, formulations and solid-state) of both salts were also studied and found to be satisfactory. The compound displays sensitivity to low pH, and the salt of the maleic acid, which is the stronger acid, shows more degradation during stability studies, in line with this observation. The presented data indicate that the substance fulfils basic requirements for further development of an IR dosage form, based on the characterization on crystalline salts of AZD5329. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Inhibition of checkpoint kinase 1 sensitizes lung cancer brain metastases to radiotherapy

    International Nuclear Information System (INIS)

    Yang, Heekyoung; Yoon, Su Jin; Jin, Juyoun; Choi, Seung Ho; Seol, Ho Jun; Lee, Jung-Il

    2011-01-01

    Research highlights: → The most important therapeutic tool in brain metastasis is radiation therapy. → Radiosensitivity of cancer cells was enhanced with treatment of Chk1 inhibitor. → Depletion of Chk1 in cancer cells showed an enhancement of sensitivity to radiation. → Chk1 can be a good target for enhancement of radiosensitivity. -- Abstract: The most important therapeutic tool in brain metastasis is radiation therapy. However, resistance to radiation is a possible cause of recurrence or treatment failure. Recently, signal pathways about DNA damage checkpoints after irradiation have been noticed. We investigated the radiosensitivity can be enhanced with treatment of Chk1 inhibitor, AZD7762 in lung cancer cell lines and xenograft models of lung cancer brain metastasis. Clonogenic survival assays showed enhancement of radiosensitivity with AZD7762 after irradiation of various doses. AZD7762 increased ATR/ATM-mediated Chk1 phosphorylation and stabilized Cdc25A, suppressed cyclin A expression in lung cancer cell lines. In xenograft models of lung cancer (PC14PE6) brain metastasis, AZD7762 significantly prolonged the median survival time in response to radiation. Depletion of Chk1 using shRNA also showed an enhancement of sensitivity to radiation in PC14PE6 cells. The results of this study support that Chk1 can be a good target for enhancement of radiosensitivity.

  8. mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity.

    Science.gov (United States)

    Jin, Zhe-Zhu; Wang, Wei; Fang, Di-Long; Jin, Yong-Jun

    2016-09-30

    We here tested the anti-colorectal cancer (CRC) activity by a first-in-class small molecule TRAIL inducer ONC201. The potential effect of mTOR on ONC201's actions was also examined. ONC201 induced moderate cytotoxicity against CRC cell lines (HT-29, HCT-116 and DLD-1) and primary human CRC cells. Significantly, AZD-8055, a mTOR kinase inhibitor, sensitized ONC201-induced cytotoxicity in CRC cells. Meanwhile, ONC201-induced TRAIL/death receptor-5 (DR-5) expression, caspase-8 activation and CRC cell apoptosis were also potentiated with AZD-8055 co-treatment. Reversely, TRAIL sequestering antibody RIK-2 or the caspase-8 specific inhibitor z-IETD-fmk attenuated AZD-8055 plus ONC201-induced CRC cell death. Further, mTOR kinase-dead mutation (Asp-2338-Ala) or shRNA knockdown significantly sensitized ONC201's activity in CRC cells, leading to profound cell death and apoptosis. On the other hand, expression of a constitutively-active S6K1 (T389E) attenuated ONC201-induced CRC cell apoptosis. For the mechanism study, we showed that ONC201 blocked Akt, but only slightly inhibited mTOR in CRC cells. Co-treatment with AZD-8055 also concurrently blocked mTOR activation. These results suggest that mTOR could be a primary resistance factor of ONC201 in CRC cells. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Canine osteosarcoma cells exhibit resistance to aurora kinase inhibitors.

    Science.gov (United States)

    Cannon, C M; Pozniak, J; Scott, M C; Ito, D; Gorden, B H; Graef, A J; Modiano, J F

    2015-03-01

    We evaluated the effect of Aurora kinase inhibitors AZD1152 and VX680 on canine osteosarcoma cells. Cytotoxicity was seen in all four cell lines; however, half-maximal inhibitory concentrations were significantly higher than in human leukaemia and canine lymphoma cells. AZD1152 reduced Aurora kinase B phosphorylation, indicating resistance was not because of failure of target recognition. Efflux mediated by ABCB1 and ABCG2 transporters is one known mechanism of resistance against these drugs and verapamil enhanced AZD1152-induced apoptosis; however, these transporters were only expressed by a small percentage of cells in each line and the effects of verapamil were modest, suggesting other mechanisms contribute to resistance. Our results indicate that canine osteosarcoma cells are resistant to Aurora kinase inhibitors and suggest that these compounds are unlikely to be useful as single agents for this disease. Further investigation of these resistance mechanisms and the potential utility of Aurora kinase inhibitors in multi-agent protocols is warranted. © 2013 Blackwell Publishing Ltd.

  10. CECs and IL-8 Have Prognostic and Predictive Utility in Patients with Recurrent Platinum-Sensitive Ovarian Cancer: Biomarker Correlates from the Randomized Phase-2 Trial of Olaparib and Cediranib Compared with Olaparib in Recurrent Platinum-Sensitive Ovarian Cancer.

    Science.gov (United States)

    Lee, Jung-Min; Trepel, Jane B; Choyke, Peter; Cao, Liang; Sissung, Tristan; Houston, Nicole; Yu, Minshu; Figg, William D; Turkbey, Ismail Baris; Steinberg, Seth M; Lee, Min-Jung; Ivy, S Percy; Liu, Joyce F; Matulonis, Ursula A; Kohn, Elise C

    2015-01-01

    Olaparib (O), a polyADPribose polymerase (PARP) inhibitor, and cediranib (C), a VEGF receptor (VEGFR)1-3 inhibitor together had greater activity than O alone in women with recurrent platinum-sensitive ovarian cancer (OvCa). The objective of this study is to identify potential lead biomarker candidates for response to O + C in the setting of a multi-institutional phase II study of O with and without C in recurrent platinum-sensitive OvCa. A self-selected group of patients participated in a prospectively planned exploratory biomarker substudy of the randomized phase II study of O versus O + C. Whole blood for peripheral blood mononuclear cell (PBMC) and plasma isolation was collected prior to and on day 3 of treatment. Quantitation of circulating endothelial cells (CEC), IL-6, IL-8, VEGF, and soluble VEGFR-2 plasma concentrations, and polyADPribose (PAR) incorporation were performed. Single nucleotide polymorphism analysis of XRCC1 280H, R194W, and Q399R was done. Dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI) was performed at baseline and day 3 of treatment. Parameter changes were compared between the two arms using an exact Wilcoxon rank sum test. Kaplan-Meier and log-rank tests were used to examine survival outcome. Thirteen patients elected to participate in the translational substudy, seven patients on O and six patients on O + C. Patients on O + C had a greater decrease in IL-8 concentration and larger CEC fold increase compared with those on O alone (p = 0.026, p = 0.032). The fold increase in CEC on day 3 was associated with duration of progression-free survival (PFS) (R (2) = 0.77, 95% CI 0.55-0.97, p < 0.001). IL-8 post-pretreatment changes correlate with PFS (p = 0.028). XRCC1 DNA polymorphisms were not related to PFS. All patients had reduction in PAR incorporation, and all except one had reduction in vascular flow on DCE-MRI. Our exploratory correlative studies indicate that CEC and IL-8 changes may be

  11. Pim kinase inhibition sensitizes FLT3-ITD acute myeloid leukemia cells to topoisomerase 2 inhibitors through increased DNA damage and oxidative stress

    Science.gov (United States)

    Doshi, Kshama A.; Trotta, Rossana; Natarajan, Karthika; Rassool, Feyruz V.; Tron, Adriana E.; Huszar, Dennis; Perrotti, Danilo; Baer, Maria R.

    2016-01-01

    Internal tandem duplication of fms-like tyrosine kinase-3 (FLT3-ITD) is frequent (30 percent) in acute myeloid leukemia (AML), and is associated with short disease-free survival following chemotherapy. The serine threonine kinase Pim-1 is a pro-survival oncogene transcriptionally upregulated by FLT3-ITD that also promotes its signaling in a positive feedback loop. Thus inhibiting Pim-1 represents an attractive approach in targeting FLT3-ITD cells. Indeed, co-treatment with the pan-Pim kinase inhibitor AZD1208 or expression of a kinase-dead Pim-1 mutant sensitized FLT3-ITD cell lines to apoptosis triggered by chemotherapy drugs including the topoisomerase 2 inhibitors daunorubicin, etoposide and mitoxantrone, but not the nucleoside analog cytarabine. AZD1208 sensitized primary AML cells with FLT3-ITD to topoisomerase 2 inhibitors, but did not sensitize AML cells with wild-type FLT3 or remission bone marrow cells, supporting a favorable therapeutic index. Mechanistically, the enhanced apoptosis observed with AZD1208 and topoisomerase 2 inhibitor combination treatment was associated with increased DNA double-strand breaks and increased levels of reactive oxygen species (ROS), and co-treatment with the ROS scavenger N-acetyl cysteine rescued FLT3-ITD cells from AZD1208 sensitization to topoisomerase 2 inhibitors. Our data support testing of Pim kinase inhibitors with topoisomerase 2 inhibitors, but not with cytarabine, to improve treatment outcomes in AML with FLT3-ITD. PMID:27374090

  12. A cladding-pumped, tunable holmium doped fiber laser.

    Science.gov (United States)

    Simakov, Nikita; Hemming, Alexander; Clarkson, W Andrew; Haub, John; Carter, Adrian

    2013-11-18

    We present a tunable, high power cladding-pumped holmium doped fiber laser. The laser generated >15 W CW average power across a wavelength range of 2.043 - 2.171 μm, with a maximum output power of 29.7 W at 2.120 μm. The laser also produced 18.2 W when operating at 2.171 µm. To the best of our knowledge this is the highest power operation of a holmium doped laser at a wavelength >2.15 µm. We discuss the significance of background losses and fiber design for achieving efficient operation in holmium doped fibers.

  13. A Sensitive and Robust Ultra HPLC Assay with Tandem Mass Spectrometric Detection for the Quantitation of the PARP Inhibitor Olaparib (AZD2281 in Human Plasma for Pharmacokinetic Application

    Directory of Open Access Journals (Sweden)

    Jeffrey Roth

    2014-06-01

    Full Text Available Olaparib (AZD2281 is an orally active PARP-1 inhibitor, primarily effective against cancers with BRCA1/2 mutations. It is currently in Phase III development and has previously been investigated in numerous clinical trials, both as a single agent and in combination with chemotherapy. Despite this widespread testing, there is only one published method that provides assay details and stability studies for olaparib alone. A more sensitive uHPLC-MS/MS method for the quantification of olaparib in human plasma was developed, increasing the range of quantification at both ends (0.5–50,000 ng/mL compared to previously published methods (10–5,000 ng/mL. The wider range encompasses CMAX levels produced by typical olaparib doses and permits better pharmacokinetic modeling of olaparib elimination. This assay also utilizes a shorter analytical runtime, allowing for more rapid quantification and reduced use of reagents. A liquid-liquid extraction was followed by chromatographic separation on a Waters UPLC® BEH C18 column (2.1 × 50 mm, 1.7 µm and mass spectrometric detection. The mass transitions m/z 435.4→281.1 and m/z 443.2→281.1 were used for olaparib and the internal standard [2H8]-olaparib, respectively. The assay proved to be accurate (<9% deviation and precise (CV < 11%. Stability studies showed that olaparib is stable at room temperature for 24 h. in whole blood, at 4 °C for 24 h post-extraction, at −80 °C in plasma for at least 19 months, and through three freeze-thaw cycles. This method proved to be robust for measuring olaparib levels in clinical samples from a Phase I trial.

  14. The synthesis of a tritium, carbon-14, and stable isotope-labeled cathepsin C inhibitors.

    Science.gov (United States)

    Allen, Paul; Bragg, Ryan A; Caffrey, Moya; Ericsson, Cecilia; Hickey, Michael J; Kingston, Lee P; Elmore, Charles S

    2017-02-01

    As part of a medicinal chemistry program aimed at developing a highly potent and selective cathepsin C inhibitor, tritium, carbon-14, and stable isotope-labeled materials were required. The synthesis of tritium-labeled methanesulfonate 5 was achieved via catalytic tritiolysis of a chloro precursor, albeit at a low radiochemical purity of 67%. Tritium-labeled AZD5248 was prepared via a 3-stage synthesis, utilizing amide-directed hydrogen isotope exchange. Carbon-14 and stable isotope-labeled AZD5248 were successfully prepared through modifications of the medicinal chemistry synthetic route, enabling the use of available labeled intermediates. Copyright © 2016 John Wiley & Sons, Ltd.

  15. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages

    Science.gov (United States)

    Peterson, Teresa E.; Kirkpatrick, Nathaniel D.; Huang, Yuhui; Farrar, Christian T.; Marijt, Koen A.; Kloepper, Jonas; Datta, Meenal; Amoozgar, Zohreh; Seano, Giorgio; Jung, Keehoon; Kamoun, Walid S.; Vardam, Trupti; Snuderl, Matija; Goveia, Jermaine; Chatterjee, Sampurna; Batista, Ana; Muzikansky, Alona; Leow, Ching Ching; Xu, Lei; Batchelor, Tracy T.; Duda, Dan G.; Fukumura, Dai; Jain, Rakesh K.

    2016-01-01

    Glioblastomas (GBMs) rapidly become refractory to anti-VEGF therapies. We previously demonstrated that ectopic overexpression of angiopoietin-2 (Ang-2) compromises the benefits of anti-VEGF receptor (VEGFR) treatment in murine GBM models and that circulating Ang-2 levels in GBM patients rebound after an initial decrease following cediranib (a pan-VEGFR tyrosine kinase inhibitor) administration. Here we tested whether dual inhibition of VEGFR/Ang-2 could improve survival in two orthotopic models of GBM, Gl261 and U87. Dual therapy using cediranib and MEDI3617 (an anti–Ang-2–neutralizing antibody) improved survival over each therapy alone by delaying Gl261 growth and increasing U87 necrosis, effectively reducing viable tumor burden. Consistent with their vascular-modulating function, the dual therapies enhanced morphological normalization of vessels. Dual therapy also led to changes in tumor-associated macrophages (TAMs). Inhibition of TAM recruitment using an anti–colony-stimulating factor-1 antibody compromised the survival benefit of dual therapy. Thus, dual inhibition of VEGFR/Ang-2 prolongs survival in preclinical GBM models by reducing tumor burden, improving normalization, and altering TAMs. This approach may represent a potential therapeutic strategy to overcome the limitations of anti-VEGFR monotherapy in GBM patients by integrating the complementary effects of anti-Ang2 treatment on vessels and immune cells. PMID:27044097

  16. PPARα regulates the hepatotoxic biomarker alanine aminotransferase (ALT1) gene expression in human hepatocytes

    International Nuclear Information System (INIS)

    Thulin, Petra; Rafter, Ingalill; Stockling, Kenneth; Tomkiewicz, Celine; Norjavaara, Ensio; Aggerbeck, Martine; Hellmold, Heike; Ehrenborg, Ewa; Andersson, Ulf; Cotgreave, Ian; Glinghammar, Bjoern

    2008-01-01

    In this work, we investigated a potential mechanism behind the observation of increased aminotransferase levels in a phase I clinical trial using a lipid-lowering drug, the peroxisome proliferator-activated receptor (PPAR) α agonist, AZD4619. In healthy volunteers treated with AZD4619, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were elevated without an increase in other markers for liver injury. These increases in serum aminotransferases have previously been reported in some patients receiving another PPARα agonist, fenofibrate. In subsequent in vitro studies, we observed increased expression of ALT1 protein and mRNA in human hepatocytes after treatment with fenofibric acid. The PPAR effect on ALT1 expression was shown to act through a direct transcriptional mechanism involving at least one PPAR response element (PPRE) in the proximal ALT1 promoter, while no effect of fenofibrate and AZD4619 was observed on the ALT2 promoter. Binding of PPARs to the PPRE located at - 574 bp from the transcriptional start site was confirmed on both synthetic oligonucleotides and DNA in hepatocytes. These data show that intracellular ALT expression is regulated by PPAR agonists and that this mechanism might contribute to increased ALT activity in serum

  17. Synergistic effects of concurrent blockade of PI3K and MEK pathways in pancreatic cancer preclinical models.

    Directory of Open Access Journals (Sweden)

    Hua Zhong

    Full Text Available Patients with pancreatic cancer have dismal prognoses, and novel therapies are urgently needed. Mutations of the KRAS oncogene occur frequently in pancreatic cancer and represent an attractive target. Direct targeting of the predominant KRAS pathways have been challenging and research into therapeutic strategies have been now refocused on pathways downstream of KRAS, phosphoinositide 3-kinase (PI3K and mitogen-activated protein kinase (MAPK [MEK]. We hypothesized that concurrent inhibition of the PI3K and MEK pathways would result in synergistic antitumor activity, as it would circumvent the compensatory feedback loop between the two pathways. We investigated the combined effect of the PI3K inhibitor, GDC0941, and the MEK inhibitor, AZD6244, on cell viability, apoptosis and cell signaling in a panel of pancreatic cancer cell lines. An in vivo analysis was conducted on pancreatic cancer xenografts. While BxPC-3 (KRAS wild type and MIA PaCa-2 (KRAS mutated cell lines were sensitive to GDC0941 and AZD6244 as single agents, synergistic inhibition of tumor cell growth and induction of apoptosis were observed in both cell lines when the two drugs were combined. Interestingly, phosphorylation of the cap-dependent translational components, 4E-binding protein (p-4E-BP1 and S6 was found to be closely associated with sensitivity to GDC0941 and AZD6244. In BxPC-3 cell xenografts, survival differences were observed between the control and the AZD6244, GDC0941, and combination groups. Our study provides the rationale for concurrent targeting of the PI3K and MEK pathways, regardless of KRAS status, and suggests that phosphorylation of 4E-BP1and S6 can serve as a predictive biomarker for response to treatment.

  18. Astrocytosis precedes amyloid plaque deposition in Alzheimer APPswe transgenic mouse brain: a correlative positron emission tomography and in vitro imaging study

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez-Vieitez, Elena; Ni, Ruiqing; Voytenko, Larysa; Marutle, Amelia [Karolinska Institutet, Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Gulyas, Balazs; Halldin, Christer [Karolinska Institutet, Centre for Psychiatric Research, Department of Clinical Neuroscience, Stockholm (Sweden); Nanyang Technological University, NTU - Imperial College, Lee Kong Chian School of Medicine, Singapore (Singapore); Toth, Miklos; Haeggkvist, Jenny [Karolinska Institutet, Centre for Psychiatric Research, Department of Clinical Neuroscience, Stockholm (Sweden); Nordberg, Agneta [Karolinska Institutet, Division of Translational Alzheimer Neurobiology, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Stockholm (Sweden); Karolinska University Hospital Huddinge, Department of Geriatric Medicine, Stockholm (Sweden)

    2015-04-17

    Pathological studies suggest that neuroinflammation is exacerbated by increased beta-amyloid (Aβ) levels in the brain early in Alzheimer's disease (AD). The time course and relationships between astrocytosis and Aβ deposition were examined using multitracer in vivo positron emission tomography (PET) imaging in an AD transgenic mouse model, followed by postmortem autoradiography and immunohistochemistry analysis. PET imaging with the amyloid plaque tracer {sup 11}C-AZD2184 and the astroglial tracer {sup 11}C-deuterium-L-deprenyl ({sup 11}C-DED) was carried out in APPswe mice aged 6, 8-15 and 18-24 months (4-6 animals/group) and in wild-type (wt) mice aged 8-15 and 18-24 months (3-6 animals/group). Tracer uptake was quantified by region of interest analysis using PMOD software and a 3-D digital mouse brain atlas. Postmortem brain tissues from the same APPswe and wt mice in all age groups were analysed for Aβ deposition and astrocytosis by in vitro autoradiography using {sup 3}H-AZD2184, {sup 3}H-Pittsburgh compound B (PIB) and {sup 3}H-L-deprenyl and immunostaining performed with antibodies for Aβ{sub 42} and glial fibrillary acidic protein (GFAP) in sagittal brain sections. {sup 11}C-AZD2184 PET retention in the cerebral cortices of APPswe mice was significantly higher at 18-24 months than in age-matched wt mice. Cortical and hippocampal {sup 11}C-DED PET binding was significantly higher at 6 months than at 8-15 months or 18-24 months in APPswe mice, and it was also higher than at 8-15 months in wt mice. In vitro autoradiography {sup 3}H-AZD2184 and {sup 3}H-PIB binding confirmed the in vivo findings with {sup 11}C-AZD2184 and demonstrated age-dependent increases in Aβ deposition in APPswe cortex and hippocampus. There were no significant differences between APPswe and wt mice in {sup 3}H-L-deprenyl autoradiography binding across age groups. Immunohistochemical quantification demonstrated more Aβ{sub 42} deposits in the cortex and hippocampus and more

  19. Castration Induced Neuroendocrine Mediated Progression of Prostate Cancer

    National Research Council Canada - National Science Library

    Evans, Christopher P

    2006-01-01

    ... enhancer region, which is primarily stimulated by androgens. We have shown that gastrin-releasing peptide prostate cancer cells have their growth in soft agar inhibited by the specific Src inhibitor AZD0530...

  20. Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation.

    Science.gov (United States)

    Kapoor, Shivani; Natarajan, Karthika; Baldwin, Patrick R; Doshi, Kshama A; Lapidus, Rena G; Mathias, Trevor J; Scarpa, Mario; Trotta, Rossana; Davila, Eduardo; Kraus, Manfred; Huszar, Dennis; Tron, Adriana E; Perrotti, Danilo; Baer, Maria R

    2018-01-01

    Purpose: fms -like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition. Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivo Results: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G 1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML. Conclusions: The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. Clin Cancer Res; 24(1); 234-47. ©2017 AACR . ©2017 American Association for Cancer Research.

  1. Simultaneous, time-resolved measurements of OH and HO2 radicals by coupling of high repetition rate LIF and cw-CRDS techniques to a laser photolysis reactor and its application to the photolysis of H2O2

    Czech Academy of Sciences Publication Activity Database

    Parker, A. E.; Jain, C.; Schoemaecker, C.; Szriftgiser, P.; Votava, Ondřej; Fittschen, Ch.

    2011-01-01

    Roč. 103, č. 3 (2011), s. 725-733 ISSN 0946-2171 Institutional research plan: CEZ:AV0Z40400503 Keywords : PRODUCT FORMATION * QUANTUM YIELDS * NM Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.189, year: 2011

  2. Drug: D00437 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available trate Same as: C07266 Therapeutic category: 2171 ATC code: C08CA05 Vasospastic angina... [DS:H01632] Chronic stable angina [DS:H01632] ... Dihydropyridine derivative CACNA1C [HSA:775] [KO:K04850

  3. Towards integration of research and monitoring at forest ecosystems in Europe

    Czech Academy of Sciences Publication Activity Database

    Danielewska, A.; Paoletti, E.; Clarke, N.; Olejnik, Janusz; Urbaniak, M.; Baran, M.; Siedlecki, P.; Hansen, K.; Lundin, L.; de Vries, W.; Mikkelsen, T. N.; Dillen, S.; Fischer, R.

    2013-01-01

    Roč. 22, č. 3 (2013), s. 535-545 ISSN 2171-5068 Grant - others:COST(IT) FP0903 Action Institutional support: RVO:67179843 Keywords : supersites * European Research Monitoring Networks * harmonization * forest Subject RIV: EH - Ecology, Behaviour Impact factor: 0.620, year: 2013

  4. Polyazido Pyrimidines: High Energy Compounds and Precursors to Carbon Nanotubes (PREPRINT)

    National Research Council Canada - National Science Library

    Ye, Chengfeng; Gao, Haoxiang; Twamley, Brendan; Shreeve, Jean'ne M; Drake, Gregory W; Boatz, Jerry A

    2006-01-01

    ...). The compound 4,4',6,6'-tetra(azido)azo-1,3,5-triazine (2), has a heat of formation of 2171 (6164 kJ kg -1). Recently it was demonstrated that 1 and 4 were good precursors to nano carbon nitride materials...

  5. The Five-Factor Model and Self-Determination Theory

    DEFF Research Database (Denmark)

    Olesen, Martin Hammershøj; Thomsen, Dorthe Kirkegaard; Schnieber, Anette

    This study investigates conceptual overlap vs. distinction between individual differences in personality traits, i.e. the Five-Factor Model; and Self-determination Theory, i.e. general causality orientations. Twelve-hundred-and-eighty-seven freshmen (mean age 21.71; 64% women) completed electronic...

  6. Effects of RU486 and indomethacin on meiotic maturation, formation of extracellular matrix, and progesterone production by porcine oocyte-cumulus complexes

    Czech Academy of Sciences Publication Activity Database

    Nagyová, Eva; Scsuková, S.; Kalous, Jaroslav; Mlynarčíková, A.

    2014-01-01

    Roč. 48, č. 1 (2014), s. 7-14 ISSN 0739-7240 R&D Projects: GA ČR GAP502/11/0593 Institutional support: RVO:67985904 Keywords : RU486 * indomethacin * oocyte * granulosa * progesterone Subject RIV: ED - Physiology Impact factor: 2.171, year: 2014

  7. Differential Reponses of Hematopoietic Stem and Progenitor Cells to mTOR Inhibition

    Directory of Open Access Journals (Sweden)

    Aimin Yang

    2015-01-01

    Full Text Available Abnormal activation of the mammalian target of rapamycin (mTOR signaling pathway has been observed in a variety of human cancers. Therefore, targeting of the mTOR pathway is an attractive strategy for cancer treatment and several mTOR inhibitors, including AZD8055 (AZD, a novel dual mTORC1/2 inhibitor, are currently in clinical trials. Although bone marrow (BM suppression is one of the primary side effects of anticancer drugs, it is not known if pharmacological inhibition of dual mTORC1/2 affects BM hematopoietic stem and progenitor cells (HSPCs function and plasticity. Here we report that dual inhibition of mTORC1/2 by AZD or its analogue (KU-63794 depletes mouse BM Lin−Sca-1+c-Kit+ cells in cultures via the induction of apoptotic cell death. Subsequent colony-forming unit (CFU assays revealed that inhibition of mTORC1/2 suppresses the clonogenic function of hematopoietic progenitor cells (HPCs in a dose-dependent manner. Surprisingly, we found that dual inhibition of mTORC1/2 markedly inhibits the growth of day-14 cobblestone area-forming cells (CAFCs but enhances the generation of day-35 CAFCs. Given the fact that day-14 and day-35 CAFCs are functional surrogates of HPCs and hematopoietic stem cells (HSCs, respectively, these results suggest that dual inhibition of mTORC1/2 may have distinct effects on HPCs versus HSCs.

  8. Characterization of collisionally pumped optical-field-ionization soft X-ray lasers

    Czech Academy of Sciences Publication Activity Database

    Mocek, Tomáš; Sebban, S.; Bettaibi, I.; Upcraft, L. M.; Balcou, P.; Breger, P.; Zeitoun, P.; Le Pape, S.; Ros, D.; Klisnick, A.; Carillon, A.; Jamelot, G.; Rus, Bedřich; Wyart, J. F.

    2004-01-01

    Roč. 78, - (2004), s. 939-944 ISSN 0946-2171 Grant - others:HPRI(XE) 199900086 Institutional research plan: CEZ:AV0Z1010921 Keywords : X-ray lasers * optical-field-ionization * collisional excitation Subject RIV: BH - Optics, Masers, Lasers Impact factor: 2.215, year: 2004

  9. Polyazidopyrimidines: High Energy Compounds and Precursors to Carbon Nanotubes (Postprint)

    National Research Council Canada - National Science Library

    Ye, Chengfeng; Gao, Haixiang; Boatz, Jerry A; Drake, Gregory W; Twamley, Brendan; Shreeve, Jean'ne M

    2006-01-01

    ...). The compound 4,4',6,6'-tetra(azido)azo-1,3,5-triazine (2), has a heat of formation of 2171 (6164 kJ kg -1) (Fig. 1). Recently it was demonstrated that 1 and 2 were good precursors to nano carbon nitride materials...

  10. Journal of Chemical Sciences | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Chemical Sciences. Fatemeh Baber Shamsi Mogoii. Articles written in Journal of Chemical Sciences. Volume 127 Issue 12 December 2015 pp 2171-2181. Synthesis, characterization and crystal structure of four new asymmetric triazene ligands: An example of linear H complex with H.

  11. Nicotine Receptor Subtype-Specific Effects on Auditory Evoked Oscillations and Potentials

    Science.gov (United States)

    Featherstone, Robert E.; Phillips, Jennifer M.; Thieu, Tony; Ehrlichman, Richard S.; Halene, Tobias B.; Leiser, Steven C.; Christian, Edward; Johnson, Edwin; Lerman, Caryn; Siegel, Steven J.

    2012-01-01

    Background Individuals with schizophrenia show increased smoking rates which may be due to a beneficial effect of nicotine on cognition and information processing. Decreased amplitude of the P50 and N100 auditory event-related potentials (ERPs) is observed in patients. Both measures show normalization following administration of nicotine. Recent studies identified an association between deficits in auditory evoked gamma oscillations and impaired information processing in schizophrenia, and there is evidence that nicotine normalizes gamma oscillations. Although the role of nicotine receptor subtypes in augmentation of ERPs has received some attention, less is known about how these receptor subtypes regulate the effect of nicotine on evoked gamma activity. Methodology/Principal Findings We examined the effects of nicotine, the α7 nicotine receptor antagonist methyllycaconitine (MLA) the α4β4/α4β2 nicotine receptor antagonist dihydro-beta-erythroidine (DHβE), and the α4β2 agonist AZD3480 on P20 and N40 amplitude as well as baseline and event-related gamma oscillations in mice, using electrodes in hippocampal CA3. Nicotine increased P20 amplitude, while DHβE blocked nicotine-induced enhancements in P20 amplitude. Conversely, MLA did not alter P20 amplitude either when presented alone or with nicotine. Administration of the α4β2 specific agonist AZD3480 did not alter any aspect of P20 response, suggesting that DHβE blocks the effects of nicotine through a non-α4β2 receptor specific mechanism. Nicotine and AZD3480 reduced N40 amplitude, which was blocked by both DHβE and MLA. Finally, nicotine significantly increased event-related gamma, as did AZD3480, while DHβE but not MLA blocked the effect of nicotine on event-related gamma. Conclusions/Significance These results support findings showing that nicotine-induced augmentation of P20 amplitude occurs via a DHβE sensitive mechanism, but suggests that this does not occur through activation of α4β2

  12. Dynamic Contractility and Efficiency Impairments in Stretch-Shortening Cycle Are Stretch-Load-Dependent After Training-Induced Muscle Damage

    NARCIS (Netherlands)

    Vaczi, Mark; Racz, Levente; Hortobagyi, Tibor; Tihanyi, Jozsef

    Vaczi, M, Racz, L, Hortobagyi, T, and Tihanyi, J. Dynamic contractility and efficiency impairments in stretch-shortening cycle are stretch-load-dependent after training-induced muscle damage. J Strength Cond Res 27(8): 2171-2179, 2013To determine the acute task and stretch-load dependency of

  13. A compact, quasi-monochromatic laser-plasma EUV source based on a double-stream gas-puff target at 13.8 nm wavelength

    Czech Academy of Sciences Publication Activity Database

    Wachulak, P.W.; Bartnik, A.; Fiedorowicz, H.; Feigl, T.; Jarocki, R.; Kostecki, J.; Rudawski, P.; Sawicka, Magdalena; Szczurek, M.; Szczurek, A.; Zawadzki, Z.

    2010-01-01

    Roč. 100, č. 3 (2010), 461-469 ISSN 0946-2171 Institutional research plan: CEZ:AV0Z10100523 Keywords : laser-plasma * EUV source * gas puff target * elliptical multi- layer * mirror * table-top setup Subject RIV: BH - Optics, Masers, Lasers Impact factor: 2.239, year: 2010

  14. File list: Oth.Bld.10.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.10.Brca1.AllCell mm9 TFs and others Brca1 Blood SRX217117,SRX217127,SRX2171...22,SRX217118,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.10.Brca1.AllCell.bed ...

  15. File list: Oth.Bld.50.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.50.Brca1.AllCell mm9 TFs and others Brca1 Blood SRX217117,SRX217122,SRX2171...18,SRX217127,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.50.Brca1.AllCell.bed ...

  16. File list: Oth.Bld.05.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.05.Brca1.AllCell mm9 TFs and others Brca1 Blood SRX217117,SRX217122,SRX2171...27,SRX217118,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.05.Brca1.AllCell.bed ...

  17. File list: Oth.Bld.20.Brca1.AllCell [Chip-atlas[Archive

    Lifescience Database Archive (English)

    Full Text Available Oth.Bld.20.Brca1.AllCell mm9 TFs and others Brca1 Blood SRX217117,SRX217122,SRX2171...18,SRX217127,SRX217126 http://dbarchive.biosciencedbc.jp/kyushu-u/mm9/assembled/Oth.Bld.20.Brca1.AllCell.bed ...

  18. Effects of lesogaberan on reflux and lower esophageal sphincter function in patients with gastroesophageal reflux disease

    NARCIS (Netherlands)

    Boeckxstaens, Guy E.; Beaumont, Hanneke; Mertens, Veerle; Denison, Hans; Ruth, Magnus; Adler, John; Silberg, Debra G.; Sifrim, Daniel

    2010-01-01

    BACKGROUND & AIMS: Transient lower esophageal sphincter relaxations (TLESRs) are a major mechanism behind reflux. This study assessed the effects of lesogaberan (AZD3355), a novel gamma-aminobutyric acid type B receptor agonist, on reflux and lower esophageal sphincter (LES) function when used as

  19. Predicting QRS and PR interval prolongations in humans using nonclinical data.

    Science.gov (United States)

    Bergenholm, L; Parkinson, J; Mettetal, J; Evans, N D; Chappell, M J; Collins, T

    2017-10-01

    Risk of cardiac conduction slowing (QRS/PR prolongations) is assessed prior to clinical trials using in vitro and in vivo studies. Understanding the quantitative translation of these studies to the clinical situation enables improved risk assessment in the nonclinical phase. Four compounds that prolong QRS and/or PR (AZD1305, flecainide, quinidine and verapamil) were characterized using in vitro (sodium/calcium channels), in vivo (guinea pigs/dogs) and clinical data. Concentration-matched translational relationships were developed based on in vitro and in vivo modelling, and the in vitro to clinical translation of AZD1305 was quantified using an in vitro model. Meaningful (10%) human QRS/PR effects correlated with low levels of in vitro Na v 1.5 block (3-7%) and Ca v 1.2 binding (13-21%) for all compounds. The in vitro model developed using AZD1305 successfully predicted QRS/PR effects for the remaining drugs. Meaningful QRS/PR changes in humans correlated with small effects in guinea pigs and dogs (QRS 2.3-4.6% and PR 2.3-10%), suggesting that worst-case human effects can be predicted by assuming four times greater effects at the same concentration from dog/guinea pig data. Small changes in vitro and in vivo consistently translated to meaningful PR/QRS changes in humans across compounds. Assuming broad applicability of these approaches to assess cardiovascular safety risk for non-arrhythmic drugs, this study provides a means of predicting human QRS/PR effects of new drugs from effects observed in nonclinical studies. © 2017 The British Pharmacological Society.

  20. Prevalence and associated factors of incidentally diagnosed ...

    African Journals Online (AJOL)

    ... prostate specific antigen and Biopsy results were analyzed using STATA 11. The prevalence of incidental prostatic cancer was calculated and logistic regression ... had PSA >10 ng/mL and in total; 33 (21.71%) had incidental prostatic carcinoma. ... prostatectomy for presumed benign prostatic hyperplasia in Tanzania with ...

  1. Sadhana | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Home; Journals; Sadhana. K NITHYAPRIYA. Articles written in Sadhana. Volume 42 Issue 12 December 2017 pp 2171-2181. Experimental studies on multicellular GFRP bridge deck panels under static and fatigue loading · M P MUTHURAJ K NITHYAPRIYA · More Details Abstract Fulltext PDF. This paper presents the ...

  2. Sadhana | Indian Academy of Sciences

    Indian Academy of Sciences (India)

    Home; Journals; Sadhana. M P MUTHURAJ. Articles written in Sadhana. Volume 42 Issue 12 December 2017 pp 2171-2181. Experimental studies on multicellular GFRP bridge deck panels under static and fatigue loading · M P MUTHURAJ K NITHYAPRIYA · More Details Abstract Fulltext PDF. This paper presents the ...

  3. Role of newly formed platelets in thrombus formation in rat after clopidogrel treatment

    DEFF Research Database (Denmark)

    Kuijpers, Marijke J E; Megens, Remco T A; Nikookhesal, Elham

    2011-01-01

    Platelet P2Y₁₂ receptors play an important role in arterial thrombosis by stimulating thrombus growth. Both irreversibly (clopidogrel) and reversibly binding (ticagrelor, AZD6140) P2Y₁₂ antagonists are clinically used for restricted periods, but possible differences in platelet function recovery ...

  4. Small molecules and targeted therapies in distant metastatic disease

    DEFF Research Database (Denmark)

    Hersey, P; Bastholt, L; Chiarion-Sileni, V

    2009-01-01

    with chemotherapy. Agents targeting mutant B-Raf (RAF265 and PLX4032), MEK (PD0325901, AZD6244), heat-shock protein 90 (tanespimycin), mTOR (everolimus, deforolimus, temsirolimus) and VEGFR (axitinib) showed some promise in earlier stages of clinical development. Receptor tyrosine-kinase inhibitors (imatinib...

  5. An analysis of key issues in the clean development mechanism based on the UNEP Risoe clean development mechanism pipeline

    DEFF Research Database (Denmark)

    Fenhann, Jørgen Villy; Staun, Frederik

    2010-01-01

    is documented. The CDM pipeline includes calculation of the investment in the CDM projects. The total investment in the 2171 registered CDM projects is approximately US$60 billion. It is shown that programmatic CDM gives hope for an increased share of projects in Africa, since 16% of the programmatic CDM...

  6. 21 CFR 21.72 - Individual consent to disclosure of records to other persons.

    Science.gov (United States)

    2010-04-01

    ... writing and shall specify the individual, organizational unit, or class of individuals or organizational... documents shall be retained for a period of at least 2 years. If such documents are used as a means of accounting for the disclosure, they shall be retained as provided in § 21.71(e)(2). ...

  7. Magnetostatic bias in a composite hard/soft/hard microlayer

    Czech Academy of Sciences Publication Activity Database

    Kraus, Luděk; Pirota, K.R.; Torrejón, J.; Vázquez, M.

    2007-01-01

    Roč. 101, č. 6 (2007), 063910/1-063910/4 ISSN 0021-8979 Grant - others:Spanish Research Project(ES) MAT2004-00150 Institutional research plan: CEZ:AV0Z10100520 Keywords : magnetic bias * amorphous alloys * geometrical dimensions Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.171, year: 2007

  8. issue 1 2008.indb

    African Journals Online (AJOL)

    6 London School of Hygiene and Tropical Medicine, Keppel Street, ... HIV testing and antiretroviral therapy (ART) has scaled ... During ART scale up, the quarterly number of clients HIV tested increased from 17977 in early 2005 to 35344 in the second quarter of 2007, equivalent to an average quarterly increase of 2171.

  9. Vortex ratchet effect in a niobium film with spacing-graded density

    Czech Academy of Sciences Publication Activity Database

    Wu, T.C.; Horng, L.; Wu, J.C.; Cao, R.; Koláček, Jan; Yang, T.-J.

    2007-01-01

    Roč. 102, č. 3 (2007), 033918/1-033918/4 ISSN 0021-8979 R&D Projects: GA ČR GA202/05/0173 Institutional research plan: CEZ:AV0Z10100521 Keywords : vortex ratchet effect * niobium film Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.171, year: 2007

  10. Association of leisure time physical activity, watching television ...

    African Journals Online (AJOL)

    The present study shows the association of leisure time physical activity (LTPA) and watching TV with lipid profile & obesity in a South Indian adult population. Methods: This cross-sectional study was performed on 2171 women and 2016 men in Mahatma Gandhi Medical College and Research Institute. The subjects were ...

  11. Evaluation of psychopathological patterns among students of two ...

    African Journals Online (AJOL)

    ... the appraisal of the severity of general psychopathology and assessing the prevalence of psychiatric morbidity, its seven sub scales measure symptoms indicative of disorder in sleep, intellect, sensation of movement, mood, head, alimentary tract and general well being. A total of 746 students (mean age=21.71, ± =3.98), ...

  12. Complete remission through icotinib treatment in Non-small cell lung cancer epidermal growth factor receptor mutation patient with brain metastasis: A case report

    Directory of Open Access Journals (Sweden)

    Wang Tao

    2016-01-01

    Full Text Available Brain metastasis (BM has been universally recognized as a poor prognostic factor in non-small cell lung cancer (NSCLC. Epidermal growth factor receptor (EGFR tyrosine kinase inhibitors (TKIs have shown efficacy in treating BM with an EGFR mutation. This paper reports a case of BM patient with EGFR-mutated NSCLC. According to the findings, a complete remission (CR of the BM was achieved by icotinib treatment without conducting a radiotherapy, which was followed by a resection of the primary lung cancer lesion and lymph nodes. After one-year follow-up, the disease progressed to liver metastasis and liver lesion biopsy showed a T790M mutation. The patient responded well to the combination treatment of AZD9291 and icotinib after the failure of transcatheter arterial chemoembolization (TACE. This case report suggests that icotinib has a sustainable anticancer response to BM and the combination with icotinib and AZD9291 is effective for liver metastasis with T790M.

  13. Landscape of Targeted Anti-Cancer Drug Synergies in Melanoma Identifies a Novel BRAF-VEGFR/PDGFR Combination Treatment.

    Directory of Open Access Journals (Sweden)

    Adam A Friedman

    Full Text Available A newer generation of anti-cancer drugs targeting underlying somatic genetic driver events have resulted in high single-agent or single-pathway response rates in selected patients, but few patients achieve complete responses and a sizeable fraction of patients relapse within a year. Thus, there is a pressing need for identification of combinations of targeted agents which induce more complete responses and prevent disease progression. We describe the results of a combination screen of an unprecedented scale in mammalian cells performed using a collection of targeted, clinically tractable agents across a large panel of melanoma cell lines. We find that even the most synergistic drug pairs are effective only in a discrete number of cell lines, underlying a strong context dependency for synergy, with strong, widespread synergies often corresponding to non-specific or off-target drug effects such as multidrug resistance protein 1 (MDR1 transporter inhibition. We identified drugs sensitizing cell lines that are BRAFV600E mutant but intrinsically resistant to BRAF inhibitor PLX4720, including the vascular endothelial growth factor receptor/kinase insert domain receptor (VEGFR/KDR and platelet derived growth factor receptor (PDGFR family inhibitor cediranib. The combination of cediranib and PLX4720 induced apoptosis in vitro and tumor regression in animal models. This synergistic interaction is likely due to engagement of multiple receptor tyrosine kinases (RTKs, demonstrating the potential of drug- rather than gene-specific combination discovery approaches. Patients with elevated biopsy KDR expression showed decreased progression free survival in trials of mitogen-activated protein kinase (MAPK kinase pathway inhibitors. Thus, high-throughput unbiased screening of targeted drug combinations, with appropriate library selection and mechanistic follow-up, can yield clinically-actionable drug combinations.

  14. Diagnostic and characterization of the VCSEL diodes based on GaSb

    Czech Academy of Sciences Publication Activity Database

    Matulková, Irena; Cihelka, Jaroslav; Vyskočil, Jan; Zelinger, Zdeněk; Hulicius, Eduard; Šimeček, Tomislav; Civiš, Svatopluk

    2010-01-01

    Roč. 99, 1-2 (2010), s. 333-338 ISSN 0946-2171 R&D Projects: GA AV ČR IAA400400705 Institutional research plan: CEZ:AV0Z40400503; CEZ:AV0Z10100521 Keywords : VCSEL diode s * FTIR * GaSb Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.239, year: 2010

  15. Student Satisfaction with Using Online Discussion Forums at Saudi Universities

    Science.gov (United States)

    Alzahrani, Majed Gharmallah

    2017-01-01

    This study aims to investigate student satisfaction with using online discussion forums (ODFs). It also aims to examine the relationships between student satisfaction with using ODFs and student demographics as well as with their experience with ICT and online education. Data are collected from 2171 students from four leading universities at Saudi…

  16. DW-MRI as a Predictive Biomarker of Radiosensitization of GBM through Targeted Inhibition of Checkpoint Kinases.

    Science.gov (United States)

    Williams, Terence M; Galbán, Stefanie; Li, Fei; Heist, Kevin A; Galbán, Craig J; Lawrence, Theodore S; Holland, Eric C; Thomae, Tami L; Chenevert, Thomas L; Rehemtulla, Alnawaz; Ross, Brian D

    2013-04-01

    The inherent treatment resistance of glioblastoma (GBM) can involve multiple mechanisms including checkpoint kinase (Chk1/2)-mediated increased DNA repair capability, which can attenuate the effects of genotoxic chemotherapies and radiation. The goal of this study was to evaluate diffusion-weighted magnetic resonance imaging (DW-MRI) as a biomarker for Chk1/2 inhibitors in combination with radiation for enhancement of treatment efficacy in GBM. We evaluated a specific small molecule inhibitor of Chk1/2, AZD7762, in combination with radiation using in vitro human cell lines and in vivo using a genetically engineered GBM mouse model. DW-MRI and T1-contrast MRI were used to follow treatment effects on intracranial tumor cellularity and growth rates, respectively. AZD7762 inhibited clonal proliferation in a panel of GBM cell lines and increased radiosensitivity in p53-mutated GBM cell lines to a greater extent compared to p53 wild-type cells. In vivo efficacy of AZD7762 demonstrated a dose-dependent inhibitory effect on GBM tumor growth rate and a reduction in tumor cellularity based on DW-MRI scans along with enhancement of radiation efficacy. DW-MRI was found to be a useful imaging biomarker for the detection of radiosensitization through inhibition of checkpoint kinases. Chk1/2 inhibition resulted in antiproliferative activity, prevention of DNA damage-induced repair, and radiosensitization in preclinical GBM tumor models, both in vitro and in vivo. The effects were found to be maximal in p53-mutated GBM cells. These results provide the rationale for integration of DW-MRI in clinical translation of Chk1/2 inhibition with radiation for the treatment of GBM.

  17. HTS Teologiese Studies / Theological Studies - Vol 41, No 4 (1985)

    African Journals Online (AJOL)

    Die funksie van die belydenis en die dogma in die struktuur van die Nederduitsch Hervormde Kerk en die implikasies daarvan vir die predikant · EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT. A.D. Pont, 519-546. http://dx.doi.org/10.4102/hts.v41i4.2171 ...

  18. Predictors of Academic Procrastination and University Life Satisfaction among Turkish Sport Schools Students

    Science.gov (United States)

    Ocal, Kubilay

    2016-01-01

    The purpose of this study was to examine the role of burnout, academic self-efficacy and academic success in predicting procrastination and university life satisfaction among sports schools students. The study sample comprised of 224 participants aged from 18 to 30 years with a mean age of 21.71 (SD = 1.94) who were attending various departments…

  19. CSF1R+ Macrophages Sustain Pancreatic Tumor Growth through T Cell Suppression and Maintenance of Key Gene Programs that Define the Squamous Subtype.

    Science.gov (United States)

    Candido, Juliana B; Morton, Jennifer P; Bailey, Peter; Campbell, Andrew D; Karim, Saadia A; Jamieson, Thomas; Lapienyte, Laura; Gopinathan, Aarthi; Clark, William; McGhee, Ewan J; Wang, Jun; Escorcio-Correia, Monica; Zollinger, Raphael; Roshani, Rozita; Drew, Lisa; Rishi, Loveena; Arkell, Rebecca; Evans, T R Jeffry; Nixon, Colin; Jodrell, Duncan I; Wilkinson, Robert W; Biankin, Andrew V; Barry, Simon T; Balkwill, Frances R; Sansom, Owen J

    2018-05-01

    Pancreatic ductal adenocarcinoma (PDAC) is resistant to most therapies including single-agent immunotherapy and has a dense desmoplastic stroma, and most patients present with advanced metastatic disease. We reveal that macrophages are the dominant leukocyte population both in human PDAC stroma and autochthonous models, with an important functional contribution to the squamous subtype of human PDAC. We targeted macrophages in a genetic PDAC model using AZD7507, a potent selective inhibitor of CSF1R. AZD7507 caused shrinkage of established tumors and increased mouse survival in this difficult-to-treat model. Malignant cell proliferation diminished, with increased cell death and an enhanced T cell immune response. Loss of macrophages rewired other features of the TME, with global changes in gene expression akin to switching PDAC subtypes. These changes were markedly different to those elicited when neutrophils were targeted via CXCR2. These results suggest targeting the myeloid cell axis may be particularly efficacious in PDAC, especially with CSF1R inhibitors. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Strong temperature effect on X-ray photo-etching of polytetrafluoroethylene using a 10Hz laser-plasma radiation source based on a gas puff target

    Czech Academy of Sciences Publication Activity Database

    Bartnik, A.; Fiedorowicz, H.; Jarocki, R.; Juha, Libor; Kostecki, J.; Rakowski, R.; Szczurek, M.

    2006-01-01

    Roč. 82, - (2006), s. 529-532 ISSN 0946-2171 R&D Projects: GA MŠk(CZ) LC510 Grant - others:Ministery of Scientific Research(PL) 3 T08C 002 27 Institutional research plan: CEZ:AV0Z10100523 Keywords : photo-etching * organic polymers * laser-produced plasmas Subject RIV: BH - Optics, Masers, Lasers Impact factor: 2.023, year: 2006

  1. Spray generator of singlet oxygen for a chemical oxygen-iodine laser

    Czech Academy of Sciences Publication Activity Database

    Jirásek, Vít; Hrubý, Jan; Špalek, Otomar; Čenský, Miroslav; Kodymová, Jarmila

    2010-01-01

    Roč. 100, č. 4 (2010), s. 779-791 ISSN 0946-2171 Grant - others:European Office of Aerospace R&D(US) FA8655-09-1-3091 Institutional research plan: CEZ:AV0Z10100523; CEZ:AV0Z20760514 Keywords : spray generator of singlet oxygen * singlet oxygen * chemical oxygen-iodine laser Subject RIV: BH - Optics, Masers, Lasers Impact factor: 2.239, year: 2010

  2. Centrifugal spray generator of singlet oxygen for a chemical oxygen-iodine laser

    Czech Academy of Sciences Publication Activity Database

    Špalek, Otomar; Hrubý, Jan; Čenský, Miroslav; Jirásek, Vít; Kodymová, Jarmila

    2010-01-01

    Roč. 100, č. 4 (2010), s. 793-802 ISSN 0946-2171 Grant - others:European Office of Aerospace R&D(US) FA8655-09-1-3091 Institutional research plan: CEZ:AV0Z10100523; CEZ:AV0Z20760514 Keywords : centrifugal generator of singlet oxygen * chemical oxygen-iodine laser Subject RIV: BH - Optics, Masers, Lasers Impact factor: 2.239, year: 2010

  3. Room temperature diode laser photoacoustic spectroscopy near 2.3 .mu.m

    Czech Academy of Sciences Publication Activity Database

    Civiš, Svatopluk; Horká-Zelenková, Veronika; Cihelka, Jaroslav; Šimeček, Tomislav; Hulicius, Eduard; Oswald, Jiří; Pangrác, Jiří; Vicet, A.; Rouillard, Y.; Salhi, A.; Alibert, C.; Werner, R.; Koeth, J.

    2005-01-01

    Roč. 81, - (2005), s. 857-861 ISSN 0946-2171 R&D Projects: GA AV ČR IAA4040104; GA MŠk OC 723.001 Grant - others:European Committee(XE) IST-2001-35178 Institutional research plan: CEZ:AV0Z40400503; CEZ:AV0Z10100521 Keywords : laser spectroscopic techniques * absorption * physical chemistry Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 2.056, year: 2005

  4. Relaxor-like behavior of lead-free Sr.sub.2./sub.LaTi.sub.2./sub.Nb.sub.3./sub.O.sub.15./sub. ceramics with tetragonal tungsten bronze structure

    Czech Academy of Sciences Publication Activity Database

    Bovtun, Viktor; Kamba, Stanislav; Veljko, Sergiy; Nuzhnyy, Dmitry; Knížek, Karel; Savinov, Maxim; Petzelt, Jan

    2007-01-01

    Roč. 101, č. 5 (2007), 054115/1-054115/6 ISSN 0021-8979 R&D Projects: GA ČR(CZ) GA202/06/0403; GA ČR GA202/04/0993; GA MŠk OC 101 Institutional research plan: CEZ:AV0Z10100520 Keywords : relaxor ferroelectrics * dielectric spectroscopy * dipolar glass * infrared spectroscopy Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.171, year: 2007

  5. Far-infrared and dielectric spectroscopy of relaxor ferroelectric (Pb.sub.1-x./sub.La.sub.x./sub.)(Zr.sub.0,4./sub.Ti.sub.0,6./sub.)O.sub.3./sub..

    Czech Academy of Sciences Publication Activity Database

    Buixaderas, Elena; Nuzhnyy, Dmitry; Veljko, Sergiy; Kamba, Stanislav; Savinov, Maxim; Petzelt, Jan; Kosec, M.

    2007-01-01

    Roč. 101, č. 7 (2007), 074106/1-074106/8 ISSN 0021-8979 R&D Projects: GA AV ČR IAA100100701; GA ČR(CZ) GA202/06/0403; GA ČR GA202/04/0993 Institutional research plan: CEZ:AV0Z10100520 Keywords : relaxor ferroelectrics * phase transitions * soft mode Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.171, year: 2007

  6. Conductors, semiconductors and insulators irradiated with short-wavelength free-electron laser

    Czech Academy of Sciences Publication Activity Database

    Krzywinski, J.; Sobierajski, R.; Jurek, M.; Nietubyc, R.; Pelka, J. B.; Juha, Libor; Bittner, Michal; Létal, V.; Vorlíček, Vladimír; Andrejczuk, A.; Feldhaus, J.; Keitel, B.; Saldin, E.; Schneidmiller, E.A.; Treusch, R.; Yurkov, M. V.

    2007-01-01

    Roč. 101, č. 4 (2007), 043107/1-043107/4 ISSN 0021-8979 R&D Projects: GA MŠk 1P04LA235; GA MŠk LC510; GA MŠk(CZ) LC528 Institutional research plan: CEZ:AV0Z10100523 Keywords : free-electron laser * extreme ultraviolet * ablation * laser-matter interaction Subject RIV: BH - Optics, Masers, Lasers Impact factor: 2.171, year: 2007

  7. Charge-Transfer Reaction of Cediranib with 2,3-Dichloro- 3,5 ...

    African Journals Online (AJOL)

    5, 6- dicyano -1, 4 - benzoquinone (DDQ) and employment of the reaction as a basis for the development of a ... association constant of the complex was 0.5 × 103 L mol−1 in 2-propanol. ..... some substituted naphthoquinones. Bull Chem Soc.

  8. Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights

    Directory of Open Access Journals (Sweden)

    Zhu Xiongpeng

    2010-04-01

    Full Text Available Abstract Prognostic markers, such as NPM1, Flt3-ITD, and cytogenetic abnormalities have made it possible to formulate aggressive treatment plans for unfavorable acute myeloid leukemia (AML. However, the long-term survival of AML with unfavorable factors remains unsatisfactory. The latest data indicate that the standard dose of daunorubicin (DNR at 45 mg/m2 is inferior to high dose 90 mg/m2 for induction therapy. The rates of complete remission and overall survival are significantly better in the high dose induction regimen. New regimens exploring the new liposomal encapsulation of Ara-C and DNR as well as addition of gemtuzumab ozogamicin monoclonal antibody have been studied. New agents, including the nucleoside analogues (clofarabine, sapacitabine, elacytarabine, FLT3 inhibitor (sorafenib, farnesyl-transferase inhibitor (tipifarnib, histone deacetylase inhibitor (vorinostat, lenalidomide, as well as DNA methyltransferase inhibitors (decitabine, azacitidine, were recently reported for AML treatment in the 2009 ASH annual meeting. This review also summarizes the updates of the clinical trials on novel agents including voreloxin, AS1413, behenoylara-C, ARRY520, ribavirin, AZD1152, AZD6244, and terameprocol (EM-1421 from the 2009 ASH annual meeting.

  9. Waveguide cores containing silicon nanocrystals as active spectral filters for silicon-based photonics

    Czech Academy of Sciences Publication Activity Database

    Pelant, Ivan; Ostatnický, T.; Valenta, J.; Luterová, Kateřina; Skopalová, Eva; Mates, Tomáš; Elliman, R. G.

    2006-01-01

    Roč. 83, - (2006), s. 87-91 ISSN 0946-2171 R&D Projects: GA ČR(CZ) GA202/03/0789; GA ČR(CZ) GP202/01/D030; GA AV ČR(CZ) IAA1010316; GA MŠk LC510 Institutional research plan: CEZ:AV0Z10100521 Keywords : silicon nanocrystals * planar waveguides * leaky modes Subject RIV: BM - Solid Matter Physics ; Magnetism Impact factor: 2.023, year: 2006

  10. Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats

    International Nuclear Information System (INIS)

    Gilmour, Peter S.; O'Shea, Patrick J.; Fagura, Malbinder; Pilling, James E.; Sanganee, Hitesh; Wada, Hiroki; Courtney, Paul F.; Kavanagh, Stefan; Hall, Peter A.; Escott, K. Jane

    2013-01-01

    Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitors caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH 1–34 or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. - Highlights: • Wnt modulation with 3 novel GSK-3 inhibitors alters bone growth. • Human stem cell osteoblastogenesis and

  11. Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process.

    Science.gov (United States)

    Lordier, Larissa; Chang, Yunhua; Jalil, Abdelali; Aurade, Frédéric; Garçon, Loïc; Lécluse, Yann; Larbret, Frédéric; Kawashima, Toshiyuki; Kitamura, Toshio; Larghero, Jérôme; Debili, Najet; Vainchenker, William

    2010-09-30

    Polyploidization of megakaryocytes (MKs), the platelet precursors, occurs by endomitosis, a mitotic process that fails at late stages of cytokinesis. Expression and function of Aurora B kinase during endomitosis remain controversial. Here, we report that Aurora B is normally expressed during the human MK endomitotic process. Aurora B localized normally in the midzone or midbody during anaphase and telophase in low ploidy megakaryocytes and in up to 16N rare endomitotic MKs was observed. Aurora B was also functional during cytokinesis as attested by phosphorylation of both its activation site and MgcRacGAP, its main substrate. However, despite its activation, Aurora B did not prevent furrow regression. Inhibition of Aurora B by AZD1152-HQPA decreased cell cycle entry both in 2N to 4N and polyploid MKs and induced apoptosis mainly in 2N to 4N cells. In both MK classes, AZD1152-HQPA induced p53 activation and retinoblastoma hypophosphorylation. Resistance of polyploid MKs to apoptosis correlated to a high BclxL level. Aurora B inhibition did not impair MK polyploidization but profoundly modified the endomitotic process by inducing a mis-segregation of chromosomes and a mitotic failure in anaphase. This indicates that Aurora B is dispensable for MK polyploidization but is necessary to achieve a normal endomitotic process.

  12. East Saint Louis and Vicinity, Illinois. Blue Waters Ditch Improvements. Final Environmental Statement.

    Science.gov (United States)

    1978-06-01

    2.1.7 CLIMATOLOGICAL ELEMENTS OF THE AMERICAN BOTTOMS 2.1.7.1 General The climate of the American Bottoms and the Blue Waters area is that of the...land be sold by the owner for urban developnient. The older farmers express an intention to remain in the alea even in the event of farm loss. Each...land use is pastureland for grazing. Such livestock activities, though important in St. Clair County agriculture, are totally lacking in the Blue

  13. Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes.

    Science.gov (United States)

    McCoull, William; Addie, Matthew S; Birch, Alan M; Birtles, Susan; Buckett, Linda K; Butlin, Roger J; Bowker, Suzanne S; Boyd, Scott; Chapman, Stephen; Davies, Robert D M; Donald, Craig S; Green, Clive P; Jenner, Chloe; Kemmitt, Paul D; Leach, Andrew G; Moody, Graeme C; Gutierrez, Pablo Morentin; Newcombe, Nicholas J; Nowak, Thorsten; Packer, Martin J; Plowright, Alleyn T; Revill, John; Schofield, Paul; Sheldon, Chris; Stokes, Steve; Turnbull, Andrew V; Wang, Steven J Y; Whalley, David P; Wood, J Matthew

    2012-06-15

    A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship. Copyright © 2012 Elsevier Ltd. All rights reserved.

  14. Durable clinical activity of single-agent bevacizumab in a nonagenarian patient with metastatic alveolar soft part sarcoma.

    Science.gov (United States)

    Mir, Olivier; Boudou-Rouquette, Pascaline; Larousserie, Frédérique; Blanchet, Benoit; Babinet, Antoine; Anract, Philippe; Goldwasser, François

    2012-08-01

    Alveolar soft part sarcoma is a rare malignancy usually considered resistant to conventional chemotherapy, but recent data suggest that the multikinase inhibitors sunitinib and cediranib could be active in this setting. A 90-year-old lady with alveolar soft part sarcoma of the leg and lung metastases was started on sunitinib 37.5 mg daily. The treatment was poorly tolerated with grade 3 hypertension and grade 3 thrombocytopenia, which persisted after dose reduction to 25 mg daily. The patient was subsequently started on bevacizumab 10 mg/kg every 2 weeks, resulting in a marked improvement in pain and a partial response on lung metastases for 16 months and ongoing. Agents targeting the vascular endothelial growth factor-signalling pathway seem to exert clinically relevant and prolonged activity against alveolar soft part sarcoma and deserve further evaluation in the treatment of this rare soft tissue sarcoma.

  15. Human stem cell osteoblastogenesis mediated by novel glycogen synthase kinase 3 inhibitors induces bone formation and a unique bone turnover biomarker profile in rats

    Energy Technology Data Exchange (ETDEWEB)

    Gilmour, Peter S., E-mail: Peter.Gilmour@astrazeneca.com [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); O' Shea, Patrick J.; Fagura, Malbinder [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Pilling, James E. [Discovery Sciences, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Sanganee, Hitesh [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Wada, Hiroki [R and I IMed, AstraZeneca R and D, Molndal (Sweden); Courtney, Paul F. [DMPK, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Kavanagh, Stefan; Hall, Peter A. [Safety Assessment, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom); Escott, K. Jane [New Opportunities Innovative Medicines group, AstraZeneca R and D, Alderley Park, Cheshire SK10 4TF (United Kingdom)

    2013-10-15

    Wnt activation by inhibiting glycogen synthase kinase 3 (GSK-3) causes bone anabolism in rodents making GSK-3 a potential therapeutic target for osteoporotic and osteolytic metastatic bone disease. To understand the wnt pathway related to human disease translation, the ability of 3 potent inhibitors of GSK-3 (AZD2858, AR79, AZ13282107) to 1) drive osteoblast differentiation and mineralisation using human adipose-derived stem cells (hADSC) in vitro; and 2) stimulate rat bone formation in vivo was investigated. Bone anabolism/resorption was determined using clinically relevant serum biomarkers as indicators of bone turnover and bone formation assessed in femurs by histopathology and pQCT/μCT imaging. GSK-3 inhibitors caused β-catenin stabilisation in human and rat mesenchymal stem cells, stimulated hADSC commitment towards osteoblasts and osteogenic mineralisation in vitro. AZD2858 produced time-dependent changes in serum bone turnover biomarkers and increased bone mass over 28 days exposure in rats. After 7 days, AZD2858, AR79 or AZ13282107 exposure increased the bone formation biomarker P1NP, and reduced the resorption biomarker TRAcP-5b, indicating increased bone anabolism and reduced resorption in rats. This biomarker profile was differentiated from anabolic agent PTH{sub 1–34} or the anti-resorptive Alendronate-induced changes. Increased bone formation in cortical and cancellous bone as assessed by femur histopathology supported biomarker changes. 14 day AR79 treatment increased bone mineral density and trabecular thickness, and decreased trabecular number and connectivity assessed by pQCT/μCT. GSK-3 inhibition caused hADSC osteoblastogenesis and mineralisation in vitro. Increased femur bone mass associated with changes in bone turnover biomarkers confirmed in vivo bone formation and indicated uncoupling of bone formation and resorption. - Highlights: • Wnt modulation with 3 novel GSK-3 inhibitors alters bone growth. • Human stem cell osteoblastogenesis

  16. Potential of mercury-resistant marine bacteria for detoxification of chemicals of environmental concern

    Digital Repository Service at National Institute of Oceanography (India)

    De, J.; Ramaiah, N.; Bhosle, N.B.; Garg, A.; Vardanyan, L.; Nagle, V.L.; Fukami, K.

    -resistant Pseudomonas putida strain. Appl. Environ. Microbiol. 65: 5279-5284. 11) Champ, M.A. 2000. A review of organotin regulatory strategies: pending actions, related costs and benefits. Sci. Total Environ. 258: 21-71. 12) Chang, J.S., R. Law, and C.C. Chang. 1997... indicating that TBT were degraded by bacterial action. With organic enrichment, the amounts of TBT degraded were similar by both strains but the degradation rate was faster. Discussion Lower costs and higher efficiency at low metal concentrations...

  17. Morphological analysis of mouse skeleton following AZD4547 treatment

    Czech Academy of Sciences Publication Activity Database

    Dosedělová, Hana; Veselá, Iva; Krejčí, P.; Kunová, M.; Buchtová, Marcela

    2015-01-01

    Roč. 159, Suppl 1 (2015), s. 58-59 ISSN 1213-8118. [Morphology 2015. International Congress of the Czech Anatomical Society /49./. Lojda Symposium on Histochemistry /52./. 06.09.2015-08.09.2015, Olomouc] R&D Projects: GA ČR(CZ) GA14-31540S Institutional support: RVO:67985904 Keywords : mouse skeleton Subject RIV: EA - Cell Biology

  18. Bibliography on Cold Regions Science and Technology. Volume 44, Part 2

    Science.gov (United States)

    1990-01-01

    eng1 44-2171 le08*3-10488 (IQk))it. i - gj 44-390" ly) Bomi Countly. Xizang (Tibet) 11989. p,148-160. chi) Lyons. weB . Niseilek. 3L. 44-2409 Diiminion... histoirical and technical dleveliopmnt Tesnsfssrmiiins andI dssisi-oi si late-fall applied sitrogen Schaytema. G.5. 11999, p. 77 -85. enpl 44-44 during...Usnn meling ice to teach radiomectric dating. Wise, Evaluating pie-winter soil preparation for reclamation 44-100 DU .. i199. p.38- 40 ,69, cng1

  19. Iodine photodissociation laser SOFIA with MOPO-HF as a solid-state oscillator

    Czech Academy of Sciences Publication Activity Database

    Dostál, Jan; Turčičová, Hana; Králiková, Božena; Král, Lukáš; Huynh, J.

    2009-01-01

    Roč. 97, č. 3 (2009), 687-694 ISSN 0946-2171 R&D Projects: GA ČR GA202/06/0814; GA MŠk(CZ) LC528; GA MŠk LN00A100 Grant - others:EC - 6FP LASERLAB-EUROPE(XE) RII3-CT-2003-506350 Program:FP6 Institutional research plan: CEZ:AV0Z10100523 Keywords : Iodine photodissociation laser * optical parametric amplification * chirped pulse * optical synchronization * stabilization of wavelength and pointing Subject RIV: BH - Optics, Masers, Lasers Impact factor: 1.992, year: 2009

  20. Early detection of diabetes after pregnancy complicated by gestational diabetes

    DEFF Research Database (Denmark)

    Nielsen, Jane Hyldgård; Overgaard, Charlotte; Olesen, Christinna Rebecca

    Title: Early detection of diabetes after pregnancy complicated by gestational diabetes Background: Women whose pregnancy was complicated by gestational diabetes have a 7-fold higher risk of developing diabetes, primarily type 2. 40% of women with a history gestational diabetes mellitus (GDM...... of health consequences for women. Aims: Examine the extent of participation in follow-up screening in the Danish Region of North Jutland, and the possible consequences of nonattendance. Methods: A register based study. In Danish national registers 2171 birthing women whose pregnancy was complicated by GDM...

  1. Time-resolved measurement of thermally induced aberrations in a cryogenically cooled Yb:YAG slab with a wavefront sensor

    Czech Academy of Sciences Publication Activity Database

    Sikocinski, Pawel; Novák, Ondřej; Smrž, Martin; Pilař, Jan; Jambunathan, Venkatesan; Jelínková, H.; Endo, Akira; Lucianetti, Antonio; Mocek, Tomáš

    2016-01-01

    Roč. 122, č. 4 (2016), 1-10, č. článku 73. ISSN 0946-2171 R&D Projects: GA MŠk ED2.1.00/01.0027; GA MŠk EE2.3.20.0143; GA MŠk LO1602; GA ČR GA14-01660S Grant - others:HILASE(XE) CZ.1.05/2.1.00/01.0027; OP VK 6(XE) CZ.1.07/2.3.00/20.0143 Institutional support: RVO:68378271 Keywords : solid-state laser * Yb-Yag Subject RIV: BH - Optics , Masers, Lasers Impact factor: 1.696, year: 2016

  2. Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC

    International Nuclear Information System (INIS)

    Lin, Zhong-Zhe; Jeng, Yung-Ming; Hu, Fu-Chang; Pan, Hung-Wei; Tsao, Hsin-Wei; Lai, Po-Lin; Lee, Po-Huang; Cheng, Ann-Lii; Hsu, Hey-Chi

    2010-01-01

    To investigate the significance of Aurora B expression in hepatocellular carcinoma (HCC). The Aurora B and Aurora A mRNA level was measured in 160 HCCs and the paired nontumorous liver tissues by reverse transcription-polymerase chain reaction. Mutations of the p53 and β-catenin genes were analyzed in 134 and 150 tumors, respectively, by direct sequencing of exon 2 to exon 11 of p53 and exon 3 of β-catenin. Anticancer effects of AZD1152-HQPA, an Aurora B kinase selective inhibitor, were examined in Huh-7 and Hep3B cell lines. Aurora B was overexpressed in 98 (61%) of 160 HCCs and in all 7 HCC cell lines examined. The overexpression of Aurora B was associated with Aurora A overexpression (P = 0.0003) and p53 mutation (P = 0.002) and was inversely associated with β-catenin mutation (P = 0.002). Aurora B overexpression correlated with worse clinicopathologic characteristics. Multivariate analysis confirmed that Aurora B overexpression was an independent poor prognostic factor, despite its interaction with Aurora A overexpression and mutations of p53 and β-catenin. In Huh-7 and Hep3B cells, AZD1152-HQPA induced proliferation blockade, histone H3 (Ser10) dephosphorylation, cell cycle disturbance, and apoptosis. Aurora B overexpression is an independent molecular marker predicting tumor invasiveness and poor prognosis of HCC. Aurora B kinase selective inhibitors are potential therapeutic agents for HCC treatment

  3. Double-electron ionization driven by inhomogeneous fields

    Czech Academy of Sciences Publication Activity Database

    Chacon, A.; Ortmann, L.; Cucchietti, F.; Suarez, N.; Perez-Hernandez, J.A.; Ciappina, Marcelo F.; Landsman, A.S.; Lewenstein, M.

    2017-01-01

    Roč. 123, č. 4 (2017), 1-11, č. článku 116. ISSN 0946-2171 R&D Projects: GA MŠk EF15_008/0000162; GA MŠk LQ1606 EU Projects: European Commission(XE) 654148 - LASERLAB-EUROPE Grant - others:ELI Beamlines(XE) CZ.02.1.01/0.0/0.0/15_008/0000162 Institutional support: RVO:68378271 Keywords : nonsequential double-ionization * harmonic-generation * laser fields * helium * model * emission * single * atom * ion * He Subject RIV: BL - Plasma and Gas Discharge Physics OBOR OECD: Fluids and plasma physics (including surface physics) Impact factor: 1.696, year: 2016

  4. Spectroscopic characterization of Yb.sup.3+./sup. - doped laser materials at cryogenic temperatures

    Czech Academy of Sciences Publication Activity Database

    Körner, J.; Jambunathan, Venkatesan; Hein, J.; Seifert, R.; Loeser, M.; Siebold, M.; Schramm, U.; Sikocinski, Pawel; Lucianetti, Antonio; Mocek, Tomáš; Kaluza, M.C.

    2014-01-01

    Roč. 116, č. 1 (2014), s. 75-81 ISSN 0946-2171 R&D Projects: GA MŠk ED2.1.00/01.0027; GA MŠk EE2.3.20.0143 Grant - others:HILASE(XE) CZ.1.05/2.1.00/01.0027; OP VK 6(XE) CZ.1.07/2.3.00/20.0143 Institutional support: RVO:68378271 Keywords : ytterbium * YAG * LuAG * CaF2 * FP15-glass * absorption * emission * gain * cross-section * cryogenic temperature Subject RIV: BH - Optics , Masers, Lasers Impact factor: 1.856, year: 2014 http://dx.doi.org/10.1007/s00340-013-5650-8

  5. Metastatic gastric cancer – focus on targeted therapies

    Directory of Open Access Journals (Sweden)

    Meza-Junco J

    2012-06-01

    Full Text Available Judith Meza-Junco, Michael B SawyerDepartment of Oncology, Cross Cancer Institute, Edmonton, Alberta, CanadaAbstract: Gastric cancer (GC is currently the second leading cause of cancer death worldwide; unfortunately, most patients will present with locally advanced or metastatic disease. Despite recent progress in diagnosis, surgery, chemotherapy, and radiotherapy, prognosis remains poor. A better understanding of GC biology and signaling pathways is expected to improve GC therapy, and the integration of targeted therapies has recently become possible and appears to be promising. This article focuses on anti-Her-2 therapy, specifically trastuzumab, as well as other epidermal growth factor receptor antagonists such as cetuximab, panitumub, matuzumab, nimotzumab, gefitinib, and erlotinib. Additionally, drugs that target angiogenesis pathways are also under investigation, particulary bevacizumab, ramucirumab, sorafenib, sunitinib, and cediranib. Other targeted agents in preclinical or early clinical development include mTOR inhibitors, anti c-MET, polo-like kinase 1 inhibitors, anti-insulin-like growth factor, anti-heat shock proteins, and small molecules targeting Hedgehog signaling.Keywords: gastric cancer, targeted therapy, antiangiogenesis drugs, anti-EGFR drugs

  6. 40 CFR 158.2171 - Experimental use permit microbial pesticides product analysis data requirements table.

    Science.gov (United States)

    2010-07-01

    ... conducted at the point in the production process after which there would be no potential for microbial... Identity R MP EP -- 885.1200 Manufacturing process R TGAI and MP TGAI and EP 1, 2 Deposition of a sample in... -- 830.6313 Stability to normal and elevated temperatures, metals and metal ions R TGAI TGAI -- 830.6317...

  7. 21 CFR 21.71 - Disclosure of records in Privacy Act Record Systems; accounting required.

    Science.gov (United States)

    2010-04-01

    ... accounting shall be made, in accordance with paragraph (e) of this section, of any disclosure under paragraph (a) of this section of a record that is not a disclosure under § 21.70. (e) Where an accounting is... of the disclosure. The accounting shall not be considered a Privacy Act Record System. (2) Retain the...

  8. Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2.

    Science.gov (United States)

    Pei, Xin-Yan; Dai, Yun; Youssefian, Leena E; Chen, Shuang; Bodie, Wesley W; Takabatake, Yukie; Felthousen, Jessica; Almenara, Jorge A; Kramer, Lora B; Dent, Paul; Grant, Steven

    2011-11-10

    Effects of Chk1 and MEK1/2 inhibition were investigated in cytokinetically quiescent multiple myeloma (MM) and primary CD138(+) cells. Coexposure to the Chk1 and MEK1/2 inhibitors AZD7762 and selumetinib (AZD6244) robustly induced apoptosis in various MM cells and CD138(+) primary samples, but spared normal CD138(-) and CD34(+) cells. Furthermore, Chk1/MEK1/2 inhibitor treatment of asynchronized cells induced G(0)/G(1) arrest and increased apoptosis in all cell-cycle phases, including G(0)/G(1). To determine whether this regimen is active against quiescent G(0)/G(1) MM cells, cells were cultured in low-serum medium to enrich the G(0)/G(1) population. G(0)/G(1)-enriched cells exhibited diminished sensitivity to conventional agents (eg, Taxol and VP-16) but significantly increased susceptibility to Chk1 ± MEK1/2 inhibitors or Chk1 shRNA knock-down. These events were associated with increased γH2A.X expression/foci formation and Bim up-regulation, whereas Bim shRNA knock-down markedly attenuated lethality. Immunofluorescent analysis of G(0)/G(1)-enriched or primary MM cells demonstrated colocalization of activated caspase-3 and the quiescent (G(0)) marker statin, a nuclear envelope protein. Finally, Chk1/MEK1/2 inhibition increased cell death in the Hoechst-positive (Hst(+)), low pyronin Y (PY)-staining (2N Hst(+)/PY(-)) G(0) population and in sorted small side-population (SSP) MM cells. These findings provide evidence that cytokinetically quiescent MM cells are highly susceptible to simultaneous Chk1 and MEK1/2 inhibition.

  9. Report from LHC MD 2171: Amplitude dependent closest tune approach from normal and skew octupoles

    CERN Document Server

    Maclean, Ewen Hamish; Persson, Tobias Hakan Bjorn; Carlier, Felix Simon; CERN. Geneva. ATS Department

    2018-01-01

    Simulation-based studies predict significant amplitude-dependent closest tune approach can be generated by skew octupole sources in conjunction with their normal octupolar counterparts. This has the potential to significantly influence Landau damping at small β∗, where skew octupole errors in the experimental IRs, together with b4 introduced by the Landau octupoles, is predicted to cause large distortion of the tune footprint. This MD aimed to perform a first exploration of these predictions with beam, by enhancing skew octupole sources in the IRs at injection and measuring amplitude detuning with free kicks in the plane approaching the coupling resonance.

  10. Radiosensitization by PARP inhibition to proton beam irradiation in cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Hirai, Takahisa [Department of Radiation Oncology, Juntendo University Faculty of Medicine, Bunkyo-ku, Tokyo (Japan); Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Saito, Soichiro; Fujimori, Hiroaki [Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Matsushita, Keiichiro; Nishio, Teiji [Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima-shi, Hiroshima (Japan); Okayasu, Ryuichi [International Open Laboratory, National Institute of Radiological Science, Chiba-shi, Chiba (Japan); Masutani, Mitsuko, E-mail: mmasutan@nagasaki-u.ac.jp [Division of Chemotherapy and Clinical Cancer Research, National Cancer Center Research Institute, Chuo-ku, Tokyo (Japan); Department of Frontier Life Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki (Japan)

    2016-09-09

    The poly(ADP-ribose) polymerase (PARP)-1 regulates DNA damage responses and promotes base excision repair. PARP inhibitors have been shown to enhance the cytotoxicity of ionizing radiation in various cancer cells and animal models. We have demonstrated that the PARP inhibitor (PARPi) AZD2281 is also an effective radiosensitizer for carbon-ion radiation; thus, we speculated that the PARPi could be applied to a wide therapeutic range of linear energy transfer (LET) radiation as a radiosensitizer. Institutes for biological experiments using proton beam are limited worldwide. This study was performed as a cooperative research at heavy ion medical accelerator in Chiba (HIMAC) in National Institute of Radiological Sciences. HIMAC can generate various ion beams; this enabled us to compare the radiosensitization effect of the PARPi on cells subjected to proton and carbon-ion beams from the same beam line. After physical optimization of proton beam irradiation, the radiosensitization effect of the PARPi was assessed in the human lung cancer cell line, A549, and the pancreatic cancer cell line, MIA PaCa-2. The effect of the PARPi, AZD2281, on radiosensitization to Bragg peak was more significant than that to entrance region. The PARPi increased the number of phosphorylated H2AX (γ-H2AX) foci and enhanced G2/M arrest after proton beam irradiation. This result supports our hypothesis that a PARPi could be applied to a wide therapeutic range of LET radiation by blocking the DNA repair response. - Highlights: • Effective radiosensitizers for particle radiation therapy have not been reported. • PARP inhibitor treatment radiosensitized after proton beam irradiation. • The sensitization at Bragg peak was greater than that at entrance region. • DSB induction and G2/M arrest is involved in the sensitization mechanism.

  11. Blockade of the ERK pathway enhances the therapeutic efficacy of the histone deacetylase inhibitor MS-275 in human tumor xenograft models

    Energy Technology Data Exchange (ETDEWEB)

    Sakamoto, Toshiaki; Ozaki, Kei-ichi; Fujio, Kohsuke; Kajikawa, Shu-hei [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Uesato, Shin-ichi [Department of Biotechnology, Faculty of Engineering, Kansai University, Osaka 564-8680 (Japan); Watanabe, Kazushi [Proubase Technology Inc., Kanagawa 211-0063 (Japan); Tanimura, Susumu [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Koji, Takehiko [Department of Histology and Cell Biology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8523 (Japan); Kohno, Michiaki, E-mail: kohnom@nagasaki-u.ac.jp [Laboratory of Cell Regulation, Department of Pharmaceutical Sciences, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8521 (Japan); Proubase Technology Inc., Kanagawa 211-0063 (Japan); Kyoto University Graduate School of Pharmaceutical Sciences, Kyoto 606-8501 (Japan)

    2013-04-19

    Highlights: •Blockade of the ERK pathway enhances the anticancer efficacy of HDAC inhibitors. •MEK inhibitors sensitize human tumor xenografts to HDAC inhibitor cytotoxicity. •Such the enhanced efficacy is achieved by a transient blockade of the ERK pathway. •This drug combination provides a promising therapeutic strategy for cancer patients. -- Abstract: The ERK pathway is up-regulated in various human cancers and represents a prime target for mechanism-based approaches to cancer treatment. Specific blockade of the ERK pathway alone induces mostly cytostatic rather than pro-apoptotic effects, however, resulting in a limited therapeutic efficacy of the ERK kinase (MEK) inhibitors. We previously showed that MEK inhibitors markedly enhance the ability of histone deacetylase (HDAC) inhibitors to induce apoptosis in tumor cells with constitutive ERK pathway activation in vitro. To evaluate the therapeutic efficacy of such drug combinations, we administered the MEK inhibitor PD184352 or AZD6244 together with the HDAC inhibitor MS-275 in nude mice harboring HT-29 or H1650 xenografts. Co-administration of the MEK inhibitor markedly sensitized the human xenografts to MS-275 cytotoxicity. A dose of MS-275 that alone showed only moderate cytotoxicity thus suppressed the growth of tumor xenografts almost completely as well as induced a marked reduction in tumor cellularity when administered with PD184352 or AZD6244. The combination of the two types of inhibitor also induced marked oxidative stress, which appeared to result in DNA damage and massive cell death, specifically in the tumor xenografts. The enhanced therapeutic efficacy of the drug combination was achieved by a relatively transient blockade of the ERK pathway. Administration of both MEK and HDAC inhibitors represents a promising chemotherapeutic strategy with improved safety for cancer patients.

  12. Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model.

    Science.gov (United States)

    Yang, Chun; Ren, Qian; Qu, Youge; Zhang, Ji-Chun; Ma, Min; Dong, Chao; Hashimoto, Kenji

    2018-01-01

    The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model (n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of (S)-ketamine, but not (R)-ketamine, in the CSDS model. Furthermore, (S)-ketamine, but not (R)-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of (R)-ketamine but not (S)-ketamine. Moreover, (R)-ketamine, but not (S)-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. This study suggests that mTOR plays a role in the antidepressant effects of (S)-ketamine, but not (R)-ketamine, and that ERK plays a role in (R)-ketamine's antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of (R)-ketamine. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  13. Dynamical 3-Space: Alternative Explanation of the "Dark Matter Ring"

    Directory of Open Access Journals (Sweden)

    Cahill R. T.

    2007-10-01

    Full Text Available NASA has claimed the discovery of a “Ring of Dark Matter” in the galaxy cluster CL 0024 +17, see Jee M.J. et al. arXiv:0705.2171, based upon gravitational lensing data. Here we show that the lensing can be given an alternative explanation that does not involve “dark matter”. This explanation comes from the new dynamics of 3-space. This dynamics involves two constant G and alpha — the fine structure constant. This dynamics has explained the bore hole anomaly, spiral galaxy flat rotation speeds, the masses of black holes in spherical galaxies, gravitational light bending and lensing, all without invoking “dark matter”, and also the supernova redshift data without the need for “dark energy”.

  14. TOR (target of rapamycin) is a key regulator of triacylglycerol accumulation in microalgae.

    Science.gov (United States)

    Imamura, Sousuke; Kawase, Yasuko; Kobayashi, Ikki; Shimojima, Mie; Ohta, Hiroyuki; Tanaka, Kan

    2016-01-01

    Most microalgae abundantly accumulate lipid droplets (LDs) containing triacylglycerols (TAGs) under several stress conditions, but the underlying molecular mechanism of this accumulation remains unclear. In a recent study, we found that inhibition of TOR (target of rapamycin), a highly conserved protein kinase of eukaryotes, by rapamycin resulted in TAG accumulation in microalgae, indicating that TOR negatively regulates TAG accumulation. Here, we show that formation of intracellular LDs and TAG accumulation were also induced in the unicellular green alga Chlamydomonas reinhardtii after exposure to Torin1 or AZD8055, which are novel TOR inhibitors that inhibit TOR activity in a manner different from rapamycin. These results supported quite well our previous conclusion that TOR is a central regulator of TAG accumulation in microalgae.

  15. Combinatorial Drug Testing in 3D Microtumors Derived from GBM Patient-Derived Xenografts Reveals Cytotoxic Synergy in Pharmacokinomics-informed Pathway Interactions.

    Science.gov (United States)

    Gilbert, Ashley N; Anderson, Joshua C; Duarte, Christine W; Shevin, Rachael S; Langford, Catherine P; Singh, Raj; Gillespie, G Yancey; Willey, Christopher D

    2018-05-30

    Glioblastoma multiforme (GBM), the most common form of primary malignant brain cancer in adults, is a devastating disease for which effective treatment has remained elusive for over 75 years. One reason for the minimal progress during this time is the lack of accurate preclinical models to represent the patient's tumor's in vivo environment, causing a disconnect in drug therapy effectiveness between the laboratory and clinic. While patient-derived xenografts (PDX's or xenolines) are excellent human tumor representations, they are not amenable to high throughput testing. Therefore, we developed a miniaturized xenoline system (microtumors) for drug testing. Nineteen GBM xenolines were profiled for global kinase (kinomic) activity revealing actionable kinase targets associated with intracranial tumor growth rate. Kinase inhibitors for these targets (WP1066, selumetinib, crizotinib, and cediranib) were selected for single and combination therapy using a fully human-derived three-dimensional (3D) microtumor model of GBM xenoline cells embedded in HuBiogel for subsequent molecular and phenotype assays. GBM microtumors closely resembled orthotopically-implanted tumors based on immunohistochemical analysis and displayed kinomic and morphological diversity. Drug response testing could be reproducibly performed in a 96-well format identifying several synergistic combinations. Our findings indicate that 3D microtumors can provide a suitable high-throughput model for combination drug testing.

  16. Perioperative Optimization of Geriatric Lower Extremity Bypass in the Era of Increased Performance Accountability.

    Science.gov (United States)

    Adkar, Shaunak S; Turley, Ryan S; Benrashid, Ehsan; Lagoo, Sandhya; Shortell, Cynthia K; Mureebe, Leila

    2017-01-01

    The initiation of bundled payment for care improvement by Centers for Medicare and Medicaid Services (CMS) has led to increased financial and performance accountability. As most vascular surgery patients are elderly and reimbursed via CMS, improving their outcomes will be critical for durable financial stability. As a first step in forming a multidisciplinary pathway for the elderly vascular patients, we sought to identify modifiable perioperative variables in geriatric patients undergoing lower extremity bypass (LEB). The 2011-2013 LEB-targeted American College of Surgeons National Surgical Quality Improvement Program database was used for this analysis (n = 5316). Patients were stratified by age <65 (n = 2171), 65-74 (n = 1858), 75-84 (n = 1190), and ≥85 (n = 394) years. Comparisons of patient- and procedure-related characteristics and 30-day postoperative outcomes stratified by age groups were performed with Pearson χ 2 tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. During the study period, 5316 total patients were identified. There were 2171 patients aged <65 years, 1858 patients in the 65-74 years age group, 1190 patients in the 75-84 years age group, and 394 patients in the ≥85 years age group. Increasing age was associated with an increased frequency of cardiopulmonary disease (P < 0.001) and a decreased frequency of diabetes, tobacco use, and prior surgical intervention (P < 0.001). Only 79% and 68% of all patients were on antiplatelet and statin therapies, respectively. Critical limb ischemia occurred more frequently in older patients (P < 0.001). Length of hospital stay, transfusion requirements, and discharge to a skilled nursing facility increased with age (P < 0.001). Thirty-day amputation rates did not differ significantly with age (P = 0.12). Geriatric patients undergoing LEB have unique and potentially modifiable perioperative factors that may improve postoperative outcomes. These

  17. Associations between follow-up screening after gestational diabetes and early detection of diabetes

    DEFF Research Database (Denmark)

    Olesen, Christinna Rebecca; Hyldgaard Nielsen, Jane; Mortensen, Rikke Nørmark

    2016-01-01

    BACKGROUND: Women whose pregnancy was complicated by gestational diabetes have a 7-fold higher risk of developing diabetes, primarily type 2. Early detection can prevent or delay the onset of late complications, for which follow-up screening is important. This study investigated the extent...... of participation in follow-up screening and the possible consequences of nonattendance in the Region of North Jutland, Denmark. METHOD: In Danish national registers covering the years 1994-2011 we identified 2171 birthing women whose pregnancy was complicated by first-time gestational diabetes. Control visits...... and treatment after gestational diabetes than women not attending. The results for women attending testing at biochemical departments also showed an increased risk of initiation of treatment. Women attending at least one general practitioners control had a significantly higher risk of early diabetes diagnosis...

  18. Reasons for women’s non-participation in follow-up screening after gestational diabetes

    DEFF Research Database (Denmark)

    Hyldgaard Nielsen, Jane; Olesen, Christinna Rebecca; Kristiansen, Tine Mechlenborg

    2016-01-01

    BACKGROUND: Women whose pregnancy was complicated by gestational diabetes have a 7-fold higher risk of developing diabetes, primarily type 2. Early detection can prevent or delay the onset of late complications, for which follow-up screening is important. This study investigated the extent...... of participation in follow-up screening and the possible consequences of nonattendance in the Region of North Jutland, Denmark. METHOD: In Danish national registers covering the years 1994-2011 we identified 2171 birthing women whose pregnancy was complicated by first-time gestational diabetes. Control visits...... and treatment after gestational diabetes than women not attending. The results for women attending testing at biochemical departments also showed an increased risk of initiation of treatment. Women attending at least one general practitioners control had a significantly higher risk of early diabetes diagnosis...

  19. Occurrences in control room equipment, procedures and personnel performances: IRS control room events

    International Nuclear Information System (INIS)

    Tolstykh, V.

    1994-01-01

    The IAEA/NEA Incident Reporting System (IRS) was established in the early 1980, its objective being to gain from operating experience achieved in countries with nuclear power programmes by means of exchanging information on events relevant to safety. Among the 2171 events in the database, 175 events (i.e. 8%) were identified as ''control room events''. It was decided to group these into three sets for further study: 65 events with common mode/cause failures (CCFs), 22 events with cognitive errors and 30 events with unforeseen interaction between NPP systems. It is expected that the pitfalls experienced in the IRS and the questions derived from this study will help to gain a better understanding of the needs and interests of specialists in advanced information methods and artificial intelligence in NPP control rooms. (author)

  20. Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells

    Science.gov (United States)

    Zeng, Yizhou; Tian, Xiaofang; Wang, Quan; He, Weiyang; Fan, Jing; Gou, Xin

    2018-01-01

    Aim The mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway. Methods and results: RAD001 strongly induced autophagy of RCC cells in a dose- and time-dependent manner, as confirmed by Western blot analysis. Importantly, suppression of autophagy by the pharmacological inhibitor chloroquine effectively enhanced RAD001-induced apoptotic cytotoxicity, as demonstrated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blot analysis, indicating a cytoprotective role for RAD001-induced autophagy. In addition, as was shown by the MTT assay, flow cytometry, and Western blot analysis, RAD001 robustly activated ERK, but not c-Jun N-terminal kinase and p38. Activation of ERK was inhibited by the pharmacological inhibitor selumetinib (AZD6244), which effectively promoted RAD001-induced cell death. Moreover, employing AZD6244 markedly attenuated RAD001-induced autophagy and enhanced RAD001-induced apoptosis, which play a central role in RAD001-induced cell death. Furthermore, RAD001-induced autophagy is regulated by ERK-mediated phosphorylation of Beclin-1 and B-cell lymphoma 2, as confirmed by Western blot analysis. Conclusion These results suggest that RAD001-induced autophagy involves activation of the ERK, which may impair cytotoxicity of RAD001 in RCC cells. Thus, inhibition of the activation of ERK pathway-mediated autophagy may be useful to overcome chemoresistance to RAD001. PMID:29719377

  1. AKT Inhibition in Solid Tumors With AKT1 Mutations.

    Science.gov (United States)

    Hyman, David M; Smyth, Lillian M; Donoghue, Mark T A; Westin, Shannon N; Bedard, Philippe L; Dean, Emma J; Bando, Hideaki; El-Khoueiry, Anthony B; Pérez-Fidalgo, José A; Mita, Alain; Schellens, Jan H M; Chang, Matthew T; Reichel, Jonathan B; Bouvier, Nancy; Selcuklu, S Duygu; Soumerai, Tara E; Torrisi, Jean; Erinjeri, Joseph P; Ambrose, Helen; Barrett, J Carl; Dougherty, Brian; Foxley, Andrew; Lindemann, Justin P O; McEwen, Robert; Pass, Martin; Schiavon, Gaia; Berger, Michael F; Chandarlapaty, Sarat; Solit, David B; Banerji, Udai; Baselga, José; Taylor, Barry S

    2017-07-10

    Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K-mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor-positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K-mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.

  2. Moving Synergistically Acting Drug Combinations to the Clinic by Comparing Sequential versus Simultaneous Drug Administrations.

    Science.gov (United States)

    Dinavahi, Saketh S; Noory, Mohammad A; Gowda, Raghavendra; Drabick, Joseph J; Berg, Arthur; Neves, Rogerio I; Robertson, Gavin P

    2018-03-01

    Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. Protein kinase B (AKT) is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 (mitotic inhibitor kinase) seems to have potential to make AKT-based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine these agents sequentially, enabling the use of existing phase I clinical trial toxicity data. Therefore, a rapid preclinical approach is needed to evaluate whether simultaneous or sequential drug treatment has maximal therapeutic efficacy, which is based on a mechanistic rationale. To develop this approach, melanoma cell lines were treated with AKT inhibitor AZD5363 [4-amino- N -[(1 S )-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperidine-4-carboxamide] and WEE1 inhibitor AZD1775 [2-allyl-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)-6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1 H -pyrazolo[3,4- d ]pyrimidin-3(2 H )-one] using simultaneous and sequential dosing schedules. Simultaneous treatment synergistically reduced melanoma cell survival and tumor growth. In contrast, sequential treatment was antagonistic and had a minimal tumor inhibitory effect compared with individual agents. Mechanistically, simultaneous targeting of AKT and WEE1 enhanced deregulation of the cell cycle and DNA damage repair pathways by modulating transcription factors p53 and forkhead box M1, which was not observed with sequential treatment. Thus, this study identifies a rapid approach to assess the drug combinations with a mechanistic basis for selection, which suggests that combining AKT and WEE1 inhibitors is needed for maximal efficacy. Copyright © 2018 by The American

  3. An integrated strategy for in vivo metabolite profiling using high-resolution mass spectrometry based data processing techniques

    International Nuclear Information System (INIS)

    Guo, Jian; Zhang, Minli; Elmore, Charles S.; Vishwanathan, Karthick

    2013-01-01

    Graphical abstract: -- Highlights: •Profiling the metabolites of model compounds in rats using high resolution mass spectrometry based data processing techniques. •Demonstrating an integrated strategy in vivo metabolite profiling using data mining tools. •Unusual metabolites generated via thiazole-ring opening were characterized based on processed LC–MS.data. -- Abstract: An ongoing challenge of drug metabolite profiling is to detect and identify unknown or low-level metabolites in complex biological matrices. Here we present a generic strategy for metabolite detection using multiple accurate-mass-based data processing tools via the analysis of rat samples of two model drug candidates, AZD6280 and AZ12488024. First, the function of isotopic pattern recognition was proved to be highly effective in the detection of metabolites derived from [ 14 C]-AZD6280 that possesses a distinct isotopic pattern. The metabolites revealed using this approach were in excellent qualitative correlation to those observed in radiochromatograms. Second, the effectiveness of accurate mass based untargeted data mining tools such as background subtraction, mass defect filtering, or a data mining package (MZmine) used for metabolomic analysis in detection of metabolites of [ 14 C]-AZ12488024 in rat urine, feces, bile and plasma samples was examined and a total of 33 metabolites of AZ12488024 were detected. Among them, at least 16 metabolites were only detected by the aid of the data mining packages and not via radiochromatograms. New metabolic pathways such as S-oxidation and thiomethylation reactions occurring on the thiazole ring were proposed based on the processed data. The results of these experiments also demonstrated that accurate mass-based mass defect filtering (MDF) and data mining techniques used in metabolomics are complementary and can be valuable tools for delineating low-level metabolites in complex matrices. Furthermore, the application of distinct multiple data

  4. Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT).

    Science.gov (United States)

    Carvajal, Richard D; Piperno-Neumann, Sophie; Kapiteijn, Ellen; Chapman, Paul B; Frank, Stephen; Joshua, Anthony M; Piulats, Josep M; Wolter, Pascal; Cocquyt, Veronique; Chmielowski, Bartosz; Evans, T R Jeffry; Gastaud, Lauris; Linette, Gerald; Berking, Carola; Schachter, Jacob; Rodrigues, Manuel J; Shoushtari, Alexander N; Clemett, Delyth; Ghiorghiu, Dana; Mariani, Gabriella; Spratt, Shirley; Lovick, Susan; Barker, Peter; Kilgour, Elaine; Lai, Zhongwu; Schwartz, Gary K; Nathan, Paul

    2018-04-20

    Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m 2 intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety

  5. Aging effects on cerebral asymmetry: a voxel-based morphometry and diffusion tensor imaging study.

    Science.gov (United States)

    Takao, Hidemasa; Abe, Osamu; Yamasue, Hidenori; Aoki, Shigeki; Kasai, Kiyoto; Sasaki, Hiroki; Ohtomo, Kuni

    2010-01-01

    The hemispheres of the human brain are functionally and structurally asymmetric. The purpose of this study was to evaluate the effects of aging on gray and white matter asymmetry. Two hundred twenty-six right-handed normal volunteers aged 21-71 years were included in this study. The effects of aging on gray matter volume asymmetry and white matter fractional anisotropy asymmetry were evaluated with use of voxel-based morphometry and voxel-based analysis of fractional anisotropy maps derived from diffusion tensor imaging (DTI), respectively. The voxel-based morphometry showed no significant correlation between age and gray matter volume asymmetry. The voxel-based analysis of DTI also showed no significant correlation between age and white matter fractional anisotropy asymmetry. Our results showed no significant effects of aging on either gray matter volume asymmetry or white matter fractional anisotropy asymmetry.

  6. Control of very heavy water inrush from sinkholes connecting with Ordovician limestone. Part 1. [China

    Energy Technology Data Exchange (ETDEWEB)

    1986-01-01

    This paper describes the comprehensive water control methods used in Fangezhuang Colliery: water drainage; cutting off of water; and sealing off the water. For water drainage, 20 large-sized submarine pumps were used in Lujiatuo and Fangezhuang collieries with a delivery of 300 m/sup 3//min to control the rising of water level. For cutting off the water, a three-section horizontal injection method and 8 grouting techniques were applied to cut off the water in 3 roadways at the boundary between Lujiatuo and Fangezhuang with water flowing at an average rate of 300 m/sup 3//min. For sealing off the water, a radio perspective instrument was used to detect the shape of No. 2171 sinkhole in Fangezhuang, and computers were employed to process the hydrogeological data. The three section vertical grouting method was introduced, and the inrush water source was sealed off with a success of over 99%.

  7. Lung Cancer Mortality and Radon Concentration in a Chronically Exposed Neighborhood in Chihuahua, Mexico: A Geospatial Analysis

    Science.gov (United States)

    Hinojosa de la Garza, Octavio R.; Sanín, Luz H.; Montero Cabrera, María Elena; Serrano Ramirez, Korina Ivette; Martínez Meyer, Enrique; Reyes Cortés, Manuel

    2014-01-01

    This study correlated lung cancer (LC) mortality with statistical data obtained from government public databases. In order to asses a relationship between LC deaths and radon accumulation in dwellings, indoor radon concentrations were measured with passive detectors randomly distributed in Chihuahua City. Kriging (K) and Inverse-Distance Weighting (IDW) spatial interpolations were carried out. Deaths were georeferenced and Moran's I correlation coefficients were calculated. The mean values (over n = 171) of the interpolation of radon concentrations of deceased's dwellings were 247.8 and 217.1 Bq/m3, for K and IDW, respectively. Through the Moran's I values obtained, correspondingly equal to 0.56 and 0.61, it was evident that LC mortality was directly associated with locations with high levels of radon, considering a stable population for more than 25 years, suggesting spatial clustering of LC deaths due to indoor radon concentrations. PMID:25165752

  8. Multilevel binomial logistic prediction model for malignant pulmonary nodules based on texture features of CT image

    International Nuclear Information System (INIS)

    Wang Huan; Guo Xiuhua; Jia Zhongwei; Li Hongkai; Liang Zhigang; Li Kuncheng; He Qian

    2010-01-01

    Purpose: To introduce multilevel binomial logistic prediction model-based computer-aided diagnostic (CAD) method of small solitary pulmonary nodules (SPNs) diagnosis by combining patient and image characteristics by textural features of CT image. Materials and methods: Describe fourteen gray level co-occurrence matrix textural features obtained from 2171 benign and malignant small solitary pulmonary nodules, which belongs to 185 patients. Multilevel binomial logistic model is applied to gain these initial insights. Results: Five texture features, including Inertia, Entropy, Correlation, Difference-mean, Sum-Entropy, and age of patients own aggregating character on patient-level, which are statistically different (P < 0.05) between benign and malignant small solitary pulmonary nodules. Conclusion: Some gray level co-occurrence matrix textural features are efficiently descriptive features of CT image of small solitary pulmonary nodules, which can profit diagnosis of earlier period lung cancer if combined patient-level characteristics to some extent.

  9. PRESENTEEISM: NEDENLERİ, YARATTIĞI ÖRGÜTSEL SORUNLAR VE ÇÖZÜM ÖNERİLERİ ÜZERİNE BİR ALANYAZIN TARAMASI

    OpenAIRE

    ÇOBAN, Ömer; HARMAN, Serhat

    2012-01-01

    Presenteeism, işgörenin rahatsızlığı bulunmasına rağmen işe gitmesini ve bu durumdan kaynaklanan verimlilik kayıplarını ifade etmektedir. Türkiye’de presenteeism ile ilgili görgül çalışma sayısı yok denecek kadar azdır. Bu nedenle, presenteeism kavramı ile ilgili daha önce yapılmış çalışmaların incelendiği alanyazın taraması niteliğinde nitel bir çalışma gerçekleştirilmiştir. Yapılan alanyazın taraması sonucunda 28 adet tam metin çalışmaya ulaşılmıştır. 28 adet çalışmanın incelenmesinin ardın...

  10. Insights into significance of combined inhibition of MEK and m-TOR signalling output in KRAS mutant non-small-cell lung cancer.

    Science.gov (United States)

    Broutin, Sophie; Stewart, Adam; Thavasu, Parames; Paci, Angelo; Bidart, Jean-Michel; Banerji, Udai

    2016-08-23

    We aimed to understand the dependence of MEK and m-TOR inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cell lines. In a panel of KRAS(M) and KRAS(WT) NSCLC cell lines, we determined growth inhibition (GI) following maximal reduction in p-ERK and p-S6RP caused by trametinib (MEK inhibitor) and AZD2014 (m-TOR inhibitor), respectively. GI caused by maximal m-TOR inhibition was significantly greater than GI caused by maximal MEK inhibition in the cell line panel (52% vs 18%, PTOR compared with maximal m-TOR+MEK inhibition. However, GI caused by the combination was significantly greater in the KRAS(M) cell lines (79% vs 61%, P=0.017). m-TOR inhibition was more critical to GI than MEK inhibition in EGFR(WT)/ALK(non-rearranged) NSCLC cells. The combination of MEK and m-TOR inhibition was most effective in KRAS(M) cells.

  11. Public attitudes to the promotion of genomic crop studies in Japan: correlations between genomic literacy, trust, and favourable attitude.

    Science.gov (United States)

    Ishiyama, Izumi; Tanzawa, Tetsuro; Watanabe, Maiko; Maeda, Tadahiko; Muto, Kaori; Tamakoshi, Akiko; Nagai, Akiko; Yamagata, Zentaro

    2012-05-01

    This study aimed to assess public attitudes in Japan to the promotion of genomic selection in crop studies and to examine associated factors. We analysed data from a nationwide opinion survey. A total of 4,000 people were selected from the Japanese general population by a stratified two-phase sampling method, and 2,171 people participated by post; this survey asked about the pros and cons of crop-related genomic studies promotion, examined people's scientific literacy in genomics, and investigated factors thought to be related to genomic literacy and attitude. The relationships were examined using logistic regression models stratified by gender. Survey results showed that 50.0% of respondents approved of the promotion of crop-related genomic studies, while 6.7% disapproved. No correlation was found between literacy and attitude towards promotion. Trust in experts, belief in science, an interest in genomic studies and willingness to purchase new products correlated with a positive attitude towards crop-related genomic studies.

  12. ASSOCIATION BETWEEN THE PRESENCE OF A 38 kDa FACTOR IN THE SEMINAL PLASMA AND INHIBITION OF SPERM MOTILITY IN JUNDIÁ FISH Rhamdia quelen

    Directory of Open Access Journals (Sweden)

    Vinicius Farias Campos

    2010-06-01

    Full Text Available Protein factors have been identified in the seminal plasmaof fish and mammal species and, in some situations, associatedto sperm quality indicators. However, for jundiá fish (Rhamdiaquelen, such factors and those potential associations remainunknown. In the present study, we aimed to identify some proteinfactors present in the seminal plasma of jundiá fish and to evaluatetheir association to sperm motility. SDS-PAGE was used to identify14 bands, with molecular weight ranging from 217.1 to 7.1 kDa.Sperm motility was evaluated for 21 males. Four protein bands(81.5; 60.4; 33.6; and 25.5 kDa were present in all seminal plasmasamples. One protein band with molecular weight of 38.3 kDa wasassociated to reduced sperm motility of jundiá (P<0.01, since itwas detected in 91.4% of the samples having motility lower than80%. These results suggest that this seminal protein band associatedto lower sperm motility may be considered a potential biochemicalmarker for sperm quality.

  13. Efficacy of group psychotherapy for social anxiety disorder: A meta-analysis of randomized-controlled trials.

    Science.gov (United States)

    Barkowski, Sarah; Schwartze, Dominique; Strauss, Bernhard; Burlingame, Gary M; Barth, Jürgen; Rosendahl, Jenny

    2016-04-01

    Group psychotherapy for social anxiety disorder (SAD) is an established treatment supported by findings from primary studies and earlier meta-analyses. However, a comprehensive summary of the recent evidence is still pending. This meta-analysis investigates the efficacy of group psychotherapy for adult patients with SAD. A literature search identified 36 randomized-controlled trials examining 2171 patients. Available studies used mainly cognitive-behavioral group therapies (CBGT); therefore, quantitative analyses were done for CBGT. Medium to large positive effects emerged for wait list-controlled trials for specific symptomatology: g=0.84, 95% CI [0.72; 0.97] and general psychopathology: g=0.62, 95% CI [0.36; 0.89]. Group psychotherapy was also superior to common factor control conditions in alleviating symptoms of SAD, but not in improving general psychopathology. No differences appeared for direct comparisons of group psychotherapy and individual psychotherapy or pharmacotherapy. Hence, group psychotherapy for SAD is an efficacious treatment, equivalent to other treatment formats. Copyright © 2016 Elsevier Ltd. All rights reserved.

  14. Entomofauna edáfica em diferentes ambientes no município de Ipu, estado do Ceará

    Directory of Open Access Journals (Sweden)

    Venância Antonia Nunes Azevedo

    2017-09-01

    Full Text Available The aim of this study was to map the soil entomofauna in two different environments, in the District of Recanto, Municipality of Ipu, in the northwest region of the state of Ceará, Brazil, using soil trap, with fortnightly collections in the period from November 2015 to March 2016. In order to characterize the insect fauna a distribution pattern was established, considering the rates of occurrence and dominance of specieswhich have been grouped by order, as an indicator of the frequency and the occurrence of the amount captured. Throughout the project, a total of 2.171 specimens of insects belonging to 8 orders: Blattodea, Coleoptera, Diptera, Hemiptera, Hymenoptera, Isoptera, Lepidoptera and Orthoptera have been collected and identified. According to the method used the order Hymenoptera was the one that stood out for having the largest number of individuals captured, due to the presence of a large amount of ants, it was considered common to the different environments studied in the caatinga biome.

  15. Practice settings and dentists' job satisfaction.

    Science.gov (United States)

    Lo Sasso, Anthony T; Starkel, Rebecca L; Warren, Matthew N; Guay, Albert H; Vujicic, Marko

    2015-08-01

    The nature and organization of dental practice is changing. The aim of this study was to explore how job satisfaction among dentists is associated with dental practice setting. A survey measured satisfaction with income, benefits, hours worked, clinical autonomy, work-life balance, emotional exhaustion, and overall satisfaction among dentists working in large group, small group, and solo practice settings; 2,171 dentists responded. The authors used logistic regression to measure differences in reported levels of satisfaction across practice settings. Dentists working in small group settings reported the most satisfaction overall. Dentists working in large group settings reported more satisfaction with income and benefits than dentists in solo practice, as well as having the least stress. Findings suggest possible advantages and disadvantages of working in different types of practice settings. Dentists working in different practice settings reported differences in satisfaction. These results may help dentists decide which practice setting is best for them. Copyright © 2015 American Dental Association. Published by Elsevier Inc. All rights reserved.

  16. Effect of binder concentration and blade gap on Yttria stabilized Zirconia tapes obtained by tape casting

    Energy Technology Data Exchange (ETDEWEB)

    Mena Garcia, J.; Reyes Rojas, A.; Rodriguez Gonzalez, C.A.; Hernandez Paz, J.; Garcia Casillas, P.E.; Enriquez Carrejo, J.L.; Camacho Montes, H.

    2016-07-01

    The tape casting method has kept its interest over the years due to the wide spectrum of its applications and its economic viability in comparison to other techniques focused on micrometric thin films. Two key parameters for tape casting are the binder relative amount and the Dr. Blade gap. The binder relative amount has a strong influence on the rheological properties for the ceramic YSZ slurry (ethanol, butanone, TEA, PVB, PEG, DEP). The coefficient K and the exponent m of the Cross model are reported to be inside the ranges 152.25-231.12 and 0.00987-0.26646 for PVB binder weight percentage concentrations between 6% and 12%. It is possible to describe the ceramic tape thickness dependence by means of a linear relation depending on the Dr. Blade gap whose linear coefficients (slope) are equal to 0.0350 and 0.2171 for green and sintered tapes respectively, with the YSZ slurry of the present work. (Author)

  17. Mutations in the Arabidopsis Lst8 and Raptor genes encoding partners of the TOR complex, or inhibition of TOR activity decrease abscisic acid (ABA) synthesis.

    Science.gov (United States)

    Kravchenko, Alena; Citerne, Sylvie; Jéhanno, Isabelle; Bersimbaev, Rakhmetkazhi I; Veit, Bruce; Meyer, Christian; Leprince, Anne-Sophie

    2015-11-27

    The Target of Rapamycin (TOR) kinase regulates essential processes in plant growth and development by modulation of metabolism and translation in response to environmental signals. In this study, we show that abscisic acid (ABA) metabolism is also regulated by the TOR kinase. Indeed ABA hormone level strongly decreases in Lst8-1 and Raptor3g mutant lines as well as in wild-type (WT) Arabidopsis plants treated with AZD-8055, a TOR inhibitor. However the growth and germination of these lines are more sensitive to exogenous ABA. The diminished ABA hormone accumulation is correlated with lower transcript levels of ZEP, NCED3 and AAO3 biosynthetic enzymes, and higher transcript amount of the CYP707A2 gene encoding a key-enzyme in abscisic acid catabolism. These results suggest that the TOR signaling pathway is implicated in the regulation of ABA accumulation in Arabidopsis. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Drosophila Cancer Models Identify Functional Differences between Ret Fusions.

    Science.gov (United States)

    Levinson, Sarah; Cagan, Ross L

    2016-09-13

    We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  19. Adventures in Scaffold Morphing: Discovery of Fused Ring Heterocyclic Checkpoint Kinase 1 (CHK1) Inhibitors.

    Science.gov (United States)

    Yang, Bin; Vasbinder, Melissa M; Hird, Alexander W; Su, Qibin; Wang, Haixia; Yu, Yan; Toader, Dorin; Lyne, Paul D; Read, Jon A; Breed, Jason; Ioannidis, Stephanos; Deng, Chun; Grondine, Michael; DeGrace, Nancy; Whitston, David; Brassil, Patrick; Janetka, James W

    2018-02-08

    Checkpoint kinase 1 (CHK1) inhibitors are potential cancer therapeutics that can be utilized for enhancing the efficacy of DNA damaging agents. Multiple small molecule CHK1 inhibitors from different chemical scaffolds have been developed and evaluated in clinical trials in combination with chemotherapeutics and radiation treatment. Scaffold morphing of thiophene carboxamide ureas (TCUs), such as AZD7762 (1) and a related series of triazoloquinolines (TZQs), led to the identification of fused-ring bicyclic CHK1 inhibitors, 7-carboxamide thienopyridines (7-CTPs), and 7-carboxamide indoles. X-ray crystal structures reveal a key intramolecular noncovalent sulfur-oxygen interaction in aligning the hinge-binding carboxamide group to the thienopyridine core in a coplanar fashion. An intramolecular hydrogen bond to an indole NH was also effective in locking the carboxamide in the preferred bound conformation to CHK1. Optimization on the 7-CTP series resulted in the identification of lead compound 44, which displayed respectable drug-like properties and good in vitro and in vivo potency.

  20. Multikinase activity of fibroblast growth factor receptor (FGFR) inhibitors SU5402, PD173074, AZD1480, AZD4547 and BGJ398 compromises the use of small chemicals targeting FGFR catalytic activity for therapy of short-stature syndromes

    Czech Academy of Sciences Publication Activity Database

    Gudernová, I.; Veselá, Iva; Balek, L.; Buchtová, Marcela; Dosedělová, Hana; Kunová, M.; Pivnička, J.; Jelínková, I.; Roubalová, L.; Kozubík, Alois; Krejčí, P.

    2016-01-01

    Roč. 25, č. 1 (2016), s. 9-23 ISSN 0964-6906 R&D Projects: GA ČR(CZ) GA14-31540S Institutional support: RVO:67985904 ; RVO:68081707 Keywords : fibroblast growth factor receptor * tyrosine kinase domain * ERK MAP kinase Subject RIV: EA - Cell Biology Impact factor: 5.340, year: 2016

  1. Gateways to clinical trials.

    Science.gov (United States)

    Bayés, M; Rabasseda, X; Prous, J R

    2007-12-01

    Gateways to Clinical Trials are a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Trials Knowledge Area of Prous Science Intergrity, the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: 249553, 2-Methoxyestradiol; Abatacept, Adalimumab, Adefovir dipivoxil, Agalsidase beta, Albinterferon alfa-2b, Aliskiren fumarate, Alovudine, Amdoxovir, Amlodipine besylate/atorvastatin calcium, Amrubicin hydrochloride, Anakinra, AQ-13, Aripiprazole, AS-1404, Asoprisnil, Atacicept, Atrasentan; Belimumab, Bevacizumab, Bortezomib, Bosentan, Botulinum toxin type B, Brivaracetam; Catumaxomab, Cediranib, Cetuximab, cG250, Ciclesonide, Cinacalcet hydrochloride, Curcumin, Cypher; Darbepoetin alfa, Denosumab, Dihydrexidine; Eicosapentaenoic acid/docosahexaenoic acid, Entecavir, Erlotinib hydrochloride, Escitalopram oxalate, Etoricoxib, Everolimus, Ezetimibe; Febuxostat, Fenspiride hydrochloride, Fondaparinux sodium; Gefitinib, Ghrelin (human), GSK-1562902A; HSV-tk/GCV; Iclaprim, Imatinib mesylate, Imexon, Indacaterol, Insulinotropin, ISIS-112989; L-Alanosine, Lapatinib ditosylate, Laropiprant; Methoxy polyethylene glycol-epoetin-beta, Mipomersen sodium, Motexafin gadolinium; Natalizumab, Nimotuzumab; OSC, Ozarelix; PACAP-38, Paclitaxel nanoparticles, Parathyroid Hormone-Related Protein-(1-36), Pasireotide, Pegfilgrastim, Peginterferon alfa-2a, Peginterferon alfa-2b, Pemetrexed disodium, Pertuzumab, Picoplatin, Pimecrolimus, Pitavastatin calcium, Plitidepsin; Ranelic acid distrontium salt, Ranolazine, Recombinant human relaxin H2, Regadenoson, RFB4(dsFv)-PE38, RO-3300074, Rosuvastatin calcium; SIR-Spheres, Solifenacin succinate, Sorafenib, Sunitinib malate; Tadalafil, Talabostat, Taribavirin hydrochloride, Taxus, Temsirolimus, Teriparatide, Tiotropium bromide, Tipifarnib, Tirapazamine, Tocilizumab; UCN-01, Ularitide

  2. Gateways to clinical trials.

    Science.gov (United States)

    Tomillero, A; Moral, M A

    2010-01-01

    (-)-Epigallocatechin gallate, Abafungin, ACE-031, Adapalene/benzoyl peroxide, AE-37, Aflibercept, AGS-003, Albiglutide, Alemtuzumab, Aliskiren fumarate, ALT-801, AN-2728, Anacetrapib, API, Aprepitant, ARQ-197, Ascorbic acid, Atazanavir sulfate, ATN-224, AVI-4658, Azacitidine, Azelnidipine; Belinostat, Bevacizumab, BI-2536, Biphasic insulin aspart, Bortezomib, Bovine lactoferrin, Bryostatin 1, Budesonide/formoterol fumarate; cAC10, Canfosfamide hydrochloride, Cediranib, Clofarabine, Cocaine conjugate vaccine; Darbepoetin alfa, Dasatinib, Denosumab, Disomotide, Doripenem, Dovitinib Lactate, Dronedarone hydrochloride, Drospirenone/estradiol, Dutasteride; Ecogramostim, Entinostat, Enzastaurin hydrochloride, Erlotinib hydrochloride, Everolimus, Exenatide, Ezetimibe, Ezetimibe/simvastatin; Fampridine, Fenretinide LXS, FFR-factor VIIa, Fingolimod hydrochloride, Frovatriptan; Gefitinib, Gimatecan, GP-2/GM-CSF; Iloperidone, Imatinib mesylate, Indibulin, Ipilimumab, Ivabradine hydrochloride; Lactobacillus rhamnosus, Lapatinib ditosylate, LC-07, Lenalidomide, Linifanib, Liposomal doxorubicin, Liposomal vincristine, Litenimod, Lutein; M-118, MDX-1401, MEDI-528, Midostaurin, Miglustat, MK-0657; Natalizumab, Nesiritide, NGR-TNF, Niacin/simvastatin; Obatoclax mesylate, Olaparib, Omacetaxine mepesuccinate; Paclitaxel nanoparticles, Paclitaxel-eluting stent, Palonosetron hydrochloride, Pazopanib hydrochloride, Pegfilgrastim, Pemetrexed disodium, PER.C-flu, Perifosine, PF-02341066, Pimecrolimus, Pitrakinra, Plerixafor hydrochloride, Posaconazole; Rasburicase, Recombinant human relaxin H2, ReoT3D, Retaspimycin hydrochloride, Riferminogene pecaplasmid, Rindopepimut, Romiplostim, Ronacaleret hydrochloride, Rosuvastatin calcium, Rotigotine; Sagopilone, sALP-FcD10, SAR-245409, SCH-697243, Selumetinib, Sirolimus-eluting stent, SIR-Spheres, Sitagliptin phosphate monohydrate, Sitaxentan sodium, Sorafenib, Sunitinib malate; Tadalafil, Tandutinib, Tasimelteon, Temsirolimus, Teriparatide

  3. New data on the toxicity and translocation of inhaled /sup 239/PuO/sub 2/ in baboons

    Energy Technology Data Exchange (ETDEWEB)

    Metivier, H.; Masse, R.; Rateau, G.; Nolibe, D.; Lafuma, J. (CEA Centre d' Etudes de Bruyeres-le-Chatel, 91 (France))

    1989-01-01

    In 1973-1974, baboons were exposed to a polydispersed aerosol of /sup 239/PuO/sub 2/, prepared at 1000/sup 0/C, at the Commissariat a l'Energie Atomique in France. The data published in 1978 for these baboons were used by Bair et al (1980), for comparison with those obtained in beagles exposed to /sup 239/PuO/sub 2/ at the Pacific Northwest Laboratory, USA. Since our 1978 publication, 8 baboons have died or were killed by euthanasia when moribund, and 11 were still alive when the present report was drafted. Two of the eight baboons died of lung squamous cell carcinoma at 2171 and 2528 days respectively. The remaining 6 died of fibrosis, interstitial pneumonia or diseases unrelated to Pu toxicity. The relationship observed in the eight baboons between initial lung burden and survival time shows that their lifespan was longer than expected from the data curve based on the findings for the first 1000 days. However, this increased survival time was not observed if the lifespan was expressed as a function of the average lung burden. (author).

  4. New data on the toxicity and translocation of inhaled 239PuO2 in baboons

    International Nuclear Information System (INIS)

    Metivier, H.; Masse, R.; Rateau, G.; Nolibe, D.; Lafuma, J.

    1989-01-01

    In 1973-1974, baboons were exposed to a polydispersed aerosol of 239 PuO 2 , prepared at 1000 0 C, at the Commissariat a l'Energie Atomique in France. The data published in 1978 for these baboons were used by Bair et al (1980), for comparison with those obtained in beagles exposed to 239 PuO 2 at the Pacific Northwest Laboratory, USA. Since our 1978 publication, 8 baboons have died or were killed by euthanasia when moribund, and 11 were still alive when the present report was drafted. Two of the eight baboons died of lung squamous cell carcinoma at 2171 and 2528 days respectively. The remaining 6 died of fibrosis, interstitial pneumonia or diseases unrelated to Pu toxicity. The relationship observed in the eight baboons between initial lung burden and survival time shows that their lifespan was longer than expected from the data curve based on the findings for the first 1000 days. However, this increased survival time was not observed if the lifespan was expressed as a function of the average lung burden. (author)

  5. “Não Preciso de Coleira Eletrônica!”: Um Estudo Sobre o Movimento de Resistência ao Celular em Blogs e Comunidades Virtuais

    Directory of Open Access Journals (Sweden)

    Tatiana Maria Bernardo da Silva

    2010-10-01

    Full Text Available Atualmente os consumidores estão mais aptos a resistir às ações de marketing das organizações. O presente trabalho trata de uma pesquisa qualitativa que pretende analisar os comportamentos e as razões de resistência ao celular em fóruns na web. Para cumprir tal objetivo, foi escolhida a netnografia como meio de investigação do comportamento dos participantes dessas comunidades. Foram escolhidos e investigados quatro blogs nacionais e uma comunidade do site de relacionamento Orkut. A imersão da pesquisadora nestes permitiu que dados fossem copiados dos fóruns e a partir das observações das interações em tais fóruns, das entrevistas realizadas com os donos dos blogs investigados e da análise do discurso, foram identificados os motivos para a resistência ao celular: o aprisionamento; a falta de educação; o consumismo; e, o uso incômodo.  DOI: 10.5585/remark.v9i2.2171

  6. College students’ perceptions of a caring climate in group physical activity classes

    Directory of Open Access Journals (Sweden)

    Newland Aubrey

    2017-02-01

    Full Text Available Study aim: Research suggests that physical activity rates decline sharply after high school. The pattern of activity or inactivity during college tends to persist into adulthood. A critical need exists for examination of strategies to engage college-age students in physical activity habits. One way to do this is through physical activity courses offered in colleges. This study examines the relationship between perceptions of a caring psychological climate and group connectedness, enjoyment, and attitudes toward classmates and the instructor in group physical activity courses. Material and methods: Participants were 174 students (107 males and 67 females; Mage = 21.71 enrolled in exercise, martial arts, and sports courses at a large university in the Mountain West. Results: Perceptions of a caring climate were significantly related to enhanced feelings of group connectedness, heightened enjoyment, and more positive attitudes toward classmates and instructor. Discussion: These findings suggest that a strategy to foster engagement in physical activity courses on campus is to train instructors to value, support, and welcome students.

  7. Crystal Structure and Regulation of the Citrus Pol III Repressor MAF1 by Auxin and Phosphorylation.

    Science.gov (United States)

    Soprano, Adriana Santos; Giuseppe, Priscila Oliveira de; Shimo, Hugo Massayoshi; Lima, Tatiani Brenelli; Batista, Fernanda Aparecida Heleno; Righetto, Germanna Lima; Pereira, José Geraldo de Carvalho; Granato, Daniela Campos; Nascimento, Andrey Fabricio Ziem; Gozzo, Fabio Cesar; de Oliveira, Paulo Sérgio Lopes; Figueira, Ana Carolina Migliorini; Smetana, Juliana Helena Costa; Paes Leme, Adriana Franco; Murakami, Mario Tyago; Benedetti, Celso Eduardo

    2017-09-05

    MAF1 is the main RNA polymerase (Pol) III repressor that controls cell growth in eukaryotes. The Citrus ortholog, CsMAF1, was shown to restrict cell growth in citrus canker disease but its role in plant development and disease is still unclear. We solved the crystal structure of the globular core of CsMAF1, which reveals additional structural elements compared with the previously available structure of hMAF1, and explored the dynamics of its flexible regions not present in the structure. CsMAF1 accumulated in the nucleolus upon leaf excision, and this translocation was inhibited by auxin and by mutation of the PKA phosphorylation site, S45, to aspartate. Additionally, mTOR phosphorylated recombinant CsMAF1 and the mTOR inhibitor AZD8055 blocked canker formation in normal but not CsMAF1-silenced plants. These results indicate that the role of TOR on cell growth induced by Xanthomonas citri depends on CsMAF1 and that auxin controls CsMAF1 interaction with Pol III in citrus. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Major clinical research advances in gynecologic cancer in 2016: 10-year special edition.

    Science.gov (United States)

    Suh, Dong Hoon; Kim, Miseon; Kim, Kidong; Kim, Hak Jae; Lee, Kyung Hun; Kim, Jae Weon

    2017-05-01

    In 2016, 13 topics were selected as major research advances in gynecologic oncology. For ovarian cancer, study results supporting previous ones regarding surgical preventive strategies were reported. There were several targeted agents that showed comparable responses in phase III trials, including niraparib, cediranib, and nintedanib. On the contrary to our expectations, dose-dense weekly chemotherapy regimen failed to prove superior survival outcomes compared with conventional triweekly regimen. Single-agent non-platinum treatment to prolong platinum-free-interval in patients with recurrent, partially platinum-sensitive ovarian cancer did not improve and even worsened overall survival (OS). For cervical cancer, we reviewed robust evidences of larger-scaled population-based study and cost-effectiveness of nonavalent vaccine for expanding human papillomavirus (HPV) vaccine coverage. Standard of care treatment of locally advanced cervical cancer (LACC) was briefly reviewed. For uterine corpus cancer, new findings about appropriate surgical wait time from diagnosis to surgery were reported. Advantages of minimally invasive surgery over conventional laparotomy were reconfirmed. There were 5 new gene regions that increase the risk of developing endometrial cancer. Regarding radiation therapy, Post-Operative Radiation Therapy in Endometrial Cancer (PORTEC)-3 quality of life (QOL) data were released and higher local control rate of image-guided adaptive brachytherapy was reported in LACC. In addition, 4 general oncology topics followed: chemotherapy at the end-of-life, immunotherapy with reengineering T-cells, actualization of precision medicine, and artificial intelligence (AI) to make personalized cancer therapy real. For breast cancer, adaptively randomized trials, extending aromatase inhibitor therapy, and ribociclib and palbociclib were introduced. Copyright © 2017. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology.

  9. Early Initiation of Antenatal Care and Factors Associated with Early Antenatal Care Initiation at Health Facilities in Southern Ethiopia

    Directory of Open Access Journals (Sweden)

    Mengesha Boko Geta

    2017-01-01

    Full Text Available Antenatal care (ANC is care given to pregnant mothers to timely identify and mitigate pregnancy related problems that can harm mother or fetus. Most of Ethiopian mothers present late for ANC. The aim of this paper was to assess determinants of early antenatal care initiation among pregnant women. Mothers attending Shebedino District Health Centers for ANC between January 12 and February 18, 2015, were invited to the study. Multistage sampling technique and structured questionnaire were used to collect data by trained data collectors. Univariate and bivariate analysis were conducted to study the association between explanatory and outcome variable. Out of 608 women, 132 [21.71%] had their first ANC within the recommended time [before or at 3 months]. Media access [AOR = 2.11 95% CI 1.00, 3.22], knowledge about the correct time of ANC booking [AOR = 4.49 95% CI 2.47, 6.16], and having been advised to book within 12 weeks [AOR = 4.14 95% CI 3.80, 5.21] were determinants of first-trimester booking. Health professionals and care providers should provide full information, advice, and appropriate care about early ANC for every eligible mother.

  10. Anther development stage and gamma radiation effects on tomato anther-derived callus formation

    International Nuclear Information System (INIS)

    Brasileiro, Ana Christina R.; Willadino, Lilia; Guerra, Marcelo; Colaco, Waldeciro; Meunier, Isabelle; Camara, Terezinha R.

    1999-01-01

    Two experiments were carried (I) to determine tomato anther development stage influence on callus production; and (II) to investigate gamma radiation effects on anther culture. In the first experiment, anthers of a tomato hybrid (IPA 5 x Rotam 4-F 1 ) were grown on three media. Although calli were induced at all stages of anther development, varying from prophase I to mono nucleate microspore, callus frequency decreased as anther development progressed and calli induction were not significantly affected by all media tested. Anthers containing prophase I meiocytes produced the highest calli frequency. Anther and flower bud length both were significantly correlated with anther development stage. In the second experiment, seed and floral buds of tomato hybrids IPA 5 x Rotam 4 (F 2 ), IPA 6 x Rotam 4 (F 2 ) and IPA 8 x 217.1 (F 2 ) were submitted to gamma-ray and anthers were plated on two media described by Gresshoff and Doy (1972) supplemented with 2.0 mg L -1 NAA + 5.0 mg L -1 KIN and 2.0 mg L -1 NAA + 1.0 mg L -1 KIN. No significant differences for genotype and dosage testes were found for calli formation. (author)

  11. Conducta sexual segura y hábitos de salud en jóvenes españoles de 14 a 24 años

    Directory of Open Access Journals (Sweden)

    José María Faílde Garrido

    2014-12-01

    Full Text Available Los jóvenes son un colectivo de especial importancia para la prevención de enfermedades de transmisión sexual y para la promoción de la salud en general, por ello resulta de interés estudiar las causas y determinantes de sus conductas de salud. El objetivo de esta investigación consistió en estudiar el grado de relación existente entre la conducta de uso del preservativo y otros hábitos de salud, en jóvenes españoles de 14 a 24 años. La muestra estuvo formada por 2171 jóvenes de las comunidades autónomas de Galicia, Andalucía y Madrid. Los resultados indican la existencia de diferencias estadísticamente significativas en función del género. En general las chicas presentan hábitos más saludables, a excepción de la práctica deportiva y el uso sistemático del preservativo masculino. Asimismo, las variables práctica deportiva e higiene buco-dental se muestran como predictores confiables de la conducta de usar el preservativo.

  12. Identifying kinase dependency in cancer cells by integrating high-throughput drug screening and kinase inhibition data.

    Science.gov (United States)

    Ryall, Karen A; Shin, Jimin; Yoo, Minjae; Hinz, Trista K; Kim, Jihye; Kang, Jaewoo; Heasley, Lynn E; Tan, Aik Choon

    2015-12-01

    Targeted kinase inhibitors have dramatically improved cancer treatment, but kinase dependency for an individual patient or cancer cell can be challenging to predict. Kinase dependency does not always correspond with gene expression and mutation status. High-throughput drug screens are powerful tools for determining kinase dependency, but drug polypharmacology can make results difficult to interpret. We developed Kinase Addiction Ranker (KAR), an algorithm that integrates high-throughput drug screening data, comprehensive kinase inhibition data and gene expression profiles to identify kinase dependency in cancer cells. We applied KAR to predict kinase dependency of 21 lung cancer cell lines and 151 leukemia patient samples using published datasets. We experimentally validated KAR predictions of FGFR and MTOR dependence in lung cancer cell line H1581, showing synergistic reduction in proliferation after combining ponatinib and AZD8055. KAR can be downloaded as a Python function or a MATLAB script along with example inputs and outputs at: http://tanlab.ucdenver.edu/KAR/. aikchoon.tan@ucdenver.edu. Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  13. Structural insights into drug development strategy targeting EGFR T790M/C797S.

    Science.gov (United States)

    Zhu, Su-Jie; Zhao, Peng; Yang, Jiao; Ma, Rui; Yan, Xiao-E; Yang, Sheng-Yong; Yang, Jing-Wen; Yun, Cai-Hong

    2018-03-02

    Treatment of non-small-cell lung cancers (NSCLCs) harboring primary EGFR oncogenic mutations such as L858R and exon 19 deletion delE746_A750 (Del-19) using gefitinib/erlotinib ultimately fails due to the emergence of T790M mutation. Though WZ4002/CO-1686/AZD9291 are effective in overcoming EGFR T790M by targeting Cys797 via covalent bonding, their efficacy is again limited due to the emergence of C797S mutation. New agents effectively inhibiting EGFR T790M without covalent linkage through Cys 797 may solve this problem. We presented here crystal structures of EGFR activating/drug-resistant mutants in complex with a panel of reversible inhibitors along with mutagenesis and enzyme kinetic data. These data revealed a previously un-described hydrophobic clamp structure in the EGFR kinase which may be exploited to facilitate development of next generation drugs targeting EGFR T790M with or without concomitant C797S. Interestingly, mutations in the hydrophobic clamp that hinder drug binding often also weaken ATP binding and/or abolish kinase activity, thus do not readily result in resistance to the drugs.

  14. Antitumor activity in RAS-driven tumors by blocking AKT and MEK.

    Science.gov (United States)

    Tolcher, Anthony W; Khan, Khurum; Ong, Michael; Banerji, Udai; Papadimitrakopoulou, Vassiliki; Gandara, David R; Patnaik, Amita; Baird, Richard D; Olmos, David; Garrett, Christopher R; Skolnik, Jeffrey M; Rubin, Eric H; Smith, Paul D; Huang, Pearl; Learoyd, Maria; Shannon, Keith A; Morosky, Anne; Tetteh, Ernestina; Jou, Ying-Ming; Papadopoulos, Kyriakos P; Moreno, Victor; Kaiser, Brianne; Yap, Timothy A; Yan, Li; de Bono, Johann S

    2015-02-15

    KRAS is the most commonly mutated oncogene in human tumors. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumors. Recommended dosing schedules were defined as MK-2206 at 135 mg weekly and selumetinib at 100 mg once daily. Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical antitumor activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Responses in KRAS-mutant cancers were generally durable. Clinical cotargeting of MEK and AKT signaling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). ©2014 American Association for Cancer Research.

  15. Anti-tumour activity in RAS-driven tumours by blocking AKT and MEK

    Science.gov (United States)

    Tolcher, Anthony W.; Khan, Khurum; Ong, Michael; Banerji, Udai; Papadimitrakopoulou, Vassiliki; Gandara, David R.; Patnaik, Amita; Baird, Richard D.; Olmos, David; Garrett, Christopher R.; Skolnik, Jeffrey M.; Rubin, Eric H.; Smith, Paul D.; Huang, Pearl; Learoyd, Maria; Shannon, Keith A.; Morosky, Anne; Tetteh, Ernestina; Jou, Ying-Ming; Papadopoulos, Kyriakos P.; Moreno, Victor; Kaiser, Brianne; Yap, Timothy A.; Yan, Li; de Bono, Johann S.

    2014-01-01

    Purpose KRAS is the most commonly mutated oncogene in human tumours. KRAS-mutant cells may exhibit resistance to the allosteric MEK1/2 inhibitor selumetinib (AZD6244; ARRY-142886) and allosteric AKT inhibitors (such as MK-2206), the combination of which may overcome resistance to both monotherapies. Experimental Design We conducted a dose/schedule-finding study evaluating MK-2206 and selumetinib in patients with advanced treatment-refractory solid tumours. Recommended dosing schedules were defined as MK-2206 135 mg weekly and selumetinib 100 mg once-daily. Results Grade 3 rash was the most common dose-limiting toxicity (DLT); other DLTs included grade 4 lipase increase, grade 3 stomatitis, diarrhoea, and fatigue, and grade 3 and grade 2 retinal pigment epithelium detachment. There were no meaningful pharmacokinetic drug-drug interactions. Clinical anti-tumour activity included RECIST 1.0-confirmed partial responses in non-small cell lung cancer and low-grade ovarian carcinoma. Conclusion Responses in KRAS-mutant cancers were generally durable. Clinical co-targeting of MEK and AKT signalling may be an important therapeutic strategy in KRAS-driven human malignancies (Trial NCT number NCT01021748). PMID:25516890

  16. Toll-like receptors as targets for allergen immunotherapy.

    Science.gov (United States)

    Aryan, Zahra; Rezaei, Nima

    2015-12-01

    Toll-like receptors (TLRs) are novel and promising targets for allergen immunotherapy. Bench studies suggest that TLR agonists reduce Th2 responses and ameliorate airway hyper-responsiveness. In addition, clinical trials are at initial phases to evaluate the safety and efficacy of TLR agonists for the allergen immunotherapy of patients with allergic rhinitis and asthma. (Figure is included in full-text article.) To date, two allergy vaccine-containing TLR agonists have been investigated in clinical trials; Pollinex Quattro and AIC. The former contains monophosphoryl lipid, a TLR4 agonist and the latter contains, CpG motifs activating the TLR9 cascade. Preseasonal subcutaneous injection of both of these allergy vaccines has been safe and efficacious in control of nasal symptoms of patients with allergic rhinitis. CRX-675 (a TLR4 agonist), AZD8848 (a TLR7 agonist), VTX-1463 (a TLR8 agonist) and 1018 ISS and QbG10 (TLR9 agonists) are currently in clinical development for allergic rhinitis and asthma. TLR agonists herald promising results for allergen immunotherapy of patients with allergic rhinitis and asthma. Future research should be directed at utilizing these agents for immunotherapy of food allergy (for instance, peanut allergy) as well.

  17. Linearly and circularly polarized laser photoinduced molecular order in azo dye doped polymer films

    Directory of Open Access Journals (Sweden)

    Saad Bendaoud

    2017-01-01

    Full Text Available Photo-induced behavior of Azo Disperse one (AZD1 doped Poly(Methyl MethAcrylate (PMMA using both linear and circular polarized light is studied. The anisotropy is not erased by the circular polarization light. The circular polarization light combined with relatively long lifetime of the cis state in azo dye doped polymers activate all transverse directions of the angular hole burning through the spot in the film inducing anisotropy. Under circular polarized light, there is no orientation perpendicularly to the helex described by the rotating electric field vector, trans molecules reorients in the propagation direction of the pump beam. The polarization state of the probe beam after propagation through the pumped spot depends strongly on the angle of incidence of both pump and probe beams on the input face. In the case where circular polarized pump and probe beams are under the same angle of incidence, the probe beam “sees” anisotropic film as if it is isotropic. Results of this work shows the possibility to reorient azobenzene-type molecules in two orthogonal directions using alternately linearly and circularly polarized beams.

  18. Relationship between Lower Tendency to Deceive in Aging and Inhibitory Compromise.

    Science.gov (United States)

    El Haj, Mohamad; Antoine, Pascal

    2018-01-01

    Deception can be associated with a heterogeneous network of concepts such as exaggeration, misleading, white lies, and faking. This paper assesses the tendency to deceive in aging. Our main aim was to assess whether older adults would demonstrate a low tendency to deceive. A total of 42 older adults (mean age 67.64 years, SD 7.87) and 45 younger adults (mean age 21.71 years, SD 2.66) were administered a deception scale including items such as "I sometimes tell lies if I have to" or "I never take things that don't belong to me." Participants were also administered an inhibition task. The results demonstrated a low tendency to deceive and low inhibition in older adults compared with younger ones. The low tendency to deceive in the older adults was significantly correlated with their diminished inhibitory ability. The low tendency to deceive in aging seems to be related to a difficulty in inhibiting an honest response. Since inhibitory compromise has been considered mainly to trigger negative consequences for cognition, the present paper illustrates how this age-related compromise can be associated with positive social outcomes, i.e., a low tendency to deceive. © 2017 S. Karger AG, Basel.

  19. Sandwich morphology and superior dye-removal performances for nanofiltration membranes self-assemblied via graphene oxide and carbon nanotubes

    Science.gov (United States)

    Kang, Hui; Shi, Jie; Liu, Liyan; Shan, Mingjing; Xu, Zhiwei; Li, Nan; Li, Jing; Lv, Hanming; Qian, Xiaoming; Zhao, Lihuan

    2018-01-01

    To tune interlayer spacing, regulate water channel and improve stability of composite membrane, graphene oxide (GO) and oxidized carbon nanotubes (OCNTs) were assembled alternately to form sandwich morphology on a polyacrylonitrile substrate by layer-by-layer self-assembly technique. Polyelectrolyte played a part in cross-linking between GO and OCNTs. The effects about concentration ratio of GO and OCNTs on nanofiltration performance were investigated in detail. The composite membrane was used for dye rejection. When composite membrane with concentration ratio of GO and OCNTs was 10:1, water flux and rejection rate for methyl blue reached 21.71 L/(m2 h) and 99.3%, respectively. Meanwhile, this composite membrane had higher flux compared with reported literatures in which rejection also reached up to 99%. When concentration ratio of composite membranes about GO and OCNTs were 10:1 and 15:1, dye rejection for methyl blue remained 99.3% and 99.6% respectively after operating time of 50 h. Irreversible fouling ratio of composite membrane in a concentration ratio of 10:1 was only 4.4%, indicating that composite membrane had excellent antifouling performance for Bovine Serum Albumin. It was speculated that proper distribution of OCNTs in the sandwich morphology formed proper support points and water channels which benefited for a more stable performance.

  20. Anther development stage and gamma radiation effects on tomato anther-derived callus formation; Efeitos do estadio de desenvolvimento da antera e da radiacao gama na formacao de calos derivados de anteras de tomate

    Energy Technology Data Exchange (ETDEWEB)

    Brasileiro, Ana Christina R.; Willadino, Lilia [Universidade Federal Rural de Pernambuco, Recife, PE (Brazil). Lab. de Cultura de Tecidos Vegetais. E-mail: lilia@truenet.com.br; Guerra, Marcelo [Pernambuco Univ., Recife, PE (Brazil). Dept. de Botanica. Lab. de Citogenetica Vegetal; Colaco, Waldeciro [Pernambuco Univ., Recife, PE (Brazil). Dept. de Energia Nuclear. Lab. de Radioagronomia; Meunier, Isabelle [Universidade Federal Rural de Pernambuco, Recife, PE (Brazil). Dept. de Engenharia Florestal; Camara, Terezinha R. [Universidade Federal Rural de Pernambuco, Recife, PE (Brazil). Dept. de Quimica. Lab. de Cultura de Tecidos Vegetais

    1999-12-01

    Two experiments were carried (I) to determine tomato anther development stage influence on callus production; and (II) to investigate gamma radiation effects on anther culture. In the first experiment, anthers of a tomato hybrid (IPA 5 x Rotam 4-F{sub 1}) were grown on three media. Although calli were induced at all stages of anther development, varying from prophase I to mono nucleate microspore, callus frequency decreased as anther development progressed and calli induction were not significantly affected by all media tested. Anthers containing prophase I meiocytes produced the highest calli frequency. Anther and flower bud length both were significantly correlated with anther development stage. In the second experiment, seed and floral buds of tomato hybrids IPA 5 x Rotam 4 (F{sub 2}), IPA 6 x Rotam 4 (F{sub 2}) and IPA 8 x 217.1 (F{sub 2}) were submitted to gamma-ray and anthers were plated on two media described by Gresshoff and Doy (1972) supplemented with 2.0 mg L{sup -1} NAA + 5.0 mg L{sup -1} KIN and 2.0 mg L{sup -1} NAA + 1.0 mg L{sup -1} KIN. No significant differences for genotype and dosage testes were found for calli formation. (author)

  1. [Effects of self-adapting G-DRG system 2004 to 2006 on in-patient services payment in pediatric hematology and oncology patients of a university hospital].

    Science.gov (United States)

    Christaras, A; Schaper, J; Strelow, H; Laws, H-J; Göbel, U

    2006-01-01

    Reimbursement of inpatient treatment by daily constant charges is replaced by diagnosis- and procedure-related group system (G-DRG) in German acute care hospitals excerpt for psychiatry since 2004. Re-designs of G-DRG system were undertaken in 2005 and 2006. Parallel to implementation requirement- and resource-based self-adjustment of this new reimbursement system has been established by law. Adjustments performed in 2005 and 2006 are examined with respect to their effect on reimbursements in treatments of children with oncological, hematological, and immunological diseases. An unchanged population of 349 patients associated with 1,731 inpatient stays of a Clinic of Pediatric Oncology, Hematology, and Immunology in 2004 was analyzed by methods and means of G-DRG systems 2004, 2005, and 2006. DRGs and additional payments for drugs and procedures eligible for all and/or individual hospitals were calculated. G-DRG system 2005 resulted in overall reimbursement loss of 3.77 % compared to G-DRG 2004. G-DRG 2006 leads to slightly improved overall reimbursements compared to G-DRG 2005 by increasing DRG-based revenues. G-DRG 2006 effects 2.40 % reduction in overall reimbursement compared to G-DRG 2004. This loss includes ameliorating effects of additional payments for drugs and blood products already. Despite introduction of additional payments especially designed for children and teenagers in 2006, additional payment volume is decreased by 21.71 % from 2005 to 2006. G-DRG 2006 yields over-all reimbursement losses of 1.45 % in comparison to G-DRG 2004. Overall reimbursements include introduced additional payments for drugs and blood products. (Reimbursements resulting out of DRG payment alone drop by 14.73 % from 2004 to 2005, and increase by 3.26 % from 2005 to 2006 (2004 vs. 2006 11.95 %). Introduction of additional payments for drugs and blood products on a Germany-wide basis introduced in 2005 dampens DRG-based reimbursement losses. Despite introduction of dosage

  2. Efeitos do estádio de desenvolvimento da antera e da radiação gama na formação de calos derivados de anteras de tomate Anther development stage and gamma radiation effects on tomato anther-derived callus formation

    Directory of Open Access Journals (Sweden)

    Ana Christina R. Brasileiro

    1999-10-01

    Full Text Available Este trabalho foi conduzido visando: (I determinar a influência do estádio de desenvolvimento de anteras de tomate sobre a formação de calos e (II analisar o efeito da radiação gama no cultivo in vitro de anteras. No primeiro experimento, anteras de híbridos de tomate IPA 5 x Rotam 4 (F1 foram cultivadas em três meios nutritivos. Apesar da formação de calos ter sido induzida em todos os estádios de desenvolvimento, variando de prófase I à micrósporo mononucleado, a freqüência de calos produzidos decresceu com o avanço do estádio de desenvolvimento e se apresentou de forma semelhante nos meios testados. Anteras contendo meiócitos em estádio de prófase I mostraram maior freqüência de formação de calos. Tanto o comprimento da antera quanto o do botão floral apresentaram correlação significativa com o estádio de desenvolvimento. No segundo experimento, sementes e botões florais dos híbridos IPA 5 x Rotam 4 (F2, IPA 6 x Rotam 4 (F2 e IPA 8 x 217.1 (F2 foram submetidos à radiação gama e suas anteras foram cultivadas em dois meios descritos por Gresshoff & Doy (1972, contendo 2,0 mg L-1 de ANA + 5,0 mg L-1 de cinetina e 2,0 mg L-1 de ANA + 1,0 mg L-1 de cinetina. Não foram constatadas diferenças significativas, no que se refere à formação de calos, para os genótipos e doses estudadas - 200 Gy, para sementes e 20 Gy, para botões florais.Two experiments were carried (I to determine tomato anther development stage influence on callus production; and (II to investigate gamma radiation effects on anther culture. In the first experiment, anthers of a tomato hybrid (IPA 5 x Rotam 4 - F1 were grown on three media. Although calli were induced at all stages of anther development, varying from prophase I to mononucleate microspore, callus frequency decreased as anther development progressed and calli induction were not significantly affected by all media tested. Anthers containing prophase I meiocytes produced the highest

  3. Strategies to mitigate dissociative and psychotomimetic effects of ketamine in the treatment of major depressive episodes: a narrative review.

    Science.gov (United States)

    Cooper, Matthew D; Rosenblat, Joshua D; Cha, Danielle S; Lee, Yena; Kakar, Ron; McIntyre, Roger S

    2017-09-01

    Objectives Replicated evidence has demonstrated that ketamine exerts rapid-acting and potent antidepressant effects. Notwithstanding, its promise to mitigate depressive symptoms and suicidality in antidepressant-resistant populations, several limitations and safety concerns accompany ketamine including, but not limited to, the potential for abuse and psychotomimetic/dissociative experiences. The focus of the current narrative review is to synthesise available evidence of strategies that may mitigate and fully prevent treatment-emergent psychotomimetic and dissociative effects associated with ketamine administration. Methods PubMed, Google Scholar and ClinicalTrials.gov were searched for relevant articles. Results Potential avenues investigated to minimise psychotomimetic effects associated with ketamine administration include the following: (1) altering dosing and infusion rates; (2) route of administration; (3) enantiomer choice; (4) co-administration with mood stabilisers of antipsychotics; and (5) use of alternative N-methyl-d-aspartate (NMDA)-modulating agents. Emerging evidence indicates that dissociative experiences can be significantly mitigated by using an intranasal route of administration, lower dosages, or use of alternative NMDA-modulating agents, namely lanicemine (AZD6765) and GLYX-13. Conclusions Currently, intranasal administration presents as the most promising strategy to mitigate dissociative and psychotomimetic effects; however, studies of strategies to mitigate the adverse events of ketamine are limited in number and quality and thus further investigation is still needed.

  4. Indomethacin promotes apoptosis in gastric cancer cells through concomitant degradation of Survivin and Aurora B kinase proteins.

    Science.gov (United States)

    Chiou, Shiun-Kwei; Hoa, Neil; Hodges, Amy; Ge, Lishen; Jadus, Martin R

    2014-09-01

    Regular usage of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced incidence of a variety of cancers. The molecular mechanisms underlying these chemopreventive effects remain poorly understood. This current investigation showed that in gastric cancer cells: (1) Indomethacin treatment enhanced the degradation of chromosomal passenger proteins, Survivin and Aurora B kinase; (2) Indomethacin treatment down-regulated Aurora B kinase activity in a cell cycle-independent fashion; (3) siRNA knockdown of Survivin level promoted Aurora B kinase protein degradation, and vice versa; (4) ectopic overexpression of Survivin blocked reduction of Aurora B kinase level and activity by indomethacin treatment, and vice versa; (5) siRNA knockdown of Aurora B kinase level and AZD1152 inhibition of its activity induced apoptosis, and overexpression of Aurora B kinase inhibited indomethacin-induced apoptosis; (6) indomethacin treatment reduced Aurora B kinase level, coinciding with reduction of Survivin level and induction of apoptosis, in KATO III and HT-29 cells, and in mouse gastric mucosa. A role for Aurora B kinase function in NSAID-induced apoptosis was not previously explored. Thus this report provides better understanding of the molecular mechanisms underlying the anti-cancer effect of NSAIDs by elucidating a significant role for Aurora B kinase in indomethacin-induced apoptosis.

  5. GTPase ROP2 binds and promotes activation of target of rapamycin, TOR, in response to auxin.

    Science.gov (United States)

    Schepetilnikov, Mikhail; Makarian, Joelle; Srour, Ola; Geldreich, Angèle; Yang, Zhenbiao; Chicher, Johana; Hammann, Philippe; Ryabova, Lyubov A

    2017-04-03

    Target of rapamycin (TOR) promotes reinitiation at upstream ORFs (uORFs) in genes that play important roles in stem cell regulation and organogenesis in plants. Here, we report that the small GTPase ROP2, if activated by the phytohormone auxin, promotes activation of TOR, and thus translation reinitiation of uORF-containing mRNAs. Plants with high levels of active ROP2, including those expressing constitutively active ROP2 (CA-ROP2), contain high levels of active TOR ROP2 physically interacts with and, when GTP-bound, activates TOR in vitro TOR activation in response to auxin is abolished in ROP-deficient rop2 rop6 ROP4 RNAi plants. GFP-TOR can associate with endosome-like structures in ROP2-overexpressing plants, indicating that endosomes mediate ROP2 effects on TOR activation. CA-ROP2 is efficient in loading uORF-containing mRNAs onto polysomes and stimulates translation in protoplasts, and both processes are sensitive to TOR inhibitor AZD-8055. TOR inactivation abolishes ROP2 regulation of translation reinitiation, but not its effects on cytoskeleton or intracellular trafficking. These findings imply a mode of translation control whereby, as an upstream effector of TOR, ROP2 coordinates TOR function in translation reinitiation pathways in response to auxin. © 2017 The Authors.

  6. Repurposing Lesogaberan to Promote Human Islet Cell Survival and β-Cell Replication

    Directory of Open Access Journals (Sweden)

    Jide Tian

    2017-01-01

    Full Text Available The activation of β-cell’s A- and B-type gamma-aminobutyric acid receptors (GABAA-Rs and GABAB-Rs can promote their survival and replication, and the activation of α-cell GABAA-Rs promotes their conversion into β-cells. However, GABA and the most clinically applicable GABA-R ligands may be suboptimal for the long-term treatment of diabetes due to their pharmacological properties or potential side-effects on the central nervous system (CNS. Lesogaberan (AZD3355 is a peripherally restricted high-affinity GABAB-R-specific agonist, originally developed for the treatment of gastroesophageal reflux disease (GERD that appears to be safe for human use. This study tested the hypothesis that lesogaberan could be repurposed to promote human islet cell survival and β-cell replication. Treatment with lesogaberan significantly enhanced replication of human islet cells in vitro, which was abrogated by a GABAB-R antagonist. Immunohistochemical analysis of human islets that were grafted into immune-deficient mice revealed that oral treatment with lesogaberan promoted human β-cell replication and islet cell survival in vivo as effectively as GABA (which activates both GABAA-Rs and GABAB-Rs, perhaps because of its more favorable pharmacokinetics. Lesogaberan may be a promising drug candidate for clinical studies of diabetes intervention and islet transplantation.

  7. Liquid chromatography-tandem mass spectrometric assay for the T790M mutant EGFR inhibitor osimertinib (AZD9291) in human plasma

    NARCIS (Netherlands)

    Rood, Johannes J M; van Bussel, Mark T J; Schellens, Jan H M; Beijnen, Jos H; Sparidans, Rolf W

    2016-01-01

    A method for the quantitative analysis by ultra-performance liquid chromatography-tandem mass spectrometry of the highly selective irreversible covalent inhibitor of EGFR-TK, osimertinib in human plasma was developed and validated, using pazopanib as an internal standard. The validation was

  8. Preclinical Activity of the Rational Combination of Selumetinib (AZD6244) in Combination with Vorinostat in KRAS-Mutant Colorectal Cancer Models

    Science.gov (United States)

    Morelli, M. Pia; Tentler, John J.; Kulikowski, Gillian N.; Tan, Aik-Choon; Bradshaw-Pierce, Erica L.; Pitts, Todd M.; Brown, Amy M.; Nallapareddy, Sujatha; Arcaroli, John J.; Serkova, Natalie J.; Hidalgo, Manuel; Ciardiello, Fortunato; Eckhardt, S. Gail

    2013-01-01

    Purpose Despite the availability of several active combination regimens for advanced colorectal cancer (CRC), the 5-year survival rate remains poor at less than 10%,supporting the development of novel therapeutic approaches. In this study, we focused on the preclinical assessment of a rationally based combination against KRAS-mutated CRC by testing the combination of the MEK inhibitor, selumetinib, and vorinostat, a histone deacetylase (HDAC) inhibitor. Experimental Design Transcriptional profiling and gene set enrichment analysis (baseline and post-treatment) of CRC cell lines provided the rationale for the combination. The activity of selumetinib and vorinostat against the KRAS-mutant SW620 and SW480 CRC cell lines was studied in vitro and in vivo. The effects of this combination on tumor phenotype were assessed using monolayer and 3-dimensional cultures, flow cytometry, apoptosis, and cell migration. In vivo, tumor growth inhibition, 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET), and proton nuclear magnetic resonance were carried out to evaluate the growth inhibitory and metabolic responses, respectively, in CRC xenografts. Results In vitro, treatment with selumetinib and vorinostat resulted in a synergistic inhibition of proliferation and spheroid formation in both CRC cell lines. This inhibition was associated with an increase in apoptosis, cell-cycle arrest in G1, and reduced cellular migration and VEGF-A secretion. In vivo, the combination resulted in additive tumor growth inhibition. The metabolic response to selumetinib and vorinostat consisted of significant inhibition of membrane phospholipids; no significant changes in glucose uptake or metabolism were observed in any of the treatment groups. Conclusion These data indicate that the rationally based combination of the mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor, selumetinib, with the HDAC inhibitor vorinostat results in synergistic antiproliferative activity against KRAS-mutant CRC cell lines in vitro. In vivo, the combination showed additive effects that were associated with metabolic changes in phospholipid turnover, but not on FDG-PET, indicating that the former is a more sensitive endpoint of the combination effects. PMID:22173548

  9. Development and evaluation of triclosan loaded poly-ε-caprolactone nanoparticulate system for the treatment of periodontal infections

    International Nuclear Information System (INIS)

    Aminu, Nafiu; Baboota, Sanjula; Pramod, K.; Singh, Manisha; Dang, Shweta; Ansari, Shahid H.; Sahni, Jasjeet K.; Ali, Javed

    2013-01-01

    Periodontal disease affects tooth-supporting structures and nanoparticles (NPs) have been a promising approach for its treatment. The purpose of the study was to develop triclosan-loaded poly-ε-caprolactone (PCL) NPs for the treatment of periodontal infections. Solvent displacement method was used to prepare NPs following Box–Behnken design. The NPs were evaluated with respect to particle size, polydispersity index, surface morphology, zeta potential, thermal properties, in vitro drug release, and cell viability assay. The optimized NPs were in the size range of 180–230 nm with a mean size of 205.61 ± 10.4 nm. Entrapment efficiency (EE) of 91.02 ± 2.4 % was obtained with a drug loading of 21.71 ± 1.3 %. About 97 % of drug was released in vitro after 3 h. NPs demonstrated almost 100 % cell viability in L929 cell lines. Shelf life of the nanoparticles was 17.07 months. PCL affected particle size whereas triclosan affected loading and EE. The optimized NPs were spherical with smooth surface and exhibited biphasic in vitro release pattern. NPs had optimum zeta potential and PDI and were stable on storage. Absence of cytotoxicity of NPs to L929 cells indicated its safety. Triclosan-loaded PCL nanoparticles could thus serve as a novel colloidal drug delivery system against periodontal infections

  10. ANALISIS KUALITAS PELAYANAN PAS BANDARA INTERNASIONAL NGURAH RAI DENGAN MENGGUNAKAN MODEL SERVQUAL

    Directory of Open Access Journals (Sweden)

    I Made Suska V

    2013-03-01

    Full Text Available Permit to a person to enter the restricted area at Ngurah Rai Airport which is called Airport Pas can be given in accordance with the duties and activities of a person at the airport. On permit service, there are disappointments and complaints of the Pas applicant that can still be found in the Pas service like duration of Pas completion and officer service at the time of application. The different perception and expectation of Pas applicant must remain in the regulation corridors and prioritize security at airports. The purpose of this research is assesing the quality of Pas service in the Airport Authority Region IV by using a SERVQUAL (Service Quality model. The model is comparing the two main factors, namely real customer perception of the service that they received (Perceived Service with the actual services expected/desirable (Expected Service which consists of 5 (five dimensions, those are Tangibles (physical, Reliability, Responsiveness, Assurance and Empathy (attention. By using these models, it is known that the quality of Pas service in the Airport Authority Region IV is still less than the expectations of the applicant and the most important dimension to enhance is Responsiveness. Gaps between perception and expectation as follows: Responsiveness (-0,2240, Assurance (-0,2171, Reliability (-0,2099, Tangibles (-0,1994, dan Empathy (-0,1373.

  11. Development and evaluation of triclosan loaded poly-ε-caprolactone nanoparticulate system for the treatment of periodontal infections

    Energy Technology Data Exchange (ETDEWEB)

    Aminu, Nafiu; Baboota, Sanjula; Pramod, K. [Jamia Hamdard, Department of Pharmaceutics, Faculty of Pharmacy (India); Singh, Manisha; Dang, Shweta [Jaypee Institute of Information Technology, Department of Biotechnology (India); Ansari, Shahid H. [Jamia Hamdard, Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy (India); Sahni, Jasjeet K.; Ali, Javed, E-mail: javedaali@yahoo.com [Jamia Hamdard, Department of Pharmaceutics, Faculty of Pharmacy (India)

    2013-11-15

    Periodontal disease affects tooth-supporting structures and nanoparticles (NPs) have been a promising approach for its treatment. The purpose of the study was to develop triclosan-loaded poly-ε-caprolactone (PCL) NPs for the treatment of periodontal infections. Solvent displacement method was used to prepare NPs following Box–Behnken design. The NPs were evaluated with respect to particle size, polydispersity index, surface morphology, zeta potential, thermal properties, in vitro drug release, and cell viability assay. The optimized NPs were in the size range of 180–230 nm with a mean size of 205.61 ± 10.4 nm. Entrapment efficiency (EE) of 91.02 ± 2.4 % was obtained with a drug loading of 21.71 ± 1.3 %. About 97 % of drug was released in vitro after 3 h. NPs demonstrated almost 100 % cell viability in L929 cell lines. Shelf life of the nanoparticles was 17.07 months. PCL affected particle size whereas triclosan affected loading and EE. The optimized NPs were spherical with smooth surface and exhibited biphasic in vitro release pattern. NPs had optimum zeta potential and PDI and were stable on storage. Absence of cytotoxicity of NPs to L929 cells indicated its safety. Triclosan-loaded PCL nanoparticles could thus serve as a novel colloidal drug delivery system against periodontal infections.

  12. Photometric Modeling of a Cometary Nucleus: Taking Hapke Modeling to the Limit

    Science.gov (United States)

    Buratti, B. J.; Hicks, M. D.; Soderblom, L.; Hillier, J.; Britt, D.

    2002-01-01

    In the past two decades, photometric models developed by Bruce Hapke have been fit to a wide range of bodies in the Solar System: The Moon, Mercury, several asteroids, and many icy and rocky satellites. These models have enabled comparative descriptions of the physical attributes of planetary surfaces, including macroscopic roughness, particle size and size-distribution, the single scattering albedo, and the compaction state of the optically active portion of the regolith. One challenging type of body to observe and model, a cometary nucleus, awaited the first space based mission to obtain images unobscured by coma. The NASA-JPL Deep Space 1 Mission (DS1) encountered the short-period Jupiter-family comet 19/P Borrelly on September 22, 2001, about 8 days after perihelion. Prior to its closest approach of 2171 km, the remote-sensing package on the spacecraft obtained 25 CCD images of the comet, representing the first closeup, unobscured view of a comet's nucleus. At closest approach, corresponding to a resolution of 47 meters per pixel, the intensity of the coma was less than 1% of that of the nucleus. An unprecedented range of high solar phase angles (52-89 degrees), viewing geometries that are in general attainable only when a comet is active, enabled the first quantitative and disk-resolved modeling of surface photometric physical parameters.

  13. Assessment of the impact of anthropic activities on carbon storage in soils of high montane ecosystems in Colombia

    Directory of Open Access Journals (Sweden)

    Orlando Zúñiga-Escobar

    2013-04-01

    Full Text Available The organic carbon in the soil was quantified to assess the impact of anthropic activities on montane ecosystems in Colombia in Chingaza Parque Nacional Natural (PNN and Los Nevados Parque Nacional Natural (PNN . For the development of the soil samples, a detailed in situ description of the edaphological profile of four ecosystems of paramo and high Andean forest areas, of both disturbed and undisturbed zones, was taken as the base. The calculation of the amount of total carbon stored by the soil profile shows that, in Colombia, undisturbed high montane ecosystems (520.9 t ha-1 in paramos and 323.6 t ha-1 in high Andean forests of Chingaza PNN , and 373.0 t ha-1 in paramos and 254.6 t ha-1 in high Andean forests of Los Nevados PNN currently have more carbon than disturbed ecosystems (135.1 t ha-1 in paramos and 141.5 t ha-1 in high Andean forests of Chingaza PNN , and 356.3 t ha-1 in paramos and 217.1 t ha-1 in high Andean forests of Los Nevados PNN . It is clear that the disturbance of high montane ecosystems decreases the amount of carbon in the soil, a situation that is more concerning in Chingaza PNN where the difference between the disturbed and undisturbed ecosystems is much more marked than in Los Nevados PNN

  14. Contrast-enhanced CT in determining resectability in patients with pancreatic carcinoma: a meta-analysis of the positive predictive values of CT

    Energy Technology Data Exchange (ETDEWEB)

    Somers, Inne; Bipat, Shandra [University of Amsterdam, Department of Radiology, Academic Medical Centre, Amsterdam (Netherlands)

    2017-08-15

    To obtain a summary positive predictive value (sPPV) of contrast-enhanced CT in determining resectability. The MEDLINE and EMBASE databases from JAN2005 to DEC2015 were searched and checked for inclusion criteria. Data on study design, patient characteristics, imaging techniques, image evaluation, reference standard, time interval between CT and reference standard, and data on resectability/unresectablity were extracted by two reviewers. We used a fixed-effects or random-effects approach to obtain sPPV for resectability. Several subgroups were defined: 1) bolus-triggering versus fixed-timing; 2) pancreatic and portal phases versus portal phase alone; 3) all criteria (liver metastases/lymphnode involvement/local advanced/vascular invasion) versus only vascular invasion as criteria for unresectability. Twenty-nine articles were included (2171 patients). Most studies were performed in multicentre settings, initiated by the department of radiology and retrospectively performed. The I{sup 2}-value was 68%, indicating heterogeneity of data. The sPPV was 81% (95%CI: 75-86%). False positives were mostly liver, peritoneal, or lymphnode metastases. Bolus-triggering had a slightly higher sPPV compared to fixed-timing, 87% (95%CI: 81-91%) versus 78% (95%CI: 66-86%) (p = 0.077). No differences were observed in other subgroups. This meta-analysis showed a sPPV of 81% for predicting resectability by CT, meaning that 19% of patients falsely undergo surgical exploration. (orig.)

  15. Identification and isolation of stimulator of interferon genes (STING): an innate immune sensory and adaptor gene from camelids.

    Science.gov (United States)

    Premraj, A; Aleyas, A G; Nautiyal, B; Rasool, T J

    2013-10-01

    The mechanism by which type I interferon-mediated antiviral response is mounted by hosts against invading pathogen is an intriguing one. Of late, an endoplasmic reticulum transmembrane protein encoded by a gene called stimulator of interferon genes (STING) is implicated in the innate signalling pathways and has been identified and cloned in few mammalian species including human, mouse and pig. In this article, we report the identification of STING from three different species of a highly conserved family of mammals - the camelids. cDNAs encoding the STING of Old World camels - dromedary camel (Camelus dromedarius) and bactrian camel (Camelus bactrianus) and a New World camel - llama (Llama glama) were amplified using conserved primers and RACE. The complete STING cDNA of dromedary camel is 2171 bp long with a 706-bp 5' untranslated regions (UTR), an 1137-bp open reading frame (ORF) and a 328-bp 3' UTR. Sequence and phylogenetic analysis of the ORF of STING from these three camelids indicate high level of similarity among camelids and conservation of critical amino acid residues across different species. Quantitative real-time PCR analysis revealed high levels of STING mRNA expression in blood, spleen, lymph node and lung. The identification of camelid STING will help in better understanding of the role of this molecule in the innate immunity of the camelids and other mammals. © 2013 John Wiley & Sons Ltd.

  16. Epidemiologic study of Organophosphate and Organochlorate pesticides poisoning in hospitalized patients in khorramabad Shohada Ashayer hospital from Mars to August 2006

    Directory of Open Access Journals (Sweden)

    ghafar ali Mahmoudi

    2008-04-01

    Full Text Available Abstract Background: poisoning is one of the most common medical emergencies. Every year many people refer to emergency wards due to poisoning and some of them are treated and some die because of severe complications. Most patients who refer to emergency wards are those who commit intentionally to suicide. This study is conducted to determine the prevalence of poisoning with pesticide (organophosphate and organochlorine in persons referred to Shohada Ashaier hospital of Khorramabad in the first six months in 2006. Metrials and methods: Required information of poisoned people with poisoning pesticide (organophosphate and organochlorine were collected using questionnaires which were distributed among the subjects. Results: In this study 153 patients including 118 patients who poisoned with organophophate and 35 patents with organochlorine were studied. Most of the patients (34.6% aged between 21-71 years including 57.5% female and 42.5% male and their education was about under secondary school, 91.5% of them attempted to suicided. The total mortality rate was 12 that 7 of them died by toxifications with organochlorine and 5 cases by organophosphate, which in turn was due to their respiratory complications like ARDS and aspiration pneumonia. Conclusion: findings indicate that due to high prevalence and mortality of poisoning with pesticides, this problem should be taken into consideration.

  17. Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

    Energy Technology Data Exchange (ETDEWEB)

    Jorge, S.E.D.C.; Kobayashi, S.S.; Costa, D.B. [Harvard Medical School, Beth Israel Deaconess Medical Center, Department of Medicine, Division of Hematology/Oncology, Boston, MA (United States)

    2014-09-05

    Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC.

  18. Bazı Ekmeklik Buğday Çeşitlerinin Kalitesi

    Directory of Open Access Journals (Sweden)

    Recai Ercan

    2015-02-01

    Full Text Available Bu çalışmada, ülkemizde yetiştirilen başlıca buğday çeşitlerinin fiziko-kimyasal, öğütme ve ekmekçilik özellikleri saptanmıştır. Araştırmada aynı çevrelerde 1987 ve 1988 yıllarında yetiştirilen 15 buğday çeşidi kullanılmış ve çeşitlerin kalitelerini belirlemek amacıyla fiziksel, kimyasal, reolojik testler ile ekmek yapma denemeleri yapılmıştır. Buğdayların ekmekçilik özeliği çeşit özelliklerine çok fazla bağlı bulunmaktadır. Buğday çeşidi hektolitre ağırlığı, camsılık ve farinogram özellikleri üzerinde önemli etkiye sahiptir. Fakat protein miktarı, un verimi üzerine etkisi azdır. Tüm teknolojik özellikler ele alındığında Bolal-2973, Odeskaya-51, Hawk (Şahin, Sadova-1 ve Katea-1 buğday çeşitlerinin diğerlerinden üstün olduğu anlaşılmıştır.

  19. Live-cell microscopy reveals small molecule inhibitor effects on MAPK pathway dynamics.

    Directory of Open Access Journals (Sweden)

    Daniel J Anderson

    Full Text Available Oncogenic mutations in the mitogen activated protein kinase (MAPK pathway are prevalent in human tumors, making this pathway a target of drug development efforts. Recently, ATP-competitive Raf inhibitors were shown to cause MAPK pathway activation via Raf kinase priming in wild-type BRaf cells and tumors, highlighting the need for a thorough understanding of signaling in the context of small molecule kinase inhibitors. Here, we present critical improvements in cell-line engineering and image analysis coupled with automated image acquisition that allow for the simultaneous identification of cellular localization of multiple MAPK pathway components (KRas, CRaf, Mek1 and Erk2. We use these assays in a systematic study of the effect of small molecule inhibitors across the MAPK cascade either as single agents or in combination. Both Raf inhibitor priming as well as the release from negative feedback induced by Mek and Erk inhibitors cause translocation of CRaf to the plasma membrane via mechanisms that are additive in pathway activation. Analysis of Erk activation and sub-cellular localization upon inhibitor treatments reveals differential inhibition and activation with the Raf inhibitors AZD628 and GDC0879 respectively. Since both single agent and combination studies of Raf and Mek inhibitors are currently in the clinic, our assays provide valuable insight into their effects on MAPK signaling in live cells.

  20. Epidermal growth factor receptor (EGFR) mutations in lung cancer: preclinical and clinical data

    International Nuclear Information System (INIS)

    Jorge, S.E.D.C.; Kobayashi, S.S.; Costa, D.B.

    2014-01-01

    Lung cancer leads cancer-related mortality worldwide. Non-small-cell lung cancer (NSCLC), the most prevalent subtype of this recalcitrant cancer, is usually diagnosed at advanced stages, and available systemic therapies are mostly palliative. The probing of the NSCLC kinome has identified numerous nonoverlapping driver genomic events, including epidermal growth factor receptor (EGFR) gene mutations. This review provides a synopsis of preclinical and clinical data on EGFR mutated NSCLC and EGFR tyrosine kinase inhibitors (TKIs). Classic somatic EGFR kinase domain mutations (such as L858R and exon 19 deletions) make tumors addicted to their signaling cascades and generate a therapeutic window for the use of ATP-mimetic EGFR TKIs. The latter inhibit these kinases and their downstream effectors, and induce apoptosis in preclinical models. The aforementioned EGFR mutations are stout predictors of response and augmentation of progression-free survival when gefitinib, erlotinib, and afatinib are used for patients with advanced NSCLC. The benefits associated with these EGFR TKIs are limited by the mechanisms of tumor resistance, such as the gatekeeper EGFR-T790M mutation, and bypass activation of signaling cascades. Ongoing preclinical efforts for treating resistance have started to translate into patient care (including clinical trials of the covalent EGFR-T790M TKIs AZD9291 and CO-1686) and hold promise to further boost the median survival of patients with EGFR mutated NSCLC

  1. SETD2 and histone H3 lysine 36 methylation deficiency in advanced systemic mastocytosis.

    Science.gov (United States)

    Martinelli, G; Mancini, M; De Benedittis, C; Rondoni, M; Papayannidis, C; Manfrini, M; Meggendorfer, M; Calogero, R; Guadagnuolo, V; Fontana, M C; Bavaro, L; Padella, A; Zago, E; Pagano, L; Zanotti, R; Scaffidi, L; Specchia, G; Albano, F; Merante, S; Elena, C; Savini, P; Gangemi, D; Tosi, P; Ciceri, F; Poletti, G; Riccioni, L; Morigi, F; Delledonne, M; Haferlach, T; Cavo, M; Valent, P; Soverini, S

    2018-01-01

    The molecular basis of advanced systemic mastocytosis (SM) is not fully understood and despite novel therapies the prognosis remains dismal. Exome sequencing of an index-patient with mast cell leukemia (MCL) uncovered biallelic loss-of-function mutations in the SETD2 histone methyltransferase gene. Copy-neutral loss-of-heterozygosity at 3p21.3 (where SETD2 maps) was subsequently found in SM patients and prompted us to undertake an in-depth analysis of SETD2 copy number, mutation status, transcript expression and methylation levels, as well as functional studies in the HMC-1 cell line and in a validation cohort of 57 additional cases with SM, including MCL, aggressive SM and indolent SM. Reduced or no SETD2 protein expression-and consequently, H3K36 trimethylation-was found in all cases and inversely correlated with disease aggressiveness. Proteasome inhibition rescued SETD2 expression and H3K36 trimethylation and resulted in marked accumulation of ubiquitinated SETD2 in SETD2-deficient patients but not in patients with near-normal SETD2 expression. Bortezomib and, to a lesser extent, AZD1775 alone or in combination with midostaurin induced apoptosis and reduced clonogenic growth of HMC-1 cells and of neoplastic mast cells from advanced SM patients. Our findings may have implications for prognostication of SM patients and for the development of improved treatment approaches in advanced SM.

  2. Combined use of high-definition and volumetric optical coherence tomography for the segmentation of neural canal opening in cases of optic nerve edema

    Science.gov (United States)

    Wang, Jui-Kai; Kardon, Randy H.; Garvin, Mona K.

    2015-03-01

    In cases of optic-nerve-head edema, the presence of the swelling reduces the visibility of the underlying neural canal opening (NCO) within spectral-domain optical coherence tomography (SD-OCT) volumes. Consequently, traditional SD-OCT-based NCO segmentation methods often overestimate the size of the NCO. The visibility of the NCO can be improved using high-definition 2D raster scans, but such scans do not provide 3D contextual image information. In this work, we present a semi-automated approach for the segmentation of the NCO in cases of optic disc edema by combining image information from volumetric and high-definition raster SD-OCT image sequences. In particular, for each subject, five high-definition OCT B-scans and the OCT volume are first separately segmented, and then the five high-definition B-scans are automatically registered to the OCT volume. Next, six NCO points are placed (manually, in this work) in the central three high-definition OCT B-scans (two points for each central B-scans) and are automatically transferred into the OCT volume. Utilizing a combination of these mapped points and the 3D image information from the volumetric scans, a graph-based approach is used to identify the complete NCO on the OCT en-face image. The segmented NCO points using the new approach were significantly closer to expert-marked points than the segmented NCO points using a traditional approach (root mean square differences in pixels: 5.34 vs. 21.71, p < 0.001).

  3. [Quality of professional life and musculoskeletal disorders in nurses].

    Science.gov (United States)

    Rodarte-Cuevas, Lilia; Araujo-Espino, Roxana; Trejo-Ortiz, Perla María; González-Tovar, José

    To characterize the conditions of quality of working life, the presence of muscle- skeletal disorders and the association between these variables in nursing staff of a public hospital in Zacatecas, Mexico. A cross-sectional study with descriptive-correlational scope was designed. A stratified random sampling per shift was used in 107 cases. The Questionnaire Professional Quality of Life (CVP-35) was applied as well as the Nordic Questionnaire Standardized for musculoskeletal pain and work-related risk factors questionnaire. The quality of working life gained an average of 55.62 (SD=13.57), the intrinsic motivation was the best rated component with (M=75.06, SD=18.44), contrary to managerial support that got the lowest scores with (M=43.74, SD=21.71). The presence of risk factors in the development work of musculoskeletal problems obtained a mean of 50.10 (SD=26.69). The main musculoskeletal disorders occurred in the neck region, lumbar spine and knees with 42.1% for each one. The quality of working life decreased in the presence of muscle-skeletal problems in the lumbar region with (-0.188, p≤.050), dorsal (-0.206, p≤.050), neck (-0.175, p≤.050) and knees (-0.220, p≤.010). It is necessary to improve the working conditions of nurses to reduce the presence of musculoskeletal problems and improve their quality of working life. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  4. The economic burden of dry eye disease in the United States: a decision tree analysis.

    Science.gov (United States)

    Yu, Junhua; Asche, Carl V; Fairchild, Carol J

    2011-04-01

    The aim of this study was to estimate both the direct and indirect annual cost of managing dry eye disease (DED) in the United States from a societal and a payer's perspective. A decision analytic model was developed to estimate the annual cost for managing a cohort of patients with dry eye with differing severity of symptoms and treatment. The direct costs included ocular lubricants, cyclosporine, punctal plugs, physician visits, and nutritional supplements. The indirect costs were measured as the productivity loss because of absenteeism and presenteeism. The model was populated with data that were obtained from surveys that were completed by dry eye sufferers who were recruited from online databases. Sensitivity analyses were employed to evaluate the impact of changes in parameters on the estimation of costs. All costs were converted to 2008 US dollars. Survey data were collected from 2171 respondents with DED. Our analysis indicated that the average annual cost of managing a patient with dry eye at $783 (variation, $757-$809) from the payers' perspective. When adjusted to the prevalence of DED nationwide, the overall burden of DED for the US healthcare system would be $3.84 billion. From a societal perspective, the average cost of managing DED was estimated to be $11,302 per patient and $55.4 billion to the US society overall. DED poses a substantial economic burden on the payer and on the society. These findings may provide valuable information for health plans or employers regarding budget estimation.

  5. Effect of Dunaliella tertiolecta organic exudates on the Fe(II) oxidation kinetics in seawater.

    Science.gov (United States)

    González, A G; Santana-Casiano, J M; González-Dávila, M; Pérez-Almeida, N; Suárez de Tangil, M

    2014-07-15

    The role played by the natural organic ligands excreted by the green algae Dunaliella tertiolecta on the Fe(II) oxidation rate constants was studied at different stages of growth. The concentration of dissolved organic carbon increased from 2.1 to 7.1 mg L(-1) over time of culture. The oxidation kinetics of Fe(II) was studied at nanomolar levels and under different physicochemical conditions of pH (7.2-8.2), temperature (5-35 °C), salinity (10-37), and dissolved organic carbon produced by cells (2.1-7.1 mg L(-1)). The experimental rate always decreased in the presence of organic exudates with respect to that in the control seawater. The Fe(II) oxidation rate constant was also studied in the context of Marcus theory, where ΔG° was 39.31-51.48 kJ mol(-1). A kinetic modeling approach was applied for computing the equilibrium and rate constants for Fe(II) and exudates present in solution, the Fe(II) speciation, and the contribution of each Fe(II) species to the overall oxidation rate constant. The best fit model took into account two acidity equilibrium constants for the Fe(II) complexing ligands with pKa,1=9.45 and pKa,2=4.9. The Fe(II) complexing constants were KFe(II)-LH=3×10(10) and KFe(II)-L=10(7), and the corresponding computed oxidation rates were 68±2 and 36±8 M(-1) min(-1), respectively.

  6. Decontamination of Hg(II) from aqueous solution using polyamine-co-thiourea inarched chitosan gel derivatives.

    Science.gov (United States)

    Liang, Wen; Li, Manlin; Zhang, Zengqiang; Jiang, Yahui; Awasthi, Mukesh Kumar; Jiang, Shuncheng; Li, Ronghua

    2018-07-01

    Ethylenediamine (EDA), triethylenetetramine (TETA) and tetraethylenepentamine (TEPA) had been successfully introduced into the structure of thiourea (TC) modified chitosan (CS) by using formaldehyde as linkage, respectively. The resulted materials, TC-CS, TC-EDA-CS, TC-TETA-CS, and TC-TEPA-CS were characterized and employed as adsorbents in batch experiment for the Hg(II) removal. We have found the modification enhanced the Hg(II) adsorption significantly in comparison with raw CS. Hg(II) adsorption amounts for all adsorbents increased gradually and reached maxima at pH≥4.0. The adsorption of Hg(II) achieved an equilibrium state within 12h with the process drove by the pseudo-second-order model. The ionic strength had no remarkable inhibition effect on Hg(II) adsorption. While the Hg(II) adsorption capacities of the adsorbents were strongly related with the modifier types and the length of the incorporating amino ligands. Langmuir model described Hg(II) adsorption well with the maximum adsorption capacities of prepared adsorbents in order of TC-EDA-CS (217.1mg/g)>TC-CS (164.8mg/g)>TC-TETA-CS (149.7mg/g)>TC-TEPA-CS (140.6mg/g) at room temperature. The FT-IR and XPS investigations implied that Hg(II) ion adsorption mechanism was characterized by a complexation reaction process. Adsorbents could be readily regenerated and had great reusability potential in Hg(II) ions capture from aqueous solution. Copyright © 2018 Elsevier B.V. All rights reserved.

  7. Gravity Modes Reveal the Internal Rotation of a Post-mass-transfer Gamma Doradus/Delta Scuti Hybrid Pulsator in Kepler Eclipsing Binary KIC 9592855

    Science.gov (United States)

    Guo, Z.; Gies, D. R.; Matson, R. A.

    2017-12-01

    We report the discovery of a post-mass-transfer Gamma Doradus/Delta Scuti hybrid pulsator in the eclipsing binary KIC 9592855. This binary has a circular orbit, an orbital period of 1.2 days, and contains two stars of almost identical masses ({M}1=1.72 {M}⊙ ,{M}2=1.71 {M}⊙ ). However, the cooler secondary star is more evolved ({R}2=1.96 {R}⊙ ), while the hotter primary is still on the zero-age-main-sequence ({R}1=1.53 {R}⊙ ). Coeval models from single-star evolution cannot explain the observed masses and radii, and binary evolution with mass-transfer needs to be invoked. After subtracting the binary light curve, the Fourier spectrum shows low-order pressure-mode pulsations, and more dominantly, a cluster of low-frequency gravity modes at about 2 day-1. These g-modes are nearly equally spaced in period, and the period spacing pattern has a negative slope. We identify these g-modes as prograde dipole modes and find that they stem from the secondary star. The frequency range of unstable p-modes also agrees with that of the secondary. We derive the internal rotation rate of the convective core and the asymptotic period spacing from the observed g-modes. The resulting values suggest that the core and envelope rotate nearly uniformly, i.e., their rotation rates are both similar to the orbital frequency of this synchronized binary.

  8. Multiaxial pedicle screw designs: static and dynamic mechanical testing.

    Science.gov (United States)

    Stanford, Ralph Edward; Loefler, Andreas Herman; Stanford, Philip Mark; Walsh, William R

    2004-02-15

    Randomized investigation of multiaxial pedicle screw mechanical properties. Measure static yield and ultimate strengths, yield stiffness, and fatigue resistance according to an established model. Compare these measured properties with expected loads in vivo. Multiaxial pedicle screws provide surgical versatility, but the complexity of their design may reduce their strength and fatigue resistance. There is no published data on the mechanical properties of such screws. Screws were assembled according to a vertebrectomy model for destructive mechanical testing. Groups of five assemblies were tested in static tension and compression and subject to three cyclical loads. Modes of failure, yield, and ultimate strength, yield stiffness, and cycles to failure were determined for six designs of screw. Static compression yield loads ranged from 217.1 to 388.0 N and yield stiffness from 23.7 to 38.0 N/mm. Cycles to failure ranged from 42 x 10(3) to 4,719 x 10(3) at 75% of static ultimate load. There were significant differences between designs in all modes of testing. Failure occurred at the multiaxial link in static and cyclical compression. Bending yield strengths just exceeded loads expected in vivo. Multiaxial designs had lower static bending yield strength than fixed screw designs. Five out of six multiaxial screw designs achieved one million cycles at 200 N in compression bending. "Ball-in-cup" multiaxial locking mechanisms were vulnerable to fatigue failure. Smooth surfaces and thicker material appeared to be protective against fatigue failure.

  9. Prácticas sexuales de chicos y chicas españoles de 14-24 años de edad Sexual behavior in a Spanish sample aged 14 to 24 years old

    Directory of Open Access Journals (Sweden)

    José María Faílde Garrido

    2008-12-01

    Full Text Available Objetivo: Describir los comportamientos y prácticas sexuales de adolescentes y jóvenes españoles en función del género. Método: La información fue recogida mediante un cuestionario, realizado en el domicilio de los participantes y con presencia del entrevistador, aplicado a una muestra aleatoria integrada por 2.171 chicos y chicas de 14-24 años de edad, representativa de las comunidades de Galicia, Madrid y Andalucía. Resultados: Un total de 1.439 sujetos (66,3% refirieron haber tenido actividad sexual en los últimos 6 meses, sin apreciarse diferencias estadísticamente significativas entre chicos (66,4% y chicas (66,2%, excepto en las siguientes variables: haber practicado el coito anal (los chicos refieren haberlo practicado en mayor proporción; número de parejas sexuales (las chicas manifestaron tener menor número de parejas, y frecuencia de coitos vaginales (las chicas presentaron una frecuencia más elevada en esta práctica. También se encontraron diferencias en frecuencia de uso del condón en las prácticas coito-anales y en las bucogenitales, en las que los chicos refirieron utilizarlo más frecuentemente. Conclusiones: Los datos de este estudio indican que los chicos y las chicas mantienen comportamientos sexuales diferenciados. En este sentido, las chicas suelen tener menor número de parejas sexuales y utilizan el preservativo en mayor medida que los chicos en las prácticas coito-vaginales; sin embargo, hacen menor uso de éste en las prácticas bucogenitales y coito-anales. En función de estos datos consideramos necesario tener en cuenta la variable género a la hora de diseñar e implementar intervenciones preventivas.Objectives: To describe the sexual behaviors and practices of Spanish adolescents and young adults according to gender. Method: Information was gathered by means of a questionnaire administered in participants' homes in the presence of an interviewer. A random sample was used, consisting of 2,171

  10. Sodium Ferulate Prevents Daunorubicin - Induced Apoptosis in H9c2 Cells via Inhibition of the ERKs Pathway

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    Zhi-Juan Wu

    2015-07-01

    Full Text Available Background: Daunorubicin (DNR-induced cardiotoxicity, which is closely associated with cardiomyocyte apoptosis, limits the drug's clinical application. The activation of the extracellular regulated protein kinases (ERKs pathway is responsible for the pro-apoptosis effect of DNR Sodium ferulate (SF has recently been found to attenuate both DNR-induced cardiotoxicity and mitochondrial apoptosis in juvenile rats. Nonetheless, the precise mechanism underlying SF-induced cardio-protection remains unclear. Methods: The DNR-injured H9c2 cell model was prepared by incubating the cells in 1 µM DNR for 24 h. Amounts of 15.6, 31.3 or 62.5 µM SF were simultaneously added to the cells. The effect of SF on the cytotoxic and apoptotic parameters of the cells was studied by monitoring apoptosis regulation via the ERKs pathway. Results: SF attenuated DNR-induced cell death (particularly apoptotic death, cTnI and β-tubulin degradation, and cellular morphological changes. SF reduced mitochondrial membrane potential depolarization, cytochrome c leakage, and caspase-9 and caspase-3 activation. SF also decreased ERK1/2, phospho-ERK1/2, p53 and Bax expression and increased Bcl-2 expression. These effects were similar to the results observed when using the pharmacological ERKs phosphorylation inhibitor, AZD6244. Conclusion: We determined that SF protects H9c2 cells from DNR-induced apoptosis through a mechanism that involves the interruption of the ERKs signaling pathway.

  11. Tomato FK506 Binding Protein 12KD (FKBP12 mediates the interaction between rapamycin and Target of Rapamycin (TOR

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    Fangjie Xiong

    2016-11-01

    Full Text Available Target of Rapamycin (TOR signaling is an important regulator in multiple organisms including yeast, plants and animals. However, the TOR signaling in plants is much less understood as compared to that in yeast and animals. TOR kinase can be efficiently suppressed by rapamycin in the presence of functional FK506 Binding Protein 12KD (FKBP12 in yeast and animals. In most examined higher plants rapamycin fails to inhibit TOR kinase due to the non-functional FKBP12. Here we find that tomato plants showed obvious growth inhibition when treated with rapamycin and the inhibitory phenotype is similar to suppression of TOR causing by active-site TOR inhibitors (asTORis such as KU63794, AZD8055 and Torin1. The chemical genetic assays using TOR inhibitors and heterologous expressing SlFKBP12 in Arabidopsis indicated that the TOR signaling is functional in tomato. The protein gel shifting and TOR inhibitors combination assays showed that SlFKBP12 can mediate the interaction between rapamycin and TOR. Furthermore, comparative expression profiling analysis between treatments with rapamycin and KU63794 identified highly overlapped Differentially Expressed Genes (DEGs which are involved in many anabolic and catabolic processes, such as photosynthesis, cell wall restructuring, and senescence in tomato. These observations suggest that SlFFBP12 is functional in tomato. The results provided basic information of TOR signaling in tomato, and also some new insights into how TOR controls plant growth and development through reprogramming the transcription profiles

  12. A new era of targeting the ancient gatekeepers of the immune system: toll-like agonists in the treatment of allergic rhinitis and asthma.

    Science.gov (United States)

    Aryan, Zahra; Holgate, Stephen T; Radzioch, Danuta; Rezaei, Nima

    2014-01-01

    Toll-like receptors (TLR) belong to a large family of pattern recognition receptors known as the ancient 'gatekeepers' of the immune system. TLRs are located at the first line of defense against invading pathogens as well as aeroallergens, making them interesting targets to modulate the natural history of respiratory allergy. Agonists of TLRs have been widely employed in therapeutic or prophylactic preparations useful for asthma/allergic rhinitis (AR) patients. MPL® (a TLR4 agonist) and the CpG oligodeoxynucleotide of 1018 ISS, a TLR9 agonist, show strong immunogenicity effects that make them appropriate adjuvants for allergy vaccines. Targeting the TLRs can enhance the efficacy of specific allergen immunotherapy, currently the only available 'curative' treatment for respiratory allergies. In addition, intranasal administration of AZD8848 (a TLR7 agonist) and VTX-1463 (a TLR8 agonist) as stand-alone therapeutics have revealed efficacy in the relief of the symptoms of AR patients. No anaphylaxis has been so far reported with such compounds targeting TLRs, with the most common adverse effects being transient and local irritation (e.g. redness, swelling and pruritus). Many other compounds that target TLRs have been found to suppress airway inflammation, eosinophilia and airway hyper-responsiveness in various animal models of allergic inflammation. Indeed, in the future a wide variability of TLR agonists and even antagonists that exhibit anti-asthma/AR effects are likely to emerge. © 2014 S. Karger AG, Basel.

  13. Tomato FK506 Binding Protein 12KD (FKBP12) Mediates the Interaction between Rapamycin and Target of Rapamycin (TOR).

    Science.gov (United States)

    Xiong, Fangjie; Dong, Pan; Liu, Mei; Xie, Gengxin; Wang, Kai; Zhuo, Fengping; Feng, Li; Yang, Lu; Li, Zhengguo; Ren, Maozhi

    2016-01-01

    Target of Rapamycin (TOR) signaling is an important regulator in multiple organisms including yeast, plants, and animals. However, the TOR signaling in plants is much less understood as compared to that in yeast and animals. TOR kinase can be efficiently suppressed by rapamycin in the presence of functional FK506 Binding Protein 12 KD (FKBP12) in yeast and animals. In most examined higher plants rapamycin fails to inhibit TOR kinase due to the non-functional FKBP12. Here we find that tomato plants showed obvious growth inhibition when treated with rapamycin and the inhibitory phenotype is similar to suppression of TOR causing by active-site TOR inhibitors (asTORis) such as KU63794, AZD8055, and Torin1. The chemical genetic assays using TOR inhibitors and heterologous expressing SlFKBP12 in Arabidopsis indicated that the TOR signaling is functional in tomato. The protein gel shifting and TOR inhibitors combination assays showed that SlFKBP12 can mediate the interaction between rapamycin and TOR. Furthermore, comparative expression profile analysis between treatments with rapamycin and KU63794 identified highly overlapped Differentially Expressed Genes (DEGs) which are involved in many anabolic and catabolic processes, such as photosynthesis, cell wall restructuring, and senescence in tomato. These observations suggest that SlFFBP12 is functional in tomato. The results provided basic information of TOR signaling in tomato, and also some new insights into how TOR controls plant growth and development through reprogramming the transcription profiles.

  14. The novel JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression of human myeloma cell growth and survival

    Czech Academy of Sciences Publication Activity Database

    Scuto, A.; Krejčí, Pavel

    2011-01-01

    Roč. 25, č. 3 (2011), s. 538-550 ISSN 0887-6924 Institutional support: RVO:68081707 Keywords : HUMAN MULTIPLE- MYELOMA * BONE-MARROW MICROENVIRONMENT * PROTEIN-KINASE CASCADE Subject RIV: BO - Biophysics Impact factor: 9.561, year: 2011

  15. Inhibition of PIM1 kinase attenuates inflammation-induced pro-labour mediators in human foetal membranes in vitro.

    Science.gov (United States)

    Lim, Ratana; Barker, Gillian; Lappas, Martha

    2017-06-01

    Does proviral integration site for Moloney murine leukaemic virus (PIM)1 kinase play a role in regulating the inflammatory processes of human labour and delivery? PIM1 kinase plays a critical role in foetal membranes in regulating pro-inflammatory and pro-labour mediators. Infection and inflammation have strong causal links to preterm delivery by stimulating pro-inflammatory cytokines and collagen degrading enzymes, which can lead to rupture of membranes. PIM1 has been shown to have a role in immune regulation and inflammation in non-gestational tissues; however, its role has not been explored in the field of human labour. PIM1 expression was analysed in myometrium and/or foetal membranes obtained at term and preterm (n = 8-9 patients per group). Foetal membranes, freshly isolated amnion cells and primary myometrial cells were used to investigate the effect of PIM1 inhibition on pro-labour mediators (n = 5 patients per treatment group). Foetal membranes, from term and preterm, were obtained from non-labouring and labouring women, and from preterm pre-labour rupture of membranes (PPROM) (n = 9 per group). Amnion was collected from women with and without preterm chorioamnionitis (n = 8 per group). Expression of PIM1 kinase was determined by qRT-PCR and western blotting. To determine the effect of PIM1 kinase inhibition on the expression of pro-inflammatory and pro-labour mediators induced by bacterial products lipopolysaccharide (LPS) (10 μg/ml) and flagellin (1 μg/ml) and pro-inflammatory cytokine tumour necrosis factor (TNF) (10 ng/ml), chemical inhibitors SMI-4a (20 μM) and AZD1208 (50 μM) were used in foetal membrane explants and siRNA against PIM1 was used in primary amnion cells. Statistical significance was set at P membranes after spontaneous term labour compared to no labour at term and in amnion with preterm chorioamnionitis compared to preterm with no chorioamnionitis. There was no change in PIM1 expression with preterm labour or PPROM

  16. Grandes organizaciones empresariales en México y Chile: un análisis de perfiles con respecto a sus comunicaciones sobre responsabilidad social

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    Teodoro R. Wendlandt Amezaga

    2015-06-01

    Full Text Available El presente estudio identificó subgrupos de empresas con base en sus comunicaciones sobre responsabilidad social (CRS y estableció diferencias entre estos en lo relativo a su país de origen, procedencia del capital, extensión en sus comunicaciones y actividad industrial. De manera no probabilística se seleccionaron un total de 300 grandes empresas de México y Chile. Mediante una prueba de conglomerados no jerárquicos K-medias, se identificaron dos subgrupos de empresas de acuerdo con sus frecuencias de CRS (principios motivacionales [F = 217.1, p < .000], procesos de gestión [F = 990.4, p < .000] y grupos de interés [F = 1317.3, p < .000]. El primer conglomerado integrado por 100 empresas (33% se denominó perfil bajo de comunicaciones sobre responsabilidad social (PB-CRS y el segundo, que incluyó a 200 empresas (67%, se denominó perfil alto de comunicaciones sobre responsabilidad social (PA-CRS. En el subgrupo PA-CRS existe una mayor proporción de empresas de origen mexicano (X2=38.50, p<.000, de capital de procedencia extranjera (X2=53.40, p<.000, con niveles de extensión media (X2=4.76, p=.029 o extensiva (X2=143.15, p<.000, con actividades industriales, de bienes de consumo (X2=10.12, p=.001, químicos (X2=16.13, p <.000, recursos naturales (X2=13.50, p<.000 y materiales-construcción (X2=6.54, p=.011

  17. Are dentists happy? A study among dental practitioners in coastal Andhra Pradesh using subjective happiness scale

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    Sudhakar Kaipa

    2017-01-01

    Full Text Available Introduction: The role of dental professionals in the society is vital. This profession allows the flexibility to balance a professional and personal life. Practice of dentistry at times is quite stressful, and stress impedes happiness and subjective well-being. Several studies have reported about stress among dental professionals and their various effects; however, studies evaluating the level of happiness (happiness index among dentists are few and lack in this geographic region. Objectives: The present study was conducted to assess the subjective happiness level among dental professionals. Materials and Methods: A cross-sectional study was conducted among 194 dentists in Andhra Pradesh, India. A questionnaire measuring dimensions of professional satisfaction by Subjective Happiness Scale was used to assess the happiness level. The results were expressed in percentages, means, and mean rank. Independent samples nonparametric tests (Mann–Whitney U-test and Kruskal–Wallis test and multivariable analyses were used to assess the determinants of happiness. Results: The mean happiness index of the respondents was 21.71 (0.26 standard error. Overall 67% of the respondents had an above average happiness score. Higher happiness score was found to be significantly associated with age, postgraduate degree, male gender, type of professional attachment, duration of practice, urban location of practice, and spouse employment status in univariate analysis. However, multivariable analysis showed association with type of professional attachment only. Conclusion: Although dentistry has been recognized as a stressful profession, majority of the dentists under study had a happiness score above the mean, and the level of satisfaction was influenced by various sociodemographic factors.

  18. Impact of gastrectomy procedural complexity on surgical outcomes and hospital comparisons.

    Science.gov (United States)

    Mohanty, Sanjay; Paruch, Jennifer; Bilimoria, Karl Y; Cohen, Mark; Strong, Vivian E; Weber, Sharon M

    2015-08-01

    Most risk adjustment approaches adjust for patient comorbidities and the primary procedure. However, procedures done at the same time as the index case may increase operative risk and merit inclusion in adjustment models for fair hospital comparisons. Our objectives were to evaluate the impact of surgical complexity on postoperative outcomes and hospital comparisons in gastric cancer surgery. Patients who underwent gastric resection for cancer were identified from a large clinical dataset. Procedure complexity was characterized using secondary procedure CPT codes and work relative value units (RVUs). Regression models were developed to evaluate the association between complexity variables and outcomes. The impact of complexity adjustment on model performance and hospital comparisons was examined. Among 3,467 patients who underwent gastrectomy for adenocarcinoma, 2,171 operations were distal and 1,296 total. A secondary procedure was reported for 33% of distal gastrectomies and 59% of total gastrectomies. Six of 10 secondary procedures were associated with adverse outcomes. For example, patients who underwent a synchronous bowel resection had a higher risk of mortality (odds ratio [OR], 2.14; 95% CI, 1.07-4.29) and reoperation (OR, 2.09; 95% CI, 1.26-3.47). Model performance was slightly better for nearly all outcomes with complexity adjustment (mortality c-statistics: standard model, 0.853; secondary procedure model, 0.858; RVU model, 0.855). Hospital ranking did not change substantially after complexity adjustment. Surgical complexity variables are associated with adverse outcomes in gastrectomy, but complexity adjustment does not affect hospital rankings appreciably. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Effects of Childhood Asthma on the Development of Obesity among School-aged Children.

    Science.gov (United States)

    Chen, Zhanghua; Salam, Muhammad T; Alderete, Tanya L; Habre, Rima; Bastain, Theresa M; Berhane, Kiros; Gilliland, Frank D

    2017-05-01

    Asthma and obesity often occur together in children. It is unknown whether asthma contributes to the childhood obesity epidemic. We aimed to investigate the effects of asthma and asthma medication use on the development of childhood obesity. The primary analysis was conducted among 2,171 nonobese children who were 5-8 years of age at study enrollment in the Southern California Children's Health Study (CHS) and were followed for up to 10 years. A replication analysis was performed in an independent sample of 2,684 CHS children followed from a mean age of 9.7 to 17.8 years. Height and weight were measured annually to classify children into normal, overweight, and obese categories. Asthma status was ascertained by parent- or self-reported physician-diagnosed asthma. Cox proportional hazards models were fitted to assess associations of asthma history with obesity incidence during follow-up. We found that children with a diagnosis of asthma at cohort entry were at 51% increased risk of developing obesity during childhood and adolescence compared with children without asthma at baseline (hazard ratio, 1.51; 95% confidence interval, 1.08-2.10) after adjusting for confounders. Use of asthma rescue medications at cohort entry reduced the risk of developing obesity (hazard ratio, 0.57; 95% confidence interval, 0.33-0.96). In addition, the significant association between a history of asthma and an increased risk of developing obesity was replicated in an independent CHS sample. Children with asthma may be at higher risk of obesity. Asthma rescue medication use appeared to reduce obesity risk independent of physical activity.

  20. Análise dos Gêneros na Linguagem: A Atuação e o Preconceito Contra os Homens na Área de Secretariado Executivo

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    Weidman Machado Bernardino

    2013-11-01

    Full Text Available Existe a concepção social de que os homens possuem maior desempenho em trabalhar no campo das engenharias, da medicina, das ciências políticas e jurídicas, enquanto as mulheres, do magistério, da economia doméstica e do secretariado. Entretanto, as teorizações dos gêneros são consideradas ferramentas utilizadas para indagarem esses “rótulos” naturalizados e cristalizados pela sociedade. Por esse motivo, essa pesquisa baseou-se em Michel Foucault (1978, Stuart Hall (2003 e Bordieu (2005 para se fazer uma reflexão sobre a pouca atuação masculina na área de Secretariado. Para isso, essa pesquisa científica tem por objetivo analisar a linguagem como ferramenta para a construção de ideias e concepções para servir a determinado propósito. Para alcançá-lo, essa investigação orientou-se pelo material de oferta de emprego divulgado no site Catho Online, referente ao período de 29 de janeiro a 23 de março de 2010, pela lei que criou o dia das Secretárias e pelo questionário aplicado aos estudantes e profissionais correlatos à área secretarial. Por último, examinaram-se, no campo da linguagem, os gêneros masculino e feminino para verificar o processo relacional de poder e saber considerando as distinções hierárquicas.DOI:10.7769/gesec.v4i2.171

  1. Sensitivity of subject-specific models to errors in musculo-skeletal geometry.

    Science.gov (United States)

    Carbone, V; van der Krogt, M M; Koopman, H F J M; Verdonschot, N

    2012-09-21

    Subject-specific musculo-skeletal models of the lower extremity are an important tool for investigating various biomechanical problems, for instance the results of surgery such as joint replacements and tendon transfers. The aim of this study was to assess the potential effects of errors in musculo-skeletal geometry on subject-specific model results. We performed an extensive sensitivity analysis to quantify the effect of the perturbation of origin, insertion and via points of each of the 56 musculo-tendon parts contained in the model. We used two metrics, namely a Local Sensitivity Index (LSI) and an Overall Sensitivity Index (OSI), to distinguish the effect of the perturbation on the predicted force produced by only the perturbed musculo-tendon parts and by all the remaining musculo-tendon parts, respectively, during a simulated gait cycle. Results indicated that, for each musculo-tendon part, only two points show a significant sensitivity: its origin, or pseudo-origin, point and its insertion, or pseudo-insertion, point. The most sensitive points belong to those musculo-tendon parts that act as prime movers in the walking movement (insertion point of the Achilles Tendon: LSI=15.56%, OSI=7.17%; origin points of the Rectus Femoris: LSI=13.89%, OSI=2.44%) and as hip stabilizers (insertion points of the Gluteus Medius Anterior: LSI=17.92%, OSI=2.79%; insertion point of the Gluteus Minimus: LSI=21.71%, OSI=2.41%). The proposed priority list provides quantitative information to improve the predictive accuracy of subject-specific musculo-skeletal models. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Environmental impacts of a large-scale incinerator with mixed MSW of high water content from a LCA perspective.

    Science.gov (United States)

    Lou, Ziyang; Bilitewski, Bernd; Zhu, Nanwen; Chai, Xiaoli; Li, Bing; Zhao, Youcai

    2015-04-01

    Large-scale incinerators are applied widely as a result of the heavy burden of municipal solid waste (MSW) generated, while strong opposition is arising from the public living nearby. A large-scale working incineration plant of 1500 ton/day was chosen for evaluation using life cycle assessment. It was found that the corresponding human toxicity impacts via soil (HTs), human toxicity impacts via water (HTw) and human toxicity impacts via air (HTa) categories are 0.213, 2.171, and 0.012 personal equivalents (PE), and global warming (GW100) and nutrient enrichment (NE) impacts are 0.002 and 0.001 PE per ton of waste burned for this plant. Heavy metals in flue gas, such as Hg and Pb, are the two dominant contributors to the toxicity impact categories, and energy recovery could reduce the GW100 and NE greatly. The corresponding HTs, HTw and HTa decrease to 0.087, 0.911 and 0.008 PE, and GW100 turns into savings of -0.007 PE due to the increase of the heating value from 3935 to 5811 kJ/kg, if a trommel screener of 40 mm mesh size is used to pre-separate MSW. MSW sorting and the reduction of water content by physical pressure might be two promising pre-treatment methods to improve the combustion performance, and the application of stricter standards for leachate discharge and the flue gas purification process are two critical factors for improvement of the environmental profile identified in this work. Copyright © 2015. Published by Elsevier B.V.

  3. Factors associated to adherence to blood glucose self-monitoring in patients with diabetes treated with insulin. The dapa study.

    Science.gov (United States)

    Vidal Florc, Mercè; Jansà Morató, Margarita; Galindo Rubio, Mercedes; Penalba Martínez, Maite

    2018-02-01

    To assess adherence to self-monitoring of blood glucose and the main factors associated with it, particularly those related to self-perception of glycemia, in patients with diabetes on insulin therapy. An epidemiological, observational, prospective, multicenter study conducted in standard clinical practice in primary care, outpatient centers, and hospitals from different Spanish regions. Sociodemographic, clinical and treatment data were collected. Patients were considered adherent to self-monitoring if they performed the minimum number of controls recommended by the Spanish Society of Diabetes (SED). Adherence was shown in 61.6% of patients. Factors associated to adherence included treatment with less than three insulin injections daily (OR 2.678; 95% CI 2.048- 3.5029; p <0.001), presence of peripheral vascular disease (OR 1.529; 95% CI 1.077 - 2.171; p=0.018), alcohol abstinence (OR 1.442; 95% CI 1.118 - 1.858; p=0.005), and collection of the glucose test strips from the pharmacy (OR 1.275; 95% CI 1.026 - 1.584; p=0.028). Adequate self-perception of glycemia was found in 21.4% of patients. Our results show a suboptimal adherence to the recommended protocol for blood glucose self-monitoring in patients with diabetes on insulin therapy. Independent variables associated to good adherence were treatment with less than three insulin injections dailyu, presence of peripheral vascular disease, alcohol abstinence, and collection of glucose test strips from the pharmacy. Copyright © 2017 SEEN y SED. Publicado por Elsevier España, S.L.U. All rights reserved.

  4. Key constructs in "classical" and "new wave" cognitive behavioral psychotherapies: relationships among each other and with emotional distress.

    Science.gov (United States)

    Cristea, Ioana A; Montgomery, Guy H; Szamoskozi, Stefan; David, Daniel

    2013-06-01

    We aimed to relate key constructs from three forms of cognitive behavioral therapy that are often placed in competition: rational emotive behavior therapy, cognitive therapy, and acceptance and commitment therapy. The key constructs of the underlying theories (i.e., irrational beliefs/unconditional self-acceptance, dysfunctional cognitions, experiential avoidance/psychological inflexibility) of these therapies have not been explicitly studied in their relationships to each other and with emotional distress. We used a cross-sectional design. The variables were selected to indicate key constructs of the three major forms of therapy considered. Study 1 used a sample of 152 students, who were assessed during a stressful period of their semester (mean age = 21.71; 118 females), while Study 2 used a clinical sample of 28 patients with generalized anxiety disorder (mean age = 26.67; 26 females). Results showed that these constructs, central in the therapies considered, had medium to high associations to each other and to distress. Experiential avoidance was found to mediate the relationship between the other, schema-type cognitive constructs and emotional distress. Moreover, multiple mediation analysis in Study 2 seemed to indicate that the influence of the more general constructs on distress was mediated by experiential avoidance, whose effect seemed to be carried on further by automatic thoughts that were the most proximal to distress. Although each of the cognitive constructs considered comes with its underlying theory, the relationships between them can no longer be ignored and cognitive behavioral therapy theoretical models reliably accounting for these relationships should be proposed and tested. © 2013 Wiley Periodicals, Inc.

  5. The Association of Individual and Regional Socioeconomic Status on Initial Peritonitis and Outcomes in Peritoneal Dialysis Patients: A Propensity Score-Matched Cohort Study.

    Science.gov (United States)

    Wang, Qin; Hu, Ke-Jie; Ren, Ye-Ping; Dong, Jie; Han, Qing-Feng; Zhu, Tong-Ying; Chen, Jiang-Hua; Zhao, Hui-Ping; Chen, Meng-Hua; Xu, Rong; Wang, Yue; Hao, Chuan-Ming; Zhang, Xiao-Hui; Wang, Mei; Tian, Na; Wang, Hai-Yan

    2016-01-01

    ♦ Research indicates that the socioeconomic status (SES) of individuals and the area where they live are related to initial peritonitis and outcomes in peritoneal dialysis (PD). We conducted a retrospective, multi-center cohort study in China to examine these associations. ♦ Data on 2,171 PD patients were collected from 7 centers, including baseline demographic, socioeconomic, and laboratory data. We explored the potential risk factors for initial peritonitis and outcomes using univariate Cox regression and unadjusted binary logistic regression. Then, we used propensity score matching to balance statistically significant risk factors for initial peritonitis and outcomes, and Kaplan-Meier survival analysis to compare differences in peritonitis-free rates between different groups of participants after matching. ♦ A total of 563 (25.9%) initial episodes of peritonitis occurred during the study period. The Kaplan-Meier peritonitis-free rate curve showed high-income patients had a significantly lower risk than low-income patients (p = 0.007) after matching for age, hemoglobin, albumin, and regional SES and PD center. The risk of treatment failure was significantly lower in the high-income than the low-income group after matching for the organism causing peritonitis and PD center: odds ratio (OR) = 0.27 (0.09 - 0.80, p = 0.018). Regional SES and education were not associated with initial peritonitis and outcomes. ♦ Our study demonstrates low individual income is a risk factor for the initial onset of peritonitis and treatment failure after initial peritonitis. Copyright © 2016 International Society for Peritoneal Dialysis.

  6. Cationic osteogenic peptide P15-CSP coatings promote 3-D osteogenesis in poly(epsilon-caprolactone) scaffolds of distinct pore size.

    Science.gov (United States)

    Li, Xian; Ghavidel Mehr, Nima; Guzmán-Morales, Jessica; Favis, Basil D; De Crescenzo, Gregory; Yakandawala, Nandadeva; Hoemann, Caroline D

    2017-08-01

    P15-CSP is a biomimetic cationic fusion peptide that stimulates osteogenesis and inhibits bacterial biofilm formation when coated on 2-D surfaces. This study tested the hypothesis that P15-CSP coatings enhance 3-D osteogenesis in a porous but otherwise hydrophobic poly-(ɛ-caprolactone) (PCL) scaffold. Scaffolds of 84 µm and 141 µm average pore size were coated or not with Layer-by-Layer polyelectrolytes followed by P15-CSP, seeded with adult primary human mesenchymal stem cells (MSCs), and cultured 10 days in proliferation medium, then 21 days in osteogenic medium. Atomic analyses showed that P15-CSP was successfully captured by LbL. After 2 days of culture, MSCs adhered and spread more on P15-CSP coated pores than PCL-only. At day 10, all constructs contained nonmineralized tissue. At day 31, all constructs became enveloped in a "skin" of tissue that, like 2-D cultures, underwent sporadic mineralization in areas of high cell density that extended into some 141 µm edge pores. By quantitative histomorphometry, 2.5-fold more tissue and biomineral accumulated in edge pores versus inner pores. P15-CSP specifically promoted tissue-scaffold integration, fourfold higher overall biomineralization, and more mineral deposits in the outer 84 µm and inner 141 µm pores than PCL-only (p pore surfaces with 3-D topography. Biomineralization deeper than 150 µm from the scaffold edge was optimally attained with the larger 141 µm peptide-coated pores. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 2171-2181, 2017. © 2017 Wiley Periodicals, Inc.

  7. Pharmacologic ATM but not ATR kinase inhibition abrogates p21-dependent G1 arrest and promotes gastrointestinal syndrome after total body irradiation.

    Science.gov (United States)

    Vendetti, Frank P; Leibowitz, Brian J; Barnes, Jennifer; Schamus, Sandy; Kiesel, Brian F; Abberbock, Shira; Conrads, Thomas; Clump, David Andy; Cadogan, Elaine; O'Connor, Mark J; Yu, Jian; Beumer, Jan H; Bakkenist, Christopher J

    2017-02-01

    We show that ATM kinase inhibition using AZ31 prior to 9 or 9.25 Gy total body irradiation (TBI) reduced median time to moribund in mice to 8 days. ATR kinase inhibition using AZD6738 prior to TBI did not reduce median time to moribund. The striking finding associated with ATM inhibition prior to TBI was increased crypt loss within the intestine epithelium. ATM inhibition reduced upregulation of p21, an inhibitor of cyclin-dependent kinases, and blocked G1 arrest after TBI thereby increasing the number of S phase cells in crypts in wild-type but not Cdkn1a(p21 CIP/WAF1 )-/- mice. In contrast, ATR inhibition increased upregulation of p21 after TBI. Thus, ATM activity is essential for p21-dependent arrest while ATR inhibition may potentiate arrest in crypt cells after TBI. Nevertheless, ATM inhibition reduced median time to moribund in Cdkn1a(p21 CIP/WAF1 )-/- mice after TBI. ATM inhibition also increased cell death in crypts at 4 h in Cdkn1a(p21 CIP/WAF1 )-/-, earlier than at 24 h in wild-type mice after TBI. In contrast, ATR inhibition decreased cell death in crypts in Cdkn1a(p21 CIP/WAF1 )-/- mice at 4 h after TBI. We conclude that ATM activity is essential for p21-dependent and p21-independent mechanisms that radioprotect intestinal crypts and that ATM inhibition promotes GI syndrome after TBI.

  8. Impact of regurgitation on health-related quality of life in gastro-oesophageal reflux disease before and after short-term potent acid suppression therapy.

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    Kahrilas, Peter J; Jonsson, Andreas; Denison, Hans; Wernersson, Börje; Hughes, Nesta; Howden, Colin W

    2014-05-01

    Limited data exist on the impact of regurgitation on health-related quality of life (HRQOL) in gastro-oesophageal reflux disease (GORD). We assessed the relationship between regurgitation frequency and HRQOL before and after acid suppression therapy in GORD. We used data from two randomised trials of AZD0865 25-75 mg/day versus esomeprazole 20 or 40 mg/day in non-erosive reflux disease (NERD) (n=1415) or reflux oesophagitis (RO) (n=1460). The Reflux Disease Questionnaire was used to select patients with frequent and intense heartburn for inclusion and to assess treatment response. The Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire was used to assess HRQOL. At baseline, 93% of patients in both the NERD and RO groups experienced regurgitation. Mean QOLRAD scores were similar for NERD and RO at baseline and at week 4 and disclosed decremental HRQOL with increasing frequency of regurgitation; a clinically relevant difference of >0.5 in mean QOLRAD scores was seen with regurgitation ≥4 days/week versus <4 days/week. The prevalence of frequent, persistent regurgitation (≥4 days/week) at week 4 among heartburn responders (≤1 day/week of mild heartburn) was 28% in NERD and 23% in RO. QOLRAD scores were higher among heartburn responders. There was a similar pattern of impact related to regurgitation frequency in heartburn responders compared with the group as a whole. Frequent regurgitation was associated with a clinically relevant, incremental decline in HRQOL beyond that associated with heartburn before and after potent acid suppression in both NERD and RO. NCT00206284 and NCT00206245.

  9. Annonaceous acetogenin mimic AA005 induces cancer cell death via apoptosis inducing factor through a caspase-3-independent mechanism.

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    Han, Bing; Wang, Tong-Dan; Shen, Shao-Ming; Yu, Yun; Mao, Chan; Yao, Zhu-Jun; Wang, Li-Shun

    2015-03-18

    Annonaceous acetogenins are a family of natural products with antitumor activities. Annonaceous acetogenin mimic AA005 reportedly inhibits mammalian mitochondrial NADH-ubiquinone reductase (Complex I) and induces gastric cancer cell death. However, the mechanisms underlying its cell-death-inducing activity are unclear. We used SW620 colorectal adenocarcinoma cells to study AA005 cytotoxic activity. Cell deaths were determined by Trypan blue assay and flow cytometry, and related proteins were characterized by western blot. Immunofluorescence and subcellular fractionation were used to evaluate AIF nuclear translocation. Reactive oxygen species were assessed by using redox-sensitive dye DCFDA. AA005 induces a unique type of cell death in colorectal adenocarcinoma cells, characterized by lack of caspase-3 activation or apoptotic body formation, sensitivity to poly (ADP-ribose) polymerase inhibitor Olaparib (AZD2281) but not pan-caspase inhibitor Z-VAD.fmk, and dependence on apoptosis-inducing factor (AIF). AA005 treatment also reduced expression of mitochondrial Complex I components, and leads to accumulation of intracellular reactive oxygen species (ROS) at the early stage. Blocking ROS formation significantly suppresses AA005-induced cell death in SW620 cells. Moreover, blocking activation of RIP-1 by necroptosis inhibitor necrotatin-1 inhibits AIF translocation and partially suppresses AA005-induced cell death in SW620 cells demonstrating that RIP-1 protein may be essential for cell death. AA005 may trigger the cell death via mediated by AIF through caspase-3 independent pathway. Our work provided new mechanisms for AA005-induced cancer cell death and novel clues for cancer treatment via AIF dependent cell death.

  10. In vitro pharmacological characterization of a novel TRPA1 antagonist and proof of mechanism in a human dental pulp model

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    Nyman E

    2013-01-01

    Full Text Available Eva Nyman,1,* Bo Franzén,1,* Andreas Nolting,1 Göran Klement,1 Gang Liu,1 Maria Nilsson,1 Annika Rosén,2 Charlotta Björk,3 Dirk Weigelt,4 Patrik Wollberg,1 Paul Karila,1 Patrick Raboisson11Neuroscience, Innovative Medicines CNS/Pain, AstraZeneca R&D, Södertälje, Sweden; 2Division of Oral and Maxillofacial Surgery, Karolinska Institute/Karolinska University Hospital, Huddinge, Sweden; 3Clinical TA NS Early Development, 4Medicinal Chemistry, Innovative Medicines CNS/Pain, AstraZeneca R&D, Södertälje, Sweden*These authors contributed equally to this workAbstract: AZ465 is a novel selective transient receptor potential cation channel, member A1 (TRPA1 antagonist identified during a focused drug discovery effort. In vitro, AZ465 fully inhibits activation by zinc, O-chlorobenzylidene malononitrile (CS, or cinnamaldehyde of the human TRPA1 channel heterologously expressed in human embryonic kidney cells. Our data using patch-clamp recordings and mouse/human TRPA1 chimeras suggest that AZ465 binds reversibly in the pore region of the human TRPA1 channel. Finally, in an ex vivo model measuring TRPA1 agonist-stimulated release of neuropeptides from human dental pulp biopsies, AZD465 was able to block 50%–60% of CS-induced calcitonin gene-related peptide release, confirming that AZ465 inhibits the native human TRPA1 channel in neuronal tissue.Keywords: pain, pharmacology, antagonist, chimeric proteins, dental pulp, inflammation, neuropeptide, calcitonin gene-related peptide, CGRP

  11. Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway.

    Science.gov (United States)

    Chen, Dongshao; Lin, Xiaoting; Zhang, Cheng; Liu, Zhentao; Chen, Zuhua; Li, Zhongwu; Wang, Jingyuan; Li, Beifang; Hu, Yanting; Dong, Bin; Shen, Lin; Ji, Jiafu; Gao, Jing; Zhang, Xiaotian

    2018-01-26

    Paclitaxel (PTX) is widely used in the front-line chemotherapy for gastric cancer (GC), but resistance limits its use. Due to the lack of proper models, mechanisms underlying PTX resistance in GC were not well studied. Using established PTX-resistant GC cell sublines HGC-27R, we for the first time integrated biological traits and molecular mechanisms of PTX resistance in GC. Data revealed that PTX-resistant GC cells were characterized by microtubular disorders, an EMT phenotype, reduced responses to antimitotic drugs, and resistance to apoptosis (marked by upregulated β-tubulin III, vimentin, attenuated changes in G 2 /M molecules or pro-apoptotic factors in response to antimitotic drugs or apoptotic inducers, respectively). Activation of the phosphoinositide 3-kinase, the serine/threonine kinase Akt and mammalian target of rapamycin (PI3K/Akt/mTOR) and mitogen-activated protein kinase (MAPK) pathways were also observed, which might be the reason for above phenotypic alternations. In vitro data suggested that targeting these pathways were sufficient to elicit antitumor responses in PTX-resistant GC, in which the dual PI3K/mTOR inhibitor BEZ235 displayed higher therapeutic efficiency than the mTOR inhibitor everolimus or the MEK inhibitor AZD6244. Antitumor effects of BEZ235 were also confirmed in mice bearing HGC-27R tumors. Thus, these data suggest that PI3K/Akt/mTOR and MAPK pathway inhibition, especially PI3K/mTOR dual blockade, might be a promising therapeutic strategy against PTX-resistant GC.

  12. Effect of Food Intake on the Pharmacodynamics of Tenapanor: A Phase 1 Study.

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    Johansson, Susanne A; Knutsson, Mikael; Leonsson-Zachrisson, Maria; Rosenbaum, David P

    2017-09-01

    Tenapanor (RDX5791/AZD1722) is a minimally systemic small-molecule inhibitor of the sodium/hydrogen exchanger NHE3. Tenapanor acts in the gut to reduce absorption of sodium and phosphate. This phase 1 open-label, 3-way crossover study (NCT02226783) evaluated the effect of food on the pharmacodynamics of tenapanor. Eighteen volunteers completed a randomized sequence of three 4-day treatments with tenapanor hydrochloride 15 mg twice daily: before food, after food, and while fasting. Participants received a diet standardized for sodium content. Stool sodium was significantly higher with tenapanor administration before versus after food (difference, +8.8 mmol/day, P = .006) or while fasting (+11.8 mmol/day, P = .0004). Differences in urinary sodium were not significant. Stool phosphorus was not significantly different with tenapanor before versus after food and significantly higher before food versus while fasting (+4.9 mmol/day, P = .006). Urinary phosphorus was significantly lower when tenapanor was administered before (-3.9 mmol/day, P = .0005) or after food (-3.7 mmol/day, P = .0009) versus while fasting. No serious adverse events were reported. These data suggest the effect of tenapanor on sodium absorption is most pronounced when administered before meals, whereas the effect on phosphate is similar whether administered before or after meals. This may support different timings of tenapanor administration with respect to food for sodium- and phosphate-related indications. © 2017 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

  13. Piperine causes G1 phase cell cycle arrest and apoptosis in melanoma cells through checkpoint kinase-1 activation.

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    Neel M Fofaria

    Full Text Available In this study, we determined the cytotoxic effects of piperine, a major constituent of black and long pepper in melanoma cells. Piperine treatment inhibited the growth of SK MEL 28 and B16 F0 cells in a dose and time-dependent manner. The growth inhibitory effects of piperine were mediated by cell cycle arrest of both the cell lines in G1 phase. The G1 arrest by piperine correlated with the down-regulation of cyclin D1 and induction of p21. Furthermore, this growth arrest by piperine treatment was associated with DNA damage as indicated by phosphorylation of H2AX at Ser139, activation of ataxia telangiectasia and rad3-related protein (ATR and checkpoint kinase 1 (Chk1. Pretreatment with AZD 7762, a Chk1 inhibitor not only abrogated the activation of Chk1 but also piperine mediated G1 arrest. Similarly, transfection of cells with Chk1 siRNA completely protected the cells from G1 arrest induced by piperine. Piperine treatment caused down-regulation of E2F1 and phosphorylation of retinoblastoma protein (Rb. Apoptosis induced by piperine was associated with down-regulation of XIAP, Bid (full length and cleavage of Caspase-3 and PARP. Furthermore, our results showed that piperine treatment generated ROS in melanoma cells. Blocking ROS by tiron protected the cells from piperine mediated cell cycle arrest and apoptosis. These results suggest that piperine mediated ROS played a critical role in inducing DNA damage and activation of Chk1 leading to G1 cell cycle arrest and apoptosis.

  14. Preclinical Data on Efficacy of 10 Drug-Radiation Combinations: Evaluations, Concerns, and Recommendations

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    Helen B. Stone

    2016-02-01

    Full Text Available BACKGROUND: Clinical testing of new therapeutic interventions requires comprehensive, high-quality preclinical data. Concerns regarding quality of preclinical data have been raised in recent reports. This report examines the data on the interaction of 10 drugs with radiation and provides recommendations for improving the quality, reproducibility, and utility of future studies. The drugs were AZD6244, bortezomib, 17-DMAG, erlotinib, gefitinib, lapatinib, oxaliplatin/Lipoxal, sunitinib (Pfizer, Corporate headquarters, New York, NY, thalidomide, and vorinostat. METHODS: In vitro and in vivo data were tabulated from 125 published papers, including methods, radiation and drug doses, schedules of administration, assays, measures of interaction, presentation and interpretation of data, dosimetry, and conclusions. RESULTS: In many instances, the studies contained inadequate or unclear information that would hamper efforts to replicate or intercompare the studies, and that weakened the evidence for designing and conducting clinical trials. The published reports on these drugs showed mixed results on enhancement of radiation response, except for sunitinib, which was ineffective. CONCLUSIONS: There is a need for improved experimental design, execution, and reporting of preclinical testing of agents that are candidates for clinical use in combination with radiation. A checklist is provided for authors and reviewers to ensure that preclinical studies of drug-radiation combinations meet standards of design, execution, and interpretation, and report necessary information to ensure high quality and reproducibility of studies. Improved design, execution, common measures of enhancement, and consistent interpretation of preclinical studies of drug-radiation interactions will provide rational guidance for prioritizing drugs for clinical radiotherapy trials and for the design of such trials.

  15. Phase 2 Study of AZD2014, a Dual mTORC1/mTORC1 Inhibitor,for NF2 Patients with Progressive or Symptomatic Meningiomas

    Science.gov (United States)

    2017-06-01

    statistical support for the clinical trial. Funding support N/A Name Nicola Gribbin, RN Project Role Research Nurse Nearest person-month worked 1...the author(s) and should not be construed as an official Department of the Army position, policy or decision unless so designated by other...Obtain institutional approval for proposed clinical trial (months 1-6) In year 1, we obtained IRB approval at MGH and USAMRMC Human Research Protection

  16. Prevalence and Determinants of the Use of Lipid-Lowering Agents in a Population of Older Hospitalized Patients: the Findings from the REPOSI (REgistro POliterapie Società Italiana di Medicina Interna) Study.

    Science.gov (United States)

    Bertolotti, Marco; Franchi, Carlotta; Rocchi, Marco B L; Miceli, Andrea; Libbra, M Vittoria; Nobili, Alessandro; Lancellotti, Giulia; Carulli, Lucia; Mussi, Chiara

    2017-04-01

    Older patients are prone to multimorbidity and polypharmacy, with an inherent risk of adverse events and drug interactions. To the best of our knowledge, available information on the appropriateness of lipid-lowering treatment is extremely limited. The aim of the present study was to quantify and characterize lipid-lowering drug use in a population of complex in-hospital older patients. We analyzed data from 87 units of internal medicine or geriatric medicine in the REPOSI (Registro Politerapie della Società Italiana di Medicina Interna) study, with reference to the 2010 and 2012 patient cohorts. Lipid-lowering drug use was closely correlated with the clinical profiles, including multimorbidity markers and polypharmacy. 2171 patients aged >65 years were enrolled (1057 males, 1114 females, mean age 78.6 years). The patients treated with lipid-lowering drugs amounted to 508 subjects (23.4%), with no gender difference. Atorvastatin (39.3%) and simvastatin (34.0%) were the most widely used statin drugs. Likelihood of treatment was associated with polypharmacy (≥5 drugs) and with higher Cumulative Illness Rating Scale (CIRS) score. At logistic regression analysis, the presence of coronary heart disease, peripheral vascular disease, and hypertension were significantly correlated with lipid-lowering drug use, whereas age showed an inverse correlation. Diabetes was not associated with drug treatment. In this in-hospital cohort, the use of lipid-lowering agents was mainly driven by patients' clinical history, most notably the presence of clinically overt manifestations of atherosclerosis. Increasing age seems to be associated with lower prescription rates. This might be indicative of cautious behavior towards a potentially toxic treatment regimen.

  17. Population-based multicase-control study in common tumors in Spain (MCC-Spain): rationale and study design.

    Science.gov (United States)

    Castaño-Vinyals, Gemma; Aragonés, Nuria; Pérez-Gómez, Beatriz; Martín, Vicente; Llorca, Javier; Moreno, Victor; Altzibar, Jone M; Ardanaz, Eva; de Sanjosé, Sílvia; Jiménez-Moleón, José Juan; Tardón, Adonina; Alguacil, Juan; Peiró, Rosana; Marcos-Gragera, Rafael; Navarro, Carmen; Pollán, Marina; Kogevinas, Manolis

    2015-01-01

    We present the protocol of a large population-based case-control study of 5 common tumors in Spain (MCC-Spain) that evaluates environmental exposures and genetic factors. Between 2008-2013, 10,183 persons aged 20-85 years were enrolled in 23 hospitals and primary care centres in 12 Spanish provinces including 1,115 cases of a new diagnosis of prostate cancer, 1,750 of breast cancer, 2,171 of colorectal cancer, 492 of gastro-oesophageal cancer, 554 cases of chronic lymphocytic leukaemia (CLL) and 4,101 population-based controls matched by frequency to cases by age, sex and region of residence. Participation rates ranged from 57% (stomach cancer) to 87% (CLL cases) and from 30% to 77% in controls. Participants completed a face-to-face computerized interview on sociodemographic factors, environmental exposures, occupation, medication, lifestyle, and personal and family medical history. In addition, participants completed a self-administered food-frequency questionnaire and telephone interviews. Blood samples were collected from 76% of participants while saliva samples were collected in CLL cases and participants refusing blood extractions. Clinical information was recorded for cases and paraffin blocks and/or fresh tumor samples are available in most collaborating hospitals. Genotyping was done through an exome array enriched with genetic markers in specific pathways. Multiple analyses are planned to assess the association of environmental, personal and genetic risk factors for each tumor and to identify pleiotropic effects. This study, conducted within the Spanish Consortium for Biomedical Research in Epidemiology & Public Health (CIBERESP), is a unique initiative to evaluate etiological factors for common cancers and will promote cancer research and prevention in Spain. Copyright © 2014 SESPAS. Published by Elsevier Espana. All rights reserved.

  18. Adiposidade corporal e hipertensão arterial em crianças e adolescentes obesos - doi:10.5020/18061230.2009.p88

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    Joel Saraiva Ferreira

    2012-01-01

    Full Text Available Objetivo: Investigar a relação entre a hipertensão arterial e adiposidade corporal em crianças e adolescentes obesos. Métodos: Estudo transversal no qual 129 crianças e adolescentes obesos de ambos os gêneros com idade variando de 7 a 14 anos foram avaliados. A adiposidade foi caracterizada a partir dos dados obtidos como: índice de massa corporal (IMC, percentual de gordura corporal (%GC e relação cintura-quadril (RCQ. O grupo foi dividido em dois subgrupos (normotensos e hipertensos mediante o nível de pressão arterial (PA. O teste estatístico de Kruskal Wallis foi empregado para determinar a significância na relação entre dados antropométricos e níveis de pressão arterial. Adotou-se um valor de p ? 0,05. Resultados: Verificou-se que 101 (78,29% participantes eram normotensos e 28 (21,71% hipertensos. Em relação à adiposidade, o grupo dos hipertensos apresentou níveis mais elevados de IMC e o %GC quando comparado com o normotenso (p<0,05. A partir dos dados da RCQ, não houve associação estatística entre a relação cintura-quadril e o nível pressórico. Conclusões: As crianças e adolescentes obesos apresentaram relação estatisticamente significativa entre adiposidade corporal e níveis de pressão arterial; no entanto, a localização da gordura não foi um fator determinante desta diferença.

  19. Social and economic burden of walking and mobility problems in multiple sclerosis

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    Pike James

    2012-09-01

    Full Text Available Abstract Background Multiple sclerosis (MS is a chronic progressive neurological disease and the majority of patients will experience some degree of impaired mobility. We evaluated the prevalence, severity and burden of walking and mobility problems (WMPs in 5 European countries. Methods This was a cross-sectional, patient record-based study involving 340 neurologists who completed detailed patient record forms (PRF for patients (>18 years attending their clinic with MS. Patients were also invited to complete a questionnaire (PSC. Information collected included demographics, disease characteristics, work productivity, quality of life (QoL; EuroQol-5D and Hamburg Quality of Life Questionnaire Multiple Sclerosis [HAQUAMS] and mobility (subjective patient-reported and objectively measured using the timed 25 foot walk test [T25FW]. Relationships between WMPs and disease and other characteristics were examined using Chi square tests. Analysis of variance was used to examine relationships between mobility measures and work productivity. Results Records were available for 3572 patients of whom 2171 also completed a PSC. WMPs were regarded as the most bothersome symptom by almost half of patients who responded (43%; 291/683. There was a clear, independent and strong directional relationship between severity of WMPs (subjective and objective and healthcare resource utilisation. Patients with longer T25FW times (indicating greater walking impairment were significantly more likely to require additional caregiver support (p Conclusions In Europe, WMPs in MS represent a considerable personal and social burden both financially and in terms of quality of life. Interventions to improve mobility could have significant benefits for patients and society as a whole.

  20. Young Cluster Berkeley 59: Properties, Evolution, and Star Formation

    Science.gov (United States)

    Panwar, Neelam; Pandey, A. K.; Samal, Manash R.; Battinelli, Paolo; Ogura, K.; Ojha, D. K.; Chen, W. P.; Singh, H. P.

    2018-01-01

    Berkeley 59 is a nearby (∼1 kpc) young cluster associated with the Sh2-171 H II region. We present deep optical observations of the central ∼2.5 × 2.5 pc2 area of the cluster, obtained with the 3.58 m Telescopio Nazionale Galileo. The V/(V–I) color–magnitude diagram manifests a clear pre-main-sequence (PMS) population down to ∼0.2 M ⊙. Using the near-infrared and optical colors of the low-mass PMS members, we derive a global extinction of A V = 4 mag and a mean age of ∼1.8 Myr, respectively, for the cluster. We constructed the initial mass function and found that its global slopes in the mass ranges of 0.2–28 M ⊙ and 0.2–1.5 M ⊙ are ‑1.33 and ‑1.23, respectively, in good agreement with the Salpeter value in the solar neighborhood. We looked for the radial variation of the mass function and found that the slope is flatter in the inner region than in the outer region, indicating mass segregation. The dynamical status of the cluster suggests that the mass segregation is likely primordial. The age distribution of the PMS sources reveals that the younger sources appear to concentrate close to the inner region compared to the outer region of the cluster, a phenomenon possibly linked to the time evolution of star-forming clouds. Within the observed area, we derive a total mass of ∼103 M ⊙ for the cluster. Comparing the properties of Berkeley 59 with other young clusters, we suggest it resembles more closely the Trapezium cluster.

  1. Prevalence and predictors of erectile dysfunction in adult male outpatient clinic attendees in Johor, Malaysia.

    Science.gov (United States)

    Nordin, Rusli Bin; Soni, Trived; Kaur, Amrina; Loh, Kean Por; Miranda, Shashi

    2018-05-18

    Erectile dysfunction (ED) is a serious burden globally that affects men as well as their partners. Therefore, the aim of this study was to determine the prevalence and predictors of ED among male outpatient clinic attendees in Johor, Malaysia. A cross-sectional study of Malaysian men aged 18 and older attending two major outpatient clinics in Johor Bahru and Segamat between 1 January and 31 March 2016 was undertaken. Subjects were chosen via simple random sampling and a sample size of 400 was recruited. The study instrument was a survey form that consisted of three sections: sociodemographic and comorbid profile, validated English and Malay version of the 15-item International Index of Erectile Function (IIEF-15) and 21-item Depression Anxiety and Stress Scale (DASS-21). The overall prevalence of self-reported ED was 81.5%. The prevalence of ED according to severity was as follows: mild (17%), mild to moderate (23.8%), moderate (11.3%), and severe (29.5%). Multivariate analysis showed that ED was associated with increasing age (odds ratio [OR] 4.023, 95% confidence interval [CI] 1.633-9.913), Indians as compared to Malays (OR 3.252, 95% CI 1.280-8.262), secondary as compared to tertiary education (OR 2.171, 95% CI 1.203-3.919), single as compared to married status (OR 6.119, 95% CI 2.542-14.734), and stress (OR 4.259, 95% CI 1.793-10.114). There is significant prevalence and severity of ED among adult male outpatient clinic attendees in Johor. Increasing age, Indian ethnicity, lower educational level, being single, and stress were significant predictors of ED.

  2. Effects of physically effective neutral detergent fiber content on dry matter intake, digestibility, and chewing activity in Korean native goats ( fed with total mixed ration

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    Se Young Jang

    2017-10-01

    Full Text Available Objective This experiment was to determine proper physical traits in the diet for goats by investigating the effects of physically effective neutral detergent fiber (peNDF content on dry matter intake (DMI, digestibility, and chewing activity in black goats fed with total mixed ration (TMR. Methods Six growing wethers of Korean native black goats (Capra hircus coreanae aged 8 months and weighing between 26.9 kg and 27.1 kg (27.03±5.05 kg were used in this experiment. Three diets of varying peNDF content were obtained by original TMR (T1, 12,000 rpm grinding (T2, and 15,500 rpm grinding (T3 of the same TMR diet. The peNDF1.18 content of the experimental diets was 23.85%, 21.71%, and 16.22% for T1, T2, and T3, respectively. Results Average daily gain (ADG was higher in T2 group compared to those of the control and T3 groups, but ADG and DMI were not affected by the dietary particle size and peNDF content. Also, there was no difference between apparent nutrient digestibility of dry matter, crude fiber, ether extract, neutral detergent fiber, and acid detergent fiber. Although there was no significant difference, rumination and total chewing time were associated with decreased peNDF content. Conclusion The feeding of peNDF-based TMR showed no impact on apparent nutrient digestibility and nitrogen balance. Further studies are required with a wider range of dietary peNDF level and particle size to better identify the effect of dietary peNDF and particle size on chewing activity and performance in goats.

  3. [The warning model and influence of climatic changes on hemorrhagic fever with renal syndrome in Changsha city].

    Science.gov (United States)

    Xiao, Hong; Tian, Huai-yu; Zhang, Xi-xing; Zhao, Jian; Zhu, Pei-juan; Liu, Ru-chun; Chen, Tian-mu; Dai, Xiang-yu; Lin, Xiao-ling

    2011-10-01

    To realize the influence of climatic changes on the transmission of hemorrhagic fever with renal syndrome (HFRS), and to explore the adoption of climatic factors in warning HFRS. A total of 2171 cases of HFRS and the synchronous climatic data in Changsha from 2000 to 2009 were collected to a climate-based forecasting model for HFRS transmission. The Cochran-Armitage trend test was employed to explore the variation trend of the annual incidence of HFRS. Cross-correlations analysis was then adopted to assess the time-lag period between the climatic factors, including monthly average temperature, relative humidity, rainfall and Multivariate Elño-Southern Oscillation Index (MEI) and the monthly HFRS cases. Finally the time-series Poisson regression model was constructed to analyze the influence of different climatic factors on the HFRS transmission. The annual incidence of HFRS in Changsha between 2000 - 2009 was 13.09/100 000 (755 cases), 9.92/100 000 (578 cases), 5.02/100 000 (294 cases), 2.55/100 000 (150 cases), 1.13/100 000 (67 cases), 1.16/100 000 (70 cases), 0.95/100 000 (58 cases), 1.40/100 000 (87 cases), 0.75/100 000 (47 cases) and 1.02/100 000 (65 cases), respectively. The incidence showed a decline during these years (Z = -5.78, P Climate factors significantly influence the incidence of HFRS. If the influence of variable-autocorrelation, seasonality, and long-term trend were controlled, the accuracy of forecasting by the time-series Poisson regression model in Changsha would be comparatively high, and we could forecast the incidence of HFRS in advance.

  4. Methane oxidation in an intensively cropped tropical rice field soil under long-term application of organic and mineral fertilizers.

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    Nayak, D R; Babu, Y Jagadeesh; Datta, A; Adhya, T K

    2007-01-01

    Methane (CH4) oxidation is the only known biological sink process for mitigating atmospheric and terrestrial emissions of CH4, a major greenhouse gas. Methane oxidation in an alluvial soil planted to rice (Oryza sativa L.) under long-term application of organic (compost with a C/N ratio of 21.71), and mineral fertilizers was measured in a field-cum-laboratory incubation study. Oxidation rates were quantified in terms of decrease in the concentration of CH4 in the headspace of incubation vessels and expressed as half-life (t(1)2) values. Methane oxidation rates significantly differed among the treatments and growth stages of the rice crop. Methane oxidation rates were high at the maximum tillering and maturity stages, whereas they were low at grain-filling stage. Methane oxidation was low (t(1)2) = 15.76 d) when provided with low concentration of CH4. On the contrary, high concentration of CH4 resulted in faster oxidation (t(1)2) = 6.67 d), suggesting the predominance of "low affinity oxidation" in rice fields. Methane oxidation was stimulated following the application of mineral fertilizers or compost implicating nutrient limitation as one of the factors affecting the process. Combined application of compost and mineral fertilizer, however, inhibited CH4 oxidation probably due to N immobilization by the added compost. The positive effect of mineral fertilizer on CH4 oxidation rate was evident only at high CH4 concentration (t(1)2 = 4.80 d), while at low CH4 concentration their was considerable suppression (t(1) = 17.60 d). Further research may reveal that long-term application of fertilizers, organic or inorganic, may not inhibit CH4 oxidation.

  5. The Role of Quality in the Adjudication of Public Tenders

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    Geo Quinot

    2014-08-01

    Full Text Available The quality of the goods or services that government procures is obviously a very important consideration in deciding which supplier should be awarded a particular public tender. It follows that in the regulation of public procurement, particular attention should be given to the role of quality (also called functionality in the adjudication of public tenders and the final award decision. In South African public procurement law, the role of functionality in public tender adjudication has been a fairly controversial issue that has resulted in a continuing interaction between courts and law-makers on how and when quality should be assessed and should impact on the final award decision within the framework for public procurement found in section 217 of the Constitution. This contribution tracks the development of the role of functionality in public tender adjudication as prescribed by public procurement regulation since the enactment of the Preferential Procurement Policy Framework Act 5 of 2000, which spearheaded the development of contemporary public procurement regulation in South Africa. The analysis shows how the role of functionality has constantly changed since the enactment of the PPPFA and remains uncertain. This uncertainty relates to different interpretations of the constitutional requirements for public procurement primarily contained in section 217(1 of the Constitution. Whether functionality is used as a qualification criterion, an award criterion or both holds particular practical implications for both suppliers and contracting authorities. It is accordingly important to have certainty on this question. However, it cannot be said that the Constitution and section 217 in particular dictates one approach rather than another. The issue should thus be resolved with reference to the statutory scheme adopted under the PPPFA.

  6. Birth data accessibility via primary care health records to classify health status in a multi-ethnic population of children: an observational study.

    Science.gov (United States)

    Bonner, Rachel; Bountziouka, Vassiliki; Stocks, Janet; Harding, Seeromanie; Wade, Angela; Griffiths, Chris; Sears, David; Fothergill, Helen; Slevin, Hannah; Lum, Sooky

    2015-01-22

    Access to reliable birth data (birthweight (BW) and gestational age (GA)) is essential for the identification of individuals who are at subsequent health risk. This study aimed to explore the feasibility of retrospectively collecting birth data for schoolchildren from parental questionnaires (PQ) and general practitioners (GPs) in primary care clinics, in inner city neighbourhoods with high density of ethnic minority and disadvantaged populations. Attempts were made to obtain birth data from parents and GPs for 2,171 London primary schoolchildren (34% White, 29% Black African origin, 25% South Asians, 12% Other) as part of a larger study of respiratory health. Information on BW and/or GA were obtained from parents for 2,052 (95%) children. Almost all parents (2,045) gave consent to access their children's health records held by GPs. On the basis of parental information, GPs of 1,785 children were successfully contacted, and GPs of 1,202 children responded. Birth data were retrieved for only 482 children (22% of 2,052). Missing birth data from GPs were associated with non-white ethnicity, non-UK born, English not the dominant language at home or socioeconomic disadvantage. Paired data were available in 376 children for BW and in 407 children for GA. No significant difference in BW or GA was observed between PQ and GP data, with data for primary schoolchildren yields high quality and rapid return of data, and it should be considered as a viable alternative in which there is limited access to birth records. It provides the potential to include children with an increased risk of health problems within epidemiological studies.

  7. Stapled trans-anal rectal resection (STARR) in the surgical treatment of the obstructed defecation syndrome: results of STARR Italian Registry.

    Science.gov (United States)

    Stuto, Angelo; Renzi, Adolfo; Carriero, Alfonso; Gabrielli, Francesco; Gianfreda, Valeria; Villani, Roberto Dino; Pietrantoni, Carmine; Seria, Giovanni; Capomagi, Antonio; Talento, Pasquale

    2011-09-01

    This study was designed to evaluate the safety and efficacy of stapled trans-anal rectal resection (STARR) in the treatment of obstructed defecation syndrome ODS by the analysis of the data collected in the STARR Italian Registry (SIR) with a special emphasis on the analysis of symptoms and quality of life. Collected data included, preoperative tests findings, and the evaluation of symptoms; the latter was obtained by using dedicated tools such as the Obstructed Defecation Syndrome Score (ODS-S), the Severity Symptom Score (SSS), and the Continence Grading Scale (CGS). Data on the quality of life were collected by Patient Assessment of Constipation Quality of Life (PAC-QoL) and the Euro Quality of Life-5 Domains Visual Analogue Scale (EQ-5D VAS). The evaluation of the symptoms and the quality of life was repeated 6 and 12 months after surgery. The SIR had collected data on 2171 patients (1653 females, 76.1%; mean age 56.2 years; range 20-96 years). A significant improvement (P < .0001) was seen between preoperative and 12-month follow-up in all scores: ODS-S (16.7 vs. 5.0), SSS (15.6 vs. 2.6), CGS (2.0 vs. 0.7), PAC-QoL (51.0 vs. 22.1), and EQ-5D VAS (57.5 vs. 85.7). Complications included defecatory urgency (4.5% at 12 months), bleeding (3.6%), perineal sepsis (3.4%), and one case of rectovaginal fistula (0.05%). The analysis of SIR data seems to confirm that STARR is a safe and effective procedure in the treatment of ODS. However, further studies are required to evaluate the long-term stability of results.

  8. Effects of age and viscosity on food transport and breathing-swallowing coordination during eating of two-phase food in nursing home residents.

    Science.gov (United States)

    Yamada, Tsuyoshi; Matsuo, Koichiro; Izawa, Masayuki; Yamada, Shizuru; Masuda, Yuji; Ogasawara, Tadashi

    2017-11-01

    When eating food that contains both liquid and solid phases, the liquid component frequently enters the hypopharynx before swallowing and can increase the risk of aspiration. Thus, we examined whether the initial viscosity of mixed consistency food could alter pre-swallow food transport and breathing-swallowing coordination in older adults. Fiberoptic endoscopy was recorded while 18 healthy young adults and 19 older adults ate 5 g of steamed rice combined with 3 mL of blue-dye water. Liquid viscosity was set at three levels by the addition of a thickening agent (0 wt%, thin; 2 wt%, thicker; 4 wt%, higher-viscosity, respectively). We measured the timing of swallow initiation and its corresponding respiratory phase for each participant. For thin mixed consistency food, whereas the timing of swallow initiation was comparable between young and older participants, swallowing was initiated during inspiration significantly more often in older participants (31.6 %) than in young participants (5.6 %). In contrast, the timing of swallow initiation was delayed in older participants for thicker and higher-viscosity foods, although swallowing was commonly initiated during expiration in both groups. In older adults, we observed that swallow initiation function was preserved for thin mixed consistency samples, but breathing-swallowing coupling was diminished. For higher-viscosity foods, swallow initiation was delayed in this group, but breathing-swallowing coordination was not disturbed, probably as a result of the slow bolus flow into the hypopharynx. Thus, it appears the initial viscosity of mixed consistency food profoundly affects food transport before swallowing as well as breathing-swallowing coordination in nursing home residents. Geriatr Gerontol Int 2017; 17: 2171-2177. © 2017 Japan Geriatrics Society.

  9. COMPARAÇÃO DE DE SUÍNOS CONVENCIONAIS E SPF (Specific pathogen Free

    Directory of Open Access Journals (Sweden)

    Luiz Fernando de Oliveira e Silva Carvalho

    1994-01-01

    Full Text Available RESUMO O experimento foi conduzido com o objetivo de qualificar e quantificar possíveis diferenças entre a produtividade de suínos convencionais e suínos SPF (Specific Pathogen Free. Foram mensurados e comparados, para tanto, a idade aos 100 quilos (IA, o ganho de peso diário (GPD, a conversão alimentar (CA e a espessura de toucinho (ET de um grupo com 42 machos, provenientes de granjas convencionais (grupo SC e outro com 113 machos, oriundos de granja SPF (grupo SPF. A média de peso corporal dos animais de ambos os grupos era de aproximadamente 30 quilos, ao início do experimento. A comparação entre as médias obtidas, para cada um dos parâmetros estudados, revelou produtividade estatisticamente significativa e superior em favor do grupo SPF. Assim, as IAs, os G PDs, as CAs e as ETs, obtidas para os grupos SPF e SC foram de, respectivamente, 150,49 e 156,4 dias, 897,78 e 955,19 gramas, 2,17:1 e 2,39:1 e 16,13 e 13,95mm. No grupo SPF, conforme evidenciado, observou-se um maior acúmulo de tecido adiposo, fato que sugere um menor dispêndio de energia para o combate a enfermidades crônicas, neste grupo de animais. Com base em projeção econômica dos resultados obtidos, os autores sugerem que a criação de animais SPF, embora possa exigir algum trabalho para sua implantação, é extremamente vantajosa, representando alternativa viável para a suinocultura brasileira.

  10. Overcoming IGF1R/IR Resistance Through Inhibition of MEK Signaling in Colorectal Cancer Models

    Science.gov (United States)

    Flanigan, Sara A.; Pitts, Todd M.; Newton, Timothy P.; Kulikowski, Gillian N.; Tan, Aik Choon; McManus, Martine C.; Spreafico, Anna; Kachaeva, Maria I.; Selby, Heather M.; Tentler, John J.; Eckhardt, S. Gail; Leong, Stephen

    2013-01-01

    Purpose Results from clinical trials involving resistance to molecularly targeted therapies have revealed the importance of rational single agent and combination treatment strategies. In this study, we tested the efficacy of a type 1 insulin-like growth factor receptor (IGF1R)/insulin receptor (IR) tyrosine kinase inhibitor (TKI), OSI-906, in combination with a MEK 1/2 inhibitor based on evidence that the MAPK pathway was upregulated in colorectal cancer (CRC) cell lines that were resistant to OSI-906. Experimental Design The antiproliferative effects of OSI-906 and the MEK 1/2 inhibitor U0126, were analyzed both as single agents and in combination in 13 CRC cell lines in vitro. Apoptosis, downstream effector proteins, and cell cycle were also assessed. Additionally, the efficacy of OSI-906 combined with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886), was evaluated in vivo using human CRC xenograft models. Results The combination of OSI-906 and U0126 resulted in synergistic effects in 11 out of 13 CRC cell lines tested. This synergy was variably associated with apoptosis or cell cycle arrest in addition to molecular effects on pro-survival pathways. The synergy was also reflected in the in vivo xenograft studies following treatment with the combination of OSI-906 and selumetinib. Conclusions Results from this study demonstrate synergistic antiproliferative effects in response to the combination of OSI-906 with a MEK 1/2 inhibitor in CRC cell line models both in vitro and in vivo, which supports the rational combination of OSI-906 with a MEK inhibitor in patients with CRC. PMID:24045180

  11. Esophageal mucosal breaks in gastroesophageal reflux disease partially responsive to proton pump inhibitor therapy.

    Science.gov (United States)

    Shaheen, Nicholas J; Denison, Hans; Björck, Karin; Silberg, Debra G

    2013-04-01

    Approximately 20-30% of patients with gastroesophageal reflux disease (GERD) do not experience complete symptom resolution during proton pump inhibitor (PPI) therapy. The aim of this study was to determine the prevalence of esophageal mucosal breaks among patients who have a partial response to PPI therapy. This was an analysis of data from a phase 2b clinical trial carried out to assess the efficacy and safety of a reflux inhibitor, lesogaberan (AZD3355), as an add-on to PPI therapy in this patient population (clinicaltrials.gov reference: NCT01005251). A total of 661 patients with persistent GERD symptoms who had received a minimum of 4 weeks of PPI therapy were included in the study. The prevalence of esophageal mucosal breaks was assessed according to (i) the most recent endoscopy results from within the previous 24 months, if available ("historical" endoscopies), and (ii) the results of endoscopies performed at study baseline ("baseline" endoscopies). Baseline endoscopies were not carried out in patients who had a historical endoscopy showing an absence of esophageal mucosal breaks. Historical endoscopy results were available for 244 patients, of whom 48 (19.7%) had esophageal mucosal breaks. Baseline endoscopies were carried out in 465 patients, of whom 146 (31.4%) had esophageal mucosal breaks. Sensitivity analyses showed a prevalence of esophageal mucosal breaks of 20-30%. In both the historical and baseline endoscopies, most esophageal mucosal breaks were Los Angeles grades A or B. In patients with GERD symptoms partially responsive to PPI therapy, mild-to-moderate severity esophageal mucosal breaks are common (prevalence 20-30%), and may contribute to symptom etiology.

  12. Efficacy and safety of lesogaberan in gastro-oesophageal reflux disease: a randomised controlled trial.

    Science.gov (United States)

    Shaheen, Nicholas J; Denison, Hans; Björck, Karin; Karlsson, Maria; Silberg, Debra G

    2013-09-01

    Lesogaberan (AZD3355) is a novel γ-aminobutyric acid B-type receptor agonist designed to treat gastro-oesophageal reflux disease (GERD) by inhibiting transient lower oesophageal sphincter relaxations. A randomised, double-blind, placebo-controlled, multi-centre phase IIb study was performed to assess the efficacy and safety of lesogaberan as an add-on to proton pump inhibitor (PPI) therapy in patients with GERD who are partially responsive to PPI therapy (ClinicalTrials.gov reference: NCT01005251). In total, 661 patients were randomised to receive 4 weeks of placebo or 60, 120, 180 or 240 mg of lesogaberan twice daily, in addition to ongoing PPI therapy. Symptoms were measured using the Reflux Symptom Questionnaire electronic Diary. Response to treatment was defined as having an average of ≥ 3 additional days per week of not more than mild GERD symptoms during treatment compared with baseline. In the primary analysis, 20.9%, 25.6%, 23.5% and 26.2% of patients responded to the 60, 120, 180 and 240 mg twice daily lesogaberan doses, respectively, and 17.9% responded to placebo. The response to the 240 mg twice daily dose was statistically significantly greater than the response to placebo using a one-sided test at the predefined significance level of p < 0.1. However, the absolute increases in the proportions of patients who responded to lesogaberan compared with placebo were low. Lesogaberan was generally well tolerated, although six patients receiving lesogaberan developed reversible elevated alanine transaminase levels. In patients with GERD symptoms partially responsive to PPI therapy, lesogaberan was only marginally superior to placebo in achieving an improvement in symptoms.

  13. Recent advances in the treatment of non-small cell and small cell lung cancer.

    Science.gov (United States)

    Stinchcombe, Thomas E

    2014-01-01

    Recent presentations at the American Society of Clinical Oncology (ASCO) meeting from 30 May to 3 June, 2014, will impact routine clinical care and the development of clinical trials in non-small cell lung cancer (NSCLC) and extensive stage small cell lung cancer (ES-SCLC). Patients with activating epidermal growth factor receptor (EGFR) mutations, defined as exon 19 and exon 21 L858R point mutations, experience a high objective response rate and prolonged progression-free survival with EGFR tyrosine kinase inhibitors. However, inevitably, patients experience disease progression and the most common mechanism of acquired resistance is an EGFR exon 20 T790M mutation. Several agents (AZD9291, CO-1686 and HM61713) have demonstrated impressive activity in patients with T790M resistance mutations. Additional data on the efficacy of first-line therapy with afatinib and the combination of erlotinib and bevacizumab for patients with EGFR mutant NSCLC were presented. The results of a phase III trial of crizotinib compared to platinum-pemetrexed in the first-line setting, and a phase I trial and expansion cohort of ceritinib, provided additional efficacy and toxicity data for patients with anaplastic lymphoma kinase rearranged NSCLC. A phase III trial of cisplatin and gemcitabine, with and without necitumumab, revealed an improvement in overall survival with the addition of necitumumab in patients with squamous NSCLC. In the second-line setting, a phase III trial of docetaxel with ramucirumab or placebo revealed an improvement in overall survival with the addition of ramucirumab. In extensive stage small cell lung cancer phase III trials of consolidative thoracic radiation therapy and prophylactic cranial radiation failed to reveal an improvement in overall survival.

  14. PARP Inhibition Restores Extrinsic Apoptotic Sensitivity in Glioblastoma

    Science.gov (United States)

    Karpel-Massler, Georg; Pareja, Fresia; Aimé, Pascaline; Shu, Chang; Chau, Lily; Westhoff, Mike-Andrew; Halatsch, Marc-Eric; Crary, John F.; Canoll, Peter; Siegelin, Markus D.

    2014-01-01

    Background Resistance to apoptosis is a paramount issue in the treatment of Glioblastoma (GBM). We show that targeting PARP by the small molecule inhibitors, Olaparib (AZD-2281) or PJ34, reduces proliferation and lowers the apoptotic threshold of GBM cells in vitro and in vivo. Methods The sensitizing effects of PARP inhibition on TRAIL-mediated apoptosis and potential toxicity were analyzed using viability assays and flow cytometry in established GBM cell lines, low-passage neurospheres and astrocytes in vitro. Molecular analyses included western blots and gene silencing. In vivo, effects on tumor growth were examined in a murine subcutaneous xenograft model. Results The combination treatment of PARP inhibitors and TRAIL led to an increased cell death with activation of caspases and inhibition of formation of neurospheres when compared to single-agent treatment. Mechanistically, pharmacological PARP inhibition elicited a nuclear stress response with up-regulation of down-stream DNA-stress response proteins, e.g., CCAAT enhancer binding protein (C/EBP) homology protein (CHOP). Furthermore, Olaparib and PJ34 increased protein levels of DR5 in a concentration and time-dependent manner. In turn, siRNA-mediated suppression of DR5 mitigated the effects of TRAIL/PARP inhibitor-mediated apoptosis. In addition, suppression of PARP-1 levels enhanced TRAIL-mediated apoptosis in malignant glioma cells. Treatment of human astrocytes with the combination of TRAIL/PARP inhibitors did not cause toxicity. Finally, the combination treatment of TRAIL and PJ34 significantly reduced tumor growth in vivo when compared to treatment with each agent alone. Conclusions PARP inhibition represents a promising avenue to overcome apoptotic resistance in GBM. PMID:25531448

  15. Morphometric magnetic resonance imaging and genetic testing in cerebellar abiotrophy in Arabian horses

    Science.gov (United States)

    2013-01-01

    Background Cerebellar abiotrophy (CA) is a rare but significant disease in Arabian horses caused by progressive death of the Purkinje cells resulting in cerebellar ataxia characterized by a typical head tremor, jerky head movements and lack of menace response. The specific role of magnetic resonance imaging (MRI) to support clinical diagnosis has been discussed. However, as yet MR imaging has only been described in one equine CA case. The role of MR morphometry in this regard is currently unknown. Due to the hereditary nature of the disease, genetic testing can support the diagnosis of CA. Therefore, the objective of this study was to perform MR morphometric analysis and genetic testing in four CA-affected Arabian horses and one German Riding Pony with purebred Arabian bloodlines in the third generation. Results CA was diagnosed pathohistologically in the five affected horses (2 months - 3 years) supported by clinical signs, necropsy, and genetic testing which confirmed the TOE1:g.2171G>A SNP genotype A/A in all CA-affected horses. On MR images morphometric analysis of the relative cerebellar size and relative cerebellar cerebrospinal fluid (CSF) space were compared to control images of 15 unaffected horses. It was demonstrated that in MR morphometric analyses, CA affected horses displayed a relatively smaller cerebellum compared to the entire brain mass than control animals (P = 0.0088). The relative cerebellar CSF space was larger in affected horses (P = 0.0017). Using a cut off value of 11.0% for relative cerebellar CSF space, the parameter differentiated between CA-affected horses and controls with a sensitivity of 100% and a specificity of 93.3%. Conclusions In conclusion, morphometric MRI and genetic analysis could be helpful to support the diagnosis of CA in vivo. PMID:23702154

  16. Date palm waste gasification in downdraft gasifier and simulation using ASPEN HYSYS

    International Nuclear Information System (INIS)

    Bassyouni, M.; Waheed ul Hasan, Syed; Abdel-Aziz, M.H.; Abdel-hamid, S.M.-S.; Naveed, Shahid; Hussain, Ahmed; Ani, Farid Nasir

    2014-01-01

    Highlights: • Simulation of date palm waste gasification using ASPEN HYSYS was studied. • A steady state simulation of downdraft gasifier has been developed. • The results were used to predict synthesis gas composition. • Simulation results and experimental results are in good agreement. - Abstract: The present research aims to study the simulation of date palm waste gasification using ASPEN HYSYS. A steady state simulation of downdraft gasifier firing date palm leaves has been developed. The model is able to predict syngas composition with sound accuracy and can be used to find optimal operating conditions of the gasifier. Biomass is defined as an unconventional hypothetical solid component in HYSYS. A set of six reactor models simulates various reaction zones of the downdraft gasifier in accordance with its hydrodynamics. Biomass decomposition into constituents in the pyrolysis zone is modeled with a conversion reactor. The combustion of char and volatiles in the combustion zone are modeled with equilibrium and Gibbs reactor models respectively. The gasification zone is modeled with a Gibbs and equilibrium reactor. The results of simulation are validated against experimental results of a parametric variability study on a lab scale gasifier. The proportion of synthesis gas increase as temperature increases (concentration, molar fraction, and partial pressure). CO 2 and CH 4 in the product gases were also found to decrease with increasing temperature. At 800 °C, the exit gas reaches a stable molar composition (H 2 = 56.27%, CO = 21.71%, CO 2 = 18.24%, CH 4 = 3.78%). Increasing steam to biomass ratio increases CO 2 and H 2 at the expense of CO, governed by shift reaction. Steam induction increases the methane contents, thereby improves the heating value of the product gas

  17. Date palm waste gasification in downdraft gasifier and simulation using ASPEN HYSYS

    Energy Technology Data Exchange (ETDEWEB)

    Bassyouni, M. [Department of Chemical and Materials Engineering, King Abdulaziz University, Rabigh 21911 (Saudi Arabia); Department of Chemical Engineering, Higher Technological Institute, Tenth of Ramdan City (Egypt); Waheed ul Hasan, Syed [Department of Chemical and Materials Engineering, King Abdulaziz University, Rabigh 21911 (Saudi Arabia); Abdel-Aziz, M.H., E-mail: helmy2002@gmail.com [Department of Chemical and Materials Engineering, King Abdulaziz University, Rabigh 21911 (Saudi Arabia); Chemical Engineering Department, Faculty of Engineering, Alexandria University, Alexandria (Egypt); Abdel-hamid, S. M.-S. [Department of Chemical Engineering, Higher Technological Institute, Tenth of Ramdan City (Egypt); Naveed, Shahid [Punjab Institute of Contemporary Sciences, 5.5 KM Raiwind Road, Lahore (Pakistan); Hussain, Ahmed [Department of Nuclear Engineering, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Ani, Farid Nasir [Faculty of Mechanical Engineering, Universiti Teknologi Malaysia, UTM 81310 Johor Bahru (Malaysia)

    2014-12-15

    Highlights: • Simulation of date palm waste gasification using ASPEN HYSYS was studied. • A steady state simulation of downdraft gasifier has been developed. • The results were used to predict synthesis gas composition. • Simulation results and experimental results are in good agreement. - Abstract: The present research aims to study the simulation of date palm waste gasification using ASPEN HYSYS. A steady state simulation of downdraft gasifier firing date palm leaves has been developed. The model is able to predict syngas composition with sound accuracy and can be used to find optimal operating conditions of the gasifier. Biomass is defined as an unconventional hypothetical solid component in HYSYS. A set of six reactor models simulates various reaction zones of the downdraft gasifier in accordance with its hydrodynamics. Biomass decomposition into constituents in the pyrolysis zone is modeled with a conversion reactor. The combustion of char and volatiles in the combustion zone are modeled with equilibrium and Gibbs reactor models respectively. The gasification zone is modeled with a Gibbs and equilibrium reactor. The results of simulation are validated against experimental results of a parametric variability study on a lab scale gasifier. The proportion of synthesis gas increase as temperature increases (concentration, molar fraction, and partial pressure). CO{sub 2} and CH{sub 4} in the product gases were also found to decrease with increasing temperature. At 800 °C, the exit gas reaches a stable molar composition (H{sub 2} = 56.27%, CO = 21.71%, CO{sub 2} = 18.24%, CH{sub 4} = 3.78%). Increasing steam to biomass ratio increases CO{sub 2} and H{sub 2} at the expense of CO, governed by shift reaction. Steam induction increases the methane contents, thereby improves the heating value of the product gas.

  18. Density dependence of dielectronic recombination in selenium

    International Nuclear Information System (INIS)

    Hagelstein, P.L.; Rosen, M.D.; Jacobs, V.L.

    1986-01-01

    Dielectronic recombination has been found to be the dominant recombination process in the determination of the ionization balance of selenium near the Ne-like sequence under conditions relevant to the exploding-foil EUV laser plasmas. The dielectronic recombination process tends to populate excited levels, and these levels in turn are more susceptible to subsequent excitation and ionization than are the ground-state ions. If one defines an effective recombination rate which includes, in addition to the primary recombination, the subsequent excitation and ionization of the additional excited-state population due to the primary recombination, then this effective recombination rate can be density-sensitive at relatively low electron density. We present results for this effective dielectronic recombination rate at an electron density of 3 x 10/sup 20/ electrons/cm 3 for recombination from Ne-like to Na-like selenium and from F-like to Ne-like selenium. In the former case, the effective recombination rate coefficient is found to be 1.8 x 10/sup -11/ cm 3 /sec at 1.0 keV, which is to be compared with the zero-density value of 2.8 x 10/sup -11/ cm 3 /sec. In the latter case (F-like to Ne-like), the effective recombination rate coefficient is found to be 1.3 x 10/sup -11/ cm 3 /sec, which is substantially reduced from the zero-density result of 3.3 x 10/sup -11/ cm 3 /sec. We have examined the effects of dielectronic recombination on the laser gain of the dominant Ne-like 3p-3s transitions and have compared our results with those presented by Whitten et al. [Phys. Rev. A 33, 2171 (1986)

  19. Eimeria spp. infecting quenda (Isoodon obesulus) in the greater Perth region, Western Australia.

    Science.gov (United States)

    Hillman, Alison E; Yang, Rongchang; Lymbery, Alan J; Thompson, R C Andrew

    2016-11-01

    Parasites of wildlife inhabiting urbanised and peri-urban environments are of interest regarding wildlife population health, and also veterinary public health in the case of parasites that can also infect humans and domestic animals. This study aimed to: identify, and estimate the prevalence of, species of Eimeria parasitic in quenda (Isoodon obesulus) in the greater Perth region, Western Australia; 2) morphologically describe and genetically characterise a novel observed species of Eimeria as E. angustus; and 3) genetically characterise E. kanyana. Eimeria spp. prevalence was 76.1% (95% CI 64.9-84.5%), and four putative species of Eimeria were identified. Eimeria kanyana was identified infecting quenda for the first time, with a prevalence of 54.9% (43.4-66.0%). Eimeria quenda was less prevalent, at 7.0% (3.1-15.5%). The novel species E. angustus was present in 45.1% of sampled quenda (34.0-56.6%). A second novel morphotype of Eimeria was present in 2.8% of sampled quenda (0.9-9.7%). Mixed Eimeria spp. infections were present in 21/71 quenda (29.6%, 95% CI 20.2-41.1%). Molecular phylogenetic analyses of E. kanyana and E. angustus were conducted at the 18S rRNA and mitochondrial cytochrome oxidase loci. At both loci, two isolates identified as E. kanyana grouped in a phylogenetic clade with E. trichosuri. Five isolates identified as the novel E. angustus were most closely related to E. tropidura at the 18S locus. At the COI locus, no sequence data were available for E. tropidura; isolates of E. angustus grouped with E. sciurorum. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Concurrent chemoradiotherapy was associated with a higher severe late toxicity rate in nasopharyngeal carcinoma patients compared with radiotherapy alone: a meta-analysis based on randomized controlled trials

    International Nuclear Information System (INIS)

    Du, Cheng-run; Ying, Hong-mei; Kong, Fang-fang; Zhai, Rui-ping; Hu, Chao-su

    2015-01-01

    To investigate the incidence and risk of severe late toxicity with concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma patients. Eligible studies included prospective randomized controlled trials (RCTs) evaluating CCRT versus radiotherapy alone in patients with nasopharyngeal carcinoma and in which data on severe late toxicities were available. Random effects or fixed effect models were applied to obtain the summary incidence, relative risks (RRs) and 95% confidence intervals (CIs). Five RCTs with 1102 patients with NPC were included in this analysis. The summary incidence of overall severe late toxicities in patients receiving CCRT was 30.7% (95% CI, 18–47.2%) and the incidence of radiotherapy alone group was 21.7% (95% CI, 13.3–33.4%). The use of concurrent chemotherapy was associated with an increased risk of severe late toxicities, with a RR of 1.349 (95% CI, 1.108–1.643; P = 0.005). As for specific late toxicity, CCRT significantly increased the risk of ear deafness/otitis (RR = 1.567; 95% CI, 1.192–2.052), but other late toxicities were not significantly different. Patients receiving concurrent chemotherapy regimens with 3-week high-dose cisplatin (HC) have a higher risk of ear deafness/otitis (RR = 1.672; 95% CI, 1.174–2.382; P = 0.026). However, there was no significant increase in the RR of severe ear complication with the addition of non-3-week high-dose cisplatin (nonHC) regimens (RR = 1.433; 95% CI, 0.946–2.171; P = 0.095). With the present evidence, the addition of concurrent chemotherapy seems to increase the risk of severe late toxicities in patients with NPC, especially when using HC regimen for the occurrence of severe ototoxicity

  1. Ethnic variability in body size, proportions and composition in children aged 5 to 11 years: is ethnic-specific calibration of bioelectrical impedance required?

    Directory of Open Access Journals (Sweden)

    Simon Lee

    Full Text Available Bioelectrical Impedance Analysis (BIA has the potential to be used widely as a method of assessing body fatness and composition, both in clinical and community settings. BIA provides bioelectrical properties, such as whole-body impedance which ideally needs to be calibrated against a gold-standard method in order to provide accurate estimates of fat-free mass. UK studies in older children and adolescents have shown that, when used in multi-ethnic populations, calibration equations need to include ethnic-specific terms, but whether this holds true for younger children remains to be elucidated. The aims of this study were to examine ethnic differences in body size, proportions and composition in children aged 5 to 11 years, and to establish the extent to which such differences could influence BIA calibration.In a multi-ethnic population of 2171 London primary school-children (47% boys; 34% White, 29% Black African/Caribbean, 25% South Asian, 12% Other detailed anthropometric measurements were performed and ethnic differences in body size and proportion were assessed. Ethnic differences in fat-free mass, derived by deuterium dilution, were further evaluated in a subsample of the population (n = 698. Multiple linear regression models were used to calibrate BIA against deuterium dilution.In children < 11 years of age, Black African/Caribbean children were significantly taller, heavier and had larger body size than children of other ethnicities. They also had larger waist and limb girths and relatively longer legs. Despite these differences, ethnic-specific terms did not contribute significantly to the BIA calibration equation (Fat-free mass = 1.12+0.71*(height2/impedance+0.18*weight.Although clear ethnic differences in body size, proportions and composition were evident in this population of young children aged 5 to 11 years, an ethnic-specific BIA calibration equation was not required.

  2. Sleep Problems Before and After Acute Myocardial Infarction: A Comparative Study

    Directory of Open Access Journals (Sweden)

    Belguzar Kara

    2012-12-01

    Full Text Available AIM: The purpose of this study was to compare patients’ sleep problems before and after acute myocardial infarction (AMI and also to determine factors affecting sleep problems in patients undergoing AMI. METHOD: This cross-sectional study was conducted at the Coronary Intensive Care Unit in a training hospital between January 1 and April 30, 2007. The sample of the study was composed of 26 patients with a first-ever AMI. Data were collected by using a questionnaire to determine the patient and illness-related descriptive characteristics and the Post Sleep Inventory Scale (PSIS. The Shapiro-Wilks test, descriptive statistics, paired samples t test, Mann Whitney U test, Wilcoxon test, reliability analysis and correlation analysis were used to analyze the data. RESULTS: The mean age of the study group was 53.2 ± 12.6 years and approximately 81% were males. The patients’ mean bedtime (t= -3.422, p= 0.001, quality of nocturnal sleep (t= -3.221, p= 0.001, awakening (t =-3.533, p<0.001 and total PSIS scores (t= -5.652, p<0.001 were significantly higher after AMI compared to before AMI. The mean PSIS scores of patients undergoing AMI were statistically significant different by gender (z= -2.164, p= 0.030 and working status (z= -2.171, p= 0.030. There was a negative correlation between the PSIS score and haemoglobin and haematocrit values (r= -0.503, p<0.01; r= -0.473, p<0.05; respectively. CONCLUSION: There were differences in the patients’ reported sleep problems between before and after AMI. The results of this study showed that sleep problems were more common among women, patients not working and those with anemia. Nurses should be aware of the sleep problems and factors that affect to sleep problems. [TAF Prev Med Bull 2012; 11(6.000: 687-694

  3. AMS 14 C dating controlled records of monsoon and Indonesian throughflow variability from the eastern Indian Ocean of the past 32,000 years

    Science.gov (United States)

    Li, Z. Y.; Chen, M. T.; Shi, X.; Liu, S.; Wang, H.

    2015-12-01

    Zi-Ye Li a, Min-Te Chen b, Hou-Jie Wang a, Sheng-Fa Liu c, Xue-Fa Shi ca College of Marine Geosciences, Ocean University of China, Qingdao 266100, P.R. Chinab Institute of Applied Geosciences, National Taiwan Ocean University, Keelung, Taiwan 20224, ROCc First Institute of Oceanography, SOA, Qingdao 266100, P.R. China Indonesian throughflow (ITF) is one of the most important currents responsible for transporting heat and moisture from the western Pacific to the Indian Oceans. The ITF is also well-known as effectively in modulating the global climate change with the interactions among ENSO and Asian monsoons. Here we present an AMS 14C dating controlled sea surface temperature (SST) record from core SO184-10043 (07°18.57'S, 105°03.53'E), which was retrieved from 2171m water depth at a north-south depression located at the southeastern offshore area of Sumatera in the eastern Indian Ocean. Based on our high-resolution SST using Mg/Ca analyses based on planktonic foraminifera shells of Globigerinoides ruber and alkenone index, U k'37-SST, oxygen isotope stratigraphy, and AMC 14C age-controls, our records show that, during the past 32,000 years, the SSTs were decreased which imply weaker ITF during Marine Isotope Stage (MIS) 2 and 3. The weaker UTF may respond to strengthened northeast monsoon during the boreal winter. During 21 to 15ka, the southeast monsoon had been stronger and the northeast monsoon was relatively weaker. During 15 to 8ka, rapid sea level rising may allow the opening of the gateways in the Makassar Strait and Lombok Strait that may have further strengthened the ITF. During the early Holocene, the northeast and southeast monsoons seem to be both strengthened. We will discuss the implications of the hydrographic variability and their age uncertainties in this paper during the meeting.

  4. Ultrasonographic patterns in patients with obstructed defaecation.

    Science.gov (United States)

    Brusciano, L; Limongelli, P; Pescatori, M; Napolitano, V; Gagliardi, G; Maffettone, V; Rossetti, G; del Genio, G; Russo, G; Pizza, F; del Genio, A

    2007-08-01

    Anal ultrasound is helpful in assessing organic anorectal lesions, but its role in functional disease is still questionable. The purpose of the present study is to assess anal-vaginal-dynamic perineal ultrasonographic findings in patients with obstructed defecation (OD) and healthy controls. Ninety-two consecutive patients (77 women; mean age 51 years; range 21-71) with symptoms of OD were retrospectively evaluated. All patients underwent digital exploration, endoanal and endovaginal ultrasound (US) with rotating probe. Forty-one patients underwent dynamic perineal US with linear probe. Anal manometry and defaecography were performed in 73 and 43 patients, respectively. Ultrasonographic findings of 92 patients with symptoms of OD were compared to 22 healthy controls. Anismus was defined on US when the difference in millimetres between the distance of the inner edge of the puborectalis muscle posteriorly and the probe at rest and on straining was less then 5 mm. Sensitivity and specificity were calculated by assuming defaecography as the gold standard for intussusception and rectocele and proctoscopy for rectal internal mucosal prolapse. Since no gold standard for the diagnosis of anismus was available in the literature, the agreement between anal US and all other diagnostic procedures was evaluated. The incidence of anismus resulted significantly higher (P anismus, anal ultrasonography resulted in agreement with perineal and vaginal US, manometry, defaecography, and digital exam (P < 0.05). Other lesions detected by US in patients with OD include solitary rectal ulcer, rectocele and enterocele. Damage of internal and/or external sphincter was diagnosed at anal US in 19/92 (20%) patients, all continent and with normal manometric values. Anal, vaginal and dynamic perineal ultrasonography can diagnose or confirm many of the abnormalities seen in patients with OD. The value of the information obtained by this non-invasive test and its role in the diagnostic algorithm

  5. Hospital electronic medical record enterprise application strategies: do they matter?

    Science.gov (United States)

    Fareed, Naleef; Ozcan, Yasar A; DeShazo, Jonathan P

    2012-01-01

    Successful implementations and the ability to reap the benefits of electronic medical record (EMR) systems may be correlated with the type of enterprise application strategy that an administrator chooses when acquiring an EMR system. Moreover, identifying the most optimal enterprise application strategy is a task that may have important linkages with hospital performance. This study explored whether hospitals that have adopted differential EMR enterprise application strategies concomitantly differ in their overall efficiency. Specifically, the study examined whether hospitals with a single-vendor strategy had a higher likelihood of being efficient than those with a best-of-breed strategy and whether hospitals with a best-of-suite strategy had a higher probability of being efficient than those with best-of-breed or single-vendor strategies. A conceptual framework was used to formulate testable hypotheses. A retrospective cross-sectional approach using data envelopment analysis was used to obtain efficiency scores of hospitals by EMR enterprise application strategy. A Tobit regression analysis was then used to determine the probability of a hospital being inefficient as related to its EMR enterprise application strategy, while moderating for the hospital's EMR "implementation status" and controlling for hospital and market characteristics. The data envelopment analysis of hospitals suggested that only 32 hospitals were efficient in the study's sample of 2,171 hospitals. The results from the post hoc analysis showed partial support for the hypothesis that hospitals with a best-of-suite strategy were more likely to be efficient than those with a single-vendor strategy. This study underscores the importance of understanding the differences between the three strategies discussed in this article. On the basis of the findings, hospital administrators should consider the efficiency associations that a specific strategy may have compared with another prior to moving toward

  6. Risk of tinnitus in patients with sleep apnea: A nationwide, population-based, case-control study.

    Science.gov (United States)

    Koo, Malcolm; Hwang, Juen-Haur

    2017-09-01

    To investigate the risk of tinnitus in patients with sleep disturbance or sleep apnea. Case control study. We identified 21,798 middle-aged and elderly patients with otolaryngologist-diagnosed tinnitus between January 1, 2000, and December 31, 2012, from the Longitudinal Health Insurance Database 2000 of the Taiwan National Health Insurance Research Database. A total of 108,990 controls were also identified from the same database based on frequency-matching on 10-year age interval, sex, and year of index date of the cases. Diagnoses of sleep disturbance (International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] codes 780.50, 780.52, 307.4) and sleep apnea (ICD-9-CM codes 780.51, 780.53, 780.57) in the cases and controls prior to the index date were assessed. The risks of tinnitus in patients with sleep disturbance and sleep apnea were separately evaluated with multivariate logistic regression analyses. The mean age of the total 130,788 patients was 59.8 years, and 47% of them were males. The risk of tinnitus was higher in patients with sleep disturbance compared to those without the condition (adjusted odds ratio [OR] = 1.13, 95% confidence interval [CI] [95% CI] = 1.11-1.17), and the risk of tinnitus was higher in patients with sleep apnea compared to those without the condition (adjusted OR = 1.36, 95% CI = 1.16-1.60). In this population-based, case-control study, the risk of tinnitus was found to be significantly higher among middle-aged and elderly Taiwanese patients with sleep disturbances, especially with sleep apnea. 3b. Laryngoscope, 127:2171-2175, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

  7. Genome-wide association study of susceptibility loci for breast cancer in Sardinian population.

    Science.gov (United States)

    Palomba, Grazia; Loi, Angela; Porcu, Eleonora; Cossu, Antonio; Zara, Ilenia; Budroni, Mario; Dei, Mariano; Lai, Sandra; Mulas, Antonella; Olmeo, Nina; Ionta, Maria Teresa; Atzori, Francesco; Cuccuru, Gianmauro; Pitzalis, Maristella; Zoledziewska, Magdalena; Olla, Nazario; Lovicu, Mario; Pisano, Marina; Abecasis, Gonçalo R; Uda, Manuela; Tanda, Francesco; Michailidou, Kyriaki; Easton, Douglas F; Chanock, Stephen J; Hoover, Robert N; Hunter, David J; Schlessinger, David; Sanna, Serena; Crisponi, Laura; Palmieri, Giuseppe

    2015-05-10

    Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p <  0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.

  8. Characterization of surface charge and mechanical properties of chitosan/alginate based biomaterials

    International Nuclear Information System (INIS)

    Verma, Devendra; Desai, Malav S.; Kulkarni, Namrata; Langrana, Noshir

    2011-01-01

    This study aims to examine mechanical properties and surface charge characteristics of chitosan/alginate-based films for biomedical applications. By varying the concentrations of chitosan and alginate, we have developed films with varying surface charge densities and mechanical characteristics. The surface charge densities of these films were determined by applying an analytical model on force curves derived from an atomic force microscope (AFM). The average surface charge densities of films containing 60% chitosan and 80% chitosan were found to be - 0.46 mC/m 2 and - 0.32 mC/m 2 , respectively. The surface charge density of 90% chitosan containing films was found to be neutral. The elastic moduli and the water content were found to be decreasing with increasing chitosan concentration. The films with 60%, 80% and 90% chitosan gained 93.5 ± 6.6%, 217.1 ± 22.1% and 396.8 ± 67.5% of their initial weight, respectively. Their elastic moduli were found to be 2.6 ± 0.14 MPa, 1.9 ± 0.27 MPa and 0.93 ± 0.12 MPa, respectively. The trend observed in the mechanical response of these films has been attributed to the combined effect of the concentration of polyelectrolyte complexes (PEC) and the amount of water absorbed. The Fourier transform infrared spectroscopy experiments indicate the presence of higher alginate on the surface of the films compared to the bulk in all films. The presence of higher alginate on surface is consistent with negative surface charge densities of these films, determined from AFM experiments. Highlights: → Chitosan/alginate based fibrous polyelectrolyte complex films were developed. → The average surface charge density of the films was determined using AFM. → Elastic modulus of the films increased with increase in PEC content. → FTIR analysis indicated higher alginate content on surface compared to bulk.

  9. Genome-wide association study of susceptibility loci for breast cancer in Sardinian population

    International Nuclear Information System (INIS)

    Palomba, Grazia; Loi, Angela; Porcu, Eleonora; Cossu, Antonio; Zara, Ilenia

    2015-01-01

    Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10 −6 level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10 −5 , we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16x10 −5 ), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population. The online version of this article (doi:10.1186/s12885-015-1392-9) contains supplementary material, which is available to authorized users

  10. Vernakalant hydrochloride for the treatment of atrial fibrillation.

    Science.gov (United States)

    Kozlowski, Dariusz; Budrejko, Szymon; Lip, Gregory Y H; Mikhailidis, Dimitri P; Rysz, Jacek; Raczak, Grzegorz; Banach, Maciej

    2009-12-01

    Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice. Rhythm control strategy for AF is limited by drug toxicity and side effects, and recent trials have shown that this strategy is not superior to a rate control one. New antiarrhythmic drugs, free of undesired effects, would enhance rhythm control, with the possibility of sinus rhythm restoration and maintenance. A promising find in the search for new antiarrhythmic therapies is atrial-tissue specific ion channels. The findings that the ultrarapid delayed rectifier (I(Kur)) and the inwardly rectifying, acetylcholine-regulated current (I(K-Ach)) exist in atrial but not ventricular tissue increase the probability that atrioselective drugs without ventricular proarrhythmic toxicity can be developed for treatment of patients with AF. There are also other potential targets for atrial-selective therapy: transient outward current (I(to)), rapidly and slowly activating delayed rectifier currents (I(Kr) and I(Ks)), atrial sodium current (I(Na)) and atrially expressed connexins. New drugs under development with promising atrial-selectivity include: tertiapin, NIP-142, NIP-141, JTV-519, AVE0118, AVE1231, DPO-1, AZD7009 and many others. Among such new agents, vernakalant hydrochloride is currently in an advanced phase of development and has already been evaluated in clinical trials. In this overview, we describe the history and current state of developmental process of the drug, as well as its mechanism of action and influence on electrophysiological parameters. Vernakalant seems to be effective in terminating recent-onset AF, but is not efficacious in long-lasting AF and atrial flutter. The drug may be relatively free of proarrhythmic effects, and exerts a protective effect on ventricular tissue and ventricular repolarization. It is expected that the intravenous formulation will soon be approved for the pharmacological termination of recent-onset AF.

  11. The inverse electron demand Diels-Alder click reaction in radiochemistry.

    Science.gov (United States)

    Reiner, Thomas; Zeglis, Brian M

    2014-04-01

    The inverse electron-demand Diels-Alder (IEDDA) cycloaddition between 1,2,4,5-tetrazines and strained alkene dienophiles is an emergent variety of catalyst-free 'click' chemistry that has the potential to have a transformational impact on the synthesis and development of radiopharmaceuticals. The ligation is selective, rapid, high-yielding, clean, and bioorthogonal and, since its advent in 2008, has been employed in a wide variety of chemical settings. In radiochemistry, the reaction has proven particularly useful with (18)  F and has already been utilized to create a number of (18)  F-labeled agents, including the PARP1-targeting small molecule (18)  F-AZD2281, the αv β3 integrin-targeting peptide (18)  F-RGD, and the GLP-1-targeting peptide (18)  F-exendin. The inherent flexibility of the ligation has also been applied to the construction of radiometal-based probes, specifically the development of a modular strategy for the synthesis of radioimmunoconjugates that effectively eliminates variability in the construction of these agents. Further, the exceptional speed and biorthogonality of the reaction have made it especially promising in the realm of in vivo pretargeted imaging and therapy, and pretargeted imaging strategies based on the isotopes (111) In, (18)  F, and (64) Cu have already proven capable of producing images with high tumor contrast and low levels of uptake in background, nontarget organs. Ultimately, the characteristics of inverse electron-demand Diels-Alder click chemistry make it almost uniquely well-suited for radiochemistry, and although the field is young, this ligation has the potential to make a tremendous impact on the synthesis, development, and study of novel radiopharmaceuticals. Copyright © 2013 John Wiley & Sons, Ltd.

  12. Potential role of mTORC2 as a therapeutic target in clear cell carcinoma of the ovary.

    Science.gov (United States)

    Hisamatsu, Takeshi; Mabuchi, Seiji; Matsumoto, Yuri; Kawano, Mahiru; Sasano, Tomoyuki; Takahashi, Ryoko; Sawada, Kenjiro; Ito, Kimihiko; Kurachi, Hirohisa; Schilder, Russell J; Testa, Joseph R; Kimura, Tadashi

    2013-07-01

    The goal of this study was to examine the role of mTOR complex 2 (mTORC2) as a therapeutic target in ovarian clear cell carcinoma (CCC), which is regarded as an aggressive, chemoresistant histologic subtype. Using tissue microarrays of 98 primary ovarian cancers [52 CCCs and 46 serous adenocarcinomas (SAC)], activation of mTORC2 was assessed by immunohistochemistry. Then, the growth-inhibitory effect of mTORC2-targeting therapy, as well as the role of mTORC2 signaling as a mechanism for acquired resistance to the mTOR complex 1 (mTORC1) inhibitor RAD001 in ovarian CCC, were examined using two pairs of RAD001-sensitive parental (RMG2 and HAC2) and RAD001-resistant CCC cell lines (RMG2-RR and HAC2-RR). mTORC2 was more frequently activated in CCCs than in SACs (71.2% vs. 45.7%). Simultaneous inhibition of mTORC1 and mTORC2 by AZD8055 markedly inhibited the proliferation of both RAD001-sensitive and -resistant cells in vitro. Treatment with RAD001 induced mTORC2-mediated AKT activation in RAD001-sensitive CCC cells. Moreover, increased activation of mTORC2-AKT signaling was observed in RAD001-resistant CCC cells compared with the respective parental cells. Inhibition of mTORC2 during RAD001 treatment enhanced the antitumor effect of RAD001 and prevented CCC cells from acquiring resistance to RAD001. In conclusion, mTORC2 is frequently activated, and can be a promising therapeutic target, in ovarian CCCs. Moreover, mTORC2-targeted therapy may be efficacious in a first-line setting as well as for second-line treatment of recurrent disease developing after RAD001-treatment.

  13. Suppressors for Human Epidermal Growth Factor Receptor 2/4 (HER2/4): A New Family of Anti-Toxoplasmic Agents in ARPE-19 Cells.

    Science.gov (United States)

    Kim, Yeong Hoon; Bhatt, Lokraj; Ahn, Hye-Jin; Yang, Zhaoshou; Lee, Won-Kyu; Nam, Ho-Woo

    2017-10-01

    The effects of tyrosine kinase inhibitors (TKIs) were evaluated on growth inhibition of intracellular Toxoplasma gondii in host ARPE-19 cells. The number of tachyzoites per parasitophorous vacuolar membrane (PVM) was counted after treatment with TKIs. T. gondii protein expression was assessed by western blot. Immunofluorescence assay was performed using Programmed Cell Death 4 (PDCD4) and T. gondii GRA3 antibodies. The TKIs were divided into 3 groups; non-epidermal growth factor receptor (non-EGFR), anti-human EGFR 2 (anti-HER2), and anti-HER2/4 TKIs, respectively. Group I TKIs (nintedanib, AZD9291, and sunitinib) were unable to inhibit proliferation without destroying host cells. Group II TKIs (lapatinib, gefitinib, erlotinib, and AG1478) inhibited proliferation up to 98% equivalent to control pyrimethamine (5 μM) at 20 μM and higher, without affecting host cells. Group III TKIs (neratinib, dacomitinib, afatinib, and pelitinib) inhibited proliferation up to 98% equivalent to pyrimethamine at 1-5 μM, but host cells were destroyed at 10-20 μM. In Group I, TgHSP90 and SAG1 inhibitions were weak, and GRA3 expression was moderately inhibited. In Group II, TgHSP90 and SAG1 expressions seemed to be slightly enhanced, while GRA3 showed none to mild inhibition; however, AG1478 inhibited all proteins moderately. Protein expression was blocked in Group III, comparable to pyrimethamine. PDCD4 and GRA3 were well localized inside the nuclei in Group I, mildly disrupted in Group II, and were completely disrupted in Group III. This study suggests the possibility of a vital T. gondii TK having potential HER2/4 properties, thus anti-HER2/4 TKIs may inhibit intracellular parasite proliferation with minimal adverse effects on host cells.

  14. Vorinostat Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and Activates STAT3/AKT/MAPK Pathways.

    Directory of Open Access Journals (Sweden)

    Valerie B Sampson

    Full Text Available Histone deacetylase inhibitors (HDACi have been evaluated in patients with Ewing sarcoma (EWS but demonstrated limited activity. To better understand the potential for HDACi in EWS, we evaluated the combination of the HDACi vorinostat, with DNA damaging agents SN-38 (the active metabolite of irinotecan and topoisomerase 1 inhibitor plus the alkylating agent temozolomide (ST. Drugs were evaluated in sequential and simultaneous combinations in two EWS cell lines. Results demonstrate that cell viability, DNA damage and reactive oxygen species (ROS production are dependent on the sequence of drug administration. Enhanced cytotoxicity is exhibited in vitro in EWS cell lines treated with ST administered before vorinostat, which was modestly higher than concomitant treatment and superior to vorinostat administered before ST. Drug combinations downregulate cyclin D1 to induce G0/G1 arrest and promote apoptosis by cleavage of caspase-3 and PARP. When ST is administered before or concomitantly with vorinostat there is activation of STAT3, MAPK and the p53 pathway. In contrast, when vorinostat is administered before ST, there is DNA repair, increased AKT phosphorylation and reduced H2B acetylation. Inhibition of AKT using the small molecule inhibitor MK-2206 did not restore H2B acetylation. Combining ST with the dual ALK and IGF-1R inhibitor, AZD3463 simultaneously inhibited STAT3 and AKT to enhance the cytotoxic effects of ST and further reduce cell growth suggesting that STAT3 and AKT activation were in part mediated by ALK and IGF-1R signaling. In summary, potent antiproliferative and proapoptotic activity were demonstrated for ST induced DNA damage before or simultaneous with HDAC inhibition and cell death was mediated through the p53 pathway. These observations may aid in designing new protocols for treating pediatric patients with high-risk EWS.

  15. Exogenous Restoration of TUSC2 Expression Induces Responsiveness to Erlotinib in Wildtype Epidermal Growth Factor Receptor (EGFR Lung Cancer Cells through Context Specific Pathways Resulting in Enhanced Therapeutic Efficacy.

    Directory of Open Access Journals (Sweden)

    Bingbing Dai

    Full Text Available Expression of the tumor suppressor gene TUSC2 is reduced or absent in most lung cancers and is associated with worse overall survival. In this study, we restored TUSC2 gene expression in several wild type EGFR non-small cell lung cancer (NSCLC cell lines resistant to the epidermal growth factor receptor (EGFR tyrosine kinase inhibitor erlotinib and analyzed their sensitivity to erlotinib in vitro and in vivo. A significant inhibition of cell growth and colony formation was observed with TUSC2 transient and stable expression. TUSC2-erlotinib cooperativity in vitro could be reproduced in vivo in subcutaneous tumor growth and lung metastasis formation lung cancer xenograft mouse models. Combination treatment with intravenous TUSC2 nanovesicles and erlotinib synergistically inhibited tumor growth and metastasis, and increased apoptotic activity. High-throughput qRT-PCR array analysis enabling multi-parallel expression profile analysis of eighty six receptor and non-receptor tyrosine kinase genes revealed a significant decrease of FGFR2 expression level, suggesting a potential role of FGFR2 in TUSC2-enhanced sensitivity to erlotinib. Western blots showed inhibition of FGFR2 by TUSC2 transient transfection, and marked increase of PARP, an apoptotic marker, cleavage level after TUSC2-erlotinb combined treatment. Suppression of FGFR2 by AZD4547 or gene knockdown enhanced sensitivity to erlotinib in some but not all tested cell lines. TUSC2 inhibits mTOR activation and the latter cell lines were responsive to the mTOR inhibitor rapamycin combined with erlotinib. These results suggest that TUSC2 restoration in wild type EGFR NSCLC may overcome erlotinib resistance, and identify FGFR2 and mTOR as critical regulators of this activity in varying cellular contexts. The therapeutic activity of TUSC2 could extend the use of erlotinib to lung cancer patients with wildtype EGFR.

  16. Structural Biology Insight for the Design of Sub-type Selective Aurora Kinase Inhibitors.

    Science.gov (United States)

    Sarvagalla, Sailu; Coumar, Mohane Selvaraj

    2015-01-01

    Aurora kinase A, B and C, are key regulators of mitosis and are over expressed in many of the human cancers, making them an ideal drug target for cancer chemotherapy. Currently, over a dozen of Aurora kinase inhibitors are in various phases of clinical development. The majority of the inhibitors (VX-680/MK-0457, PHA-739358, CYC116, SNS-314, AMG 900, AT-9283, SCH- 1473759, ABT-348, PF-03814735, R-763/AS-703569, KW-2449 and TAK-901) are pan-selective (isoform non-selective) and few are Aurora A (MLN8054, MLN8237, VX-689/MK5108 and ENMD 2076) and Aurora B (AZD1152 and GSK1070916) sub-type selective. Despite the intensive research efforts in the past decade, no Aurora kinase inhibitor has reached the market. Recent evidence suggests that the sub-type selective Aurora kinase A inhibitor could possess advantages over pan-selective Aurora inhibitors, by avoiding Aurora B mediated neutropenia. However, sub-type selective Aurora kinase A inhibitor design is very challenging due to the similarity in the active site among the isoforms. Structural biology and computational aspects pertaining to the design of Aurora kinase inhibitors were analyzed and found that a possible means to develop sub-type selective inhibitor is by targeting Aurora A specific residues (Leu215, Thr217 and Arg220) or Aurora B specific residues (Arg159, Glu161 and Lys164), near the solvent exposed region of the protein. Particularly, a useful strategy for the design of sub-type selective Aurora A inhibitor could be by targeting Thr217 residue as in the case of MLN8054. Further preclinical and clinical studies with the sub-type selective Aurora inhibitors could help bring them to the market for the treatment of cancer.

  17. Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin.

    Science.gov (United States)

    Marchiq, Ibtissam; Le Floch, Renaud; Roux, Danièle; Simon, Marie-Pierre; Pouyssegur, Jacques

    2015-01-01

    Rapidly growing glycolytic tumors require energy and intracellular pH (pHi) homeostasis through the activity of two major monocarboxylate transporters, MCT1 and the hypoxia-inducible MCT4, in intimate association with the glycoprotein CD147/BASIGIN (BSG). To further explore and validate the blockade of lactic acid export as an anticancer strategy, we disrupted, via zinc finger nucleases, MCT4 and BASIGIN genes in colon adenocarcinoma (LS174T) and glioblastoma (U87) human cell lines. First, we showed that homozygous loss of MCT4 dramatically sensitized cells to the MCT1 inhibitor AZD3965. Second, we demonstrated that knockout of BSG leads to a decrease in lactate transport activity of MCT1 and MCT4 by 10- and 6-fold, respectively. Consequently, cells accumulated an intracellular pool of lactic and pyruvic acids, magnified by the MCT1 inhibitor decreasing further pHi and glycolysis. As a result, we found that these glycolytic/MCT-deficient cells resumed growth by redirecting their metabolism toward OXPHOS. Third, we showed that in contrast with parental cells, BSG-null cells became highly sensitive to phenformin, an inhibitor of mitochondrial complex I. Phenformin addition to these MCT-disrupted cells in normoxic and hypoxic conditions induced a rapid drop in cellular ATP-inducing cell death by "metabolic catastrophe." Finally, xenograft analysis confirmed the deleterious tumor growth effect of MCT1/MCT4 ablation, an action enhanced by phenformin treatment. Collectively, these findings highlight that inhibition of the MCT/BSG complexes alone or in combination with phenformin provides an acute anticancer strategy to target highly glycolytic tumors. This genetic approach validates the anticancer potential of the MCT1 and MCT4 inhibitors in current development. ©2014 American Association for Cancer Research.

  18. Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study.

    Science.gov (United States)

    Miner, Philip B; Silberg, Debra G; Ruth, Magnus; Miller, Frank; Pandolfino, John

    2014-11-18

    The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders. In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance-pH measurements were taken. Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment. Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events. ClinicalTrials.gov identifier: NCT01043185.

  19. Vorinostat Enhances Cytotoxicity of SN-38 and Temozolomide in Ewing Sarcoma Cells and Activates STAT3/AKT/MAPK Pathways.

    Science.gov (United States)

    Sampson, Valerie B; Vetter, Nancy S; Kamara, Davida F; Collier, Anderson B; Gresh, Renee C; Kolb, E Anders

    2015-01-01

    Histone deacetylase inhibitors (HDACi) have been evaluated in patients with Ewing sarcoma (EWS) but demonstrated limited activity. To better understand the potential for HDACi in EWS, we evaluated the combination of the HDACi vorinostat, with DNA damaging agents SN-38 (the active metabolite of irinotecan and topoisomerase 1 inhibitor) plus the alkylating agent temozolomide (ST). Drugs were evaluated in sequential and simultaneous combinations in two EWS cell lines. Results demonstrate that cell viability, DNA damage and reactive oxygen species (ROS) production are dependent on the sequence of drug administration. Enhanced cytotoxicity is exhibited in vitro in EWS cell lines treated with ST administered before vorinostat, which was modestly higher than concomitant treatment and superior to vorinostat administered before ST. Drug combinations downregulate cyclin D1 to induce G0/G1 arrest and promote apoptosis by cleavage of caspase-3 and PARP. When ST is administered before or concomitantly with vorinostat there is activation of STAT3, MAPK and the p53 pathway. In contrast, when vorinostat is administered before ST, there is DNA repair, increased AKT phosphorylation and reduced H2B acetylation. Inhibition of AKT using the small molecule inhibitor MK-2206 did not restore H2B acetylation. Combining ST with the dual ALK and IGF-1R inhibitor, AZD3463 simultaneously inhibited STAT3 and AKT to enhance the cytotoxic effects of ST and further reduce cell growth suggesting that STAT3 and AKT activation were in part mediated by ALK and IGF-1R signaling. In summary, potent antiproliferative and proapoptotic activity were demonstrated for ST induced DNA damage before or simultaneous with HDAC inhibition and cell death was mediated through the p53 pathway. These observations may aid in designing new protocols for treating pediatric patients with high-risk EWS.

  20. Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer.

    Science.gov (United States)

    Choueiri, Toni K; Plimack, Elizabeth; Arkenau, Hendrik-Tobias; Jonasch, Eric; Heng, Daniel Y C; Powles, Thomas; Frigault, Melanie M; Clark, Edwin A; Handzel, Amir A; Gardner, Humphrey; Morgan, Shethah; Albiges, Laurence; Pal, Sumanta Kumar

    2017-09-10

    Purpose Patients with advanced papillary renal cell carcinoma (PRCC) have limited therapeutic options. PRCC may involve activation of the MET pathway, for example, through gene amplification or mutations. Savolitinib (AZD6094, HMPL-504, volitinib) is a highly selective MET tyrosine kinase inhibitor. We report results of a single-arm, multicenter, phase II study evaluating the safety and efficacy of savolitinib in patients with PRCC according to MET status. Patients and Methods Patients with histologically confirmed locally advanced or metastatic PRCC were enrolled and received savolitinib 600 mg orally once daily. MET-driven PRCC was defined as any of the following: chromosome 7 copy gain, focal MET or HGF gene amplification, or MET kinase domain mutations. Efficacy was assessed according to MET status. Safety, toxicity, and patient-reported health-related quality-of-life outcomes were assessed in all patients. Results Of 109 patients treated, PRCC was MET driven in 44 (40%) and MET independent in 46 (42%); MET status was unknown in 19 (17%). MET-driven PRCC was strongly associated with response; there were eight confirmed partial responders with MET-driven disease (18%), but none with MET-independent disease ( P = .002). Median progression-free survival for patients with MET-driven and MET-independent PRCC was 6.2 months (95% CI, 4.1 to 7.0 months) and 1.4 months (95% CI, 1.4 to 2.7 months), respectively (hazard ratio, 0.33; 95% CI, 0.20 to 0.52; log-rank P < .001). The most frequent adverse events associated with savolitinib were nausea, fatigue, vomiting, and peripheral edema. Conclusion These data show activity and tolerability of savolitinib in the subgroup of patients with MET-driven PRCC. Furthermore, molecular characterization of MET status was more predictive of response to savolitinib than a classification based on pathology. These findings justify investigating savolitinib in MET-driven PRCC.

  1. Stand-Alone Personalized Normative Feedback for College Student Drinkers: A Meta-Analytic Review, 2004 to 2014.

    Directory of Open Access Journals (Sweden)

    Keri B Dotson

    Full Text Available Norms clarification has been identified as an effective component of college student drinking interventions, prompting research on norms clarification as a single-component intervention known as Personalized Normative Feedback (PNF. Previous reviews have examined PNF in combination with other components but not as a stand-alone intervention.To investigate the degree to which computer-delivered stand-alone personalized normative feedback interventions reduce alcohol consumption and alcohol-related harms among college students and to compare gender-neutral and gender-specific PNF.Electronic databases were searched systematically through November 2014. Reference lists were reviewed manually and forward and backward searches were conducted.Outcome studies that compared computer-delivered, stand-alone PNF intervention with an assessment only, attention-matched, or active treatment control and reported alcohol use and harms among college students.Between-group effect sizes were calculated as the standardized mean difference in change scores between treatment and control groups divided by pooled standard deviation. Within-group effect sizes were calculated as the raw mean difference between baseline and follow-up divided by pooled within-groups standard deviation.Eight studies (13 interventions with a total of 2,050 participants were included. Compared to control participants, students who received gender-neutral (dbetween = 0.291, 95% CI [0.159, 0.423] and gender-specific PNF (dbetween = 0.284, 95% CI [0.117, 0.451] reported greater reductions in drinking from baseline to follow-up. Students who received gender-neutral PNF reported 3.027 (95% CI [2.171, 3.882] fewer drinks per week at first follow-up and gender-specific PNF reported 3.089 (95% CI [0.992, 5.186] fewer drinks. Intervention effects were small for harms (dbetween = 0.157, 95% CI [0.037, 0.278].Computer-delivered PNF is an effective stand-alone approach for reducing college student

  2. Changes in soil physical and chemical properties in long term improved natural and traditional agroforestry management systems of cacao genotypes in Peruvian Amazon.

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    Arévalo-Gardini, Enrique; Canto, Manuel; Alegre, Julio; Loli, Oscar; Julca, Alberto; Baligar, Virupax

    2015-01-01

    Growing cacao (Theobroma cacao L.) in an agroforestry system generates a productive use of the land, preserves the best conditions for physical, chemical and biological properties of tropical soils, and plays an important role in improving cacao production and fertility of degraded tropical soils. The aim of this study was to evaluate the impact of two long term agroforestry systems of cacao management on soil physical and chemical properties in an area originally inhabited by 30 years old native secondary forest (SF). The two agroforestry systems adapted were: improved natural agroforestry system (INAS) where trees without economic value were selectively removed to provide 50% shade and improved traditional agroforestry system (ITAS) where all native trees were cut and burnt in the location. For evaluation of the changes of soil physical and chemical properties with time due to the imposed cacao management systems, plots of 10 cacao genotypes (ICS95, UF613, CCN51, ICT1112, ICT1026, ICT2162, ICT2171, ICT2142, H35, U30) and one plot with a spontaneous hybrid were selected. Soil samples were taken at 0-20, 20-40 and 40-60 cm depths before the installation of the management systems (2004), and then followed at two years intervals. Bulk density, porosity, field capacity and wilting point varied significantly during the years of assessment in the different soil depths and under the systems assessed. Soil pH, CEC, exchangeable Mg and sum of the bases were higher in the INAS than the ITAS. In both systems, SOM, Ext. P, K and Fe, exch. K, Mg and Al+H decreased with years of cultivation; these changes were more evident in the 0-20 cm soil depth. Overall improvement of SOM and soil nutrient status was much higher in the ITAS than INAS. The levels of physical and chemical properties of soil under cacao genotypes showed a marked difference in both systems.

  3. Survey of owner motivations and veterinary input of owners feeding diets containing raw animal products

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    Stewart K. Morgan

    2017-03-01

    Full Text Available Background The practice of feeding of diets containing raw animal products (RAP to pets (dogs and cats is discouraged by veterinary organizations and governmental public health organizations. Nevertheless, the practice of feeding RAP to pets is increasing in popularity. Pet owner motivations for feeding RAP diets to pets have not been explored and the benefits of RAP diets remain largely anecdotal. We hypothesized that pet owners feeding RAP diets would not rely on veterinary advice in choosing their pet’s diet. We also hypothesized that these owners would have lower levels of trust in veterinary advice with respect to nutrition relative to pet owners not feeding RAP. Methods An anonymous web-based survey was developed to identify pet owner motivations for feeding RAP diets, and to characterize the veterinarian-client relationships of individuals feeding RAP diets. Results There were 2,337 respondents and 2,171 completed surveys. Of survey respondents, 804 reported feeding RAP at the time of the survey. While 20% of pet owners feeding RAP relied on online resources to determine what or how much RAP to feed, only 9% reported consulting with a veterinarian in making decisions about feeding RAP. Pet owners feeding RAP reported lower levels of trust in veterinary advice both ‘in general’ and ‘with respect to nutrition’ than pet owners not feeding RAP. Most pet owners reported that a discussion regarding their pet’s nutrition does not occur at every veterinary appointment. Discussion Pet owners feeding a RAP diet have lower trust in veterinary advice than pet owners not feeding a RAP diet. Owners feeding RAP are more reliant on online resources than their own veterinarian in deciding what and how much RAP to feed. Pet owners perceive that nutrition is not discussed at most veterinary appointments. Therefore, there is room for improvement in the veterinarian-client communication with regards to nutrition.

  4. Preliminary investigation of hybrid bioartificial liver support system in treatment of HBV-related acute-on-chronic liver failure

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    YOU Shaoli

    2013-09-01

    Full Text Available ObjectiveTo construct a hybrid bioartificial liver support system and to investigate its safety and efficacy in patients with hepatitis B virus (HBV-related acute-on-chronic liver failure (ACLF. MethodsA hollow fiber bioreactor was constructed using cultured HepG2 cells transfected with human augmenter of liver regeneration gene. Patients with HBV-related ACLF who were hospitalized in our hospital from May 2009 to August 2011 were randomly divided into treatment group (n=10 and control group (n=10. The treatment group was treated using the hybrid bioartificial liver support system, while the control group was treated with conventional plasma exchange. Comparison of means between the two groups was made by independent-samples t test, and comparison of variables before and after treatment was made by paired t test. ResultsOf the 10 patients in treatment group, 7 had improvement in clinical symptoms and were discharged, 1 died of hepatic encephalopathy, 1 died of hepatorenal syndrome, and 1 died of liver failure after discharge. Of the 10 patients in control group, 5 survived, 1 underwent liver transplantation, and 4 died of liver failure. Before treatment, the treatment group and control group had model for end-stage liver disease (MELD scores of 24.26±2.54 and 24.71±2.79, respectively, without significant difference between the two groups (t=1.971, P=0.064. The treatment group had MELD scores of 21.71±2.92, 22.10±4.46, and 19.90±5.43 after 3 days, 1 week, and 4 weeks, respectively, of treatment. At the end of one-year follow-up, the mean serum alpha-fetoprotein levels were 14.24 ng/ml in treatment group and 11.32 ng/ml in control group, and no space-occupying lesions in the liver were found through abdominal ultrasound. ConclusionThe constructed hybrid bioartificial liver support system is effective and safe in the treatment of HBV-related ACLF.

  5. Determinants of anemia among 6-59 months aged children in Bangladesh: evidence from nationally representative data.

    Science.gov (United States)

    Khan, Jahidur Rahman; Awan, Nabil; Misu, Farjana

    2016-01-11

    Anemia is a global public health problem but the burden of anemia is disproportionately borne among children in developing countries. Anemia in early stages of life has serious consequences on the growth and development of the children. We examine the prevalence of anemia, possible association between anemia and different socio-economic, demographic, health and other factors among children with ages from 6 to 59 months from the nationally representative 2011 Bangladesh Demographic and Health Survey (BDHS). Data on hemoglobin (Hb) concentration among the children aged 6-59 months from the most recent BDHS (2011) were used. This nationally representative survey allowed a multistage stratified cluster sampling design and provided data on a wide range of indicators such as fertility, mortality, women and child health, nutrition and other background characteristics. Anemia status was determined using hemoglobin level (<11.0 g/dl), and weighted prevalence of childhood anemia along with 95 % confidence intervals were provided. We also examined the distribution of weighted anemia prevalence across different groups and performed logistic regression to assess the association of anemia with different factors. A total of 2171 children aged 6-59 months were identified for this analysis, with weighted prevalence of anemia being 51.9 % overall- 47.4 % in urban and 53.1 % in rural regions. Results of a multivariable logistic regression analysis showed that, children below 24 months of age (odds ratio, [OR] 3.01; 95 % confidence interval [CI] 2.38-3.81), and those from an anemic mother (OR 1.80; 95 % CI 1.49-2.18) were at higher risk of anemia. Childhood anemia was significantly associated with chronic malnutrition of child, source of drinking water, household wealth and geographical location (defined by division). A high prevalence of anemia among 6-59 months aged children was observed in Bangladesh. Given the negative impact of anemia on the development of children in

  6. [The incidence of oral candidiasis in patients with human immunodeficiency virus infection/acquired immunodeficiency syndrome from Yunnan, China].

    Science.gov (United States)

    Wen, Yan; Li, Chengwen; Pei, Junhaoxiang; Bai, Jinsong; Yang, Xianghong; Duan, Kaiwen

    2014-08-01

    To assess the incidence of oral candidiasis and its influencing factors in patients with human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS). An oral examination was conducted in the 1 566 HIV/AIDS patients in the Third Hospital of Kunming from March 2008 to September 2012 (M/F: 1 062/504, age range: 0.2 to 84.0 years old). The HIV viral load (HIV- RNA) and peripheral blood CD4 count were respectively analyzed by Bayer Q340 fluorescence signal surveying instrument (bDNA method) and flow cytometry analysis. The information on usage of highly active anti-retroviral (HAART) drugs and transmission of HIV were obtained through questionnaires. The incidence of oral candidiasis in patients with different HIV-RNA levels and CD4 count and the use of HAART was analyzed and compared. The total incidence of oral candidosis was 31.0% (486/1 566) and there was no difference in sex. The oral lesions were presented by three types, psudomembranous candidosis (PC), erythematous candidosis (EC) and angular cheilitis (AC), and the morbidity was 13.9% (217/1 566), 17.0% (267/1 566) and 4.9% (77/1 566), respectively. The average level of CD4 count in psudomembranous candidosis, erythematous candidosis and angular cheilitis [81.0 (146.0), 74.0 (152.0) and 69.0 (121.5) cell/µl] showed no significant difference (P > 0.05). The incidence of oral candidiasis in non-HAART and HAART subjects were 36.3% (402/1 107) and 18.3% (84/459), respectively (P = 0.000). The CD4 count and absolute counts of HIV viral load in oral candidiasis patients and non-oral candidiasis patients had significant difference (Z = -10.261, P = 0.000 and Z = -4.762, P = 0.000). The morbidity of oral candidiasis in HIV/AIDS patients in Yunnan Province was high, including PC, EC and AC and hyperplastic candidosis was not detected. The incidence was related to the degree of immune suppression and HIV viral load.

  7. The effect of intravitreal bevacizumab and transpupillary thermotherapy on choroidal metastases and literature review

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    Chun-Ju Lin

    2015-01-01

    Full Text Available Aims : To represent the effects of transpupillary thermotherapy (TTT and intravitreal bevacizumab on choroidal metastases and review the literature. Settings and Design : A retrospective, interventional, noncomparative case series. Materials and Methods : A retrospective, interventional, noncomparative case series of five eyes in three patients with choroidal metastases was conducted. Fundus findings of choroidal metastases were divided into two types: Solitary or diffuse type. The size of the tumor was termed small (15 mm diameter. All eyes received one session of TTT followed by 3 weekly intravitreal bevacizumab injections as an adjuvant therapy. The parameters of treatment for TTT were 1.2-3 mm spot size, 150-300 mW, 60 s with the whole lesion covered confluently. The changes in preoperative and postoperative best-corrected visual acuity (BCVA were recorded. Serial color fundus photography and optical coherent tomography were performed to measure the treatment efficacy. Results : All eight choroidal metastases were solitary type. The size of six tumors was small, the size of one tumor was medium, and the size of one tumor was large. All five eyes of the three patients had improvement of BCVA after treatment. Fundus photos revealed tumor shrinkage and the mean shrinkage percentage was 61.27 ± 21.71%. Optical coherence tomography revealed complete resolution of serous retinal detachment. There was no recurrence after 6 months follow-up. Conclusions : TTT combined with intravitreal bevacizumab injections brought about beneficial effects in reducing tumor size and improving vision in all five eyes of the three patients. Despite the retrospective nature of our study, the absence of control group and the size limitation that, of course, limit the statistical power, TTT combined with intravitreal bevacizumab seems to be efficient in providing another cost-reducing and time-saving treatment option for patients with choroidal metastases. The

  8. Metagenome-assembled genomes of deep-branching magnetotactic bacteria in the Nitrospirae phylum

    Science.gov (United States)

    Zhang, W.; He, M.; Gu, L.; Tang, X.; Pan, Y.; Lin, W.

    2017-12-01

    , 2017a. Origin of microbial biomineralization and magnetotaxis during the Archean. Proc Natl Acad Sci U S A, 114, 2171-2176. Lin W, Pan Y, Bazylinski DA, 2017b. Diversity and ecology of and biomineralization by magnetotactic bacteria. Environ Microbiol Rep, 9 (4), 345-356.

  9. Sick Leave within 5 Years of Whiplash Trauma Predicts Recovery: A Prospective Cohort and Register-Based Study.

    Science.gov (United States)

    Carstensen, Tina Birgitte Wisbech; Fink, Per; Oernboel, Eva; Kasch, Helge; Jensen, Troels Staehelin; Frostholm, Lisbeth

    2015-01-01

    10-22% of individuals sustaining whiplash trauma develop persistent symptoms resulting in reduced working ability and decreased quality of life, but it is poorly understood why some people do not recover. Various collision and post-collision risk factors have been studied, but little is known about pre-collision risk factors. In particular, the impact of sickness and socioeconomic factors before the collision on recovery is sparsely explored. The aim of this study was to examine if welfare payments received within five years pre-collision predict neck pain and negative change in provisional situation one year post-collision. 719 individuals with acute whiplash trauma consecutively recruited from emergency departments or primary care after car accidents in Denmark completed questionnaires on socio-demographic and health factors immediately after the collision. After 12 months, a visual analogue scale on neck pain intensity was completed. 3595 matched controls in the general population were sampled, and national public register data on social benefits and any other welfare payments were obtained for participants with acute whiplash trauma and controls from five years pre-collision to 15 months after. Participants with acute whiplash trauma who had received sickness benefit for more than 12 weeks pre-collision had increased odds for negative change in future provisional situation (Odds Ratio (OR) (95% Confidence Interval (CI) = 3.8 (2.1;7.1)) and future neck pain (OR (95%CI) = 3.3 (1.8;6.3)), controlling for other known risk factors. Participants with acute whiplash trauma had weaker attachment to labour market (more weeks of sick leave (χ2(2) = 36.7, p whiplash trauma raised the odds for future negative change in provisional situation (OR (95%CI) = 3.1 (2.3;4.4)) compared with controls. Sick leave before the collision strongly predicted prolonged recovery following whiplash trauma. Participants with acute whiplash trauma had weaker attachment to labour market pre

  10. Paleomagnetism of the Cretaceous Galula Formation and implications for vertebrate evolution

    Science.gov (United States)

    Widlansky, Sarah J.; Clyde, William C.; O'Connor, Patrick M.; Roberts, Eric M.; Stevens, Nancy J.

    2018-03-01

    This study uses magnetostratigraphy to help constrain the age of the paleontologically important Galula Formation (Rukwa Rift Basin, southwestern Tanzania). The formation preserves a Cretaceous vertebrate fauna, including saurischian dinosaurs, a putative gondwanatherian mammal, and notosuchian crocodyliforms. With better dating, the Galula Formation and its fossils help fill a temporal gap in our understanding of vertebrate evolution in continental Africa, enabling better evaluation of competing paleobiogeographic hypotheses concerning faunal exchange throughout Gondwana during the Cretaceous. Paleomagnetic samples for this study were collected from the Namba (higher in section) and Mtuka (lower in section) members of the Galula Formation and underwent stepwise thermal demagnetization. All samples displayed a strong normal magnetic polarity overprint, and maximum unblocking temperatures at approximately 690 °C. Three short reversed intervals were identified in the Namba Member, whereas the Mtuka Member lacked any clear reversals. Given the relatively limited existing age constraints, one interpretation correlates the Namba Member to Chron C32. An alternative correlation assigns reversals in the Namba Member to recently proposed short reversals near the end of the Cretaceous Normal Superchron (Chron C34), a time that is traditionally interpreted as having stable normal polarity. The lack of reversals in the Mtuka Member supports deposition within Chron C34. These data suggest that the Namba Member is no older than Late Cretaceous (Cenomanian-Campanian), with the Mtuka Member less well constrained to the middle Cretaceous (Aptian-Cenomanian). The paleomagnetic results are supported by the application of fold and reversal tests for paleomagnetic stability, and paleomagnetic poles for the Namba (246.4°/77.9°, α95 5.9°) and Mtuka (217.1°/72.2°, α95 11.1°) members closely matching the apparent polar wander path for Africa during the Late Cretaceous. These

  11. Stand-Alone Personalized Normative Feedback for College Student Drinkers: A Meta-Analytic Review, 2004 to 2014.

    Science.gov (United States)

    Dotson, Keri B; Dunn, Michael E; Bowers, Clint A

    2015-01-01

    Norms clarification has been identified as an effective component of college student drinking interventions, prompting research on norms clarification as a single-component intervention known as Personalized Normative Feedback (PNF). Previous reviews have examined PNF in combination with other components but not as a stand-alone intervention. To investigate the degree to which computer-delivered stand-alone personalized normative feedback interventions reduce alcohol consumption and alcohol-related harms among college students and to compare gender-neutral and gender-specific PNF. Electronic databases were searched systematically through November 2014. Reference lists were reviewed manually and forward and backward searches were conducted. Outcome studies that compared computer-delivered, stand-alone PNF intervention with an assessment only, attention-matched, or active treatment control and reported alcohol use and harms among college students. Between-group effect sizes were calculated as the standardized mean difference in change scores between treatment and control groups divided by pooled standard deviation. Within-group effect sizes were calculated as the raw mean difference between baseline and follow-up divided by pooled within-groups standard deviation. Eight studies (13 interventions) with a total of 2,050 participants were included. Compared to control participants, students who received gender-neutral (dbetween = 0.291, 95% CI [0.159, 0.423]) and gender-specific PNF (dbetween = 0.284, 95% CI [0.117, 0.451]) reported greater reductions in drinking from baseline to follow-up. Students who received gender-neutral PNF reported 3.027 (95% CI [2.171, 3.882]) fewer drinks per week at first follow-up and gender-specific PNF reported 3.089 (95% CI [0.992, 5.186]) fewer drinks. Intervention effects were small for harms (dbetween = 0.157, 95% CI [0.037, 0.278]). Computer-delivered PNF is an effective stand-alone approach for reducing college student drinking and

  12. Effects of Dietary Approach to Stop Hypertension diet on androgens, antioxidant status and body composition in overweight and obese women with polycystic ovary syndrome: a randomised controlled trial.

    Science.gov (United States)

    Azadi-Yazdi, M; Karimi-Zarchi, M; Salehi-Abargouei, A; Fallahzadeh, H; Nadjarzadeh, A

    2017-06-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disease in reproductive age women. The present study aimed to determine the effects of Dietary Approaches to Stop Hypertension (DASH) diet on reproductive hormones, plasma total antioxidant status and anthropometric indices in overweight and obese PCOS women. In this randomised controlled clinical trial, 60 women with PCOS were randomly assigned to one of two diets with energy restriction: the DASH diet and a control diet. The DASH and control diets consisted of 50-55% carbohydrate, 15-20% protein and 25-30% total fat. The DASH diet was designed to be rich in vegetables, fruits, whole grains and low-fat dairy products, as well as low in saturated fats, cholesterol, refined grains and sweets. In the present study, the anthropometric indices, body composition, total testosterone, androstenedione, sex hormone binding globulin (SHBG), free androgen index and 2,2'-diphenyl-1-picryylhydrazyl (DPPH) scavenging activity were measured before and after 3 months. The consumption of DASH diet compared to the control diet was associated with a significant reduction in weight [-5.78 (1.91) kg versus -4.34 (2.87) kg, P = 0.032], body mass index (BMI) [-2.29 (0.15) kg m -2 versus -1.69 (0.20) kg m -2 , P = 0.02], fat mass [-3.23(1.66) kg versus -2.13 (1.26) kg, P = 0.008] and serum androstenedione [-1.75 (1.39) ng mL -1 versus -1.02 (0.72) ng mL -1 , P-value = 0.019]. Increased concentrations of SHBG [28.80 (21.71) versus 11.66(18.82) nmol L -1 , P = 0.003) and DPPH scavenging activity [30.23% (19.09) versus 12.97% (25.12) were also found in the DASH group. The DASH diet could improve weight loss, BMI and fat mass. Furthermore, it could result in a significant reduction in serum androstenedione and a significant increase in antioxidant status and SHBG. © 2016 The British Dietetic Association Ltd.

  13. The association between stress and headache: A longitudinal population-based study.

    Science.gov (United States)

    Schramm, Sara H; Moebus, Susanne; Lehmann, Nils; Galli, Ursula; Obermann, Mark; Bock, Eva; Yoon, Min-Suk; Diener, Hans-Christoph; Katsarava, Zaza

    2015-09-01

    We studied the association between stress intensity and headache frequency for tension-type headache (TTH), migraine and migraine with coexisting TTH (MigTTH). We studied a population-based sample of 5159 participants (21-71 years) who were asked quarterly between March 2010 and April 2012 about headache and stress. Log-linear regression in the framework of generalized estimating equations was used to estimate regression coefficients presented as percent changes to describe the association between stress intensity (modified visual analog scale (VAS) from 0 to 100) and headache frequency (days/month) stratified by headache subtypes and age groups and adjusted for sex, age, frequent intake of acute pain drugs, drinking, smoking, BMI and education. TTH was reported in 31% participants (48.1 ± 12.5years, 51.5% women, 2.2 ± 3.9 mean headache days/month, 52.3 ± 26.7 mean stress), migraine in 14% (44.8 ± 11.3years, 73.3%, 4.5 ± 5.2 days/month, 62.4 ± 23.3), MigTTH in 10.6% (43.5 ± 11.5 years, 61.0%, 3.6 ± 4.8 days/month, 58.6 ± 24.1), 23.6% were unclassifiable, and 20.8% had no headache. In participants with TTH an increase of 10 points on VAS was associated with an increase of headaches days/month of 6.0% (adjusted). Higher effects were observed in younger age groups (21-30/31-40/41-50/51-60/61-71 years: 9.8/10.2/7.0/6.5/3.5%). Slightly lower effects were observed for migraine (4.3%, 8.1/5.1/3.4/6.3/0.3%) and MigTTH (4.2%, 5.5/6.8/6.9/5.8/-0.7%). Our study provides evidence for an association between stress intensity and headache frequency. © International Headache Society 2014.

  14. Trophic dynamics of few selected nearshore coastal finfishes with emphasis on prawns as prey item

    Science.gov (United States)

    Velip, Dinesh T.; Rivonker, Chandrashekher U.

    2018-06-01

    A trophic dynamic study of marine finfishes was undertaken based on stomach content analysis of twenty four species (N = 1742) collected from the nearshore coastal waters off Goa, west coast of India (15°29‧07.6″ N to 15°34‧44.3″ N, and 73°38‧10.5″ E to 73°46‧03.1″ E) during November 2010 to May 2013. This study aimed to thoroughly understand the feeding attributes of finfishes, and comprehend the possible effects of bycatch-related loss of biomass on trophic ecology. The study assessed diet preferences of the finfishes, their feeding guilds, significance of prawns as prey items, and the influence of mouth parts in prey selection. Altogether 84 prey taxa were identified from the stomach contents. Percentage Index of Relative Importance (IRI) values revealed that zooplankton (34.74), prawns (21.71), phytoplankton (19.80), and teleosts (18.62) were the major prey categories, and, among prawns, Metapenaeus dobsoni (%IRI = 19.34) was the single-most important prey item. Cluster analysis revealed three major trophic guilds namely 'teleost feeders' (mean Trophic Level (TrL) = 4.06 ± 0.42; mean B = 0.46 ± 0.24), 'zooplankton feeders' (mean TrL = 3.43 ± 0.29; mean B = 0.23 ± 0.13), and 'prawn feeders' (mean TrL = 3.86 ± 0.25; mean B = 0.48 ± 0.32), with low diet overlap among them. Principal Component Analysis of prey categories and mouth parts of finfishes suggested that zooplanktivory is associated with gill raker density as well as number of gill arches bearing rakers, whereas gape height determined the size of large-sized prey (fish and invertebrates). The study identified M. dobsoni, mysis and teleosts as highly influential prey for predatory finfishes. The present results could be useful to resolve broader issues in fisheries management.

  15. [Influencing factors for job satisfaction in train drivers in a railway bureau: an analysis of 1413 cases].

    Science.gov (United States)

    Gu, G Z; Yu, S F; Zhou, W H; Wu, H; Kang, L; Chen, R

    2017-01-20

    Objective: To investigate the influencing factors for job satisfaction in train drivers. Methods: In March 2012, cluster sampling was used to conduct a cross-sectional survey in 1413 male train drivers (including 301 passenger train drivers, 683 freight train drivers, 350 passenger shunting train drivers, and 79 high-speed train drivers) from a locomotive depot of a railway bureau. The occupational stress instruments, job content questionnaire, and effort-reward imbalance questionnaire were used to analyze job satisfaction, occupational stress factors, stress reaction, individual characteristics, coping strategies, and social support. Results: There were significant differences in job satisfaction score between the drivers with different posts, working years, ages, smoking status, and drinking status ( P analysis revealed that job satisfaction score was positively correlated with reward, working stability, promotion opportunity, positive emotion, social support, self-esteem, and coping strategy scores ( P analysis of variance showed that compared with the moderate and low job satisfaction groups, the high job satisfaction group had significantly higher reward, positive emotion, promotion opportunity, and role ambiguity scores ( P job satisfaction groups the low job satisfaction group had significantly higher scores of psychological needs, effort, role conflict, sleep disorders, daily stress, depressive symptom, negative emotion, drug use, intragroup conflict, and social support ( P job satisfaction group had a significantly higher score of self-esteem than the other two groups ( P analysis showed that the risk of job dissatisfaction in the drivers with low so-cial support and high daily stress was more than 2 times that in those with high social support and low daily stress ( OR =2.176 and 2.171) , and sleep disorders, effort, depressive symptom, low self-esteem, and role conflict were risk factors for job dissatisfaction ( OR =1.48-1.625). Conclusion: Occupational

  16. (R)-(3-amino-2-fluoropropyl) phosphinic acid (AZD3355), a novel GABAB receptor agonist, inhibits transient lower esophageal sphincter relaxation through a peripheral mode of action

    DEFF Research Database (Denmark)

    Lehmann, Anders; Antonsson, Madeleine; Holmberg, Ann Aurell

    2009-01-01

    Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition...

  17. Additive effects of low concentrations of estradiol-17β and progesterone on nitric oxide production by human vascular endothelial cells through shared signaling pathways.

    Science.gov (United States)

    Pang, Yefei; Thomas, Peter

    2017-01-01

    Potential cardiovascular benefits of low-dose formulations of estrogens and progesterone (P4) for treating climacteric symptoms in postmenopausal women remain unclear because information is lacking on their combined vascular effects. Protective effects of low concentrations (5nM) of P4 and estradiol-17β (E2), alone and in combination (P4+E2), were investigated in a nongenomic model of vascular protection which measured acute increases in nitric oxide (NO) production by cultured human umbilical vein endothelial cells (HUVECs). Treatment with 5nM P4+E2 for twenty minutes significantly increased NO production and endothelial NO synthase (eNOS) phosphorylation, whereas 5nM treatments with either steroid alone were ineffective. The 5nM P4+E2 treatment also increased phosphorylation of ERK and Akt, mimicking the effects of higher concentrations of P4 and E2 alone. Pre-treatment with inhibitors of PI3K (wortmannin), Akt (ML-9), and MAP kinase (AZD6244 and U0126) completely blocked the NO response to 5nM P4+E2. Combined 5nM treatments with specific estrogen and progesterone receptor agonists showed an involvement of membrane progesterone receptor alpha (mPRα, also known as PAQR7), G protein-coupled estrogen receptor 1 (GPER), and estrogen receptor alpha (ERα), but not ERβ, in P4+E2 stimulation of NO production. P4+E2 also exerted genomic actions, increasing mPRα, GPER, cyclooxygenase-1, and prostacyclin-synthase mRNA levels. Taken together, the results show that a low concentration of P4+E2 rapidly increases NO production in HUVECs through mPRα, ERα, and GPER and involves common signaling pathways, PI3K/Akt and MAP kinase. These in vitro findings suggest that low doses of E2 and P4 may also have some beneficial cardiovascular effects in vivo when administered as hormone replacement therapy (HRT) for post-menopausal women. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. Longitudinal assessment of daily activity patterns on weight change after involuntary job loss: the ADAPT study protocol

    Directory of Open Access Journals (Sweden)

    Patricia L. Haynes

    2017-10-01

    Full Text Available Abstract Background The World Health Organization has identified obesity as one of the most visible and neglected public health problems worldwide. Meta-analytic studies suggest that insufficient sleep increases the risk of developing obesity and related serious medical conditions. Unfortunately, the nationwide average sleep duration has steadily declined over the last two decades with 25% of U.S. adults reporting insufficient sleep. Stress is also an important indirect factor in obesity, and chronic stress and laboratory-induced stress negatively impact sleep. Despite what we know from basic sciences about (a stress and sleep and (b sleep and obesity, we know very little about how these factors actually manifest in a natural environment. The Assessing Daily Activity Patterns Through Occupational Transitions (ADAPT study tests whether sleep disruption plays a key role in the development of obesity for individuals exposed to involuntary job loss, a life event that is often stressful and disrupting to an individual’s daily routine. Methods This is an 18-month closed, cohort research design examining social rhythms, sleep, dietary intake, energy expenditure, waist circumference, and weight gain over 18 months in individuals who have sustained involuntary job loss. Approximately 332 participants who lost their job within the last 3 months are recruited from flyers within the Arizona Department of Economic Security (AZDES Unemployment Insurance Administration application packets and other related postings. Multivariate growth curve modeling will be used to investigate the temporal precedence of changes in social rhythms, sleep, and weight gain. Discussion It is hypothesized that: (1 unemployed individuals with less consistent social rhythms and worse sleep will have steeper weight gain trajectories over 18 months than unemployed individuals with stable social rhythms and better sleep; (2 disrupted sleep will mediate the relationship between

  19. Longitudinal assessment of daily activity patterns on weight change after involuntary job loss: the ADAPT study protocol.

    Science.gov (United States)

    Haynes, Patricia L; Silva, Graciela E; Howe, George W; Thomson, Cynthia A; Butler, Emily A; Quan, Stuart F; Sherrill, Duane; Scanlon, Molly; Rojo-Wissar, Darlynn M; Gengler, Devan N; Glickenstein, David A

    2017-10-10

    The World Health Organization has identified obesity as one of the most visible and neglected public health problems worldwide. Meta-analytic studies suggest that insufficient sleep increases the risk of developing obesity and related serious medical conditions. Unfortunately, the nationwide average sleep duration has steadily declined over the last two decades with 25% of U.S. adults reporting insufficient sleep. Stress is also an important indirect factor in obesity, and chronic stress and laboratory-induced stress negatively impact sleep. Despite what we know from basic sciences about (a) stress and sleep and (b) sleep and obesity, we know very little about how these factors actually manifest in a natural environment. The Assessing Daily Activity Patterns Through Occupational Transitions (ADAPT) study tests whether sleep disruption plays a key role in the development of obesity for individuals exposed to involuntary job loss, a life event that is often stressful and disrupting to an individual's daily routine. This is an 18-month closed, cohort research design examining social rhythms, sleep, dietary intake, energy expenditure, waist circumference, and weight gain over 18 months in individuals who have sustained involuntary job loss. Approximately 332 participants who lost their job within the last 3 months are recruited from flyers within the Arizona Department of Economic Security (AZDES) Unemployment Insurance Administration application packets and other related postings. Multivariate growth curve modeling will be used to investigate the temporal precedence of changes in social rhythms, sleep, and weight gain. It is hypothesized that: (1) unemployed individuals with less consistent social rhythms and worse sleep will have steeper weight gain trajectories over 18 months than unemployed individuals with stable social rhythms and better sleep; (2) disrupted sleep will mediate the relationship between social rhythm disruption and weight gain; and (3

  20. EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs.

    Science.gov (United States)

    Kobayashi, Yoshihisa; Togashi, Yosuke; Yatabe, Yasushi; Mizuuchi, Hiroshi; Jangchul, Park; Kondo, Chiaki; Shimoji, Masaki; Sato, Katsuaki; Suda, Kenichi; Tomizawa, Kenji; Takemoto, Toshiki; Hida, Toyoaki; Nishio, Kazuto; Mitsudomi, Tetsuya

    2015-12-01

    Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18. Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined. Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11-50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼ 80%) than to 1G TKIs (35%-56%) by compilation of data in the literature. Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations. ©2015 American Association for Cancer Research.

  1. Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells

    International Nuclear Information System (INIS)

    Tang, Zheng-Hai; Cao, Wen-Xiang; Su, Min-Xia; Chen, Xiuping; Lu, Jin-Jian

    2017-01-01

    Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-L-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells. - Highlights: • Osimertinib induced the expressions of cytoplasmic vacuoles and autophagic markers in different cancer cells. • Osimertinib induced autophagic flux in NSCLC NCI-H1975 and HCC827 cell lines. • ROS generation contributed to osimertinib-induced cytoplasmic

  2. Osimertinib induces autophagy and apoptosis via reactive oxygen species generation in non-small cell lung cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tang, Zheng-Hai; Cao, Wen-Xiang; Su, Min-Xia; Chen, Xiuping; Lu, Jin-Jian, E-mail: jinjianlu@umac.mo

    2017-04-15

    Osimertinib (OSI), also known as AZD9291, is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that has been approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR T790M mutation. Herein, we indicated for the first time that OSI increased the accumulations of cytoplasmic vacuoles, the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II), and the formation of GFP-LC3 puncta in various cancer cells. The OSI-induced expression of LC3-II was further increased when combined treatment with chloroquine (CQ), an autophagy inhibitor, and the mRFP-EGFP-LC3 plasmid-transfected cells exposed to OSI led to the production of more red-fluorescent puncta than green-fluorescent puncta, indicating OSI induced autophagic flux in the NSCLC cells. Knockdown of EGFR showed no effect on the OSI-induced expression of LC3-II in NCI-H1975 cells. In addition, OSI increased reactive oxygen species (ROS) generation and scavenge of ROS via pretreatment with N-acetyl-L-cysteine (NAC), catalase (CAT), or vitamin E (Vita E) significantly inhibited OSI-induced the accumulations of cytoplasmic vacuoles, the expression of LC3-II, as well as the formation of GFP-LC3 puncta. Combinative treatment with CQ could not remarkably change the OSI-induced cell viability decrease, whereas the OSI-induced cell viability decrease and apoptosis could be reversed through pretreatment with NAC, CAT, and Vita E, respectively. Taken together, this is the first report that OSI induces an accompanied autophagy and the generation of ROS is critical for the OSI-induced autophagy, cell viability decrease, and apoptosis in NSCLC cells. - Highlights: • Osimertinib induced the expressions of cytoplasmic vacuoles and autophagic markers in different cancer cells. • Osimertinib induced autophagic flux in NSCLC NCI-H1975 and HCC827 cell lines. • ROS generation contributed to osimertinib-induced cytoplasmic

  3. Disease patterns and clinical outcomes of patients admitted in intensive care units of tertiary referral hospitals of Tanzania.

    Science.gov (United States)

    Sawe, Hendry R; Mfinanga, Juma A; Lidenge, Salum J; Mpondo, Boniventura C T; Msangi, Silas; Lugazia, Edwin; Mwafongo, Victor; Runyon, Michael S; Reynolds, Teri A

    2014-09-23

    In sub-Saharan Africa the availability of intensive care unit (ICU) services is limited by a variety of factors, including lack of financial resources, lack of available technology and well-trained staff. Tanzania has four main referral hospitals, located in zones so as to serve as tertiary level referral centers. All the referral hospitals have some ICU services, operating at varying levels of equipment and qualified staff. We analyzed and describe the disease patterns and clinical outcomes of patients admitted in ICUs of the tertiary referral hospitals of Tanzania. This was a retrospective analysis of ICU patient records, for three years (2009 to 2011) from all tertiary referral hospitals of Tanzania, namely Muhimbili National Hospital (MNH), Kilimanjaro Christian Medical Centre (KCMC), Mbeya Referral Hospital (MRH) and Bugando Medical Centre (BMC). MNH is the largest of the four referral hospitals with 1300 beds, and MRH is the smallest with 480 beds. The ratio of hospital beds to ICU beds is 217:1 at MNH, 54:1 at BMC, 39:1 at KCMC, and 80:1 at MRH. KCMC had no infusion pumps. None of the ICUs had a point-of-care (POC) arterial blood gas (ABG) analyzer. None of the ICUs had an Intensive Care specialist or a nutritionist. A masters-trained critical care nurse was available only at MNH. From 2009-2011, the total number of patients admitted to the four ICUs was 5627, male to female ratio 1.4:1, median age of 34 years. Overall, Trauma (22.2%) was the main disease category followed by infectious disease (19.7%). Intracranial injury (12.5%) was the leading diagnosis in all age groups, while pneumonia (11.7%) was the leading diagnosis in pediatric patients (<18 years). Patients with tetanus (2.4%) had the longest median length ICU stay: 8 (5,13) days. The overall in-ICU mortality rate was 41.4%. The ICUs in tertiary referral hospitals of Tanzania are severely limited in infrastructure, personnel, and resources, making it difficult or impossible to provide optimum care

  4. Determinants of infant and young child feeding practices by mothers in two rural districts of Sindh, Pakistan: a cross-sectional survey.

    Science.gov (United States)

    Khan, Gul Nawaz; Ariff, Shabina; Khan, Ubaidullah; Habib, Atif; Umer, Muhammad; Suhag, Zamir; Hussain, Imtiaz; Bhatti, Zaid; Ullah, Asmat; Turab, Ali; Khan, Ali Ahmad; Garzon, Alba Cecilia; Khan, Mohammad Imran; Soofi, Sajid

    2017-01-01

    Infant and young child feeding (IYCF) practices during the first two years of life are important for the growth and development of a child. The aim of this study was to assess IYCF practices and its associated factors in two rural districts of Pakistan. A cross-sectional study was conducted in two rural districts of Sindh province, Pakistan as part of a stunting prevention project between May and August 2014. A standard questionnaire on IYCF practices recommended by World Health Organization was used to collect information from 2013 mothers who had a child aged between 0 and 23 months. Only 49% of mothers initiated breastfeeding within one hour of birth. Thirty-seven percent of mothers exclusively breastfed their infants for six months. Seventy-percent mothers introduced complementary feeding at 6-8 months of age. Eighty-two percent of mothers continued breastfeeding for at least one year and 75% for at least two years of age. IYCF practices were not significantly different for boys and girls in the study area. Being an employed mother (AOR 2.14; 95% CI 1.02, 4.51) was positively associated with the early initiation of breastfeeding. Children who were born at a health facility (AOR 0.65; 95% CI 0.50, 0.84) and were aged six to eleven months (AOR 0.70; 95% CI 0.54, 0.90) were less likely to be have an early initiation of breastfeeding. Mothers aged 25 to 29 years (AOR 1.83; 95% CI 1.05, 3.18), being literate (AOR 1.79; 95% CI 1.15, 2.78), and higher income (AOR 10.6; 95% CI 4.40, 25.30) were more likely to have an improved dietary diversity. Being an employed mother (AOR 2.18; 95% CI 1.77, 4.03) and higher income were more likely to have minimum acceptable diet (AOR 9.7; 95% CI 4.33, 21.71). IYCF practices were below the acceptable level and associated with maternal age, maternal illiteracy, unemployment, and poor household wealth status. Emphasis should be given to improve maternal literacy and reduction in poverty to improve IYCF practices.

  5. Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases and angiogenic cytokines in peripheral blood of patients with thyroid cancer.

    Science.gov (United States)

    Komorowski, Jan; Pasieka, Z; Jankiewicz-Wika, J; Stepień, H

    2002-08-01

    Stimulation of growth of endothelial cells from preexisting blood vessels, i.e., angiogenesis, is one of the essential elements necessary to create a permissive environment in which a tumor can grow. During angiogenesis, the matrix metalloproteinase (MMP) family of tissue enzymes contributes to normal (embriogenesis or wound repair) and pathologic tissue remodeling (chronic inflammation and tumor genesis). The proposed pathogenic roles of MMPs in cancer are tissue breakdown and remodeling during invasive tumor growth and tumor angiogenesis. Tissue inhibitors of metalloproteinases (TIMPs) form a complex with MMPs, which in turn inhibits active MMPs. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are unique among mediators of angiogenesis with synergistic effect, and both can also be secreted by thyroid cancer cells. The goal of the study was to evaluate the plasma blood concentration of VEGF, bFGF, MMP-1, MMP-2, MMP-3, MMP-8, MMP-9, TIMP-1, and TIMP-2 in patients with cancer and in normal subjects. Twenty-two patients with thyroid cancers (papillary cancer, 11; partly papillary and partly follicular cancer, 3; anaplastic cancer, 5; medullary cancer, 3) and 16 healthy subjects (controls) were included in the study. VEGF, bFGF MMPs, and TIMPs were evaluated by enzyme-linked immunosorbent assay (ELISA). In patients with thyroid cancer, normal VEGF concentrations (74.29 +/- 13.38 vs. 84.85 +/- 21.71 pg/mL; p > 0.05) and increased bFGF (29.52 +/- 4.99 vs. 6.05 +/- 1.43 pg/mL; p < 0.001), MMP-2 (605.95 +/- 81.83 vs. 148.75 +/- 43.53 ng/mL; p < 0.001), TIMP-2 (114.19 +/- 6.62 vs. 60.75 +/- 9.18 ng/mL; p < 0.001), as well as lower MMP-1 (0.70 +/- 0.42 vs. 3.87 +/- 0.53; p < 0.001) levels have been noted. Increased plasma levels of MMP-3 and MMP-9 were also found in patients with medullary carcinoma. In conclusion, predominance of MMP-2 over TIMP-2 and TIMP-1 over MMP-1 as well as increased concentration of bFGF in peripheral blood are

  6. Metabolic Response to Omega-3 Fatty Acids and Vitamin E Co-Supplementation in Patients with Fibrocystic Breast Disease: A Randomized, Double-Blind, Placebo-Controlled Trial.

    Science.gov (United States)

    Mirhashemi, Seyyed Mehdi; Sahmani, Mehdi; Salehi, Behnaz; Zavar Reza, Javad; Taghizadeh, Mohsen; Moussavi, Nushin; Badehnoosh, Bita; Asemi, Zatollah

    2017-08-01

    There is scarce data on the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic status in patients with fibrocystic breast disease (FBD). The current study was carried out to determine the effects of omega-3 fatty acids and vitamin E co-supplementation on metabolic status in patients with FBD. A randomized clinical trial was conducted on 56 patients with FBD. Participants were randomly divided into two groups to receive either 1000 mg omega-3 fatty acids plus 400 mg vitamin E (n = 28) or placebo (n = 28) for 12 weeks. Fasting blood samples were taken at the beginning of the study and after 12 weeks of intervention to determine inflammatory factors, biomarkers of oxidative stress, and metabolic profiles. After 12 weeks of intervention, changes in serum high-sensitivity C-reactive protein (-2171.4 ± 3189.1 vs. +696.9 ± 2774.8 ng/mL, P = 0.001) and plasma nitric oxide (+1.8 ± 4.0 vs. -0.1 ± 2.4 µmol/L, P = 0.04) in supplemented women were significantly different from those in the placebo group. In addition, compared to the placebo group, subjects who consumed omega-3 fatty acids plus vitamin E supplements had significantly decreased serum insulin concentrations (-3.2 ± 6.5 vs. -0.2 ± 1.7 µIU/mL, P = 0.01), the homeostasis model of assessment-estimated insulin resistance (-0.8 ± 1.7 vs. -0.02 ± 0.4, P = 0.03), serum triglycerides levels (-11.5 ± 47.3 vs. +10.6 ± 24.3 mg/dL, P = 0.03) and VLDL-cholesterol (-2.3 ± 9.5 vs. +2.1 ± 4.9 mg/dL, P = 0.03), as well as increased quantitative insulin sensitivity check index (+0.01 ± 0.01 vs. +0.001 ± 0.007, P = 0.001) and HDL-cholesterol (+3.4 ± 6.0 vs. -1.3 ± 4.3 mg/dL, P = 0.001). Overall, omega-3 fatty acids and vitamin E co-supplementation for 12 weeks had beneficial effects on inflammatory markers and metabolic profiles in patients with FBD.

  7. Experimental study on acute toxicity of Qingnao tablet to mice

    Science.gov (United States)

    Xie, Guoqi; Wang, Huamin; Ma, Zhenzhen; Hao, Shaojun; Li, Jun; Wang, Hongyu; Wen, Zhonghua; Zhang, Zhengchen

    2018-04-01

    To investigate the effect of Qingnao tablets on acute toxicity in mice. Forty mice, half male and half female, were randomly divided into normal saline group and Qingnao tablet group. After fasting for 12 hours, the mice were given 0. 4 ml / 10 g in maximum volume. In 1st, the rats were perfused 3 times (every 8 hours). The rats in the saline group were perfused with the same volume of saline in the same way. The mice were observed continuously within 3 hours and then every hour. The mice were given a normal diet for 14 consecutive days, and the changes of autonomous activity, reaction, diet, stool, secretion, eye and nose were observed daily. The mice fasted on the 13th day and weighed on the 14th day. And then put the mice to death, The changes of the liver, heart, spleen, lung, kidney, stomach, intestines, and brain were observed by the naked eye. There was no obvious abnormality in normal saline group. The autonomous activity of mice in the administration group decreased after initial administration, and gradually returned to normal after 2 hours of administration. On the day of administration, the stool of the mice became dark brown, and the feces returned to normal after 1.1 days of normal urination. No other mice had abnormal secretion, reaction, eye nose, diet, etc. On the 14th day, there were no visible heart, liver, spleen, lung, kidney, gastrointestinal tract in normal saline group and Qingnao tablet group. Abnormal changes in brain and other organs (edema, color, etc.). In the normal saline group and Qingnao tablet group, the initial weight of the mice was: 21.70 ± 0.97N 21.71 ± 1.13, and the weight of the mice on the 7th day was 29.70 ± 2.4c28.65 ± 3.11. On the 14th day, the body weight was 32.38 ± 3.40, 33.77 ± 3.82. Qingnao tablet has no obvious toxicity to the main organs of mice, so it can be considered safe in clinical use.

  8. In vitro utilization of lime treated olive cake as a component of complete feed for small ruminants.

    Science.gov (United States)

    Ishfaq, A; Sharma, R K; Rastogi, A; Malla, B A; Farooq, J

    2015-01-01

    The current in vitro study was carried out to determine the chemical composition and inclusion level of lime treated olive cake on acid detergent fiber (ADF) replacement basis in adult male goats. Crude olive cake was collected and evaluated for proximate composition and protein fractionation. It was treated with 6% lime and incubated for 1 week under room temperature in 2 kg sealed polythene bags and was evaluated for proximate composition after incubation. Different isonitrogenous complete diets containing 0-50% of lime treated olive cake on ADF replacement basis were formulated as per the requirement of adult male goats. In ADF replacement, fiber and concentrate sources were replaced by lime treated olive cake by replacing the 0-50% ADF percentage of the total 40% ADF value of complete feed. The formulated complete diets were tested for in vitro degradation parameters. Treatment of olive cake with 6% slaked lime increased availability of cellulose and alleviated digestibility depression caused by high ether extract percentage. Organic matter, nitrogen free extract, ADF and neutral detergent fiber were significantly lowered by lime treatment of olive cake. The cornell net carbohydrate and protein system analysis showed that non-degradable protein represented by acid detergent insoluble nitrogen (ADIN) was 21.71% whereas the non-available protein represented by neutral detergent insoluble nitrogen (NDIN) was 38.86% in crude olive cake. The in vitro dry matter degradation (IVDMD) values were comparable at all replacement levels. However, a point of inflection was observed at 40% ADF replacement level, which was supported by truly degradable organic matter (TDOM), microbial biomass production (MBP), efficiency of MBP and partitioning factor values (PF). In our study, we concluded that there is comparable difference in composition of Indian olive cake when compared with European olive cake. The most important finding was that about 78% of nitrogen present in Indian

  9. Sick Leave within 5 Years of Whiplash Trauma Predicts Recovery: A Prospective Cohort and Register-Based Study

    Science.gov (United States)

    Carstensen, Tina Birgitte Wisbech; Fink, Per; Oernboel, Eva; Kasch, Helge; Jensen, Troels Staehelin; Frostholm, Lisbeth

    2015-01-01

    Background 10–22% of individuals sustaining whiplash trauma develop persistent symptoms resulting in reduced working ability and decreased quality of life, but it is poorly understood why some people do not recover. Various collision and post-collision risk factors have been studied, but little is known about pre-collision risk factors. In particular, the impact of sickness and socioeconomic factors before the collision on recovery is sparsely explored. The aim of this study was to examine if welfare payments received within five years pre-collision predict neck pain and negative change in provisional situation one year post-collision. Methods and Findings 719 individuals with acute whiplash trauma consecutively recruited from emergency departments or primary care after car accidents in Denmark completed questionnaires on socio-demographic and health factors immediately after the collision. After 12 months, a visual analogue scale on neck pain intensity was completed. 3595 matched controls in the general population were sampled, and national public register data on social benefits and any other welfare payments were obtained for participants with acute whiplash trauma and controls from five years pre-collision to 15 months after. Participants with acute whiplash trauma who had received sickness benefit for more than 12 weeks pre-collision had increased odds for negative change in future provisional situation (Odds Ratio (OR) (95% Confidence Interval (CI) = 3.8 (2.1;7.1)) and future neck pain (OR (95%CI) = 3.3 (1.8;6.3)), controlling for other known risk factors. Participants with acute whiplash trauma had weaker attachment to labour market (more weeks of sick leave (χ2(2) = 36.7, p whiplash trauma raised the odds for future negative change in provisional situation (OR (95%CI) = 3.1 (2.3;4.4)) compared with controls. Conclusions Sick leave before the collision strongly predicted prolonged recovery following whiplash trauma. Participants with acute whiplash trauma

  10. In vitro utilization of lime treated olive cake as a component of complete feed for small ruminants

    Directory of Open Access Journals (Sweden)

    A. Ishfaq

    2015-01-01

    Full Text Available Aim: The current in vitro study was carried out to determine the chemical composition and inclusion level of lime treated olive cake on acid detergent fiber (ADF replacement basis in adult male goats. Materials and Methods: Crude olive cake was collected and evaluated for proximate composition and protein fractionation. It was treated with 6% lime and incubated for 1 week under room temperature in 2 kg sealed polythene bags and was evaluated for proximate composition after incubation. Different isonitrogenous complete diets containing 0-50% of lime treated olive cake on ADF replacement basis were formulated as per the requirement of adult male goats. In ADF replacement, fiber and concentrate sources were replaced by lime treated olive cake by replacing the 0-50% ADF percentage of the total 40% ADF value of complete feed. The formulated complete diets were tested for in vitro degradation parameters. Results: Treatment of olive cake with 6% slaked lime increased availability of cellulose and alleviated digestibility depression caused by high ether extract percentage. Organic matter, nitrogen free extract, ADF and neutral detergent fiber were significantly lowered by lime treatment of olive cake. The cornell net carbohydrate and protein system analysis showed that non-degradable protein represented by acid detergent insoluble nitrogen (ADIN was 21.71% whereas the non-available protein represented by neutral detergent insoluble nitrogen (NDIN was 38.86% in crude olive cake. The in vitro dry matter degradation (IVDMD values were comparable at all replacement levels. However, a point of inflection was observed at 40% ADF replacement level, which was supported by truly degradable organic matter (TDOM, microbial biomass production (MBP, efficiency of MBP and partitioning factor values (PF. Conclusion: In our study, we concluded that there is comparable difference in composition of Indian olive cake when compared with European olive cake. The most

  11. Brand name and generic proton pump inhibitor prescriptions in the United States: insights from the national ambulatory medical care survey (2006-2010).

    Science.gov (United States)

    Gawron, Andrew J; Feinglass, Joseph; Pandolfino, John E; Tan, Bruce K; Bove, Michiel J; Shintani-Smith, Stephanie

    2015-01-01

    , patient visits at academic medical centers (IRR 4.2, 95% CI 2.2-8.0), physician-owned practices (IRR 3.9, 95% CI 2.1-7.1), and community health centers (IRR 3.6, 95% CI 1.9-6.6) were all more likely to have brand name PPIs. Conclusion. PPI prescriptions with brand name only formulations are most strongly associated with physician practice type.

  12. Psychosocial predictors of nonadherence to medical management among patients on maintenance dialysis

    Directory of Open Access Journals (Sweden)

    Alosaimi FD

    2016-10-01

    Full Text Available Fahad Dakheel Alosaimi,1 Mohammed Asiri,2 Saleh Alsuwayt,2 Tariq Alotaibi,2 Mohammed Bin Mugren,2 Abdulmalik Almufarrih,2 Saad Almodameg,2 1Department of Psychiatry, King Saud University, Riyadh, Saudi Arabia; 2College of Medicine, King Saud University, Riyadh, Saudi Arabia Background: A number of reports suggest a link between depression and nonadherence to recommended management for end-stage renal disease (ESRD patients on maintenance dialysis. However, the relationship between nonadherence and other psychosocial factors have been inadequately examined. Objectives: To examine the prevalence of psychosocial factors including depression, anxiety, insecure attachment style, as well as cognitive impairment and their associations with adherence to recommended management of ESRD. Methods: A cross-sectional observational study was carried out from 2014 to 2015. Chronic dialysis patients were recruited conveniently from four major dialysis units in Riyadh, Saudi Arabia. Nonadherence was defined as decreased attendance in dialysis sessions, failure to take prescribed medications, and/or follow food/fluid restrictions and exercise recommendations. Results: A total of 234 patients (147 males and 87 females were included in this analysis, with 45 patients (19.2% considered as nonadherent (visual analog scale < 8. Approximately 17.9% of the patients had depression (Patient Health Questionnaire score ≥10, 13.2% had anxiety (Hospital Anxiety and Depression scale-anxiety >7, while 77.4% had cognitive impairment (Montreal Cognitive Assessment score <26. Nonadherence was significantly associated with depression and anxiety (p<0.001 for both but not cognitive impairment (p=0.266. The Experiences in Close Relationships – Modified 16 (ECR-M16 scale score was 27.99±10.87 for insecure anxiety and 21.71±9.06 for insecure avoidance relationship, with nonadherence significantly associated with anxiety (p=0.001 but not avoidance (p=0.400. Conclusion: Nonadherence

  13. Study of Asparagus Radiopreservation (Asparagus Officinalis)

    International Nuclear Information System (INIS)

    Linares A, M.

    1990-01-01

    The main purpose of this work were find the suitable dose to extend the useful life of this vegetable (asparagus). In addition, physical and chemical changes that could be induced were studied the bio burden of this vegetable. The asparagus sorted, cleaned and cut, was irradiated in Gamma cell 220; the analyzed dose were 0.5, 1.0, 1.5, 2.0 and 4.18 KGy. According to these date, and increased irradiation dose cause that pH and titrated acidity grow rapidly day by day, because of glucose, fructose; exist since small presence of volatile acid or the glucose formed from glucose an fructose exist moisture loss produce weight loss in the asparagus. Dose that gave better results were: 1.5, 2.0 and 0.5 KGy; moisture loss produce acids concentration and des favourable appearance observed in organoleptic analysis. The fibres formed were least in all cases to irradiated asparagus, especially for 1.5 and 2.0 KGy, there were not fat and protein content changes (in that case only there was a test to control and 2.0 KGy). The percent weigh loss and percent size diminution, were less when store conditions were the best (90-95% H.R. and 1-2 o C), the maximum loss was 14.88% to the control and 11.06% to the irradiated product (1.5 KGy). Ascorbic acid content of control was 57.0%, in irradiated products were 21.71% and 37.68% for 2.0 and 1.5 KGy, after storing the products 30 days approximately. Because asparagus bio burden vary in a range from 10 5 to 10 6 , this is reduce by cleaning up to 10 3 , the irradiation let us reduce in one order. Let's conclude that the best dose to asparagus conservation was 1.5 KGy, the useful life time was 32 days, in store conditions of 90-95 H>R. and temperature 1-2 o C. The irradiation let inhibit microorganisms action until a 15 days period, after this, there was tendency to growth. The least moisture loss and fibre formation were favoured. (author). 28 refs., 33 tabs., 27 ills

  14. Degassing Processes at Persistently Active Explosive Volcanoes

    Science.gov (United States)

    Smekens, Jean-Francois

    Among volcanic gases, sulfur dioxide (SO2) is by far the most commonly measured. More than a monitoring proxy for volcanic degassing, SO 2 has the potential to alter climate patterns. Persistently active explosive volcanoes are characterized by short explosive bursts, which often occur at periodic intervals numerous times per day, spanning years to decades. SO 2 emissions at those volcanoes are poorly constrained, in large part because the current satellite monitoring techniques are unable to detect or quantify plumes of low concentration in the troposphere. Eruption plumes also often show high concentrations of ash and/or aerosols, which further inhibit the detection methods. In this work I focus on quantifying volcanic gas emissions at persistently active explosive volcanoes and their variations over short timescales (minutes to hours), in order to document their contribution to natural SO2 flux as well as investigate the physical processes that control their behavior. In order to make these measurements, I first develop and assemble a UV ground-based instrument, and validate it against an independently measured source of SO2 at a coal-burning power plant in Arizona. I establish a measurement protocol and demonstrate that the instrument measures SO 2 fluxes with Indonesia), a volcano that has been producing cycles of repeated explosions with periods of minutes to hours for the past several decades. Semeru produces an average of 21-71 tons of SO2 per day, amounting to a yearly output of 8-26 Mt. Using the Semeru data, along with a 1-D transient numerical model of magma ascent, I test the validity of a model in which a viscous plug at the top of the conduit produces cycles of eruption and gas release. I find that it can be a valid hypothesis to explain the observed patterns of degassing at Semeru. Periodic behavior in such a system occurs for a very narrow range of conditions, for which the mass balance between magma flux and open-system gas escape repeatedly

  15. Diversity and aggregation patterns of plant species in a grass community

    Directory of Open Access Journals (Sweden)

    Ran Li

    2014-09-01

    Full Text Available Both composition and aggregation patterns of species in a community are the outcome of community self-organizing. In this paper we conducted analysis on species diversity and aggregation patterns of plant species in a grass community, Zhuhai, China. According to the sampling survey, in total of 47 plant species, belonging to 16 families, were found. Compositae had 10 species (21.3%, seconded by Gramineae (9 species, 19.1%, Leguminosae (6 species, 12.8%, Cyperaceae (4 species, 8.5%, and Malvaceae (3 species, 6.4%. The results revealed that the means of aggregation indices Iδ, I and m*/m were 21.71, 15.71 and 19.89 respectively and thus individuals of most of plant species strongly followed aggregative distribution. Iwao analysis indicated that both individuals of all species and clumps of all individuals of all species followed aggregative distribution. Taylor's power law indicated that individuals of all species followed aggregative distribution and aggregation intensity strengthened as the increase of mean density. We held that the strong aggregation intensity of a species has been resulted from the strong adaptation ability to the environment, the strong interspecific competition ability and the earlier establishment of the species. Fitting goodness of the mean, I, Iδ, m*/m with probability distributions demonstrated that the mean (density, I, Iδ, and m*/m over all species followed Weibull distribution rather than normal distribution. Lophatherum gracile, Paederia scandens (Lour. Merr., Eleusine indica, and Alternanthera philoxeroides (Mart. Griseb. were mostly aggregative, and Oxalis sp., Eleocharis plantagineiformis, Vernonia cinerea (L. Less., and Sapium sebiferum (L. Roxb, were mostly uniform in the spatial distribution. Importance values (IV showed that Cynodon dactylon was the most important species, seconded by Desmodium triflorum (L. DC., Cajanus scarabaeoides (L. Benth., Paspalum scrobiculatum L., and Rhynchelytrum repens. Oxalis

  16. Characterizing and predicting ultrafine particle counts in Canadian classrooms during the winter months: model development and evaluation.

    Science.gov (United States)

    Weichenthal, Scott; Dufresne, André; Infante-Rivard, Claire; Joseph, Lawrence

    2008-03-01

    School classrooms are potentially important micro-environments for childhood exposures owing to the large amount of time children spend in these locations. While a number of airborne contaminants may be present in schools, to date few studies have examined ultrafine particle (0.02-1 microm) (UFP) levels in classrooms. In this study, our objective was to characterize UFP counts (cm(-3)) in classrooms during the winter months and to develop a model to predict such exposures based on ambient weather conditions and outdoor UFPs, as well as classroom characteristics such as size, temperature, relative humidity, and carbon dioxide levels. In total, UFP count data were collected on 60 occasions in 37 occupied classrooms at one elementary school and one secondary school in Pembroke, Ontario. On average, outdoor UFP levels exceeded indoor measures by 8989 cm(-3) (95% confidence interval (CI): 6382, 11596), and classroom UFP counts were similar at both schools with a combined average of 5017 cm(-3) (95% CI: 4300, 5734). Of the variables examined only wind speed and outdoor UFPs were important determinants of classrooms UFP levels. Specifically, each 10 km/h increase in wind speed corresponded to an 1873 cm(-3) (95% CI: 825, 2920) decrease in classroom UFP counts, and each 10000 cm(-3) increase in outdoor UFPs corresponded to a 1550 cm(-3) (95% CI: 930, 2171) increase in classroom UFP levels. However, high correlations between these two predictors meant that the independent effects of wind speed and outdoor UFPs could not be separated in multivariable models, and only outdoor UFP counts were included in the final predictive model. To evaluate model performance, classroom UFP counts were collected for 8 days at two new schools and compared to predicted values based on outdoor UFP measures. A moderate correlation was observed between measured and predicted classroom UFP counts (r=0.63) for both schools combined, but this relationship was not valid on days in which a strong

  17. Characterizing and predicting ultrafine particle counts in Canadian classrooms during the winter months: Model development and evaluation

    International Nuclear Information System (INIS)

    Weichenthal, Scott; Dufresne, Andre; Infante-Rivard, Claire; Joseph, Lawrence

    2008-01-01

    School classrooms are potentially important micro-environments for childhood exposures owing to the large amount of time children spend in these locations. While a number of airborne contaminants may be present in schools, to date few studies have examined ultrafine particle (0.02-1 μm) (UFP) levels in classrooms. In this study, our objective was to characterize UFP counts (cm -3 ) in classrooms during the winter months and to develop a model to predict such exposures based on ambient weather conditions and outdoor UFPs, as well as classroom characteristics such as size, temperature, relative humidity, and carbon dioxide levels. In total, UFP count data were collected on 60 occasions in 37 occupied classrooms at one elementary school and one secondary school in Pembroke, Ontario. On average, outdoor UFP levels exceeded indoor measures by 8989 cm -3 (95% confidence interval (CI): 6382, 11 596), and classroom UFP counts were similar at both schools with a combined average of 5017 cm -3 (95% CI: 4300, 5734). Of the variables examined only wind speed and outdoor UFPs were important determinants of classrooms UFP levels. Specifically, each 10 km/h increase in wind speed corresponded to an 1873 cm -3 (95% CI: 825, 2920) decrease in classroom UFP counts, and each 10 000 cm -3 increase in outdoor UFPs corresponded to a 1550 cm -3 (95% CI: 930, 2171) increase in classroom UFP levels. However, high correlations between these two predictors meant that the independent effects of wind speed and outdoor UFPs could not be separated in multivariable models, and only outdoor UFP counts were included in the final predictive model. To evaluate model performance, classroom UFP counts were collected for 8 days at two new schools and compared to predicted values based on outdoor UFP measures. A moderate correlation was observed between measured and predicted classroom UFP counts (r=0.63) for both schools combined, but this relationship was not valid on days in which a strong indoor UFP

  18. Detection by hyperspectral imaging of shiga toxin-producing Escherichia coli serogroups O26, O45, O103, O111, O121, and O145 on rainbow agar.

    Science.gov (United States)

    Windham, William R; Yoon, Seung-Chul; Ladely, Scott R; Haley, Jennifer A; Heitschmidt, Jerry W; Lawrence, Kurt C; Park, Bosoon; Narrang, Neelam; Cray, William C

    2013-07-01

    The U.S. Department of Agriculture, Food Safety Inspection Service has determined that six non-O157 Shiga toxin-producing Escherichia coli (STEC) serogroups (O26, O45, O103, O111, O121, and O145) are adulterants in raw beef. Isolate and phenotypic discrimination of non-O157 STEC is problematic due to the lack of suitable agar media. The lack of distinct phenotypic color variation among non-O157serogroups cultured on chromogenic agar poses a challenge in selecting colonies for confirmation. In this study, visible and near-infrared hyperspectral imaging and chemometrics were used to detect and classify non-O157 STEC serogroups grown on Rainbow agar O157. The method was first developed by building spectral libraries for each serogroup obtained from ground-truth regions of interest representing the true identity of each pixel and thus each pure culture colony in the hyperspectral agar-plate image. The spectral library for the pure-culture non-O157 STEC consisted of 2,171 colonies, with spectra derived from 124,347 of pixels. The classification models for each serogroup were developed with a k nearest-neighbor classifier. The overall classification training accuracy at the colony level was 99%. The classifier was validated with ground beef enrichments artificially inoculated with 10, 50, and 100 CFU/ml STEC. The validation ground-truth regions of interest of the STEC target colonies consisted of 606 colonies, with 3,030 pixels of spectra. The overall classification accuracy was 98%. The average specificity of the method was 98% due to the low false-positive rate of 1.2%. The sensitivity ranged from 78 to 100% due to the false-negative rates of 22, 7, and 8% for O145, O45, and O26, respectively. This study showed the potential of visible and near-infrared hyperspectral imaging for detecting and classifying colonies of the six non-O157 STEC serogroups. The technique needs to be validated with bacterial cultures directly extracted from meat products and positive

  19. Sick Leave within 5 Years of Whiplash Trauma Predicts Recovery: A Prospective Cohort and Register-Based Study.

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    Tina Birgitte Wisbech Carstensen

    Full Text Available 10-22% of individuals sustaining whiplash trauma develop persistent symptoms resulting in reduced working ability and decreased quality of life, but it is poorly understood why some people do not recover. Various collision and post-collision risk factors have been studied, but little is known about pre-collision risk factors. In particular, the impact of sickness and socioeconomic factors before the collision on recovery is sparsely explored. The aim of this study was to examine if welfare payments received within five years pre-collision predict neck pain and negative change in provisional situation one year post-collision.719 individuals with acute whiplash trauma consecutively recruited from emergency departments or primary care after car accidents in Denmark completed questionnaires on socio-demographic and health factors immediately after the collision. After 12 months, a visual analogue scale on neck pain intensity was completed. 3595 matched controls in the general population were sampled, and national public register data on social benefits and any other welfare payments were obtained for participants with acute whiplash trauma and controls from five years pre-collision to 15 months after. Participants with acute whiplash trauma who had received sickness benefit for more than 12 weeks pre-collision had increased odds for negative change in future provisional situation (Odds Ratio (OR (95% Confidence Interval (CI = 3.8 (2.1;7.1 and future neck pain (OR (95%CI = 3.3 (1.8;6.3, controlling for other known risk factors. Participants with acute whiplash trauma had weaker attachment to labour market (more weeks of sick leave (χ2(2 = 36.7, p < 0.001 and unemployment (χ2(2 = 12.5, p = 0.002 pre-collision compared with controls. Experiencing a whiplash trauma raised the odds for future negative change in provisional situation (OR (95%CI = 3.1 (2.3;4.4 compared with controls.Sick leave before the collision strongly predicted prolonged recovery

  20. Visceral obesity, fat mass/muscle mass ratio and atherogenic dyslipidemia: cross-sectional study. Riobamba, Ecuador

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    Tomas Marcelo Nicolalde Cifuentes

    2015-10-01

    Full Text Available Introduction: The distribution and composition of fat mass is associated with different metabolic risks. The predominance of brown visceral fat is associated with risk factors for cardiovascular disease (CVD, such as: high triglycerides and apolipoprotein B, increased LDL cholesterol, ratio triglycerides/low HDL cholesterol elevated (atherogenic dyslipidemia indicator, insulin resistance, hyperinsulinemia and cardiovascular risk (CVR. Sarcopenia and obesity may act synergistically in functional and metabolic disorders. The aim of this study was to determine the relationship between visceral obesity, fat mass/muscular mass ratio and atherogenic dyslipidemia in adult individuals in order to determine the association pattern between these variables and set strategies for focused attention.Material and Methods: In a sample of 307 subjects of both sexes (21-71 years there was measured atherogenic dyslipidemia as the ratio of triglyceride/HDL cholesterol, visceral obesity measured by bio impedance as the relative score of visceral fat, and the ratio fat mass/lean mass.Results: A cluster analysis was performed to establish the structure of association between these variables with different risk groups. Three groups were identified: the first had visceral obesity with an average relative level of visceral fat of 13.6, the second group with an average of 8.9 and in the third group were placed individuals with the lowest visceral obesity score averaging 6.5. As for the fat mass/lean mas ratio the first two groups had a similar average of this index with a value of 1.56 and 1.69 respectively and the third group with the lowest average value of 1.3. Group 1 presented visceral obesity and impaired fat mass/lean mass ratio and had a high value of triglyceride/HDL ratio 4.1. Group 2 without visceral obesity and a deterioration in the relative fat mass/lean mass ratio had a triglyceride/HDL cholesterol of 3.6 and Group 3; not recorded visceral obesity or

  1. mTOR inhibitors alone and in combination with JAK2 inhibitors effectively inhibit cells of myeloproliferative neoplasms.

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    Costanza Bogani

    Full Text Available BACKGROUND: Dysregulated signaling of the JAK/STAT pathway is a common feature of chronic myeloproliferative neoplasms (MPN, usually associated with JAK2V617F mutation. Recent clinical trials with JAK2 inhibitors showed significant improvements in splenomegaly and constitutional symptoms in patients with myelofibrosis but meaningful molecular responses were not documented. Accordingly, there remains a need for exploring new treatment strategies of MPN. A potential additional target for treatment is represented by the PI3K/AKT/mammalian target of rapamycin (mTOR pathway that has been found constitutively activated in MPN cells; proof-of-evidence of efficacy of the mTOR inhibitor RAD001 has been obtained recently in a Phase I/II trial in patients with myelofibrosis. The aim of the study was to characterize the effects in vitro of mTOR inhibitors, used alone and in combination with JAK2 inhibitors, against MPN cells. FINDINGS: Mouse and human JAK2V617F mutated cell lines and primary hematopoietic progenitors from MPN patients were challenged with an allosteric (RAD001 and an ATP-competitive (PP242 mTOR inhibitor and two JAK2 inhibitors (AZD1480 and ruxolitinib. mTOR inhibitors effectively reduced proliferation and colony formation of cell lines through a slowed cell division mediated by changes in cell cycle transition to the S-phase. mTOR inhibitors also impaired the proliferation and prevented colony formation from MPN hematopoietic progenitors at doses significantly lower than healthy controls. JAK2 inhibitors produced similar antiproliferative effects in MPN cell lines and primary cells but were more potent inducers of apoptosis, as also supported by differential effects on cyclinD1, PIM1 and BcLxL expression levels. Co-treatment of mTOR inhibitor with JAK2 inhibitor resulted in synergistic activity against the proliferation of JAK2V617F mutated cell lines and significantly reduced erythropoietin-independent colony growth in patients with

  2. Trastuzumab anti-tumor efficacy in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models

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    Wu Xianhua

    2012-08-01

    Full Text Available Abstract Background Trastuzumab is currently approved for the clinical treatment of breast and gastric cancer patients with HER-2 positive tumors, but not yet for the treatment of esophageal carcinoma patients, whose tumors typically show 5 ~ 35% HER-2 gene amplification and 0 ~ 56% HER-2 protein expression. This study aimed to investigate the therapeutic efficacy of Trastuzumab in patient-derived esophageal squamous cell carcinoma xenograft (PDECX mouse models. Methods PDECX models were established by implanting patient esophageal squamous cell carcinoma (ESCC tissues into immunodeficient (SCID/nude mice. HER-2 gene copy number (GCN and protein expression were determined in xenograft tissues and corresponding patient EC samples by FISH and IHC analysis. Trastuzumab anti-tumor efficacy was evaluated within these PDECX models (n = 8 animals/group. Furthermore, hotspot mutations of EGFR, K-ras, B-raf and PIK3CA genes were screened for in the PDECX models and their corresponding patient’s ESCC tissues. Similarity between the PDECX models and their corresponding patient’s ESCC tissue was confirmed by histology, morphology, HER-2 GCN and mutation. Results None of the PDECX models (or their corresponding patient’s ESCC tissues harbored HER-2 gene amplification. IHC staining showed HER-2 positivity (IHC 2+ in 2 PDECX models and negativity in 3 PDECX models. Significant tumor regression was observed in the Trastuzumab-treated EC044 HER-2 positive model (IHC 2+. A second HER-2 positive (IHC 2+ model, EC039, harbored a known PIK3CA mutation and showed strong activation of the AKT signaling pathway and was insensitive to Trastuzumab treatment, but could be resensitised using a combination of Trastuzumab and AKT inhibitor AZD5363. In summary, we established 5 PDECX mouse models and demonstrated tumor regression in response to Trastuzumab treatment in a HER-2 IHC 2+ model, but resistance in a HER-2 IHC 2+/PIK3CA mutated model. Conclusions

  3. Perinatal outcome of twin pregnancies delivered in a teaching hospital Resultado perinatal de gestações gemelares com parto em hospital universitário

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    Renata Almeida de Assunção

    2010-01-01

    Full Text Available OBJECTIVE: This study aimed to evaluate the perinatal outcome of twin pregnancies delivered in a tertiary teaching hospital according to chorionicity. METHODS: A retrospective study involving 289 twin pregnancies delivered from January 2003 to December 2006 was carried out. Maternal and perinatal data were obtained from hospital charts and delivery logs. Chorionicity was determined by ultrasonography or histopathological study. RESULTS: Incidence of twin gestations was 3.4% and 96.4% were spontaneously conceived. 60.5% were dichorionic (DC, 30.8% of monochorionic diamniotic (MCDA, 6.6% monochorionic monoamniotic (MCMA and for 2.1% chorionicity was unknown. The mean gestation age at delivery was respectively 35.4, 33.6, 32.9 for DC, MCDA and MCMA. The mean birth weight was 2.171, 1.832 and 1.760 g respectively for DC, MC and MCMA. The proportion of fetuses delivered with less than 34 weeks in DC was of 21.7%, while in MCDA it was of 39.3% and in MCMA of 42.1%. Birth weight below the 10th centile occurred in 15.7% for DC, 22.5% for MCDA and 26.3% in MCMA. Congenital anomalies were observed in 21.3% in monochorionic and in 7.4% in the dichorionic. Lenght of hospital stay was shorter for DC when compared to MCDA and MCMA twins (13.1, 17.3 and 23.3 days, respectively. The proportion of twin pregnancies with both babies discharged alive were 85.7% in DC and 61.1% in MC. CONCLUSION: The rate of preterm deliveries and low birth weight is higher in monochorionic pregnancies when compared to dichorionic twins. However, when adjusted for complications such as fetal abnormalities and twin-twin transfusion syndrome, double survival rates were similar in the two groups.OBJETIVO: Avaliar o resultado perinatal nas gestações gemelares com partos em hospital universitário segundo a corionicidade. MÉTODOS: Estudo retrospectivo de 289 gestações gemelares com partos no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, no per

  4. [The concept of nutritional self-sufficiency and the demographic equilibrium of Rwanda].

    Science.gov (United States)

    Habimana Nyirasafari, G

    1987-12-01

    Achieving food self-sufficiency is the basic strategy of Rwanda's 4th 5-year plan covering 1987-91. The population growth rate has increased from 3% in 1970 to 3.7% in 1983, with the population doubling between 1964 and 1985. Food production grew by about 4%/year between 1966-83, creating a slight increase in per capita food availability, but the 2171 calories available per capita is dangerously close to the theoretical minimum requirement of 2100 per day. The theoretical protein requirement is almost covered, but there is a serious shortage of oils. The increase in production since 1966 has been due almost exclusively to the extension of cultivated land. But the land supply is limited, and future production increases will need to be based on increased yields per unit cultivated. The National Office of Population has developed a simulation model that analyzes the parallel evolution of population and production so as to identify demographic and development policies that will assure food self-sufficiency and an improvement in living conditions. The population subsystem subjects the population divided by age and sex to the effects of fertility, migration, and mortality. Births are the result of 36 different fertility rates applied to the population of women aged 14-49 years. The agricultural subsystem is tied to the population subsystem by comparison of the volume of population to that of production, by estimation of the proportion of the population living exclusively by subsistence agriculture, by calculation of the potential emigration resulting from overpopulation of the countryside, and by estimation of the links between nutritional level, mortality, and duration of breastfeeding. 5 annexes contain subsystems showing effects of demographic growth on education, employment, and health. The model has various limitations including those of the reliability of its data, but it is sufficiently precise for its main function of clarifying the choices facing policymakers. 6

  5. Caracterización psicológica y sintomatología depresiva de los adolescentes de 12 a 18 años

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    Luz Marina Bautista-Rodriguez

    2008-12-01

    Full Text Available La presente investigación desarrolló una metodología descriptiva comparativa, donde planteó la identificación de sintomatología depresiva en una muestra comprendida por 193 estudiantes de bachillerato del colegio oriental Nº 26 del barrio Prados Norte de la ciudad de Cúcuta, con edades comprendidas entre los 12 a 18 años; para lo cual se desarrolló una metodología descriptiva comparativa, por medio de la utilización de dos instrumentos: el primero, el inventario de depresión de Beck, el cual identifica la sintomatología depresiva de los adolescentes ; el segundo, es un formato de recolección de información sobre las características psicológicas del adolescente (CPA creado por las investigadoras de este estudio, bajo la auditoria de asesores expertos en el tema, como psicólogos y enfermeras especialistas en el área de salud mental; además, se realizó la caracterización sociodemográfica de la muestra. Posterior a la aplicación de los instrumentos se encontró que existe prevalencia de sintomatología depresiva en el 38.4% de la muestra, de los cuales los niveles más afectados según el instrumento fueron el afectivo, seguido del cognitivo, el motor y por último el somático. Un dato relevante, es la prevalencia de ideación suicida en el 30%, tanto en los estudiantes sintomáticos depresivos (21.71% y en los no sintomáticos depresivos (8.28%; con respecto a las Características Psicológicas de los adolescentes, el 90.2% de los alumnos presentaron algún grado de afectación de las CPA, mostrando así, que las características más afectadas en los jóvenes de la muestra eran: la identidad personal (en las dimensiones de la autonomía, autoimagen y autoconcepto, la estabilidad emocional, el pensamiento formal y la motivación. Referente a lo sociodemográfico se encontró que la sintomatología de presiva afectó significativamente al sexo femenino, con edad promedio de 14 años, la convivencia uniparental del

  6. The Vertical Drop Jump Is a Poor Screening Test for ACL Injuries in Female Elite Soccer and Handball Players: A Prospective Cohort Study of 710 Athletes.

    Science.gov (United States)

    Krosshaug, Tron; Steffen, Kathrin; Kristianslund, Eirik; Nilstad, Agnethe; Mok, Kam-Ming; Myklebust, Grethe; Andersen, Thor Einar; Holme, Ingar; Engebretsen, Lars; Bahr, Roald

    2016-04-01

    The evidence linking knee kinematics and kinetics during a vertical drop jump (VDJ) to anterior cruciate ligament (ACL) injury risk is restricted to a single small sample. Still, the VDJ test continues to be advocated for clinical screening purposes. To test whether 5 selected kinematic and kinetic variables were associated with future ACL injuries in a large cohort of Norwegian female elite soccer and handball players. Furthermore, we wanted to assess whether the VDJ test can be recommended as a screening test to identify players with increased risk. Cohort study; Level of evidence, 2. Elite female soccer and handball players participated in preseason screening tests from 2007 through 2014. The tests included marker-based 3-dimensional motion analysis of a drop-jump landing. We followed a predefined statistical protocol in which we included the following candidate risk factors in 5 separate logistic regression analyses, with new ACL injury as the outcome: (1) knee valgus angle at initial contact, (2) peak knee abduction moment, (3) peak knee flexion angle, (4) peak vertical ground-reaction force, and (5) medial knee displacement. A total of 782 players were tested (age, 21 ± 4 years; height, 170 ± 7 cm; body mass, 67 ± 8 kg), of which 710 were included in the analyses. We registered 42 new noncontact ACL injuries, including 12 in previously ACL-injured players. Previous ACL injury (relative risk, 3.8; 95% CI, 2.1-7.1) and medial knee displacement (odds ratio, 1.40; 95% CI, 1.12-1.74 per 1-SD change) were associated with increased risk for injury. However, among the 643 players without previous injury, we found no association with medial knee displacement. A receiver operating characteristic curve analysis of medial knee displacement showed an area under the curve of 0.6, indicating a poor-to-failed combined sensitivity and specificity of the test, even when including previously injured players. Of the 5 risk factors considered, medial knee displacement was the

  7. Effect of Community-Based Social Skills Training and Tai-Chi Exercise on Outcomes in Patients with Chronic Schizophrenia: A Randomized, One-Year Study.

    Science.gov (United States)

    Kang, Ruiying; Wu, Yeqing; Li, Zhiwu; Jiang, Jun; Gao, Qi; Yu, Yuncui; Gao, Keming; Yan, Yuxiang; He, Yan

    between the two groups (PANSS total score: t = 4.839, p social domain: t = -2.171, p = 0.031). Multiple linear regression analysis also showed that the intervention was significantly effective for changes from baseline to 12 months on PANSS total score (B = 0.804, p social domain of quality of life (B = -0.673, p = 0.044). This study suggested that the community-based integrated intervention such as social skills training plus Tai-chi should be part of a rehabilitation effort for patients with schizophrenia in order to improve clinical symptoms, quality of life, and medication adherence. © 2016 S. Karger AG, Basel.

  8. A two-stage approach for improved prediction of residue contact maps

    Directory of Open Access Journals (Sweden)

    Pollastri Gianluca

    2006-03-01

    Full Text Available Abstract Background Protein topology representations such as residue contact maps are an important intermediate step towards ab initio prediction of protein structure. Although improvements have occurred over the last years, the problem of accurately predicting residue contact maps from primary sequences is still largely unsolved. Among the reasons for this are the unbalanced nature of the problem (with far fewer examples of contacts than non-contacts, the formidable challenge of capturing long-range interactions in the maps, the intrinsic difficulty of mapping one-dimensional input sequences into two-dimensional output maps. In order to alleviate these problems and achieve improved contact map predictions, in this paper we split the task into two stages: the prediction of a map's principal eigenvector (PE from the primary sequence; the reconstruction of the contact map from the PE and primary sequence. Predicting the PE from the primary sequence consists in mapping a vector into a vector. This task is less complex than mapping vectors directly into two-dimensional matrices since the size of the problem is drastically reduced and so is the scale length of interactions that need to be learned. Results We develop architectures composed of ensembles of two-layered bidirectional recurrent neural networks to classify the components of the PE in 2, 3 and 4 classes from protein primary sequence, predicted secondary structure, and hydrophobicity interaction scales. Our predictor, tested on a non redundant set of 2171 proteins, achieves classification performances of up to 72.6%, 16% above a base-line statistical predictor. We design a system for the prediction of contact maps from the predicted PE. Our results show that predicting maps through the PE yields sizeable gains especially for long-range contacts which are particularly critical for accurate protein 3D reconstruction. The final predictor's accuracy on a non-redundant set of 327 targets is 35

  9. Influência da suplementação com Concentrados nas características de carcaça de bovinos F1 Limousin - Nelore, não-castrados, durante a seca, em pastagens de Brachiaria decumbens

    Directory of Open Access Journals (Sweden)

    Santos Eduardo Destéfani Guimarães

    2002-01-01

    Full Text Available Este trabalho foi realizado na Fazenda Experimental de Felixlândia (MG, da EPAMIG, no período de julho a outubro de 1997, com o objetivo de estudar a influência da suplementação com concentrados sobre as características físicas e o rendimento dos cortes da carcaça em 20 novilhos Limousin-Nelore, não-castrados, com 22-23 meses de idade e peso médio de 459 kg ao abate. Retiraram-se, aleatoriamente, quatro animais de cada um dos cinco tratamentos a que foram submetidos durante 112 dias na época seca, em pastagens diferidas de Brachiaria decumbens. No tratamento T1 (referência, os animais nas pastagens receberam apenas sal mineralizado; nos tratamentos T2 (75% milho, T3 (50% milho, T4 (25% milho e T5 (farelo de trigo, foram fornecidas quantidades médias diárias por animal de 3,70 kg de MS de concentrados (equivalente, em matéria natural, a 1% do PV com 24,1% de PB e NDT variando de 67,8% (T5 - farelo de trigo a 85,6% (T2 - 75% milho. Avaliaram-se as características peso, rendimento e comprimento de carcaça, rendimentos de paleta, acém completo, ponta de agulha, alcatra completa e coxão, espessura de gordura subcutânea, área de olho de lombo, porcentagens na carcaça de tecido adiposo, músculos e ossos e a relação músculo/osso. O fornecimento de suplementos proporcionou a obtenção de carcaças mais pesadas (257,0 vs. 203,9 kg, com menor proporção de ossos (15,76 vs. 21,71%, maior relação músculo:osso (3,6 vs. 2,9 e melhor acabamento quando comparado às carcaças dos animais não-suplementados. Os animais suplementados e não-suplementados não diferiram em relação a rendimento e comprimento de carcaça, rendimentos de paleta, acém completo, alcatra completa e coxão, área de olho de lombo (AOL e porcentagem de músculos na carcaça.

  10. Análise de regressão logística na combinação de métodos propedêuticos no diagnóstico do glaucoma

    Directory of Open Access Journals (Sweden)

    Leonardo Reichmann Fasolo

    2013-12-01

    Full Text Available OBJETIVOS: Estudar a habilidade diagnóstica do tomógrafo retiniano de Heidelberg (HRT II, GDx analisador de fibras nervosas (GDx, perimetria azul-amarelo (SWAP, tecnologia de frequência duplicada (FDT isoladamente e em conjunto no diagnóstico do glaucoma. MÉTODOS: Sessenta glaucomatosos e 60 pacientes normais foram submetidos a exames de HRT II, GDx, SWAP e FDT. HRT foi considerado alterado quando pelo menos uma região do anel neurorretiniano esteve fora dos limites da normalidade, conforme a análise de regressão de Moorfields. GDx alterado foi definido quando pelo menos um índice foi considerado pelo programa do equipamento como fora dos limites normais, excluindo-se o índice simetria, ou ainda quando no gráfico "the deviation from normal graph" apareceu um quadrante com significância abaixo de 5%. O FDT foi considerado anormal quando pelo menos uma região testada apresentou-se com defeito severo ou com a presença de dois defeitos moderados contíguos. Para o SWAP foram adotados os critérios de anormalidade propostos por Anderson. Análise de regressão logística foi realizada. RESULTADOS: Quando foram estudadas as tecnologias isoladamente, a análise de regressão logística apresentou melhores índices de razão das chances para glaucoma com exames positivos para o HRT (22,49, seguido pelo SWAP (21,71. FDT (3,97 e GDx (2,73. Quando se associaram exames positivos de diferentes tecnologias, as razões das chances aumentaram. Nos casos com exames de HRT, FDT e SWAP fora dos limites normais, a razão das chances foi de 252,6 e com HRT, SWAP e GDx alterados, 173,1. Quando associamos exames positivos de diferentes tecnologias, a razão das chances dos pacientes serem glaucomatosos aumentou consideravelmente, chegando a 689,7 com todos os exames fora dos limites normais, o que ocorreu em 26 pacientes deste estudo. CONCLUSÕES: A análise de regressão logística confirmou que a presença de exames alterados de HRT ou SWAP apresentam

  11. [School Entrance Examination for Lateral Entrants - What Can and What Should They be Able to Do? A Discussion Contribution Based on the Data from the Health Authority Frankfurt am Main 2006-2016].

    Science.gov (United States)

    Karathana, Maria; Krackhardt, Bernhard; Schade, Manuela; Heudorf, Ursel

    2018-04-01

    The medical investigation of school beginners is one of the essential tasks of the child and youth services of the health authorities. While in all federal states in Germany, the examination of all school beginners is legally clearly stipulated, the situation for "lateral entry", that is, children of school age, who are moving from a foreign country to a local German community and attending school there, is not clearly regulated in the respective school laws. This article presents the experiences of the lateral entry investigations in Frankfurt am Main. All children of school age who moved to Frankfurt from abroad undergo a health check. This encompasses a standardized questionnaire-based history with the help of interpreters, including a review of the available vaccination document (case history sheets are available in different languages), an eye examination, hearing test and a physical examination. Children over the age of 15 who came from countries with a high prevalence for tuberculosis had chest x-ray. Between 2006 and June 2016, a total of 8245 children and adolescents were examined, in 4% of the children abnormalities in hearing, and in 22% in visual screening showed noticeable problems, with an increasing trend in recent years. The vaccination status was unknown in two-thirds of the children, one quarter of the children were sufficiently vaccinated against tetanus, diphtheria, polio and pertussis, and 19.5% were immunized against measles (vaccine or disease). Diseases of the respiratory tract, the heart and the circulation were predominant with a total of 4%, followed by musculoskeletal disorders with 3%. Lice infestation was found in 1.7% of children. In 0,7% of 2171 children with chest-X-rays, a conspicuous pulmonary lesion was diagnosed, but no tuberculosis. The focus of the lateral entrance examination is a school-related health status. On the basis of experience gained in Frankfurt am Main, it should be pointed out that investigations by the lateral

  12. Inclusion of mobile phone numbers into an ongoing population health survey in New South Wales, Australia: design, methods, call outcomes, costs and sample representativeness.

    Science.gov (United States)

    Barr, Margo L; van Ritten, Jason J; Steel, David G; Thackway, Sarah V

    2012-11-22

    In Australia telephone surveys have been the method of choice for ongoing jurisdictional population health surveys. Although it was estimated in 2011 that nearly 20% of the Australian population were mobile-only phone users, the inclusion of mobile phone numbers into these existing landline population health surveys has not occurred. This paper describes the methods used for the inclusion of mobile phone numbers into an existing ongoing landline random digit dialling (RDD) health survey in an Australian state, the New South Wales Population Health Survey (NSWPHS). This paper also compares the call outcomes, costs and the representativeness of the resultant sample to that of the previous landline sample. After examining several mobile phone pilot studies conducted in Australia and possible sample designs (screening dual-frame and overlapping dual-frame), mobile phone numbers were included into the NSWPHS using an overlapping dual-frame design. Data collection was consistent, where possible, with the previous years' landline RDD phone surveys and between frames. Survey operational data for the frames were compared and combined. Demographic information from the interview data for mobile-only phone users, both, and total were compared to the landline frame using χ2 tests. Demographic information for each frame, landline and the mobile-only (equivalent to a screening dual frame design), and the frames combined (with appropriate overlap adjustment) were compared to the NSW demographic profile from the 2011 census using χ2 tests. In the first quarter of 2012, 3395 interviews were completed with 2171 respondents (63.9%) from the landline frame (17.6% landline only) and 1224 (36.1%) from the mobile frame (25.8% mobile only). Overall combined response, contact and cooperation rates were 33.1%, 65.1% and 72.2% respectively. As expected from previous research, the demographic profile of the mobile-only phone respondents differed most (more that were young, males, Aboriginal

  13. Screening antimicrobial activity of various extracts of Urtica dioica.

    Science.gov (United States)

    Modarresi-Chahardehi, Amir; Ibrahim, Darah; Fariza-Sulaiman, Shaida; Mousavi, Leila

    2012-12-01

    Urtica dioica or stinging nettle is traditionally used as an herbal medicine in Western Asia. The current study represents the investigation of antimicrobial activity of U. dioica from nine crude extracts that were prepared using different organic solvents, obtained from two extraction methods: the Soxhlet extractor (Method I), which included the use of four solvents with ethyl acetate and hexane, or the sequential partitions (Method II) with a five solvent system (butanol). The antibacterial and antifungal activities of crude extracts were tested against 28 bacteria, three yeast strains and seven fungal isolates by the disc diffusion and broth dilution methods. Amoxicillin was used as positive control for bacteria strains, vancomycin for Streptococcus sp., miconazole nitrate (30 microg/mL) as positive control for fungi and yeast, and pure methanol (v/v) as negative control. The disc diffusion assay was used to determine the sensitivity of the samples, whilst the broth dilution method was used for the determination of the minimal inhibition concentration (MIC). The ethyl acetate and hexane extract from extraction method I (EA I and HE I) exhibited highest inhibition against some pathogenic bacteria such as Bacillus cereus, MRSA and Vibrio parahaemolyticus. A selection of extracts that showed some activity was further tested for the MIC and minimal bactericidal concentrations (MBC). MIC values of Bacillus subtilis and Methicillin-resistant Staphylococcus aureus (MRSA) using butanol extract of extraction method II (BE II) were 8.33 and 16.33mg/mL, respectively; while the MIC value using ethyl acetate extract of extraction method II (EAE II) for Vibrio parahaemolyticus was 0.13mg/mL. Our study showed that 47.06% of extracts inhibited Gram-negative (8 out of 17), and 63.63% of extracts also inhibited Gram-positive bacteria (7 out of 11); besides, statistically the frequency of antimicrobial activity was 13.45% (35 out of 342) which in this among 21.71% belongs to

  14. Screening antimicrobial activity of various extracts of Urtica dioica

    Directory of Open Access Journals (Sweden)

    Amir Modarresi-Chahardehi

    2012-12-01

    Full Text Available Urtica dioica or stinging nettle is traditionally used as an herbal medicine in Western Asia. The current study represents the investigation of antimicrobial activity of U. dioica from nine crude extracts that were prepared using different organic solvents, obtained from two extraction methods: the Soxhlet extractor (Method I, which included the use of four solvents with ethyl acetate and hexane, or the sequential partitions (Method II with a five solvent system (butanol. The antibacterial and antifungal activities of crude extracts were tested against 28 bacteria, three yeast strains and seven fungal isolates by the disc diffusion and broth dilution methods. Amoxicillin was used as positive control for bacteria strains, vancomycin for Streptococcus sp., miconazole nitrate (30µg/mL as positive control for fungi and yeast, and pure methanol (v/v as negative control. The disc diffusion assay was used to determine the sensitivity of the samples, whilst the broth dilution method was used for the determination of the minimal inhibition concentration (MIC. The ethyl acetate and hexane extract from extraction method I (EA I and HE I exhibited highest inhibition against some pathogenic bacteria such as Bacillus cereus, MRSA and Vibrio parahaemolyticus. A selection of extracts that showed some activity was further tested for the MIC and minimal bactericidal concentrations (MBC. MIC values of Bacillus subtilis and Methicillin-resistant Staphylococcus aureus (MRSA using butanol extract of extraction method II (BE II were 8.33 and 16.33mg/mL, respectively; while the MIC value using ethyl acetate extract of extraction method II (EAE II for Vibrio parahaemolyticus was 0.13mg/mL. Our study showed that 47.06% of extracts inhibited Gram-negative (8 out of 17, and 63.63% of extracts also inhibited Gram-positive bacteria (7 out of 11; besides, statistically the frequency of antimicrobial activity was 13.45% (35 out of 342 which in this among 21.71% belongs to

  15. Clinical application of human adipose tissue-derived mesenchymal stem cells in progressive hemifacial atrophy (Parry-Romberg disease) with microfat grafting techniques using 3-dimensional computed tomography and 3-dimensional camera.

    Science.gov (United States)

    Koh, Kyung Suk; Oh, Tae Suk; Kim, Hoon; Chung, In Wook; Lee, Kang Woo; Lee, Hyo Bo; Park, Eun Jung; Jung, Jae Seob; Shin, Il Seob; Ra, Jeong Chan; Choi, Jong Woo

    2012-09-01

    Parry-Romberg disease is a rare condition that results in progressive hemifacial atrophy, involving the skin, dermis, subcutaneous fat, muscle, and, finally, cartilage and bone. Patients have been treated with dermofat or fat grafts or by microvascular free flap transfer. We hypothesized that adipose-derived stem cells (ASCs) may improve the results of microfat grafting through enhancing angiogenesis. We evaluated the utility of ASC in microfat grafting of patients with Parry-Romberg disease by measuring the change in the hemifacial volumes after injection of ASCs with microfat grafts or microfat grafts alone. In April 2008, this investigation was approved by the Korean Food and Drug Administration and the institutional review board of the Asan Medical Center (Seoul, Korea) that monitor investigator-initiated trials. Between May 2008 and January 2009, 10 volunteers with Parry-Romberg disease (5 men and 5 women; mean age, 28 y) were recruited; 5 received ASC and microfat grafts and 5 received microfat grafts only. The mean follow-up period was 15 months. Adipose-derived stem cells were obtained from abdominal fat by liposuction and were cultured for 2 weeks. On day 14, patients were injected with fat grafts alone or plus (in the test group) 1 × 10 ASCs. Patients were evaluated postoperatively using a 3-dimensional camera and 3-dimensional CT scans, and grafted fat volumes were objectively calculated. Successful outcomes were evident in all 5 patients receiving microfat grafts and ASCs, and the survival of grafted fat was better than in patients receiving microfat grafts alone. Before surgery, the mean difference between ipsilateral and contralateral hemiface volume in patients receiving microfat grafts and ASCs was 21.71 mL decreasing to 4.47 mL after surgery. Overall resorption in this ASC group was 20.59%. The mean preoperative difference in hemiface volume in those receiving microfat grafts alone was 8.32 mL decreasing to 3.89 mL after surgery. Overall

  16. The combination of olaparib and camptothecin for effective radiosensitization

    International Nuclear Information System (INIS)

    Miura, Katsutoshi; Sakata, Koh-ichi; Someya, Masanori; Matsumoto, Yoshihisa; Matsumoto, Hideki; Takahashi, Akihisa; Hareyama, Masato

    2012-01-01

    Poly (ADP-ribose) polymerase-1 (PARP-1) is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281) enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT). Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent. DLD-1 cells (a human colorectal cancer cell line) and H1299 cells (a non-small cell lung cancer cell line) with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The γH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT. A radiosensitizing effect of olaparib was seen even at 0.01 μM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 μM, and its sensitizing effect was the same at both 0.01 μM and 1 μM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the γH2AX focus assay corresponded with the clonogenic assay findings. Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib was not dependent on the p53 status of tumor cells. These

  17. Poly(ADP-ribose) polymerase as a novel regulator of 17β-estradiol-induced cell growth through a control of the estrogen receptor/IGF-1 receptor/PDZK1 axis.

    Science.gov (United States)

    Kim, Hogyoung; Tarhuni, Abdelmetalab; Abd Elmageed, Zakaria Y; Boulares, A Hamid

    2015-07-17

    We and others have extensively investigated the role of PARP-1 in cell growth and demise in response to pathophysiological cues. Most of the clinical trials on PARP inhibitors are targeting primarily estrogen receptor (ER) negative cancers with BRCA-deficiency. It is surprising that the role of the enzyme has yet to be investigated in ER-mediated cell growth. It is noteworthy that ER is expressed in the majority of breast cancers. We recently showed that the scaffolding protein PDZK1 is critical for 17β-estradiol (E2)-induced growth of breast cancer cells. We demonstrated that E2-induced PDZK1 expression is indirectly regulated by ER and requires IGF-1 receptor (IGF-1R). The breast cancer cell lines MCF-7 and BT474 were used as ER(+) cell culture models. Thieno[2,3-c]isoquinolin-5-one (TIQ-A) and olaparib (AZD2281) were used as potent inhibitors of PARP. PARP-1 knockdown by shRNA was used to show specificity of the effects to PARP-1. In this study, we aimed to determine the effect of PARP inhibition on estrogen-induced growth of breast cancer cells and examine whether the potential effect is linked to PDZK1 and IGF-1R expression. Our results show that PARP inhibition pharmacologically by TIQ-A or olaparib or by PARP-1 knockdown blocked E2-dependent growth of MCF-7 cells. Such inhibitory effect was also observed in olaparib-treated BT474 cells. The effect of PARP inhibition on cell growth coincided with an efficient reduction in E2-induced PDZK1 expression. This effect was accompanied by a similar decrease in the cell cycle protein cyclin D1. PARP appeared to regulate E2-induced PDZK1 at the mRNA level. Such regulation may be linked to a modulation of IGF-1R as PARP inhibition pharmacologically or by PARP-1 knockdown efficiently reduced E2-induced expression of the receptor at the protein and mRNA levels. Overall, our results show for the first time that PARP regulates E2-mediated cell growth by controlling the ER/IGF-1R/PDZK1 axis. These findings suggest that the

  18. Sources of traffic and visitors' preferences regarding online public reports of quality: web analytics and online survey results.

    Science.gov (United States)

    Bardach, Naomi S; Hibbard, Judith H; Greaves, Felix; Dudley, R Adams

    2015-05-01

    In the context of the Affordable Care Act, there is extensive emphasis on making provider quality transparent and publicly available. Online public reports of quality exist, but little is known about how visitors find reports or about their purpose in visiting. To address this gap, we gathered website analytics data from a national group of online public reports of hospital or physician quality and surveyed real-time visitors to those websites. Websites were recruited from a national group of online public reports of hospital or physician quality. Analytics data were gathered from each website: number of unique visitors, method of arrival for each unique visitor, and search terms resulting in visits. Depending on the website, a survey invitation was launched for unique visitors on landing pages or on pages with quality information. Survey topics included type of respondent (eg, consumer, health care professional), purpose of visit, areas of interest, website experience, and demographics. There were 116,657 unique visitors to the 18 participating websites (1440 unique visitors/month per website), with most unique visitors arriving through search (63.95%, 74,606/116,657). Websites with a higher percent of traffic from search engines garnered more unique visitors (P=.001). The most common search terms were for individual hospitals (23.25%, 27,122/74,606) and website names (19.43%, 22,672/74,606); medical condition terms were uncommon (0.81%, 605/74,606). Survey view rate was 42.48% (49,560/116,657 invited) resulting in 1755 respondents (participation rate=3.6%). There were substantial proportions of consumer (48.43%, 850/1755) and health care professional respondents (31.39%, 551/1755). Across websites, proportions of consumer (21%-71%) and health care professional respondents (16%-48%) varied. Consumers were frequently interested in using the information to choose providers or assess the quality of their provider (52.7%, 225/427); the majority of those choosing a

  19. Sources of Traffic and Visitors’ Preferences Regarding Online Public Reports of Quality: Web Analytics and Online Survey Results

    Science.gov (United States)

    Hibbard, Judith H; Greaves, Felix; Dudley, R Adams

    2015-01-01

    Background In the context of the Affordable Care Act, there is extensive emphasis on making provider quality transparent and publicly available. Online public reports of quality exist, but little is known about how visitors find reports or about their purpose in visiting. Objective To address this gap, we gathered website analytics data from a national group of online public reports of hospital or physician quality and surveyed real-time visitors to those websites. Methods Websites were recruited from a national group of online public reports of hospital or physician quality. Analytics data were gathered from each website: number of unique visitors, method of arrival for each unique visitor, and search terms resulting in visits. Depending on the website, a survey invitation was launched for unique visitors on landing pages or on pages with quality information. Survey topics included type of respondent (eg, consumer, health care professional), purpose of visit, areas of interest, website experience, and demographics. Results There were 116,657 unique visitors to the 18 participating websites (1440 unique visitors/month per website), with most unique visitors arriving through search (63.95%, 74,606/116,657). Websites with a higher percent of traffic from search engines garnered more unique visitors (P=.001). The most common search terms were for individual hospitals (23.25%, 27,122/74,606) and website names (19.43%, 22,672/74,606); medical condition terms were uncommon (0.81%, 605/74,606). Survey view rate was 42.48% (49,560/116,657 invited) resulting in 1755 respondents (participation rate=3.6%). There were substantial proportions of consumer (48.43%, 850/1755) and health care professional respondents (31.39%, 551/1755). Across websites, proportions of consumer (21%-71%) and health care professional respondents (16%-48%) varied. Consumers were frequently interested in using the information to choose providers or assess the quality of their provider (52.7%, 225

  20. Sr3Fe5/4Mo3/4O6.9, an n = 2 Ruddlesen-Popper Phase: Synthesis and Properties

    International Nuclear Information System (INIS)

    Whaley, L.; Lobanov, M.; Sehptyakov, D.; Croft, M.; Ramanujachary, K.; Lofland, S.; Stephens, P.; Her, J.; Van Tendeloo, G.

    2006-01-01

    In a systematic search for an oxygen-stoichiometric phase, Sr 3 (FeMo)O 7 , in a range of iron-to-molybdenum ratios greater than 1:1 that typically give phase mixtures, we have found an n = 2 Ruddlesden-Popper phase, Sr 3 Fe 5/4 Mo 3/4 O 6.9 , as supported by synchrotron powder X-ray diffraction (SPXD), high-resolution transmission electron microscopy (HREM), and powder neutron diffraction (PND) results. By SPXD, this oxygen-deficient, B-site disordered, two-dimensional analogue of Sr2FeMoO6 adopts tetragonal I4/mmm symmetry (a = b = 3.92449(5) Angstroms; c = 20.3423(3) Angstroms) with vacancies at the O(1) oxygen site and with a composition that refines to a nominal stoichiometry Sr 3 Fe 5/4 Mo 3/4 O 6.9 . The two-phase SPXD refinement includes Sr 3 Fe 5/4 Mo 3/4 O 6.9 (95.7%) and a double-perovskite (DP) intergrowth, Sr 2 FeMoO 6 (4.3%), consistent with HREM studies in which DP intergrowths but no individual DP grains were found. The G-type antiferromagnetically (AFM)-ordered structure of the phase, with the magnetic cell a m = √2a ∼ 5.548 Angstroms, c m = c ∼ 20.35 Angstroms, derived from PND data, displays a saturated moment of 2.17(1) μ B at 9 K and an asynchronous decrease of the in-plane component of the Fe/Mo moment (μ xy ), with respect to the out-of-plane moment (μ z ) upon increasing temperature from 9 K up to the Neel temperature, TN ∼ 150 K. No structural transitions were observed over the entire temperature range studied: from 1.5 to 500 K. The temperature-dependent resistivity is consistent with Efros-Shklovskii variable-range hopping, applicable to two ranges of temperature (189 K RT ∼ 3 μ(Omega)·cm). A small negative magnetoresistance is observed (∼2.5%) at 5 T near the ordering temperature (∼150 K). The temperature-dependent magnetic susceptibility shows an inflection between 125 and 150 K, consistent with the AFM ordering temperature (∼150 K) observed by PND. X-ray near-edge spectroscopy data are consistent with formal

  1. Ion Composition of Comet 19P/Borrelly as Measured by the PEPE Ion Mass Spectrometer on DS1

    Science.gov (United States)

    Nordholt, J. E.; Reisenfeld, D. B.; Wiens, R. C.; Gary, P.

    2002-12-01

    Cometary compositions are of great interest because they hold important clues to the formation of the outer solar system, and to the sources of volatiles in the solar system, including the terrestrial planets. In order to understand the primordial compositions of cometary nuclei, it is important to also understand their evolution, as many of the comets most accessible to spacecraft are highly evolved. It is also important to understand the ion and neutral chemistry that occurs in the coma surrounding the nucleus if the coma ion composition is to be used to determine the original composition of the nucleus. Deep Space One (DS1) was only the second spacecraft, after Giotto, to use an ion mass-resolving instrument to explore cometary coma compositions in-situ, which it did during the flyby of Comet Borrelly on September 22, 2001. Borrelly is significantly more evolved than Halley. In addition, the encounter occurred at a significantly greater distance from the sun (1.36 AU vs 0.9 AU for Giotto at Halley). The Plasma Experiment for Planetary Exploration (PEPE) on board DS1 was capable of resolving electron and ion energy, angle of incidence, and ion mass composition. The PEPE ion data from the seven minutes surrounding closest approach (2171 km) have been extensively analyzed. The instrument response was modeled using SIMION and TRIM codes for all of the major species through 20 AMU plus CO (at its operating voltage PEPE was very insensitive to heavier molecules). Chi-squared minimization analysis is being carried out to determine the best fit and the uncertainties. Preliminary results for the predominant heavy ions are OH+ at (72 +/- 9)% of the total water-group ion density, H2O+ at (25 +/- 7)%, CH3+ at (5 +/- 3)%, and O+ at (4 +/- 5)%. Uncertainties are quoted at the 90% confidence level. Comparison with reported Halley compositions from Giotto shows that Borrelly clearly has a lower H3O+ abundance (< 9%), consistent with a more evolved comet. The presence of

  2. Weak ferromagnetism and magnetoelectric effect in multiferroic xBa{sub 0.95}Sr{sub 0.05}TiO{sub 3}–(1−x)BiFe{sub 0.9}Gd{sub 0.1}O{sub 3} relaxors

    Energy Technology Data Exchange (ETDEWEB)

    Miah, M.J. [Department of Physics, Bangladesh University of Engineering and Technology (Bangladesh); Department of Physics, Comilla University, Comilla (Bangladesh); Khan, M.N.I. [Materials Science Division, Atomic Energy Center, Dhaka (Bangladesh); Hossain, A.K.M. Akther, E-mail: akmhossain@phy.buet.ac.bd [Department of Physics, Bangladesh University of Engineering and Technology (Bangladesh)

    2016-03-01

    Multiferroic xBa{sub 0.95}Sr{sub 0.05}TiO{sub 3}–(1−x)BiFe{sub 0.9}Gd{sub 0.1}O{sub 3} [xBST–(1−x)BFGO], where x=0.00−0.40, have been synthesized by the conventional solid-state reaction method. The crystalline phase, microstructure, relaxor behavior, ac conductivity, impedance spectroscopy, dc magnetic properties, complex initial permeability and magnetoelectric coefficient of these solid solutions have been investigated. The crystal structure is found to change from rhombohedral in BFGO rich compositions to cubic when x≥0.30. Room temperature dielectric properties are investigated within the frequency range from 1 kHz to 1 MHz and found to increase with BST content. The frequency dependence of high temperature dielectric measurements indicated that the composites with x≥0.20, exhibit relaxor ferroelectric behavior. The ac conductivity obeys the Jonscher’s universal power law and BST helps to enhance the electrical conductivity of the composites. Studies of impedance spectroscopy suggest that only grains have the contribution to the conductivity mechanism in this material. Magnetizations as a function of applied magnetic field measurements show weak ferromagnetism for 0.10≤x≤0.30 composites. The maximum value of remnant magnetization is found to be 0.565×10{sup 3} A/m (=0.08 emu/g) for x=0.25 which is better than previously reported BaTiO{sub 3}–BiFeO{sub 3} systems. The complex initial permeability is found to improve with the increase in BST concentration due to the reduction of oxygen vacancies. In addition, an enhanced magnetoelectric (ME) coupling is also observed and determined by the ME coefficient. The maximum value of ME coefficient is found to be 21.71×10{sup −4} V/A (=1.67 mV/cm Oe) for the x=0.25 composition. The BST–BFGO solid solutions show high-performance multiferroic properties and can be selected for further investigation. - Highlights: • Phase pure multiferroic xBa{sub 0.95}Sr{sub 0.05}TiO{sub 3}–(1−x)BiFe{sub 0

  3. The combination of olaparib and camptothecin for effective radiosensitization

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    Miura Katsutoshi

    2012-04-01

    Full Text Available Abstract Background Poly (ADP-ribose polymerase-1 (PARP-1 is a key enzyme involved in the repair of radiation-induced single-strand DNA breaks. PARP inhibitors such as olaparib (KU-0059436, AZD-2281 enhance tumor sensitivity to radiation and to topoisomerase I inhibitors like camptothecin (CPT. Olaparib is an orally bioavailable inhibitor of PARP-1 and PARP-2 that has been tested in multiple clinical trials. The purpose of this study was to investigate the characteristics of the sensitizing effect of olaparib for radiation and CPT in order to support clinical application of this agent. Methods DLD-1 cells (a human colorectal cancer cell line and H1299 cells (a non-small cell lung cancer cell line with differences of p53 gene status were used. The survival of these cells was determined by clonogenic assay after treatment with drugs and X-ray irradiation. The γH2AX focus formation assay was performed to examine the influence of olaparib on induction and repair of double-stranded DNA breaks after exposure to radiation or CPT. Results A radiosensitizing effect of olaparib was seen even at 0.01 μM. Its radiosensitizing effect after exposure for 2 h was similar to that after 24 h. H1299 cells with depletion or mutation of p53 were more radioresistant than H1299 cells with wild-type p53. However, similar enhancement of radiosensitization by olaparib was observed with all of the tested cell lines regardless of the p53 status. Olaparib also sensitized cells to CPT. This sensitizing effect was seen at low concentrations of olaparib such as 0.01 μM, and its sensitizing effect was the same at both 0.01 μM and 1 μM. The combination of olaparib and CPT had a stronger radiosensitizing effect. The results of the γH2AX focus assay corresponded with the clonogenic assay findings. Conclusion Olaparib enhanced sensitivity to radiation and CPT at low concentrations and after relatively short exposure times such as 2 h. The radiosensitizing effect of olaprib

  4. Screening antimicrobial activity of various extracts of Urtica dioica

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    Amir Modarresi-Chahardehi

    2012-12-01

    Full Text Available Urtica dioica or stinging nettle is traditionally used as an herbal medicine in Western Asia. The current study represents the investigation of antimicrobial activity of U. dioica from nine crude extracts that were prepared using different organic solvents, obtained from two extraction methods: the Soxhlet extractor (Method I, which included the use of four solvents with ethyl acetate and hexane, or the sequential partitions (Method II with a five solvent system (butanol. The antibacterial and antifungal activities of crude extracts were tested against 28 bacteria, three yeast strains and seven fungal isolates by the disc diffusion and broth dilution methods. Amoxicillin was used as positive control for bacteria strains, vancomycin for Streptococcus sp., miconazole nitrate (30µg/mL as positive control for fungi and yeast, and pure methanol (v/v as negative control. The disc diffusion assay was used to determine the sensitivity of the samples, whilst the broth dilution method was used for the determination of the minimal inhibition concentration (MIC. The ethyl acetate and hexane extract from extraction method I (EA I and HE I exhibited highest inhibition against some pathogenic bacteria such as Bacillus cereus, MRSA and Vibrio parahaemolyticus. A selection of extracts that showed some activity was further tested for the MIC and minimal bactericidal concentrations (MBC. MIC values of Bacillus subtilis and Methicillin-resistant Staphylococcus aureus (MRSA using butanol extract of extraction method II (BE II were 8.33 and 16.33mg/mL, respectively; while the MIC value using ethyl acetate extract of extraction method II (EAE II for Vibrio parahaemolyticus was 0.13mg/mL. Our study showed that 47.06% of extracts inhibited Gram-negative (8 out of 17, and 63.63% of extracts also inhibited Gram-positive bacteria (7 out of 11; besides, statistically the frequency of antimicrobial activity was 13.45% (35 out of 342 which in this among 21.71% belongs to

  5. Adesividade e purulência de secreções respiratórias: implicações no transporte mucociliar em pacientes com bronquiectasias Adhesiveness and purulence of respiratory secretions: implications for mucociliary transport in patients with bronchiectasis

    Directory of Open Access Journals (Sweden)

    Joana Tambascio

    2010-10-01

    samples (7.57 ± 0.22 cm vs. 9.04 ± 2.48 cm and 25.61 ± 6.12º vs. 21.71 ± 5.89º; p < 0.05 for both. There were no significant differences in RTV among the groups of samples, although the values were low regardless of the surface properties (adhesive: 0.81 ± 0.20; nonadhesive: 0.68 ± 0.24 or the aspect (purulent: 0.74 ± 0.22; mucoid: CONCLUSIONS: The respiratory secretions of patients with bronchiectasis showed decreased mucociliary transport. Increased adhesiveness and purulence cause the worsening of transport properties, as demonstrated by the lesser displacement in the SCM and the higher CA.

  6. PET/CT assessment in follicular lymphoma using standardized criteria: central review in the PRIMA study

    Energy Technology Data Exchange (ETDEWEB)

    Tychyj-Pinel, Christelle [Service de Medecine Nucleaire, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Benite (France); Ricard, Fabien [Service de Medecine Nucleaire, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Benite (France); Universite de Lyon, Faculte de Medecine, UCB Lyon 1, Lyon (France); Fulham, Michael [Royal Prince Alfred Hospital, Department of PET and Nuclear Medicine, Sydney (Australia); University of Sydney, Sydney Medical School, Sydney (Australia); Fournier, Marion [Centre Hospitalier Lyon Sud, The Lymphoma Academic Research Organisation (LYSARC), Pierre-Benite (France); Meignan, Michel [CHU Henri Mondor, Medicine Nucleaire, Creteil (France); Lamy, Thierry [Service d' Hematologie, CHU, Rennes (France); Vera, Pierre [Centre Henri Becquerel, Service de Medecine Nucleaire, Rouen (France); Rouen University, QuantIF (Litis EA4108), Rouen (France); Salles, Gilles [Universite de Lyon, Faculte de Medecine, UCB Lyon 1, Lyon (France); Service d' Hematologie, Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre-Benite (France); Trotman, Judith [University of Sydney, Sydney Medical School, Sydney (Australia); Concord Hospital, Department of Haematology, Concord, NSW (Australia)

    2014-03-15

    We aimed to compare the standardized central review of {sup 18}F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT scans performed after induction therapy for follicular lymphoma (FL) in the PRIMA study (Salles et al., Lancet 377:42-51, 2011; Trotman et al., J Clin Oncol 29:3194-3200, 2011) to scan review at local centres. PET/CT scans were independently evaluated by two nuclear medicine physicians using the 2007 International Harmonization Project (IHP) criteria (Cheson et al., J Clin Oncol 25:579-586, 2007; Juweid et al., J Clin Oncol 25:571-578, 2007; Shankar et al., J Nucl Med 47:1059-1066, 2006) and Deauville 5-point scale (5PS) criteria (Meignan et al., Leuk Lymphoma 50:1257-1260, 2009; Meignan et al., Leuk Lymphoma 51:2171-2180, 2010; Barrington et al., Eur J Nucl Med Mol Imaging 37:1824-1833, 2010). PET/CT status was compared with prospectively recorded patient outcomes. Central evaluation was performed on 119 scans. At diagnosis, 58 of 59 were recorded as positive, with a mean maximum standardized uptake value (SUV{sub max}) of 11.7 (range 4.6-35.6). There was no significant association between baseline SUV{sub max} and progression-free survival (PFS). Sixty post-induction scans were interpreted using both the IHP criteria and 5PS. Post-induction PET-positive status failed to predict progression when applying the IHP criteria [p = 0.14; hazard ratio (HR) 1.9; 95 % confidence interval (CI) 0.8-4.6] or 5PS with a cut-off ≥3 (p = 0.12; HR 2.0; 95 % CI 0.8-4.7). However, when applying the 5PS with a cut-off ≥4, there was a significantly inferior 42-month PFS in PET-positive patients of 25.0 % (95 % CI 3.7-55.8 %) versus 61.4 % (95 % CI 45.4-74.1 %) in PET-negative patients (p = 0.01; HR 3.1; 95 % CI 1.2-7.8). The positive predictive value (PPV) of post-induction PET with this liver cut-off was 75 %. The 42-month PFS for patients remaining PET-positive by local assessment was 31.1 % (95 % CI 10.2-55.0 %) vs 64.6 % (95 % CI 47.0-77.6 %) for PET

  7. Developing a weighting strategy to include mobile phone numbers into an ongoing population health survey using an overlapping dual-frame design with limited benchmark information.

    Science.gov (United States)

    Barr, Margo L; Ferguson, Raymond A; Hughes, Phil J; Steel, David G

    2014-09-04

    In 2012 mobile phone numbers were included into the ongoing New South Wales Population Health Survey (NSWPHS) using an overlapping dual-frame design. Previously in the NSWPHS the sample was selected using random digit dialing (RDD) of landline phone numbers. The survey was undertaken using computer assisted telephone interviewing (CATI). The weighting strategy needed to be significantly expanded to manage the differing probabilities of selection by frame, including that of children of mobile-only phone users, and to adjust for the increased chance of selection of dual-phone users. This paper describes the development of the final weighting strategy to properly combine the data from two overlapping sample frames accounting for the fact that population benchmarks for the different sampling frames were not available at the state or regional level. Estimates of the number of phone numbers for the landline and mobile phone frames used to calculate the differing probabilities of selection by frame, for New South Wales (NSW) and by stratum, were obtained by apportioning Australian estimates as none were available for NSW. The weighting strategy was then developed by calculating person selection probabilities, selection weights, applying a constant composite factor to the dual-phone users sample weights, and benchmarking to the latest NSW population by age group, sex and stratum. Data from the NSWPHS for the first quarter of 2012 was used to test the weighting strategy. This consisted of data on 3395 respondents with 2171 (64%) from the landline frame and 1224 (36%) from the mobile frame. However, in order to calculate the weights, data needed to be available for all core weighting variables and so 3378 respondents, 2933 adults and 445 children, had sufficient data to be included. Average person weights were 3.3 times higher for the mobile-only respondents, 1.3 times higher for the landline-only respondents and 1.7 times higher for dual-phone users in the mobile frame

  8. Closed cervix is associated with more severe illness in dogs with pyometra.

    Science.gov (United States)

    Jitpean, Supranee; Ambrosen, Aime; Emanuelson, Ulf; Hagman, Ragnvi

    2017-01-05

    Pyometra, a life-threatening bacterial infection of the uterus, is classified as open or closed depending on the functional patency of the cervix i.e. presence or absence of vaginal discharge. In closed cervix pyometra, pus and bacterial products accumulate in the uterus, which is thought to induce a more severe illness. The aim of this study was to investigate whether disease severity or outcome differed in dogs with open or closed cervix pyometra. Prospectively collected data from 111 female dogs diagnosed with pyometra at the University Animal Hospital, Swedish University of Agricultural Sciences, Uppsala, intermittently during 2005-2012 was analyzed. Seventy-two dogs (65%) had open cervix, whereas 39 dogs (35%) had closed cervix. Differences between the two groups were explored by Wilcoxon Two Sample Test for continuous variables and Chi-square or Fisher's exact test for categorical variables. P cervix the median age was 9.0 years and the median weight 26.0 kg. In dogs with closed cervix the median age was 9.6 years and the median weight 25.0 kg, with no significant differences between the groups (p = 0.69 and 0.24, respectively). Five dogs (4.5%) died, all with open cervix, and 16 dogs (14%) had complications. The general physical condition was moderately or severely depressed in 30% (21/71) of dogs with open cervix (severely depressed in 4 dogs, moderately depressed in 17 dogs) and in 56% (22/39) of dogs with closed cervix (severely depressed in 3 dogs, moderately depressed in 19 dogs). The general physical condition was mildly depressed in 41 dogs with open cervix and 16 dogs with closed cervix, whereas it was normal in nine dogs with open cervix and one dog with closed cervix. None of the included dogs had very severely depressed general physical condition or were non-responsive. Leukocytosis, neutrophilia, monocytosis and moderately to severely depressed general condition was more commonly found in dogs with closed cervix (p = 0.003, p

  9. A phase 1b study of Selumetinib in combination with Cisplatin and Gemcitabine in advanced or metastatic biliary tract cancer: the ABC-04 study

    International Nuclear Information System (INIS)

    Bridgewater, John; Lopes, Andre; Beare, Sandra; Duggan, Marian; Lee, Dymphna; Ricamara, Maravic; McEntee, Delyth; Sukumaran, Ajithkumar; Wasan, Harpreet; Valle, Juan W.

    2016-01-01

    Combined treatment with cisplatin and gemcitabine (CisGem) is the standard of care for patients with advanced biliary tract cancer (ABC). Selumetinib (AZD6244, ARRY-142886) potently and selectively inhibits MEK1/2, an intracellular kinase and has shown activity in ABC. The objective of the ABC-04 trial was to establish the recommended dose of selumetinib in combination with CisGem in patients with ABC. Eligible patients were ≥ 18 years, had histologically or cytologically-confirmed unresectable recurrent or metastatic biliary tract, gallbladder or ampullary carcinoma, WHO performance status 0–2, and adequate major organ function. Patients may have had prior surgery, radiotherapy or adjuvant chemotherapy, but no prior CisGem and no prior chemotherapy for locally advanced or metastatic disease. Patients received cisplatin 25 mg/m 2 plus gemcitabine 1000 mg/m 2 intravenously on days 1 and 8 of a 21-day cycle. Selumetinib capsules were taken daily. Patients received up to 8 cycles of CisGem and could receive selumetinib until disease progression. A dose de-escalation scheme was used to determine the recommended dose of selumetinib. The first dose level was 75 mg bd. Patients were recruited in cohorts of 3 and assessed for dose limiting toxicity (DLT) during the first cycle of treatment. Thirteen patients were recruited, of whom 12 were evaluable for DLT (1 did not start treatment). All evaluable patients received the starting dose of selumetinib 75 mg bd and one patient experienced a DLT (cardiac chest pain). The median number of days selumetinib was taken (adjusted for the number of days of dose interruptions) was 171.5 (IQR: 75.5 to 344). Two patients remained on treatment at 14 and 19 months post registration. There were 3 temporary and 1 permanent interruptions of selumetinib in cycle 1. Eight patients were evaluable for objective response (RECIST v1.1): 3 had a partial response and 5 stable disease. The median PFS was 6.4 months (IQR 5.2 to 13.7). Toxicities

  10. Expression and characterization of highly antigenic domains of chicken anemia virus viral VP2 and VP3 subunit proteins in a recombinant E. coli for sero-diagnostic applications

    Science.gov (United States)

    2013-01-01

    Background Chicken anemia virus (CAV) is an important viral pathogen that causes anemia and severe immunodeficiency syndrome in chickens worldwide. Generally, CAV infection occurs via vertical transmission in young chicks that are less than two weeks old, which are very susceptible to the disease. Therefore, epidemiological investigations of CAV infection and/or the evaluation of the immunization status of chickens is necessary for disease control. Up to the present, systematically assessing viral protein antigenicity and/or determining the immunorelevant domain(s) of viral proteins during serological testing for CAV infection has never been performed. The expression, production and antigenic characterization of CAV viral proteins such as VP1, VP2 and VP3, and their use in the development of diagnostic kit would be useful for CAV infection prevention. Results Three CAV viral proteins VP1, VP2 and VP3 was separately cloned and expressed in recombinant E. coli. The purified recombinant CAV VP1, VP2 and VP3 proteins were then used as antigens in order to evaluate their reactivity against chicken sera using indirect ELISA. The results indicated that VP2 and VP3 show good immunoreactivity with CAV-positive chicken sera, whereas VP1 was found to show less immunoreactivity than VP2 and VP3. To carry out the further antigenic characterization of the immunorelevant domains of the VP2 and VP3 proteins, five recombinant VP2 subunit proteins (VP2-435N, VP2-396N, VP2-345N, VP2-171C and VP2-318C) and three recombinant VP3 subunit proteins (VP3-123N, VP3-246M, VP3-366C), spanning the defined regions of VP2 and VP3 were separately produced by an E. coli expression system. These peptides were then used as antigens in indirect ELISAs against chicken sera. The results of these ELISAs using truncated recombinant VP2 and VP3 subunit proteins as coating antigen showed that VP2-345N, VP2-396N and VP3-246M gave good immunoreactivity with CAV-positive chicken sera compared to the other

  11. Tax-Assisted Approaches for Helping Canadians Meet Out-of-Pocket Health-Care Costs

    Directory of Open Access Journals (Sweden)

    J.C. Herbert Emery

    2016-06-01

    Full Text Available Canadians are not saving for the inevitable costs of drugs and long-term care which they will have to pay for out of pocket in their old age, and these costs could potentially be financially devastating for them. Later in life, when out-of-pocket health-care costs mount, those who previously enjoyed the security of a workplace insurance plan to cover such expenses will face a grim financial reality. Many aspects of care for older Canadians aren’t covered by this country’s single-payer health-care system. Besides prescription drugs, these include management of chronic conditions by ancillary health professionals, home care, long-term care, and dental and vision care. Statistics show that in 2012, Canadians’ private spending on health care totaled $60 billion, with private health insurance covering $24.5 billion of that amount. Coverage of health-care costs that don’t fall under Medicare’s purview is at present rather piecemeal. The non-refundable federal Medical Expense Tax Credit covers expenses only after the three-per-cent minimum, or first $2,171, of out-of-pocket costs have been paid by the individual. The Disability Tax Credit is available to those with a certified chronic disability, and these individuals are eligible for further support via the Registered Disability Savings Plan. A Caregiver Tax Credit is also available. The federal government has a golden opportunity to provide an incentive for Canadians to set aside money to pay not only for the often catastrophic medical and drug costs that can come with aging, but also to save so they can afford long-term care, or purchase private health insurance. Too many Canadians, unfortunately, believe that the federal government picks up the tab for long-term care. In fact, provincial subsidies are provided on a means-testing basis, thus leaving many better-off Canadians in the lurch when they can no longer live alone and must make the transition to long-term care. Providing more

  12. Contribution of harbour activities to atmospheric aerosol in the Brindisi area

    Science.gov (United States)

    Donateo, Antonio; Cesari, Daniela; Nocioni, Alessandra; Grasso, Fabio M.; Merico, Eva; Giua, Roberto; Contini, Daniele

    2013-04-01

    devoted to high temporal resolution (1 second) measurements of PM2.5 mass and number particle concentrations. Results show that the contribution of port activities (ship traffic and loading/unloading of ships) is not easily distinguishable in the daily average concentration as it was also observed in the port of Venice (Contini et al., 2011). Average long-term concentrations of PM10 and PM2.5 in the port are smaller than those observed in the urban area, but numerous short peaks (durations variable between 10 and 100 minutes) of concentration were observed associated to harbour activities in which the PM2.5 concentrations increase of 3-4 times and number particle concentrations increase up to a factor 10. These concentration peaks were analysed using a statistical methodology that takes into account the wind direction and the actual ships traffic to quantitatively characterize the contribution of vessels traffic emissions during arrive and departure operations or during loading/unloading. Results will be presented and compared to those obtained in other harbour areas in Europe. Contini D. et al., 2011. Journal of Environmental Management: 92, 2119-2129 Dalsøren, S.B. et al., 2009. Atmospheric Chemistry and Physics 9, 2171-2194 Fagerli, H., Tarrason, L., 2001. Website. http://www.europa.eu.int/comm/environment/air/pdf/particulates.pdf

  13. Contribution of long-range transport to the ozone levels recorded in the Northeast of Portugal

    Science.gov (United States)

    Gama, C.; Nunes, T.; Marques, M. C.; Ferreira, F.

    2009-04-01

    levels were calculated for each cluster and the differences between the groups were validated using the Kruskal-Wallis statistical test. The results have shown a significant influence of the transport path on ozone concentrations, which is more noticeable when the probability of occurring photochemical pollution phenomena is higher. Air masses from Europe (Spain, France, United Kingdom, etc.) generally originate higher ozone levels than the ones arriving from the Atlantic Ocean. This feature shows the role of photochemical production along long-range transport phenomena, and the input of pollutants into air masses, along their path. A more detailed analysis at local/regional scale, supported mainly by an intensive field campaign performed during spring/summer of 2006 in the vicinity of Alvão Natural Park (FOTONET Project), at different altitudes, together with pollutant measurements from rural air quality stations in the north of Portugal and one from Spain (Peñausende) was carried out in order to evaluate the extension of photochemical pollution in the Northeast of Portugal. Ozone concentrations measurements in the region showed a noticeable decrease with altitude, mainly at night. In resume back trajectories based analysis has demonstrated that other countries, mainly Spain, contribute decisively to the ozone levels registered in the station used for this study. Backed on this knowledge we point out towards the need of considering common international policies when dealing with controlling ozone levels in the environment. References: Monks, P. (2000): A review of the observations and origins of the spring ozone maximum. Atmospheric Environment 34, 3545-3561. Vingarzan, R., Taylor, B. (2003): Trend analysis of ground level ozone in the greater Vancouver / Fraser Valley area of British Columbia. Atmospheric Environment 37, 2159-2171. EMPA (2008): Air mass trajectory clustering. Retrieved 01 November 2008 from: http://www.empa.ch/plugin/template/empa/*/63288/—/l=1

  14. Interventions for treating inadvertent postoperative hypothermia.

    Science.gov (United States)

    Warttig, Sheryl; Alderson, Phil; Campbell, Gillian; Smith, Andrew F

    2014-11-20

    not possible. This may have influenced results, but it is unclear how the results may have been influenced. Active warming was found to reduce the mean time taken to achieve normothermia by about 30 minutes in comparison with use of warmed cotton blankets (mean difference (MD) -32.13 minutes, 95% confidence interval (CI) -42.55 to -21.71; moderate-quality evidence), but no significant difference in shivering was noted. Active warming was found to reduce mean time taken to achieve normothermia by almost an hour and a half in comparison with use of unwarmed cotton blankets (MD -88.86 minutes, 95% CI -123.49 to -54.23; moderate-quality evidence), and people in the active warming group were less likely to shiver than those in the unwarmed cotton blanket group (Relative Risk=0.61 95% CI= 0.42 to 0.86; low quality evidence). There was no effect on mean temperature difference in degrees celsius at 60 minutes (MD=0.18°C, 95% CI=-0.10 to 0.46; moderate quality evidence), and no data were available in relation to major cardiovascular complications. Forced air warming was found to reduce time taken to achieve normothermia by about one hour in comparison to circulating hot water devices (MD=-54.21 minutes 95% CI= -94.95, -13.47). There was no statistically significant difference between thermal insulation and cotton blankets on mean time to achieve normothermia (MD =-0.29 minutes, 95% CI=-25.47 to 24.89; moderate quality evidence) or shivering (Relative Risk=1.36 95% CI= 0.69 to 2.67; moderate quality evidence), and no data were available for mean temperature difference or major cardiovascular complications. Insufficient evidence was available about other comparisons, adverse effects or any other secondary outcomes. Active warming, particularly forced air warming, appears to offer a clinically important reduction in mean time taken to achieve normothermia (normal body temperature between 36°C and 37.5°C) in patients with postoperative hypothermia. However, high

  15. An Evaluation of Complications in Ultrasound-Guided Central Venous Catheter Insertion in the Emergency Department

    Directory of Open Access Journals (Sweden)

    Engin OZAKIN

    2014-06-01

    lçümü gereken durumlarda hastalar için santral damar yolu gerekmektedir. Acil serviste, ultrasonografi (USG kılavuzluğunda uygulanan acil santral venöz katater girişimi sürecinde ve uygulamayı takip eden 15 gün içerisinde komplikasyon varlığını değerlendirmek amacı ile bu çalışma yapıldı. Gereç ve Yöntem: Sekiz aylık sürede acil servise başvuran ve acil santral katater gereksinimi olan hastalar ileriye dönük olarak incelendi. Hastaların yaşı, cinsiyeti, eşlik eden hastalıkları ile tercih edilen girişimin yolu, saati, süresi ve endikasyonu kaydedildi. Ayrıca girişimi yapan hekimin çalışma yılı da değerlendirmeye dahil edildi. Bulgular: Ultrasonografi eşliğinde santral venöz katater takılan 74 (40 erkek, 34 kadın hastanın 65'inde (%87.8 internal juguler ven, dokuzunda (%12.2 femoral ven girişim için kullanıldı. Uygulama olguların 55'inde (%74.3 acil diyaliz ihtiyacı, üçünde (%4.1 CVP ölçümü, altısında (%8.1 ciddi hipovolemi için sıvı desteği, 10'unda (%13.5 periferik damar yolu güçlüğü nedeniyle yapıldı. Hastaların hiçbirinde işlem esnasında ve sonrasında komplikasyon izlenmedi. Yatırıldıkları bölümde takiplerinde 15 günlük süre içerisinde katater ile ilişkili enfeksiyon da saptanmadı. Sonuç: Acil servislerde santral damar yolu gereksinimi sıktır. Kılavuzların önerisi doğrultusunda USG eşliğinde uygun şartlar altında yapılan girişimlerde komplikasyon riski yok denecek kadar azdır. Key words: Central venous catheter, emergency department, ultrasound-guided, Anahtar sözcükler: Santral venöz katater, acil servis, ultrason kılavuzluğu

  16. Çocuk Eğitiminde Reiki Yöntemi Reiki Method Of Children's Education

    Directory of Open Access Journals (Sweden)

    Hatice YALÇIN

    2013-07-01

    ılarından birinde tıkanıklık oluşursa, vücudun enerji alımının zorlanması temeline dayanır. Bu enerji tıkanıklıkları sonucunda rahatsızlıkların ve davranış değişikliklerinin ortaya çıktığına inanılmaktadır. Bu çakralar omurga boyunca yer alır; salgı bezleri ve sinir ağı merkezleriyle kesişir. Böylece reiki, çakralar ve salgı bezlerinin ortak çalışması ile beden üzerinde bir hareket kabiliyeti kazanmaktadır. Hormonları ve beden hareketlerini temel alan bu yöntem, çocuk gelişiminde ve çocuklarda olumlu davranış geliştirilmesinde de önemli bir yer tutar. Reiki uygulamaları sırasında eller, baş, boyun, göğüs, karın boşluğu, kasıklara dokunmak suretiyle her bir pozisyonda 3-5 dakika tutulur. Problemli bölgelerde bu süre 10-20 dakikaya uzayabilir. Uygulama süresi ortalama 30-90 dakika, çocukluk yaşlarında ise 20-30 dakika sürer. Çocuk eğitiminde alternatif yöntemlerin çok çeşitli olması, ilgili merkezlerin dışında alternatif yöntemlerin uygulanması, bu yöntemlerin güvenilirliği konusunda bilimsel çalışma yapılmasını güçleştirmektedir. Çocuk eğitiminde kullanılan alternatif yöntemler ile ilgili bilimsel çalışma son derece azdır. Bu çalışma ülkemizde çocuklarda biyomanyetik alan konusunda yeterince çalışmanın mevcut olmaması nedeniyle hem bilgilendirici hem de bundan sonraki çalışmalara yardımcı nitelikte olacaktır.

  17. 45 Numaralı Konya Şeriyye Sicil Defterindeki Menzil Satışları Işığında Yol Ağları ve Kat Sayısına Göre Konut Tipolojisi (1714-1715 In Numbered 45 Konya Şeriyye Registry Book in the Light of Range Sale; Housing Typology According to and Road Network and Coefficient (1714-1715

    Directory of Open Access Journals (Sweden)

    Hicran Hanım HALAÇ

    2012-09-01

    Full Text Available Most of the investigations which take hand Ottoman period of Turkey’s social and cultural history are limited to Istanbul. The works about dwelling deal with monumental buildings like palace or mansion. The investigations about the cities of architectural housing except for Istanbul are very restricted. . This situation is the same with the capital of Anatolian Seljuks, which is Konya. Beginning from Seljuk Empire, the historical monuments of Konya account for castles and mosques. There is no early period of housing which lasts contemporary. In case of absence of housing belongs to 18th century and even the beginning of 19th century; therefore, this causes generally accepted evaluations. The works which focus on architectural housing and domestic culture belonging to 19th century and before, this necessitate the exploitation of Ottoman documents composing of primary sources. This research article gives information about Konya’s two years between 1714 and 1715. This information is obtained from numbered 45 Şeriyye registry and from range information. In order to enlighten a part of the housing archtecture located in Konya using only road and floor information of range, the housing types of Konya and the housing typology of Konya at the beginning of the 18th century are determined. Osmanlı Dönemi Türkiye’sinin konut mimarisi ve domestik kültürüne ait araştırmaların çoğunlukla İstanbul odaklı gerçekleştiği, konutlara eğilen çalışmaların ise, saray ve köşk gibi anıtsal yapıları ele aldıkları görülmektedir. İstanbul dışındaki şehirlerin konut mimarisini ele alan çalışmaları oldukça azdır. Anadolu Selçuklularının başşehri olan Konya için de durum böyledir. Konya’nın Selçuklu Dönemi’ne kadar geriye giden tarihi eserlerini saray, kale, cami, türbe gibi anıtsal yapılar teşkil etmekte, günümüze gelebilmiş erken dönem konutları bulunmamaktadır. 18. yüzyıl, hatta erken 19. yüzyıl

  18. Mahalli Fıkra Tipine Bir Örnek: Erzurumlu Naim Hoca One Type of Anecdote of Local Example: Hoca Erzurumlu Naim

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    Yusuf KOTAN

    2012-09-01

    ılık, bazı dönemlerde sekmeye uğramış olsa da hiç şüphesiz ki fıkralar, hemen her milletin sosyal ve kültürel hayatında mühim bir yer edinir. Bir milletin duyuş ve düşünüşünü, zekâsını, esprilerini, muhakeme gücünü ve en önemlisi de ortak görüşlerini yansıtması bakımından fıkraların önemi büyüktür. Bu fıkraların oluşumunda yer alan önemli öğelerden biri de fıkra tipleridir. Bu tipler, hem anlatılan fıkranın kahramanı olup, hem de yaşadığı toplumun ortak özelliklerini dile getirmeleri bakımından önemlidir. Anadolu coğrafyasının hemen her yöresinde bu tiplerle karşılaşılmakta ve onların bu anlatılarından yararlanmaktayız. Yaşadıkları yörenin özelliklerini yansıtması bakımından oldukça önem arz eden bu tiplemeler, özellikle mahalli ifadelere yer vererek bir temsil özelliği sergilerler. Erzurum folkloru, Türk folkloru için oldukça zengin bir kaynaktır. Bu zengin kaynak üzerine pek çok araştırmalar yapılmış olsa da folklorumuzun bir parçası olan fıkralar üzerine yapılmış çalışmalar yok denecek kadar azdır. Biz de bu yaklaşımlardan yola çıkarak hem Erzurum folkloruna bir katkı sağlamaya hem de Erzurum’daki fıkra tipleri içerisinde, söylemiş olduğu fıkralarıyla halkımızın hafızasında önemli bir yer edinen Naim Hoca’yı sizlere tanıtıp, bu değerli insanın fıkralarını sizlerle paylaşmaya çalışacağız.

  19. 1714-1715 Yılları Arasında Konya’daki Mahallelerin Konut Yayılımlarının 45 Numaralı Şeriye Sicil Defterindeki Menzil Satış Belgeleri Işığında Çözümlemesi The Solution In The Light Of Documentation Sell Houses That Is In 45 Numbered Seriye Registry Notebook Of Expansion Of The Houses Of Districts Of Konya Between The Years Of 1714 And 1715

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    Hicran Hanım HALAÇ

    2012-12-01

    etiketlenecek durumları aydınlatacak verilere nispeten daha rahat ulaşılabilir. Ancak konu geçmişin kentlerindeki mahalleleri oluşturan konut dağılımları olunca birincil kaynakların kullanıldığı spesifik çalışmalar yok denecek kadar azdır. Genelde hukuk tarihi ve sosyo-ekonomik tarih yazımında kullanılan XIX. yüzyılın son çeyreğine kadar yalnız adlî değil, aynı zamanda idarî ve beledî fonksiyonlar da yüklenmiş şeriye sicilleri, Osmanlı tarihinin sosyal, siyasi, idarî, iktisadî ve kültürel pek çok bakımdan bilinmeyen yönlerini aydınlatacak veya eksik kalan yönlerini tamamlayacak mahiyette kaynaklardır. Şeriye sicilleri gibi genelde hukuk tarihi ve sosyo-ekonomik tarih yazımında kullanılan bir kaynak grubunun içerisinden ki metinlerden tespit edilen bir kısım küçük noktasal mimari verileri gün ışığına çıkararak nokta bulutlarına dönüştürmeyi hedeflemektedir.Bu araştırma makalesinde, Türklerin Anadolu ile buluştuğu andan itibaren önemini gün geçtikçe arttıran Konya’nın, 1714-1715 yılları arasındaki iki yıllık periyod içinde, 45 Numaralı Konya Şeriye Sicil Defterlerindeki menzil satış belgelerindeki konutlara ait verilerin çözümlemeci tipolojiyi kullanarak, birincil kaynaktan elde edilen somut veriler ışığında yapılan çözümlemeler yardımıyla Konya’nın konutlarından mahallelerine yolculuk yapıp gizemli kalanları ortaya çıkarmaya çalışarak kent restitüsyonu çalışmalarında kullanılabilirliğinin fark ettirilmeye çalışılmıştır. Bu makale, aynı zamanda mimarlık tarihçileri, restorasyon uzmanları ve tarihçilerin bir araya geldiklerinde ortaya çıkabilecek sentezlerin de küçük bir başka örneğini daha ortaya koymaktadır.

  20. JUAN GOYTISOLO’NUN KIRK GÜNLÜK SÜRE ADLI ROMANINDA DİNSEL BAĞLAMDA KÜLTÜRLER ARASI DİYALOG / THE INTERCULTURAL DIALOGUE IN RELIGIOUS CONTEXT IN JUAN GOYTISOLO’S “QUARANTINE” NOVEL

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    Yasemin DEMİR ÖZGÜN

    2015-07-01

    Full Text Available Juan Goytisolo Çağdaş İspanyol Edebiyatı’nın en önemli yazarlarından birisidir. Yazarın birçok kitabı Türkçe’ye çevrilmesine ve özellikle son dönemlerde yazdığı kitaplarında Türk kültürünün unsurlarına yer vermesine rağmen kendisi hakkında dilimizde yapılan çalışmalar yok denecek kadar azdır. Bu makalenin amaçlarından birincisi yazarın Kırk Günlük Süre adlı romanında Hristiyanlık ve Müslümanlık unsurlarını ele alarak Batı ve Doğu kültürlerini incelemek; ikincisi ise İspanyol Edebiyatı üzerine çalışmalar yapan kişilerin dikkatini yazara ve eserlerine çekmektir.İspanya İç Savaşı’ndan (1936-1939  kısa bir süre önce 1931 yılında Barselona’da doğan Goytisolo iç savaş sırasında çocukluğunu yaşamış talihsiz 30’lar kuşağı yazarlarındandır. Yazar iç savaş sonrası başlayan General Franco’nun Hristiyanlıktan başka dinlere ve kültürlere karşı katı ve hoşgörüsüz olan diktatörlüğü döneminde gençlik yıllarını geçirmiştir. 1956 yılında kesin olarak Paris’e yerleşen yazar bulduğu özgürlük ortamıyla farklı din ve kültürlerle de ilgilenmeye başlamıştır. Doğu kültürü ile tanışması Cezayir olayları nedeniyle olmuştur. Cezayir bağımsızlık savaşı sırasında Fransız hükümetinin ve aydınlarının gösterdikleri davranışlardan dolayı yazar hayal kırıklığına uğramış ve Fransa’da yaşayan birçok Afrika kökenli kişinin polis tarafından tutuklanması yazarın Avrupa’ya ve içinde bulunduğu kültüre karşı bakış açısının değişmesine ve Doğu felsefesini ve kültürünü incelemesine neden olmuştur.İslamiyet’in Batı dünyasında yanlış anlaşıldığını düşünen Goytisolo İslam kültürü ilgili birçok yazı yazmış ve romanlarında sadece Hristiyanlık öğelerini değil İslam kültürünün unsurlarını da kullanmıştır. Her iki kültürü birlikte kullandığı yap

  1. PISA Sonuçları Açısından Ülkelerin Eğitimli Olmayan Nüfus Yapısının Analizi: Uluslararası Bir Perspektif An Analysis Of Countries’ Uneducated Population In Terms Of PISA Results: An International Perspective

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    İlknur MAYA

    2013-09-01

    elde edilmiştir. Bu araştırmada kullanılan dokümanlar, resmi istatistiklerden elde edildiği için verilerin geçerliliğinin ve güvenirliliğinin yüksek olduğu söylenebilir. Sonuç olarak PISA sonuçlarında en yüksek başarı gösteren ülkelerde, ilköğretim ve ortaöğretim kademesinde okul dışında kalan çocuk nüfusu daha düşüktür. Başarılı ülkelerin okuryazar olmayan genç ve yetişkin nüfusu başarısı düşük ülkelere göre daha azdır.

  2. Ketamine and other glutamate receptor modulators for depression in adults.

    Science.gov (United States)

    Caddy, Caroline; Amit, Ben H; McCloud, Tayla L; Rendell, Jennifer M; Furukawa, Toshi A; McShane, Rupert; Hawton, Keith; Cipriani, Andrea

    2015-09-23

    Considering the ample evidence of involvement of the glutamate system in the pathophysiology of depression, pre-clinical and clinical studies have been conducted to assess the antidepressant efficacy of glutamate inhibition, and glutamate receptor modulators in particular. This review focuses on the use of glutamate receptor modulators in unipolar depression. To assess the effects - and review the acceptability - of ketamine and other glutamate receptor modulators in comparison to placebo (or saline placebo), other pharmacologically active agents, or electroconvulsive therapy (ECT) in alleviating the acute symptoms of depression in people with unipolar major depressive disorder. We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR, to 9 January 2015). This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). We did not apply any restrictions to date, language or publication status. Double- or single-blind RCTs comparing ketamine, memantine, or other glutamate receptor modulators with placebo (or saline placebo), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression. Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes for this review were response rate and adverse events. We included 25 studies (1242 participants) on ketamine (9 trials), memantine (3), AZD6765 (3), D-cycloserine (2), Org26576 (2), atomoxetine (1), CP-101,606 (1), MK-0657 (1), N-acetylcysteine (1), riluzole (1) and sarcosine (1). Twenty-one studies were placebo-controlled and the majority were two-arm studies (23 out of 25). Twenty-two studies defined an inclusion criteria specifying the severity of depression; 11 specified at least moderate depression; eight, severe depression; and the remaining three

  3. Rainfall simulation experiments and Water Drop Penetration Time measurements shed light on the impact of water repellency on soils under organic farming management in Eastern Spain

    Science.gov (United States)

    Cerdà, Artemi; González, Óscar; León, Javier; Jordán, Antonio

    2015-04-01

    -159. Cerdà, A. 1998b. The influence of aspect and vegetation on seasonal changes in erosion under rainfall simulation on a clay soil in Spain. Canadian Journal of Soil Science, 78, 321-330. Cerdà, A., Jurgensen, M. F. 2011. Ant mounds as a source of sediment on citrus orchard plantations in eastern Spain. A three-scale rainfall simulation approach. Catena, 85(3), 231-236. Dougherty, W. J., Mason, S. D., Burkitt, L. L., Milham, P. J. 2011. Relationship between phosphorus concentration in surface runoff and a novel soil phosphorus test procedure (DGT) under simulated rainfall. Soil Research, 49(6), 523-528. Dunkerley, D. 2012. Effects of rainfall intensity fluctuations on infiltration and runoff: rainfall simulation on dryland soils, Fowlers Gap, Australia. Hydrological Processes, 26(15), 2211-2224. García-Moreno, J., Gordillo-Rivero, Á. J., Zavala, L. M., Jordán, A., & Pereira, P. 2013. Mulch application in fruit orchards increases the persistence of soil water repellency during a 15-years period. Soil and Tillage Research, 130, 62-68. Garel, E., Marc, V., Ruy, S., Cognard-Plancq, A. L., Klotz, S., Emblanch, C., Simler, R. 2012. Large scale rainfall simulation to investigate infiltration processes in a small landslide under dry initial conditions: the Draix hillslope experiment. Hydrological Processes, 26(14), 2171-2186. González-Peñaloza, F.A., Cerdà, A., Zavala, L.M., Jordán, A., Giménez-Morera, A., Arcenegui, V. 2012. Do conservative agriculture practices increase soil water repellency? A case study in citrus-cropped soils. Soil and Tillage Research, 124, 233-239. http://dx.doi.org/10.1016/j.still.2012.06.015 Granged, A. J., Jordán, A., Zavala, L. M., Bárcenas, G. (2011): Fire-induced changes in soil water repellency increased fingered flow and runoff rates following the 2004 Huelva wildfire. Hydrological Processes, 25: 1614-1629. Iserloh, T., Ries, J.B., Arnaez, J., Boix Fayos, C., Butzen, V., Cerdà, A., Echeverría, M.T., Fernández-Gálvez, J., Fister, W

  4. Dergilerden Özetler

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    Mete Korkut Gülmen

    1996-10-01

    Elektron Microscobu ile elde edilebimektedir. Mineralize diş dokularının yapısal organizasyon bilgisine dayanılarak, fiziksel ve kimyasal değişimlerin farklı teşhisleri yapılabilir. Adli diş hekimliğinin mine ve dentine, dişte ve onarıcı dental materyallerin yapısında dişteki pozisyonuna göre birkaç yıl içinde ortaya çıkabilecek tortu bırakan (deposit farklı travmalar gösteren bir referans materyaller toplamına tanınmasında işbirliği içinde olması önerilmektedir. Bu çalışmada, dört farklı olgu sunulmuştur. KÖPEKLERDE TATLI VE TUZLU SOĞUK SUDA BOĞULMA ÜZERİNE BİR ÇALIŞMA A canine study of cold water drowning in fresh versus salt water. Conn AW, Miyasaka K, Katayama M. et al. Crit Care Med. 1995; 23/12: 2029-2037. Amaç: Yaşama kabiliyeti ile ilgili soğuk tatlı su ve soğuk tuzlu su içinde suda boğulma sırasında oluşan patofizyolojik değişikliklerin karşılaştırılması. Plan: Randomize edilmiş, prospektif, karşılaştırılan iki sıvıda kontrollü olarak suya batırma deneyleri. Deney yeri: Tıbbi bir kuruluşla yakın ilişkisi bulunan büyük bir üniversitenin laboratuarı. Denekler: onüç adet sağlıklı, anestezi altındaki değişik cinste köpekler. Üç köpek kontrollü olarak çalışıldı, su içinde idiler (immersiyon ama su altında kalmadılar (submersiyon. Geri kalanlar 4°C'deki soğuk tatlı ve tuzlu su içinde kaldılar. Girişim: Femoral artere, sağ carotid artere ve sağ internal jugular vene katater yerleştirildi. Elektrokardi- yogram, pnömogram ve rektal sıcaklıklar su içinde/sıı altında kalmada sürekli olarak ölçüldü. Ölçümler ve ana sonuçlar: Soğuk suda (submersiyon boğulmada, carotid arter sıcaklığında başlangıçta büyük bir azalma oldu (ilk 2 dakikada ~ 7.5°C, su içinde kalmada (im- mersiyon azalma diğerine oranla çok azdır (0,8°C. Tatlı su ile tuzlu su arasında sıcaklık azalma hızı açısından önemli bir farklılık tespit edilmedi. So

  5. Dergilerden Özetler

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    Şebnem Korur Fincancı

    1999-04-01

    Full Text Available BİYOLUMİNESAN İLE BEYİNDE ATP DÜZEYİ ÇALIŞMASI: ÖLÜM ZAMANI BELİRLEME YÖNTEMİ Study on cerebral ATP level with bioluminescent: method to estimate the time of death "Makale Çincedir" Cben Y. Fa I Hsueh Tsa Chih 1997;13(3>138-9. Bu yazı değişik ölüm zamanlarında köpek beynindeki ATP düzeylerini bildirmektedir. ATP düzeyleri biyoluminesan yöntemi ile saptanmıştır. Sonuçlar ATP konsantrasyonunun ölüm zamanı ile birlikte yavaşça azaldığını göstermiştir. Adli uygulamada ölüm zamanının belirlenmesi için bu çalışma değer taşımaktadır. SÜTÇOCUĞU VE KÜÇÜK ÇOCUKLARIN KAZADIŞI KAFA TRAVMASINDA YARALANMA ıLE AĞIR SEMPTOMLAR ARASINDA GEÇEN ZAMAN Interval duration between injury and severe symptoms in nonaccidental head trauma in infants and young children. Gilliland MG. J Forensic Sci. 1998 May;43(3:723-5. Adli patologların sık sık çocuk istismarındaki kafa travması ölümlerinde yaralanma ile semptomların ortaya çıkışı arasında geçen zamanı belirlemeleri istenmektedir. Bu bilgilerin elde edilebildiği 76 kafa travması ile ölüm olgusunda yaralanmadan semptomların ortaya çıkışına kadar geçen süre, prospektif bir postmortem çalışmada araştırılmıştır. Kafa travması ölümleri yaralanma mekanizmasına göre sınıflan- mıştır. Mekanizmalar saısma(darbe yok, sarsma ve künt darbe birlikte ve künt darbe(sarsma öyküsü yok idi. Sarsma olgularının %80’inde, birlikte olanda %71.9 ve künt travmada % 69.2’sinde geçen zaman 24 saatten azdı. Son iki grubun herbirinin %25’inclen fazlasında geçen zaman 24 saatten fazla ve 4 çocukta da 72 saatten daha geçti. Yaralanma ile semptomların ortaya çıkışı arasındaki zamanın değişkenliği bu konuda yapılacak değerlendirmelerin ihtiyatlı olması gerektiğini göstermektedir. Bilginin fail dışında kişilerden alındığı tüm olgularda çocuğun bu zaman diliminde normal olmadığının

  6. Journal Abstracts

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    Mete Korkut Gülmen

    1996-07-01

    kanına difüzyon daha azdı. Sol böbrek ve sol akciğer, sağ böbrek ve sağ akciğerden daha fazla etkilenmişti, aynısı sol ve sağ psoas kasları için de doğmdur. En az etkilenenler ise karaciğerin ön lobu ve akciğer apeksleridir. Bu olay karaciğerde ve vücut organlarından alınan kanlarda ilaç konsantrasyonlarını, sonuç olarakta karaciğer/kan ilaç oranlarını anlamlı olarak etkileyebilmektedir. Mideden postmortem ilaç difüzyonunıın etkilerini azaltmak için, örneklerin periferik kan damarlarından, bir ekstremitedeki iskelet kaslarından, karaciğer sağ lobunun derin bölgelerinden ve akciğerin tabanından çok apeklerinden alınması önerilmektedir. POSTMORTEM ETANOL ÜRETİMİ VE DEĞERLENDİRMEYİ ETKİLEYEN FAKTÖRLER Postmortem production of ethanol and factors that influence interpretation Pounder DJ, Cox DE, Kuroda N. Am J Forensic Med Pathol. 1996; 17(1: 8-20. Etanol incelemesi adli toksikoloji laboratuvarlarında en sık yapılan incelemedir. Postmortem etanol incelemesi sıklıkla postmortem etanol üretimi sebebi ile zorlaşmaktadır. Bir çok bakteri türleri, kültür mantarları ve küf mantarları çeşitli maddelerden etanol üretebilmektedir. Ölüm ve otopsi yapılması arasındaki süre ve saklama sıcaklığı arttıkça etanol sentezi olasılığı da artmaktadır. Postmortem alkol üretimi ve antemoıtem alkol aliminin ayırımı sıklıkla zor olmaktadır. Bu derlemede postmortem etanol sentezinin tanınma kriterleri ve postmortem etanol bulgularının yommlanmasında dikkate alınacak faktörler sunulmuştur. Kriterler olgu hikayesi, örneklerin saklama şartları, var olan mikrop tipleri, eta- nolün atipik sıvı ve doku dağılımı, etanol konsantrasyonu, diğer alkol ve uçucu maddelerin tespit edilmesidir. Elde edilebilen tüm bilgilerin dikkatlice değerlendirilmesi ile etanolün antemortem veya postmortem kaynaklı olduğunun geçerli bir yorumu yapılabilmektadir. KAPALI KAFA TRAVMASI SONUCUNDA GEL