Sensitizing Triple-Negative Breast Cancer to PI3K Inhibition by Cotargeting IGF1R.

PubMed

de Lint, Klaas; Poell, Jos B; Soueidan, Hayssam; Jastrzebski, Katarzyna; Vidal Rodriguez, Jordi; Lieftink, Cor; Wessels, Lodewyk F A; Beijersbergen, Roderick L

2016-07-01

Targeted therapies have proven invaluable in the treatment of breast cancer, as exemplified by tamoxifen treatment for hormone receptor-positive tumors and trastuzumab treatment for HER2-positive tumors. In contrast, a subset of breast cancer negative for these markers, triple-negative breast cancer (TNBC), has met limited success with pathway-targeted therapies. A large fraction of TNBCs depend on the PI3K pathway for proliferation and survival, but inhibition of PI3K alone generally has limited clinical benefit. We performed an RNAi-based genetic screen in a human TNBC cell line to identify kinases whose knockdown synergizes with the PI3K inhibitor GDC-0941 (pictilisib). We discovered that knockdown of insulin-like growth factor-1 receptor (IGF1R) expression potently increased sensitivity of these cells to GDC-0941. Pharmacologic inhibition of IGF1R using OSI-906 (linsitinib) showed a strong synergy with PI3K inhibition. Furthermore, we found that the combination of GDC-0941 and OSI-906 is synergistic in 8 lines from a panel of 18 TNBC cell lines. In these cell lines, inhibition of IGF1R further decreases the activity of downstream PI3K pathway components when PI3K is inhibited. Expression analysis of the panel of TNBC cell lines indicates that the expression levels of IGF2BP3 can be used as a potential predictor for sensitivity to the PI3K/IGF1R inhibitor combination. Our data show that combination therapy consisting of PI3K and IGF1R inhibitors could be beneficial in a subset of TNBCs. Mol Cancer Ther; 15(7); 1545-56. ©2016 AACR. ©2016 American Association for Cancer Research.

CXCR6 identifies a putative population of retained human lung T cells characterised by co-expression of activation markers.

PubMed

Morgan, Angela J; Guillen, Cristina; Symon, Fiona A; Birring, Surinder S; Campbell, James J; Wardlaw, Andrew J

2008-01-01

Expressions of activation markers have been described on the surface of T cells in the blood and the lung in both health and disease. We have studied the distribution of activation markers on human lung T cells and have found that only certain populations exist. Importantly, the presence or absence of some markers appears to predict those of others, in particular cells which express CD103 also express CD49a and CD69, whereas cells which do not express CD69 also do not express CD49a or CD103. In view of the paucity of activation marker expression in the peripheral blood, we have hypothesised that these CD69+, CD49a+, and CD103+ (triple positive) cells are retained in the lung, possess effector function (IFNgamma secretion) and express particular chemokine receptors which allow them to be maintained in this environment. We have found that the ability of the triple negative cells to secrete IFNgamma is significantly less than the triple positive cells, suggesting that the expression of activation markers can highlight a highly specialised effector cell. We have studied the expression of 14 chemokine receptors and have found that the most striking difference between the triple negative cells and the triple positive cells is the expression of CXCR6 with 12.8+/-9.8% of triple negative cells expressing CXCR6 compared to 89.5+/-5.5% of triple positive cells. We propose therefore that CXCR6 may play an important role in the retention of T cells within the lung.

Evaluation of a combined triple method to detect causative HPV in oral and oropharyngeal squamous cell carcinomas: p16 Immunohistochemistry, Consensus PCR HPV-DNA, and In Situ Hybridization

PubMed Central

2012-01-01

Background Recent emerging evidences identify Human Papillomavirus (HPV) related Head and Neck squamous cell carcinomas (HN-SCCs) as a separate subgroup among Head and Neck Cancers with different epidemiology, histopathological characteristics, therapeutic response to chemo-radiation treatment and clinical outcome. However, there is not a worldwide consensus on the methods to be used in clinical practice. The endpoint of this study was to demonstrate the reliability of a triple method which combines evaluation of: 1. p16 protein expression by immunohistochemistry (p16-IHC); 2. HPV-DNA genotyping by consensus HPV-DNA PCR methods (Consensus PCR); and 3 viral integration into the host by in situ hybridization method (ISH). This triple method has been applied to HN-SCC originated from oral cavity (OSCC) and oropharynx (OPSCC), the two anatomical sites in which high risk (HR) HPVs have been clearly implicated as etiologic factors. Methylation-Specific PCR (MSP) was performed to study inactivation of p16-CDKN2a locus by epigenetic events. Reliability of multiple methods was measured by Kappa statistics. Results All the HN-SCCs confirmed HPV positive by PCR and/or ISH were also p16 positive by IHC, with the latter showing a very high level of sensitivity as single test (100% in both OSCC and OPSCC) but lower specificity level (74% in OSCC and 93% in OPSCC). Concordance analysis between ISH and Consensus PCR showed a faint agreement in OPSCC (κ = 0.38) and a moderate agreement in OSCC (κ = 0.44). Furthermore, the addition of double positive score (ISHpositive and Consensus PCR positive) increased significantly the specificity of HR-HPV detection on formalin-fixed paraffin embedded (FFPE) samples (100% in OSCC and 78.5% in OPSCC), but reduced the sensitivity (33% in OSCC and 60% in OPSCC). The significant reduction of sensitivity by the double method was compensated by a very high sensitivity of p16-IHC detection in the triple approach. Conclusions Although HR-HPVs detection is of utmost importance in clinical settings for the Head and Neck Cancer patients, there is no consensus on which to consider the 'golden standard' among the numerous detection methods available either as single test or combinations. Until recently, quantitative E6 RNA PCR has been considered the 'golden standard' since it was demonstrated to have very high accuracy level and very high statistical significance associated with prognostic parameters. In contrast, quantitative E6 DNA PCR has proven to have very high level of accuracy but lesser prognostic association with clinical outcome than the HPV E6 oncoprotein RNA PCR. However, although it is theoretically possible to perform quantitative PCR detection methods also on FFPE samples, they reach the maximum of accuracy on fresh frozen tissue. Furthermore, worldwide diagnostic laboratories have not all the same ability to analyze simultaneously both FFPE and fresh tissues with these quantitative molecular detection methods. Therefore, in the current clinical practice a p16-IHC test is considered as sufficient for HPV diagnostic in accordance with the recently published Head and Neck Cancer international guidelines. Although p16-IHC may serve as a good prognostic indicator, our study clearly demonstrated that it is not satisfactory when used exclusively as the only HPV detecting method. Adding ISH, although known as less sensitive than PCR-based detection methods, has the advantage to preserve the morphological context of HPV-DNA signals in FFPE samples and, thus increase the overall specificity of p16/Consensus PCR combination tests. PMID:22376902

Pembrolizumab and Enobosarm in Treating Patients With Androgen Receptor Positive Metastatic Triple Negative Breast Cancer

ClinicalTrials.gov

2018-04-05

Androgen Receptor Positive; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage III Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Triple p-positive parenting program for mothers of ADHD children.

PubMed

Aghebati, Asma; Gharraee, Banafsheh; Hakim Shoshtari, Mitra; Gohari, Mahmood Reza

2014-01-01

Attention deficit hyperactivity disorder (ADHD) is a chronic, highly prevalent neurodevelopmental disorder which affects 9% of school-age children. Triple P-Positive Parenting Program is an evidence-based parenting program reported to be useful in the management of this disorder. The aim of this randomized controlled trial was to evaluate the effectiveness of Triple P in mothers of ADHD children. In this study, 30 mothers with ADHD children aged between 6 to 10 were randomly assigned to two groups (15 participants in each group). Parenting style, mother-child relationship, maternal depression, anxiety and stress, and children's behavioral problems were evaluated. The intervention group received 120 minute sessions for 5 weeks and 15-30 minute telephone contacts for 3 weeks while no intervention was done for the control group. Analysis of covariance revealed that mothers of the Triple P group showed significant (p < 0.01) improvements in parenting style, mother-child relationship, and considerable decrease in depression, anxiety and stress. Women trained in the Triple P group also reported significantly lower rates of child misbehavior than women of the control group. Triple P-Positive Parenting intervention is effective and acceptable for mothers of ADHD children. None. Clinical Trial Registration-URL: http://www.irct.ir. Unique identifier: IRCT201111288234N1.

Realizing the full potential of a RITA spectrometer

NASA Astrophysics Data System (ADS)

Lefmann, K.; Niedermayer, Ch.; Abrahamsen, A. B.; Bahl, C. R. H.; Christensen, N. B.; Jacobsen, H. S.; Larsen, T. L.; Häfliger, P.; Filges, U.; Rønnow, H. M.

2006-11-01

The “re-invented triple-axis spectrometer (RITA) concept has existed for a decade. Recent developments at RITA-2 at PSI, have revealed more of the potential of this instrument class. We demonstrate the performance of the multi-blade imaging mode, which has been applied e.g. to studies of dispersion relations and emphasize the power of this mode in combination with the low background of RITA-2. In addition, we present other ways of utilizing the position sensitive detector in a RITA instrument. Simulations of a planned upgrade of the guide-monochromator system at RITA-2 have shown a potential to increase the flux at the sample position by a factor 5.

Mirvetuximab Soravtansine and Gemcitabine Hydrochloride in Treating Patients With FRa-Positive Recurrent Ovarian, Primary Peritoneal, Fallopian Tube, Endometrial, or Triple Negative Breast Cancer

ClinicalTrials.gov

2018-02-21

Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Recurrent Uterine Corpus Carcinoma; Triple-Negative Breast Carcinoma; Folate Receptor Alpha Positive

Rapid and sensitive analysis of phthalate metabolites, bisphenol A, and endogenous steroid hormones in human urine by mixed-mode solid-phase extraction, dansylation, and ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry.

PubMed

Wang, He-xing; Wang, Bin; Zhou, Ying; Jiang, Qing-wu

2013-05-01

Steroid hormone levels in human urine are convenient and sensitive indicators for the impact of phthalates and/or bisphenol A (BPA) exposure on the human steroid hormone endocrine system. In this study, a rapid and sensitive method for determination of 14 phthalate metabolites, BPA, and ten endogenous steroid hormones in urine was developed and validated on the basis of ultra-performance liquid chromatography coupled with electrospray ionization triple quadrupole mass spectrometry. The optimized mixed-mode solid phase-extraction separated the weakly acidic or neutral BPA and steroid hormones from acidic phthalate metabolites in urine: the former were determined in positive ion mode with a methanol/water mobile phase containing 10 mM ammonium formate; the latter were determined in negative ion mode with a acetonitrile/water mobile phase containing 0.1 % acetic acid, which significantly alleviated matrix effects for the analysis of BPA and steroid hormones. Dansylation of estrogens and BPA realized simultaneous and sensitive analysis of the endogenous steroid hormones and BPA in a single chromatographic run. The limits of detection were less than 0.84 ng/mL for phthalate metabolites and less than 0.22 ng/mL for endogenous steroid hormones and BPA. This proposed method had satisfactory precision and accuracy, and was successfully applied to the analyses of human urine samples. This method could be valuable when investigating the associations among endocrine-disrupting chemicals, endogenous steroid hormones, and relevant adverse outcomes in epidemiological studies.

The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.

Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods: Three TNBCmore » cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. - Highlights: • TNBC cells are sensitive to sigma-2 receptor targeted drug conjugate SW IV-134. • MDA-MB-231 displayed the highest amount of sigma-2 receptors and corresponded well with sensitivity. • The sigma-2 receptor is a potential biomarker in TNBC for prognosis and therapy.« less

Erratum to: An Analysis of Training, Generalization, and Maintenance Effects of Primary Care Triple P for Parents of Preschool-Aged Children with Disruptive Behavior.

PubMed

Boyle, Cynthia L; Sanders, Matthew R; Lutzker, John R; Prinz, Ronald J; Shapiro, Cheri; Whitaker, Daniel J

2015-10-01

The Triple P-Positive Parenting Program is owned by the University of Queensland (UQ). The University through its main technology transfer company UniQuest Pty Limited has licensed Triple P International Pty Ltd to disseminate the program worldwide. Royalties stemming from this dissemination activity are distributed to the Parenting and Family Support Centre, School of Psychology, UQ; Faculty of Health and Behavioural Sciences at UQ; and contributory authors. No author has any share or ownership in Triple P International Pty Ltd. Matthew Sanders is the founder and an author on various Triple P programs and a consultant to Triple P International. Karen Turner is an author of various Triple P programs. Ronald Prinz is a consultant to Triple P International. Cheri Shapiro is a consultant to Triple P America.

Tumor-initiating CD49f cells are a hallmark of chemoresistant triple negative breast cancer.

PubMed

Gomez-Miragaya, Jorge; González-Suárez, Eva

2017-01-01

Taxanes are mainstay treatment of triple negative breast cancer (TNBC) patients but resistance often develops. Using TNBC patient-derived orthoxenografts (PDX) we have recently discovered that a CD49f+ chemoresistant population with tumor-initiating ability is present in sensitive tumors and expands in tumors that have acquired resistance. Importantly, sensitivity to taxanes is recovered after long-term drug interruption. The characterization of this chemoresistant CD49f+ cells provides a unique opportunity to identify novel targets for the treatment of chemoresistant TNBC.

Near-field fluorescence thermometry using highly efficient triple-tapered near-field optical fiber probe.

PubMed

Fujii, T; Taguchi, Y; Saiki, T; Nagasaka, Y

2012-12-01

A novel local temperature measurement method using fluorescence near-field optics thermal nanoscopy (Fluor-NOTN) has been developed. Fluor-NOTN enables nanoscale temperature measurement in situ by detecting the temperature-dependent fluorescence lifetime of CdSe quantum dots (QDs). In this paper, we report a novel triple-tapered near-field optical fiber probe that can increase the temperature measurement sensitivity of Fluor-NOTN. The performance of the proposed probe was numerically evaluated by the finite difference time domain method. Due to improvements in both the throughput and collection efficiency of near-field light, the sensitivity of the proposed probe was 1.9 times greater than that of typical double-tapered probe. The proposed shape of the triple-tapered core was successfully fabricated utilizing a geometrical model. The detected signal intensity of dried layers of QDs was greater by more than two orders than that of auto-fluorescence from the fiber core. In addition, the near-field fluorescence lifetime of the QDs and its temperature dependence were successfully measured by the fabricated triple-tapered near-field optical fiber probe. These measurement results verified the capability of the proposed triple-tapered near-field optical fiber probe to improve the collection efficiency of near-field fluorescence.

Pregnancy failure in patients with obstetric antiphospholipid syndrome with conventional treatment: the influence of a triple positive antibody profile.

PubMed

Latino, J O; Udry, S; Aranda, F M; Perés Wingeyer, S D A; Fernández Romero, D S; de Larrañaga, G F

2017-08-01

Conventional treatment of obstetric antiphospholipid syndrome fails in approximately 20-30% of pregnant women without any clearly identified risk factor. It is important to identify risk factors that are associated with these treatment failures. This study aimed to assess the impact of risk factors on pregnancy outcomes in women with obstetric antiphospholipid syndrome treated with conventional treatment. We carefully retrospectively selected 106 pregnancies in women with obstetric antiphospholipid syndrome treated with heparin + aspirin. Pregnancy outcomes were evaluated according to the following associated risk factors: triple positivity profile, double positivity profile, single positivity profile, history of thrombosis, autoimmune disease, more than four pregnancy losses, and high titers of anticardiolipin antibodies and/or anti-βeta-2-glycoprotein-I (aβ2GPI) antibodies. To establish the association between pregnancy outcomes and risk factors, a single binary logistic regressions analysis was performed. Risk factors associated with pregnancy loss with conventional treatment were: the presence of triple positivity (OR = 5.0, CI = 1.4-16.9, p = 0.01), high titers of aβ2GPI (OR = 4.4, CI = 1.2-16.1, p = 0.023) and a history of more than four pregnancy losses (OR = 3.5, CI = 1.2-10.0, p = 0.018). The presence of triple positivity was an independent risk factor associated with gestational complications (OR = 4.1, CI = 1.2-13.9, p = 0.02). Our findings reinforce the idea that triple positivity is a categorical risk factor for poor response to conventional treatment.

A Novel Anti-classification Approach for Knowledge Protection.

PubMed

Lin, Chen-Yi; Chen, Tung-Shou; Tsai, Hui-Fang; Lee, Wei-Bin; Hsu, Tien-Yu; Kao, Yuan-Hung

2015-10-01

Classification is the problem of identifying a set of categories where new data belong, on the basis of a set of training data whose category membership is known. Its application is wide-spread, such as the medical science domain. The issue of the classification knowledge protection has been paid attention increasingly in recent years because of the popularity of cloud environments. In the paper, we propose a Shaking Sorted-Sampling (triple-S) algorithm for protecting the classification knowledge of a dataset. The triple-S algorithm sorts the data of an original dataset according to the projection results of the principal components analysis so that the features of the adjacent data are similar. Then, we generate noise data with incorrect classes and add those data to the original dataset. In addition, we develop an effective positioning strategy, determining the added positions of noise data in the original dataset, to ensure the restoration of the original dataset after removing those noise data. The experimental results show that the disturbance effect of the triple-S algorithm on the CLC, MySVM, and LibSVM classifiers increases when the noise data ratio increases. In addition, compared with existing methods, the disturbance effect of the triple-S algorithm is more significant on MySVM and LibSVM when a certain amount of the noise data added to the original dataset is reached.

Detection of reactive metabolites using isotope-labeled glutathione trapping and simultaneous neutral loss and precursor ion scanning with ultra-high-pressure liquid chromatography triple quadruple mass spectrometry.

PubMed

Huang, Ke; Huang, Lingyi; van Breemen, Richard B

2015-04-07

Metabolic activation of drugs to electrophilic species is responsible for over 60% of black box warnings and drug withdrawals from the market place in the United States. Reactive metabolite trapping using glutathione (GSH) and analysis using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) or HPLC with high resolution mass spectrometry (mass defect filtering) have enabled screening for metabolic activation to become routine during drug development. However, current MS-based approaches cannot detect all GSH conjugates present in complex mixtures, especially those present in extracts of botanical dietary supplements. To overcome these limitations, a fast triple quadrupole mass spectrometer-based approach was developed that can detect positively and negatively charged GSH conjugates in a single analysis without the need for advanced knowledge of the elemental compositions of potential conjugates and while avoiding false positives. This approach utilized UHPLC instead of HPLC to shorten separation time and enhance sensitivity, incorporated stable-isotope labeled GSH to avoid false positives, and used fast polarity switching electrospray MS/MS to detect GSH conjugates that form positive and/or negative ions. The general new method was then used to test the licorice dietary supplement Glycyrrhiza glabra, which was found to form multiple GSH conjugates upon metabolic activation. Among the GSH conjugates found in the licorice assay were conjugates with isoliquiritigenin and glabridin, which is an irreversible inhibitor of cytochrome P450 enzymes.

Erratum to: Reducing Preschoolers' Disruptive Behavior in Public with a Brief Parent Discussion Group.

PubMed

Joachim, Sabine; Sanders, Matthew R; Turner, Karen M T

2015-10-01

The Triple P-Positive Parenting Program is owned by the University of Queensland (UQ). The University through its main technology transfer company UniQuest Pty Limited has licensed Triple P International Pty Ltd to disseminate the program worldwide. Royalties stemming from this dissemination activity are distributed to the Parenting and Family Support Centre, School of Psychology, UQ; Faculty of Health and Behavioural Sciences at UQ; and contributory authors. No author has any share or ownership in Triple P International Pty Ltd. Matthew Sanders is the founder and an author on various Triple P programs and a consultant to Triple P International. Karen Turner is an author of various Triple P programs.

Constraints from triple gauge couplings on vectorlike leptons

DOE PAGES

Bertuzzo, Enrico; Machado, Pedro A. N.; Perez-Gonzalez, Yuber F.; ...

2017-08-30

Here, we study the contributions of colorless vectorlike fermions to the triple gauge couplings W +W -γ and W +W -Z 0. We consider models in which their coupling to the Standard Model Higgs boson is allowed or forbidden by quantum numbers. We assess the sensitivity of the future accelerators FCC-ee, ILC, and CLIC to the parameters of these models, assuming they will be able to constrain the anomalous triple gauge couplings with precision δ κV~O(10 -4), V = γ,Z 0. We show that the combination of measurements at different center-of-mass energies helps to improve the sensitivity to the contributionmore » of vectorlike fermions, in particular when they couple to the Higgs. In fact, the measurements at the FCC-ee and, especially, the ILC and the CLIC, may turn the triple gauge couplings into a new set of precision parameters able to constrain the models better than the oblique parameters or the H → γγ decay, even assuming the considerable improvement of the latter measurements achievable at the new machines.« less

Constraints from triple gauge couplings on vectorlike leptons

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bertuzzo, Enrico; Machado, Pedro A. N.; Perez-Gonzalez, Yuber F.

Here, we study the contributions of colorless vectorlike fermions to the triple gauge couplings W +W -γ and W +W -Z 0. We consider models in which their coupling to the Standard Model Higgs boson is allowed or forbidden by quantum numbers. We assess the sensitivity of the future accelerators FCC-ee, ILC, and CLIC to the parameters of these models, assuming they will be able to constrain the anomalous triple gauge couplings with precision δ κV~O(10 -4), V = γ,Z 0. We show that the combination of measurements at different center-of-mass energies helps to improve the sensitivity to the contributionmore » of vectorlike fermions, in particular when they couple to the Higgs. In fact, the measurements at the FCC-ee and, especially, the ILC and the CLIC, may turn the triple gauge couplings into a new set of precision parameters able to constrain the models better than the oblique parameters or the H → γγ decay, even assuming the considerable improvement of the latter measurements achievable at the new machines.« less

Risk of abnormal triple screen for Down syndrome is significantly higher in patients with female fetuses.

PubMed

Spong, C Y; Ghidini, A; Stanley-Christian, H; Meck, J M; Seydel, F D; Pezzullo, J C

1999-04-01

Previous studies have shown that mid-trimester maternal serum alpha-fetoprotein (AFP) levels are significantly higher and human chorionic gonadotrophin (hCG) levels significantly lower in women with male compared with female fetuses. We have evaluated whether triple-screen criteria are more likely to identify women with female fetuses as at risk for Down syndrome. From the Georgetown University genetics database we obtained the absolute values and corresponding multiples of the median (MoM) for AFP, hCG and unconjugated oestriol (uE3) in singleton gestations for the period database November 1992 July 1996. A Down syndrome risk of 1/270 or greater at mid-trimester was considered as high risk. A total of 977 patients with triple screen and outcome information were identified, including 502 female and 475 male fetuses. Patients with female fetuses were significantly more likely to have lower serum AFP (p=0.003) and a positive triple screen for Down syndrome (72 (14 per cent) versus 45 (9 per cent), p<0.02) than those with male fetuses. The gestational age at triple screen, maternal serum hCG and uE3, race and diabetes were not significantly different between the two groups. Since Down syndrome is less common in female than male fetuses, and the rates of female and male Down syndrome fetuses detected by triple screen and subsequent amniocentesis are not significantly different, the excess of positive mid-trimester maternal serum triple screen in women with female fetuses is likely due to false-positive results.

Molecular subtype shift in breast cancer upon trastuzumab treatment: a case report.

PubMed

Āboliņš, Arnis; Vanags, Andrejs; Trofimovičs, Genadijs; Miklaševičs, Edvīns; Gardovskis, Jānis; Štrumfa, Ilze

2011-01-01

Breast cancer is the most common cancer in women. The mortality remains significant despite advanced treatment possibilities. The management of breast cancer is guided by immunohistochemical data that are summarized into molecular subtypes, namely, luminal A, luminal B, HER2 positive and triple negative. HER2 positive and triple negative subtypes of breast cancer are considered to be biologically distinct. We present a case of clinically aggressive breast cancer in a 58-year-old female. Along the course of the disease, the molecular type switched from HER2 positive to triple negative. The patient deteriorated despite combined therapy. We recommend making a possible change of the molecular subtype and employing repeated immunohistochemical investigation in case of relapse.

On line separation of overlapped signals from multi-time photons for the GEM-based detection system

NASA Astrophysics Data System (ADS)

Czarski, T.; Pozniak, K. T.; Chernyshova, M.; Malinowski, K.; Kasprowicz, G.; Kolasinski, P.; Krawczyk, R.; Wojenski, A.; Zabolotny, W.

2015-09-01

The Triple Gas Electron Multiplier (T-GEM) is presented as soft X-ray (SXR) energy and position sensitive detector for high-resolution X-ray diagnostics of magnetic confinement fusion plasmas. Multi-channel measurement system and serial data acquisition for X-ray energy and position recognition is described. Fundamental characteristics are presented for two dimensional detector structure. Typical signals of ADC - Analog to Digital Converter are considered for charge value and position estimation. Coinciding signals for high flux radiation cause the problem for cluster charge identification. The amplifier with shaper determines time characteristics and limits the pulses frequency. Separation of coincided signals was introduced and verified for simulation experiments. On line separation of overlapped signals was implemented applying the FPGA technology with relatively simple firmware procedure. Representative results for reconstruction of coinciding signals are demonstrated.

Three-frequency BDS precise point positioning ambiguity resolution based on raw observables

NASA Astrophysics Data System (ADS)

Li, Pan; Zhang, Xiaohong; Ge, Maorong; Schuh, Harald

2018-02-01

All BeiDou navigation satellite system (BDS) satellites are transmitting signals on three frequencies, which brings new opportunity and challenges for high-accuracy precise point positioning (PPP) with ambiguity resolution (AR). This paper proposes an effective uncalibrated phase delay (UPD) estimation and AR strategy which is based on a raw PPP model. First, triple-frequency raw PPP models are developed. The observation model and stochastic model are designed and extended to accommodate the third frequency. Then, the UPD is parameterized in raw frequency form while estimating with the high-precision and low-noise integer linear combination of float ambiguity which are derived by ambiguity decorrelation. Third, with UPD corrected, the LAMBDA method is used for resolving full or partial ambiguities which can be fixed. This method can be easily and flexibly extended for dual-, triple- or even more frequency. To verify the effectiveness and performance of triple-frequency PPP AR, tests with real BDS data from 90 stations lasting for 21 days were performed in static mode. Data were processed with three strategies: BDS triple-frequency ambiguity-float PPP, BDS triple-frequency PPP with dual-frequency (B1/B2) and three-frequency AR, respectively. Numerous experiment results showed that compared with the ambiguity-float solution, the performance in terms of convergence time and positioning biases can be significantly improved by AR. Among three groups of solutions, the triple-frequency PPP AR achieved the best performance. Compared with dual-frequency AR, additional the third frequency could apparently improve the position estimations during the initialization phase and under constraint environments when the dual-frequency PPP AR is limited by few satellite numbers.

Maintenance of Treatment Gains: A Comparison of Enhanced, Standard, and Self-Directed Triple P-Positive Parenting Program

ERIC Educational Resources Information Center

Sanders, Matthew R.; Bor, William; Morawska, Alina

2007-01-01

This report describes the 3 year outcomes of three different variants of the Triple P-Positive Parenting Program, a behavioural family intervention. Families were randomly assigned to one of three intervention conditions or to a waitlist condition. At 1 year follow-up there were similar improvements on observational and self-report measures of…

Effectiveness of Group Positive Parenting Program (Triple P) in Changing Child Behavior, Parenting Style, and Parental Adjustment: An Intervention Study in Japan

ERIC Educational Resources Information Center

Fujiwara, Takeo; Kato, Noriko; Sanders, Matthew R.

2011-01-01

The purpose of this study is to investigate the effectiveness of a group-based family intervention program known as the Group Positive Parenting Program (Triple P), with families in Japan. Reductions in children's behavioral problems, changes in dysfunctional parenting practices, and affects on parenting adjustment were examined. Participants of…

Does Parental Attributional Retraining and Anger Management Enhance the Effects of the Triple P-Positive Parenting Program with Parents at Risk of Child Maltreatment?

ERIC Educational Resources Information Center

Sanders, Matthew R.; Pidgeon, Aileen M.; Gravestock, Fred; Connors, Mark D.; Brown, Samantha; Young, Ross W.

2004-01-01

Ninety-eight parents experiencing significant difficulties in managing their own anger in their interactions with their preschool-aged children were randomly assigned either to an enhanced group-administered behavioral family intervention program based on the Triple P-Positive Parenting Program that incorporated attributional retraining and anger…

A Single Crossing-Over Event in Voltage-Sensitive Na+ Channel Genes May Cause Critical Failure of Dengue Mosquito Control by Insecticides

PubMed Central

Hirata, Koichi; Komagata, Osamu; Itokawa, Kentaro; Yamamoto, Atsushi; Tomita, Takashi; Kasai, Shinji

2014-01-01

The voltage-sensitive sodium (Na+) channel (Vssc) is the target site of pyrethroid insecticides. Pest insects develop resistance to this class of insecticide by acquisition of one or multiple amino acid substitution(s) in this channel. In Southeast Asia, two major Vssc types confer pyrethroid resistance in the dengue mosquito vector Aedes aegypti, namely, S989P+V1016G and F1534C. We expressed several types of Vssc in Xenopus oocytes and examined the effect of amino acid substitutions in Vssc on pyrethroid susceptibilities. S989P+V1016G and F1534C haplotypes reduced the channel sensitivity to permethrin by 100- and 25-fold, respectively, while S989P+V1016G+F1534C triple mutations reduced the channel sensitivity to permethrin by 1100-fold. S989P+V1016G and F1534C haplotypes reduced the channel sensitivity to deltamethrin by 10- and 1-fold (no reduction), respectively, but S989P+V1016G+F1534C triple mutations reduced the channel sensitivity to deltamethrin by 90-fold. These results imply that pyrethroid insecticides are highly likely to lose their effectiveness against A. aegypti if such a Vssc haplotype emerges as the result of a single crossing-over event; thus, this may cause failure to control this key mosquito vector. Here, we strongly emphasize the importance of monitoring the occurrence of triple mutations in Vssc in the field population of A. aegypti. PMID:25166902

Critical comparison of mass analyzers for forensic hair analysis by ambient ionization mass spectrometry.

PubMed

Duvivier, Wilco F; van Beek, Teris A; Nielen, Michel W F

2016-11-15

Recently, several direct and/or ambient mass spectrometry (MS) approaches have been suggested for drugs of abuse imaging in hair. The use of mass spectrometers with insufficient selectivity could result in false-positive measurements due to isobaric interferences. Different mass analyzers have been evaluated regarding their selectivity and sensitivity for the detection of Δ9-tetrahydrocannabinol (THC) from intact hair samples using direct analysis in real time (DART) ionization. Four different mass analyzers, namely (1) an orbitrap, (2) a quadrupole orbitrap, (3) a triple quadrupole, and (4) a quadrupole time-of-flight (QTOF), were evaluated. Selectivity and sensitivity were assessed by analyzing secondary THC standard dilutions on stainless steel mesh screens and blank hair samples, and by the analysis of authentic cannabis user hair samples. Additionally, separation of isobaric ions by use of travelling wave ion mobility (TWIM) was investigated. The use of a triple quadrupole instrument resulted in the highest sensitivity; however, transitions used for multiple reaction monitoring were only found to be specific when using high mass resolution product ion measurements. A mass resolution of at least 30,000 FWHM at m/z 315 was necessary to avoid overlap of THC with isobaric ions originating from the hair matrix. Even though selectivity was enhanced by use of TWIM, the QTOF instrument in resolution mode could not indisputably differentiate THC from endogenous isobaric ions in drug user hair samples. Only the high resolution of the (quadrupole) orbitrap instruments and the QTOF instrument in high-resolution mode distinguished THC in hair samples from endogenous isobaric interferences. As expected, enhanced selectivity compromises sensitivity and THC was only detectable in hair from heavy users. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

MYC/BCL2/BCL6 triple hit lymphoma: a study of 40 patients with a comparison to MYC/BCL2 and MYC/BCL6 double hit lymphomas.

PubMed

Huang, Wenting; Medeiros, L Jeffrey; Lin, Pei; Wang, Wei; Tang, Guilin; Khoury, Joseph; Konoplev, Sergej; Yin, C Cameron; Xu, Jie; Oki, Yasuhiro; Li, Shaoying

2018-05-21

High-grade B-cell lymphomas with MYC, BCL2, and BCL6 rearrangements (triple hit lymphoma) are uncommon. We studied the clinicopathologic features of 40 patients with triple hit lymphoma and compared them to 157 patients with MYC/BCL2 double hit lymphoma and 13 patients with MYC/BCL6 double hit lymphoma. The triple hit lymphoma group included 25 men and 15 women with a median age of 61 years (range, 34-85). Nine patients had a history of B-cell lymphoma. Histologically, 23 (58%) cases were diffuse large B-cell lymphoma and 17 cases had features of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Most cases of triple hit lymphoma were positive for CD10 (100%), BCL2 (95%), BCL6 (82%), MYC (74%), and 71% with MYC and BCL2 coexpression. P53 was overexpressed in 29% of triple hit lymphoma cases. The clinicopathological features of triple hit lymphoma patients were similar to patients with MYC/BCL2 and MYC/BCL6 double hit lymphoma, except that triple hit lymphoma cases were more often CD10 positive compared with MYC/BCL6 double hit lymphoma (p < 0.05). Induction chemotherapy used was similar for patients with triple hit lymphoma and double hit lymphoma and overall survival in triple hit lymphoma patients was 17.6 months, similar to the overall survival of patients with double hit lymphoma (p = 0.67). Patients with triple hit lymphoma showing P53 overexpression had significantly worse overall survival compared with those without P53 overexpression (p = 0.04). On the other hand, double expressor status and prior history of B-cell lymphoma did not correlate with overall survival. In conclusion, most patients with triple hit lymphoma have an aggressive clinical course and poor prognosis and these tumors have a germinal center B-cell immunophenotype, similar to patients with double hit lymphomas. P53 expression is a poor prognostic factor in patients with triple hit lymphoma.

Correlation between y-type ions observed in ion trap and triple quadrupole mass spectrometers.

PubMed

Sherwood, Carly A; Eastham, Ashley; Lee, Lik Wee; Risler, Jenni; Vitek, Olga; Martin, Daniel B

2009-09-01

Multiple reaction monitoring mass spectrometry (MRM-MS) is a technique for high-sensitivity targeted analysis. In proteomics, MRM-MS can be used to monitor and quantify a peptide based on the production of expected fragment peaks from the selected peptide precursor ion. The choice of which fragment ions to monitor in order to achieve maximum sensitivity in MRM-MS can potentially be guided by existing MS/MS spectra. However, because the majority of discovery experiments are performed on ion trap platforms, there is concern in the field regarding the generalizability of these spectra to MRM-MS on a triple quadrupole instrument. In light of this concern, many operators perform an optimization step to determine the most intense fragments for a target peptide on a triple quadrupole mass spectrometer. We have addressed this issue by targeting, on a triple quadrupole, the top six y-ion peaks from ion trap-derived consensus library spectra for 258 doubly charged peptides from three different sample sets and quantifying the observed elution curves. This analysis revealed a strong correlation between the y-ion peak rank order and relative intensity across platforms. This suggests that y-type ions obtained from ion trap-based library spectra are well-suited for generating MRM-MS assays for triple quadrupoles and that optimization is not required for each target peptide.

Robot acting on moving bodies (RAMBO): Preliminary results

NASA Technical Reports Server (NTRS)

Davis, Larry S.; Dementhon, Daniel; Bestul, Thor; Ziavras, Sotirios; Srinivasan, H. V.; Siddalingaiah, Madju; Harwood, David

1989-01-01

A robot system called RAMBO is being developed. It is equipped with a camera, which, given a sequence of simple tasks, can perform these tasks on a moving object. RAMBO is given a complete geometric model of the object. A low level vision module extracts and groups characteristic features in images of the object. The positions of the object are determined in a sequence of images, and a motion estimate of the object is obtained. This motion estimate is used to plan trajectories of the robot tool to relative locations nearby the object sufficient for achieving the tasks. More specifically, low level vision uses parallel algorithms for image enchancement by symmetric nearest neighbor filtering, edge detection by local gradient operators, and corner extraction by sector filtering. The object pose estimation is a Hough transform method accumulating position hypotheses obtained by matching triples of image features (corners) to triples of model features. To maximize computing speed, the estimate of the position in space of a triple of features is obtained by decomposing its perspective view into a product of rotations and a scaled orthographic projection. This allows the use of 2-D lookup tables at each stage of the decomposition. The position hypotheses for each possible match of model feature triples and image feature triples are calculated in parallel. Trajectory planning combines heuristic and dynamic programming techniques. Then trajectories are created using parametric cubic splines between initial and goal trajectories. All the parallel algorithms run on a Connection Machine CM-2 with 16K processors.

Effects of double and triple bonds on the spatial representations of odorants in the rat olfactory bulb.

PubMed

Johnson, Brett A; Ong, Joan; Lee, Kaman; Ho, Sabrina L; Arguello, Spart; Leon, Michael

2007-02-01

Many naturally occurring volatile chemicals that are detected through the sense of smell contain unsaturated (double or triple) carbon-carbon bonds. These bonds can affect odors perceived by humans, yet in a prior study of unsaturated hydrocarbons we found only very minor effects of unsaturated bonds. In the present study, we tested the possibility that unsaturated bonds affect the recognition of oxygen-containing functional groups, because humans perceive odor differences between such molecules. We therefore compared spatial activity patterns across the entire glomerular layer of the rat olfactory bulb evoked by oxygen-containing odorants differing systematically in the presence, position, number, and stereochemistry of unsaturated bonds. We quantified activity patterns by mapping [(14)C]2-deoxyglucose uptake into anatomically standardized data matrices, which we compared statistically. We found that the presence and number of unsaturated bonds consistently affected activity patterns, with the largest effect related to the presence of a triple bond. Effects of bond saturation included a loss of activity in glomeruli strongly activated by the corresponding saturated odorants and/or the presence of activity in areas not stimulated by the corresponding saturated compounds. The position of double bonds also affected patterns of activity, but cis vs. trans configuration had no measurable impact in all five sets of stereoisomers that we studied. These results simultaneously indicate the importance of interactions between carbon-carbon bond types and functional groups in the neural coding of odorant chemical information and highlight the emerging concept that the rat olfactory system is more sensitive to certain types of chemical differences than others. (c) 2006 Wiley-Liss, Inc.

Geodynamical simulation of the RRF triple junction

NASA Astrophysics Data System (ADS)

Wang, Z.; Wei, D.; Liu, M.; Shi, Y.; Wang, S.

2017-12-01

Triple junction is the point at which three plate boundaries meet. Three plates at the triple junction form a complex geological tectonics, which is a natural laboratory to study the interactions of plates. This work studies a special triple junction, the oceanic transform fault intersects the collinear ridges with different-spreading rates, which is free of influence of ridge-transform faults and nearby hotspots. First, we build 3-D numerical model of this triple junction used to calculate the stead-state velocity and temperature fields resulting from advective and conductive heat transfer. We discuss in detail the influence of the velocity and temperature fields of the triple junction from viscosity, spreading rate of the ridge. The two sides of the oceanic transform fault are different sensitivities to the two factors. And, the influence of the velocity mainly occurs within 200km of the triple junction. Then, we modify the model by adding a ridge-transform fault to above model and directly use the velocity structure of the Macquarie triple junction. The simulation results show that the temperature at both sides of the oceanic transform fault decreases gradually from the triple junction, but the temperature difference between the two sides is a constant about 200°. And, there is little effect of upwelling velocity away from the triple junction 100km. The model results are compared with observational data. The heat flux and thermal topography along the oceanic transform fault of this model are consistent with the observed data of the Macquarie triple junction. The earthquakes are strike slip distributed along the oceanic transform fault. Their depths are also consistent with the zone of maximum shear stress. This work can help us to understand the interactions of plates of triple junctions and help us with the foundation for the future study of triple junctions.

Stepping Stones Triple P: An RCT of a Parenting Program with Parents of a Child Diagnosed with an Autism Spectrum Disorder

ERIC Educational Resources Information Center

Whittingham, Koa; Sofronoff, Kate; Sheffield, Jeanie; Sanders, Matthew R.

2009-01-01

Whilst the Triple P Positive Parenting Program has a large evidence base (Sanders, "Clinical Child and Family Psychology Review" 2:71-90, 1999; Sanders, "Journal of Consulting and Clinical Psychology" 68:624-640, 2000) and preliminary evidence indicates that Stepping Stones Triple P is also efficacious (Roberts, "Journal of Clinical Child and…

Polygonal Triples and the Double Ruling of a Hyperboloid

ERIC Educational Resources Information Center

Yiu, Paul

2012-01-01

For a given positive integer k [not equal] 4, let "P[subscript k,n]" denote the "n"-th "k"-gonal number. We study "k"-gonal triples ("a", "b", "c") satisfying P[subscript k,a] + P[subscript k,b] = P[subscript k,c]. A "k"-gonal triple corresponds to a rational point on the rectangular hyperboloid x[squared] + y[squared] = z[squared] + 1. The simple…

Acoustic radiation force impulse elastography in evaluation of triple-negative breast cancer: A preliminary experience.

PubMed

Wan, Jing; Wu, Rong; Yao, Minghua; Xu, Guang; Liu, Hui; Pu, Huan; Xiang, Lihua; Zhang, Shupin

2018-05-19

To assess the elastographic features of triple-negative breast cancers and evaluate the diagnostic value of acoustic radiation force impulse imaging (ARFI) for the characterization of triple-negative breast cancers. This study analyzed data from 234 women with breast cancer. Patients were categorized into three groups; 1) triple-negative breast cancers (n = 48); 2) ER-positive tumors (n = 128) and 3) HER2-positive tumors (n = 58). Mean tumor stiffness was evaluated by virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ) and quantified as both qualitative scores (1-5) and shear wave velocity (SWV) (m/s). The relationship between mean SWV and tumor parameters, including tumor size, tumor type, histologic grade and lymph node status, were investigated using multiple linear regression. Triple-negative tumor were more likely to have a large invasive size (p = 0.002), high histological grade (p < 0.001), lymph node involvement (p = 0.022) and strong ki-67 expression (p < 0.001). The highest mean SWV value were recorded in triple-negative tumors (7.36 m/s±1.83), followed by HER2+ tumors (6.65 m/s±2.26) and ER+ tumors (6.60 m/s±2.35) (p = 0.122). Triple-negative tumors were also associated with increased stiffness than ER+ tumors and HER2+ tumors (p = 0.016), as measured by qualitative VTI scores. Tumor size was independently associated with mean SWV value on adjusted regression (p < 0.001). Triple-negative breast cancer is associated with high stiffness scores and SWV in ARFI. The latter may be considered a useful complementary tool in evaluation of triple-negative breast cancer.

A Comprehensive Meta-Analysis of Triple P-Positive Parenting Program Using Hierarchical Linear Modeling: Effectiveness and Moderating Variables

ERIC Educational Resources Information Center

Nowak, Christoph; Heinrichs, Nina

2008-01-01

A meta-analysis encompassing all studies evaluating the impact of the Triple P-Positive Parenting Program on parent and child outcome measures was conducted in an effort to identify variables that moderate the program's effectiveness. Hierarchical linear models (HLM) with three levels of data were employed to analyze effect sizes. The results (N =…

IN12-UFO: new frontiers for cold triple-axis spectroscopy

NASA Astrophysics Data System (ADS)

Schmidt, Wolfgang; Ohl, Michael

2006-11-01

The IN12 instrument is operated by the Research Centre at Jülich in collaboration with CEA Grenoble as a CRG-B instrument at the Institute Laue Langevin in Grenoble. As a triple-axis spectrometer for cold neutrons it is dedicated for high-resolution studies of low-energy excitations. To meet further challenges as a state-of-the-art instrument we will now upgrade IN12 with a multi-analyzer option. IN12 will then be equipped with a large 2-dimensional position sensitive detector and an array of 15 individual analyser blades which can be rotated and positioned separately in order to map the scattered beam on a user-chosen path in Q- ω-space. We refer to this set-up as IN12-UFO (Universal Focusing Option). The innovative flexibility of the analyzer array is realized by completely non-magnetic drive mechanisms where all relevant parameters are controlled by an absolute encoding system. This mechanics allows to position the individual analyzers so that (a) there are no gaps or overlaps as seen from the sample (optimum coverage) and (b) all reflected beams from the analyzers meet at one single focus point on their way to different spots on the detector surface. The focus point is controlled by a movable diaphragm and provides the only opening between analyzer and detector shielding to prevent cross-talk and to keep the background low. We will present further details of this set-up and demonstrate its flexibility and multiplex advantages for specific physical applications.

ACA and the Triple Aim: Musings of a Health Care Actuary.

PubMed

McCarthy, Mac

2015-01-01

In 2008, the Institute for Healthcare Improvement (IHI) promulgated the Triple Aim, which advocates simultaneous improvements in patient experiences, improved population health and lower cost per capita. In 2010, the Patient Protection and Affordable Care Act (ACA) promised quality, affordable health care for all Americans. It's fair to assume that the framers of ACA were aware of the Triple Aim, and it is likely that much of ACA was heavily influenced by IHI's positions. So it is reasonable, from time to time, to assess ACA's impact on health care against the Triple Aim principles.

Triple-Negative or HER2-Positive Status Predicts Higher Rates of Locoregional Recurrence in Node-Positive Breast Cancer Patients After Mastectomy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang Shulian; Li Yexiong, E-mail: yexiong@yahoo.com; Song Yongwen

2011-07-15

Purpose: To evaluate the prognostic value of determining estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression in node-positive breast cancer patients treated with mastectomy. Methods and Materials: The records of 835 node-positive breast cancer patients who had undergone mastectomy between January 2000 and December 2004 were analyzed retrospectively. Of these, 764 patients (91.5%) received chemotherapy; 68 of 398 patients (20.9%) with T1-2N1 disease and 352 of 437 patients (80.5%) with T3-4 or N2-3 disease received postoperative radiotherapy. Patients were classified into four subgroups according to hormone receptor (Rec+ or Rec-) and HER2 expression profiles:more » Rec-/HER2- (triple negative; n = 141), Rec-/HER2+ (n = 99), Rec+/HER2+ (n = 157), and Rec+/HER2- (n = 438). The endpoints were the duration of locoregional recurrence-free survival, distant metastasis-free survival, disease-free survival, and overall survival. Results: Patients with triple-negative, Rec-/HER2+, and Rec+/HER2+ expression profiles had a significantly lower 5-year locoregional recurrence-free survival than those with Rec+/HER2- profiles (86.5% vs. 93.6%, p = 0.002). Compared with those with Rec+/HER2+ and Rec+/HER2- profiles, patients with Rec-/HER2- and Rec-/HER2+ profiles had significantly lower 5-year distant metastasis-free survival (69.1% vs. 78.5%, p = 0.000), lower disease-free survival (66.6% vs. 75.6%, p = 0.000), and lower overall survival (71.4% vs. 84.2%, p = 0.000). Triple-negative or Rec-/HER2+ breast cancers had an increased likelihood of relapse and death within the first 3 years after treatment. Conclusions: Triple-negative and HER2-positive profiles are useful markers of prognosis for locoregional recurrence and survival in node-positive breast cancer patients treated with mastectomy.« less

Combinatorial Effects of Lapatinib and Rapamycin in Triple-Negative Breast Cancer Cells

PubMed Central

Liu, Tongrui; Yacoub, Rami; Taliaferro-Smith, LaTonia D.; Sun, Shi-Yong; Graham, Tisheeka R.; Dolan, Ryan; Lobo, Christine; Tighiouart, Mourad; Yang, Lily; Adams, Amy; O'Regan, Ruth M.

2016-01-01

Triple-negative breast cancers, which lack estrogen receptor, progesterone receptor, and HER2/neu overexpression, account for approximately 15% of breast cancers, but occur more commonly in African Americans. The poor survival outcomes seen with triple-negative breast cancers patients are, in part, due to a lack of therapeutic targets. Epidermal growth factor receptor (EGFR) is overexpressed in 50% of triple-negative breast cancers, but EGFR inhibitors have not been effective in patients with metastatic breast cancers. However, mTOR inhibition has been shown to reverse resistance to EGFR inhibitors. We examined the combination effects of mTOR inhibition with EGFR inhibition in triple-negative breast cancer in vitro and in vivo. The combination of EGFR inhibition by using lapatinib and mTOR inhibition with rapamycin resulted in significantly greater cytotoxicity than the single agents alone and these effects were synergistic in vitro. The combination of rapamycin and lapatinib significantly decreased growth of triple-negative breast cancers in vivo compared with either agent alone. EGFR inhibition abrogated the expression of rapamycin-induced activated Akt in triple-negative breast cancer cells in vitro. The combination of EGFR and mTOR inhibition resulted in increased apoptosis in some, but not all, triple-negative cell lines, and these apoptotic effects correlated with a decrease in activated eukaryotic translation initiation factor (eIF4E). These results suggest that mTOR inhibitors could sensitize a subset of triple-negative breast cancers to EGFR inhibitors. Given the paucity of effective targeted agents in triple-negative breast cancers, these results warrant further evaluation. PMID:21690228

Does Self-Directed and Web-Based Support for Parents Enhance the Effects of Viewing a Reality Television Series Based on the Triple P--Positive Parenting Programme?

ERIC Educational Resources Information Center

Sanders, Matthew; Calam, Rachel; Durand, Marianne; Liversidge, Tom; Carmont, Sue Ann

2008-01-01

Background: This study investigated whether providing self-directed and web-based support for parents enhanced the effects of viewing a reality television series based on the Triple P--Positive Parenting Programme. Method: Parents with a child aged 2 to 9 (N=454) were randomly assigned to either a standard or enhanced intervention condition. In…

Isolated orbital mass as the primary presentation of a triple-hit lymphoma transformed from a systemic follicular lymphoma.

PubMed

Zhou, Xiao Yi; Lu, Xinyan; Raparia, Kirtee; Chen, Yi-Hua

2018-06-01

Triple-hit lymphoma is a highly aggressive B-cell lymphoma. We report a case of triple-hit lymphoma transformed from systemic follicular lymphoma (FL) after 9-year remission and presented primarily as an isolated orbital mass without systemic symptoms or lymphadenopathy. A 58-year-old female presented with intermittent vertical binocular diplopia, left upper eyelid swelling and pain and was found to have a 2.9 cm orbital mass. Histological section revealed a CD10-positive large B-cell lymphoma, consistent with transformation of FL. Fluorescent in situ hybridization (FISH) analysis demonstrated rearrangements involving C-MYC, BCL-2 and BCL-6 genes, indicating a high grade, triple-hit lymphoma. Triple-hit lymphoma transformed from a low-grade lymphoma may initially present as an isolated orbital mass without systemic evidence of transformation. Early recognition of double or triple-hit lymphomas is important since these patients require aggressive chemotherapy.

Folding and conformational consequences of glycine to alanine replacements at different positions in a collagen model peptide.

PubMed

Bhate, Manjiri; Wang, Xin; Baum, Jean; Brodsky, Barbara

2002-05-21

The collagen model peptide T1-892 includes a C-terminal nucleation domain, (Gly-Pro-Hyp)(4), and an N-terminal (Gly-X-Y)(6) sequence taken from type I collagen. In osteogenesis imperfecta (OI) and other collagen diseases, single base mutations often convert one Gly to a larger residue, and T1-892 homologues modeling such mutations were synthesized with Gly to Ala substitutions in either the (Gly-Pro-Hyp)(4) domain, Gly25Ala, or the (Gly-X-Y)(6) domain, Gly10Ala. CD and NMR studies show the Gly10Ala peptide forms a normal triple-helix at the C-terminal end and propagates from the C- to the N-terminus until the Gly --> Ala substitution is encountered. At this point, triple-helix folding is terminated and cannot be reinitiated, leaving a nonhelical N-terminus. A decreased thermal stability is observed as a result of the shorter length of the triple-helix. In contrast, introduction of the Gly to Ala replacement at position 25, in the nucleation domain, shifts the monomer/trimer equilibrium toward the monomer form. The increased monomer and lower trimer populations are reflected in the dramatic decrease in triple-helix content and stability. Unlike the Ala replacement at position 10, the Ala substitution in the (Gly-Pro-Hyp)(4) region can still be incorporated into a triple-helix, but at a greatly decreased rate of folding, since the original efficient nucleation site is no longer operative. The specific consequences of Gly to Ala replacements in two distinctive sequences in this triple-helical peptide may help clarify the variability in OI clinical severity resulting from mutations at different sites along type I collagen chains.

Strategy for Restoring Drug Sensitivity to Triple-Negative Breast Cancer

DTIC Science & Technology

2011-09-01

tocopherol ether-linked acetic acid analog -TEA), a non-hydrolyzable ether analog of RRR- - tocopherol in p53 mutant TNBC cells, and to understand...cells with a unique analog of vitamin E (alpha- tocopherol ether-linked acetic acid analog; abbreviated α-TEA) in combination with chemotherapeutic...p53-mutant, triple-negative breast cancer (TNBC) cells with a unique analog of vitamin E (alpha- tocopherol ether-linked acetic acid analog

The Contribution of Interchain Salt Bridges to Triple-Helical Stability in Collagen

PubMed Central

Gurry, Thomas; Nerenberg, Paul S.; Stultz, Collin M.

2010-01-01

Abstract Studies on collagen and collagen-like peptides suggest that triple-helical stability can vary along the amino acid chain. In this regard, it has been shown that lysine residues in the Y position and acidic residues in the X′ position of (GPO)3GXYGX′Y′(GPO)3 peptides lead to triple-helical structures with melting temperatures similar to (GPO)8 (where O is hydroxyproline), which is generally regarded as the most stable collagen-like sequence of this length. This enhanced stability has been attributed to the formation of salt bridges between adjacent collagen chains. In this study, we explore the relationship between interchain salt bridge formation and triple-helical stability using detailed molecular simulations. Although our results confirm that salt bridges promote triple-helical stability, we find that not all salt bridges are created equal. In particular, lysine-glutamate salt bridges are most stabilizing when formed between residues in the middle strand (B) and the trailing strand (C), whereas lysine-aspartate salt bridges are most stabilizing when formed between residues in the leading (A) and middle (B) strand—the latter observation being consistent with recent NMR data on a heterotrimeric model peptide. Overall, we believe these data clarify the role of salt bridges in modulating triple-helical stability and can be used to guide the design of collagen-like peptides that have specific interchain interactions. PMID:20513408

Breast Cancer Subtypes and Response to Docetaxel in Node-Positive Breast Cancer: Use of an Immunohistochemical Definition in the BCIRG 001 Trial

PubMed Central

Hugh, Judith; Hanson, John; Cheang, Maggie Chon U.; Nielsen, Torsten O.; Perou, Charles M.; Dumontet, Charles; Reed, John; Krajewska, Maryla; Treilleux, Isabelle; Rupin, Matthieu; Magherini, Emmanuelle; Mackey, John; Martin, Miguel; Vogel, Charles

2009-01-01

Purpose To investigate the prognostic and predictive significance of subtyping node-positive early breast cancer by immunohistochemistry in a clinical trial of a docetaxel-containing regimen. Methods Pathologic data from a central laboratory were available for 1,350 patients (91%) from the BCIRG 001 trial of docetaxel, doxorubicin, and cyclophosphamide (TAC) versus fluorouracil, doxorubicin, and cyclophosphamide (FAC) for operable node-positive breast cancer. Patients were classified by tumor characteristics as (1) triple negative (estrogen receptor [ER]–negative, progesterone receptor [PR]–negative, HER2/neu [HER2]–negative), (2) HER2 (HER2-positive, ER-negative, PR-negative), (3) luminal B (ER-positive and/or PR-positive and either HER2-positive and/or Ki67high), and (4) luminal A (ER-positive and/or PR-positive and not HER2-positive or Ki67high), and assessed for prognostic significance and response to adjuvant chemotherapy. Results Patients were subdivided into triple negative (14.5%), HER2 (8.5%), luminal B (61.1%), and luminal A (15.9%). Three-year disease-free survival (DFS) rates (P values with luminal B as referent) were 67% (P < .0001), 68% (P = .0008), 82% (referent luminal B), and 91% (P = .0027), respectively, with hazard ratios of 2.22, 2.12, and 0.46. Improved 3-year DFS with TAC was found in the luminal B group (P = .025) and a combined ER-positive/HER2-negative group treated with tamoxifen (P = .041), with a marginal trend in the triple negatives (P = .051) and HER2 (P = .068) subtypes. No DFS advantage was seen in the luminal A population. Conclusion A simple immunopanel can divide breast cancers into biologic subtypes with strong prognostic effects. TAC significantly complements endocrine therapy in patients with luminal B subtype and, in the absence of targeted therapy, is effective in the triple-negative population. PMID:19204205

Complex interaction of subsequent surface streamers via deposited charge: a high-resolution experimental study

NASA Astrophysics Data System (ADS)

Hoder, T.; Synek, P.; Chorvát, D.; Ráhel', J.; Brandenburg, R.; Černák, M.

2017-07-01

The coplanar barrier discharge in synthetic air at 30 kPa pressure was studied by time-correlated single photon counting enhanced optical emission spectroscopy, far-field microscopy enhanced intensified CCD camera and sensitive current measurements. The discharge operated in a regime where two subsequent microdischarges appeared within the same voltage half-period. The electrical analysis of the barrier discharge setup enabled us to quantify charge transfer and the effective electric field development. During the second microdischarge the positive surface streamers follow the interface (triple-line) between the area of deposited charge from the previous one and the area of uncharged dielectric surface. It is shown that additional branching and flashes of surface streamers are responsible for the increased spatial complexity of the deposited surface charges at high overvoltage. A suppressed streamer propagating over the area of deposited surface charge was tracked and the evidence of surface streamer reconnection is presented. A spatiotemporal distribution (resolution of 120 ps and 100 μm) of the reduced electric field strength was obtained for both microdischarges from the recorded luminosities of the molecular nitrogen. The reduced electric field of positive streamers in the first microdischarge reached 1200 Td. For the second one, the electric field values for the streamer at the triple-line are slightly lower than that, while for the suppressed streamers are even higher.

α-Fetoprotein is a surrogate marker for predicting treatment failure in telaprevir-based triple combination therapy for genotype 1b chronic hepatitis C Japanese patients with the IL28B minor genotype.

PubMed

Shimada, Noritomo; Tsubota, Akihito; Atsukawa, Masanori; Abe, Hiroshi; Ika, Makiko; Kato, Keizo; Sato, Yoshiyuki; Kondo, Chisa; Sakamoto, Choitsu; Tanaka, Yasuhito; Aizawa, Yoshio

2014-03-01

Even when treated with telaprevir-based triple therapy, some patients fail to achieve a sustained virological response. This study identified factors related closely to treatment failure. A total of 146 Japanese genotype 1b chronic hepatitis C patients were enrolled in this prospective, multicenter study and received a 24-week regimen of triple therapy. The end-of-treatment response rate was significantly lower in patients with the interleukin 28B (IL28B) (rs8099917) non-TT genotype (85.2%) than in those with the TT genotype (100%, P = 0.0002). Multiple logistic regression analysis identified high α-fetoprotein levels as an independent factor related to non-end-of-treatment response in patients with the non-TT genotype. A cut-off value of 20 ng/ml was determined for a non-end-of-treatment response; sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 75.0%, 95.7%, 75.0%, 75.0%, and 92.6%, respectively. Multiple logistic regression analysis for a sustained virological response identified the IL28B TT genotype, low α-fetoprotein levels, non-responders, and a rapid virological response. The sustained virological response rate was significantly lower in patients with the non-TT genotype (59.3%) than in those with the TT genotype (96.7%, P < 0.0001). In patients with the non-TT genotype, α-fetoprotein was the most significant predictor for non-sustained virological response by univariate analysis. A cut-off value of 7.4 ng/ml α-fetoprotein was determined for non-sustained virological response; sensitivity, specificity, PPV, NPV, and accuracy were 63.6%, 87.5%, 77.8%, 77.8%, and 77.8%, respectively. For the non-TT patients, serum α-fetoprotein levels may be a surrogate marker for predicting treatment failure in telaprevir-based therapy for genotype 1b chronic hepatitis C. © 2013 Wiley Periodicals, Inc.

Robot Acting on Moving Bodies (RAMBO): Interaction with tumbling objects

NASA Technical Reports Server (NTRS)

Davis, Larry S.; Dementhon, Daniel; Bestul, Thor; Ziavras, Sotirios; Srinivasan, H. V.; Siddalingaiah, Madhu; Harwood, David

1989-01-01

Interaction with tumbling objects will become more common as human activities in space expand. Attempting to interact with a large complex object translating and rotating in space, a human operator using only his visual and mental capacities may not be able to estimate the object motion, plan actions or control those actions. A robot system (RAMBO) equipped with a camera, which, given a sequence of simple tasks, can perform these tasks on a tumbling object, is being developed. RAMBO is given a complete geometric model of the object. A low level vision module extracts and groups characteristic features in images of the object. The positions of the object are determined in a sequence of images, and a motion estimate of the object is obtained. This motion estimate is used to plan trajectories of the robot tool to relative locations rearby the object sufficient for achieving the tasks. More specifically, low level vision uses parallel algorithms for image enhancement by symmetric nearest neighbor filtering, edge detection by local gradient operators, and corner extraction by sector filtering. The object pose estimation is a Hough transform method accumulating position hypotheses obtained by matching triples of image features (corners) to triples of model features. To maximize computing speed, the estimate of the position in space of a triple of features is obtained by decomposing its perspective view into a product of rotations and a scaled orthographic projection. This allows use of 2-D lookup tables at each stage of the decomposition. The position hypotheses for each possible match of model feature triples and image feature triples are calculated in parallel. Trajectory planning combines heuristic and dynamic programming techniques. Then trajectories are created using dynamic interpolations between initial and goal trajectories. All the parallel algorithms run on a Connection Machine CM-2 with 16K processors.

Instantaneous Real-Time Kinematic Decimeter-Level Positioning with BeiDou Triple-Frequency Signals over Medium Baselines.

PubMed

He, Xiyang; Zhang, Xiaohong; Tang, Long; Liu, Wanke

2015-12-22

Many applications, such as marine navigation, land vehicles location, etc., require real time precise positioning under medium or long baseline conditions. In this contribution, we develop a model of real-time kinematic decimeter-level positioning with BeiDou Navigation Satellite System (BDS) triple-frequency signals over medium distances. The ambiguities of two extra-wide-lane (EWL) combinations are fixed first, and then a wide lane (WL) combination is reformed based on the two EWL combinations for positioning. Theoretical analysis and empirical analysis is given of the ambiguity fixing rate and the positioning accuracy of the presented method. The results indicate that the ambiguity fixing rate can be up to more than 98% when using BDS medium baseline observations, which is much higher than that of dual-frequency Hatch-Melbourne-Wübbena (HMW) method. As for positioning accuracy, decimeter level accuracy can be achieved with this method, which is comparable to that of carrier-smoothed code differential positioning method. Signal interruption simulation experiment indicates that the proposed method can realize fast high-precision positioning whereas the carrier-smoothed code differential positioning method needs several hundreds of seconds for obtaining high precision results. We can conclude that a relatively high accuracy and high fixing rate can be achieved for triple-frequency WL method with single-epoch observations, displaying significant advantage comparing to traditional carrier-smoothed code differential positioning method.

Does test-enhanced learning transfer for triple associates?

PubMed

Pan, Steven C; Wong, Carol M; Potter, Zachary E; Mejia, Jonathan; Rickard, Timothy C

2016-01-01

Test-enhanced learning and transfer for triple-associate word stimuli was assessed in three experiments. In each experiment, training and final-test trials involved the presentation of two words per triple associate (triplet), with the third word having to be retrieved. In agreement with the prior literature on different stimuli, training through testing with feedback yielded markedly better final-test performance than did restudy. However, in contrast to the positive transfer reported for paired associate stimuli, minimal or no positive transfer was observed, relative to a restudy control, from a trained cue combination (e.g., A, B, ?) to other cue combinations from the same triplet that required a different response (e.g., B, C, ?). That result also held when two unique cue combinations per triplet were tested during training, and for triplets with low and high average associative strengths. Supplementary analyses provided insight into the overall transfer effect: An incorrect response during training appears to yield positive transfer relative to restudy, whereas a correct response appears to yield no, or even negative, transfer. Cross-experiment analyses indicated that test-enhanced learning is not diminished when two or three cue combinations are presented during training. Thus, even though learning through testing is highly specific, testing on all possible stimulus-response combinations remains the most efficient strategy for the learning of triple associates.

Functional proteomics outlines the complexity of breast cancer molecular subtypes.

PubMed

Gámez-Pozo, Angelo; Trilla-Fuertes, Lucía; Berges-Soria, Julia; Selevsek, Nathalie; López-Vacas, Rocío; Díaz-Almirón, Mariana; Nanni, Paolo; Arevalillo, Jorge M; Navarro, Hilario; Grossmann, Jonas; Gayá Moreno, Francisco; Gómez Rioja, Rubén; Prado-Vázquez, Guillermo; Zapater-Moros, Andrea; Main, Paloma; Feliú, Jaime; Martínez Del Prado, Purificación; Zamora, Pilar; Ciruelos, Eva; Espinosa, Enrique; Fresno Vara, Juan Ángel

2017-08-30

Breast cancer is a heterogeneous disease comprising a variety of entities with various genetic backgrounds. Estrogen receptor-positive, human epidermal growth factor receptor 2-negative tumors typically have a favorable outcome; however, some patients eventually relapse, which suggests some heterogeneity within this category. In the present study, we used proteomics and miRNA profiling techniques to characterize a set of 102 either estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+) or triple-negative formalin-fixed, paraffin-embedded breast tumors. Protein expression-based probabilistic graphical models and flux balance analyses revealed that some ER+/PR+ samples had a protein expression profile similar to that of triple-negative samples and had a clinical outcome similar to those with triple-negative disease. This probabilistic graphical model-based classification had prognostic value in patients with luminal A breast cancer. This prognostic information was independent of that provided by standard genomic tests for breast cancer, such as MammaPrint, OncoType Dx and the 8-gene Score.

[A case of mucosa-associated lymphoid tissue lymphoma with penicillin allergy successfully treated with levofloxacin, minomycin and rabeprazole].

PubMed

Konno, Tomoko; Motoori, Shigeatsu; Iwamoto, Nozomi; Miyazawa, Tomoe; Saito, Shigeyo; Kitagawa, Naoko; Saisho, Hiromitsu; Furuse, Junji; Itabashi, Masayuki

2010-10-01

A 52-year-old Japanese woman was referred to our Institute because of Helicobacter pylori(H. pylori)-positive gastric mucosa-associated lymphoid tissue(MALT)lymphoma. Since she had a penicillin allergy, we could not eradicate H. pylori using the standard triple therapy including amoxicillin. Additionally, H. pylori was resistant to both clarithromycin and metronidazole. So she was treated with minomycin (MINO), levofloxacin (LVFX), and rabeprazole (RPZ) based on a drug sensitivity test. MINO+LVFX+RPZ appear to be a promising, appropriate, and well-tolerated eradication regimen for H. pylori demonstrating resistance to both clarithromycin and metronidazole, and for patients who are allergic to penicillin.

Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT).

PubMed

Niwińska, A; Murawska, M; Pogoda, K

2010-05-01

Patients with breast cancer brain metastasis are a heterogeneous group in relation to tumor biology and outcome. The group of 222 breast cancer patients with brain metastasis was divided into three biological subgroups. The propensity of biological subtypes for metastases to the brain and survivals depending on biological subtype, recursive partitioning analysis of Radiation Therapy Oncology Group (RPA RTOG) prognostic class and the use of systemic treatment after whole-brain radiotherapy were assessed. The rate of patients with triple-negative, human epidermal growth factor receptor 2 (HER2)-positive and luminal breast cancer with brain metastases was 28%, 53% and 19%, respectively. Median survival from brain metastases in triple-negative, HER2-positive and luminal subtype was 3.7, 9 and 15 months, respectively. Median survival from brain metastases in RPA RTOG prognostic class I, II and III was 15, 11 and 3 months, respectively. In the luminal and in the triple-negative subtype, systemic therapy prolonged survival from 3 to 14 months and from 3 to 4 months, respectively. In HER2-positive subtype, median survival without further treatment, after chemotherapy and after chemotherapy with targeted therapy were 3, 8 and 11 months, respectively. HER2-positive and triple-negative breast cancers have special predilection for metastases to the brain. Survival from brain metastases depended on performance status and the use of systemic treatment.

Characterization of triple layers

NASA Astrophysics Data System (ADS)

Otero, Toribio F.; Cortes, M. Teresa

2001-07-01

We reported the characterization of a macroscopic electrochemomechanical actuator like triple layer (3x1 cm) formed by polypyrrole)/double- sided, non-conducting and flexible tape/ polypyrrole that works in liquid electrolytes under electrochemical control. This triple layer has characteristics of artificial muscle. The influence of variables that control the volume change in the polymer as electrolyte concentration, or temperature has been studied. Variations of time, energy and charge under different conditions are described. We have found that the triple layer acts, at the same time, as sensor and actuator. Therefore, physical magnitudes like the electrolyte concentration or the temperature in the cell can be obtained from electrical energy consumed by a muscle. We have evaluated the influence of variables as area of the triple layer or the trailing weight, which don't participate in the electrochemical reaction. We propose an explication to the results, which show a correlation between the trailed mass and the consumed charge required to move a constant angle those masses by the triple layer. When different surface areas of the triple layer has been evaluated we found that the consumed electrical charge is proportional to area (the mass) of the triple layer. The triple layer can make macroscopical movements in short times, their position is absolutely controlled with the electrical charge, and it has capacity to lift masses. These characteristics allow their use in the design of tools. So, we present a macroscopic tool constituted by two triple layers, which allows catch and translate objects in liquid medium (nipper).

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhang, Aiwu; Hohlmann, Marcus; Azmoun, Babak

Here, we study the position sensitivity of radial zigzag strips intended to read out large GEM detectors for tracking at future experiments. Zigzag strips can cover a readout area with fewer strips than regular straight strips while maintaining good spatial resolution. Consequently, they can reduce the number of required electronic channels and related cost for large-area GEM detector systems. A non-linear relation between incident particle position and hit position measured from charge sharing among zigzag strips was observed in a previous study. We significantly reduce this non-linearity by improving the interleaving of adjacent physical zigzag strips. Zigzag readout structures aremore » implemented on PCBs and on a flexible foil and are tested using a 10 cm × 10 cm triple-GEM detector scanned with a strongly collimated X-ray gun on a 2D motorized stage. Lastly, angular resolutions of 60–84 μrad are achieved with a 1.37 mrad angular strip pitch at a radius of 784 mm. On a linear scale this corresponds to resolutions below 100 μm.« less

Using snowflake surface-area-to-volume ratio to model and interpret snowfall triple-frequency radar signatures

NASA Astrophysics Data System (ADS)

Gergely, Mathias; Cooper, Steven J.; Garrett, Timothy J.

2017-10-01

The snowflake microstructure determines the microwave scattering properties of individual snowflakes and has a strong impact on snowfall radar signatures. In this study, individual snowflakes are represented by collections of randomly distributed ice spheres where the size and number of the constituent ice spheres are specified by the snowflake mass and surface-area-to-volume ratio (SAV) and the bounding volume of each ice sphere collection is given by the snowflake maximum dimension. Radar backscatter cross sections for the ice sphere collections are calculated at X-, Ku-, Ka-, and W-band frequencies and then used to model triple-frequency radar signatures for exponential snowflake size distributions (SSDs). Additionally, snowflake complexity values obtained from high-resolution multi-view snowflake images are used as an indicator of snowflake SAV to derive snowfall triple-frequency radar signatures. The modeled snowfall triple-frequency radar signatures cover a wide range of triple-frequency signatures that were previously determined from radar reflectivity measurements and illustrate characteristic differences related to snow type, quantified through snowflake SAV, and snowflake size. The results show high sensitivity to snowflake SAV and SSD maximum size but are generally less affected by uncertainties in the parameterization of snowflake mass, indicating the importance of snowflake SAV for the interpretation of snowfall triple-frequency radar signatures.

An outcome evaluation of the implementation of the Triple P-Positive Parenting Program in Hong Kong.

PubMed

Leung, Cynthia; Sanders, Matthew R; Leung, Shirley; Mak, Rose; Lau, Joseph

2003-01-01

The present study evaluated the effectiveness of the Positive Parenting Program (Triple P) with a sample of Chinese parents of children with early onset conduct-related problems in Hong Kong. The participants consisted of 91 parents whose children attended maternal and child health centers and child assessment centers for service, and were between three to seven years old. Participants were randomly assigned to the intervention (TP) and a waitlist control group (WL). There was no significant difference in pre-intervention measures between the two groups. However, at post intervention, participants in the TP group reported significantly lower levels of child behavior problems, lower dysfunctional parenting styles, and higher parent sense of competence, compared to the WL group. Implications of these findings for the use of Triple P with families of Chinese descent are discussed.

Improving Ambiguity Resolution for Medium Baselines Using Combined GPS and BDS Dual/Triple-Frequency Observations.

PubMed

Gao, Wang; Gao, Chengfa; Pan, Shuguo; Wang, Denghui; Deng, Jiadong

2015-10-30

The regional constellation of the BeiDou navigation satellite system (BDS) has been providing continuous positioning, navigation and timing services since 27 December 2012, covering China and the surrounding area. Real-time kinematic (RTK) positioning with combined BDS and GPS observations is feasible. Besides, all satellites of BDS can transmit triple-frequency signals. Using the advantages of multi-pseudorange and carrier observations from multi-systems and multi-frequencies is expected to be of much benefit for ambiguity resolution (AR). We propose an integrated AR strategy for medium baselines by using the combined GPS and BDS dual/triple-frequency observations. In the method, firstly the extra-wide-lane (EWL) ambiguities of triple-frequency system, i.e., BDS, are determined first. Then the dual-frequency WL ambiguities of BDS and GPS were resolved with the geometry-based model by using the BDS ambiguity-fixed EWL observations. After that, basic (i.e., L1/L2 or B1/B2) ambiguities of BDS and GPS are estimated together with the so-called ionosphere-constrained model, where the ambiguity-fixed WL observations are added to enhance the model strength. During both of the WL and basic AR, a partial ambiguity fixing (PAF) strategy is adopted to weaken the negative influence of new-rising or low-elevation satellites. Experiments were conducted and presented, in which the GPS/BDS dual/triple-frequency data were collected in Nanjing and Zhengzhou of China, with the baseline distance varying from about 28.6 to 51.9 km. The results indicate that, compared to the single triple-frequency BDS system, the combined system can significantly enhance the AR model strength, and thus improve AR performance for medium baselines with a 75.7% reduction of initialization time on average. Besides, more accurate and stable positioning results can also be derived by using the combined GPS/BDS system.

Improving Ambiguity Resolution for Medium Baselines Using Combined GPS and BDS Dual/Triple-Frequency Observations

PubMed Central

Gao, Wang; Gao, Chengfa; Pan, Shuguo; Wang, Denghui; Deng, Jiadong

2015-01-01

The regional constellation of the BeiDou navigation satellite system (BDS) has been providing continuous positioning, navigation and timing services since 27 December 2012, covering China and the surrounding area. Real-time kinematic (RTK) positioning with combined BDS and GPS observations is feasible. Besides, all satellites of BDS can transmit triple-frequency signals. Using the advantages of multi-pseudorange and carrier observations from multi-systems and multi-frequencies is expected to be of much benefit for ambiguity resolution (AR). We propose an integrated AR strategy for medium baselines by using the combined GPS and BDS dual/triple-frequency observations. In the method, firstly the extra-wide-lane (EWL) ambiguities of triple-frequency system, i.e., BDS, are determined first. Then the dual-frequency WL ambiguities of BDS and GPS were resolved with the geometry-based model by using the BDS ambiguity-fixed EWL observations. After that, basic (i.e., L1/L2 or B1/B2) ambiguities of BDS and GPS are estimated together with the so-called ionosphere-constrained model, where the ambiguity-fixed WL observations are added to enhance the model strength. During both of the WL and basic AR, a partial ambiguity fixing (PAF) strategy is adopted to weaken the negative influence of new-rising or low-elevation satellites. Experiments were conducted and presented, in which the GPS/BDS dual/triple-frequency data were collected in Nanjing and Zhengzhou of China, with the baseline distance varying from about 28.6 to 51.9 km. The results indicate that, compared to the single triple-frequency BDS system, the combined system can significantly enhance the AR model strength, and thus improve AR performance for medium baselines with a 75.7% reduction of initialization time on average. Besides, more accurate and stable positioning results can also be derived by using the combined GPS/BDS system. PMID:26528977

First-line eradication for Helicobacter pylori-positive gastritis by esomeprazole-based triple therapy is influenced by CYP2C19 genotype

PubMed Central

Saito, Yoshimasa; Serizawa, Hiroshi; Kato, Yukako; Nakano, Masaru; Nakamura, Masahiko; Saito, Hidetsugu; Suzuki, Hidekazu; Kanai, Takanori

2015-01-01

AIM: To evaluate the effect of first line esomeprazole (EPZ)-based triple therapy on Helicobacter pylori (H. pylori) eradication. METHODS: A total of 80 Japanese patients with gastritis who were diagnosed as positive for H. pylori infection by endoscopic biopsy-based or 13C-urea breath tests were included in this study. The average age of the patients was 57.2 years (male/female, 42/38). These patients were treated by first-line eradication therapy with EPZ 40 mg/d, amoxicillin 1500 mg/d, and clarithromycin 400 mg/d for 7 d. All drugs were given twice per day. Correlations between H. pylori eradication, CYP2C19 genotype, and serum pepsinogen (PG) level were analyzed. This study was registered with the UMIN Clinical Trials Registry (UMIN000009642). RESULTS: The H. pylori eradication rates by EPZ-based triple therapy evaluated by intention-to-treat and per protocol were 67.5% and 68.4%, respectively, which were similar to triple therapies with other first-generation proton pump inhibitors (PPIs). The eradication rates in three different CYP2C19 genotypes, described as extensive metabolizer (EM), intermediate metabolizer, and poor metabolizer, were 52.2%, 72.1%, and 84.6%, respectively. The H. pylori eradication rate was significantly lower in EM than non-EM (P < 0.05). The serum PG I level and PG I/II ratio were significantly increased after eradication of H. pylori (P < 0.01), suggesting that gastric atrophy was improved by H. pylori eradication. Thus, first-line eradication by EPZ-based triple therapy for patients with H. pylori-positive gastritis was influenced by CYP2C19 genotype, and the eradication rate was on the same level with other first-generation PPIs in the Japanese population. CONCLUSION: The results from this study suggest that there is no advantage to EPZ-based triple therapy on H. pylori eradication compared to other first-generation PPIs. PMID:26730167

Trace determination of 13 haloacetamides in drinking water using liquid chromatography triple quadrupole mass spectrometry with atmospheric pressure chemical ionization.

PubMed

Chu, Wenhai; Gao, Naiyun; Yin, Daqiang; Krasner, Stuart W; Templeton, Michael R

2012-04-27

The haloacetamides (HAcAms) are disinfection by-products (DBPs) in drinking water which are currently receiving increased scientific attention due to their elevated toxicity relative to regulated disinfection by-products. A simultaneous determination method of 13 HAcAms, combining solid-phase extraction (SPE) enrichment, liquid chromatographic (LC) separation, and triple quadrupole mass spectrometry (tqMS) detection with atmospheric pressure chemical ionization (APCI) using selective reaction monitoring in positive mode, was developed to measure HAcAms, including chlorinated, brominated, and iodinated analogs. Ammonium chloride and Oasis HLB were selected as the dechlorinating reagent and polymeric SPE sorbent of HAcAm samples. The used tqMS apparatus showed higher sensitivity for the studied HAcAms in the APCI mode than electrospray ionization. 13 HAcAms were separated by LC in 9.0 min, and the detection limits ranged from 7.6 to 19.7 ng/L. The SPE-LC/tqMS method was successfully applied to quantify 13 HAcAms in drinking water samples for the first time, and first indentified tribromoacetamide and chloroiodoacetamide as DBPs in drinking water. Copyright © 2012 Elsevier B.V. All rights reserved.

Investigation of an enhanced resolution triple quadrupole mass spectrometer for high-throughput liquid chromatography/tandem mass spectrometry assays.

PubMed

Yang, Liyu; Amad, Ma'an; Winnik, Witold M; Schoen, Alan E; Schweingruber, Hans; Mylchreest, Iain; Rudewicz, Patrick J

2002-01-01

Triple quadrupole mass spectrometers, when operated in multiple reaction monitoring (MRM) mode, offer a unique combination of sensitivity, specificity, and dynamic range. Consequently, the triple quadrupole is the workhorse for high-throughput quantitation within the pharmaceutical industry. However, in the past, the unit mass resolution of quadrupole instruments has been a limitation when interference from matrix or metabolites cannot be eliminated. With recent advances in instrument design, triple quadrupole instruments now afford mass resolution of less than 0.1 Dalton (Da) full width at half maximum (FWHM). This paper describes the evaluation of an enhanced resolution triple quadrupole mass spectrometer for high-throughput bioanalysis with emphasis on comparison of selectivity, sensitivity, dynamic range, precision, accuracy, and stability under both unit mass (1 Da FWHM) and enhanced (

Double-membrane triple-electrolyte redox flow battery design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yushan, Yan; Gu, Shuang; Gong, Ke

A redox flow battery is provided having a double-membrane (one cation exchange membrane and one anion exchange membrane), triple-electrolyte (one electrolyte in contact with the negative electrode, one electrolyte in contact with the positive electrode, and one electrolyte positioned between and in contact with the two membranes). The cation exchange membrane is used to separate the negative or positive electrolyte and the middle electrolyte, and the anion exchange membrane is used to separate the middle electrolyte and the positive or negative electrolyte. This design physically isolates, but ionically connects, the negative electrolyte and positive electrolyte. The physical isolation offers greatmore » freedom in choosing redox pairs in the negative electrolyte and positive electrolyte, making high voltage of redox flow batteries possible. The ionic conduction drastically reduces the overall ionic crossover between negative electrolyte and positive one, leading to high columbic efficiency.« less

Efficacy of two different toothbrush heads on a sonic power toothbrush compared to a manual toothbrush on established gingivitis and plaque.

PubMed

Nathoo, Salim; Mateo, Luis R; Chaknis, Patricia; Kemp, James H; Gatzemeyer, John; Morrison, Boyce M; Panagakos, Fotinos

2014-01-01

To evaluate the efficacy of a power toothbrush with distinct multi-directional cleaning action using two different heads (Colgate ProClinical C200 toothbrush with either a triple clean head or a sensitive head) as compared to a manual flat-trim toothbrush (Oral B Indicator toothbrush) on supragingival plaque and established gingivitis. This examiner-blind, randomized, controlled, three-treatment, parallel-group clinical research study assessed plaque removal via the comparison of pre- to post-brushing after a single use and again after four weeks of use, using the Rustogi Modified Navy Plaque Index. This study also assessed gingivitis at four weeks using the Löe-Silness Gingival Index. Qualifying adult male and female subjects from the central New Jersey, USA area reported to the study site after refraining from any oral hygiene procedures for 24 hours, and from eating, drinking, and smoking for four hours. Following an examination for plaque and gingivitis, they were randomized into three balanced groups. Subjects were instructed to brush their teeth for two minutes under supervision with their assigned toothbrush and a commercially available toothpaste (Colgate Cavity Protection toothpaste), after which they were again evaluated for plaque. Subjects were dismissed from the study site with the toothpaste and their assigned toothbrush to use at home twice daily for the next four weeks. They reported to the study site after four weeks of product use, at which time they were evaluated for plaque and gingivitis. One hundred twenty (120) enrolled subjects complied with the protocol and completed the clinical study. The results of the study indicated that all three test products provided statistically significant reductions in pre-brushing to post-brushing plaque scores for whole mouth and interproximal sites after a single use. For gingival margin plaque sites, only the Colgate ProClinical C200 toothbrush, with either the triple clean head or the sensitive head, provided statistically significant reductions in pre- to post-brushing plaque scores. After four weeks of product use, all three test products provided statistically significant reductions in baseline to four-week whole mouth and interproximal site plaque scores, but only the Colgate ProClinical C200 toothbrush, with either the triple clean head or the sensitive head, provided a statistically significant reduction in plaque scores at gingival margin sites. All three test products provided statistically significant reductions in gingival and gingivitis severity index scores after four weeks of product use. Relative to the manual toothbrush group, after a single tooth brushing the Colgate ProClinical C200 toothbrush, with either the triple clean head or sensitive head, provided statistically significantly greater reductions in whole mouth plaque index scores (51.9% and 59.3%, respectively), in gingival margin plaque index scores (700% and 650%, respectively), and interproximal plaque index scores (64.2% and 60.4%, respectively). Relative to the manual toothbrush group, after four weeks of use the Colgate ProClinical C200 toothbrush, with either the triple clean head or sensitive head, provided statistically significantly greater reductions in whole mouth plaque index scores (78.6%, and 82.1%, respectively), in gingival margin plaque index scores (3700% and 3400%, respectively), and interproximal plaque index scores (50.8% and 52.5%, respectively). Relative to the manual toothbrush group, after four weeks of use the Colgate ProClinical C200 toothbrush, with either the triple clean head or sensitive head, provided statistically significantly greater reductions in gingival index scores of 900% and 833%, respectively, and in gingivitis severity index scores of 466.7% and 600%, respectively. All statistically significant reductions were at the p ≤ 0.05 level. There were no statistically significant differences between the scores of the Colgate ProClinical C200 toothbrush with triple clean head and the scores of the Colgate ProClinical C200 toothbrush with sensitive head at any comparison time point. The Colgate ProClinicaI C200 toothbrush, with either a triple clean head or a sensitive head, provides statistically significant and clinically relevant levels of efficacy in the removal of supragingival dental plaque in the whole mouth, at the gingival margin, and interproximally after a single tooth brushing and after four weeks of use, as well as a statistically significantly greater level of efficacy in the reduction of gingivitis and gingival bleeding when compared to a manual flat-trim toothbrush.

A comparative study of broccoli sprouts powder and standard triple therapy on cardiovascular risk factors following H.pylori eradication: a randomized clinical trial in patients with type 2 diabetes

PubMed Central

2014-01-01

Background In this clinical trial we compared the effects of broccoli sprouts powder, as an alternative and complementary treatment, to those of standard triple therapy, as a common medical treatment, on cardiovascular risk factors following the H.pylori eradication in patients with type 2 diabetes. Methods Eighty-six type 2 diabetic patients with positive H.pylori stool antigen test (HpSAg) were randomized to receive one of the three following regimens: STT) Standard triple therapy (omeprazole 20 mg, clarithromycin 500 mg, amoxicillin 1000 mg, twice a day for 14 days), BSP) 6 g/d broccoli sprouts powder for 28 days, and combination of these as STT + BSP. After 4 weeks of treatment, H.pylori eradication rates were assessed by HpSAg. Anthropometric measures, blood pressure, serum lipids and lipoproteins as well as serum high sensitive- C reactive protein were also assessed at baseline and at the second examination. Results Seventy-seven participants completed the study [STT (n = 28), BSP (n = 25), STT + BSP (n = 24)]. The H.pylori eradication rates were 89.3%, 56.0% and 91.7% in STT, BSP and STT + BSP groups, respectively. After the treatment, both systolic and diastolic blood pressure significantly decreased in STT + BSP group (P < 0.05). Serum triglycerides and TG/HDL-C ratio increased in STT patients group (<0.05). Serum hs-CRP levels significantly decreased in the patients who were treated with BSP per se (3.0 ± 2.5 at baseline vs. 2.3 ± 2.1 after the treatment, P < 0.05). Conclusion Compared to standard triple therapy, BSP regimen in addition to considerable effects on H.pylori eradication had also favorable properties on cardiovascular risk factors following the H.pylori eradication. PMID:24940565

The combination of three autoantibodies, ACPA, RF and anti-CarP antibodies is highly specific for rheumatoid arthritis: implications for very early identification of individuals at risk to develop rheumatoid arthritis.

PubMed

Verheul, Marije K; Böhringer, Stefan; van Delft, Myrthe A M; Jones, Jonathan D; Rigby, William F C; Gan, Ryan W; Holers, V Michael; Edison, Jess D; Deane, Kevin D; Janssen, Koen M J; Westra, Johanna; Brink, Mikael; Rantapää-Dahlqvist, Solbritt; Huizinga, Tom W J; van der Helm-van Mil, Annette H M; van der Woude, Diane; Toes, Rene E M; Trouw, Leendert A

2018-05-21

In rheumatoid arthritis(RA), the autoantibodies anti-citrullinated protein antibodies(ACPA) and rheumatoid factor(RF) are commonly used to aid RA diagnosis. Although these autoantibodies are mainly found in RA, their specificity is not optimal. It is therefore difficult to identify RA patients, especially in very early disease, based on the presence of ACPA and RF alone. Also, anti-carbamylated protein(anti-CarP) antibodies have diagnostic and prognostic value as the presence of anti-CarP antibodies associates with joint damage in RA patients and with future RA development in arthralgia patients. Therefore, we aimed to investigate the value of combined antibody testing in relation to prediction and diagnosis of (early) RA. A literature search resulted in twelve studies, consisting of RA patients, pre-RA individuals, disease controls, healthy first-degree relatives of RA patients or healthy controls, in which data on RF, ACPA and anti-CarP antibody-status was available. Random effects meta-analyses were carried out for several antibody combinations. The individual antibodies are highly prevalent in RA(34%-80%) compared to the control groups, but are also present in non-RA controls(0%-23%). To classify most people correctly as RA or non-RA, the combination of ACPA and/or RF often performs well(specificity:65-100, sensitivity:59-88). However, triple positivity for ACPA, RF and anti-CarP antibodies results in a higher specificity(98-100) (accompanied by a lower sensitivity(11-39)). As the rheumatology field is moving towards very early identification of RA and possible screening for individuals at maximum risk in populations with a low pre-test probability, triple positivity provides interesting information on individuals at risk to develop RA. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Highly sensitive simultaneous quantification of estrogenic tamoxifen metabolites and steroid hormones by LC-MS/MS.

PubMed

Johänning, Janina; Heinkele, Georg; Precht, Jana C; Brauch, Hiltrud; Eichelbaum, Michel; Schwab, Matthias; Schroth, Werner; Mürdter, Thomas E

2015-09-01

Tamoxifen is a mainstay in the treatment of estrogen receptor-positive breast cancer and is metabolized to more than 30 different compounds. Little is known about in vivo concentrations of estrogenic metabolites E-metabolite E, Z-metabolite E, and bisphenol and their relevance for tamoxifen efficacy. Therefore, we developed a highly sensitive HPLC-ESI-MS/MS quantification method for tamoxifen metabolites bisphenol, E-metabolite E, and Z-metabolite E as well as for the sex steroid hormones estradiol, estrone, testosterone, androstenedione, and progesterone. Plasma samples were subjected to protein precipitation followed by solid phase extraction. Upon derivatization with 3-[(N-succinimide-1-yl)oxycarbonyl]-1-methylpyridinium iodide, all analytes were separated on a sub-2-μm column with a gradient of acetonitrile in water with 0.1 % of formic acid. Analytes were detected on a triple-quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction monitoring mode. Our method demonstrated high sensitivity, accuracy, and precision. The lower limits of quantification were 12, 8, and 25 pM for bisphenol, E-metabolite E, and Z-metabolite E, respectively, and 4 pM for estradiol and estrogen, 50 pM for testosterone and androstenedione, and 25 pM for progesterone. The method was applied to plasma samples of postmenopausal patients taken at baseline and under tamoxifen therapy. Graphical Abstract Sample preparation and derivatization for highly sensitive quantification of estrogenic tamoxifen metabolites and steroid hormones by HPLC-MS/MS.

Geographic differences in the distribution of molecular subtypes of breast cancer in Brazil

PubMed Central

2014-01-01

Background To compare the distribution of the intrinsic molecular subtypes of breast cancer based on immunohistochemical profile in the five major geographic regions of Brazil, a country of continental dimension, with a wide racial variation of people. Methods The study was retrospective observational. We classified 5,687 invasive breast cancers by molecular subtype based on immunohistochemical expression of estrogen-receptor (ER), progesterone-receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 proliferation index. Cases were classified as luminal A (ER and/or PR positive and HER2 negative, Ki-67 < 14%), luminal B (ER and/or PR positive, HER2 negative, and Ki-67 > 14%), triple-positive (ER and/or PR positive and HER2 positive), HER2-enriched (ER and PR negative, and HER2- positive), and triple-negative (TN) (ER negative, PR negative, and HER2- negative). Comparisons of the ages of patients and molecular subtypes between different geographic regions were performed. Results South and Southeast regions with a higher percentage of European ancestry and higher socioeconomic status presented with the highest proportion of luminal tumors. The North region presented with more aggressive subtypes (HER2-enriched and triple-negative), while the Central-West region predominated triple-positive carcinomas. The Northeast—a region with a high African influence—presented intermediate frequency of the different molecular subtypes. The differences persisted in subgroups of patients under and over 50 years. Conclusions The geographic regions differ according to the distribution of molecular subtypes of breast cancer. However, other differences, beside those related to African ancestry, such as socioeconomic, climatic, nutritional, and geographic, have to be considered to explain our results. The knowledge of the differences in breast cancer characteristics among the geographic regions may help to organize healthcare programs in large countries like Brazil with diverse economic and race composition among different geographic regions. PMID:25174527

Stepping Stones Triple P-Positive Parenting Program for Children with Disability: A Systematic Review and Meta-Analysis

ERIC Educational Resources Information Center

Tellegen, Cassandra L.; Sanders, Matthew R.

2013-01-01

This systematic review and meta-analysis evaluated the treatment effects of a behavioral family intervention, Stepping Stones Triple P (SSTP) for parents of children with disabilities. SSTP is a system of five intervention levels of increasing intensity and narrowing population reach. Twelve studies, including a total of 659 families, met…

Relationship between bony tunnel and knee function in patients after patellar dislocation triple surgeries—a CT-based study

NASA Astrophysics Data System (ADS)

Qin, Le; Li, Mei; Yao, Weiwu; Shen, Ji

2017-01-01

We aimed to assess the CT-based bony tunnel valuations and their correlation with knee function after patellar dislocation triple surgeries. A retrospective study was performed on 66 patients (70 knees) who underwent patellar dislocation triple surgeries. The surgery was MPFL reconstruction primarily, combined with lateral retinaculum release and tibial tubercle osteotomy. CT examinations were performed to determine the femoral tunnel position, along with the patellar and femoral tunnel width 3 days and more than 1 year after operation for follow-up. Functional evaluation based on Kujala and Lysholm scores was also implemented. We compared tunnel width of the first and last examinations and correlated femoral tunnel position of the last examination with knee function. At the last follow-up, femoral tunnel position in the anterior-posterior direction was moderately correlated with knee function. Femoral tunnel position in the proximal-distal direction was not associated with postoperative knee function. Patellar and femoral tunnel width increased significantly at the last follow-up. However, no significant functional difference was found between patients with and without femoral tunnel enlargement. Our results suggested that the tunnel malposition in anterior-posterior position based on CT was related to impaired knee function during the follow-ups.

Long-term outcome of a randomized controlled universal prevention trial through a positive parenting program: is it worth the effort?

PubMed

Hahlweg, Kurt; Heinrichs, Nina; Kuschel, Annett; Bertram, Heike; Naumann, Sebastian

2010-05-16

Approximately 20% of children experience internalizing or externalizing DSM-IV-TR disorders. This prevalence rate cannot be reduced through treatment only. Effective preventive interventions are therefore urgently needed. The aim of the current investigation is to evaluate the two-year efficacy of the group Triple P parenting program administered universally for the prevention of child behavior problems. Based on their respective preschool, N = 280 families were randomly assigned either to the parent training or to the control group. The efficacy was analyzed using multi-source assessments, including questionnaires by mother and father, behavioral observation of mother-child interaction, and teacher evaluations. At the 2-year follow-up, both parents in the Triple P intervention reported significant reductions in dysfunctional parenting behavior, and mothers also an increase in positive parenting behavior. In addition, mothers reported significant reductions in internalizing and externalizing child behavior. Single-parent mothers in the Triple P intervention did not report significant changes in parenting or child problem behavior which is primarily due to inexplicable high positive effects in single parent mothers of the control group. Neither mother-child interactions nor teacher ratings yielded significant results. The results support the long-term efficacy of the Triple P - group program as a universal prevention intervention for changing parenting behavior in two-parent households, but not necessarily in single-parent mothers.

Replacing Alpha-Fetoprotein With Alpha-Fetoprotein-L3 Increases the Sensitivity of Prenatal Screening for Trisomy 21.

PubMed

Huai, Lei; Leng, Jianhang; Ma, Shenglin; Huang, Fang; Shen, Junya; Ding, Yu

This study aimed to investigate the serum concentration of alpha-fetoprotein (AFP)-L3 in midterm pregnancies and its potential application in prenatal trisomy screening. The serum samples from 27 women with trisomy 21 fetuses and 800 women with normal fetuses were examined to measure the concentrations of AFP, AFP-L3, human chorionic gonadotropin (hCG), unconjugated estriol (uE3), and inhibin-A. The screening results of various tests consisting of these markers were analyzed. In normal pregnancies within 15-20 weeks of gestation, the medians of serum AFP-L3 were 4.63, 5.70, 5.78, 6.58, 7.03, and 7.25 pg/mL. The median of AFP-L3 MoM in the trisomy 21 group was 0.46, which was significantly lower than the value of 1 in the normal group (P < 0.05). When using a cutoff value of 1/270, the sensitivity of the triple marker test (AFP, hCG, uE3) was improved from 74% to 81% by replacing AFP with AFP-L3, with the false-positive rate slightly increased from 5.4% to 6.8%. Similarly, the sensitivity of the quad marker test (AFP, hCG, uE3, inhibin-A) was improved from 81% to 89% by replacing AFP with AFP-L3, with the false-positive rate slightly increased from 4.6% to 5.6%. Serum AFP-L3 concentration increases along with more weeks of gestation in the midterm pregnancies. Trisomy 21 screening tests with AFP replaced by AFP-L3 have higher sensitivities at the expense of slightly increased false-positive rates. This improvement in screening may help to better prepare the parents and caregivers for the special needs of newborns with trisomy 21.

Selective killing of Helicobacter pylori with pH-responsive helix–coil conformation transitionable antimicrobial polypeptides

PubMed Central

Xiong, Menghua; Bao, Yan; Xu, Xin; Wang, Hua; Han, Zhiyuan; Wang, Zhiyu; Liu, Yeqing; Huang, Songyin; Song, Ziyuan; Chen, Jinjing; Peek, Richard M.; Yin, Lichen; Chen, Lin-Feng; Cheng, Jianjun

2017-01-01

Current clinical treatment of Helicobacter pylori infection, the main etiological factor in the development of gastritis, gastric ulcers, and gastric carcinoma, requires a combination of at least two antibiotics and one proton pump inhibitor. However, such triple therapy suffers from progressively decreased therapeutic efficacy due to the drug resistance and undesired killing of the commensal bacteria due to poor selectivity. Here, we report the development of antimicrobial polypeptide-based monotherapy, which can specifically kill H. pylori under acidic pH in the stomach while inducing minimal toxicity to commensal bacteria under physiological pH. Specifically, we designed a class of pH-sensitive, helix–coil conformation transitionable antimicrobial polypeptides (HCT-AMPs) (PGA)m-r-(PHLG-MHH)n, bearing randomly distributed negatively charged glutamic acid and positively charged poly(γ-6-N-(methyldihexylammonium)hexyl-l-glutamate) (PHLG-MHH) residues. The HCT-AMPs showed unappreciable toxicity at physiological pH when they adopted random coiled conformation. Under acidic condition in the stomach, they transformed to the helical structure and exhibited potent antibacterial activity against H. pylori, including clinically isolated drug-resistant strains. After oral gavage, the HCT-AMPs afforded comparable H. pylori killing efficacy to the triple-therapy approach while inducing minimal toxicity against normal tissues and commensal bacteria, in comparison with the remarkable killing of commensal bacteria by 65% and 86% in the ileal contents and feces, respectively, following triple therapy. This strategy renders an effective approach to specifically target and kill H. pylori in the stomach while not harming the commensal bacteria/normal tissues. PMID:29133389

External Beam Accelerated Partial-Breast Irradiation Using 32 Gy in 8 Twice-Daily Fractions: 5-Year Results of a Prospective Study

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pashtan, Itai M.; Recht, Abram; Ancukiewicz, Marek

Purpose: External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. Methods and Materials: From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% hadmore » a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). Results: Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P=.0537). Conclusions: Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates.« less

External beam accelerated partial-breast irradiation using 32 gy in 8 twice-daily fractions: 5-year results of a prospective study.

PubMed

Pashtan, Itai M; Recht, Abram; Ancukiewicz, Marek; Brachtel, Elena; Abi-Raad, Rita F; D'Alessandro, Helen A; Levy, Antonin; Wo, Jennifer Y; Hirsch, Ariel E; Kachnic, Lisa A; Goldberg, Saveli; Specht, Michelle; Gadd, Michelle; Smith, Barbara L; Powell, Simon N; Taghian, Alphonse G

2012-11-01

External beam accelerated partial breast irradiation (APBI) is an increasingly popular technique for treatment of patients with early stage breast cancer following breast-conserving surgery. Here we present 5-year results of a prospective trial. From October 2003 through November 2005, 98 evaluable patients with stage I breast cancer were enrolled in the first dose step (32 Gy delivered in 8 twice-daily fractions) of a prospective, multi-institutional, dose escalation clinical trial of 3-dimensional conformal external beam APBI (3D-APBI). Median age was 61 years; median tumor size was 0.8 cm; 89% of tumors were estrogen receptor positive; 10% had a triple-negative phenotype; and 1% had a HER-2-positive subtype. Median follow-up was 71 months (range, 2-88 months; interquartile range, 64-75 months). Five patients developed ipsilateral breast tumor recurrence (IBTR), for a 5-year actuarial IBTR rate of 5% (95% confidence interval [CI], 1%-10%). Three of these cases occurred in patients with triple-negative disease and 2 in non-triple-negative patients, for 5-year actuarial IBTR rates of 33% (95% CI, 0%-57%) and 2% (95% CI, 0%-6%; P<.0001), respectively. On multivariable analysis, triple-negative phenotype was the only predictor of IBTR, with borderline statistical significance after adjusting for tumor grade (P=.0537). Overall outcomes were excellent, particularly for patients with estrogen receptor-positive disease. Patients in this study with triple-negative breast cancer had a significantly higher IBTR rate than patients with other receptor phenotypes when treated with 3D-APBI. Larger, prospective 3D-APBI clinical trials should continue to evaluate the effect of hormone receptor phenotype on IBTR rates. Copyright © 2012 Elsevier Inc. All rights reserved.

Novel MEMS-based thermometer with low power consumption for health-monitoring network application

NASA Astrophysics Data System (ADS)

Zhang, Y.; Ikehara, T.; Lu, J.; Kobayashi, T.; Ichiki, M.; Itoh, T.; Maeda, R.

2007-12-01

We proposed one novel MEMS-based thermometer with low power-consumption for animal/human health-monitoring network application. The novel MEMS-based thermometer was consisted of triple-beam bimorph arrays so that it could work in a continuous temperature range. Neither continuous electric supply nor A/D converter interface is required by the novel thermometer owing to the well-known deflection of bimaterials cantilever upon temperature changes. The triple-beam structure also facilitated the novel thermometer with excellent fabrication feasibility by conventional microfabrication technology. The parameters of the triple-beam bimorph arrays were determined by finite element analysis with ANSYS program. Low stress Au and Mo metal films were used as top and bottom layer, respectively. The deflection of the triple-beam bimorphs were measured on a home-made heating stage by a confocal scanning laser microscopy. The novel bimorphs had temperature responses similar to traditional single-beam bimorphs. Initial bend of the prepared triple-beam bimorphs were dominantly determined by their side beams. The sensitivity of the novel thermometer was as high as 0.1°C. Experimental results showed that the novel thermometer is attractive for network sensing applications where the power capacity is limited.

Measurement of the quadratic hyperpolarizability of the collagen triple helix and application to second harmonic imaging of natural and biomimetic collagenous tissues

NASA Astrophysics Data System (ADS)

Deniset-Besseau, A.; Strupler, M.; Duboisset, J.; De Sa Peixoto, P.; Benichou, E.; Fligny, C.; Tharaux, P.-L.; Mosser, G.; Brevet, P.-F.; Schanne-Klein, M.-C.

2009-09-01

Collagen is a major protein of the extracellular matrix that is characterized by triple helical domains. It plays a central role in the formation of fibrillar and microfibrillar networks, basement membranes, as well as other structures of the connective tissue. Remarkably, fibrillar collagen exhibits efficient Second Harmonic Generation (SHG) so that SHG microscopy proved to be a sensitive tool to probe the three-dimensional architecture of fibrillar collagen and to assess the progression of fibrotic pathologies. We obtained sensitive and reproducible measurements of the fibrosis extent, but we needed quantitative data at the molecular level to further process SHG images. We therefore performed Hyper- Rayleigh Scattering (HRS) experiments and measured a second order hyperpolarisability of 1.25 10-27 esu for rat-tail type I collagen. This value is surprisingly large considering that collagen presents no strong harmonophore in its aminoacid sequence. In order to get insight into the physical origin of this nonlinear process, we performed HRS measurements after denaturation of the collagen triple helix and for a collagen-like short model peptide [(Pro-Pro- Gly)10]3. It showed that the collagen large nonlinear response originates in the tight alignment of a large number of weakly efficient harmonophores, presumably the peptide bonds, resulting in a coherent amplification of the nonlinear signal along the triple helix. To illustrate this mechanism, we successfully recorded SHG images in collagenous biomimetic matrices.

Multiple-membrane multiple-electrolyte redox flow battery design

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yan, Yushan; Gu, Shuang; Gong, Ke

A redox flow battery is provided. The redox flow battery involves multiple-membrane (at least one cation exchange membrane and at least one anion exchange membrane), multiple-electrolyte (one electrolyte in contact with the negative electrode, one electrolyte in contact with the positive electrode, and at least one electrolyte disposed between the two membranes) as the basic characteristic, such as a double-membrane, triple electrolyte (DMTE) configuration or a triple-membrane, quadruple electrolyte (TMQE) configuration. The cation exchange membrane is used to separate the negative or positive electrolyte and the middle electrolyte, and the anion exchange membrane is used to separate the middle electrolytemore » and the positive or negative electrolyte.« less

Semiconductor switch geometry with electric field shaping

DOEpatents

Booth, R.; Pocha, M.D.

1994-08-23

An optoelectric switch is disclosed that utilizes a cylindrically shaped and contoured GaAs medium or other optically active semiconductor medium to couple two cylindrically shaped metal conductors with flat and flared termination points each having an ovoid prominence centrally extending there from. Coupling the truncated ovoid prominence of each conductor with the cylindrically shaped optically active semiconductor causes the semiconductor to cylindrically taper to a triple junction circular line at the base of each prominence where the metal conductor conjoins with the semiconductor and a third medium such as epoxy or air. Tapering the semiconductor at the triple junction inhibits carrier formation and injection at the triple junction and thereby enables greater current carrying capacity through and greater sensitivity of the bulk area of the optically active medium. 10 figs.

Semiconductor switch geometry with electric field shaping

DOEpatents

Booth, Rex; Pocha, Michael D.

1994-01-01

An optoelectric switch is disclosed that utilizes a cylindrically shaped and contoured GaAs medium or other optically active semiconductor medium to couple two cylindrically shaped metal conductors with flat and flared termination points each having an ovoid prominence centrally extending there from. Coupling the truncated ovoid prominence of each conductor with the cylindrically shaped optically active semiconductor causes the semiconductor to cylindrically taper to a triple junction circular line at the base of each prominence where the metal conductor conjoins with the semiconductor and a third medium such as epoxy or air. Tapering the semiconductor at the triple junction inhibits carrier formation and injection at the triple junction and thereby enables greater current carrying capacity through and greater sensitivity of the bulk area of the optically active medium.

Therapeutic Implications of the Molecular and Immune Landscape of Triple-Negative Breast Cancer.

PubMed

Gregório, Ana C; Lacerda, Manuela; Figueiredo, Paulo; Simões, Sérgio; Dias, Sérgio; Moreira, João Nuno

2017-09-14

Treatment and management of breast cancer imposes a heavy burden on public health care, and incidence rates continue to increase. Breast cancer is the most common female neoplasia and primary cause of death among women worldwide. The recognition of breast cancer as a complex and heterogeneous disease, comprising different molecular entities, was a landmark in our understanding of this malignancy. Valuing the impact of the molecular characteristics on tumor behavior enabled a better assessment of a patient's prognosis and increased the predictive power to therapeutic response and clinical outcome. Molecular heterogeneity is also prominent in the triple-negative breast cancer subtype, and is reflected by the distinct prognostic and patient's sensitivity to treatment, being chemotherapy the only systemic treatment currently available. From a therapeutic perspective, gene expression profiling of triple-negative tumors has notably contributed to the exploration of new druggable targets and brought to light the need to align these patients to the various therapies according to their triple-negative subtype. Additionally, the higher amount of tumor infiltrating lymphocytes, and the prevalence of an increased expression of PD-1 receptor and its ligand, PD-L1, in triple-negative tumors, created a new treatment opportunity with immune checkpoint inhibitors. This manuscript addresses the current knowledge on the molecular and immune profiles of breast cancer, and its impact on the development of targeted therapies, with a particular emphasis on the triple-negative subtype.

Impact of Stepping Stones Triple P on Parents with a Child Diagnosed with Autism Spectrum Disorder: Implications for School Psychologists

ERIC Educational Resources Information Center

VanVoorhis, Richard W.; Miller, Kenneth L.; Miller, Susan M.; Stull, Judith C.

2015-01-01

The Stepping Stones Positive Parenting Program (Stepping Stones Triple P; SSTP) was designed for caregivers of children with disabilities to improve select parental variables such as parenting styles, parental satisfaction, and parental competency, and to reduce parental stress and child problem behaviors. This study focused on SSTP training for…

Stress Reduction at the Work-Family Interface: Positive Parenting and Self-Efficacy as Mechanisms of Change in Workplace Triple P

ERIC Educational Resources Information Center

Hartung, Doreen; Hahlweg, Kurt

2011-01-01

Workplace Triple P (WPTP) is a group-based parenting skills training specifically designed to meet the needs of employed parents. Several randomized controlled trials have demonstrated the training's efficacy. This study examined possible mechanisms of change that account for the stress reduction effects of this parenting skills training at the…

Geometric Construction of Pythagorean Triangles

ERIC Educational Resources Information Center

Chandrupatla, Tirupathi R.; Osler, Thomas J.

2004-01-01

A right triangle with legs x and y and hypotenuse z in which x, y and z are all positive integers is called a Pythagorean triangle (PT) and the triple denoted by [x,y,z] is a Pythagorean triple. If x, y and z are all relatively prime (gcd is 1), then the triangle is called a primitive Pythagorean triangle (PPT) and the tripe a primitive…

Does adding an emotion component enhance the Triple P-Positive Parenting Program?

PubMed

Salmon, Karen; Dittman, Cassandra; Sanders, Matthew; Burson, Rebecca; Hammington, Josie

2014-04-01

This pilot study aimed to compare the efficacy of a regular offering of the group-delivered Triple P-Positive Parenting Program for child behavior problems with an enhanced version tailored to promote child emotion competence. Families of children between ages 3 and 6 years displaying early-onset conduct problems were randomly assigned to Group Triple P (GTP; final n = 18) or Emotion Enhanced Triple P (EETP; final n = 18), in which parents were encouraged to incorporate emotion labels and causes and to coach emotion competence during discussions of everyday emotional experiences with their child. Compared with parents who received GTP, parents who received EETP increased their discussion of emotion labels and emotion causes in conversations with their child at postintervention, but this advantage was lost by the 4-month follow-up. Parents in the EETP condition also used more emotion coaching postintervention and at follow-up. There were no differences at postintervention or follow-up in children's emotion knowledge skills. Postintervention improvement in disruptive child behavior was greater for GTP, but the groups converged at follow-up. Parents were similarly satisfied with both interventions. Overall, EETP showed little advantage over regular GTP delivery. PsycINFO Database Record (c) 2014 APA, all rights reserved.

Cycle simulation of the low-temperature triple-effect absorption chiller with vapor compression unit

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, J.S.; Lee, H.

1999-07-01

The construction of a triple-effect absorption chiller machine using the lithium bromide-water solution as a working fluid is strongly limited by corrosion problems caused by the high generator temperature. In this work, three new cycles having the additional vapor compression units were suggested in order to lower the generator temperature of a triple-effect absorption chiller. Each new cycle has one compressor located at the different position which was used to elevate the pressure of the refrigerant vapor. Computer simulations were carried out in order to examine both the basic triple-effect cycle and three new cycles. All types of triple-effect absorptionmore » chiller cycles were found to be able to lower the temperature of high-temperature generator to the more favorable operation range. The COPs of three cycles calculated by considering the additional compressor works showed a small level of decrease or increase compared with that of the basic triple-effect cycle. Consequently, a low-temperature triple-effect absorption chiller can be possibly constructed by adapting one of three new cycles. A great advantage of these new cycles over the basic one is that the conventionally used lithium bromide-water solution can be successfully used as a working fluid without the danger of corrosion.« less

Hydroxyproline Ring Pucker Causes Frustration of Helix Parameters in the Collagen Triple Helix

NASA Astrophysics Data System (ADS)

Ying Chow, W.; Bihan, Dominique; Forman, Chris J.; Slatter, David A.; Reid, David G.; Wales, David J.; Farndale, Richard W.; Duer, Melinda J.

2015-07-01

Collagens, the most abundant proteins in mammals, are defined by their triple-helical structures and distinctive Gly-Xaa-Yaa repeating sequence, where Xaa is often proline and Yaa, hydroxyproline (Hyp/O). It is known that hydroxyproline in the Yaa position stabilises the triple helix, and that lack of proline hydroxylation in vivo leads to dysfunctional collagen extracellular matrix assembly, due to a range of factors such as a change in hydration properties. In addition, we note that in model peptides, when Yaa is unmodified proline, the Xaa proline has a strong propensity to adopt an endo ring conformation, whilst when Yaa is hydroxyproline, the Xaa proline adopts a range of endo and exo conformations. Here we use a combination of solid-state NMR spectroscopy and potential energy landscape modelling of synthetic triple-helical collagen peptides to understand this effect. We show that hydroxylation of the Yaa proline causes the Xaa proline ring conformation to become metastable, which in turn confers flexibility on the triple helix.

Hydroxyproline Ring Pucker Causes Frustration of Helix Parameters in the Collagen Triple Helix

PubMed Central

Ying Chow, W.; Bihan, Dominique; Forman, Chris J.; Slatter, David A.; Reid, David G.; Wales, David J.; Farndale, Richard W.; Duer, Melinda J.

2015-01-01

Collagens, the most abundant proteins in mammals, are defined by their triple-helical structures and distinctive Gly-Xaa-Yaa repeating sequence, where Xaa is often proline and Yaa, hydroxyproline (Hyp/O). It is known that hydroxyproline in the Yaa position stabilises the triple helix, and that lack of proline hydroxylation in vivo leads to dysfunctional collagen extracellular matrix assembly, due to a range of factors such as a change in hydration properties. In addition, we note that in model peptides, when Yaa is unmodified proline, the Xaa proline has a strong propensity to adopt an endo ring conformation, whilst when Yaa is hydroxyproline, the Xaa proline adopts a range of endo and exo conformations. Here we use a combination of solid-state NMR spectroscopy and potential energy landscape modelling of synthetic triple-helical collagen peptides to understand this effect. We show that hydroxylation of the Yaa proline causes the Xaa proline ring conformation to become metastable, which in turn confers flexibility on the triple helix. PMID:26220399

Preemptive Use of Naproxen on Tooth Sensitivity Caused by In-Office Bleaching: A Triple-Blind, Crossover, Randomized Clinical Trial.

PubMed

Fernandes, M T; Vaez, S C; Lima, C M; Nahsan, F P; Loguércio, A D; Faria-E-Silva, A L

A triple-blind, randomized, crossover clinical trial evaluated prior use of nonsteroidal anti-inflammatory naproxen on sensitivity reported by patients undergoing in-office tooth bleaching. Fifty patients were subjected to two sessions of in-office tooth bleaching with 35% hydrogen peroxide in a single application of 40 minutes for two sessions, with an interval of seven days between applications. One hour prior to the procedure, each patient randomly received a single dose of naproxen (500 mg) or placebo. The patient's sensitivity level was evaluated during and immediately after the bleaching using two scales (verbal and visual analog); the verbal scale only was repeated after 24 hours. The effectiveness of the bleaching procedures was evaluated with the Bleachedguide scale. Relative risk to sensitivity was calculated and adjusted by session, while comparison of overall risk was performed by the McNemar test. Data on the sensitivity level for both scales and shade were subjected to the Friedman, Wilcoxon, and Mann-Whitney tests (α=0.05). The use of naproxen only decreased the absolute risk and intensity of tooth sensitivity reported immediately after the second session. On the other hand, no measurable effect was observed during or 24 hours after either session. The sequence of drug administration did not affect the bleaching effectiveness. Preemptive use of naproxen only reduced tooth sensitivity reported by patients immediately after the second session of bleaching.

53BP1 depletion causes PARP inhibitor resistance in ATM-deficient breast cancer cells.

PubMed

Hong, Ruoxi; Ma, Fei; Zhang, Weimin; Yu, Xiying; Li, Qing; Luo, Yang; Zhu, Changjun; Jiang, Wei; Xu, Binghe

2016-09-09

Mutations in DNA damage response factors BRCA1 and BRCA2 confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors in breast and ovarian cancers. BRCA1/BRCA2-defective tumors can exhibit resistance to PARP inhibitors via multiple mechanisms, one of which involves loss of 53BP1. Deficiency in the DNA damage response factor ataxia-telangiectasia mutated (ATM) can also sensitize tumors to PARP inhibitors, raising the question of whether the presence or absence of 53BP1 can predict sensitivity of ATM-deficient breast cancer to these inhibitors. Cytotoxicity of PARP inhibitor and ATM inhibitor in breast cancer cell lines was assessed by MTS, colony formation and apoptosis assays. ShRNA lentiviral vectors were used to knockdown 53BP1 expression in breast cancer cell lines. Phospho-ATM and 53BP1 protein expressions were determined in human breast cancer tissues by immunohistochemistry (IHC). We show that inhibiting ATM increased cytotoxicity of PARP inhibitor in triple-negative and non-triple-negative breast cancer cell lines, and depleting the cells of 53BP1 reduced this cytotoxicity. Inhibiting ATM abrogated homologous recombination induced by PARP inhibitor, and down-regulating 53BP1 partially reversed this effect. Further, overall survival was significantly better in triple-negative breast cancer patients with lower levels of phospho-ATM and tended to be better in patients with negative 53BP1. These results suggest that 53BP1 may be a predictor of PARP inhibitor resistance in patients with ATM-deficient tumors.

Next-generation sequencing of circulating tumor DNA to predict recurrence in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy.

PubMed

Chen, Yu-Hsiang; Hancock, Bradley A; Solzak, Jeffrey P; Brinza, Dumitru; Scafe, Charles; Miller, Kathy D; Radovich, Milan

2017-01-01

Next-generation sequencing to detect circulating tumor DNA is a minimally invasive method for tumor genotyping and monitoring therapeutic response. The majority of studies have focused on detecting circulating tumor DNA from patients with metastatic disease. Herein, we tested whether circulating tumor DNA could be used as a biomarker to predict relapse in triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy. In this study, we analyzed samples from 38 early-stage triple-negative breast cancer patients with matched tumor, blood, and plasma. Extracted DNA underwent library preparation and amplification using the Oncomine Research Panel consisting of 134 cancer genes, followed by high-coverage sequencing and bioinformatics. We detected high-quality somatic mutations from primary tumors in 33 of 38 patients. TP53 mutations were the most prevalent (82%) followed by PIK3CA (16%). Of the 33 patients who had a mutation identified in their primary tumor, we were able to detect circulating tumor DNA mutations in the plasma of four patients (three TP53 mutations, one AKT1 mutation, one CDKN2A mutation). All four patients had recurrence of their disease (100% specificity), but sensitivity was limited to detecting only 4 of 13 patients who clinically relapsed (31% sensitivity). Notably, all four patients had a rapid recurrence (0.3, 4.0, 5.3, and 8.9 months). Patients with detectable circulating tumor DNA had an inferior disease free survival ( p  < 0.0001; median disease-free survival: 4.6 mos. vs. not reached; hazard ratio = 12.6, 95% confidence interval: 3.06-52.2). Our study shows that next-generation circulating tumor DNA sequencing of triple-negative breast cancer patients with residual disease after neoadjuvant chemotherapy can predict recurrence with high specificity, but moderate sensitivity. For those patients where circulating tumor DNA is detected, recurrence is rapid.

The "3 in 1" Study: Pooling Self-Taken Pharyngeal, Urethral, and Rectal Samples into a Single Sample for Analysis for Detection of Neisseria gonorrhoeae and Chlamydia trachomatis in Men Who Have Sex with Men.

PubMed

Sultan, B; White, J A; Fish, R; Carrick, G; Brima, N; Copas, A; Robinson, A; Gilson, R; Mercey, D; Benn, P

2016-03-01

Triple-site testing (using pharyngeal, rectal, and urethral/first-void urine samples) for Neisseria gonorrhoeae and Chlamydia trachomatis using nucleic acid amplification tests detects greater numbers of infections among men who have sex with men (MSM). However, triple-site testing represents a cost pressure for services. MSM over 18 years of age were eligible if they requested testing for sexually transmitted infections (STIs), reported recent sexual contact with either C. trachomatis or N. gonorrhoeae, or had symptoms of an STI. Each patient underwent standard-of-care (SOC) triple-site testing, and swabs were taken to form a pooled sample (PS) (pharyngeal, rectal, and urine specimens). The PS was created using two methods during different periods at one clinic, but we analyzed the data in combination because the sensitivity of the two methods did not differ significantly for C. trachomatis (P = 0.774) or N. gonorrhoeae (P = 0.163). The sensitivity of PS testing (92%) was slightly lower than that of SOC testing (96%) for detecting C. trachomatis (P = 0.167). For N. gonorrhoeae, the sensitivity of PS testing (90%) was significantly lower than that of SOC testing (99%) (P < 0.001). When pharynx-only infections were excluded, the sensitivity of PS testing to detect N. gonorrhoeae infections increased to 94%. Our findings show that pooling of self-taken samples could be an effective and cost-saving method, with high negative predictive values. (Interim results of this study were presented at the BASHH 2013 summer meeting.). Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Pannus Formation Leads to Valve Malfunction in the Tricuspid Position 19 Years after Triple Valve Replacement.

PubMed

Alskaf, Ebraham; McConkey, Hannah; Laskar, Nabila; Kardos, Attila

2016-06-20

The Medtronic ATS Open Pivot mechanical valve has been successfully used in heart valve surgery for more than two decades. We present the case of a patient who, 19 years following a tricuspid valve replacement with an ATS prosthesis as part of a triple valve operation following infective endocarditis, developed severe tricuspid regurgitation due to pannus formation.

Cisplatin plus gemcitabine for treatment of breast cancer patients with brain metastases; a preferential option for triple negative patients?

PubMed

Erten, Cigdem; Demir, Lutfiye; Somali, Isil; Alacacioglu, Ahmet; Kucukzeybek, Yuksel; Akyol, Murat; Can, Alper; Dirican, Ahmet; Bayoglu, Vedat; Tarhan, Mustafa Oktay

2013-01-01

To assess the efficacy and tolerability of Cisplatin plus Gemcitabine combination in patients with brain metastases (BM) from breast cancer (BC). Eighteen BC patients with BM who were treated with Cisplatin plus Gemcitabine regimen between 2003-2011 were evaluated. A median of 6 cycles of this regimen were received, in fifteen patients (83.3%) as first-line chemotherapy, in 2 as second- line and in 1 as third-line after diagnosis of BM. Dose reduction was performed in 11 (61.1%) patients; major reasons were neutropenia and leukopenia. Grade III neutropenia and Grade II trombocytopenia rates were 33.3% and 16.7% respectively. Overall response rate (ORR; complete+partial response rate) was 33.4% (n=6) for the entire study population; triple negative patients achieved an 66.6% ORR while hormone receptor (HR) positive patients had 25% and HER2 positive patients 12.5%. Median progression-free survival was 5.6 months (2.4-8.8 months, 95%CI) and longer in patients with triple negative breast cancer (TNBC) (median 7.4 months, 95%CI, 2.4-12.3 months) than the patients with other subtypes (median 5 months for HER2 positive and 3.6 months for HR positive patients). Median PFS of the patients with TNBC who received this regimen as first-line was 9.2 months (5.2-13.2 months, 95%CI). Cisplatin plus Gemcitabine may be a treatment option for patients with BM from breast cancer. Longer PFS and higher response rates are results that support the usage of this regimen especially for the triple negative subtype. However, further prospective and randomized trials are clearly required to provide more exact information.

Triple Quenching of a Novel Self-Enhanced Ru(II) Complex by Hemin/G-Quadruplex DNAzymes and Its Potential Application to Quantitative Protein Detection.

PubMed

Zhao, Min; Liao, Ni; Zhuo, Ying; Chai, Ya-Qin; Wang, Ji-Peng; Yuan, Ruo

2015-08-04

Herein, a novel "on-off" electrochemiluminescence (ECL) aptasensor for highly sensitive determination of thrombin has been constructed based on the triple quenching of the effect of hemin/G-quadruplex DNAzymes upon the Ru(II) complex-based ECL system. First, a strong initial ECL signal was achieved by the dual amplification strategies of (i) intramolecular coreaction of a self-enhanced Ru(II)-based molecule (PTCA-PEI-Ru(II)) and (ii) intermolecular coreaction between PTCA-PEI-Ru(II) and nicotinamide adenine dinucleotide (NADH), which was named the signal-on state. Then, a novel triple quenching of the effect of multifunctional hemin/G-quadruplex DNAzymes upon the Ru(II) complex-based ECL system was designed to realize the desirable signal-off state, which was outlined as follows: (i) the hemin/G-quadruplex DNAzymes mimicked NADH oxidase to oxidize NADH and in situ generate the H2O2, consuming the coreactant of NADH; (ii) its active center of hemin could oxidize the excited state PTCA-PEI-Ru(II)* to PTCA-PEI-Ru(III), making the energy and electron transfer quench; (iii) it also acted as horseradish peroxidase (HRP) to catalyze the H2O2 for in situ producing the quencher of O2. Based on triple quenching of the effect of hemin/G-quadruplex DNAzymes, the highly sensitive "on-off" thrombin aptasensor was developed with a wide linear detection range of 1.0 × 10(-14) M to 1.0 × 10(-10) M and a detection limit down to the femtomolar level.

Co-targeting the HER and IGF/insulin receptor axis in breast cancer, with triple targeting with endocrine therapy for hormone-sensitive disease.

PubMed

Chakraborty, Ashok; Hatzis, Christos; DiGiovanna, Michael P

2017-05-01

Interactions between HER2, estrogen receptor (ER), and insulin-like growth factor I receptor (IGF1R) are implicated in resistance to monotherapies targeting these receptors. We have previously shown in pre-clinical studies synergistic anti-tumor effects for co-targeting each pairwise combination of HER2, IGF1R, and ER. Strikingly, synergy for HER2/IGF1R targeting occurred not only in a HER2+ model, but also in a HER2-normal model. The purpose of the current study was therefore to determine the generalizability of synergistic anti-tumor effects of co-targeting HER2/IGF1R, the anti-tumor activity of triple-targeting HER2/IGF1R/ER in hormone-dependent cell lines, and the effect of using the multi-targeting drugs neratinib (pan-HER) and BMS-754807 (dual IGF1R/insulin receptor). Proliferation and apoptosis assays were performed in a large panel of cell lines representing varying receptor expression levels. Mechanistic effects were studied using phospho-protein immunoblotting. Analyses of drug interaction effects were performed using linear mixed-effects regression models. Enhanced anti-proliferative effects of HER/IGF-insulin co-targeting were seen in most, though not all, cell lines, including HER2-normal lines. For ER+ lines, triple targeting with inclusion of anti-estrogen generally resulted in the greatest anti-tumor effects. Double or triple targeting generally resulted in marked increases in apoptosis in the sensitive lines. Mechanistic studies demonstrated that the synergy between drugs was correlated with maximal inhibition of Akt and ERK pathway signaling. Dual HER/IGF-insulin targeting, and triple targeting with inclusion of anti-estrogen drugs, shows striking anti-tumor activity across breast cancer types, and drugs with broader receptor specificity may be more effective than single receptor selective drugs, particularly for ER- cells.

Facility Overview and Double-Focusing Thermal Triple-Axis Spectrometer at the NCNR

NASA Astrophysics Data System (ADS)

Lynn, Jeffrey

2012-02-01

We will briefly overview the neutron scattering instrumentation at the NCNR, but will focus the talk on the capabilities of the new thermal triple-axis spectrometer is located at the BT-7 beam port [1]. This spectrometer takes full advantage of the large 165 mm diameter reactor beam to tailor the dual 20x20 cm^2 double-focusing monochromator system to provide monochromatic fluxes exceeding 10^8 n/cm^2/s onto the sample. The two monochromators installed are PG(002) and Cu(220), which provide incident energies for 5 meV to above 500 meV. The computer controlled analyzer system offers six standard modes of operation, including a diffraction detector, a position-sensitive detector (PSD) in diffraction mode, horizontal energy focusing analyzer with detector, a Q-E mode employing a flat analyzer and PSD, a constant-E mode with the analyzer crystal system and PSD, and a conventional mode with a selection of S"oller collimators and detector. Additional configurations for specific measurement needs are also available. The capabilities and performance will be discussed and examples of published data presented. [4pt] [1] J. W. Lynn, Y. Chen, S. Chang, Y. Zhao, S. Chi, W. Ratcliff, II, B. G. Ueland, and R. W. Erwin, J. Research NIST 117 (in press).

A GEM readout with radial zigzag strips and linear charge-sharing response

DOE PAGES

Zhang, Aiwu; Hohlmann, Marcus; Azmoun, Babak; ...

2018-01-10

Here, we study the position sensitivity of radial zigzag strips intended to read out large GEM detectors for tracking at future experiments. Zigzag strips can cover a readout area with fewer strips than regular straight strips while maintaining good spatial resolution. Consequently, they can reduce the number of required electronic channels and related cost for large-area GEM detector systems. A non-linear relation between incident particle position and hit position measured from charge sharing among zigzag strips was observed in a previous study. We significantly reduce this non-linearity by improving the interleaving of adjacent physical zigzag strips. Zigzag readout structures aremore » implemented on PCBs and on a flexible foil and are tested using a 10 cm × 10 cm triple-GEM detector scanned with a strongly collimated X-ray gun on a 2D motorized stage. Lastly, angular resolutions of 60–84 μrad are achieved with a 1.37 mrad angular strip pitch at a radius of 784 mm. On a linear scale this corresponds to resolutions below 100 μm.« less

A GEM readout with radial zigzag strips and linear charge-sharing response

NASA Astrophysics Data System (ADS)

Zhang, Aiwu; Hohlmann, Marcus; Azmoun, Babak; Purschke, Martin L.; Woody, Craig

2018-04-01

We study the position sensitivity of radial zigzag strips intended to read out large GEM detectors for tracking at future experiments. Zigzag strips can cover a readout area with fewer strips than regular straight strips while maintaining good spatial resolution. Consequently, they can reduce the number of required electronic channels and related cost for large-area GEM detector systems. A non-linear relation between incident particle position and hit position measured from charge sharing among zigzag strips was observed in a previous study. We significantly reduce this non-linearity by improving the interleaving of adjacent physical zigzag strips. Zigzag readout structures are implemented on PCBs and on a flexible foil and are tested using a 10 cm × 10 cm triple-GEM detector scanned with a strongly collimated X-ray gun on a 2D motorized stage. Angular resolutions of 60-84 μrad are achieved with a 1.37 mrad angular strip pitch at a radius of 784 mm. On a linear scale this corresponds to resolutions below 100 μm.

Evaluation of rapid diagnostic test kits for feline leukemia virus infection using samples from naturally infected cats.

PubMed

Liu, Jiayou; O'Connor, Thomas; Beall, Melissa; Chandrashekar, Ramaswamy; Lappin, Michael

2016-01-01

Feline leukemia virus (FeLV) is a potentially life-threatening oncogenic retrovirus. The p27 viral core protein is produced by the virus in infected feline cells, is found in the cytoplasm in several blood cells and can be free in the serum and plasma. ELISA or particle-based immunoassay are commonly used to detect the presence of the p27 core protein in samples obtained from blood. The objective of this study was to compare the performance of several in-clinic tests: the SNAP Feline Triple Test (IDEXX Laboratories), the WITNESS FeLV-FIV Test (Zoetis) and the VetScan Feline FeLV/FIV Rapid Test (Abaxis). The sample population (100 positive, 105 negative samples) consisted of serum and plasma samples submitted to IDEXX's worldwide reference laboratory for feline retrovirus testing. Virus isolation and reverse transcriptase PCR results were not available and so samples were judged to be positive or negative based on the results of the ViraCHEK FeLV (Zoetis) microtiter plate assay. The percentage of samples positive and negative for FeLV p27 antigen using the three in-clinic tests compared with the ViraCHEK method were as follows: IDEXX Feline Triple (positive 98.0%, negative 100%); Zoetis WITNESS (positive 79.0%, negative 97.1%); Abaxis VetScan (positive 73.0%, negative 97.1%). The SNAP Feline Triple Test demonstrated a high level of agreement for FeLV-positive and FeLV-negative samples when assessed in this model. Results of FeLV assays can vary among tests.

Rational Design of Multilayer Collagen Nanosheets with Compositional and Structural Control.

PubMed

Jiang, Tao; Vail, Owen A; Jiang, Zhigang; Zuo, Xiaobing; Conticello, Vincent P

2015-06-24

Two collagen-mimetic peptides, CP(+) and CP(-), are reported in which the sequences comprise a multiblock architecture having positively charged N-terminal (Pro-Arg-Gly)3 and negatively charged C-terminal (Glu-Hyp-Gly)3 triad extensions, respectively. CP(+) rapidly self-associates into positively charged nanosheets based on a monolayer structure. In contrast, CP(-) self-assembles to form negatively charged monolayer nanosheets at a much slower rate, which can be accelerated in the presence of calcium(II) ion. A 2:1 mixture of unassociated CP(-) peptide with preformed CP(+) nanosheets generates structurally defined triple-layer nanosheets in which two CP(-) monolayers have formed on the identical surfaces of the CP(+) nanosheet template. Experimental data from electrostatic force microscopy (EFM) image analysis, zeta potential measurements, and charged nanoparticle binding assays support a negative surface charge state for the triple-layer nanosheets, which is the reverse of the positive surface charge state observed for the CP(+) monolayer nanosheets. The electrostatic complementarity between the CP(+) and CP(-) triple helical cohesive ends at the layer interfaces promotes a (CP(-)/CP(+)/CP(-)) compositional gradient along the z-direction of the nanosheet. This structurally informed approach represents an attractive strategy for the fabrication of two-dimensional nanostructures with compositional control.

Pilot Scale Production and Testing of a Recombinant Staphylococcal Enterotoxin (SEB) Triple Mutant

DTIC Science & Technology

2017-09-01

1 PILOT-SCALE PRODUCTION AND TESTING OF A RECOMBINANT STAPHYLOCOCCAL ENTEROTOXIN (SEB) TRIPLE MUTANT ECBC...Disclaimer The findings in this report are not to be construed as an official Department of the Army position unless so designated by other authorizing...TYPE Final 3. DATES COVERED (From - To) Mar 2010 – Dec 2011 4. TITLE AND SUBTITLE Pilot-Scale Production and Testing of a Recombinant

Modifying the 'Positive Parenting Program' for parents with intellectual disabilities.

PubMed

Glazemakers, I; Deboutte, D

2013-07-01

Many parents with intellectual disabilities (ID) want and/or need professional guidance and support to learn skills and strategies to prevent and manage child behaviour problems. However, the available support is rarely suitable, and suitable support is rarely available. The aim of this study was to determine whether a popular mainstream parenting training programme, known as 'Group Triple P' (Positive Parenting Program), could be successfully modified for this parent group. A pilot study was undertaken to determine whether a modified version of Group Triple P would engage and retain parents with ID. A non-experimental, pre-test post-test study, involving a total of 30 parents with ID, was then undertaken to obtain preliminary efficacy data. Parent engagement and participation levels were high. No parent 'dropped out' of the programme. After completing the modified Group Triple P programme, parents reported a decrease in psychological distress, maladaptive parenting and child conduct problems. Parents reported high levels of satisfaction with the information and support they received. Research-informed adaptation of mainstream behavioural family interventions, such as Group Triple P, could make 'suitable support' more readily available, and more engaging for parents with ID. © 2012 The Authors. Journal of Intellectual Disability Research © 2012 John Wiley & Sons Ltd, MENCAP & IASSID.

Prospective audit of a one-centre combined nuchal translucency and triple test programme for the detection of trisomy 21.

PubMed

Babbur, Vijayalakshmi; Lees, Christoph C; Goodburn, Sandra F; Morris, Nigel; Breeze, Andrew C G; Hackett, Gerald A

2005-06-01

To determine detection and false-positive rates for trisomy 21 using two-stage combined nuchal translucency (NT) and triple testing, whilst disclosing abnormal nuchal measurements at the scan. A prospective audit in a UK women's hospital, of 3188 women with singleton pregnancies, requesting screening for trisomy 21. Median age was 37 years (range 19-46). Women were offered NT screening at 11 to 14 weeks. Those with NT > or =3 mm were offered chorionic villus sampling. Those declining CVS, and those with NT <3 mm, were offered early triple tests. Women with a term combined risk of trisomy 21 > or = 1:250, based on age, NT, and triple test results were offered amniocentesis. Using a 3-mm NT 'cut-off' identified 16/25 cases of trisomy 21 (64%; 95% CI 38.8, 78.9). Of 2725 women who had a combined nuchal plus triple test assessment, 79 (2.6%) had a > or = 1:250 term risk of trisomy 21. Forty (1.3%) had amniocentesis identifying 6/9 remaining cases (67%:95% CI:27.9, 92.5). Overall, the detection rate was 88% (95% CI:68.8, 97.5) for a 4.8% FPR. For the screened population, to achieve an 88% detection rate using the triple test alone, the predicted FPR would be 20%. Conversely, for an FPR of 4.8% using the triple test alone, the detection rate would be only 60%. In a high-risk group, the combination of NT with triple test offers detection of trisomy 21 at least equivalent to either test, while allowing disclosure of an abnormal NT at the scan and reducing the FPR. Importantly, the FPR is less than 5%, considerably lower than expected for triple test alone for this population.

Modeling and Assessment of Precise Time Transfer by Using BeiDou Navigation Satellite System Triple-Frequency Signals.

PubMed

Tu, Rui; Zhang, Pengfei; Zhang, Rui; Liu, Jinhai; Lu, Xiaochun

2018-03-29

This study proposes two models for precise time transfer using the BeiDou Navigation Satellite System triple-frequency signals: ionosphere-free (IF) combined precise point positioning (PPP) model with two dual-frequency combinations (IF-PPP1) and ionosphere-free combined PPP model with a single triple-frequency combination (IF-PPP2). A dataset with a short baseline (with a common external time frequency) and a long baseline are used for performance assessments. The results show that IF-PPP1 and IF-PPP2 models can both be used for precise time transfer using BeiDou Navigation Satellite System (BDS) triple-frequency signals, and the accuracy and stability of time transfer is the same in both cases, except for a constant system bias caused by the hardware delay of different frequencies, which can be removed by the parameter estimation and prediction with long time datasets or by a priori calibration.

Development of a single-photon-counting camera with use of a triple-stacked micro-channel plate.

PubMed

Yasuda, Naruomi; Suzuki, Hitoshi; Katafuchi, Tetsuro

2016-01-01

At the quantum-mechanical level, all substances (not merely electromagnetic waves such as light and X-rays) exhibit wave–particle duality. Whereas students of radiation science can easily understand the wave nature of electromagnetic waves, the particle (photon) nature may elude them. Therefore, to assist students in understanding the wave–particle duality of electromagnetic waves, we have developed a photon-counting camera that captures single photons in two-dimensional images. As an image intensifier, this camera has a triple-stacked micro-channel plate (MCP) with an amplification factor of 10(6). The ultra-low light of a single photon entering the camera is first converted to an electron through the photoelectric effect on the photocathode. The electron is intensified by the triple-stacked MCP and then converted to a visible light distribution, which is measured by a high-sensitivity complementary metal oxide semiconductor image sensor. Because it detects individual photons, the photon-counting camera is expected to provide students with a complete understanding of the particle nature of electromagnetic waves. Moreover, it measures ultra-weak light that cannot be detected by ordinary low-sensitivity cameras. Therefore, it is suitable for experimental research on scintillator luminescence, biophoton detection, and similar topics.

Fabrication of triple-labeled polyelectrolyte microcapsules for localized ratiometric pH sensing.

PubMed

Song, Xiaoxue; Li, Huanbin; Tong, Weijun; Gao, Changyou

2014-02-15

Encapsulation of pH sensitive fluorophores as reporting molecules provides a powerful approach to visualize the transportation of multilayer capsules. In this study, two pH sensitive dyes (fluorescein and oregon green) and one pH insensitive dye (rhodamine B) were simultaneously labeled on the microcapsules to fabricate ratiometric pH sensors. The fluorescence of the triple-labeled microcapsule sensors was robust and nearly independent of other intracellular species. With a dynamic pH measurement range of 3.3-6.5, the microcapsules can report their localized pH at a real time. Cell culture experiments showed that the microcapsules could be internalized by RAW 246.7 cells naturally and finally accumulated in acidic organelles with a pH value of 5.08 ± 0.59 (mean ± s.d.; n=162). Copyright © 2013 Elsevier Inc. All rights reserved.

Chest wall leiomyosarcoma after breast-conservative therapy for early-stage breast cancer in a young woman with Li-Fraumeni syndrome.

PubMed

Henry, Eve; Villalobos, Victor; Million, Lynn; Jensen, Kristin C; West, Robert; Ganjoo, Kristen; Lebensohn, Alexandra; Ford, James M; Telli, Melinda L

2012-08-01

Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor-positive/progesterone receptor-positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Catoire, F.; Staicu-Casagrande, E. M.; Lahmam-Bennani, A.

We describe new developments aimed to extend the capabilities and the sensitivity of the (e,2e)/(e,3e) multicoincidence spectrometer at Orsay University [Duguet et al., Rev. Sci. Instrum. 69, 3524 (1998)]. The spectrometer has been improved by the addition of a third multiangle detection channel for the fast ''scattered'' electron. The present system is unique in that it is the only system which combines three toroidal analyzers all equipped with position sensitive detectors, thus allowing the triple coincidence detection of the three electrons present in the final state of an electron impact double ionization process. The setup allows measurement of the angularmore » and energy distributions of the ejected electrons over almost the totality of the collision plane as well as that of the scattered electron over a large range of scattering angles in the forward direction. The resulting gain in sensitivity ({approx}25) has rendered feasible a whole class of experiments which could not be otherwise envisaged. The setup is described with a special emphasis on the new toroidal analyzer, data acquisition hardware, and data analysis procedures. The performances are illustrated by selected results of (e,2e) and (e,3e) experiments on the rare gases.« less

Pedagogical alternatives for triple integrals: moving towards more inclusive and personalized learning

NASA Astrophysics Data System (ADS)

Tisdell, Christopher C.

2018-07-01

This paper is based on the presumption that teaching multiple ways to solve the same problem has academic and social value. In particular, we argue that such a multifaceted approach to pedagogy moves towards an environment of more inclusive and personalized learning. From a mathematics education perspective, our discussion is framed around pedagogical approaches to triple integrals seen in a standard multivariable calculus curriculum. We present some critical perspectives regarding the dominant and long-standing approach to the teaching of triple integrals currently seen in hegemonic calculus textbooks; and we illustrate the need for more diverse pedagogical methods. Finally, we take a constructive position by introducing a new and alternate pedagogical approach to solve some of the classical problems involving triple integrals from the literature through a simple application of integration by parts. This pedagogical alternative for triple integrals is designed to question the dominant one-size-fits-all approach of rearranging the order of integration and the privileging of graphical methods; and to enable a shift towards a more inclusive, enhanced and personalized learning experience.

Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer

PubMed Central

Uchibori, Ken; Inase, Naohiko; Araki, Mitsugu; Kamada, Mayumi; Sato, Shigeo; Okuno, Yasushi; Fujita, Naoya; Katayama, Ryohei

2017-01-01

Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR–tyrosine kinase inhibitors (EGFR–TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR–TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure–activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR. PMID:28287083

Brigatinib combined with anti-EGFR antibody overcomes osimertinib resistance in EGFR-mutated non-small-cell lung cancer

NASA Astrophysics Data System (ADS)

Uchibori, Ken; Inase, Naohiko; Araki, Mitsugu; Kamada, Mayumi; Sato, Shigeo; Okuno, Yasushi; Fujita, Naoya; Katayama, Ryohei

2017-03-01

Osimertinib has been demonstrated to overcome the epidermal growth factor receptor (EGFR)-T790M, the most relevant acquired resistance to first-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs). However, the C797S mutation, which impairs the covalent binding between the cysteine residue at position 797 of EGFR and osimertinib, induces resistance to osimertinib. Currently, there are no effective therapeutic strategies to overcome the C797S/T790M/activating-mutation (triple-mutation)-mediated EGFR-TKI resistance. In the present study, we identify brigatinib to be effective against triple-mutation-harbouring cells in vitro and in vivo. Our original computational simulation demonstrates that brigatinib fits into the ATP-binding pocket of triple-mutant EGFR. The structure-activity relationship analysis reveals the key component in brigatinib to inhibit the triple-mutant EGFR. The efficacy of brigatinib is enhanced markedly by combination with anti-EGFR antibody because of the decrease of surface and total EGFR expression. Thus, the combination therapy of brigatinib with anti-EGFR antibody is a powerful candidate to overcome triple-mutant EGFR.

The Structural Basis for Matrix Metalloproteinase 1 Catalyzed Collagenolysis

PubMed Central

Bertini, Ivano; Fragai, Marco; Luchinat, Claudio; Melikian, Maxime; Toccafondi, Mirco; Lauer, Janelle L.; Fields, Gregg B.

2012-01-01

The proteolysis of collagen triple-helical structure (collagenolysis) is a poorly understood yet critical physiological process. Presently, matrix metalloproteinase 1 (MMP-1) and collagen triple-helical peptide models have been utilized to characterize the events and calculate the energetics of collagenolysis via NMR spectroscopic analysis of 12 enzyme-substrate complexes. The triple-helix is bound initially by the MMP-1 hemopexin-like (HPX) domain via a four amino acid stretch (analogous to type I collagen residues 782–785). The triple-helix is then presented to the MMP-1 catalytic (CAT) domain in a distinct orientation. The HPX and CAT domains are rotated with respect to one another compared with the X-ray “closed” conformation of MMP-1. Back-rotation of the CAT and HPX domains to the X-ray closed conformation releases one chain out of the triple-helix, and this chain is properly positioned in the CAT domain active site for subsequent hydrolysis. The aforementioned steps provide a detailed, experimentally-derived, and energetically favorable collagenolytic mechanism, as well as significant insight into the roles of distinct domains in extracellular protease function. PMID:22239621

Initiation of Detonation in Multiple Shock-Compressed Liquid Explosives

NASA Astrophysics Data System (ADS)

Yoshinaka, A. C.; Zhang, F.; Petel, O. E.; Higgins, A. J.

2006-07-01

Initiation and resulting propagation of detonation via multiple shock reverberations between two high impedance plates has been investigated in amine-sensitized nitromethane. Experiments were designed so that the first reflected shock strength was below the critical value for initiation found previously. Luminosity combined with a distinct pressure hump indicated onset of reaction and successful initiation after double or triple shock reflection off the bottom plate. Final temperature estimates for double or triple shock reflection immediately before initiation lie between 700-720 K, consistent with those found previously for both incident and singly reflected shock initiation.

Laser photolysis studies of ω-bond dissociation in aromatic carbonyls with a C-C triple bond stimulated by triplet sensitization.

PubMed

Yamaji, Minoru; Horimoto, Ami; Marciniak, Bronislaw

2017-07-14

We have prepared three types of carbonyl compounds, benzoylethynylmethyl phenyl sulfide (2@SPh), (p-benzoyl)phenylethynylmethyl phenyl sulfide (3@SPh) and p-(benzoylethynyl)benzyl phenyl sulfide (4@SPh) with benzoyl and phenylthiylmethyl groups, which are interconnected with a C-C triple bond and a phenyl ring. Laser flash photolysis of 3@SPh and 4@SPh in acetonitrile provided the transient absorption spectra of the corresponding triplet states where no chemical reactions were recognized. Upon laser flash photolysis of 2@SPh, the absorption band due to the phenylthiyl radical (PTR) was obtained, indicating that the C-S bond cleaved in the excited state. Triplet sensitization of these carbonyl compounds using acetone and xanthone was conducted using laser photolysis techniques. The formation of triplet 3@SPh was seen in the transient absorption, whereas the PTR formation was observed for 2@SPh and 4@SPh, indicating that the triplet states were reactive for the C-S bond dissociation. The C-S bond dissociation mechanism for 4@SPh upon triplet sensitization is discussed in comparison with those for 2@SPh and 3@SPh.

Simultaneous determination of three major lignans in rat plasma by LC-MS/MS and its application to a pharmacokinetic study after oral administration of Diphylleia sinensis extract.

PubMed

Zhao, Chengliang; Zhang, Nan; He, Weiyan; Li, Rui; Shi, Dan; Pang, Li; Dong, Ning; Xu, Hong; Ji, Honglei

2014-04-01

A sensitive and selective liquid chromatography tandem mass spectrometry was developed and validated for the simultaneous determination of three major lignans (podophyllotoxin, epipodophyllotoxin, and 4'-demethylpodophyllotoxin) in rat plasma using diphenhydramine as the internal standard. The analytes were detected using a triple quadrupole mass spectrometer that was equipped with an electrospray ionization source in the positive ion and selected reaction monitoring modes. The linearity of the calibration curve was good, with coefficients of determination (r(2) ) >0.9914 for all of the analytes. The developed method was successfully applied for the simultaneous determination of the three lignans in rat plasma following oral administration of Diphylleia sinensis extract to rats. Copyright © 2013 John Wiley & Sons, Ltd.

A New Real-Time Cycle Slip Detection and Repair Method under High Ionospheric Activity for a Triple-Frequency GPS/BDS Receiver.

PubMed

Liu, Wanke; Jin, Xueyuan; Wu, Mingkui; Hu, Jie; Wu, Yun

2018-02-01

Cycle slip detection and repair is a prerequisite for high-precision global navigation satellite system (GNSS)-based positioning. With the modernization and development of GNSS systems, more satellites are available to transmit triple-frequency signals, which allows the introduction of additional linear combinations and provides new opportunities for cycle slip detection and repair. In this paper, we present a new real-time cycle slip detection and repair method under high ionospheric activity for undifferenced Global Positioning System (GPS)/BeiDou Navigation Satellite System (BDS) triple-frequency observations collected with a single receiver. First, three optimal linearly independent geometry-free pseudorange minus phase combinations are selected to correctly and uniquely determine the cycle slips on the original triple-frequency carrier phase observations. Then, a second-order time-difference algorithm is employed for the pseudorange minus phase combinations to mitigate the impact of between-epoch ionospheric residuals on cycle slip detection, which is especially beneficial under high ionospheric activity. The performance of the approach is verified with static GPS/BDS triple-frequency observations that are collected with a 30 s sampling interval under active ionospheric conditions, and observations are manually inserted with simulated cycle slips. The results show that the method can correctly detect and repair cycle slips at a resolution as small as 1 cycle. Moreover, kinematic data collected from car-driven and airborne experiments are also processed to verify the performance of the method. The experimental results also demonstrate that the method is effective in processing kinematic data.

A New Real-Time Cycle Slip Detection and Repair Method under High Ionospheric Activity for a Triple-Frequency GPS/BDS Receiver

PubMed Central

Liu, Wanke; Wu, Mingkui; Hu, Jie; Wu, Yun

2018-01-01

Cycle slip detection and repair is a prerequisite for high-precision global navigation satellite system (GNSS)-based positioning. With the modernization and development of GNSS systems, more satellites are available to transmit triple-frequency signals, which allows the introduction of additional linear combinations and provides new opportunities for cycle slip detection and repair. In this paper, we present a new real-time cycle slip detection and repair method under high ionospheric activity for undifferenced Global Positioning System (GPS)/BeiDou Navigation Satellite System (BDS) triple-frequency observations collected with a single receiver. First, three optimal linearly independent geometry-free pseudorange minus phase combinations are selected to correctly and uniquely determine the cycle slips on the original triple-frequency carrier phase observations. Then, a second-order time-difference algorithm is employed for the pseudorange minus phase combinations to mitigate the impact of between-epoch ionospheric residuals on cycle slip detection, which is especially beneficial under high ionospheric activity. The performance of the approach is verified with static GPS/BDS triple-frequency observations that are collected with a 30 s sampling interval under active ionospheric conditions, and observations are manually inserted with simulated cycle slips. The results show that the method can correctly detect and repair cycle slips at a resolution as small as 1 cycle. Moreover, kinematic data collected from car-driven and airborne experiments are also processed to verify the performance of the method. The experimental results also demonstrate that the method is effective in processing kinematic data. PMID:29389879

Flies and humans share a motion estimation strategy that exploits natural scene statistics

PubMed Central

Clark, Damon A.; Fitzgerald, James E.; Ales, Justin M.; Gohl, Daryl M.; Silies, Marion A.; Norcia, Anthony M.; Clandinin, Thomas R.

2014-01-01

Sighted animals extract motion information from visual scenes by processing spatiotemporal patterns of light falling on the retina. The dominant models for motion estimation exploit intensity correlations only between pairs of points in space and time. Moving natural scenes, however, contain more complex correlations. Here we show that fly and human visual systems encode the combined direction and contrast polarity of moving edges using triple correlations that enhance motion estimation in natural environments. Both species extract triple correlations with neural substrates tuned for light or dark edges, and sensitivity to specific triple correlations is retained even as light and dark edge motion signals are combined. Thus, both species separately process light and dark image contrasts to capture motion signatures that can improve estimation accuracy. This striking convergence argues that statistical structures in natural scenes have profoundly affected visual processing, driving a common computational strategy over 500 million years of evolution. PMID:24390225

Prem Baby Triple P: a randomised controlled trial of enhanced parenting capacity to improve developmental outcomes in preterm infants.

PubMed

Colditz, Paul; Sanders, Matthew R; Boyd, Roslyn; Pritchard, Margo; Gray, Peter; O'Callaghan, Michael J; Slaughter, Virginia; Whittingham, Koa; O'Rourke, Peter; Winter, Leanne; Evans, Tracey; Herd, Michael; Ahern, Jessica; Jardine, Luke

2015-03-04

Very preterm birth (<32 weeks gestation) is associated with motor, cognitive, behavioural and educational problems in children and maternal depression and withdrawal. Early interventions that target parenting have the greatest potential to create sustained effects on child development and parental psychopathology. Triple P (Positive Parenting Program) has shown positive effects on child behaviour and adjustment, parenting practices and family functioning. Baby Triple P for Preterm infants, has been developed to target parents of very preterm infants. This study tests the effectiveness of Baby Triple P for Preterm infants in improving child and parent/couple outcomes at 24 months corrected age (CA). Families will be randomised to receive either Baby Triple P for Preterm infants or Care as Usual (CAU). Baby Triple P for Preterm infants involves 4 × 2 hr group sessions at the hospital plus 4 × 30 min telephone consultations soon after transfer (42 weeks C.A.). After discharge participants will be linked to community based Triple P and intervention maintenance up to 24 months C.A. Assessments will be: baseline, post-intervention (6 weeks C.A.), at 12 and 24 months C.A. The primary outcome measure is the Infant Toddler Social & Emotional Assessment (ITSEA) at 24 months C.A. Child behavioural and emotional problems will be coded using the mother-toddler version of the Family Observation Schedule at 24 months C.A. Secondary outcome will be the Bayley Scales of Infant and Toddler Development (BSID III) cognitive development, language and motor abilities. Proximal targets of parenting style, parental self-efficacy, parental mental health, parental adjustment, parent-infant attachment, couple relationship satisfaction and couple communication will also be assessed. Our sample size based on the ITSEA, has 80% power, predicted effect size of 0.33 and an 85% retention rate, requires 165 families are required in each group (total sample of 330 families). This protocol presents the study design, methods and intervention to be analysed in a randomised trial of Baby Triple P for Preterm infants compared to Care as Usual (CAU) for families of very preterm infants. Publications of all outcomes will be published in peer reviewed journals according to CONSORT guidelines. Australian New Zealand Clinical Trials Registry: ACTRN12612000194864.

Rapid and sensitive determination of major polyphenolic components in Euphoria longana Lam. seeds using matrix solid-phase dispersion extraction and UHPLC with hybrid linear ion trap triple quadrupole mass spectrometry.

PubMed

Rathore, Atul S; Sathiyanarayanan, L; Deshpande, Shreekant; Mahadik, Kakasaheb R

2016-11-01

A rapid and sensitive method for the extraction and determination of four major polyphenolic components in Euphoria longana Lam. seeds is presented for the first time based on matrix solid-phase dispersion extraction followed by ultra high performance liquid chromatography with hybrid triple quadrupole linear ion trap mass spectrometry. Matrix solid-phase dispersion method was designed for the extraction of Euphoria longana seed constituents and compared with microwave-assisted extraction and ultrasonic-assisted extraction methods. An Ultra high performance liquid chromatography with hybrid triple quadrupole linear ion-trap mass spectrometry method was developed for quantitative analysis in multiple-reaction monitoring mode in negative electrospray ionization. The chromatographic separation was accomplished using an ACQUITY UPLC BEH C 18 (2.1 mm × 50 mm, 1.7 μm) column with gradient elution of 0.1% aqueous formic acid and 0.1% formic acid in acetonitrile. The developed method was validated with acceptable linearity (r 2 > 0.999), precision (RSD ≤ 2.22%) and recovery (RSD ≤ 2.35%). The results indicated that matrix solid-phase dispersion produced comparable extraction efficiency compared with other methods nevertheless was more convenient and time-saving with reduced requirements on sample and solvent volumes. The proposed method is rapid and sensitive in providing a promising alternative for extraction and comprehensive determination of active components for quality control of Euphoria longana products. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Genetic analysis of microglandular adenosis and acinic cell carcinomas of the breast provides evidence for the existence of a low-grade triple-negative breast neoplasia family.

PubMed

Geyer, Felipe C; Berman, Samuel H; Marchiò, Caterina; Burke, Kathleen A; Guerini-Rocco, Elena; Piscuoglio, Salvatore; Ng, Charlotte Ky; Pareja, Fresia; Wen, Hannah Y; Hodi, Zoltan; Schnitt, Stuart J; Rakha, Emad A; Ellis, Ian O; Norton, Larry; Weigelt, Britta; Reis-Filho, Jorge S

2017-01-01

Acinic cell carcinoma is an indolent form of invasive breast cancer, whereas microglandular adenosis has been shown to be a neoplastic proliferation. Both entities display a triple-negative phenotype, and may give rise to and display somatic genomic alterations typical of high-grade triple-negative breast cancers. Here we report on a comparison of previously published data on eight carcinoma-associated microglandular adenosis and eight acinic cell carcinomas subjected to targeted massively parallel sequencing targeting all exons of 236 genes recurrently mutated in breast cancer and/or DNA repair-related. Somatic mutations, insertions/ deletions, and copy number alterations were detected using state-of-the-art bioinformatic algorithms. All cases were of triple-negative phenotype. A median of 4.5 (1-13) and 4.0 (1-7) non-synonymous somatic mutations per carcinoma-associated microglandular adenosis and acinic cell carcinoma were identified, respectively. TP53 was the sole highly recurrently mutated gene (75% in microglandular adenosis versus 88% in acinic cell carcinomas), and TP53 mutations were consistently coupled with loss of heterozygosity of the wild-type allele. Additional somatic mutations shared by both groups included those in BRCA1, PIK3CA, and INPP4B. Recurrent (n=2) somatic mutations restricted to microglandular adenosis or acinic cell carcinomas included those affecting PTEN and MED12 or ERBB4, respectively. No significant differences in the repertoire of somatic mutations were detected between microglandular adenosis and acinic cell carcinomas, and between this group of lesions and 77 triple-negative carcinomas from The Cancer Genome Atlas. Microglandular adenosis and acinic cell carcinomas, however, were genetically distinct from estrogen receptor-positive and/or HER2-positive breast cancers from The Cancer Genome Atlas. Our findings support the contention that microglandular adenosis and acinic cell carcinoma are part of the same spectrum of lesions harboring frequent TP53 somatic mutations, and likely represent low-grade forms of triple-negative disease with no/minimal metastatic potential, of which a subset has the potential to progress to high-grade triple-negative breast cancer.

Genetic Analysis of Microglandular Adenosis and Acinic Cell Carcinomas of the Breast Provides Evidence for the Existence of a Low-grade Triple-Negative Breast Neoplasia Family

PubMed Central

Geyer, Felipe C; Berman, Samuel H.; Marchiò, Caterina; Burke, Kathleen A; Guerini-Rocco, Elena; Piscuoglio, Salvatore; Ng, Charlotte K Y; Pareja, Fresia; Wen, Hannah Y; Hodi, Zoltan; Schnitt, Stuart J; Rakha, Emad A; Ellis, Ian O; Norton, Larry; Weigelt, Britta; Reis-Filho, Jorge S

2016-01-01

Acinic cell carcinoma is an indolent form of invasive breast cancer, whereas microglandular adenosis has been shown to be a neoplastic proliferation. Both entities display a triple-negative phenotype, and may give rise to and display somatic genomic alterations typical of high-grade triple-negative breast cancers. Here we report on a comparison of previously published data on eight carcinoma-associated microglandular adenosis and eight acinic cell carcinomas subjected to targeted massively parallel sequencing targeting all exons of 236 genes recurrently mutated in breast cancer and/or DNA repair-related. Somatic mutations, insertions/deletions and copy number alterations were detected using state-of-the-art bioinformatic algorithms. All cases were of triple-negative phenotype. A median of 4.5 (1–13) and 4.0 (1–7) non-synonymous somatic mutations per carcinoma-associated microglandular adenosis and acinic cell carcinoma were identified, respectively. TP53 was the sole highly recurrently mutated gene (75% in microglandular adenosis versus 88% in acinic cell carcinomas), and TP53 mutations were consistently coupled with loss of heterozygosity of the wild-type allele. Additional somatic mutations shared by both groups included those in BRCA1, PIK3CA and INPP4B. Recurrent (n=2) somatic mutations restricted to microglandular adenosis or acinic cell carcinomas included those affecting PTEN and MED12, or ERBB4, respectively. No significant differences in the repertoire of somatic mutations were detected between microglandular adenosis and acinic cell carcinomas, and between this group of lesions and 77 triple-negative carcinomas from The Cancer Genome Atlas. Microglandular adenosis and acinic cell carcinomas, however, were genetically distinct from estrogen receptor-positive and/or HER2-positive breast cancers from The Cancer Genome Atlas. Our findings support the contention that microglandular adenosis and acinic cell carcinoma are part of the same spectrum of lesions harboring frequent TP53 somatic mutations, and likely represent low-grade forms of triple-negative disease with no/minimal metastatic potential, of which a subset has the potential to progress to high-grade triple-negative breast cancer. PMID:27713419

Evaluation of a novel triple-channel radiochromic film analysis procedure using EBT2.

PubMed

van Hoof, Stefan J; Granton, Patrick V; Landry, Guillaume; Podesta, Mark; Verhaegen, Frank

2012-07-07

A novel approach to read out radiochromic film was introduced recently by the manufacturer of GafChromic film. In this study, the performance of this triple-channel film dosimetry method was compared against the conventional single-red-channel film dosimetry procedure, with and without inclusion of a pre-irradiation (pre-IR) film scan, using EBT2 film and kilo- and megavoltage photon beams up to 10 Gy. When considering regions of interest averaged doses, the triple-channel method and both single-channel methods produced equivalent results. Absolute dose discrepancies between the triple-channel method, both single-channel methods and the treatment planning system calculated dose values, were no larger than 5 cGy for dose levels up to 2.2 Gy. Signal to noise in triple-channel dose images was found to be similar to signal to noise in single-channel dose images. The accuracy of resulting dose images from the triple- and single-channel methods with inclusion of pre-IR film scan was found to be similar. Results of a comparison of EBT2 data from a kilovoltage depth dose experiment to corresponding Monte Carlo depth dose data produced dose discrepancies of 9.5 ± 12 cGy and 7.6 ± 6 cGy for the single-channel method with inclusion of a pre-IR film scan and the triple-channel method, respectively. EBT2 showed to be energy sensitive at low kilovoltage energies with response differences of 11.9% and 15.6% in the red channel at 2 Gy between 50-225 kVp and 80-225 kVp photon spectra, respectively. We observed that the triple-channel method resulted in non-uniformity corrections of ±1% and consistency values of 0-3 cGy for the batches and dose levels studied. Results of this study indicate that the triple-channel radiochromic film read-out method performs at least as well as the single-channel method with inclusion of a pre-IR film scan, reduces film non-uniformity and saves time with elimination of a pre-IR film scan.

Reducing and preventing internalizing and externalizing behavior problems in children with type 1 diabetes: a randomized controlled trial of the Triple P-Positive Parenting Program.

PubMed

Westrupp, E M; Northam, E; Lee, K J; Scratch, S E; Cameron, F

2015-11-01

Children with type 1 diabetes are at increased risk of mental health problems, which in turn are associated with poor glycemic control, diabetes-related complications, and long-term psychiatric morbidity. We tested the efficacy of the Triple P-Positive Parenting Program in reducing or preventing mental health problems and improving glycemic control in children with type 1 diabetes in a randomized controlled trial. Participants were recruited from the Diabetes Clinic, Royal Children's Hospital, Melbourne, Australia, and randomized to Triple P or standard diabetes care. The primary outcome was child internalizing and externalizing behavior problems 3 and 12 months postrandomization. Secondary outcomes were glycemic control, parent mental health, parenting skills, and family functioning at 3 and 12 months, and glycemic control at 24 months. A total of 76 participants were randomized (38 to intervention and 38 to control), 60 completed 3-month, and 57 completed 12-month assessments. Benefits of Triple P were evident at 3 months for parent mental health, parenting skills, and family functioning (p < 0.05), but not for child mental health or glycemic control, with little effect at 12 months. Prespecified subgroup analyses for children with pre-existing internalizing or externalizing behavior problems indicated greater improvements in child mental health, parent mental health, parenting skills, and diabetes family conflict (p < 0.05), but lower parenting self-efficacy at 3 months. Improvements in parent mental health and parenting competency associated with Triple P were sustained to 12 months for children with pre-existing mental health problems. This study provides some support for the efficacy of Triple P in improving parent and family outcomes, and reducing child internalizing and externalizing behavior problems primarily in children who have pre-existing mental health problems. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Incidence and risk factors for breast cancer subtypes in three distinct South-East Asian ethnic groups: Chinese, Malay and natives of Sarawak, Malaysia.

PubMed

Devi, C R Beena; Tang, Tieng Swee; Corbex, Marilys

2012-12-15

We determined the incidences of the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) subtypes among breast cancer cases in Sarawak, Malaysia and their correlation with various risk factors in the three ethnic groups: Chinese, Malay and native. Subtype status was ascertained for 1,034 cases of female breast cancer (93% of all cases diagnosed since 2003), and the age-standardized incidence rates (ASRs) of each subtype were inferred. Case-case comparisons across subtypes were performed for reproductive risk factors. We found 48% luminal A (ER+/PR+/HER2-), 29% triple-negative (ER-/PR-/HER2-), 12% triple-positive (ER+/PR+/HER2+) and 11% HER2-overexpressing (ER-/PR-/HER2+) subtypes, with ASRs of 10.6, 6.0, 2.8 and 2.8 per 100,000, respectively. The proportions of subtypes and ASRs differed significantly by ethnic groups: HER2-positive cases were more frequent in Malays (29%; 95% CI [23;35]) than Chinese (22%; [19;26] and natives (21%; [16;26]); triple-negative cases were less frequent among Chinese (23%; [20;27]) than Malays (33%; [27;39]) and natives (37%; [31;43]). The results of the case-case comparison were in accordance with those observed in western case series. Some uncommon associations, such as between triple-negative subtype and older age at menopause (OR, 1.59; p < 0.05), were found. The triple-negative and HER2+ subtypes predominate in our region, with significant differences among ethnic groups. Our results support the idea that the risk factors for different subtypes vary markedly. Westernized populations are more likely to have factors that increase the risk for the luminal A type, while risk factors for the triple-negative type are more frequent in local populations. Copyright © 2012 UICC.

Mutational Evidence for the Critical Role of CBF Transcription Factors in Cold Acclimation in Arabidopsis1

PubMed Central

Zhang, Zhengjing; Li, Yuanya

2016-01-01

The three tandemly arranged CBF genes, CBF1, CBF2, and CBF3, are involved in cold acclimation. Due to the lack of stable loss-of-function Arabidopsis (Arabidopsis thaliana) mutants deficient in all three CBF genes, it is still unclear whether the CBF genes are essential for freezing tolerance and whether they may have other functions besides cold acclimation. In this study, we used the CRISPR/Cas9 system to generate cbf single, double, and triple mutants. Compared to the wild type, the cbf triple mutants are extremely sensitive to freezing after cold acclimation, demonstrating that the three CBF genes are essential for cold acclimation. Our results show that the three CBF genes also contribute to basal freezing tolerance. Unexpectedly, we found that the cbf triple mutants are defective in seedling development and salt stress tolerance. Transcript profiling revealed that the CBF genes regulate 414 cold-responsive (COR) genes, of which 346 are CBF-activated genes and 68 are CBF-repressed genes. The analysis suggested that CBF proteins are extensively involved in the regulation of carbohydrate and lipid metabolism, cell wall modification, and gene transcription. Interestingly, like the triple mutants, cbf2 cbf3 double mutants are more sensitive to freezing after cold acclimation compared to the wild type, but cbf1 cbf3 double mutants are more resistant, suggesting that CBF2 is more important than CBF1 and CBF3 in cold acclimation-dependent freezing tolerance. Our results not only demonstrate that the three CBF genes together are required for cold acclimation and freezing tolerance, but also reveal that they are important for salt tolerance and seedling development. PMID:27252305

Investigation of NS3 Protease Resistance-Associated Variants and Phenotypes for the Prediction of Treatment Response to HCV Triple Therapy.

PubMed

Dietz, Julia; Rupp, Daniel; Susser, Simone; Vermehren, Johannes; Peiffer, Kai-Henrik; Filmann, Natalie; Bon, Dimitra; Kuntzen, Thomas; Mauss, Stefan; Grammatikos, Georgios; Perner, Dany; Berkowski, Caterina; Herrmann, Eva; Zeuzem, Stefan; Bartenschlager, Ralf; Sarrazin, Christoph

2016-01-01

Triple therapy of chronic hepatitis C virus (HCV) infection with boceprevir (BOC) or telaprevir (TVR) leads to virologic failure in many patients which is often associated with the selection of resistance-associated variants (RAVs). These resistance profiles are of importance for the selection of potential rescue treatment options. In this study, we sequenced baseline NS3 RAVs population-based and investigated the sensitivity of NS3 phenotypes in an HCV replicon assay together with clinical factors for a prediction of treatment response in a cohort of 165 German and Swiss patients treated with a BOC or TVR-based triple therapy. Overall, the prevalence of baseline RAVs was low, although the frequency of RAVs was higher in patients with virologic failure compared to those who achieved a sustained virologic response (SVR) (7% versus 1%, P = 0.06). The occurrence of RAVs was associated with a resistant NS3 quasispecies phenotype (P<0.001), but the sensitivity of phenotypes was not associated with treatment outcome (P = 0.2). The majority of single viral and host predictors of SVR was only weakly associated with treatment response. In multivariate analyses, low AST levels, female sex and an IFNL4 CC genotype were independently associated with SVR. However, a combined analysis of negative predictors revealed a significantly lower overall number of negative predictors in patients with SVR in comparison to individuals with virologic failure (P<0.0001) and the presence of 2 or less negative predictors was indicative for SVR. These results demonstrate that most single baseline viral and host parameters have a weak influence on the response to triple therapy, whereas the overall number of negative predictors has a high predictive value for SVR.

Inhibition of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Feng; Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030; Yang, Yong, E-mail: yyang@houstonmethodist.org

2014-11-21

Highlights: • Suppression of PKM2 sensitizes triple-negative breast cancer cells to doxorubicin. • Repression of PKM2 affects the glycolysis and decreases ATP production. • Downregulation of PKM2 increases the intracellular accumulation of doxorubicin. • Inhibition of PKM2 enhances the antitumor efficacy of doxorubicin in vivo. - Abstract: Cancer cells alter regular metabolic pathways in order to sustain rapid proliferation. One example of metabolic remodeling in cancerous tissue is the upregulation of pyruvate kinase isoenzyme M2 (PKM2), which is involved in aerobic glycolysis. Indeed, PKM2 has previously been identified as a tumor biomarker and as a potential target for cancer therapy.more » Here, we examined the effects of combined treatment with doxorubicin and anti-PKM2 small interfering RNA (siRNA) on triple-negative breast cancer (TNBC). The suppression of PKM2 resulted in changes in glucose metabolism, leading to decreased synthesis of adenosine triphosphate (ATP). Reduced levels of ATP resulted in the intracellular accumulation of doxorubicin, consequently enhancing the therapeutic efficacy of this drug in several triple-negative breast cancer cell lines. Furthermore, the combined effect of PKM2 siRNA and doxorubicin was evaluated in an in vivo MDA-MB-231 orthotopic breast cancer model. The siRNA was systemically administered through a polyethylenimine (PEI)-based delivery system that has been extensively used. We demonstrate that the combination treatment showed superior anticancer efficacy as compared to doxorubicin alone. These findings suggest that targeting PKM2 can increase the efficacy of chemotherapy, potentially providing a new approach for improving the outcome of chemotherapy in patients with TNBC.« less

Metalloproteins and phytochelatin synthase may confer protection against zinc oxide nanoparticle induced toxicity in Caenorhabditis elegans.

PubMed

Polak, Natasa; Read, Daniel S; Jurkschat, Kerstin; Matzke, Marianne; Kelly, Frank J; Spurgeon, David J; Stürzenbaum, Stephen R

2014-03-01

Zinc oxide nanoparticles (ZnONPs) are used in large quantities by the cosmetic, food and textile industries. Here we exposed Caenorhabditis elegans wild-type and a metal sensitive triple knockout mutant (mtl-1;mtl-2;pcs-1) to ZnONPs (0-50mg/L) to study strain and exposure specific effects on transcription, reactive oxygen species generation, the biomolecular phenotype (measured by Raman microspectroscopy) and key endpoints of the nematode life cycle (growth, reproduction and lifespan). A significant dissolution effect was observed, where dissolved ZnO constituted over 50% of total Zn within a two day exposure to the test medium, suggesting that the nominal exposure to pure ZnONPs represents in vivo, at best, a mixture exposure of ionic zinc and nanoparticles. Nevertheless, the analyses provided evidence that the metallothioneins (mtl-1 and mtl-2), the phytochelatin synthase (pcs-1) and an apoptotic marker (cep-1) were transcriptionally activated. In addition, the DCFH-DA assay provided in vitro evidence of the oxidative potential of ZnONPs in the metal exposure sensitive triple mutant. Raman spectroscopy highlighted that the biomolecular phenotype changes significantly in the mtl-1;mtl-2;pcs-1 triple knockout worm upon ZnONP exposure, suggesting that these metalloproteins are instrumental in the protection against cytotoxic damage. Finally, ZnONP exposure was shown to decrease growth and development, reproductive capacity and lifespan, effects which were amplified in the triple knockout. By combining diverse toxicological strategies, we identified that individuals (genotypes) housing mutations in key metalloproteins and phytochelatin synthase are more susceptible to ZnONP exposure, which underlines their importance to minimize ZnONP induced toxicity. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with primary progressive multiple sclerosis.

PubMed Central

Filippi, M; Campi, A; Martinelli, V; Colombo, B; Yousry, T; Canal, N; Scotti, G; Comi, G

1995-01-01

This study was performed to evaluate whether a triple dose of gadolinium-DTPA (Gd-DTPA) increases the sensitivity of brain MRI for detecting enhancing lesions in patients with primary progressive multiple sclerosis (PPMS). T1 weighted brain MRI was obtained for 10 patients with PPMS in two sessions. In the first session, one scan was obtained five to seven minutes after the injection of 0.1 mmol/kg Gd-DTPA (standard dose). In the second session, six to 24 hours later, one scan before and two scans five to seven minutes and one hour after the injection of 0.3 mmol/kg Gd-DTPA (triple dose) were obtained. Four enhancing lesions were detected in two patients when the standard dose of Gd-DTPA was used. The numbers of enhancing lesions increased to 13 and the numbers of patients with such lesions to five when the triple dose of Gd-DTPA was used and to 14 and six in the one hour delayed scans. The mean contrast ratio for enhancing lesions detected with the triple dose of Gd-DTPA was higher than those for lesions present in both the standard dose (P < 0.0009) and the one hour delayed scans (P = 0.04). These data indicate that with a triple dose of Gd-DTPA many more enhancing lesions can be detected in patients with PPMS. This is important both for planning clinical trials and for detecting the presence of inflammation in vivo in the lesions of such patients. Images PMID:8530944

Nonlinear optical response of the collagen triple helix and second harmonic microscopy of collagen liquid crystals

NASA Astrophysics Data System (ADS)

Deniset-Besseau, A.; De Sa Peixoto, P.; Duboisset, J.; Loison, C.; Hache, F.; Benichou, E.; Brevet, P.-F.; Mosser, G.; Schanne-Klein, M.-C.

2010-02-01

Collagen is characterized by triple helical domains and plays a central role in the formation of fibrillar and microfibrillar networks, basement membranes, as well as other structures of the connective tissue. Remarkably, fibrillar collagen exhibits efficient Second Harmonic Generation (SHG) and SHG microscopy proved to be a sensitive tool to score fibrotic pathologies. However, the nonlinear optical response of fibrillar collagen is not fully characterized yet and quantitative data are required to further process SHG images. We therefore performed Hyper-Rayleigh Scattering (HRS) experiments and measured a second order hyperpolarisability of 1.25 10-27 esu for rat-tail type I collagen. This value is surprisingly large considering that collagen presents no strong harmonophore in its amino-acid sequence. In order to get insight into the physical origin of this nonlinear process, we performed HRS measurements after denaturation of the collagen triple helix and for a collagen-like short model peptide [(Pro-Pro-Gly)10]3. It showed that the collagen large nonlinear response originates in the tight alignment of a large number of weakly efficient harmonophores, presumably the peptide bonds, resulting in a coherent amplification of the nonlinear signal along the triple helix. To illustrate this mechanism, we successfully recorded SHG images in collagen liquid solutions by achieving liquid crystalline ordering of the collagen triple helices.

Palliative systemic therapy and overall survival of 1,395 patients with advanced breast cancer - Results from the prospective German TMK cohort study.

PubMed

Fietz, Thomas; Tesch, Hans; Rauh, Jacqueline; Boller, Emil; Kruggel, Lisa; Jänicke, Martina; Marschner, Norbert

2017-08-01

Data on treatment and outcome of advanced breast cancer in routine practice are rare, especially concerning recurrent disease, but important to complement the results from clinical trials and to improve the standard of care. We present data on choice of systemic first-line treatment, number of treatment lines, and survival of patients treated by medical oncologists in Germany. 1395 patients recruited by 124 sites at start of first-line therapy into the ongoing, prospective German clinical cohort study TMK (Tumour Registry Breast Cancer) between February 2007 and October 2015 were analysed. The median OS was 33.8 months (95% CI 30.2-40.2) for HR-positive/HER2-negative, 38.2 months (95% CI 31.3-43.0) for HER2-positive and 16.8 months (95% CI 11.5-22.0) for triple negative breast cancer. Patients with triple negative tumours more often died before start of a third-line therapy than patients with HR-positive or HER2-positive tumours (44% vs. 25%). Use of taxane-based chemotherapies has increased since 2007, with 65% of all first-line chemotherapy-treatments containing taxanes in 2013-15 (60% HR-positive/HER2-negative, 75% HER2-positive, 56% triple negative). 52% of the patients with HR-positive/HER2-negative tumours received first-line endocrine therapy in 2013-15; when restricted to patients with only non-visceral metastases this percentage increased to 63%. To our knowledge, this is the first cohort study showing systemic first-line therapy for all subtypes of advanced breast cancer. Overall survival in the TMK is comparable to that reported by clinical trials despite the inclusion of older and comorbid patients. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Knockdown of CAVEOLIN-1 Sensitizes Human Basal-Like Triple-Negative Breast Cancer Cells to Radiation.

PubMed

Zou, Man; Li, Yanhui; Xia, Shu; Chu, Qian; Xiao, Xiaoguang; Qiu, Hong; Chen, Yu; Zheng, Zu'an; Liu, Fei; Zhuang, Liang; Yu, Shiying

2017-01-01

Triple-negative breast cancer (TNBC) is a high-risk breast cancer phenotype without specific targeted therapy options and is significantly associated with increased local recurrence in patients treated with radiotherapy. CAVEOLIN-1 (CAV-1)-mediated epidermal growth factor receptor (EGFR) nuclear translocation following irradiation promotes DNA repair and thus induces radiation resistance. In this study, we aimed to determine whether knockdown of CAV-1 enhances the radiosensitivity of basal-like TNBC cell lines and to explore the possible mechanisms. Western blotting was used to compare protein expression in a panel of breast cancer cell lines. Nuclear accumulation of EGFR as well as DNA repair and damage at multiple time points following irradiation with or without CAV-1 siRNA pretreatment were investigated using western blotting and confocal microscopy. The radiosensitizing effect of CAV-1 siRNA was evaluated using a clonogenic assay. Flowcytometry was performed to analyse cell apoptosis and cell cycle alteration. We found that CAV-1 is over-expressed in basal-like TNBC cell lines and barely expressed in HER-2-positive cells; additionally, we observed that HER-2-positive cell lines are more sensitive to irradiation than basal-like TNBC cells. Our findings revealed that radiation-induced EGFR nuclear translocation was impaired by knockdown of CAV-1. In parallel, radiation-induced elevation of DNA repair proteins was also hampered by pretreatment with CAV-1 siRNA before irradiation. Silencing of CAV-1 also promoted DNA damage 24 h after irradiation. Colony formation assays verified that cells could be radiosensitized after knockdown of CAV-1. Furthermore, G2/M cell cycle arrest and apoptosis enhancement may also contribute to the radiosensitizing effect of CAV-1 siRNA. Our results support the hypothesis that CAV-1 knockdown by siRNA causes increased radiosensitivity in basal-like TNBC cells. The mechanisms associated with this effect are reduced DNA repair through delayed CAV-1-associated EGFR nuclear accumulation and induction of G2/M arrest and apoptosis through the combined effects of CAV-1 siRNA and radiation. © 2017 The Author(s). Published by S. Karger AG, Basel.

Metformin sensitizes triple-negative breast cancer to proapoptotic TRAIL receptor agonists by suppressing XIAP expression.

PubMed

Strekalova, Elena; Malin, Dmitry; Rajanala, Harisha; Cryns, Vincent L

2017-06-01

Despite robust antitumor activity in diverse preclinical models, TNF-related apoptosis-inducing ligand (TRAIL) receptor agonists have not demonstrated efficacy in clinical trials, underscoring the need to identify agents that enhance their activity. We postulated that the metabolic stress induced by the diabetes drug metformin would sensitize breast cancer cells to TRAIL receptor agonists. Human triple (estrogen receptor, progesterone receptor, and HER2)-negative breast cancer (TNBC) cell lines were treated with TRAIL receptor agonists (monoclonal antibodies or TRAIL peptide), metformin, or the combination. The effects on cell survival, caspase activation, and expression of TRAIL receptors and the antiapoptotic protein XIAP were determined. In addition, XIAP was silenced by RNAi in TNBC cells and the effects on sensitivity to TRAIL were determined. The antitumor effects of metformin, TRAIL, or the combination were evaluated in an orthotopic model of metastatic TNBC. Metformin sensitized diverse TNBC cells to TRAIL receptor agonists. Metformin selectively enhanced the sensitivity of transformed breast epithelial cells to TRAIL receptor agonist-induced caspase activation and apoptosis with little effect on untransformed breast epithelial cells. These effects of metformin were accompanied by robust reductions in the protein levels of XIAP, a negative regulator of TRAIL-induced apoptosis. Silencing XIAP in TNBC cells mimicked the TRAIL-sensitizing effects of metformin. Metformin also enhanced the antitumor effects of TRAIL in a metastatic murine TNBC model. Our findings indicate that metformin enhances the activity of TRAIL receptor agonists, thereby supporting the rationale for additional translational studies combining these agents.

Diagnostic features of Alzheimer's disease extracted from PET sinograms

NASA Astrophysics Data System (ADS)

Sayeed, A.; Petrou, M.; Spyrou, N.; Kadyrov, A.; Spinks, T.

2002-01-01

Texture analysis of positron emission tomography (PET) images of the brain is a very difficult task, due to the poor signal to noise ratio. As a consequence, very few techniques can be implemented successfully. We use a new global analysis technique known as the Trace transform triple features. This technique can be applied directly to the raw sinograms to distinguish patients with Alzheimer's disease (AD) from normal volunteers. FDG-PET images of 18 AD and 10 normal controls obtained from the same CTI ECAT-953 scanner were used in this study. The Trace transform triple feature technique was used to extract features that were invariant to scaling, translation and rotation, referred to as invariant features, as well as features that were sensitive to rotation but invariant to scaling and translation, referred to as sensitive features in this study. The features were used to classify the groups using discriminant function analysis. Cross-validation tests using stepwise discriminant function analysis showed that combining both sensitive and invariant features produced the best results, when compared with the clinical diagnosis. Selecting the five best features produces an overall accuracy of 93% with sensitivity of 94% and specificity of 90%. This is comparable with the classification accuracy achieved by Kippenhan et al (1992), using regional metabolic activity.

CdTe-based Light-Controllable Frequency-Selective Photonic Crystal Switch for Millimeter Waves

DTIC Science & Technology

2011-09-01

position (magenta curves with circular points which correspond to different light pulses) 23 Fig. 11.3. (a) Phase of transmission wave (in...11.4. Transmission spectra of plastic-air PC with CdTe-coated triple -quartz-wafer insertion of the kind ‘6t-qvqvqs-6t’ (computed yellow and measured...experimental requirements of matching the frequency band of VNA facility (f = 75–110 GHz), PC structures with triple -wafer insertion layers

Hepatic insulin sensitivity in healthy and prediabetic subjects: from a dual- to a single-tracer oral minimal model.

PubMed

Visentin, Roberto; Dalla Man, Chiara; Basu, Rita; Basu, Ananda; Rizza, Robert A; Cobelli, Claudio

2015-07-15

Recently, a model was proposed to assess hepatic insulin sensitivity during a meal, i.e., the ability of insulin to suppress glucose production (EGP), SI (P). The model was developed on EGP data obtained from a triple-tracer meal and the tracer-to-tracee clamp technique and validated against the euglycemic hyperinsulinemic clamp. The aim of this study was to assess whether SI (P) can be obtained from plasma concentrations measured after a single-tracer meal by incorporating the above EGP model into the oral glucose minimal model by describing both glucose production and disposal (OMM(PD)). Triple-tracer meal data of two databases (20 healthy and 60 healthy and prediabetic subjects) were used. Virtually model-independent EGP estimates were calculated. OMM(PD) was identified on exogenous and endogenous glucose concentrations, providing indices of SI (P), disposal insulin sensitivity (SI (D)), and EGP. The model fitted the data well, and SI (P) and SI (D) were estimated with precision in both databases (SI (P) = 5.48 ± 0.54 10(-4) dl·kg(-1)·min(-1) per μU/ml and SI (D) = 9.93 ± 2.18 10(-4) dl·kg(-1)·min(-1) per μU/ml in healthy; SI (P) = 5.41 ± 3.55 10(-4) dl·kg(-1)·min(-1) per μU/ml and SI (D) = 5.34 ± 6.17 10(-4) dl·kg(-1)·min(-1) per μU/ml, in healthy and prediabetic subjects). Estimated SI (P) and that derived from the triple-tracer EGP model were very similar on average. Moreover, the time course of EGP normalized to basal EGP (EGPb), and EGP/EGPb agreed with the results obtained using the triple-tracer method. In this study, we have demonstrated that SI (P), SI (D), and EGP/EGPb time course can be estimated reliably from a single-tracer meal protocol in both healthy and prediabetic subjects. Copyright © 2015 the American Physiological Society.

Indirect enzyme-linked immunosorbent assay method based on Streptococcus agalactiae rSip-Pgk-FbsA fusion protein for detection of bovine mastitis.

PubMed

Bu, Ri-E; Wang, Jin-Liang; Wu, Jin-Hua; Xilin, Gao-Wa; Chen, Jin-Long; Wang, Hua

2017-03-01

The aim of this study was to establish a rapid and accurate method for the detection of the Streptococcus agalactiae antibody (SA-Ab) to determine the presence of the bovine mastitis (BM)-causative pathogen. The multi-subunit fusion protein rSip-Pgk-FbsA was prokaryotically expressed and purified. The triple activities of the membrane surface-associated proteins Sip, phosphoglycerate kinase (Pgk), and fibronectin (FbsA) were used as the diagnostic antigens to establish an indirect enzyme-linked immunosorbent assay (ELISA) method for the detection of SA-Ab in BM. The optimal antigen coating concentration was 2 μg/mL, the optimal serum dilution was 1:160, and the optimal dilution of the enzyme-labeled secondary antibody was 1:6000. The sensitivity, specificity, and repeatability tests showed that the method established in this study had no cross-reaction with antibodies to Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus, and Staphylococcus epidermidis in the sera. The results of the sensitivity test showed that a positive result could be obtained even if the serum dilution reached 1:12,800, indicating the high sensitivity and good repeatability of the method. The positive coincidence rate of this method was 98.6%, which is higher than that of previous tests established with the Sip or Pgk mono-antigen fusion protein, respectively, demonstrating the relatively higher sensitivity of this newly established method. The detection rate for 389 clinical samples was 46.53%. The indirect ELISA method established in this study could provide a more accurate and reliable serological method for the rapid detection of S. agalactiae in cases of BM.

Lifestyle Triple P: a parenting intervention for childhood obesity.

PubMed

Gerards, Sanne M P L; Dagnelie, Pieter C; Jansen, Maria W J; van der Goot, Lidy O H M; de Vries, Nanne K; Sanders, Matthew R; Kremers, Stef P J

2012-04-03

Reversing the obesity epidemic requires the development and evaluation of childhood obesity intervention programs. Lifestyle Triple P is a parent-focused group program that addresses three topics: nutrition, physical activity, and positive parenting. Australian research has established the efficacy of Lifestyle Triple P, which aims to prevent excessive weight gain in overweight and obese children. The aim of the current randomized controlled trial is to assess the effectiveness of the Lifestyle Triple P intervention when applied to Dutch parents of overweight and obese children aged 4-8 years. This effectiveness study is called GO4fit. Parents of overweight and obese children are being randomized to either the intervention or the control group. Those assigned to the intervention condition receive the 14-week Lifestyle Triple P intervention, in which they learn a range of nutritional, physical activity and positive parenting strategies. Parents in the control group receive two brochures, web-based tailored advice, and suggestions for exercises to increase active playing at home. Measurements are taken at baseline, directly after the intervention, and at one year follow-up. Primary outcome measure is the children's body composition, operationalized as BMI z-score, waist circumference, and fat mass (biceps and triceps skinfolds). Secondary outcome measures are children's dietary behavior and physical activity level, parenting practices, parental feeding style, parenting style, parental self-efficacy, and body composition of family members (parents and siblings). Our intervention is characterized by a focus on changing general parenting styles, in addition to focusing on changing specific parenting practices, as obesity interventions typically do. Strengths of the current study are the randomized design, the long-term follow-up, and the broad range of both self-reported and objectively measured outcomes. Current Controlled Trials NTR 2555 MEC AZM/UM: NL 31988.068.10 / MEC 10-3-052.

Neuroanatomical evidence for a role of central melanocortin-4 receptors and oxytocin in the efferent control of the rodent clitoris and vagina.

PubMed

Gelez, Helene; Poirier, Sarah; Facchinetti, Patricia; Allers, Kelly A; Wayman, Chris; Alexandre, Laurent; Giuliano, François

2010-06-01

The clitoris and the vagina are the main peripheral anatomical structures involved in physiological changes related to sexual arousal and orgasm. Their efferent control and, more particularly, the neurochemical phenotype of these descending neuronal pathways remain largely uncharacterized. To examine if brain neurons involved in the efferent control of the clitoris and the vagina possess melanocortin-4 receptor (MC4-R) and/or contain oxytocin (OT). Neurons involved in the efferent control of the vagina and clitoris were identified following visualization of pseudorabies virus (PRV) retrograde tracing. PRV was injected into the vagina and clitoris in adult rats in estrous. On the fifth day postinjection, animals were humanely sacrificed, and brains were removed and sectioned, and processed for PRV visualization. The neurochemical phenotype of PRV-positive neurons was identified using double or triple immunocytochemical labeling against PRV, MC4-R, and OT. Double and triple labeling were quantified using confocal laser scanning microscopy. Neuroanatomical brain distribution, number and percentage of double-labeled PRV/MC4-R and PRV-/OT-positive neurons, and triple PRV-/MC4-R-/OT-labeled neurons. The majority of PRV immunopositive neurons which also expressed immunoreactivity for MC4-R were located in the paraventricular and arcuate nuclei of the hypothalamus. The majority of PRV positive neurons which were immunoreactive (IR) for OT were located in the paraventricular nucleus (PVN), medial preoptic area (MPOA), and lateral hypothalamus. PRV positive neurons were more likely to be IR for MC4-R than for OT. Scattered triple-labeled PRV/MC4-R/OT neurons were detected in the MPOA and the PVN. These data strongly suggest that MC4-R and, to a less extent, OT are involved in the efferent neuronal control of the clitoris and vagina, and consequently facilitate our understanding of how the melanocortinergic pathway regulates female sexual function.

Bridging disparate symptoms of schizophrenia: a triple network dysfunction theory

PubMed Central

Nekovarova, Tereza; Fajnerova, Iveta; Horacek, Jiri; Spaniel, Filip

2014-01-01

Schizophrenia is a complex neuropsychiatric disorder with variable symptomatology, traditionally divided into positive and negative symptoms, and cognitive deficits. However, the etiology of this disorder has yet to be fully understood. Recent findings suggest that alteration of the basic sense of self-awareness may be an essential distortion of schizophrenia spectrum disorders. In addition, extensive research of social and mentalizing abilities has stressed the role of distortion of social skills in schizophrenia.This article aims to propose and support a concept of a triple brain network model of the dysfunctional switching between default mode and central executive network (CEN) related to the aberrant activity of the salience network. This model could represent a unitary mechanism of a wide array of symptom domains present in schizophrenia including the deficit of self (self-awareness and self-representation) and theory of mind (ToM) dysfunctions along with the traditional positive, negative and cognitive domains. We review previous studies which document the dysfunctions of self and ToM in schizophrenia together with neuroimaging data that support the triple brain network model as a common neuronal substrate of this dysfunction. PMID:24910597

The XENONnT Dark Matter Experiment

NASA Astrophysics Data System (ADS)

Aprile, Elena; Xenon Collaboration

2017-01-01

With XENON1T ready to search for dark matter with the highest sensivity of any experiment to-date the XENON collaboration started to secure funding and resources to upgrade the detector by the end of 2018- phase which we refer to as XENONnT. The XENONnT experiment will utilize the already-built-and-tested XENON1T infrastructures, such as the cryogenic system, Kr distillation system and Xe storage and recovery system, with the main upgrade of the time projection chamber (TPC). The upgraded XENONnT detector will be filled with 7.5-ton ultra-pure liquid xenon, tripling the active liquid xenon target mass of XENON1T. About 500 low-radioactive three-inch R11410 PMTs will be used. Background from internal sources such as radon will be reduced. It will enable another order of magnitude improvement in dark matter search sensitivity compared to that of XENON1T, or accumulate statistics if a positive dark matter signal is observed by XENON1T. The detailed TPC upgrade plan, the background control and reduction techniques, the predicted sensitivity reach will be presented.

High Expression of CCR7 Predicts Lymph Node Metastasis and Good Prognosis in Triple Negative Breast Cancer.

PubMed

Li, Xuelu; Sun, Siwen; Li, Ning; Gao, Jiyue; Yu, Jing; Zhao, Jinbo; Li, Man; Zhao, Zuowei

2017-01-01

Previous preclinical and clinical studies have reported a positive correlation between the expression of the C-C chemokine receptor 7 (CCR7) and the incidence of lymph node metastasis in breast cancer. However, the prognostic relevance of CCR7 expression in breast cancer remains contradictory till now. The aim of this study is to assess the correlation of the CCR7 expression with other clinicopathological features and prognosis in breast cancer. The CCR7 gene amplification and mRNA expression levels from approximately 3,000 patients were retrieved from human breast cancer databases and analyzed. Furthermore, a total of 188 primary triple negative breast cancer patients were enrolled in this study (diagnosed since January 2009 to January 2013 from the Second Hospital of Dalian Medical University). The protein levels of CCR7 were examined by immunohistochemistry using paraffin-embedded tumor tissues. The analysis of gene amplification and mRNA levels showed the expression of CCR7 in breast cancer correlated with better prognosis. When we compared the CCR7 expressions in different subtypes, the basal-like group showed the highest expression of CCR7 and exhibited a better prognosis. Consistently, Kaplan-Meier analysis of 188 triple negative breast cancer patients showed that the prognosis of patients with positive CCR7 expression was significantly better than those with negative expression (HR=0.642, p=0.0275). Additionally, we also observed a positive correlation between lymph node metastasis and the CCR7 expression (p=0.0096). Our results indicated that elevated CCR7 expression as a marker for increased lymph node metastasis, in addition to serve as an independent prognostic indicator for better overall survival in triple negative breast cancer patients. © 2017 The Author(s). Published by S. Karger AG, Basel.

Clinicopathology Figures and Long-term Effects of Tamoxifen Plus Radiation on Survival of Women with Invasive Ductal Carcinoma and Triple Negative Breast Cancer.

PubMed

Payandeh, Mehrdad; Sadeghi, Masoud; Sadeghi, Edris; Aeinfar, Mehrnoush

2015-01-01

Triple negative breast cancer (TNBC), characterized as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 Her2 negative and accounting for 10-17% of all breast carcinomas, is only partially responsive to chemotherapy and suffers from a lack of clinically established targeted therapies. The aim of the current study was to evaluate the patterns of treatment and clinicopathology figures in Kurdish patients with triple-negative breast cancer, and to compare these to other reports. Between 2001 and 2014, 950 breast cancer patients were referred to our clinic. There were 74 female patients with TNBC, including 70 patients was invasive ductal carcinoma entered into our study. ER and PR positivity was defined as positive immunohistochemical staining in more than 10% of tumor cells. Immunohistochemistry assay with anti-HER2 antibodies was used to identify HER negative (0 and 1+) or positive (2+ and 3+). HER2 gene amplification was determined by fluorescent in situ hybridization (FISH). Overall survival (OS) was plotted with GraphPad Prism 5 Software using Kaplan-Meier and log-rank tests for comparison of results. The mean age in the first diagnosis for 70 patients with triple TNBC and invasive ductal carcinoma was 49.6 years that range of age was 27-82 years. All of the patients were female. Of 70 patients, 23 patients had metastasis. Thirty-two patients (45.7%) were treated with tamoxifen and 39 (55.7%) with radiotherapy. Three-year, 5-year and 10-year OS rates for all patients were 82%, 72% and 64%, respectively. The OS in our West Iran TNBC patients is less than reported elsewhere. However, treatment with combination of tamoxifen plus radiation increases the OS and reduces the mortality rate.

Mechanistic characterization of the HDV genomic ribozyme: a mutant of the C41 motif provides insight into the positioning and thermodynamic linkage of metal ions and protons.

PubMed

Nakano, Shu-ichi; Bevilacqua, Philip C

2007-03-20

Binding of two Mg2+ and two H+ ions influences the self-cleavage activity of the genomic HDV ribozyme. The positioning of these four ligands and their thermodynamic linkage are not fully resolved. Protonated C41 engages in a base triple, whereas protonated C75 has been implicated as an acid-base catalyst in bond cleavage. Prior studies led to the identification of one structural inner-sphere ion and one catalytic outer-sphere ion. In the present study, the contributions of the C41 base triple to the metal ion- and pH-dependence of the reaction are examined. Experiments were conducted on a CG to UA double mutant (DM), which changes the base triple to one involving an unprotonated C41. Below pH 6, the DM has a steeper dependence on pH than the wild-type (WT), consistent with a single protonation misfolding the core; this conclusion is also supported by thermal denaturation studies. Between pH 6 and 8, the WT and DM display nearly identical catalytic metal ion and H+ binding profiles. In contrast, over the same pH range, the WT and DM have distinct structural ion binding profiles; for the WT, binding is favored at lower pH, whereas the DM shows no pH dependence. These data localize the structural ion to the vicinity of the C41 motif. An overall model is presented that accommodates binding affinity, coupling, and positioning of the two metal ions and the two protons within the ribozyme. The data suggest that a protonated base triple allows the WT ribozyme to maintain appreciable activity at acidic pH, which could play an important role in the life cycle of the virus.

Heat waves and their significance for a temperate benthic community: A near-natural experimental approach.

PubMed

Pansch, Christian; Scotti, Marco; Barboza, Francisco R; Al-Janabi, Balsam; Brakel, Janina; Briski, Elizabeta; Bucholz, Björn; Franz, Markus; Ito, Maysa; Paiva, Filipa; Saha, Mahasweta; Sawall, Yvonne; Weinberger, Florian; Wahl, Martin

2018-04-23

Climate change will not only shift environmental means but will also increase the intensity of extreme events, exerting additional stress on ecosystems. While field observations on the ecological consequences of heat waves are emerging, experimental evidence is rare, and lacking at the community level. Using a novel "near-natural" outdoor mesocosms approach, this study tested whether marine summer heat waves have detrimental consequences for macrofauna of a temperate coastal community, and whether sequential heat waves provoke an increase or decrease of sensitivity to thermal stress. Three treatments were applied, defined and characterized through a statistical analysis of 15 years of temperature records from the experimental site: (1) no heat wave, (2) two heat waves in June and July followed by a summer heat wave in August and (3) the summer heat wave only. Overall, 50% of the species showed positive, negative or positive/negative responses in either abundance and/or biomass. We highlight four possible ways in which single species responded to either three subsequent heat waves or one summer heat wave: (1) absence of a response (tolerance, 50% of species), (2) negative accumulative effects by three subsequent heat waves (tellinid bivalve), (3) buffering by proceeding heat waves due to acclimation and/or shifts in phenology (spionid polychaete) and (4) an accumulative positive effect by subsequent heat waves (amphipod). The differential responses to single or sequential heat waves at the species level entailed shifts at the community level. Community-level differences between single and triple heat waves were more pronounced than those between regimes with vs. without heat waves. Detritivory was reduced by the single heat wave while suspension feeding was less common in the triple heat wave regime. Critical extreme events occur already today and will occur more frequently in a changing climate, thus, leading to detrimental impacts on coastal marine systems. © 2018 John Wiley & Sons Ltd.

Design, assembly, and testing of a high-resolution relay lens used for holography with operation at both doubled and tripled Nd:YAG laser wavelengths

NASA Astrophysics Data System (ADS)

Malone, Robert M.; Capelle, Gene A.; Cox, Brian C.; Frogget, Brent C.; Grover, Mike; Kaufman, Morris I.; Pazuchanics, Peter; Sorenson, Danny S.; Stevens, Gerald D.; Tibbitts, Aric; Turley, William D.

2009-08-01

The design and assembly of a nine-element lens that achieves >2000 lp/mm resolution at a 355-nm wavelength (ultraviolet) has been completed. By adding a doublet to this lens system, operation at a 532-nm wavelength (green) with >1100 lp/mm resolution is achieved. This lens is used with high-power laser light to record holograms of fast-moving ejecta particles from a shocked metal surface located inside a test package. Part of the lens and the entire test package are under vacuum with a 1-cm air gap separation. Holograms have been recorded with both doubled and tripled Nd:YAG laser light. The UV operation is very sensitive to the package window's tilt. If this window is tilted by more than 0.1 degrees, the green operation performs with better resolution than that of the UV operation. The setup and alignment are performed with green light, but the dynamic recording can be done with either UV light or green light. A resolution plate can be temporarily placed inside the test package so that a television microscope located beyond the hologram position can archive images of resolution patterns that prove that the calibration wires, interference filter, holographic plate, and relay lenses are in their correct positions. Part of this lens is under vacuum, at the point where the laser illumination passes through a focus. Alignment and tolerancing of this high-resolution lens are presented. Resolution variation across the 12-mm field of view and throughout the 5-mm depth of field is discussed for both wavelengths.

Modeling and Assessment of Precise Time Transfer by Using BeiDou Navigation Satellite System Triple-Frequency Signals

PubMed Central

Zhang, Pengfei; Zhang, Rui; Liu, Jinhai; Lu, Xiaochun

2018-01-01

This study proposes two models for precise time transfer using the BeiDou Navigation Satellite System triple-frequency signals: ionosphere-free (IF) combined precise point positioning (PPP) model with two dual-frequency combinations (IF-PPP1) and ionosphere-free combined PPP model with a single triple-frequency combination (IF-PPP2). A dataset with a short baseline (with a common external time frequency) and a long baseline are used for performance assessments. The results show that IF-PPP1 and IF-PPP2 models can both be used for precise time transfer using BeiDou Navigation Satellite System (BDS) triple-frequency signals, and the accuracy and stability of time transfer is the same in both cases, except for a constant system bias caused by the hardware delay of different frequencies, which can be removed by the parameter estimation and prediction with long time datasets or by a priori calibration. PMID:29596330

Orthogonal Injection Ion Funnel Interface Providing Enhanced Performance for Selected Reaction Monitoring-Triple Quadrupole Mass Spectrometry

DOE PAGES

Chen, Tsung-Chi; Fillmore, Thomas L.; Prost, Spencer A.; ...

2015-06-24

The electrodynamic ion funnel facilitates efficient focusing and transfer of charged particles in the higher pressure regions (e.g. ion source interfaces) of mass spectrometers, and thus providing increased sensitivity. An “off-axis” ion funnel design has been developed to reduce the source contamination and interferences from, e.g. ESI droplet residue and other poorly focused neutral or charged particles with very high mass-to charge ratios. In this study a dual ion funnel interface consisting of an orthogonal higher pressure electrodynamic ion funnel (HPIF) and an ion funnel trap combined with a triple quadruple mass spectrometer was developed and characterized. An orthogonal ionmore » injection inlet and a repeller plate electrode was used to direct ions to an ion funnel HPIF at 9-10 Torr pressure. Several critical factors for the HPIF were characterized, including the effects of RF amplitude, DC gradient and operating pressure. Compared to the triple quadrupole standard interface more than 4-fold improvement in the limit of detection for the direct quantitative MS analysis of low abundance peptides was observed. Lastly, the sensitivity enhancement in liquid chromatography selected reaction monitoring (SRM) analyses of low abundance peptides spiked into a highly complex mixture was also compared with that obtained using a both commercial s-lens interface and a in-line dual ion funnel interface.« less

Orthogonal Injection Ion Funnel Interface Providing Enhanced Performance for Selected Reaction Monitoring-Triple Quadrupole Mass Spectrometry

PubMed Central

Chen, Tsung-Chi; Fillmore, Thomas L.; Prost, Spencer A.; Moore, Ronald J.; Ibrahim, Yehia M.; Smith, Richard D.

2016-01-01

The electrodynamic ion funnel facilitates efficient focusing and transfer of charged particles in the higher-pressure regions (e.g., ion source interfaces) of mass spectrometers, thus providing increased sensitivity. An “off-axis” ion funnel design has been developed to reduce the source contamination and interferences from, e.g. ESI droplet residue and other poorly focused neutral or charged particles with very high mass-to-charge ratios. In this study, a dual ion funnel interface consisting of an orthogonal higher pressure electrodynamic ion funnel (HPIF) and an ion funnel trap combined with a triple quadrupole mass spectrometer was developed and characterized. An orthogonal ion injection inlet and a repeller plate electrode was used to direct ions to an ion funnel HPIF at a pressure of 9–10 Torr. Key factors for the HPIF performance characterized included the effects of RF amplitude, the DC gradient, and operating pressure. Compared to the triple quadrupole standard interface more than 4-fold improvement in the limit of detection for the direct quantitative MS analysis of low abundance peptides was observed. The sensitivity enhancement in liquid chromatography selected reaction monitoring (LC-SRM) analyses of low-abundance peptides spiked into a highly complex mixture was also compared with that obtained using both a commercial S-lens interface and an in-line dual-ion funnel interface. PMID:26107611

Clinicopathological Features, Patterns of Recurrence, and Survival Among Women With Triple-Negative Breast Cancer in the National Comprehensive Cancer Network

PubMed Central

Lin, Nancy U.; Vanderplas, Ann; Hughes, Melissa E.; Theriault, Richard L.; Edge, Stephen B.; Wong, Yu-Ning; Blayney, Douglas W.; Niland, Joyce C.; Winer, Eric P.; Weeks, Jane C.

2012-01-01

Background We aimed to describe clinicopathological features, patterns of recurrence, and survival according to breast cancer subtype, with a focus on triple-negative tumors. Methods We evaluated 15,204 women presenting to NCCN centers with stage I-III breast cancer between January 2000 and December 2006. Tumors were classified as hormone receptor positive [HR+]/HER2− (ER+ and/or PR+, and HER2−), HER2+ (HER2+, any ER or PR), or triple-negative (ER−, PR−, and HER2−). Results Subtype distribution was: triple-negative 17% (n=2,569), HER2+ 17% (n=2,602), HR+/HER2− 66% (n=10,033). Triple-negative subtype was more frequent in African-Americans, compared with Caucasians (adjusted odds ratio [OR] 1.98; p<0.0001). Premenopausal, but not postmenopausal, women with high body mass index had an increased likelihood of triple negative subtype (p=0.02). Women with triple-negative cancers were less likely to present on the basis of an abnormal screening mammogram (29% vs. 48%, p<0.0001), more likely to present with higher T stage, but less likely to have nodal involvement. Relative to HR+/HER2− tumors, triple-negative tumors were associated with a higher risk of brain or lung metastases, and had worse breast cancer-specific and overall survival, even after adjusting for age, stage, race, grade, and receipt of adjuvant chemotherapy (adjusted hazard ratio [HR] for overall survival 2.72, 95% CI 2.39–3.10, p<0.0001). The difference in risk of death by subtype was most dramatic within the first two years after diagnosis (HR for OS for 0 to 2 yrs 6.10 [95% CI 4.81, 7.74]). Conclusions Triple-negative tumors are associated with unique risk factors and worse outcomes compared to HR+/HER2− tumors. PMID:22544643

Treatment of clinically diagnosed laryngopharyngeal reflux disease.

PubMed

Youssef, Tarek Fouad; Ahmed, Mohamed Rifaat

2010-11-01

To determine the incidence of Helicobacter pylori (HP) stool antigen (HPSA) in patients with laryngopharyngeal reflux disease (LPRD), and to make a comparison of 2 treatment regimens that have been used based on the presence or absence of HPSA positivity in patients with LPRD. Randomized controlled study. Suez Canal University Hospital, Ismalia, Egypt. A total of 212 patients with symptoms of LPRD. Patients were evaluated by laryngoscopy, ambulatory pH monitoring for 24 hours, and HPSA testing. Esomeprazole magnesium as a monotherapy was evaluated vs triple therapy in patients with HP infection. To determine the incidence of HPSA in patients with LPRD, and to make a comparison of 2 treatment regimens that have been used based on the presence or absence of HPSA positivity in patients with LPRD. Persistent dry cough and a feeling of a lump in the throat (globus sensation) were the most frequent symptoms of LPRD, while posterior laryngeal inflammation was the main laryngoscopic finding. Results from the HPSA test were positive in 57% of the studied group. Patients with negative HPSA were treated with esomeprazole as single modality with a reported improvement score of 96.6%. Patients with positive HPSA test results were divided into 2 groups: 1 received only esomeprazole, with reported improvement in 40%, whereas the second group was treated with esomeprazole, plus amoxicillin sodium and clarithromycin (triple therapy) and reported a 90% incidence of symptom improvement. The incidence of HP infection in patients with LPRD in our study was 57%. Triple therapy showed a higher cure rate in patients with HPSA-positive test results.

Improved sensitivity of ochratoxin A analysis in coffee using high-performance liquid chromatography with hybrid triple quadrupole-linear ion trap mass spectrometry (LC-QqQLIT-MS/MS).

PubMed

Kokina, Aija; Pugajeva, Iveta; Bartkevics, Vadims

2016-01-01

A novel and sensitive method utilising high-performance liquid chromatography coupled to triple quadrupole-linear ion trap mass spectrometry (LC-QqQLIT-MS/MS) was developed in order to analyse the content of ochratoxin A (OTA) in coffee samples. The introduction of the triple-stage MS scanning mode (MS(3)) has been shown to increase greatly sensitivity and selectivity by eliminating the high chromatographic baseline caused by interference of complex coffee matrices. The analysis included the sample preparation procedure involving extraction of OTA using a methanol-water mixture and clean-up by immunoaffinity columns and detection using the MS(3) scanning mode of LC-QqQLIT-MS/MS. The proposed method offered a good linear correlation (r(2) > 0.998), excellent precision (RSD < 2.9%) and recovery (94%). The limit of quantification (LOQ) for coffee beans and espresso beverages was 0.010 and 0.003 µg kg(-1), respectively. The developed procedure was compared with traditional methods employing liquid chromatography coupled to fluorescent and tandem quadrupole detectors in conjunction with QuEChERS and solid-phase extraction. The proposed method was successfully applied to the determination of OTA in 15 samples of coffee beans and in 15 samples of espresso coffee beverages obtained from the Latvian market. OTA was found in 10 samples of coffee beans and in two samples of espresso in the ranges of 0.018-1.80 µg kg(-1) and 0.020-0.440 µg l(-1), respectively. No samples exceeded the maximum permitted level of OTA in the European Union (5.0 µg kg(-1)).

A Magnetic Survey Of The MTJ(Mangatolu Triple Junction) Caldera On Lau Basin

NASA Astrophysics Data System (ADS)

Kwak, J.; Won, J.; Park, C.; Ko, Y.; Kim, C.; Jeong, E.; Yu, S.

2006-12-01

We have performed a magnetic survey to understand magnetic distribution and characteristics of the MTJ(Mangatolu Triple Junction) caldera. MTJ caldera(15°25'S, 174°00'W) is located between MTJ northeast extending branch which connects to the northeast Tonga trench[Wright et al, 2000] and the main line of Tofua volcanic arc. The caldera results from coupling between the crust of the Tonga microplate and the subducting Pacific plate[Macleod, 1996]. The MTJ is characterized severe deformation and neovolcanism[Parson and Tiffin, 1993], and has been reoriented during the Brunhes Chron[Zellmer et al, 2001]. Generally, low magnetization at crust is highly correlated with active hydrothermal vent field. The acidic and corrosive fluids that constitute marine hydrothermal vent systems can quickly alter or replace the iron-rich magnetic minerals, which reduce the magnetic remanence of the crustal rocks, in some cases to zero. Magnetic field data were observed by using high sensitivity proton magnetometer which is towed 300m behind the ship(R/V Onnuri). The data were first merged with the ship navigation. Then magnetic field was inverted for crustal magnetization using Parker[1974] inversion approach, which takes bathymetry into account assuming a constant layer thickness and then sufficient annihilator is added to magnetization solution to balance the positive and reverse polarity amplitudes. In this study, all inversions are calculated assuming a 500m source thickness.

Strongly Misaligned Triple System in SR 24 Revealed by ALMA

NASA Astrophysics Data System (ADS)

Fernández-López, M.; Zapata, L. A.; Gabbasov, R.

2017-08-01

We report the detection of the 1.3 mm continuum and the molecular emission of the disks of the young triple system SR24 by analyzing ALMA (The Atacama Large Millimeter/Submillimter Array) subarcsecond archival observations. We estimate the mass of the disks (0.025 M ⊙ and 4 × 10-5 M ⊕ for SR24S and SR24N, respectively) and the dynamical mass of the protostars (1.5 M ⊙ and 1.1 M ⊙). A kinematic model of the SR24S disk to fit its C18O (2-1) emission allows us to develop an observational method to determine the tilt of a rotating and accreting disk. We derive the size, inclination, position angle, and sense of rotation of each disk, finding that they are strongly misaligned (108^\\circ ) and possibly rotate in opposite directions as seen from Earth, in projection. We compare the ALMA observations with 12CO SMA archival observations, which are more sensitive to extended structures. We find three extended structures and estimate their masses: a molecular bridge joining the disks of the system, a molecular gas reservoir associated with SR24N, and a gas streamer associated with SR24S. Finally, we discuss the possible origin of the misaligned SR24 system, concluding that a closer inspection of the northern gas reservoir is needed to better understand it.

The PIKfyve–ArPIKfyve–Sac3 triad in human breast cancer: Functional link between elevated Sac3 phosphatase and enhanced proliferation of triple negative cell lines

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ikonomov, Ognian C., E-mail: oikonomo@med.wayne.edu; Filios, Catherine, E-mail: cfilios@med.wayne.edu; Sbrissa, Diego, E-mail: dsbrissa@med.wayne.edu

2013-10-18

Highlights: •We assess PAS complex proteins and phosphoinositide levels in breast cancer cells. •Sac3 and ArPIKfyve are markedly elevated in triple-negative breast cancer cells. •Sac3 silencing inhibits proliferation in triple-negative breast cancer cell lines. •Phosphoinositide profiles are altered in breast cancer cells. •This is the first evidence linking high Sac3 with breast cancer cell proliferation. -- Abstract: The phosphoinositide 5-kinase PIKfyve and 5-phosphatase Sac3 are scaffolded by ArPIKfyve in the PIKfyve–ArPIKfyve–Sac3 (PAS) regulatory complex to trigger a unique loop of PtdIns3P–PtdIns(3,5)P{sub 2} synthesis and turnover. Whereas the metabolizing enzymes of the other 3-phosphoinositides have already been implicated in breast cancer,more » the role of the PAS proteins and the PtdIns3P–PtdIns(3,5)P{sub 2} conversion is unknown. To begin elucidating their roles, in this study we monitored the endogenous levels of the PAS complex proteins in cell lines derived from hormone-receptor positive (MCF7 and T47D) or triple-negative breast cancers (TNBC) (BT20, BT549 and MDA-MB-231) as well as in MCF10A cells derived from non-tumorigenic mastectomy. We report profound upregulation of Sac3 and ArPIKfyve in the triple negative vs. hormone-sensitive breast cancer or non-tumorigenic cells, with BT cell lines showing the highest levels. siRNA-mediated knockdown of Sac3, but not that of PIKfyve, significantly inhibited proliferation of BT20 and BT549 cells. In these cells, knockdown of ArPIKfyve had only a minor effect, consistent with a primary role for Sac3 in TNBC cell proliferation. Intriguingly, steady-state levels of PtdIns(3,5)P{sub 2} in BT20 and T47D cells were similar despite the 6-fold difference in Sac3 levels between these cell lines. However, steady-state levels of PtdIns3P and PtdIns5P, both regulated by the PAS complex, were significantly reduced in BT20 vs. T47D or MCF10A cell lines, consistent with elevated Sac3 affecting directly or indirectly the homeostasis of these lipids in TNBC. Together, our results uncover an unexpected role for Sac3 phosphatase in TNBC cell proliferation. Database analyses, discussed herein, reinforce the involvement of Sac3 in breast cancer pathogenesis.« less

CRITICAL CURVES AND CAUSTICS OF TRIPLE-LENS MODELS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Daněk, Kamil; Heyrovský, David, E-mail: kamil.danek@utf.mff.cuni.cz, E-mail: heyrovsky@utf.mff.cuni.cz

2015-06-10

Among the 25 planetary systems detected up to now by gravitational microlensing, there are two cases of a star with two planets, and two cases of a binary star with a planet. Other, yet undetected types of triple lenses include triple stars or stars with a planet with a moon. The analysis and interpretation of such events is hindered by the lack of understanding of essential characteristics of triple lenses, such as their critical curves and caustics. We present here analytical and numerical methods for mapping the critical-curve topology and caustic cusp number in the parameter space of n-point-mass lenses.more » We apply the methods to the analysis of four symmetric triple-lens models, and obtain altogether 9 different critical-curve topologies and 32 caustic structures. While these results include various generic types, they represent just a subset of all possible triple-lens critical curves and caustics. Using the analyzed models, we demonstrate interesting features of triple lenses that do not occur in two-point-mass lenses. We show an example of a lens that cannot be described by the Chang–Refsdal model in the wide limit. In the close limit we demonstrate unusual structures of primary and secondary caustic loops, and explain the conditions for their occurrence. In the planetary limit we find that the presence of a planet may lead to a whole sequence of additional caustic metamorphoses. We show that a pair of planets may change the structure of the primary caustic even when placed far from their resonant position at the Einstein radius.« less

Effect of topical application of dipyrone on dental sensitivity reduction after in-office dental bleaching: A randomized, triple-blind multicenter clinical trial.

PubMed

Rezende, Márcia; Chemin, Kaprice; Vaez, Savil Costa; Peixoto, Aline Carvalho; Rabelo, Jéssica de Freitas; Braga, Stella Sueli Lourenço; Faria-E-Silva, André Luis; Silva, Gisele Rodrigues da; Soares, Carlos José; Loguercio, Alessandro D; Reis, Alessandra

2018-05-01

Tooth sensitivity commonly occurs during and immediately after dental bleaching. The authors conducted a trial to compare tooth sensitivity after in-office bleaching after the use of either a topical dipyrone or placebo gel. A split-mouth, triple-blind, randomized, multicenter clinical trial was conducted among 120 healthy adults having teeth that were shade A2 or darker. The facial tooth surfaces of the right or left sides of the maxillary arch of each patient were randomly assigned to receive either topical dipyrone or placebo gel before 2 in-office bleaching sessions (35% hydrogen peroxide) separated by 2 weeks. Visual analog and numerical rating scales were used to record tooth sensitivity during and up to 48 hours after bleaching. Tooth color change from baseline to 1 month after bleaching was measured with shade guide and spectrophotometer measures. The primary outcome variable was absolute risk of tooth sensitivity. An intention-to-treat analysis was used to analyze data from all patients who were randomly assigned to receive the dipyrone and placebo gels. No statically significant difference was found in the absolute risk of tooth sensitivity between the dipyrone and placebo gels (83% and 90%, respectively, P = .09; relative risk, 0.92; 95% confidence interval, 0.8 to 1.0). A whitening effect was observed in both groups with no statistically significant difference (P > .05) between them. No adverse effects were observed. Topical use of dipyrone gel before tooth bleaching, at the levels used in this study, did not reduce the risk or intensity of bleaching-induced tooth sensitivity. Topical application of dipyrone gel does not reduce bleaching-induced tooth sensitivity. Copyright © 2018 American Dental Association. Published by Elsevier Inc. All rights reserved.

The Role of Novel Substituted Diindolyl Methane Analogues in the Treatment of Triple-Negative and ErbB2-Positive Breast Cancer

DTIC Science & Technology

2016-05-01

patients are diagnosed with TNBC, which do not express estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2...and EPBC are high risk breast cancers and the choice of orally available chemotherapeutic agents is limited. Hormonal therapy (ER modulators) and HER...antibody based therapy are far safer than cytotoxic drug based regimens. But triple negative breast cancers are not responsive to hormonal or HER

PARP1 impact on DNA repair of platinum adducts: preclinical and clinical read-outs.

PubMed

Olaussen, Ken A; Adam, Julien; Vanhecke, Elsa; Vielh, Philippe; Pirker, Robert; Friboulet, Luc; Popper, Helmut; Robin, Angélique; Commo, Fréderic; Thomale, Jürgen; Kayitalire, Louis; Filipits, Martin; Le Chevalier, Thierry; André, Fabrice; Brambilla, Elisabeth; Soria, Jean-Charles

2013-05-01

Evaluation of DNA repair proteins might provide meaningful information in relation to prognosis and chemotherapy efficacy in Non-Small Cell Lung Cancer (NSCLC) patients. The role of Poly(ADP-Ribose) Polymerase (PARP) in DNA repair of platinum adducts has not been firmly established. We used a DNA repair functional test based on antibody recognition of cisplatin intrastrand platinum adducts on DNA. We evaluated the effect of PARP inhibition on DNA repair functionality in a panel of cisplatin cell lines treated by the clinical-grade pharmacological inhibitor CEP8983 (a 4-methoxy-carbazole derivate) and the commercially available inhibitor PJ34 (phenanthridinone). We determined PARP1 protein expression in whole tumor sections from the International Adjuvant Lung cancer Trial (IALT)-bio study and tested a 3-marker PARP1/MSH2/ERCC1 algorithm combining PARP1 tumor status with previously published data. Chemosensitivity of cisplatin in NSCLC cell lines was correlated with the accumulation of cisplatin DNA adducts (P=0.0004). Further, the pharmacological inhibition of PARP induced a 1.7 to 2.3-fold increase in platinum adduct accumulation (24h) in A549 cell line suggesting a slow-down of platinum DNA-adduct repair capacity. In parallel, PARP1 inhibition increased the sensitivity to cisplatin treatment. In patient samples, PARP1 expression levels did not influence patient survival or the effect of platinum-based post-operative chemotherapy in the global IALT-bio population (interaction P=0.79). Among cases with high expression of all three markers (triple positive), untreated patients had prolonged survival with a median DFS of 7.8 years, (HR=0.34, 95%CI [0.19-0.61], adjusted P=0.0003) compared to triple negative patients (1.4 years). Remarkably, triple positive patients suffered from a detrimental effect (4.9-year reduction of median DFS) by post-operative cisplatin-based chemotherapy (HR=1.79, 95%CI [1.01-3.17], adjusted P=0.04, chemotherapy vs. control). Combinatorial sub-group analysis of the 3 markers further suggested that PARP1 tumor positivity might constitute a molecular context with high theranostic interest of ERCC1 and MSH2 in NSCLC. In conclusion, our data confirm that platinum DNA adduct accumulation is linked to chemosensitivity, which increase by pharmacological PARP inhibitors points to a role of PARP-dependent DNA repair in the process. We further suggest DNA repair biomarkers should be analyzed in a larger context of multiple DNA repair pathway regulation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

NARRAGANSETT-3VS MODEL OVERVIEW (Information Sheet)

EPA Science Inventory

In an effort to advance sustainability, EPA Region 1 (New England) and the EPA Office of Research and Development (ORD) are collaborating on a project to address the problem of nutrient impairment to ecological functions in sensitive waterways. The project is based on the Triple...

Oxygen-dependent regulation of tumor growth and metastasis in human breast cancer xenografts.

PubMed

Yttersian Sletta, Kristine; Tveitarås, Maria K; Lu, Ning; Engelsen, Agnete S T; Reed, Rolf K; Garmann-Johnsen, Annette; Stuhr, Linda

2017-01-01

Tumor hypoxia is relevant for tumor growth, metabolism, resistance to chemotherapy and metastasis. We have previously shown that hyperoxia, using hyperbaric oxygen treatment (HBOT), attenuates tumor growth and shifts the phenotype from mesenchymal to epithelial (MET) in the DMBA-induced mammary tumor model. This study describes the effect of HBOT on tumor growth, angiogenesis, chemotherapy efficacy and metastasis in a triple negative MDA-MB-231 breast cancer model, and evaluates tumor growth using a triple positive BT-474 breast cancer model. 5 x 105 cancer cells were injected s.c. in the groin area of NOD/SCID female mice. The BT-474 group was supplied with Progesterone and Estradiol pellets 2-days prior to tumor cell injection. Mice were divided into controls (1 bar, pO2 = 0.2 bar) or HBOT (2.5 bar, pO2 = 2.5 bar, 90 min, every third day until termination of the experiments). Treatment effects were determined by assessment of tumor growth, proliferation (Ki67-staining), angiogenesis (CD31-staining), metastasis (immunostaining), EMT markers (western blot), stromal components collagen type I, Itgb1 and FSP1 (immunostaining) and chemotherapeutic efficacy (5FU). HBOT significantly suppressed tumor growth in both the triple positive and negative tumors, and both MDA-MB-231 and BT-474 showed a decrease in proliferation after HBOT. No differences were found in angiogenesis or 5FU efficacy between HBOT and controls. Nevertheless, HBOT significantly reduced both numbers and total area of the metastastatic lesions, as well as reduced expression of N-cadherin, Axl and collagen type I measured in the MDA-MB-231 model. No change in stromal Itgb1 and FSP1 was found in either tumor model. Despite the fact that behavior and prognosis of the triple positive and negative subtypes of cancer are different, the HBOT had a similar suppressive effect on tumor growth, indicating that they share a common oxygen dependent anti-tumor mechanism. Furthermore, HBOT significantly reduced the number and area of metastatic lesions in the triple negative model as well as a significant reduction in the EMT markers N-cadherin, Axl and density of collagen type I.

Development of a monoclonal-based enzyme-linked immunoassay for saxitoxin-induced protein.

PubMed

Smith, D S; Kitts, D D

1994-03-01

A monoclonal antibody was generated against saxitoxin-induced protein (SIP) from the small shore crab Hemigrapsus oregenesis. SIP was induced by saxitoxin injection and could be detected in the crude crab extracts with both polyclonal and monoclonal antibody preparations. On Western blots, the polyclonal serum reacted against several bands which were induced by saxitoxin in the crude extracts. These bands represented proteins related to SIP. The monoclonal (4G5), however, was specific for the 79,000 mol. wt subunit of SIP. A triple antibody sandwich ELISA was developed in which polyclonal anti-SIP IgG was used as a trapping layer and monoclonal 4G5 was used as the detection layer. This assay was shown to be more specific and more accurate than a direct bind assay which employed the polyclonal antiserum alone. Although the polyclonal serum was more sensitive than the monoclonal on Western blots, the triple antibody sandwich and direct bind ELISAs were of comparable sensitivity.

Personalized cost-effectiveness of boceprevir-based triple therapy for untreated patients with genotype 1 chronic hepatitis C.

PubMed

Petta, Salvatore; Cabibbo, Giuseppe; Enea, Marco; Macaluso, Fabio Salvatore; Plaia, Antonella; Bruno, Raffaele; Gasbarrini, Antonio; Bruno, Savino; Craxì, Antonio; Cammà, Calogero

2014-10-01

We assessed the cost-effectiveness of boceprevir-based triple therapy compared to peginterferon alpha and ribavirin dual therapy in untreated patients with genotype 1 chronic hepatitis C; patients were discriminated according to the combination of baseline plus on-treatment predictors of boceprevir-based triple therapy. Cost-effectiveness analysis performed according to data from the available published literature. The target population was composed of untreated Caucasian patients, aged 50 years, with genotype 1 chronic hepatitis C, and these were evaluated over a lifetime horizon by Markov model. The study was carried out from the perspective of the Italian National Health Service. Outcomes included discounted costs (in euro, at 2013 value), life-years gained, quality-adjusted life year, and incremental cost-effectiveness ratio. The robustness of the results was evaluated by multivariable probabilistic sensitivity analyses. According to the baseline predictors of sustained virological response (genotype 1b, low viral load, fibrosis F0-F3, and body mass index) and the 1Log drop of HCV-RNA after the dual therapy lead-in period, boceprevir was cost-effective in different patient profiles. In untreated genotype 1b chronic hepatitis C patients, the cost-effectiveness of boceprevir-based triple therapy widely ranges according to different profiles of sustained virological response predictors, allowing optimization and personalization of triple therapy. Copyright © 2014 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

H(C)P and H(P)C triple-resonance experiments at natural abundance employing long-range couplings.

PubMed

Malon, Michal; Koshino, Hiroyuki

2007-09-01

Modified two-dimensional (2D) triple-resonance H(C)P and H(P)C experiments based on INEPT/HMQC and double-INEPT schemes are applied to the study of organophosphorus compounds at natural abundances. The implementation of effective (1)H--(13)C gradient selection, additional purging pulsed field gradients, spinlock pulses, and improved phase cycling is demonstrated to allow weak correlation signals based on long-range couplings to be readily observed. Through the combination of two heteronuclear long-range coupling constants, (n)J(CH) and (n)J(PC) in H(C)P experiments or (n)J(PH) and (n)J(PC) in H(P)C experiments, protons can be correlated to a second heteronucleus through 4-7 chemical bonds. These experiments thus overcome the inherit limitations of classical (1)H-X HMBC experiments, which require a nonzero value of the heteronuclear coupling constant (n)J(XH). Ultra-broadband inversion composite pulses are successfully employed in the H(P)C INEPT/HMQC and H(P)C double-INEPT pulse sequences to increase the utility of the experiments and the quality of obtained spectra. This work extends and completes a set of 2D phase-sensitive triple-resonance experiments applicable at natural abundances, and also offers insight into the methodology of triple-resonance experiments and the application of pulsed field gradients. A one-dimensional triple-resonance experiment employing carbon detection is suggested for accurate determination of small (n)J(PC).

MK2206 in Treating Patients With Stage I, Stage II, or Stage III Breast Cancer

ClinicalTrials.gov

2017-08-01

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

Viral Therapy In Treating Patients With Recurrent or Metastatic Squamous Cell Carcinoma of the Head and Neck Cancer or Metastatic Breast Cancer

ClinicalTrials.gov

2018-02-16

Estrogen Receptor Negative; Estrogen Receptor Positive; Head and Neck Squamous Cell Carcinoma; HER2/Neu Negative; HER2/Neu Positive; Invasive Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Head and Neck Carcinoma; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Incremental cancer detection using breast ultrasonography versus breast magnetic resonance imaging in the evaluation of newly diagnosed breast cancer patients.

PubMed

He, Hongying; Plaxco, Jeri S; Wei, Wei; Huo, Lei; Candelaria, Rosalind P; Kuerer, Henry M; Yang, Wei T

2016-09-01

To compare the incremental cancer detection rate (ICDR) using bilateral whole-breast ultrasonography (BWBUS) vs dynamic contrast-enhanced MRI in patients with primary breast cancer. A retrospective database search in a single institution identified 259 patients with breast cancer diagnosed from January 2011 to August 2014 who underwent mammography, BWBUS and MRI before surgery. Patient characteristics, tumour characteristics and lesions seen on each imaging modality were recorded. The sensitivity, specificity and accuracy for each modality were calculated. ICDRs according to index tumour histology and receptor status were also evaluated. The effect of additional cancer detection on surgical planning was obtained from the medical records. A total of 266 additional lesions beyond 273 index malignancies were seen on at least 1 modality, of which 121 (45%) lesions were malignant and 145 (55%) lesions were benign. MRI was significantly more sensitive than BWBUS (p = 0.01), while BWBUS was significantly more accurate and specific than MRI (p < 0.0001). Compared with mammography, the ICDRs using BWBUS and MRI were significantly higher for oestrogen receptor-positive and triple-negative cancers, but not for human epidermal growth factor receptor 2-positive cancers. 22 additional malignant lesions in 18 patients were seen on MRI only. Surgical planning remained unchanged in 8 (44%) of those 18 patients. MRI was more sensitive than BWBUS, while BWBUS was more accurate and specific than MRI. MRI-detected additional malignant lesions did not change surgical planning in almost half of these patients. BWBUS may be a cost-effective and practical tool in breast cancer staging.

The proteomic landscape of triple-negative breast cancer.

PubMed

Lawrence, Robert T; Perez, Elizabeth M; Hernández, Daniel; Miller, Chris P; Haas, Kelsey M; Irie, Hanna Y; Lee, Su-In; Blau, C Anthony; Villén, Judit

2015-04-28

Triple-negative breast cancer is a heterogeneous disease characterized by poor clinical outcomes and a shortage of targeted treatment options. To discover molecular features of triple-negative breast cancer, we performed quantitative proteomics analysis of twenty human-derived breast cell lines and four primary breast tumors to a depth of more than 12,000 distinct proteins. We used this data to identify breast cancer subtypes at the protein level and demonstrate the precise quantification of biomarkers, signaling proteins, and biological pathways by mass spectrometry. We integrated proteomics data with exome sequence resources to identify genomic aberrations that affect protein expression. We performed a high-throughput drug screen to identify protein markers of drug sensitivity and understand the mechanisms of drug resistance. The genome and proteome provide complementary information that, when combined, yield a powerful engine for therapeutic discovery. This resource is available to the cancer research community to catalyze further analysis and investigation. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

High quality lamella preparation of gallium nitride compound semiconductor using Triple Beam™ system

NASA Astrophysics Data System (ADS)

Sato, T.; Nakano, K.; Matsumoto, H.; Torikawa, S.; Nakatani, I.; Kiyohara, M.; Isshiki, T.

2017-09-01

Gallium nitride (GaN) compound semiconductors have been known to be very sensitive to Ga focused ion beam (FIB) processing. Due to the nature of GaN based materials it is often difficult to produce damage-free lamellae, therefore applying the Triple Beam™ system which incorporates an enhanced method for amorphous removal is presented to make a high quality lamella. The damage or distortion layer thickness of GaN single crystal prepared with 30 kV Ga FIB and 1 kV Ga FIB were about 17 nm and 1.5 nm respectively. The crystallinity at the uppermost surface remained unaffected when the condition of 1 kV Ar ion milling with the Triple Beam™ system was used. The technique of combining traditional Ga FIB processing with an enhanced method for amorphous layer removal by low energy Ar ion milling allows us to analyse the InGaN/GaN interface using aberration corrected scanning transmission electron microscopy at atomic resolution levels.

Recovering the triple coincidence of non-pure positron emitters in preclinical PET

NASA Astrophysics Data System (ADS)

Lin, Hsin-Hon; Chuang, Keh-Shih; Chen, Szu-Yu; Jan, Meei-Ling

2016-03-01

Non-pure positron emitters, with their long half-lives, allow for the tracing of slow biochemical processes which cannot be adequately examined by the commonly used short-lived positron emitters. Most of these isotopes emit high-energy cascade gamma rays in addition to positron decay that can be detected and create a triple coincidence with annihilation photons. Triple coincidence is discarded in most scanners, however, the majority of the triple coincidence contains true photon pairs that can be recovered. In this study, we propose a strategy for recovering triple coincidence events to raise the sensitivity of PET imaging for non-pure positron emitters. To identify the true line of response (LOR) from a triple coincidence, a framework utilizing geometrical, energy and temporal information is proposed. The geometrical criterion is based on the assumption that the LOR with the largest radial offset among the three sub pairs of triple coincidences is least likely to be a true LOR. Then, a confidence time window is used to test the valid LOR among those within triple coincidence. Finally, a likelihood ratio discriminant rule based on the energy probability density distribution of cascade and annihilation gammas is established to identify the true LOR. An Inveon preclinical PET scanner was modeled with GATE (GEANT4 application for tomographic emission) Monte Carlo software. We evaluated the performance of the proposed method in terms of identification fraction, noise equivalent count rates (NECR), and image quality on various phantoms. With the inclusion of triple coincidence events using the proposed method, the NECR was found to increase from 11% to 26% and 19% to 29% for I-124 and Br-76, respectively, when 7.4-185 MBq of activity was used. Compared to the reconstructed images using double coincidence, this technique increased the SNR by 5.1-7.3% for I-124 and 9.3-10.3% for Br-76 within the activity range of 9.25-74 MBq, without compromising the spatial resolution or contrast. We conclude that the proposed method can improve the counting statistics of PET imaging for non-pure positron emitters and is ready to be implemented on current PET systems. Parts of this work were presented at the 2012 Annual Congress of the European Association of Nuclear Medicine.

[Comparison of the diagnostic utility from visual inspection with acetic acid and cervical cytology].

PubMed

Velázquez-Hernández, Nadia; Sánchez-Anguiano, Luis Francisco; Lares-Bayona, Edgar Felipe; Cisneros-Pérez, Vicente; Milla-Villeda, Reinaldo Humberto; Arreola-Herrera, Francisco de Asís; Navarrete-Flores, José Antonio; Aguilar-Durán, Maricela; Núñez-Márquez, Teresita; Rueda-Cisneros, Dora Alicia

2010-05-01

In Mexico, cervical cancer is the second leading cause of death in women after breast cancer. The human papillomavirus is associated with intraepithelial lesions, detected up to 99.7% of cervical carcinomas. Despite being easy to detect is a condition that many women suffer. To determine the diagnostic utility of the visual inspection with acetic acid of the uterine cervix compared with the cervical cytology. Study of diagnostic tests. The study was realized in the Centro de Atención Materno Infantil y Planificación Familiar of the Instituto de Investigación Científica, Durango, Mexico, research of the Juárez University of the State of Durango, from August 23, 2005 to November 13, 2006. 1,521 participants were examined who went consecutively to opportune detection of cervical cancer. One doctor practiced the test of acetic acid and cervical cytology to them, and one digital photograph, which was evaluated by three inter-observers triple blind. Those that was positive to anyone of these tests, were remitted to colposcopy and/or biopsy; also to 10% of selected negative population randomly was realized this procedure. Sensitivity, specificity, positive and negative predictive values and exactitude were determined. For the agreement inter-observer index of Kappa was used. Sensitivity, specificity, values predictive positive, negative and exactitude for the visual inspection with acetic acid were 20, 97, 5 and 99%, respectively. For the cervical cytology were of 80, 99, 57 and 99%, respectively. The force of agreement between the interobservant was poor. In this study cervical cytology was more useful than visual inspection with acetic acid to detect dysplasias or cervical cancer opportunely, due to detect all the positive true cases confirmed by biopsy.

Non-iterative triple excitations in equation-of-motion coupled-cluster theory for electron attachment with applications to bound and temporary anions.

PubMed

Jagau, Thomas-C

2018-01-14

The impact of residual electron correlation beyond the equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) approximation on positions and widths of electronic resonances is investigated. To establish a method that accomplishes this task in an economical manner, several approaches proposed for the approximate treatment of triple excitations are reviewed with respect to their performance in the electron attachment (EA) variant of EOM-CC theory. The recently introduced EOM-CCSD(T)(a)* method [D. A. Matthews and J. F. Stanton, J. Chem. Phys. 145, 124102 (2016)], which includes non-iterative corrections to the reference and the target states, reliably reproduces vertical attachment energies from EOM-EA-CC calculations with single, double, and full triple excitations in contrast to schemes in which non-iterative corrections are applied only to the target states. Applications of EOM-EA-CCSD(T)(a)* augmented by a complex absorbing potential (CAP) to several temporary anions illustrate that shape resonances are well described by EOM-EA-CCSD, but that residual electron correlation often makes a non-negligible impact on their positions and widths. The positions of Feshbach resonances, on the other hand, are significantly improved when going from CAP-EOM-EA-CCSD to CAP-EOM-EA-CCSD(T)(a)*, but the correct energetic order of the relevant electronic states is still not achieved.

Non-iterative triple excitations in equation-of-motion coupled-cluster theory for electron attachment with applications to bound and temporary anions

NASA Astrophysics Data System (ADS)

Jagau, Thomas-C.

2018-01-01

The impact of residual electron correlation beyond the equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) approximation on positions and widths of electronic resonances is investigated. To establish a method that accomplishes this task in an economical manner, several approaches proposed for the approximate treatment of triple excitations are reviewed with respect to their performance in the electron attachment (EA) variant of EOM-CC theory. The recently introduced EOM-CCSD(T)(a)* method [D. A. Matthews and J. F. Stanton, J. Chem. Phys. 145, 124102 (2016)], which includes non-iterative corrections to the reference and the target states, reliably reproduces vertical attachment energies from EOM-EA-CC calculations with single, double, and full triple excitations in contrast to schemes in which non-iterative corrections are applied only to the target states. Applications of EOM-EA-CCSD(T)(a)* augmented by a complex absorbing potential (CAP) to several temporary anions illustrate that shape resonances are well described by EOM-EA-CCSD, but that residual electron correlation often makes a non-negligible impact on their positions and widths. The positions of Feshbach resonances, on the other hand, are significantly improved when going from CAP-EOM-EA-CCSD to CAP-EOM-EA-CCSD(T)(a)*, but the correct energetic order of the relevant electronic states is still not achieved.

Targeting the androgen receptor in triple-negative breast cancer.

PubMed

Gucalp, Ayca; Traina, Tiffany A

Triple-negative breast cancer represents approximately 15%-20% of all newly diagnosed breast cancers, but it accounts for a disproportionate number of breast cancer-related deaths each year. Owing to the lack of estrogen, progesterone, and human epidermal growth factor receptor 2 expression, patients with triple-negative breast cancer do not benefit from generally well-tolerated and effective therapies targeting the estrogen and human epidermal growth factor receptor 2 signaling pathways and are faced with an increased risk of disease progression and poorer overall survival. The heterogeneity of triple-negative breast cancer has been increasingly recognized and this may lead to therapeutic opportunities because of newly defined oncogenic drivers and targets. A subset of triple-negative breast tumors expresses the androgen receptor (AR) and this may benefit from treatments that inhibit the AR-signaling pathway. The first proof-of-concept trial established activity of the AR antagonist, bicalutamide, in patients with advanced AR+ triple-negative breast cancer. Since that time, evidence further supports the activity of other next-generation AR-targeted agents such as enzalutamide. Not unlike in estrogen receptor-positive breast cancer, mechanisms of resistance are being investigated and rationale exists for thoughtful, well-designed combination regimens such as AR antagonism with CDK4/6 pathway inhibitors or PI3K inhibitors. Furthermore, novel agents developed for the treatment of prostate cancer, which reduce androgen production such as abiraterone acetate and seviteronel, are being tested as well. This review summarizes the underlying biology of AR signaling in breast cancer development and the available clinical trial data for the use of anti-androgen therapy in the treatment of AR+ triple-negative breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

Three-Point Gear/Lead Screw Positioning

NASA Technical Reports Server (NTRS)

Calco, Frank S.

1993-01-01

Triple-ganged-lead-screw positioning mechanism drives movable plate toward or away from fixed plate and keeps plates parallel to each other. Designed for use in tuning microwave resonant cavity. Other potential applications include adjustable bed plates and cantilever tail stocks in machine tools, adjustable platforms for optical equipment, and lifting platforms.

Risk of locoregional recurrence by receptor status in breast cancer patients receiving modern systemic therapy and post-mastectomy radiation.

PubMed

Panoff, J E; Hurley, J; Takita, C; Reis, I M; Zhao, W; Sujoy, V; Gomez, C R; Jorda, M; Koniaris, L; Wright, J L

2011-08-01

We assessed differences in locoregional outcome based on receptor status combinations in a cohort of stage II-III breast cancer patients treated with modern trimodality therapy. Medical records of 582 consecutively treated patients receiving post-mastectomy radiation (PMRT) between 1/1999 and 12/2009 were reviewed. Rate of local regional recurrence (LRR) was estimated by the method of cumulative incidence allowing for competing risks. The effect of prognostic factors was examined by Gray's test and by Fine and Gray's modeling approach. Median follow-up was 44.7 months. Five-year progression-free survival (PFS) was 73.9% and overall survival (OS) was 84%. The cumulative 5-year incidence of LRR as first site of failure was 6.2% (95% CI 4.2-8.7). Five-year cumulative incidence of LRR was 8.6 versus 4.4% for estrogen receptor (ER) negative versus ER positive (P = 0.017), 8.5 versus 3.4% for progesterone receptor (PR) negative versus PR positive (P = 0.011), and 1.7 versus 7.5% for HER2 positive (86% received trastuzamab) versus HER2 negative (P = 0.032). Five-year cumulative incidence of LRR was 11.8% for the triple negative subtype and 3.9% for other receptor combinations (P < 0.001). Among patients whose disease is ER positive, 5-year LRR rate was 7.8 versus 3.4% for PR negative versus PR positive (P = 0.130). The prognostic value of the triple negative and HER2 negative subtypes was maintained on multivariate analysis. In the era of HER-2 targeted therapy, tumors that are HER-2 over expressing and are treated with trastuzumab have a very low rate of LRR. ER negative, PR negative, and triple negative status are associated with increased risk of LRR.

19p13.1 is a triple-negative-specific breast cancer susceptibility locus.

PubMed

Stevens, Kristen N; Fredericksen, Zachary; Vachon, Celine M; Wang, Xianshu; Margolin, Sara; Lindblom, Annika; Nevanlinna, Heli; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Vrieling, Alina; Flesch-Janys, Dieter; Sinn, Hans-Peter; Wang-Gohrke, Shan; Nickels, Stefan; Brauch, Hiltrud; Ko, Yon-Dschun; Fischer, Hans-Peter; Schmutzler, Rita K; Meindl, Alfons; Bartram, Claus R; Schott, Sarah; Engel, Christoph; Godwin, Andrew K; Weaver, Joellen; Pathak, Harsh B; Sharma, Priyanka; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Miron, Penelope; Yannoukakos, Drakoulis; Stavropoulou, Alexandra; Fountzilas, George; Gogas, Helen J; Swann, Ruth; Dwek, Miriam; Perkins, Annie; Milne, Roger L; Benítez, Javier; Zamora, María Pilar; Pérez, José Ignacio Arias; Bojesen, Stig E; Nielsen, Sune F; Nordestgaard, Børge G; Flyger, Henrik; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Cordina-Duverger, Emilie; Burwinkel, Barbara; Marmé, Frederick; Schneeweiss, Andreas; Sohn, Christof; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J; Peto, Julian; Johnson, Nichola; Fletcher, Olivia; Dos Santos Silva, Isabel; Fasching, Peter A; Beckmann, Matthias W; Hartmann, Arndt; Ekici, Arif B; Lophatananon, Artitaya; Muir, Kenneth; Puttawibul, Puttisak; Wiangnon, Surapon; Schmidt, Marjanka K; Broeks, Annegien; Braaf, Linde M; Rosenberg, Efraim H; Hopper, John L; Apicella, Carmel; Park, Daniel J; Southey, Melissa C; Swerdlow, Anthony J; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk J; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Huan-Ming; Hsiung, Chia-Ni; Hamann, Ute; Dünnebier, Thomas; Rüdiger, Thomas; Ulmer, Hans Ulrich; Pharoah, Paul P; Dunning, Alison M; Humphreys, Manjeet K; Wang, Qin; Cox, Angela; Cross, Simon S; Reed, Malcom W; Hall, Per; Czene, Kamila; Ambrosone, Christine B; Ademuyiwa, Foluso; Hwang, Helena; Eccles, Diana M; Garcia-Closas, Montserrat; Figueroa, Jonine D; Sherman, Mark E; Lissowska, Jolanta; Devilee, Peter; Seynaeve, Caroline; Tollenaar, Rob A E M; Hooning, Maartje J; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; John, Esther M; Miron, Alexander; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børresen-Dale, Anne-Lise; Giles, Graham G; Baglietto, Laura; McLean, Catriona A; Severi, Gianluca; Kosel, Matthew L; Pankratz, V S; Slager, Susan; Olson, Janet E; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Lambrechts, Diether; Hatse, Sigrid; Dieudonne, Anne-Sophie; Christiaens, Marie-Rose; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M; Soini, Ylermi; Easton, Douglas F; Couch, Fergus J

2012-04-01

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with the risk of ovarian cancer. Here, we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 OR, 1.10; 95% confidence interval (CI), 1.05-1.15; P = 3.49 × 10(-5)] and triple-negative (ER-, PR-, and HER2-negative) breast cancer (rs8170: OR, 1.22; 95% CI, 1.13-1.31; P = 2.22 × 10(-7)). However, rs8170 was no longer associated with ER-negative breast cancer risk when triple-negative cases were excluded (OR, 0.98; 95% CI, 0.89-1.07; P = 0.62). In addition, a combined analysis of triple-negative cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC; N = 3,566) identified a genome-wide significant association between rs8170 and triple-negative breast cancer risk (OR, 1.25; 95% CI, 1.18-1.33; P = 3.31 × 10(-13)]. Thus, 19p13.1 is the first triple-negative-specific breast cancer risk locus and the first locus specific to a histologic subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple-negative tumors and other subtypes likely arise through distinct etiologic pathways. ©2012 AACR.

A New Approach To Selectively Identify And Quantify Perfluorochemicals In Complex Matrices Using Ion Trap Time-Of-Flight Mass Spectrometry

EPA Science Inventory

Most of the published studies focusing on the environmental and biological distribution of perfluorinated alkyl compounds (PFCs) have used triple quadrupole mass spectrometers for compound identification and quantitation. Multiple-reaction-monitoring (MRM) is a sensitive mass sp...

Analysis of ecologically relevant pharmaceuticals in wastewater and surface water using selective solid phase extraction and UPLC/MS/MS

EPA Science Inventory

A rapid and sensitive method has been developed for the analysis of 48 human prescription active pharmaceutical ingredients (APIs) and 6 metabolites of interest, utilizing selective solid-phase extraction (SPE) and ultra performance liquid chromatography in combination with tripl...

Development of GEM gas detectors for X-ray crystal spectrometry

NASA Astrophysics Data System (ADS)

Chernyshova, M.; Czarski, T.; Dominik, W.; Jakubowska, K.; Rzadkiewicz, J.; Scholz, M.; Pozniak, K.; Kasprowicz, G.; Zabolotny, W.

2014-03-01

Two Triple Gas Electron Multiplier (Triple-GEM) detectors were developed for high-resolution X-ray spectroscopy measurements for tokamak plasma to serve as plasma evolution monitoring in soft X-ray region (SXR). They provide energy resolved fast dynamic plasma radiation imaging in the SXR with 0.1 kHz frequency. Detectors were designed and constructed for continuous data-flow precise energy and position measurement of plasma radiation emitted by metal impurities, W46+ and Ni26+ ions, at 2.4 keV and 7.8 keV photon energies, respectively. High counting rate capability of the detecting units has been achieved with good position resolution. This article presents results of the laboratory and tokamak experiments together with the system performance under irradiation by photon flux from the plasma core.

An evaluation of the efficacy of a triple P-positive parenting program podcast series.

PubMed

Morawska, Alina; Tometzki, Helen; Sanders, Matthew R

2014-01-01

Parenting programs based on cognitive-behavioral and social learning principles are effective in changing child behavior problems and parenting styles. However, such programs typically have limited population reach. The current study aimed to evaluate the efficacy of a brief radio series that provided parenting advice based on the Triple P-Positive Parenting Program. One hundred thirty-nine parents of children aged 2 to 10 years who had concerns about their child's behavioral and/or emotional adjustment were recruited, randomly assigned to either an intervention or waitlist control group, and completed online self-report measures. Parents in the intervention group were given access to seven Triple P podcasts online over a period of 2 weeks. Parents in the intervention group improved significantly more than parents in the control group, from pre- to postintervention, on measures of child behavioral problems and parenting style, self-efficacy, and confidence. These short-term intervention effects were maintained at the 6-month follow-up. These results suggest that brief radio and online parenting programs can be effective and have the potential to reach a large proportion of parents experiencing child behavior problems. Limitations, clinical significance, and future research suggestions are discussed.

Subtypes of breast cancer show different spatial distributions of brain metastases.

PubMed

Kyeong, Sunghyon; Cha, Yoon Jin; Ahn, Sung Gwe; Suh, Sang Hyun; Son, Eun Ju; Ahn, Sung Jun

2017-01-01

The aim of our study was to test the hypothesis that the spatial distribution of breast cancer brain metastases (BM) differ according to their biological subtypes. MR images of 100 patients with BM from primary breast cancer were retrospectively reviewed. Patients were divided according to the biological subtype of the primary tumor, (triple-negative: 24, HER2 positive: 48, luminal: 28). All images marked with BMs were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Distribution pattern of BM was evaluated with intra-group and intergroup analysis. In intra-group analysis, hot spots of metastases from triple-negative are evenly distributed in the brain, meanwhile BMs from HER2 positive and luminal type occur dominantly in occipital lobe and cerebellum. In intergroup analysis, BMs from triple-negative type occurred more often in frontal lobe, limbic region, and parietal lobe, compared with other types (P < .05). Breast cancer subtypes tend to demonstrate different spatial distributions of their BMs. These findings may have direct implications for dose modulation in prophylactic irradiation as well as for differential diagnoses. Thus, this result should be validated in future study with a larger population.

[18F]fluorodeoxyglucose triple-head coincidence imaging as an adjunct to 131I scanning for follow-up of papillary thyroid carcinoma.

PubMed

Gonzalo, Irene T Gaw; Itti, Emmanuel; Mlikotic, Anton; Pham, Le H; Cesar, Romeo B; Meignan, Michel; Mishkin, Fred S

2003-01-01

To evaluate the feasibility of using [(18)F]fluorodeoxyglucose ((18)FDG) triple-head coincidence imaging as a potential cost-effective alternative to positron emission tomography in the setting of suspected recurrence of papillary thyroid carcinoma. We retrospectively studied 10 patients with suspected recurrence of papillary carcinoma of the thyroid, who underwent (18)FDG coincidence imaging,(131)I scanning, and a reference anatomic scan (computed tomography, magnetic resonance imaging, or both) within 1 year in most cases. The (131)I scan detected the recurrence in five patients (62.5%) and failed to reveal recurrent cancer in three patients (37.5%); in contrast,(18)FDG imaging detected the recurrence in eight patients (100%) and was true negative in two patients in whom the scans were performed more than 1 year after effective therapy for the recurrence. The sensitivity of detection was unrelated to lesion size. The (18)FDG imaging results led to additional radiotherapy in all (131)I-negative patients, two of whom had high thyroglobulin levels and one of whom had a low thyroglobulin concentration but the presence of antithy-roglobulin antibodies. We conclude that (18)FDG triple-head coincidence imaging is useful for routine management of patients with thyroid cancer who have no abnormalities detected on (131)I scans but have high serum thyroglobulin levels. This technique, however, may not be as sensitive as a dedicated positron emission tomographic device, particularly for the assessment of small tumors.

Stepping Stones Triple P: an RCT of a parenting program with parents of a child diagnosed with an autism spectrum disorder.

PubMed

Whittingham, Koa; Sofronoff, Kate; Sheffield, Jeanie; Sanders, Matthew R

2009-05-01

Whilst the Triple P Positive Parenting Program has a large evidence base (Sanders, Clinical Child and Family Psychology Review 2:71-90, 1999; Sanders, Journal of Consulting and Clinical Psychology 68:624-640, 2000) and preliminary evidence indicates that Stepping Stones Triple P is also efficacious (Roberts, Journal of Clinical Child and Adolescent Psychology, 35(2):180-193, 2006), to date Stepping Stones has not been evaluated with the ASD population. Fifty-nine families with a child with ASD aged between 2 and 9 participated in this randomized controlled trial. The results demonstrate significant improvements in parental reports of child behaviour and parenting styles with the treatment effects for child behaviour, parental over reactivity and parental verbosity being maintained at follow-up 6 months later. Further, the results suggest significant improvements in parental satisfaction and conflict about parenting as well as a sleeper effect for parental efficacy. The results indicate that Stepping Stones Triple P is a promising intervention for parents of children with ASD. Limitations and future research are also addressed.

The noninvasive mouse ear swelling assay. I. Refinements for detecting weak contact sensitizers.

PubMed

Thorne, P S; Hawk, C; Kaliszewski, S D; Guiney, P D

1991-11-01

The noninvasive mouse ear swelling assay (MESA) is a model for delayed-type hypersensitivity that holds promise as a testing protocol for allergic contact dermatitis (ACD). The MESA employs only topical sensitization on the abdomen and does not use injections, adjuvants, anesthesia, occlusion, or disruption of the stratum corneum. Five days after induction, the ears are challenged topically and ear swelling measurements taken at 24, 48, and 72 hr indicate the extent of ACD. In this study, refinements of the assay were explored in BALB/cBy mice using dinitrofluorobenzene (DNFB) and dinitrochlorobenzene (DNCB). A complete dose-response curve was developed for DNFB and the dose which sensitized half the mice in a group (SD50, 0.001%, w/v) was used to test noninvasive enhancement protocols. Several triple-dose protocols tested produced no increase in responsiveness and daily dosing showed a trend toward tolerance induction yielding 20% positive responses. Dietary vitamin A supplementation produced a dramatic enhancement of the responses: ear thickness increase was doubled and the SD50 sensitized 94 to 100% of the mice in the vitamin A groups. We conclude that the MESA allowed identification of ACD potency for known sensitizers at very low concentrations which do not produce ACD with other techniques. The importance of dose-response studies for avoiding the high-dose reduced-response region was also shown. Based on the observation that the vitamin A-augmented MESA was considerably more sensitive than with regular feed, a companion study (P.S. Thorne. C. Hawk, S.D. Kaliszewski, P.D. Guiney, Fundam. Appl. Tox. 17, 807-820, 1991) presents tests of the enhancements to the MESA developed in this work, using weak sensitizers and complex mixtures.

Progressive accumulation of ubiquitin and disappearance of alpha-synuclein epitope in multiple system atrophy-associated glial cytoplasmic inclusions: triple fluorescence study combined with Gallyas-Braak method.

PubMed

Sakamoto, Masaki; Uchihara, Toshiki; Nakamura, Ayako; Mizutani, Toshio; Mizusawa, Hidehiro

2005-10-01

Alpha-synuclein (alphaS) and ubiquitin (Ub) are shared constituents of glial cytoplasmic inclusions (GCIs) and Lewy bodies (LBs), both composed of fibrillary structures. Staining profiles of GCIs were investigated with triple immunofluorescence involving immunostaining for alphaS and Ub, both amplified with catalyzed reporter deposition, and a fluorochrome, thiazin red (TR) that has an affinity to fibrillary structures. After observation for the triple-fluorescent images, the sections were subsequently stained with the Gallyas-Braak method. Sections of putamen, cerebellar white matter and motor cortex from patients suffering from multiple system atrophy (MSA) with varying duration of the disease (4-15 years) were quantified for these staining profiles of Gallyas-positive GCIs. Although most of GCIs were positive for Ub and variably positive for alphaS, they were consistently negative for TR. The result was opposite in LBs in Lewy body disease with variable affinity to TR, suggesting that the construction of GCIs is different from that of LBs. These four staining features (alphaS, Ub, TR and Gallyas) alone failed to exhibit apparent correlation with disease duration, lesion site or severity of degeneration as reported previously. The fraction of alphaS-negative and Ub-positive GCIs, however, linearly increased along the disease progression, while that of alphaS-positive and Ub-negative GCIs decreased in contrast. This reciprocal change suggests that alphaS immunoreactivity in GCIs is being replaced by Ub immunoreactivity during the disease progression, which resulted in the ultimate predominance of alphaS-negative and Ub-positive GCIs in the most advanced case. Interestingly, this predominance of alphaS-negative and Ub-positive GCIs was a feature of motor cortex, where degeneration usually remains mild in spite of robust appearance of Gallyas-positive GCIs. Another fraction, alphaS-positive and Ub-positive GCIs were frequent in cerebellar white matter, suggesting that GCI evolution is heterogeneous and dependent also on area examined. Progressive accumulation of Ub with concomitant disappearance of alphaS epitope and their colocalization, partly shared with LBs, may represent a process of GCI formation, possibly linked to an aspect of degeneration in MSA.

Triple dividends of water consumption charges in South Africa

NASA Astrophysics Data System (ADS)

Letsoalo, Anthony; Blignaut, James; de Wet, Theuns; de Wit, Martin; Hess, Sebastiaan; Tol, Richard S. J.; van Heerden, Jan

2007-05-01

The South African government is exploring ways to address water scarcity problems by introducing a water resource management charge on the quantity of water used in sectors such as irrigated agriculture, mining, and forestry. It is expected that a more efficient water allocation, lower use, and a positive impact on poverty can be achieved. This paper reports on the validity of these claims by applying a computable general equilibrium model to analyze the triple dividend of water consumption charges in South Africa: reduced water use, more rapid economic growth, and a more equal income distribution. It is shown that an appropriate budget-neutral combination of water charges, particularly on irrigated agriculture and coal mining, and reduced indirect taxes, particularly on food, would yield triple dividends, that is, less water use, more growth, and less poverty.

Feline mammary basal-like adenocarcinomas: a potential model for human triple-negative breast cancer (TNBC) with basal-like subtype.

PubMed

Wiese, David A; Thaiwong, Tuddow; Yuzbasiyan-Gurkan, Vilma; Kiupel, Matti

2013-09-03

Breast cancer is one of the leading causes of cancer deaths. Triple-negative breast cancer (TNBC), an immunophenotype defined by the absence of immunolabeling for estrogen receptor (ER), progesterone receptor (PR) and HER2 protein, has a highly aggressive behavior. A subpopulation of TNBCs exhibit a basal-like morphology with immunohistochemical positivity for cytokeratins 5/6 (CK5/6) and/or epidermal growth factor receptor (EGFR), and have a high incidence of BRCA (breast cancer susceptibility) mutations. Feline mammary adenocarcinomas (FMAs) are highly malignant and share a similar basal-like subtype. The purpose of this study was to classify FMAs according to the current human classification of breast cancer that includes evaluation of ER, PR and HER2 status and expression of basal CK 5/6 and EGFR. Furthermore, we selected triple negative, basal-like FMAs to screen for BRCA mutations similar to those described in human TNBC. Twenty four FMAs were classified according to the current human histologic breast cancer classification including immunohistochemistry (IHC) for ER, PR HER2, CK5/6 and EGFR. Genetic alteration and loss of heterozygosity of BRCA1 and BRCA2 genes were analyzed in triple negative, basal-like FMAs. IHC for ER, PR and HER2 identified 14 of the 24 (58%) FMAs as a triple negative. Furthermore, 11 of these 14 (79%) triple negative FMAs had a basal-like subtype. However, no genetic abnormalities were detected in BRCA1 and BRCA2 by direct sequencing and loss of heterozygosity analysis. FMAs are highly aggressive neoplasms that are commonly triple negative and exhibit a basal-like morphology. This is similar to human TNBC that are also commonly classified as a basal-like subtype. While sequencing of a select number of triple negative, basal-like FMAs and testing for loss of heterozygosity of BRCA1 and BRCA2 did not identify mutations similar to those described in human TNBC, further in-depth evaluation is required to elucidate a potential role of BRCA in the tumorigenesis of triple negative, basal-like FMAs. The strong similarities in clinical behavior, morphology and IHC phenotype suggest that triple negative, basal-like FMAs may be a suitable spontaneous animal model for studying novel therapeutic approaches against human basal-like TNBC.

GPS satellite clock determination in case of inter-frequency clock biases for triple-frequency precise point positioning

NASA Astrophysics Data System (ADS)

Guo, Jiang; Geng, Jianghui

2017-12-01

Significant time-varying inter-frequency clock biases (IFCBs) within GPS observations prevent the application of the legacy L1/L2 ionosphere-free clock products on L5 signals. Conventional approaches overcoming this problem are to estimate L1/L5 ionosphere-free clocks in addition to their L1/L2 counterparts or to compute IFCBs between the L1/L2 and L1/L5 clocks which are later modeled through a harmonic analysis. In contrast, we start from the undifferenced uncombined GNSS model and propose an alternative approach where a second satellite clock parameter dedicated to the L5 signals is estimated along with the legacy L1/L2 clock. In this manner, we do not need to rely on the correlated L1/L2 and L1/L5 ionosphere-free observables which complicates triple-frequency GPS stochastic models, or account for the unfavorable time-varying hardware biases in undifferenced GPS functional models since they can be absorbed by the L5 clocks. An extra advantage over the ionosphere-free model is that external ionosphere constraints can potentially be introduced to improve PPP. With 27 days of triple-frequency GPS data from globally distributed stations, we find that the RMS of the positioning differences between our GPS model and all conventional models is below 1 mm for all east, north and up components, demonstrating the effectiveness of our model in addressing triple-frequency observations and time-varying IFCBs. Moreover, we can combine the L1/L2 and L5 clocks derived from our model to calculate precisely the L1/L5 clocks which in practice only depart from their legacy counterparts by less than 0.006 ns in RMS. Our triple-frequency GPS model proves convenient and efficient in combating time-varying IFCBs and can be generalized to more than three frequency signals for satellite clock determination.

Lifestyle Triple P: a parenting intervention for childhood obesity

PubMed Central

2012-01-01

Background Reversing the obesity epidemic requires the development and evaluation of childhood obesity intervention programs. Lifestyle Triple P is a parent-focused group program that addresses three topics: nutrition, physical activity, and positive parenting. Australian research has established the efficacy of Lifestyle Triple P, which aims to prevent excessive weight gain in overweight and obese children. The aim of the current randomized controlled trial is to assess the effectiveness of the Lifestyle Triple P intervention when applied to Dutch parents of overweight and obese children aged 4–8 years. This effectiveness study is called GO4fit. Methods/Design Parents of overweight and obese children are being randomized to either the intervention or the control group. Those assigned to the intervention condition receive the 14-week Lifestyle Triple P intervention, in which they learn a range of nutritional, physical activity and positive parenting strategies. Parents in the control group receive two brochures, web-based tailored advice, and suggestions for exercises to increase active playing at home. Measurements are taken at baseline, directly after the intervention, and at one year follow-up. Primary outcome measure is the children’s body composition, operationalized as BMI z-score, waist circumference, and fat mass (biceps and triceps skinfolds). Secondary outcome measures are children’s dietary behavior and physical activity level, parenting practices, parental feeding style, parenting style, parental self-efficacy, and body composition of family members (parents and siblings). Discussion Our intervention is characterized by a focus on changing general parenting styles, in addition to focusing on changing specific parenting practices, as obesity interventions typically do. Strengths of the current study are the randomized design, the long-term follow-up, and the broad range of both self-reported and objectively measured outcomes. Trial Registration Current Controlled Trials NTR 2555 MEC AzM/UM NL 31988.068.10 / MEC 10-3-052 PMID:22471971

The effectiveness of lifestyle triple P in the Netherlands: a randomized controlled trial.

PubMed

Gerards, Sanne M P L; Dagnelie, Pieter C; Gubbels, Jessica S; van Buuren, Stef; Hamers, Femke J M; Jansen, Maria W J; van der Goot, Odilia H M; de Vries, Nanne K; Sanders, Matthew R; Kremers, Stef P J

2015-01-01

Lifestyle Triple P is a general parenting intervention which focuses on preventing further excessive weight gain in overweight and obese children. The objective of the current study was to assess the effectiveness of the Lifestyle Triple P intervention in the Netherlands. We used a parallel randomized controlled design to test the effectiveness of the intervention. In total, 86 child-parent triads (children 4-8 years old, overweight or obese) were recruited and randomly assigned (allocation ratio 1:1) to the Lifestyle Triple P intervention or the control condition. Parents in the intervention condition received a 14-week intervention consisting of ten 90-minute group sessions and four individual telephone sessions. Primary outcome measure was the children's body composition (BMI z-scores, waist circumference and skinfolds). The research assistant who performed the measurements was blinded for group assignment. Secondary outcome measures were the children's dietary behavior and physical activity level, parenting practices, parental feeding style, parenting style, and parental self-efficacy. Outcome measures were assessed at baseline and 4 months (short-term) and 12 months (long-term) after baseline. Multilevel multiple regression analyses were conducted to determine the effect of the intervention on primary and secondary outcome measures. No intervention effects were found on children's body composition. Analyses of secondary outcomes showed positive short-term intervention effects on children's soft-drink consumption and parental responsibility regarding physical activity, encouragement to eat, psychological control, and efficacy and satisfaction with parenting. Longer-term intervention effects were found on parent's report of children's time spent on sedentary behavior and playing outside, parental monitoring food intake, and responsibility regarding nutrition. Although the Lifestyle Triple P intervention showed positive effects on some parent reported child behaviors and parenting measures, no effects were visible on children's body composition or objectively measured physical activity. Several adjustments of the intervention content are recommended, for example including a booster session. Nederlands Trial Register NTR 2555.

Two-color detection with charge sensitive infrared phototransistors

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Sunmi, E-mail: kimsunmi@iis.u-tokyo.ac.jp; Kajihara, Yusuke; Komiyama, Susumu

2015-11-02

Highly sensitive two-color detection is demonstrated at wavelengths of 9 μm and 14.5 μm by using a charge sensitive infrared phototransistor fabricated in a triple GaAs/AlGaAs quantum well (QW) crystal. Two differently thick QWs (7 nm- and 9 nm-thicknesses) serve as photosensitive floating gates for the respective wavelengths via intersubband excitation: The excitation in the QWs is sensed by a third QW, which works as a conducting source-drain channel in the photosensitive transistor. The two spectral bands of detection are shown to be controlled by front-gate biasing, providing a hint for implementing voltage tunable ultra-highly sensitive detectors.

Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Older Patients With Locally Advanced or Metastatic Breast Cancer

ClinicalTrials.gov

2018-03-05

Male Breast Cancer; Recurrent Breast Cancer; Stage IV Breast Cancer; Estrogen Receptor-negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2-negative Breast Cancer; HER2-positive Breast Cancer; Progesterone Receptor-negative Breast Cancer; Progesterone Receptor-positive Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Triple-negative Breast Cancer

Brainstem Alzheimer’s-Like Pathology in the Triple Transgenic Mouse Model of Alzheimer’s Disease

PubMed Central

Overk, Cassia R.; Kelley, Christy M.; Mufson, Elliott J.

2011-01-01

The triple transgenic mouse (3xTgAD), harboring human APPSwe, PS1M146V and TauP301L genes, develops age-dependent forebrain intraneuronal Aβ and tau and extraneuronal plaques. We evaluated brainstem AD-like pathology using 6E10, AT8, and Alz50 antibodies and unbiased stereology in young and old 3xTgAD mice. Intraneuronal Aβ occurred in the tectum, periaqueductal gray, substantia nigra, red nucleus, tegmentum and mesencephalic V nucleus at all ages. Aβ-positive neuron numbers significantly decreased in the superior colliculus and substantia nigra while AT8-positive superior colliculus, red nucleus, principal sensory V, vestibular nuclei, and tegmental neurons significantly increased between 2 and 12 months. Alz50-positive neuron numbers increased only in the inferior colliculus between these ages. Dual labeling revealed a few Aβ- and tau- positive neurons. Plaques occurred only in the pons of female 3xTgAD mice starting at 9 months. 3xTgAD mice provide a platform to define in vivo mechanisms of Aβ and tau brainstem pathology. PMID:19524671

Methionine Deprivation Induces a Targetable Vulnerability in Triple-negative Breast Cancer Cells by Enhancing TRAIL Receptor-2 Expression

PubMed Central

Strekalova, Elena; Malin, Dmitry; Good, David M.; Cryns, Vincent L.

2015-01-01

Purpose Many neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists. Experimental Design Human triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media. The effects of methionine depletion on TRAIL receptor expression and sensitivity to chemotherapy or a humanized agonistic TRAIL-R2 monoclonal antibody (lexatumumab) were determined. The melanoma-associated antigen MAGED2 was silenced to delineate its functional role in sensitizing TNBC cells to methionine stress. An orthotopic TNBC model was utilized to evaluate the effects of dietary methionine deficiency, lexatumumab or the combination. Results Methionine depletion sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis by increasing TRAIL-R2 mRNA and cell surface expression. MCF-10A cells transformed by oncogenic H-Ras, but not untransformed cells, and matrix-detached TNBC cells were highly sensitive to the combination of lexatumumab and methionine depletion. Proteomics analyses revealed that MAGED2, which has been reported to reduce TRAIL-R2 expression, was suppressed by methionine stress. Silencing MAGED2 recapitulated features of methionine deprivation, including enhanced mRNA and cell surface expression of TRAIL receptors and increased sensitivity to TRAIL receptor agonists. Dietary methionine deprivation enhanced the antitumor effects of lexatumumab in an orthotopic metastatic TNBC model. Conclusion Methionine depletion exposes a targetable defect in TNBC cells by increasing TRAIL-R2 expression. Our findings provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists. PMID:25724522

Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro

PubMed Central

Weingartshofer, Sigrid; Grunt, Thomas W.; Mairhofer, Mario; Tan, Yen; Gamper, Jutta; Singer, Christian F.

2017-01-01

Background Zoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro. Materials and methods Using assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol. Results In the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively). Conclusion We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status. PMID:28945801

Estradiol impairs the antiproliferative and proapoptotic effect of Zoledronic acid in hormone sensitive breast cancer cells in vitro.

PubMed

Gschwantler-Kaulich, Daphne; Weingartshofer, Sigrid; Grunt, Thomas W; Mairhofer, Mario; Tan, Yen; Gamper, Jutta; Singer, Christian F

2017-01-01

Zoledronic acid (ZA) has antiresorptive effects and protects from bone metastasis in women with early breast cancer. In addition, in postmenopausal women with endocrine responsive breast cancer ZA prolongs DFS. The exact mechanism is still unclear. We have therefore investigated the effect of increasing concentrations of ZA in breast cancer cell lines in the absence or presence of estradiol to mimic the hormonal environment in vitro. Using assays for cell proliferation (EZ4U, BrdU) and cell death (Annexin/PI), we have analyzed the dose-dependent antiproliferative and pro-apoptotic effects of ZA in two hormone sensitive cell lines (MCF-7 and T47D) and a hormone insensitive, triple negative cell line (MDA-MB-231) in the presence of 0, 1 and 10 nM estradiol. In the absence of estradiol, ZA exerts dose-dependent antiproliferative and pro-apoptotic antitumor effects in both, hormone sensitive (MCF-7, T47D) and -insensitive (MDA-MB-231) breast cancer cell lines (p<0.0001). In the presence of estradiol, the antitumoral effect of ZA was significantly decreased only in the hormone sensitive MCF-7 and T47D cell lines (p = 0.0008 and p = 0.0008, respectively). We have demonstrated that estradiol impairs the antiproliferative and proapoptotic effect of ZA in hormone sensitive, but not in hormone insensitive breast cancer cell lines. Our findings provide a possible explanation for the differential effect of ZA on DFS in pre- and postmenopausal patients with hormone sensitive early breast cancer, which has been demonstrated clinically. We further hypothesize that endocrine insensitive tumors such as triple negative breast cancer (TNBC) should benefit from ZA irrespective of their menopausal status.

Dual antiplatelet therapy after percutaneous coronary intervention with stent implantation in patients taking chronic oral anticoagulation.

PubMed

Rogacka, Renata; Chieffo, Alaide; Michev, Iassen; Airoldi, Flavio; Latib, Azeem; Cosgrave, John; Montorfano, Matteo; Carlino, Mauro; Sangiorgi, Giuseppe M; Castelli, Alfredo; Godino, Cosmo; Magni, Valeria; Aranzulla, Tiziana C; Romagnoli, Enrico; Colombo, Antonio

2008-02-01

The purpose of this study was to evaluate the safety of dual antiplatelet therapy in patients in whom long-term anticoagulation (AC) with warfarin is recommended. The optimal antithrombotic strategy after percutaneous coronary intervention (PCI) for patients receiving AC is unclear. Consecutive patients who underwent stent implantation and were discharged on triple therapy (defined as the combination of aspirin and thienopyridines and AC) were analyzed. Of the 127 patients with 224 lesions, 86.6% were men, with a mean age of 69.9 +/- 8.8 years. Drug-eluting stents (DES) were positioned in 71 (55.9%), and bare-metal stents (BMS) were positioned in 56 (44.1%) patients. Atrial fibrillation (AF) was the main indication (59.1%) for AC treatment. The mean triple therapy duration was 5.6 +/- 4.6 months, and clinical follow-up was 21.0 +/- 19.8 months. During the triple therapy period, 6 patients (4.7%) developed major bleeding complications; 67% occurred within the first month. No significant differences between DES and BMS were observed in the incidence of major (5.6% vs. 3.6%, respectively, p = 1.0) and minor (1.4% vs. 3.6%, respectively, p = 0.57) bleeding and mortality (5.6% vs. 1.8%, respectively, p = 0.39). A significant difference was observed in favor of DES in target vessel revascularization (14.1% vs. 26.8%, p = 0.041). While receiving triple therapy, major bleeding occurred in 4.7% of patients; one-half of the events were lethal, and most occurred within the first month.

Pre-operative use of dexamethasone does not reduce incidence or intensity of bleaching-induced tooth sensitivity. A triple-blind, parallel-design, randomized clinical trial.

PubMed

da Costa Poubel, Luiz Augusto; de Gouvea, Cresus Vinicius Deppes; Calazans, Fernanda Signorelli; Dip, Etyene Castro; Alves, Wesley Veltri; Marins, Stella Soares; Barcelos, Roberta; Barceleiro, Marcos Oliveira

2018-04-25

This study evaluated the effect of the administration of pre-operative dexamethasone on tooth sensitivity stemming from in-office bleaching. A triple-blind, parallel-design, randomized clinical trial was conducted on 70 volunteers who received dexamethasone or placebo capsules. The drugs were administered in a protocol of three daily 8-mg doses of the drug, starting 48 h before the in-office bleaching treatment. Two bleaching sessions with 37.5% hydrogen peroxide gel were performed with a 1-week interval. Tooth sensitivity (TS) was recorded on visual analog scales (VAS) and numeric rating scales (NRS) in different periods up to 48 h after bleaching. The color evaluations were also performed. The absolute risk of TS and its intensity were evaluated by using Fisher's exact test. Comparisons of the TS intensity (NRS and VAS data) were performed by using the Mann-Whitney U test and a two-way repeated measures ANOVA and Tukey's test, respectively. In both groups, a high risk of TS (Dexa 80% x Placebo 94%) was detected. No significant difference was observed in terms of TS intensity. A whitening of approximately 3 shade guide units of the VITA Classical was detected in both groups, which were statistically similar. It was concluded that the administration pre-operatively of dexamethasone, in the proposed protocol, does not reduce the incidence or intensity of bleaching-induced tooth sensitivity. The use of dexamethasone drug before in-office bleaching treatment does not reduce incidence or intensity of tooth sensitivity. NCT02956070.

A Bright Side to the Work-Family Interface: Husbands' Support as a Resource in Double-and-Triple-Duty Caregiving Wives' Work Lives.

PubMed

DePasquale, Nicole; Polenick, Courtney A; Davis, Kelly D; Berkman, Lisa F; Cabot, Thomas D

2017-06-16

This study examined how women who combine long-term care employment with unpaid, informal caregiving roles for children (double-duty-child caregivers), older adults (double-duty-elder caregivers), and both children and older adults (triple-duty caregivers) differed from their workplace-only caregiving counterparts on workplace factors related to job retention (i.e., job satisfaction and turnover intentions) and performance (i.e., perceived obligation to work while sick and emotional exhaustion). The moderating effects of perceived spouse support were also examined. Regression analyses were conducted on survey data from 546 married, heterosexual women employed in U.S.-based nursing homes. Compared to workplace-only caregivers, double-duty-elder and triple-duty caregivers reported more emotional exhaustion. Double-duty-child caregivers reported lower turnover intentions and both double-and-triple-duty caregivers felt less obligated to work while sick when perceiving greater support from husbands. Results indicate that double-and-triple-duty caregiving women's job retention and obligation to work while sick may depend on perceived spouse support, highlighting the important role husbands play in their wives' professional lives. Findings also lend support to the emerging literature on marriage-to-work positive spillover, and suggest that long-term care organizations should target marital relationships in family-friendly initiatives to retain and engage double-and-triple-duty caregiving employees. © The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Study on pharmacokinetics of 3,4-divanillyltetrahydrofuran in rats by ultra-fast liquid chromatography/tandem mass spectrometry.

PubMed

Shan, Chen-Xiao; Cui, Xiao-Bing; Yu, Sheng; Chai, Chuan; Wen, Hong-Mei; Wang, Xin-Zhi; Sun, Xue

2016-01-01

3,4-Divanillyltetrahydrofuran is the main active ingredient of nettle root which can increase steroid hormones in the bloodstream for many of bodybuilders. To better understand its pharmacological activities, we need to determine its pharmacokinetic profiles. In this study, a rapid and sensitive ultra-fast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method has been developed for the determination of 3,4-divanillyltetrahydrofuran in the plasma of rats. Chromatographic separation was performed on a C18 column at 40°C, with a gradient elution consisting of methanol and water containing 0.3% (v/v) formic acid at a flow rate of 0.8mL/min. The detection was performed using an electrospray triple-quadrupole MS/MS via positive ion multiple reaction monitoring mode. The lower limits-of-quantification determined were 0.5ng/mL. The intra- and inter-day precision (RSD%) was found to be within 15% and the accuracy (RE%) ranged from -4.0% to 7.0%. This simple yet sensitive method was fully validated and could be successfully applied to the study on pharmacokinetics of 3, 4-divanillyltetrahydrofuran. Copyright © 2015 Elsevier B.V. All rights reserved.

Black phosphorus nanosheets for rapid microRNA detection.

PubMed

Zhou, Jie; Li, Zhongjun; Ying, Ming; Liu, Maixian; Wang, Xiaomei; Wang, Xianyou; Cao, Liwei; Zhang, Han; Xu, Gaixia

2018-03-15

Herein, for the first time, a sensitive sensing platform for rapid detection of microRNA was developed by employing black phosphorus nanosheets as the fluorescence quenching material. The biosensor displayed a good linear response to microRNA ranging from 10 nM to 1000 nM. Moreover, the biosensor could distinguish triple nucleotide polymorphism.

A sensitive Faraday rotation setup using triple modulation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Phelps, G.; Abney, J.; Broering, M.

2015-07-15

The utilization of polarized targets in scattering experiments has become a common practice in many major accelerator laboratories. Noble gases are especially suitable for such applications, since they can be easily hyper-polarized using spin exchange or metastable pumping techniques. Polarized helium-3 is a very popular target because it often serves as an effective polarized neutron due to its simple nuclear structure. A favorite cell material to generate and store polarized helium-3 is GE-180, a relatively dense aluminosilicate glass. In this paper, we present a Faraday rotation method, using a new triple modulation technique, where the measurement of the Verdet constantsmore » of SF57 flint glass, pyrex glass, and air was tested. The sensitivity obtained shows that this technique may be implemented in future cell wall characterization and thickness measurements. We also discuss the first ever extraction of the Verdet constant of GE-180 glass for four wavelength values of 632 nm, 773 nm, 1500 nm, and 1547 nm, whereupon the expected 1/λ{sup 2} dependence was observed.« less

A novel colorimetric triple-helix molecular switch aptasensor for ultrasensitive detection of tetracycline.

PubMed

Ramezani, Mohammad; Mohammad Danesh, Noor; Lavaee, Parirokh; Abnous, Khalil; Mohammad Taghdisi, Seyed

2015-08-15

Detection methods of antibiotic residues in blood serum and animal derived foods are of great interest. In this study a colorimetric aptasensor was designed for sensitive, selective and fast detection of tetracycline based on triple-helix molecular switch (THMS) and gold nanoparticles (AuNPs). As a biosensor, THMS shows distinct advantages including high stability, sensitivity and preserving the selectivity and affinity of the original aptamer. In the absence of tetracycline, THMS is stable, leading to the aggregation of AuNPs by salt and an obvious color change from red to blue. In the presence of tetracycline, aptamer binds to its target, signal transduction probe (STP) leaves the THMS and adsorbs on the surface of AuNPs. So the well-dispersed AuNPs remain stable against salt-induced aggregation with a red color. The presented aptasensor showed high selectivity toward tetracyclines with a limit of detection as low as 266 pM for tetracycline. The designed aptasensor was successfully applied to detect tetracycline in serum and milk. Copyright © 2015 Elsevier B.V. All rights reserved.

Conformational assembly and biological properties of collagen mimetic peptides and their thermally responsive polymer conjugates

NASA Astrophysics Data System (ADS)

Krishna, Ohm Divyam

2011-12-01

Collagens are one of the most abundant proteins found in body tissues and organs, endowing structural integrity, mechanical strength, and multiple biological functions. Destabilized collagen inside human body leads to various degenerative diseases (ex. osteoarthritis) and ageing. This has continued to motivate the design of synthetic peptides and bio-synthetic polypeptides to closely mimic the native collagens in terms of triple helix structure and stability, potential for higher order assembly, and biological properties. However, the widespread application of de novo collagens has been limited in part by the need for hydroxylated proline in the formation of stable triple helical structures. To address this continued need, a hydroxyproline-free, thermally stable collagen-mimetic peptide (CLP-Cys) was rationally designed via the incorporation of electrostatically stabilized amino acid triplets. CLP-Cys was synthesized via solid phase peptide synthesis. The formation and stability of the triple helical structure were indicated via circular dichroism (CD) experiments and confirmed via differential scanning calorimetry (DSC) results. CLP-Cys also self-assembled into nano-rods and micro-fibrils, as evidenced via a combination of dynamic light scattering and transmission electron microscopy. Given the high thermal stability and its propensity for higher-order assembly, CLP-Cys was further functionalized at both the ends with a thermally responsive polymer, poly(diethylene glycol methyl ether methacrylate), (PDEGMEMA) to synthesize a biohybrid triblock copolymer. The CD results indicated that the triple helical form is retained, the thermal unfolding is sustained and helix to coil transition is reversible in the triblock hybrid context. The LCST of PDEGMEMA homopolymer (26 °C) is increased (to 35 °C) upon conjugation to the hydrophilic collagen peptide domain. Further, a combination of static light scattering, Cryo-SEM, TEM and confocal microscopy elucidated that the collapse of the thermo-responsive polymer upon heating (to above the LCST) leads to the assembly of these hybrid materials as micrometer sized spheres. At 75 °C a morphological transformation from spheres to fibrils were observed. These studies provided unique perspectives about the impact of stimuli-responsive polymers and the triple-helix forming peptides on each other; and how temperature as a stimulus can be employed to sequentially guide the assembly. The development of self-assembling hybrid materials with multiple sensitivities to temperature would offer useful opportunities in the design of stimuli-responsive nano-materials. The CLP-Cys peptide sequence has been designed to incorporate biologically relevant amino acid triplets (GEKGER) and its positive impact was seen via recruitment of human mesenchymal stem cells (hMSCs) for adhesion, spreading and proliferation on CLP-Cys functionalized glass and hyaluronic acid based hydrogel surfaces. Therefore, the prospects of these materials in biomedical applications including wound healing and tissue engineering are promising.

GATA-3 and FOXA1 expression is useful to differentiate breast carcinoma from other carcinomas.

PubMed

Davis, Drew G; Siddiqui, Momin T; Oprea-Ilies, Gabriela; Stevens, Keith; Osunkoya, Adeboye O; Cohen, Cynthia; Li, Xiaoxian Bill

2016-01-01

GATA-3, a member of the GATA family of zinc-finger DNA binding proteins, and FOXA1, a member of the forkhead transcription factor family, are both associated with estrogen receptor expression. Both GATA-3 and FOXA1 are useful markers for breast carcinoma, but their expression in the different breast cancer subtypes and other neoplasms has not been thoroughly evaluated. We examined the expression of GATA-3 and FOXA1 in estrogen receptor-positive, Her2/neu-positive, and triple-negative breast carcinomas as well as in 10 other common carcinomas, including hepatocellular, colonic, pancreatic, gastric, endometrial (endometrioid), lung, prostatic, renal cell, urothelial, and ovarian serous carcinomas. Primary and metastatic melanomas and mesotheliomas were also evaluated. GATA-3 and FOXA1 staining of estrogen receptor-positive breast carcinomas was seen in 96.6% and 96.2%, respectively. In triple-negative breast carcinomas, GATA-3 and FOXA1 staining was seen in 21.6% and 15.9%, respectively. Among the other tumors, GATA-3 staining was only seen in urothelial carcinoma (70.9%) and FOXA1 staining was only seen in prostatic (87.5%), urothelial (5.1%) carcinomas, and mesotheliomas (40.0%). In conclusion, GATA-3 and FOXA1 are excellent breast carcinoma markers; however, their utility is limited in the triple-negative subtype. The utility of FOXA1 in diagnosing prostatic carcinoma and mesothelioma warrants further investigation. Copyright © 2015 Elsevier Inc. All rights reserved.

Study of plasma parameters in a pulsed plasma accelerator using triple Langmuir probe

NASA Astrophysics Data System (ADS)

Borthakur, S.; Talukdar, N.; Neog, N. K.; Borthakur, T. K.

2018-01-01

A Triple Langmuir Probe (TLP) has been used to study plasma parameters of a transient plasma produced in a newly developed Pulsed Plasma Accelerator system. In this experiment, a TLP with a capacitor based current mode biasing circuit was used that instantaneously gives voltage traces in an oscilloscope which are directly proportional to the plasma electron temperature and density. The electron temperature (Te) and plasma density (ne) of the plasma are measured with the help of this probe and found to be 24.13 eV and 3.34 × 1021/m3 at the maximum energy (-15 kV) of the system, respectively. An attempt was also made to analyse the time-dependent fluctuations in plasma parameters detected by the highly sensitive triple probe. In addition to this, the variation of these parameters under different discharge voltages was studied. The information obtained from these parameters is the initial diagnostics of a new device which is to be dedicated to study the impact of high heat flux plasma stream upon material surfaces inside an ITER like tokamak.

Polymer-Coated Hollow Mesoporous Silica Nanoparticles for Triple-Responsive Drug Delivery.

PubMed

Zhang, Yuanyuan; Ang, Chung Yen; Li, Menghuan; Tan, Si Yu; Qu, Qiuyu; Luo, Zhong; Zhao, Yanli

2015-08-19

In this study, pH, reduction and light triple-responsive nanocarriers based on hollow mesoporous silica nanoparticles (HMSNs) modified with poly(2-(diethylamino)ethyl methacrylate) (PDEAEMA) were developed via surface-initiated atom transfer radical polymerization. Both reduction-cleavable disulfide bond and light-cleavable o-nitrobenzyl ester were used as the linkages between HMSNs and pH-sensitive PDEAEMA polymer caps. A series of characterization techniques were applied to characterize and confirm the structures of the intermediates and final nanocarriers. Doxorubicin (DOX) was easily encapsulated into the nanocarriers with a high loading capacity, and quickly released in response to the stimuli of reducing agent, acid environment or UV light irradiation. In addition, flow cytometry analysis, confocal laser scanning microscopy observations and cytotoxicity studies indicated that the nanocarriers were efficiently internalized by HeLa cancer cells, exhibiting (i) enhanced release of DOX into the cytoplasm under external UV light irradiation, (ii) better cytotoxicity against HeLa cells, and (iii) superior control over drug delivery and release. Thus, the triple-responsive nanocarriers present highly promising potentials as a drug delivery platform for cancer therapy.

Immunotherapeutic interventions of Triple Negative Breast Cancer.

PubMed

Li, Zehuan; Qiu, Yiran; Lu, Weiqi; Jiang, Ying; Wang, Jin

2018-05-30

Triple Negative Breast Cancer (TNBC) is a highly heterogeneous subtype of breast cancer that lacks the expression of oestrogen receptors, progesterone receptors and human epidermal growth factor receptor 2. Although TNBC is sensitive to chemotherapy, the overall outcomes of TNBC are worse than for other breast cancers, and TNBC is still one of the most fatal diseases for women. With the discovery of antigens specifically expressed in TNBC cells and the developing technology of monoclonal antibodies, chimeric antigen receptors and cancer vaccines, immunotherapy is emerging as a novel promising option for TNBC. This review is mainly focused on the tumour microenvironment and host immunity, Triple Negative Breast Cancer and the clinical treatment of TNBC, novel therapies for cancer and immunotherapy for TNBC, and the future outlook for the treatment for TNBC and the interplay between the therapies, including immune checkpoint inhibitors, combination of immune checkpoint inhibitors with targeted treatments in TNBC, adoptive cell therapy, cancer vaccines. The review also highlights recent reports on the synergistic effects of immunotherapy and chemotherapy, antibody-drug conjugates, and exosomes, as potential multifunctional therapeutic agents in TNBC.

Turbulence measurements in a swirling confined jet flowfield using a triple hot-wire probe

NASA Technical Reports Server (NTRS)

Janjua, S. I.; Mclaughlin, D. K.

1982-01-01

An axisymmetric swirling confined jet flowfield, similar to that encountered in gas turbine combustors was investigated using a triple hot-wire probe. The raw data from the three sensors were digitized using ADC's and stored on a Tektronix 4051 computer. The data were further reduced on the computer to obtain time-series for the three instantaneous velocity components in the flowfield. The time-mean velocities and the turbulence quantities were deduced. Qualification experiments were performed and where possible results compared with independent measurements. The major qualification experiments involved measurements performed in a non-swirling flow compared with conventional X-wire measurements. In the swirling flowfield, advantages of the triple wire technique over the previously used multi-position single hot-wire method are noted. The measurements obtained provide a data base with which the predictions of turbulence models in a recirculating swirling flowfield can be evaluated.

Viscoplastic sculpting in stable triple layer heavy oil transport flow

NASA Astrophysics Data System (ADS)

Sarmadi, Parisa; Hormozi, Sarah; A. Frigaard, Ian

2017-11-01

In we introduced a novel methodology for efficient transport of heavy oil via a triple layer core-annular flow. Pumping pressures are significantly reduced by concentrating high shear rates to a lubricating layer, while ideas from Visco-Plastic Lubrication are used to eliminate interfacial instabilities. We purposefully position a shaped unyielded skin of a viscoplastic fluid between the transported oil and the lubricating fluid layer to balance the density difference between the fluids. Here we address the sculpting of the shaped skin within a concentric inflow manifold. We use the quasi-steady model to provide inputs to an axisymmetric triple layer computation, showing the development of the streamwise skin profile and establishment of the flow. For this, we use a finite element discretization with the augmented-Lagrangian method to represent the yield surface behaviour accurately and a PLIC method to track the interface motion.

A Synthetic Triterpenoid CDDO-Im Inhibits Tumorsphere Formation by Regulating Stem Cell Signaling Pathways in Triple-Negative Breast Cancer

PubMed Central

Wahler, Joseph; Liby, Karen T.; Sporn, Michael B.; Suh, Nanjoo

2014-01-01

Triple-negative breast cancer is associated with poor prognosis because of a high rate of tumor recurrence and metastasis. Previous studies demonstrated that the synthetic triterpenoid, CDDO-Imidazolide (CDDO-Im) induced cell cycle arrest and apoptosis in triple-negative breast cancer. Since a small subpopulation of cancer stem cells has been suggested to be responsible for drug resistance and metastasis of tumors, our present study determined whether the effects of CDDO-Im in triple-negative breast cancer are due to the inhibition of a cancer stem cell subpopulation. CDDO-Im treatment markedly induced cell cycle arrest at G2/M-phase and apoptosis in the triple-negative breast cancer cell lines, SUM159 and MDA-MB-231. Because SUM159 cells were more sensitive to CDDO-Im than MDA-MB-231 cells, the effects of CDDO-Im on the cancer stem cell subpopulation were further investigated in SUM159 cells. SUM159 cells formed tumorspheres in culture, and the cancer stem cell subpopulation, CD24−/EpCAM+ cells, was markedly enriched in SUM159 tumorspheres. The CD24−/EpCAM+ cells in SUM159 tumorspheres were significantly inhibited by CDDO-Im treatment. CDDO-Im also significantly decreased sphere forming efficiency and tumorsphere size in both primary and secondary sphere cultures. PCR array of stem cell signaling genes showed that expression levels of many key molecules in the stem cell signaling pathways, such as Notch, TGF-β/Smad, Hedgehog and Wnt, were significantly down-regulated by CDDO-Im in SUM159 tumorspheres. Protein levels of Notch receptors (c-Notch1, Notch1 and Notch3), TGF-β/Smad (pSmad2/3) and Hedgehog downstream effectors (GLI1) also were markedly reduced by CDDO-Im. In conclusion, the present study demonstrates that the synthetic triterpenoid, CDDO-Im, is a potent anti-cancer agent against triple-negative breast cancer cells by targeting the cancer stem cell subpopulation. PMID:25229616

Effects of H{sub 2} enrichment on the propagation characteristics of CH{sub 4}-air triple flames

DOE Office of Scientific and Technical Information (OSTI.GOV)

Briones, Alejandro M.; Aggarwal, Suresh K.; Katta, Viswanath R.

The effects of H{sub 2} enrichment on the propagation of laminar CH{sub 4}-air triple flames in axisymmetric coflowing jets are numerically investigated. A comprehensive, time-dependent computational model, which employs a detailed description of chemistry and transport, is used to simulate the transient ignition and flame propagation phenomena. Flames are ignited in a jet-mixing layer far downstream of the burner. Following ignition, a well-defined triple flame is formed that propagates upstream along the stoichiometric mixture fraction line with a nearly constant displacement velocity. As the flame approaches the burner, it transitions to a double flame, and subsequently to a burner-stabilized nonpremixedmore » flame. Predictions are validated using measurements of the displacement flame velocity. As the H{sub 2} concentration in the fuel blend is increased, the displacement flame velocity and local triple flame speed increase progressively due to the enhanced chemical reactivity, diffusivity, and preferential diffusion caused by H{sub 2} addition. In addition, the flammability limits associated with the triple flames are progressively extended with the increase in H{sub 2} concentration. The flame structure and flame dynamics are also markedly modified by H{sub 2} enrichment, which substantially increases the flame curvature and mixture fraction gradient, as well as the hydrodynamic and curvature-induced stretch near the triple point. For all the H{sub 2}-enriched methane-air flames investigated in this study, there is a negative correlation between flame speed and stretch, with the flame speed decreasing almost linearly with stretch, consistent with previous studies. The H{sub 2} addition also modifies the flame sensitivity to stretch, as it decreases the Markstein number (Ma), implying an increased tendency toward diffusive-thermal instability (i.e. Ma {yields} 0). These results are consistent with the previously reported experimental results for outwardly propagating spherical flames burning a mixture of natural gas and hydrogen. (author)« less

National variation in use of Immunosuppression for kidney transplantation: A call for evidence-based regimen selection

PubMed Central

Axelrod, David; Naik, Abhijit S.; Schnitzler, Mark A.; Segev, Dorry L.; Dharnidharka, Vikas R.; Brennan, Daniel C.; Bae, Sunjae; Chen, Jiajing; Massie, Allan; Lentine, Krista L.

2017-01-01

Immunosuppression management in kidney transplantation has evolved to include an increasingly diverse choice of medications. While informed by patient and donor characteristics, choice of immunosuppression regimen varies widely across transplant programs. Using a novel database integrating national transplant registry and pharmacy fill records, immunosuppression use 6–12 and 12–24 months post-transplant was evaluated for 22,453 patients transplanted at 249 U.S. programs in 2005–2010. Use of triple immunosuppression comprising tacrolimus, mycophenolic acid or azathioprine, and steroids varied widely (0–100% of patients per program), as did use of steroid-sparing regimens (0–77%), in sirolimus-based regimens (0–100%) and cyclosporine-based regimens (0–78%). Use of triple therapy was more common in highly sensitized patients, women, and recipients with dialysis duration > 5 years. Sirolimus use appeared to diminish over the study period. Overall, patient and donor characteristics explained only a limited amount of the observed variation in regimen use, while center choice explained 30–46% of the use of non-triple therapy immunosuppression. The majority of patients who received triple therapy (79%), cyclosporine-based (87.6%) and sirolimus-based regimens (84.3%) continued these regimens in the second year post-transplant. This population-based study of immunosuppression practice demonstrates substantial variation in center practice beyond that is explained by differences in patient and donor characteristics. PMID:26901466

ONC201 demonstrates anti-tumor effects in both triple negative and non-triple negative breast cancers through TRAIL-dependent and TRAIL-independent mechanisms

PubMed Central

Ralff, Marie D.; Kline, Christina L.B.; Küçükkase, Ozan C; Wagner, Jessica; Lim, Bora; Dicker, David T.; Prabhu, Varun V.; Oster, Wolfgang; El-Deiry, Wafik S.

2017-01-01

Breast cancer is a major cause of cancer-related death. TRAIL has been of interest as a cancer therapeutic, but only a subset of triple negative breast cancers (TNBC) is sensitive to TRAIL. The small molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n=13). A subset of TNBC and non-TNBC cells succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8) ONC201 has an anti-proliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G1 phase of the cell cycle. pRb expression is associated with sensitivity to the anti-proliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n=5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n=2) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. PMID:28424227

ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms.

PubMed

Ralff, Marie D; Kline, Christina L B; Küçükkase, Ozan C; Wagner, Jessica; Lim, Bora; Dicker, David T; Prabhu, Varun V; Oster, Wolfgang; El-Deiry, Wafik S

2017-07-01

Breast cancer is a major cause of cancer-related death. TNF-related apoptosis-inducing ligand (TRAIL) has been of interest as a cancer therapeutic, but only a subset of triple-negative breast cancers (TNBC) is sensitive to TRAIL. The small-molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here, we show that ONC201 is efficacious against both TNBC and non-TNBC cells ( n = 13). A subset of TNBC and non-TNBC cells succumbs to ONC201-induced cell death. In 2 of 8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The proapoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8), ONC201 has an antiproliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G 1 phase of the cell cycle. pRb expression is associated with sensitivity to the antiproliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells ( n = 5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset ( n = 2) shows PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL independent. Our data demonstrate that ONC201 has potent antiproliferative and proapoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a preclinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. Mol Cancer Ther; 16(7); 1290-8. ©2017 AACR . ©2017 American Association for Cancer Research.

Cloning-Independent and Counterselectable Markerless Mutagenesis System in Streptococcus mutans▿

PubMed Central

Xie, Zhoujie; Okinaga, Toshinori; Qi, Fengxia; Zhang, Zhijun; Merritt, Justin

2011-01-01

Insertion duplication mutagenesis and allelic replacement mutagenesis are among the most commonly utilized approaches for targeted mutagenesis in bacteria. However, both techniques are limited by a variety of factors that can complicate mutant phenotypic studies. To circumvent these limitations, multiple markerless mutagenesis techniques have been developed that utilize either temperature-sensitive plasmids or counterselectable suicide vectors containing both positive- and negative-selection markers. For many species, these techniques are not especially useful due to difficulties of cloning with Escherichia coli and/or a lack of functional negative-selection markers. In this study, we describe the development of a novel approach for the creation of markerless mutations. This system employs a cloning-independent methodology and should be easily adaptable to a wide array of Gram-positive and Gram-negative bacterial species. The entire process of creating both the counterselection cassette and mutation constructs can be completed using overlapping PCR protocols, which allows extremely quick assembly and eliminates the requirement for either temperature-sensitive replicons or suicide vectors. As a proof of principle, we used Streptococcus mutans reference strain UA159 to create markerless in-frame deletions of 3 separate bacteriocin genes as well as triple mutants containing all 3 deletions. Using a panel of 5 separate wild-type S. mutans strains, we further demonstrated that the procedure is nearly 100% efficient at generating clones with the desired markerless mutation, which is a considerable improvement in yield compared to existing approaches. PMID:21948849

AXL Inhibition Suppresses the DNA Damage Response and Sensitizes Cells to PARP Inhibition in Multiple Cancers

PubMed Central

Diao, Lixia; Tong, Pan; Fan, Youhong; Carey, Jason PW; Bui, Tuyen N.; Warner, Steve; Heymach, John V; Hunt, Kelly K; Wang, Jing

2016-01-01

Epithelial to mesenchymal transition (EMT) is associated with a wide range of changes in cancer cells, including stemness, chemo- and radio-resistance and metastasis. The mechanistic role of upstream mediators of EMT has not yet been well characterized. Recently, we showed that non-small cell lung cancers (NSCLCs) that have undergone EMT overexpress AXL, a receptor tyrosine kinase. AXL is also overexpressed in a subset of triple-negative breast cancers (TNBCs) and head and neck squamous cell carcinomas (HNSCCs) and its overexpression has been associated with more aggressive tumor behavior and linked to resistance to chemotherapy, radiation, and targeted therapy. Since the DNA repair pathway is also altered in patient tumor specimens overexpressing AXL, it is hypothesized that modulation of AXL in cells that have undergone EMT will sensitize them to agents targeting the DNA repair pathway. Downregulation or inhibition of AXL directly reversed the EMT phenotype, led to decreased expression of DNA repair genes and diminished efficiency of homologous recombination (HR) and RAD51 foci formation. As a result, AXL inhibition caused a state of HR-deficiency in the cells, making them sensitive to inhibition of the DNA repair protein, PARP1. AXL inhibition synergized with PARP inhibition, leading to apoptotic cell death. AXL expression also associated positively with markers of DNA repair across TNBC, HNSCC and NSCLC patient cohorts. PMID:27671334

Neoadjuvant Pembrolizumab + Decitabine Followed by Std Neoadj Chemo for Locally Advanced HER2- Breast Ca

ClinicalTrials.gov

2018-04-17

Breast Adenocarcinoma; Estrogen Receptor- Negative Breast Cancer; Estrogen Receptor-positive Breast Cancer; HER2/Neu Negative; Invasive Breast Carcinoma; Progesterone Receptor Negative; Progesterone Receptor Positive Tumor; Stage II Breast Cancer; Stage IIA Breast Cancer; Stage IIB Breast Cancer; Stage IIIA Breast Cancer; Stage IIIB Breast Cancer; Triple-negative Breast Carcinoma

A Palladium-Catalyzed Carbonylation Approach to Eight-Membered Lactam Derivatives with Antitumor Activity.

PubMed

Mancuso, Raffaella; Raut, Dnyaneshwar S; Marino, Nadia; De Luca, Giorgio; Giordano, Cinzia; Catalano, Stefania; Barone, Ines; Andò, Sebastiano; Gabriele, Bartolo

2016-02-24

The reactivity of 2-(2-alkynylphenoxy)anilines under PdI2 /KI-catalyzed oxidative carbonylation conditions has been studied. Although a different reaction pathway could have been operating, N-palladation followed by CO insertion was the favored pathway with all substrates tested, including those containing an internal or terminal triple bond. This led to the formation of a carbamoylpalladium species, the fate of which, as predicted by theoretical calculations, strongly depended on the nature of the substituent on the triple bond. In particular, 8-endo-dig cyclization preferentially occurred when the triple bond was terminal, leading to the formation of carbonylated ζ-lactam derivatives, the structures of which have been confirmed by XRD analysis. These novel medium-sized heterocyclic compounds showed antitumor activity against both estrogen receptor-positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cell lines. In particular, ζ-lactam 3 j' may represent a novel and promising antitumor agent because biological tests clearly demonstrate that this compound significantly reduces cell viability and motility in both MCF-7 and MDA-MB-231 breast cancer cell lines, without affecting normal breast epithelial cell viability. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The nonlinear oil-water two-phase flow behavior for a horizontal well in triple media carbonate reservoir

NASA Astrophysics Data System (ADS)

Wang, Yong; Tao, Zhengwu; Chen, Liang; Ma, Xin

2017-10-01

Carbonate reservoir is one of the important reservoirs in the world. Because of the characteristics of carbonate reservoir, horizontal well has become a key technology for efficiently developing carbonate reservoir. Establishing corresponding mathematical models and analyzing transient pressure behaviors of this type of well-reservoir configuration can provide a better understanding of fluid flow patterns in formation as well as estimations of important parameters. A mathematical model for a oil-water two-phase flow horizontal well in triple media carbonate reservoir by conceptualizing vugs as spherical shapes are presented in this article. A semi-analytical solution is obtained in the Laplace domain using source function theory, Laplace transformation, and superposition principle. Analysis of transient pressure responses indicates that seven characteristic flow periods of horizontal well in triple media carbonate reservoir can be identified. Parametric analysis shows that water saturation of matrix, vug and fracture system, horizontal section length, and horizontal well position can significantly influence the transient pressure responses of horizontal well in triple media carbonate reservoir. The model presented in this article can be applied to obtain important parameters pertinent to reservoir by type curve matching.

Targeting the host immune system: PD-1 and PD-L1 antibodies and breast cancer.

PubMed

Dawood, Shaheenah; Rugo, Hope S

2016-12-01

This article describes the role of the PD-1 axis and reviews current data and future directions inhibiting PD-1 and PD-L1 in breast cancer. Four phase I monotherapy expansion trials in patients with metastatic breast cancer have demonstrated low but durable single agent responses to PD-1 and PD-L1 inhibitors, ranging from 4.8 to 19%. Higher response rates are seen in triple negative breast cancer, compared with hormone receptor positive disease. Variability in requirements for tumor PD-L1 expression, and variations in testing complicate cross trial comparisons. A fifth phase Ib trial reported a 38% response rate in metastatic triple negative breast cancer treated with the combination of a PD-L1 inhibitor and nab-paclitaxel chemotherapy. Treatment is generally well tolerated, with low rates of immune toxicity including hypothyroidism, pneumonitis, hepatitis, colitis, and hypophysitis, occurring even months after the end of therapy. Immune checkpoint inhibitor therapy has recently been shown to have clinical efficacy in the treatment of breast cancer. The most compelling data are in the triple negative subtype, with responses documented in hormone receptor positive disease as well. Numerous trials are evaluating various combination strategies and biomarkers in early and late stage disease to enhance immunogenicity and response.

Evaluation of an interlaced triple procedure: penetrating keratoplasty, extracapsular cataract extraction, and nonopen-sky intraocular lens implantation.

PubMed

Yang, Shuo; Wang, Bin; Zhang, Yangyang; Zhai, Hualei; Wang, Junyi; Wang, Shuang; Xie, Lixin

2017-09-01

To evaluate an interlaced triple procedure that involved penetrating keratoplasty (PKP), extracapsular cataract extraction (ECCE) using diathermy capsulotomy, and nonopen-sky intraocular lens (IOL) implantation.This retrospective study involved data from 34 patients who were diagnosed with severe corneal opacities and cataracts. These patients were divided into an interlaced procedure group (21 patients) and a traditional procedure group (13 patients). In the interlaced group, the method of continuous curvilinear capsulorhexis (CCC) was completed via diathermy capsulotomy. The donor corneal button was sutured at 8 positions (at equal intervals) using 10-0 nylon sutures, and the IOL was inserted into the capsular bag using a closed anterior chamber approach at the 10:30 to 12 o'clock positions between the sutures. In the traditional group, CCC was completed using side-port capsular forceps, and the IOL was implanted using an open anterior chamber approach.In the interlaced group, the CCC, open-sky, and total operation times were significantly shorter than in the traditional group (P < .05). Neither the best-corrected visual acuity (BCVA) nor corneal endothelial cell density was significantly different between the groups at 1 and 6 months after the operation.This interlaced triple procedure for the treatment of corneal diseases with cataracts appears to be feasible and practical.

Identification of 6-octadecynoic acid from a methanol extract of Marrubium vulgare L. as a peroxisome proliferator-activated receptor γ agonist

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ohtera, Anna; Miyamae, Yusaku; Nakai, Naomi

Highlights: •6-ODA, a rare fatty acid with a triple bond, was identified from Marrubium vulgare. •6-ODA was synthesized from petroselinic acid as a starting material. •6-ODA stimulated lipid accumulation in HSC-T6 and 3T3-L1 cells. •The first report of a fatty acid with a triple bond functioning as a PPARγ agonist. •This study sheds light on novel functions of a fatty acid with a triple bond. -- Abstract: 6-Octadecynoic acid (6-ODA), a fatty acid with a triple bond, was identified in the methanol extract of Marrubium vulgare L. as an agonist of peroxisome proliferator-activated receptor γ (PPARγ). Fibrogenesis caused by hepaticmore » stellate cells is inhibited by PPARγ whose ligands are clinically used for the treatment of diabetes. Plant extracts of Marrubium vulgare L., were screened for activity to inhibit fibrosis in the hepatic stellate cell line HSC-T6 using Oil Red-O staining, which detects lipids that typically accumulate in quiescent hepatic stellate cells. A methanol extract with activity to stimulate accumulation of lipids was obtained. This extract was found to have PPARγ agonist activity using a luciferase reporter assay. After purification using several chromatographic methods, 6-ODA, a fatty acid with a triple bond, was identified as a candidate of PPARγ agonist. Synthesized 6-ODA and its derivative 9-octadecynoic acid (9-ODA), which both have a triple bond but in different positions, activated PPARγ in a luciferase reporter assay and increased lipid accumulation in 3T3-L1 adipocytes in a PPARγ-dependent manner. There is little information about the biological activity of fatty acids with a triple bond, and to our knowledge, this is the first report that 6-ODA and 9-ODA function as PPARγ agonists.« less

Age/race differences in HER2 testing and in incidence rates for breast cancer triple subtypes: a population-based study and first report.

PubMed

Lund, Mary Jo; Butler, Ebonee N; Hair, Brionna Y; Ward, Kevin C; Andrews, Judy H; Oprea-Ilies, Gabriella; Bayakly, A Rana; O'Regan, Ruth M; Vertino, Paula M; Eley, J William

2010-06-01

Although US year 2000 guidelines recommended characterizing breast cancers by human epidermal growth factor receptor 2 (HER2), national cancer registries do not collect HER2, rendering a population-based understanding of HER2 and clinical "triple subtypes" (estrogen receptor [ER] / progesterone receptor [PR] / HER2) largely unknown. We document the population-based prevalence of HER2 testing / status, triple subtypes and present the first report of subtype incidence rates. Medical records were searched for HER2 on 1842 metropolitan Atlanta females diagnosed with breast cancer during 2003-2004. HER2 testing/status and triple subtypes were analyzed by age, race/ethnicity, tumor factors, socioeconomic status, and treatment. Age-adjusted incidence rates were calculated. Over 90% of cases received HER2 testing: 12.6% were positive, 71.7% negative, and 15.7% unknown. HER2 testing compliance was significantly better for women who were younger, of Caucasian or African-American descent, or diagnosed with early stage disease. Incidence rates (per 100,000) were 21.1 for HER2+ tumors and 27.8 for triple-negative tumors, the latter differing by race (36.3 and 19.4 for black and white women, respectively). HER2 recommendations are not uniformly adhered to. Incidence rates for breast cancer triple subtypes differ by age/race. As biologic knowledge is translated into the clinical setting eg, HER2 as a biomarker, it will be incumbent upon national cancer registries to report this information. Incidence rates cautiously extrapolate to an annual burden of 3000 and 17,000 HER2+ tumors for black and white women, respectively, and triple-negative tumors among 5000 and 16,000 respectively. Testing, rate, and burden variations warrant population-based in-depth exploration and clinical translation. (c) 2010 American Cancer Society.

Omitting duodenal biopsy in children with suspected celiac disease and extra-intestinal symptoms.

PubMed

Bozzola, Mauro; Meazza, Cristina; Gertosio, Chiara; Pagani, Sara; Larizza, Daniela; Calcaterra, Valeria; Luinetti, Ombretta; Farello, Giovanni; Tinelli, Carmine; Iughetti, Lorenzo

2017-07-15

The aim of our study is to evaluate if in children with highly positive serology and HLA-DQ2/DQ8 (triple test, TT) and only extra-intestinal symptoms, it is possible to omit performing an intestinal biopsy for celiac disease (CD) diagnosis, as suggested by the new European Society for Pediatric Gastroenterology, Hepatology and Nutrition ESPGHAN guidelines. In this retrospective study a total of 105 patients, suspected of having CD because of extra-intestinal symptoms and showing serum tissue transglutaminase antibody (anti-tTG) and anti-endomysial antibody (EMA) measurements and HLA genotyping, were considered for the final analysis (33 boys and 72 girls; age range 1.5-17.6 years). Histological findings confirmed diagnosis of CD in 97 (92.4%) patients. Forty-one patients (39%) showed anti-tTG >10 times normal values, positive EMA and positive HLA-DQ2/DQ8 (positive TT). All of them had a diagnosis of CD, therefore there were no false positive cases. Sixty-four patients were negative for the TT. In eight cases, CD was ruled out and these were considered true negative cases. In the remaining 56 negative TT patients, intestinal biopsy confirmed CD diagnosis and they were considered false negatives. Based on these results, specificity for the TT was 100% and sensitivity was 42.3%. On the basis of the present study, diagnosis of CD can be reliably performed without a duodenal biopsy in children with only extra-intestinal symptoms.

Typical motions in multiple systems

NASA Technical Reports Server (NTRS)

Anosova, Joanna P.

1990-01-01

In very old times, people counted - one, two, many. The author wants to show that they were right. Consider the motions of isolated bodies: (1) N = 1 - simple motion; (2) N = 2 - Keplerian orbits; and (3) N = 3 - this is the difficult problem. In general, this problem can be studied only by computer simulations. The author studied this problem over many years (see, e.g., Agekian and Anosova, 1967; Anosova, 1986, 1989 a,b). The principal result is that two basic types of dynamics take place in triple systems. The first special type is the stable hierarchical systems with two almost Keplerian orbits. The second general type is the unstable triple systems with complicated motions of the bodies. By random choice of the initial conditions, by the Monte-Carlo method, the stable systems comprised about approx. 10% of the examined cases; the unstable systems comprised the other approx. 90% of cases under consideration. In N greater than 3, the studies of dynamics of such systems by computer simulations show that we have in general also the motions roughly as at the cases 1 - 3 with the relative negative or positive energies of the bodies. In the author's picture, the typical trajectories of the bodies in unstable triple systems of the general type of dynamics are seen. Such systems are disrupted always after close triple approaches of the bodies. These approaches play a role like the gravitational slingshot. Often, the velocities of escapers are very large. On the other hand, the movie also shows the dynamical processes of a formation, dynamical evolution and disruption of the temporary wide binaries in triples and a formation of final hard massive binaries in the final evolution of triples.

Baseline blood immunological profiling differentiates between Her2-breast cancer molecular subtypes: implications for immunomediated mechanisms of treatment response.

PubMed

Tudoran, Oana; Virtic, Oana; Balacescu, Loredana; Lisencu, Carmen; Fetica, Bogdan; Gherman, Claudia; Balacescu, Ovidiu; Berindan-Neagoe, Ioana

2015-01-01

Breast cancer patients' response to treatment is highly dependent on the primary tumor molecular features, with triple-negative breast tumors having the worst prognosis of all subtypes. According to the molecular features, tumors stimulate the microenvironment to induce distinct immune responses, baseline immune activation being associated with higher likelihood of pathologic response. In this study, we investigated the deconvolution of the immunological status of triple-negative tumors in comparison with luminal tumors and the association with patients' clinicopathological characteristics. Gene expression of 84 inflammatory molecules and their receptors were analyzed in 40 peripheral blood samples from patients with Her2- primary breast cancer tumors. We studied the association of triple-negative phenotype with age, clinical stage, tumor size, lymph nodes, and menopausal status. We observed that more patients with estrogen (ER)/progesterone (PR)-negative tumors had grade III, while more patients with ER/PR-positive tumors had grade II tumors. Gene expression analysis revealed a panel of 14 genes to have differential expression between the two groups: several interleukins: IL13, IL16, IL17C and IL17F, IL1A, IL3; interleukin receptors: IL10RB, IL5RA; chemokines: CXCL13 and CCL26; and cytokines: CSF2, IFNA2, OSM, TNSF13. The expression levels of these genes have been previously shown to be associated with reduced immunological status; indeed, the triple-negative breast cancer patients presented with lower counts of lymphocytes and eosinophils than the ER/PR-positive ones. These results contribute to a better understanding of the possible role of antitumor immune responses in mediating the clinical outcome.

Selective androgen receptor modulators (SARMs) negatively regulate triple-negative breast cancer growth and epithelial:mesenchymal stem cell signaling.

PubMed

Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D; Yepuru, Muralimohan; Miller, Duane D; Steiner, Mitchell S; Dalton, James T

2014-01-01

The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75-95% of estrogen receptor (ER)-positive and 40-70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer.

Selective Androgen Receptor Modulators (SARMs) Negatively Regulate Triple-Negative Breast Cancer Growth and Epithelial:Mesenchymal Stem Cell Signaling

PubMed Central

Narayanan, Ramesh; Ahn, Sunjoo; Cheney, Misty D.; Yepuru, Muralimohan; Miller, Duane D.; Steiner, Mitchell S.; Dalton, James T.

2014-01-01

Abstract Introduction The androgen receptor (AR) is the most highly expressed steroid receptor in breast cancer with 75–95% of estrogen receptor (ER)-positive and 40–70% of ER-negative breast cancers expressing AR. Though historically breast cancers were treated with steroidal androgens, their use fell from favor because of their virilizing side effects and the emergence of tamoxifen. Nonsteroidal, tissue selective androgen receptor modulators (SARMs) may provide a novel targeted approach to exploit the therapeutic benefits of androgen therapy in breast cancer. Materials and Methods Since MDA-MB-453 triple-negative breast cancer cells express mutated AR, PTEN, and p53, MDA-MB-231 triple-negative breast cancer cells stably expressing wildtype AR (MDA-MB-231-AR) were used to evaluate the in vitro and in vivo anti-proliferative effects of SARMs. Microarray analysis and epithelial:mesenchymal stem cell (MSC) co-culture signaling studies were performed to understand the mechanisms of action. Results Dihydrotestosterone and SARMs, but not bicalutamide, inhibited the proliferation of MDA-MB-231-AR. The SARMs reduced the MDA-MB-231-AR tumor growth and tumor weight by greater than 90%, compared to vehicle-treated tumors. SARM treatment inhibited the intratumoral expression of genes and pathways that promote breast cancer development through its actions on the AR. SARM treatment also inhibited the metastasis-promoting paracrine factors, IL6 and MMP13, and subsequent migration and invasion of epithelial:MSC co-cultures. Conclusion 1. AR stimulation inhibits paracrine factors that are important for MSC interactions and breast cancer invasion and metastasis. 2. SARMs may provide promise as novel targeted therapies to treat AR-positive triple-negative breast cancer. PMID:25072326

An outcomes analysis of five prenatal screening strategies for trisomy 21 in women younger than 35 years.

PubMed

Biggio, Joseph R; Morris, T Christopher; Owen, John; Stringer, Jeffery S A

2004-03-01

This study was undertaken to examine the cost-effectiveness and procedural-related losses associated with 5 prenatal screening strategies for fetal aneuploidy in women under 35 years old. Five prenatal screening strategies were compared in a decision analysis model: triple screen: maternal age and midtrimester serum alpha-fetoprotein, human chorionic gonadotropin (hCG), and unconjugated estriol; quad screen: triple screen plus serum dimeric inhibin A; first-trimester screen: maternal age, serum pregnancy-associated plasma protein A and free beta-hCG and fetal nuchal translucency at 10 to 14 weeks' gestation; integrated screen: first-trimester screen plus quad screen, but first-trimester results are withheld until the quad screen is completed when a composite result is provided; sequential screen: first-trimester screen plus quad screen, but the first-trimester screen results are provided immediately and prenatal diagnosis offered if positive; later prenatal diagnosis is available if the quad screen is positive. Model estimates were literature derived, and cost estimates also included local sources. The 5 strategies were compared for cost, the numbers of Down syndrome fetuses detected and live births averted, and the number of procedure-related euploid losses. Sensitivity analyses were performed for parameters with imprecise point estimates. In the baseline analysis, sequential screening was the least expensive strategy ($455 million). It detected the most Down syndrome fetuses (n=1213), averted the most Down syndrome live births (n=678), but led to the highest number of procedure-related euploid losses (n=859). The integrated screen had the fewest euploid losses (n=62) and averted the second most Down syndrome live births (n=520). If fewer than 70% of women diagnosed with fetal Down syndrome elect to abort, the quad screen became the least expensive strategy. Although sequential screening was the most cost-effective prenatal screening strategy for fetal trisomy 21, it had the highest procedure-related euploid loss rate. The patient's perspective on detection versus fetal safety may help define the optimal screening strategy.

Tectonic history of the north portion of the San Andreas fault system, California, inferred from gravity and magnetic anomalies

USGS Publications Warehouse

Griscom, A.; Jachens, R.C.

1989-01-01

Geologic and geophysical data for the San Andreas fault system north of San Francisco suggest that the eastern boundary of the Pacific plate migrated eastward from its presumed original position at the base of the continental slope to its present position along the San Andreas transform fault by means of a series of eastward jumps of the Mendocino triple junction. These eastward jumps total a distance of about 150 km since 29 Ma. Correlation of right-laterally displaced gravity and magnetic anomalies that now have components at San Francisco and on the shelf north of Point Arena indicates that the presently active strand of the San Andreas fault north of the San Francisco peninsula formed recently at about 5 Ma when the triple junction jumped eastward a minimum of 100 km to its present location at the north end of the San Andreas fault. -from Authors

Defined-size DNA triple crossover construct for molecular electronics: modification, positioning and conductance properties.

PubMed

Linko, Veikko; Leppiniemi, Jenni; Paasonen, Seppo-Tapio; Hytönen, Vesa P; Toppari, J Jussi

2011-07-08

We present a novel, defined-size, small and rigid DNA template, a so-called B-A-B complex, based on DNA triple crossover motifs (TX tiles), which can be utilized in molecular scale patterning for nanoelectronics, plasmonics and sensing applications. The feasibility of the designed construct is demonstrated by functionalizing the TX tiles with one biotin-triethylene glycol (TEG) and efficiently decorating them with streptavidin, and furthermore by positioning and anchoring single thiol-modified B-A-B complexes to certain locations on a chip via dielectrophoretic trapping. Finally, we characterize the conductance properties of the non-functionalized construct, first by measuring DC conductivity and second by utilizing AC impedance spectroscopy in order to describe the conductivity mechanism of a single B-A-B complex using a detailed equivalent circuit model. This analysis also reveals further information about the conductivity of DNA structures in general.

Coexistence of anti-β2-glycoprotein I domain I and anti-phosphatidylserine/prothrombin antibodies suggests strong thrombotic risk.

PubMed

Lee, Jee-Soo; Gu, JaYoon; Park, Hee Sue; Yoo, Hyun Ju; Kim, Hyun Kyung

2017-05-01

Highly specific assays for measuring antiphospholipid antibodies (aPLs) are required for accurate assessment of thrombotic risk. aPLs against β2-glycoprotein I domain I (anti-β2GPIdI) and against prothrombin complexed with phosphatidylserine (anti-PS/PT) have been recently identified as being associated with a hypercoagulable state. This study evaluated the synergism between anti-β2GPIdI and anti-PS/PT for predicting thrombotic events. A total of 180 patients with clinical suspicion of hypercoagulability were evaluated. The plasma levels of lupus anticoagulant (LA) and antibodies against anticardiolipin (anti-CL) (IgG and IgM), β2GPI (IgG and IgM), PS/PT (IgG and IgM), and β2GPI dI (IgG) were measured. IgG anti-β2GPIdI and LA were highly associated with thrombosis. Mean values and positivity rates of IgG anti-β2GPI dI and IgG anti-PS/PT were significantly higher in the triple-positive group (LA+, IgG anti-CL+, IgG anti-β2GPI+) than in the other groups. Interestingly, the thrombotic risk [odds ratio (OR) 24.400, 95% confidence interval (CI) 1.976-63.273, p<0.001] of the newly defined triple positive group (LA+, IgG anti-CL+, IgG anti-β2GPIdI+; OR 11.182, 95% CI 1.976-63.273, p=0.006) was more than twice that of the triple-positive group (LA+, IgG anti-CL+, IgG anti-β2GPI+). Double positivity for IgG anti-PS/PT and IgG anti-β2GPI also indicated significant thrombotic risk (OR 7.467, 95% CI 2.350-23.729, p=0.001). Furthermore, the thrombotic risk associated with double positivity for IgG anti-PS/PT and IgG anti-β2GPIdI was markedly elevated (OR 33.654, 95% CI 6.322-179.141, p<0.001). Our data suggest that simultaneous measurement of IgG anti-β2GPIdI and IgG anti-PS/PT may improve clinical decision-making for aPL-positive patients.

Investigation of Ion Transmission Effects on Intact Protein Quantification in a Triple Quadrupole Mass Spectrometer

NASA Astrophysics Data System (ADS)

Wang, Evelyn H.; Appulage, Dananjaya Kalu; McAllister, Erin A.; Schug, Kevin A.

2017-09-01

Recently, direct intact protein quantitation using triple quadrupole mass spectrometry (QqQ-MS) and multiple reaction monitoring (MRM) was demonstrated (J. Am. Soc. Mass Spectrom. 27, 886-896 (2016)). Even though QqQ-MS is known to provide extraordinary detection sensitivity for quantitative analysis, we found that intact proteins exhibited a less than 5% ion transmission from the first quadrupole to the third quadrupole mass analyzer in the presence of zero collision energy (ZCE). With the goal to enhance intact protein quantitation sensitivity, ion scattering effects, proton transfer effects, and mass filter resolution widths were examined for their contributions to the lost signal. Protein standards myoglobin and ubiquitin along with small molecules reserpine and vancomycin were analyzed together with various collision induced dissociation (CID) gases (N2, He, and Ar) at different gas pressures. Mass resolution settings played a significant role in reducing ion transmission signal. By narrowing the mass resolution window by 0.35 m/z on each side, roughly 75%-90% of the ion signal was lost. The multiply charged proteins experienced additional proton transfer effects, corresponding to 10-fold signal reduction. A study of increased sensitivity of the method was also conducted with various MRM summation techniques. Although the degree of enhancement was analyte-dependent, an up to 17-fold increase in sensitivity was observed for ubiquitin using a summation of multiple MRM transitions. Biological matrix, human urine, and equine plasma were spiked with proteins to demonstrate the specificity of the method. This study provides additional insight into optimizing the use and sensitivity of QqQ-MS for intact protein quantification. [Figure not available: see fulltext.

Race and hormone receptor-positive breast cancer outcomes in a randomized chemotherapy trial.

PubMed

Sparano, Joseph A; Wang, Molin; Zhao, Fengmin; Stearns, Vered; Martino, Silvana; Ligibel, Jennifer A; Perez, Edith A; Saphner, Tom; Wolff, Antonio C; Sledge, George W; Wood, William C; Davidson, Nancy E

2012-03-07

The association between black race and worse outcomes in operable breast cancer reported in previous studies has been attributed to a higher incidence of more aggressive triple-negative disease, disparities in care, and comorbidities. We evaluated associations between black race and outcomes, by tumor hormone receptor and HER2 expression, in patients who were treated with contemporary adjuvant therapy. The effect of black race on disease-free and overall survival was evaluated using Cox proportional hazards models adjusted for multiple covariates in a clinical trial population that was treated with anthracycline- and taxane-containing chemotherapy. Categorical variables were compared using the Fisher exact test. All P values are two-sided. Of 4817 eligible patients, 405 (8.4%) were black. Compared with nonblack patients, black patients had a higher rate of triple-negative disease (31.9% vs 17.2%; P < .001) and a higher body mass index (median: 31.7 vs 27.4 kg/m(2); P < .001). Black race was statistically significantly associated with worse disease-free survival (5-year disease-free survival, black vs nonblack: 76.7% vs 84.5%; hazard ratio of recurrence or death = 1.58, 95% confidence interval = 1.19 to 2.10, P = .0015) and overall survival (5-year overall survival, black vs nonblack: 87.6% vs 91.9%; hazard ratio of death = 1.49, 95% confidence interval = 1.05 to 2.12, P = .025) in patients with hormone receptor-positive HER2-negative disease but not in patients with triple-negative or HER2-positive disease. In a model that included black race, hormone receptor-positive HER2-negative disease vs other subtypes, and their interaction, the interaction term was statistically significant for disease-free survival (P = .027) but not for overall survival (P = .086). Factors other than disparities in care or aggressive disease contribute to increased recurrence in black women with hormone receptor-positive breast cancer.

Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes.

PubMed

von Minckwitz, Gunter; Untch, Michael; Blohmer, Jens-Uwe; Costa, Serban D; Eidtmann, Holger; Fasching, Peter A; Gerber, Bernd; Eiermann, Wolfgang; Hilfrich, Jörn; Huober, Jens; Jackisch, Christian; Kaufmann, Manfred; Konecny, Gottfried E; Denkert, Carsten; Nekljudova, Valentina; Mehta, Keyur; Loibl, Sibylle

2012-05-20

The exact definition of pathologic complete response (pCR) and its prognostic impact on survival in intrinsic breast cancer subtypes is uncertain. Tumor response at surgery and its association with long-term outcome of 6,377 patients with primary breast cancer receiving neoadjuvant anthracycline-taxane-based chemotherapy in seven randomized trials were analyzed. Disease-free survival (DFS) was significantly superior in patients with no invasive and no in situ residuals in breast or nodes (n = 955) compared with patients with residual ductal carcinoma in situ only (n = 309), no invasive residuals in breast but involved nodes (n = 186), only focal-invasive disease in the breast (n = 478), and gross invasive residual disease (n = 4,449; P < .001). Hazard ratios for DFS comparing patients with or without pCR were lowest when defined as no invasive and no in situ residuals (0.446) and increased monotonously when in situ residuals (0.523), no invasive breast residuals but involved nodes (0.623), and focal-invasive disease (0.727) were included in the definition. pCR was associated with improved DFS in luminal B/human epidermal growth factor receptor 2 (HER2) -negative (P = .005), HER2-positive/nonluminal (P < .001), and triple-negative (P < .001) tumors but not in luminal A (P = .39) or luminal B/HER2-positive (P = .45) breast cancer. pCR in HER2-positive (nonluminal) and triple-negative tumors was associated with excellent prognosis. pCR defined as no invasive and no in situ residuals in breast and nodes can best discriminate between patients with favorable and unfavorable outcomes. Patients with noninvasive or focal-invasive residues or involved lymph nodes should not be considered as having achieved pCR. pCR is a suitable surrogate end point for patients with luminal B/HER2-negative, HER2-positive (nonluminal), and triple-negative disease but not for those with luminal B/HER2-positive or luminal A tumors.

Picogram determination of N-nitrosodimethylamine in water.

PubMed

Hu, Ruikang; Zhang, Lifeng; Yang, Zhaoguang

2008-01-01

N-nitrosodimethylamine (NDMA) persistence within surface waters is a major concern for downstream communities exploiting these waters as drinking water supplies. The objective of this study is to develop a novel and efficient analytical method for NDMA via different technologies: pulsed splitless gas chromatography-nitrogen phosphorus detector (GC-NPD), large volume injection (LVI) gas chromatography-mass spectrometry (GC/MS) via programmable temperature vaporizer (PTV) inlet or PTV-gas chromatography-triple quadruple mass spectrometry (GC-MS/MS) and continuous liquid-liquid extraction. It was found that the sensitivity required for NDMA analysis by GC-NPD can only be achieved when the NPD bead is extremely clean. LVI via PTV can greatly improve GC-MS system sensitivity for analyzing NDMA. With the help of DB-624 (25 m x 200 microm x 1.12 microm) connected with DB-5MS (30 m x 250 microm x 0.25 microm) in series, PTV-GC/MS could overcome the matrix interference for the trace analysis of NDMA. Variable instrument conditions were studied in detail, with the optimized process being validated via precision and accuracy studies. PTV- triple quadruple GC-MS/MS system could efficiently remove the interference on a single DB-5MS (30 m x 250 microm x 0.25 microm) column with good sensitivity and selectivity. The developed methods have been successfully applied to test NDMA in different types of water samples with satisfactory results. (c) IWA Publishing 2008.

Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer.

PubMed

Agyeman, Abena S; Jun, Wesley J; Proia, David A; Kim, Caroline R; Skor, Maxwell N; Kocherginsky, Masha; Conzen, Suzanne D

2016-04-01

Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g., ganetespib and NVP-AUY922) have demonstrated improved safety and activity profiles over the first-generation ansamycin class. In breast cancer, clinical responses have been observed in a subset of TNBC patients following ganetespib monotherapy; however, the underlying biology of Hsp90 inhibitor treatment and tumor response is not well understood. Glucocorticoid receptor (GR) activity in TNBC is associated with chemotherapy resistance. Here, we find that treatment of TNBC cell lines with ganetespib resulted in GR degradation and decreased GR-mediated gene expression. Ganetespib-associated GR degradation also sensitized TNBC cells to paclitaxel-induced cell death both in vitro and in vivo. The beneficial effect of the Hsp90 inhibitor on paclitaxel-induced cytotoxicity was reduced when GR was depleted in TNBC cells but could be recovered with GR overexpression. These findings suggest that GR-regulated anti-apoptotic and pro-proliferative signaling networks in TNBC are disrupted by Hsp90 inhibitors, thereby sensitizing TNBC to paclitaxel-induced cell death. Thus, GR+ TNBC patients may be a subgroup of breast cancer patients who are most likely to benefit from adding an Hsp90 inhibitor to taxane therapy.

Veliparib and Carboplatin in Treating Patients With HER2-Negative Metastatic Breast Cancer

ClinicalTrials.gov

2018-04-20

BRCA1 Gene Mutation; BRCA2 Gene Mutation; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Progesterone Receptor Negative; Progesterone Receptor Positive; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma

Practical guidelines for characterization of O-diglycosyl flavonoid isomers by triple quadrupole MS and their applications for identification of some fruit juices flavonoids.

PubMed

Abad-García, B; Garmón-Lobato, S; Berrueta, L A; Gallo, B; Vicente, F

2009-07-01

Fifteen flavonoid O-diglycosides with different interglycosidic linkage isomery and glycosylation position have been studied in order to analyze their fragmentation patterns. Initial separation was carried out using high performance liquid chromatography with diode array detection (HPLC/DAD) coupled to an electrospray ionization (ESI) interface and a triple quadrupole mass spectrometer. Some useful differences in their MS spectra have been found and discussed. As it has already been reported, [Y*]+/[Y0]+ ratio for flavanones and [Y1]+/[Y0]+ ratio for other flavonoids is specific for each isomeric interglycosidic linkage. In this work it has also been observed that the abundance of these ions is dependent on the position of glycosylation. On the basis of these differences, systematic guidelines for our experimental conditions have been proposed for the differentiation of not only isomeric interglycosidic linkage but also glycosylation position using collision-induced dissociation MS/MS (CID-MS/MS) spectra in positive mode. These results have been successfully applied for the characterization of three diglycosyl flavonoids found in Citrus fruit juices and these conclusions have also been extrapolated for characterizing two triglycosides in the same fruits. Copyright 2009 John Wiley & Sons, Ltd.

GATA3 expression in clinically useful groups of breast carcinoma: a comparison with GCDFP15 and mammaglobin for identifying paired primary and metastatic tumors.

PubMed

Yang, Yuqiong; Lu, Shanming; Zeng, Wenqin; Xie, Shoucheng; Xiao, Shengjun

2017-02-01

GATA3 has been recognized as the novel marker for identifying primary and metastatic breast carcinomas, consistently showing that GATA3 was significantly more sensitive than traditional markers gross cystic disease fluid protein 15 (GCDFP15) and mammaglobin (MGB). However, clinically useful groups of breast carcinomas status were not identified, which were determining appropriate treatment strategy, affecting the prognosis. In this study, we undertook a comparative study of the marker GATA3 and GCDFP15 and MGB in clinically useful groups of paired primary and metastatic breast cancer. We retrieved 64 cases of matched primary and metastatic breast cancer from the surgical pathology archive at our institution. According to the emerging 2015 St. Gallen Consensus, the clinically useful groups were divided into ER and/or PR (+), HER2 (-), abbreviated as A; ER and/or PR (+), HER2 (+), abbreviated as B; ER and PR (-), HER2 (+), abbreviated as C; ER, PR and HER2 (-), abbreviated as D; each group contained 16 cases (n=16). Tissue microarrays were created, with three 1-mm punch specimens from each case. The tissue microarrays were cut at 4-μm thickness and stained with monoclonal antibodies to GATA3, GCDFP15, and MGB. Staining intensity (0-3+) and extent (0%-100%) were scored with an H-score calculated (range, 0-300). Sensitivities by varying H-score cutoffs (any; ≥50; ≥150) for a positive result in the clinically useful groups of matched primary or metastatic breast cancer among GATA3, GCDFP15, and MGB. GATA3 was significantly more sensitive than GCDFP15 and MGB A and B groups (P<.05) rather than C and D groups (P>.05). However, GATA3 in conjunction with GCDFP15 and MGB detection could improve the sensitivity of C group (P<.05) rather than D group (P>.05). Significantly, good coincidence was observed between primary and metastatic tumor GATA3 expression (κ value = 0.826 >0.75) as compared with the coincidence of GCDFP15 (κ value =0.492 <0.75) and MGB (κ value =0.593 <0.75) (both P<.05). In conclusion, GATA3 expression did not show the same sensitivity for the clinically useful groups of breast cancer. GATA3 expression is positively correlated with ER-positive, PR-positive, and HER2-positive carcinomas. In addition, the matched primary and metastatic tumor expression of GATA3 shows good coincidence. We propose the careful selection of GATA3 for identifying hormone receptor negativity of breast cancer, especially in the case of triple-negative breast cancer. Copyright © 2016 Elsevier Inc. All rights reserved.

GENETIC MUTATIONS AFFECTING THE FIRST LINE ERADICATION THERAPY OF Helicobacter pylori-INFECTED EGYPTIAN PATIENTS.

PubMed

Ramzy, Iman; Elgarem, Hassan; Hamza, Iman; Ghaith, Doaa; Elbaz, Tamer; Elhosary, Waleed; Mostafa, Gehan; Elzahry, Mohammad A Mohey Eldin

2016-12-08

Several genetic mutations affect the first-line triple therapy for Helicobacter pylori. We aimed to study the most common genetic mutations affecting the metronidazole and clarithromycin therapy for H. pylori-infected Egyptian patients. In our study, we included 100 successive dyspeptic patients scheduled for diagnosis through upper gastroscopy at Cairo's University Hospital, Egypt. Gastric biopsies were tested for the presence of H. pylori by detection of the 16S rRNA gene. Positive biopsies were further studied for the presence of the rdxA gene deletion by Polymerase Chain Reaction (PCR), while clarithromycin resistance was investigated by the presence of nucleotide substitutions within H. pylori 23S rRNA V domain using MboII and BsaI to carry out a Restricted Fragment Length Polymorphism (RFLP) assay. Among 70 H. pylori positive biopsies, the rdxA gene deletion was detected in 44/70 (62.9%) samples, while predominance of the A2142G mutations within the H. pylori 23S rRNA V domain was evidenced in 39/70 (55.7%) of the positive H. pylori cases. No statistically significant difference was found between the presence of gene mutations and different factors such as patients 'age, gender, geographic distribution, symptoms and endoscopic findings. Infection with mutated H. pylori strains is considerably high, a finding that imposes care in the use of the triple therapy to treat H. pylori in Egypt, since the guidelines recommend to abandon the standard triple therapy when the primary clarithromycin resistance rate is over 20%1.

Improved method increases sensitivity for circulating hepatocellular carcinoma cells

PubMed Central

Liu, Hui-Ying; Qian, Hai-Hua; Zhang, Xiao-Feng; Li, Jun; Yang, Xia; Sun, Bin; Ma, Jun-Yong; Chen, Lei; Yin, Zheng-Feng

2015-01-01

AIM: To improve an asialoglycoprotein receptor (ASGPR)-based enrichment method for detection of circulating tumor cells (CTCs) of hepatocellular carcinoma (HCC). METHODS: Peripheral blood samples were collected from healthy subjects, patients with HCC or various other cancers, and patients with hepatic lesions or hepatitis. CTCs were enriched from whole blood by extracting CD45-expressing leukocytes with monoclonal antibody coated-beads following density gradient centrifugation. The remaining cells were cytocentrifuged on polylysine-coated slides. Isolated cells were treated by triple immunofluorescence staining with CD45 antibody and a combination of antibodies against ASGPR and carbamoyl phosphate synthetase 1 (CPS1), used as liver-specific markers, and costained with DAPI. The cell slide was imaged and stained tumor cells that met preset criteria were counted. Recovery, sensitivity and specificity of the detection methods were determined and compared by spiking experiments with various types of cultured human tumor cell lines. Expression of ASGPR and CPS1 in cultured tumor cells and tumor tissue specimens was analyzed by flow cytometry and triple immunofluorescence staining, respectively. RESULTS: CD45 depletion of leukocytes resulted in a significantly greater recovery of multiple amounts of spiked HCC cells than the ASGPR+ selection (Ps < 0.05). The expression rates of either ASGPR or CPS1 were different in various liver cancer cell lines, ranging between 18% and 99% for ASGPR and between 9% and 98% for CPS1. In both human HCC tissues and liver cancer cell lines, there were a few HCC cells that did not stain positive for ASGPR or CPS1. The mixture of monoclonal antibodies against ASGPR and CPS1 identified more HCC cells than either antibody alone. However, these antibodies did not detect any tumor cells in blood samples spiked with the human breast cancer cell line MCF-7 and the human renal cancer cell line A498. ASGPR+ or/and CPS1+ CTCs were detected in 29/32 (91%) patients with HCC, but not in patients with any other kind of cancer or any of the other test subjects. Furthermore, the improved method detected a higher CTC count in all patients examined than did the previous method (P = 0.001), and consistently achieved 12%-21% higher sensitivity of CTC detection in all seven HCC patients with more than 40 CTCs. CONCLUSION: Negative depletion enrichment combined with identification using a mixture of antibodies against ASGPR and CPS1 improves sensitivity and specificity for detecting circulating HCC cells. PMID:25780289

A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12-1).

PubMed

Bonnefoi, H; Grellety, T; Tredan, O; Saghatchian, M; Dalenc, F; Mailliez, A; L'Haridon, T; Cottu, P; Abadie-Lacourtoisie, S; You, B; Mousseau, M; Dauba, J; Del Piano, F; Desmoulins, I; Coussy, F; Madranges, N; Grenier, J; Bidard, F C; Proudhon, C; MacGrogan, G; Orsini, C; Pulido, M; Gonçalves, A

2016-05-01

Several expression array studies identified molecular apocrine breast cancer (BC) as a subtype that expresses androgen receptor (AR) but not estrogen receptor α. We carried out a multicentre single-arm phase II trial in women with AR-positive, estrogen, progesterone receptor and HER2-negative (triple-negative) metastatic or inoperable locally advanced BC to assess the efficacy and safety of abiraterone acetate (AA) plus prednisone. Patients with a metastatic or locally advanced, centrally reviewed, triple-negative and AR-positive (≥10% by immunohistochemistry, IHC) BC were eligible. Any number of previous lines of chemotherapy was allowed. AA (1000 mg) was administered once a day with prednisone (5 mg) twice a day until disease progression or intolerance. The primary end point was clinical benefit rate (CBR) at 6 months defined as the proportion of patients presenting a complete response (CR), partial response (PR) or stable disease (SD) ≥6 months. Secondary end points were objective response rate (ORR), progression-free survival (PFS) and safety. One hundred and forty-six patients from 27 centres consented for IHC central review. Of the 138 patients with sufficient tissue available, 53 (37.6%) were AR-positive and triple-negative, and 34 of them were included from July 2013 to December 2014. Thirty patients were eligible and evaluable for the primary end point. The 6-month CBR was 20.0% [95% confidence interval (CI) 7.7%-38.6%], including 1 CR and 5 SD ≥6 months, 5 of them still being under treatment at the time of analysis (6.4+, 9.2+, 14.5+, 17.6+, 23.4+ months). The ORR was 6.7% (95% CI 0.8%-22.1%). The median PFS was 2.8 months (95% CI 1.7%-5.4%). Fatigue, hypertension, hypokalaemia and nausea were the most common drug-related adverse events; the majority of them being grade 1 or 2. AA plus prednisone treatment is beneficial for some patients with molecular apocrine tumours and five patients are still on treatment. NCT01842321. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Simultaneous determination of triple therapy for Helicobacter pylori in human plasma by reversed phase chromatography with online wavelength switching

NASA Astrophysics Data System (ADS)

Ahmed, Sameh; Atia, Noha N.

2015-02-01

The infection of gastric mucosa by Helicobacter pylori (HP) is an essential cofactor in the aetiology of gastroduodenal ulcer and gastric carcinoma. Because of the bacterial resistance, combination therapy containing omeprazole (OME), tinidazole (TNZ) and clarithromycin (CLA) is commonly used for eradication of HP. However, the simultaneous determination of the triple therapy in human plasma was not reported. A simple, reproducible, and selective HPLC method was developed for the simultaneous determination of the triple therapy mixture used for management of HP infections in human plasma. An HPLC procedure based on a liquid-liquid extraction, enrichment of the analytes and subsequent reversed-phase chromatography with UV detection was used. To enable sensitive and selective detection, the method involved the use of online wavelength switching detection, with two different detection wavelengths; 280 nm for detection of OME and TNZ and 210 nm for detection of CLA. Separations were performed on C18 analytical column with acetonitrile-10 mM phosphate buffer of pH = 3.0 at flow rate of 1.0 mL min-1. The linear ranges in human plasma were 0.05-10 μg mL-1 with correlation coefficients >0.9990. The detection limits in human plasma were 0.02-0.07 μg mL-1. Validation parameters were assessed in compliance with US-FDA guidelines. The method proved to be valuable for the therapeutic drug monitoring after oral administration of triple therapy tablets.

The Effectiveness of Lifestyle Triple P in the Netherlands: A Randomized Controlled Trial

PubMed Central

Gerards, Sanne M. P. L.; Dagnelie, Pieter C.; Gubbels, Jessica S.; van Buuren, Stef; Hamers, Femke J. M.; Jansen, Maria W. J.; van der Goot, Odilia H. M.; de Vries, Nanne K.; Sanders, Matthew R.; Kremers, Stef P. J.

2015-01-01

Introduction Lifestyle Triple P is a general parenting intervention which focuses on preventing further excessive weight gain in overweight and obese children. The objective of the current study was to assess the effectiveness of the Lifestyle Triple P intervention in the Netherlands. Method We used a parallel randomized controlled design to test the effectiveness of the intervention. In total, 86 child-parent triads (children 4–8 years old, overweight or obese) were recruited and randomly assigned (allocation ratio 1:1) to the Lifestyle Triple P intervention or the control condition. Parents in the intervention condition received a 14-week intervention consisting of ten 90-minute group sessions and four individual telephone sessions. Primary outcome measure was the children’s body composition (BMI z-scores, waist circumference and skinfolds). The research assistant who performed the measurements was blinded for group assignment. Secondary outcome measures were the children’s dietary behavior and physical activity level, parenting practices, parental feeding style, parenting style, and parental self-efficacy. Outcome measures were assessed at baseline and 4 months (short-term) and 12 months (long-term) after baseline. Multilevel multiple regression analyses were conducted to determine the effect of the intervention on primary and secondary outcome measures. Results No intervention effects were found on children’s body composition. Analyses of secondary outcomes showed positive short-term intervention effects on children’s soft-drink consumption and parental responsibility regarding physical activity, encouragement to eat, psychological control, and efficacy and satisfaction with parenting. Longer-term intervention effects were found on parent’s report of children’s time spent on sedentary behavior and playing outside, parental monitoring food intake, and responsibility regarding nutrition. Conclusion Although the Lifestyle Triple P intervention showed positive effects on some parent reported child behaviors and parenting measures, no effects were visible on children’s body composition or objectively measured physical activity. Several adjustments of the intervention content are recommended, for example including a booster session. Trial Registration Nederlands Trial Register NTR 2555 PMID:25849523

Effect of consecutive alternating administration (CAA) of a triple anti-enteroviral combination on Coxsackievirus B1 neuroinfection in mice.

PubMed

Stoyanova, Adelina; Nikolova, Ivanka; Galabov, Angel S

2015-09-01

Currently, clinically effective antivirals for use in the treatment of enteroviral (EV) infections do not exist. The main reason is the development of drug resistance, the principle obstacle in the development of EV infection chemotherapy, based til now on monotherapy. The most important achievement of our previous studies was the development of a novel scheme for in vivo application of a triple combination of EV inhibitors with different modes of action against Coxsackievirus B (CVB) infections in mice. It consists of consecutive alternating administration (CAA) of the substances in the combination. Here, we tested the effect of the triple combination pleconaril, guanidine-HCl, and oxoglaucine (PGO) via CAA in newborn mice infected with a neurotropic strain of CVB1 (20 LD50 per mouse). This combination manifested a considerable protective effect with pleconaril doses of 25-200mg/kg: it decreased mortality rate (protection index, PI, between 31.3% and 67.7%) and increased mean survival time (MST) by 4-6days. Pleconaril monotherapy demonstrated activity similar to that of PGO via CAA, as measured by PI values, but MST values were slightly lower. However, it also greatly suppressed growth of infected suckling mice, especially at 200mg/kg. This toxic effect was avoided with CAA of PGO at pleconaril doses of 25-100mg/kg. Pleconaril monotherapy administered every 3days was ineffective. The PGO with CAA treatment course decreased infectious virus content, whereas pleconaril monotherapy did not. Analysis of drug-sensitivity in brain samples from CVB1 infected mice, based on IC50 (50% inhibitory concentration) values from cell culture experiments, showed that the CAA course counteracted the development of drug resistance to pleconaril and oxoglaucine in the triple PGO combination and increased drug sensitivity. In contrast, pleconaril and oxoglaucine monotherapies resulted in drug resistance. This data clearly proves the effectiveness of the proposed novel approach-the CAA treatment course-for combined application of EV replication inhibitors. Copyright © 2015 Elsevier B.V. All rights reserved.

A deep-time CO2 barometer based on triple oxygen isotope compositions of dinosaurian eggshell carbonate

NASA Astrophysics Data System (ADS)

Hu, H.; Passey, B. H.; Montanari, S.; Levin, N.; Li, S.

2013-12-01

Photochemical reactions in the stratosphere lead to mass independent fractionation of oxygen isotopes: oxygen exchange among O2, O3, and CO2 produces 17O-enriched O3 and CO2, and 17O-depleted O2. This effect increases with increasing atmospheric CO2 concentration, and thus the 17O anomaly of O2, Δ17O (O2), is reflective of pCO2. Animals incorporate this signal into body water via respiration, and minerals such as bioapatite and eggshell calcite forming in equilibrium with body water can preserve the signal for millions of years. We contribute to the development of this new pCO2 barometer by developing analytical methods for high-precision triple oxygen isotope analysis of carbonates, by developing an ecophysiological model of body water triple oxygen isotopes, and by applying the method to eggshell from modern birds and late Cretaceous (Campanian and Maastrichtian) dinosaur eggshells. Our findings include the following: (1) If animal ecophysiology and climatic context are perfectly known, the sensitivity of Δ17O (body water) to atmospheric CO2 is on the order of 0.01 ‰ per 100 ppm CO2; our analytical precision is ~ 0.01 ‰, thus ultimately permitting sub -100 ppm - level pCO2 reconstructions. (2) However, the effect of ecophysiology and climate can lead to a range in Δ17O (body water) of about 0.15 ‰ for animals living under the same Δ17O (O2); this prediction, confirmed by analyses of eggshells and body water of modern birds, translates to an apparent pCO2 range of about 1500 ppm. (3) Animals that are highly dependent on unevaporated free surface water ('drinking water') and live in humid climates have Δ17O (body water) signals that mimic low pCO2, whereas animals that consume primarily evaporated water (e.g., leaf water) and living in arid environments have Δ17O (body water) signals that mimic high pCO2. (4) There is an upper limit to this 'evaporation / aridity' effect mimicking high pCO2, so Δ17O (fossil eggshell) can be modeled assuming such upper limits to produce conservative lower limits on estimates of past pCO2. (5) We find that late Cretaceous Δ17O (fossil eggshell) is generally lower than modern Δ17O (eggshell), implying generally higher pCO2 during the late Cretaceous. The lowest observed Δ17O (fossil eggshell) value implies CO2 levels of at least 1200 ppm, and probably closer to 2000 ppm, for at least a short interval of Campanian time. Overall, this triple oxygen isotope approach shows promise for placing constraints on past CO2 levels. While somewhat limited in precision, it has the benefits of little appreciable loss of sensitivity with increasing pCO2, no presently-known mechanism for generating 'false positive' estimates of high pCO2 (except for extremely low atmospheric O2 levels and low primary productivity), and a basis that is fundamentally different from existing methods, thus allowing for independent new constraints on past CO2 levels.

Phosphoethanolamine Transferase LptA in Haemophilus ducreyi Modifies Lipid A and Contributes to Human Defensin Resistance In Vitro.

PubMed

Trombley, Michael P; Post, Deborah M B; Rinker, Sherri D; Reinders, Lorri M; Fortney, Kate R; Zwickl, Beth W; Janowicz, Diane M; Baye, Fitsum M; Katz, Barry P; Spinola, Stanley M; Bauer, Margaret E

2015-01-01

Haemophilus ducreyi resists the cytotoxic effects of human antimicrobial peptides (APs), including α-defensins, β-defensins, and the cathelicidin LL-37. Resistance to LL-37, mediated by the sensitive to antimicrobial peptide (Sap) transporter, is required for H. ducreyi virulence in humans. Cationic APs are attracted to the negatively charged bacterial cell surface. In other gram-negative bacteria, modification of lipopolysaccharide or lipooligosaccharide (LOS) by the addition of positively charged moieties, such as phosphoethanolamine (PEA), confers AP resistance by means of electrostatic repulsion. H. ducreyi LOS has PEA modifications at two sites, and we identified three genes (lptA, ptdA, and ptdB) in H. ducreyi with homology to a family of bacterial PEA transferases. We generated non-polar, unmarked mutants with deletions in one, two, or all three putative PEA transferase genes. The triple mutant was significantly more susceptible to both α- and β-defensins; complementation of all three genes restored parental levels of AP resistance. Deletion of all three PEA transferase genes also resulted in a significant increase in the negativity of the mutant cell surface. Mass spectrometric analysis revealed that LptA was required for PEA modification of lipid A; PtdA and PtdB did not affect PEA modification of LOS. In human inoculation experiments, the triple mutant was as virulent as its parent strain. While this is the first identified mechanism of resistance to α-defensins in H. ducreyi, our in vivo data suggest that resistance to cathelicidin LL-37 may be more important than defensin resistance to H. ducreyi pathogenesis.

Probing anomalous W W γ triple gauge bosons coupling at the LHeC

NASA Astrophysics Data System (ADS)

Li, Ruibo; Shen, Xiao-Min; Wang, Kai; Xu, Tao; Zhang, Liangliang; Zhu, Guohuai

2018-04-01

The precision measurement of the W W γ vertex at the future Large Hadron electron Collider (LHeC) at CERN is discussed in this paper. We propose to measure this vertex in the e-p →e-W±j channel as a complement to the conventional charged current νeγ j channel. In addition to the cross section measurement, χ2 method studies of angular variables provide powerful tools to probe the anomalous structure of triple gauge boson couplings. We study the distribution of the well-known azimuthal angle between the final state forward electron and jet in this vector-boson fusion process. On the other hand, full reconstruction of leptonic W decay opens a new opportunity to measure W polarization that is also sensitive to the anomalous triple gauge boson couplings. Taking into consideration the superior determination of parton distribution functions based on future LHeC data, the constraints of λγ and Δ κγ might reach up to O (10-3) level in the most ideal case with the 2 - 3 ab-1 data set, which shows a potential advantage compared to those from LHC and Large Electron-Positron Collider (LEP) data.

Design and reliability analysis of DP-3 dynamic positioning control architecture

NASA Astrophysics Data System (ADS)

Wang, Fang; Wan, Lei; Jiang, Da-Peng; Xu, Yu-Ru

2011-12-01

As the exploration and exploitation of oil and gas proliferate throughout deepwater area, the requirements on the reliability of dynamic positioning system become increasingly stringent. The control objective ensuring safety operation at deep water will not be met by a single controller for dynamic positioning. In order to increase the availability and reliability of dynamic positioning control system, the triple redundancy hardware and software control architectures were designed and developed according to the safe specifications of DP-3 classification notation for dynamically positioned ships and rigs. The hardware redundant configuration takes the form of triple-redundant hot standby configuration including three identical operator stations and three real-time control computers which connect each other through dual networks. The function of motion control and redundancy management of control computers were implemented by software on the real-time operating system VxWorks. The software realization of task loose synchronization, majority voting and fault detection were presented in details. A hierarchical software architecture was planed during the development of software, consisting of application layer, real-time layer and physical layer. The behavior of the DP-3 dynamic positioning control system was modeled by a Markov model to analyze its reliability. The effects of variation in parameters on the reliability measures were investigated. The time domain dynamic simulation was carried out on a deepwater drilling rig to prove the feasibility of the proposed control architecture.

PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.

PubMed

Brasó-Maristany, Fara; Filosto, Simone; Catchpole, Steven; Marlow, Rebecca; Quist, Jelmar; Francesch-Domenech, Erika; Plumb, Darren A; Zakka, Leila; Gazinska, Patrycja; Liccardi, Gianmaria; Meier, Pascal; Gris-Oliver, Albert; Cheang, Maggie Chon U; Perdrix-Rosell, Anna; Shafat, Manar; Noël, Elodie; Patel, Nirmesh; McEachern, Kristen; Scaltriti, Maurizio; Castel, Pau; Noor, Farzana; Buus, Richard; Mathew, Sumi; Watkins, Johnathan; Serra, Violeta; Marra, Pierfrancesco; Grigoriadis, Anita; Tutt, Andrew N

2016-11-01

Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Here we identified increased copy number and expression of the PIM1 proto-oncogene in genomic data sets of patients with TNBC. TNBC cells, but not nonmalignant mammary epithelial cells, were dependent on PIM1 for proliferation and protection from apoptosis. PIM1 knockdown reduced expression of the anti-apoptotic factor BCL2, and dynamic BH3 profiling of apoptotic priming revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. In TNBC tumors and their cellular models, PIM1 expression was associated with several transcriptional signatures involving the transcription factor MYC, and PIM1 depletion in TNBC cell lines decreased, in a MYC-dependent manner, cell population growth and expression of the MYC target gene MCL1. Treatment with the pan-PIM kinase inhibitor AZD1208 impaired the growth of both cell line and patient-derived xenografts and sensitized them to standard-of-care chemotherapy. This work identifies PIM1 as a malignant-cell-selective target in TNBC and the potential use of PIM1 inhibitors for sensitizing TNBC to chemotherapy-induced apoptotic cell death.

Highly improved photo-induced bias stability of sandwiched triple layer structure in sol-gel processed fluorine-doped indium zinc oxide thin film transistor

NASA Astrophysics Data System (ADS)

Kim, Dongha; Park, Hyungjin; Bae, Byeong-Soo

2016-03-01

In order to improve the reliability of TFT, an Al2O3 insulating layer is inserted between active fluorine doped indium zinc oxide (IZO:F) thin films to form a sandwiched triple layer. All the thin films were fabricated via low-cost sol-gel process. Due to its large energy bandgap and high bonding energy with oxygen atoms, the Al2O3 layer acts as a photo-induced positive charge blocking layer that effectively blocks the migration of both holes and V o2+ toward the interface between the gate insulator and the semiconductor. The inserted Al2O3 triple layer exhibits a noticeably low turn on voltage shift of -0.7 V under NBIS as well as the good TFT performance with a mobility of 10.9 cm2/V ṡ s. We anticipate that this approach can be used to solve the stability issues such as NBIS, which is caused by inescapable oxygen vacancies.

Synthesis oftrans-3-hexadecenoic acid and oftrans-3-hexadecenoic-1-C(14) acid.

PubMed

Knipprath, W G; Stein, R A

1966-01-01

Thetrans-3-hexadecenoic acid has been synthesized. Physical properties and chemical degradation prove its identity with the acid earlier isolated from several plant lipids. In the sequence of the synthesis, the introduction of a terminal triple bond into commercially available 1-tetradecene was performed by bromination and debromination with KOH and NaNH(2). Chain elongation by a Grignard reaction with CO(2) gave a carboxylic acid with a triple bond in the 2-position. Reduction with LiAlH(4) yielded the corresponding alcohol, and reduction of the triple to thetrans double bond was accomplished with Na in ethanol. Bromination of the alcohol with PBr(3) and conversion of the bromide to the nitrile with KCN or KC(14)N elongated the carbon chain to the desired length. Methanolysis with HCl in methanol and saponification with KOH formed the acid with acceptable yields, and in the case of the C(14)-labeled carboxyl, group, with high specific activity.

In-tank thermodynamics of slush hydrogen for the National Aerospace Plane

NASA Astrophysics Data System (ADS)

Cady, E. C.; Flaska, T. L.; Worrell, P. K.

A series of 14 pressurization and expulsion tests were performed with triple point and slush hydrogen in a horizontally positioned 1.9 cu m (500-gallon) cryogenic tank. The tank was instrumented to determine temperature distribution in the ullage gas and liquid/slush. The pressurization gas was nominally 80 K gaseous helium (GHe) and/or 300 K gaseous hydrogen (GH). The test results showed that there were marked differences in pressurization performance between GHe and GH, and with liquid or slush hydrogen. Pressurization of slush hydrogen with warm GH was much more rapid and efficient than with cold GHe. In addition, GHe pressurization of slush hydrogen took twice as long as pressurization of triple point hydrogen, while GH pressurization of triple point and slush hydrogen took about the same time. Pressurization and expulsion pressurization using GH resulted in substantial ullage pressure collapse at initiation of expulsion (possibly due to surging in the warm outflow line leading to interface disruption and ullage condensation.

Evaluation of the Dutch BRCA1/2 clinical genetic center referral criteria in an unselected early breast cancer population

PubMed Central

van den Broek, Alexandra J; de Ruiter, Karen; van 't Veer, Laura J; Tollenaar, Rob A E M; van Leeuwen, Flora E; Verhoef, Senno; Schmidt, Marjanka K

2015-01-01

In this study, we evaluated the diagnostic value of the Dutch Clinical Genetic Center (CGC) referral guidelines for BRCA1/2 mutation testing in 903 early breast cancer patients, unselected for family history, diagnosed in a cancer hospital before the age of 50 years in 1974–2002; most prevalent Dutch pathogenic BRCA1/2 mutations had been analyzed on coded DNA in a research setting. Forty-nine (5.4%) of the patients were proven to be BRCA1/2 mutation carriers. We found that 78% and 69% of BRCA1 and BRCA2 mutation carriers identified met the criteria for referral to the CGC based on age, family history and synchronous multiple tumors; reflected by a combined sensitivity of 75.5% and specificity of 63.2%. More than half of the BRCA1 mutation carriers, that is, 58% had a triple-negative tumor. The highest AUC was obtained by shifting the age at diagnosis threshold criterion from 40 to 35 years and by adding a ‘triple-negative breast cancer' criterion with an age threshold of 45 years; the specificity increased to 71.2%, whereas the sensitivity remained the same; that is, a referral of fewer patients will lead to the identification of at least the same number of BRCA1/2 mutation carriers. Two-thirds of the BRCA1/2 mutation carriers identified in this research setting had been referred for counseling and testing. Our results indicate that, awaiting a possibly more extended mutation screening of all breast cancer patients, the triple-negative status of a breast cancer should be added to the CGC referral criteria. PMID:25138101

On the Chern-Gauss-Bonnet Theorem and Conformally Twisted Spectral Triples for C*-Dynamical Systems

NASA Astrophysics Data System (ADS)

Fathizadeh, Farzad; Gabriel, Olivier

2016-02-01

The analog of the Chern-Gauss-Bonnet theorem is studied for a C^*-dynamical system consisting of a C^*-algebra A equipped with an ergodic action of a compact Lie group G. The structure of the Lie algebra g of G is used to interpret the Chevalley-Eilenberg complex with coefficients in the smooth subalgebra A subset A as noncommutative differential forms on the dynamical system. We conformally perturb the standard metric, which is associated with the unique G-invariant state on A, by means of a Weyl conformal factor given by a positive invertible element of the algebra, and consider the Hermitian structure that it induces on the complex. A Hodge decomposition theorem is proved, which allows us to relate the Euler characteristic of the complex to the index properties of a Hodge-de Rham operator for the perturbed metric. This operator, which is shown to be selfadjoint, is a key ingredient in our construction of a spectral triple on A and a twisted spectral triple on its opposite algebra. The conformal invariance of the Euler characteristic is interpreted as an indication of the Chern-Gauss-Bonnet theorem in this setting. The spectral triples encoding the conformally perturbed metrics are shown to enjoy the same spectral summability properties as the unperturbed case.

[Triple no loop Endobutton plate combined with Orthcord line for the treatment of acromioclavicular dislocation of Tossy type III].

PubMed

Xia, Ming-Hua; Xie, Shui-Hua; Wu, Jun; Zhang, Wen-Qing; Chen, Wei-Dong; He, Jian-Hua; Ding, Hao; Hu, Qian-Qin; Wang, Xiao-Peng

2016-07-25

To explore the clinical effects of the triple no loop Endobutton plate combined with Orthcord line in treating acromioclavicular dislocation of Tossy type III. Between February 2011 and September 2013, 36 patients with acromioclavicular dislocation of Tossy type III were treated with triple no loop Endobutton plate and Orthcord line. There were 21 males and 15 females, aged from 9 to 48 years old with an average of (26.41±14.05) years. Couse of disease was from 2 to 7 days in the patients. The patients had the clinical manifestations such as shoulder pain, extension limited, acromioclavicular tenderness, positive organ point sign. Clinical effects were assessed by acromioclavicular scoring system. Thirty six patients were followed up from 8 to 15 months with an average of (12.2±4.3) months. All incisions got primary healing. At the final follow up, all shoulder pain vanished, acromioclavicular joints without tenderness, negative organ point sign. No redislocation and steel plate loosening were found. According to the acromioclavicular scoring system, 31 cases obtained excellent results, 5 good. The method of triple no loop Endobutton plate combined with Orthcord line for acromioclavicular dislocation of Tossy type III has advantage of less risk and complication, good functional rehabilitation and is an ideal method.

Prognostic relevance of biological subtype overrides that of TNM staging in breast cancer: discordance between stage and biology.

PubMed

Jung, Hyun Ae; Park, Yeon Hee; Kim, Moonjin; Kim, Sungmin; Chang, Won Jin; Choi, Moon Ki; Hong, Jung Yong; Kim, Seok Won; Kil, Won Ho; Lee, Jeong Eon; Nam, Seok Jin; Ahn, Jin Seok; Im, Young-Hyuck

2015-02-01

Recently, we faced difficult treatment decisions regarding appropriate adjuvant systemic treatment, especially for patients who show discordance between stage and tumor biology. The aim of this study was to compare the prognostic relevance of the TNM staging system with that of intrinsic subtype in breast cancer. We retrospectively identified women patients who received curative surgery for stage I-III breast cancer with available data on immunohistochemistry profiles including hormone receptor (HR) status, human epidermal growth factor receptor 2 (HER2) status, and Ki 67 staining at the Samsung Medical Center from January 2004 to September 2008. Primary outcomes were recurrence-free survival (RFS) and overall survival (OS). A total of 1145 patients were diagnosed with breast cancer and received curative surgery. Of these, 463 (40.4%) patients were stage I, and 682 (59.6%) were stage II or III. In addition, 701 (61.2%) patients were HR positive, 239 (20.9%) were HER2 positive, and 205 (20.9%) had triple-negative breast cancer. The 5-year RFS for the patients who were HR positive and HER2 negative with a low Ki 67 staining score (0-25%) was 99%. The 5-year RFS for patients who were HER2-positive or had triple-negative breast cancer were 89 and 83%, respectively (P value = <0.001). In multivariate analysis, advanced stage (II/III) and unfavorable biology (HER2 positive or triple negative) retained their statistical significance as predictors of decreased RFS and OS. Patients with advanced-stage disease (II or III) but favorable tumor biology (HR positive and HER2 negative and low Ki 67) had better clinical outcomes than those with stage I disease and unfavorable tumor biology in terms of RFS (99 versus 92%, P value = 0.011) and OS (99 versus 96%, P value = 0.03) at 5 years. The current results showed that intrinsic subtype has a greater prognostic impact in predicting clinical outcomes in subpopulations of patients with stage I-III breast cancer who show discordance between stage and biologic subtypes.

Detection of early metabolic alterations in the ocular fundus of diabetic patients by time-resolved autofluorescence of endogenous fluorophores

NASA Astrophysics Data System (ADS)

Schweitzer, D.; Klemm, M.; Quick, S.; Deutsch, L.; Jentsch, S.; Hammer, M.; Dawczynski, J.; Kloos, C. H.; Mueller, U. A.

2011-07-01

Measurements of time-resolved autofluorescence (FLIM) at the human ocular fundus of diabetic patients permit the detection of early pathologic alterations before signs of diabetic retinopathy are visible. The measurements were performed by the Jena Fluorescence Lifetime Laser Scanner Ophthalmoscope applying time-correlated single photon counting (TCSPC) in two spectral channels (K1: 490-560 nm, K2:560-700ps). The fluorescence was excited by 70 ps pulses (FWHM) at 448 nm. The decay of fluorescence intensity was triple-exponentially approximated. The frequency of amplitudes, lifetimes, and relative contributions was compared in fields of the same size and position in healthy subjects and in diabetic patients. The most sensitive parameter was the lifetime T2 in the short-wavelength channel, which corresponds to the neuronal retina. The changes in lifetime point to a loss of free NADH and an increased contribution of protein-bound NADH in the pre-stage of diabetic retinopathy.

CAMEA—A novel multiplexing analyzer for neutron spectroscopy

NASA Astrophysics Data System (ADS)

Groitl, Felix; Graf, Dieter; Birk, Jonas Okkels; Markó, Márton; Bartkowiak, Marek; Filges, Uwe; Niedermayer, Christof; Rüegg, Christian; Rønnow, Henrik M.

2016-03-01

The analyzer detector system continuous angle multiple energy analysis will be installed on the cold-neutron triple-axis spectrometer RITA-2 at SINQ, PSI. CAMEA is optimized for efficiency in the horizontal scattering plane enabling rapid and detailed mapping of excitations. As a novelty the design employs a series of several sequential upward scattering analyzer arcs. Each arc is set to a different, fixed, final energy and scatters neutrons towards position sensitive detectors. Thus, neutrons with different final energies are recorded simultaneously over a large angular range. In a single data-acquisition many entire constant-energy lines in the horizontal scattering plane are recorded for a quasi-continuous angular coverage of about 60°. With a large combined coverage in energy and momentum, this will result in a very efficient spectrometer, which will be particularly suited for parametric studies under extreme conditions with restrictive sample environments (high field magnets or pressure cells) and for small samples of novel materials. In this paper we outline the concept and the specifications of the instrument currently under construction.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Groitl, Felix, E-mail: felix.groitl@psi.ch; Paul Scherrer Institute, Laboratory for Neutron Scattering and Imaging, 5232 Villigen; Graf, Dieter

The analyzer detector system continuous angle multiple energy analysis will be installed on the cold-neutron triple-axis spectrometer RITA-2 at SINQ, PSI. CAMEA is optimized for efficiency in the horizontal scattering plane enabling rapid and detailed mapping of excitations. As a novelty the design employs a series of several sequential upward scattering analyzer arcs. Each arc is set to a different, fixed, final energy and scatters neutrons towards position sensitive detectors. Thus, neutrons with different final energies are recorded simultaneously over a large angular range. In a single data-acquisition many entire constant-energy lines in the horizontal scattering plane are recorded formore » a quasi-continuous angular coverage of about 60°. With a large combined coverage in energy and momentum, this will result in a very efficient spectrometer, which will be particularly suited for parametric studies under extreme conditions with restrictive sample environments (high field magnets or pressure cells) and for small samples of novel materials. In this paper we outline the concept and the specifications of the instrument currently under construction.« less

Evaluation of Nitrofurantoin Combination Therapy of Metronidazole-Sensitive and -Resistant Helicobacter pylori Infections in Mice

PubMed Central

Jenks, Peter J.; Ferrero, Richard L.; Tankovic, Jacques; Thiberge, Jean-Michel; Labigne, Agnès

2000-01-01

The main objectives of this study were to determine whether the nitroreductase enzyme encoded by the rdxA gene of Helicobacter pylori was responsible for reductive activation of nitrofurantoin and whether a triple-therapy regimen with nitrofurantoin was able to eradicate metronidazole-sensitive and -resistant H. pylori infections from mice. The susceptibilities to nitrofurantoin of parent and isogenic rdxA mutant strains (three pairs), as well as a series of matched metronidazole-sensitive and -resistant strains isolated from mice (30) and patients (20), were assessed by agar dilution determination of the MIC. Groups of mice colonized with the metronidazole-sensitive H. pylori SS1 strain or a metronidazole-resistant rdxA SS1 mutant were treated with either metronidazole or nitrofurantoin as part of a triple-therapy regimen. One month after the completion of treatment the mice were sacrificed and their stomachs were cultured for H. pylori. The nitrofurantoin MICs for all strains tested were between 0.5 and 4.0 μg/ml. There was no significant difference between the susceptibility to nitrofurantoin of the parental strains and those of respective rdxA mutants or between those of matched metronidazole-sensitive and -resistant H. pylori isolates. The regimen with metronidazole eradicated infection from all eight SS1-infected mice and from one of eight mice inoculated with the rdxA mutant (P ≤ 0.001). The regimen with nitrofurantoin failed to eradicate infection from any of the six SS1-infected mice (P ≤ 0.001) and cleared infection from one of seven mice inoculated with the rdxA mutant. These results demonstrate that, despite the good in vitro activity of nitrofurantoin against H. pylori and the lack of cross-resistance between metronidazole and nitrofurantoin, eradication regimens involving nitrofurantoin are unable to eradicate either metronidazole-sensitive or -resistant H. pylori infections from mice. PMID:10991835

Methionine Deprivation Induces a Targetable Vulnerability in Triple-Negative Breast Cancer Cells by Enhancing TRAIL Receptor-2 Expression.

PubMed

Strekalova, Elena; Malin, Dmitry; Good, David M; Cryns, Vincent L

2015-06-15

Many neoplasms are vulnerable to methionine deficiency by mechanisms that are poorly understood. Because gene profiling studies have revealed that methionine depletion increases TNF-related apoptosis-inducing ligand receptor-2 (TRAIL-R2) mRNA, we postulated that methionine stress sensitizes breast cancer cells to proapoptotic TRAIL-R2 agonists. Human triple (ER/PR/HER2)-negative breast carcinoma cell lines were cultured in control or methionine-free media. The effects of methionine depletion on TRAIL receptor expression and sensitivity to chemotherapy or a humanized agonistic TRAIL-R2 monoclonal antibody (lexatumumab) were determined. The melanoma-associated antigen MAGED2 was silenced to delineate its functional role in sensitizing TNBC cells to methionine stress. An orthotopic TNBC model was utilized to evaluate the effects of dietary methionine deficiency, lexatumumab, or the combination. Methionine depletion sensitized TNBC cells to lexatumumab-induced caspase activation and apoptosis by increasing TRAIL-R2 mRNA and cell surface expression. MCF-10A cells transformed by oncogenic H-Ras, but not untransformed cells, and matrix-detached TNBC cells were highly sensitive to the combination of lexatumumab and methionine depletion. Proteomics analyses revealed that MAGED2, which has been reported to reduce TRAIL-R2 expression, was suppressed by methionine stress. Silencing MAGED2 recapitulated features of methionine deprivation, including enhanced mRNA and cell surface expression of TRAIL receptors and increased sensitivity to TRAIL receptor agonists. Dietary methionine deprivation enhanced the antitumor effects of lexatumumab in an orthotopic metastatic TNBC model. Methionine depletion exposes a targetable defect in TNBC cells by increasing TRAIL-R2 expression. Our findings provide the foundation for a clinical trial combining dietary methionine restriction and TRAIL-R2 agonists. Clin Cancer Res; 21(12); 2780-91. ©2015 AACR. ©2015 American Association for Cancer Research.

Comparison of the clinical and cognitive features of genetically positive ALS patients from the largest tertiary center in Serbia.

PubMed

Marjanović, Ivan V; Selak-Djokić, Biljana; Perić, Stojan; Janković, Milena; Arsenijević, Vladimir; Basta, Ivana; Lavrnić, Dragana; Stefanova, Elka; Stević, Zorica

2017-06-01

Discovering novel mutations in C9orf72, FUS, ANG, and TDP-43 genes in ALS patients arises necessities for better clinical characterizations of these subjects. The aim is to determine clinical and cognitive profile of genetically positive Serbian ALS patients. 241 ALS patients were included in the study (17 familiar and 224 apparently sporadic). The following genes were analyzed: SOD1, C9orf72, ANG, FUS, and TDP-43. An extensive battery of classic neuropsychological tests was used in 27 ALS patients (22 SOD1 positive and 5 SOD1 negative) and 82 healthy controls (HCs). Overall 37 (15.4%) of 241 ALS patients carried mutations in tested genes-among 17 familiar ALS patients 16 (94.1%) were positive and among 224 apparently sporadic 21 (9.4%) had causative mutation. Mutations in SOD1 gene were the most common, representing 27 (73.0%) of all genetically positive ALS patients. The main clinical characteristics of SOD1 positive patients were: spinal onset in lower extremities, common sphincter and sensitive disturbances, and dysexecutive syndrome. Within SOD1 positive patients, we noticed somewhat earlier onset in patients with A145G, sensory and sphincter disturbances were dominant in patients with L144F, while D90A patients had significant sensory involvement. SOD1 negative group consisted of ten (27.0%) patients (six C9orf72, two ANG, one TDP-43, and one patient baring triple FUS, C9orf72 expansion, and ANG variants). Bulbar involvement and more extensive neuropsychological impairment (including executive, visuospatial, and memory difficulties) were the main features of SOD1 negative cohort. Our results suggest that meaningful clinical suspicion of certain ALS genotype might be made based on thorough clinical evaluation of patients.

Advanced receiver autonomous integrity monitoring using triple frequency data with a focus on treatment of biases

NASA Astrophysics Data System (ADS)

El-Mowafy, Ahmed

2017-04-01

Most current Advanced Receiver Autonomous Integrity Monitoring (ARAIM) methods are designed to use dual-frequency ionosphere-free observations. These methods assume that receiver bias is absorbed in the common receiver clock offset and bound satellite biases by nominal values. However, most multi-constellation Global Navigation Satellite Systems (GNSS) can offer triple frequency data that can be used for civilian applications in the future, which can improve observation redundancy, solution precision and detection of faults. In this contribution, we explore the use of this type of observations from GPS, Galileo and BeiDou in ARAIM. Nevertheless, the use of triple frequency data introduces receiver differential biases that have to be taken into consideration. To demonstrate the significance of these additional biases we first present a method to quantify them at stations of known coordinates and using available products from the International GNSS service (IGS). To deal with the additional receiver biases, we use a between-satellite single difference (BSSD) observation model that eliminates their effect. A pilot test was performed to evaluate ARAIM availability for Localizer Performance with Vertical guidance down to 200 feet (LPV-200) when using the triple-frequency observations. Real data were collected for one month at stations of known coordinates located in regions of different satellite coverage characteristics. The BSSD triple-frequency model was evaluated to give early indication about its feasibility, where the implementation phase still requires further comprehensive studies. The vertical position error was always found to be bounded by the protection level proven initial validity of the proposed integrity model.

A novel UPLC-MS/MS method for sensitive quantitation of boldine in plasma, a potential anti-inflammatory agent: application to a pharmacokinetic study in rats.

PubMed

Zeng, Rong-Jie; Li, Yu; Chen, Jian-Zhong; Chou, Gui-Xin; Gao, Yu; Shao, Jing-Wei; Jia, Lee; Wu, Sheng-Dong; Wu, Shui-Sheng

2015-03-01

Boldine is a potential anti-inflammatory agent found in several different plants. Published bioanalytical methods using HPLC with ultraviolet and fluorescent detection lacked enough sensitivity and required tedious sample preparation procedures. Herein, we describe the development of a novel ultra-high performance LC with MS/MS for determination of boldine in plasma. Boldine in plasma was recovered by liquid-liquid extraction using 1 mL of methyl tert-butyl ether. Chromatographic separation was performed on a C18 column at 45°C, with a gradient elution consisting of acetonitrile and water containing 0.1% (v/v) formic acid at a flow rate of 0.3 mL/min. The detection was performed on an electrospray triple-quadrupole MS/MS by positive ion multiple reaction monitoring mode. Good linearity (r(2) > 0.9926) was achieved in a concentration range of 2.555-2555 ng/mL with a lower limit of quantification of 2.555 ng/mL for boldine. The intra- and inter-day precisions of the assay were 1.2-6.0 and 1.8-7.4% relative standard deviation with an accuracy of -6.0-8.0% relative error. This newly developed method was successfully applied to a single low-dose pharmacokinetic study in rats and was demonstrated to be simpler and more sensitive than the published methods, allowing boldine quantification in reduced plasma volume. Copyright © 2014 John Wiley & Sons, Ltd.

Sensitive method for the quantitative determination of proguanil and its metabolites in rat blood and plasma by liquid chromatography-mass spectrometry.

PubMed

Leveque, Nathalie L; Charman, William N; Chiu, Francis C K

2006-01-18

A sensitive, simple and fast liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for the determination of proguanil (PG) and its metabolites, cycloguanil (CG) and 1-(4-chlorophenyl)biguanide (4CPB), was developed and validated over a concentration range of 1-2000 ng/mL using only 50 microL of blood or plasma. After a simple solvent precipitation procedure, the supernatant was analysed directly by HPLC-MS/MS. Separation was achieved using an ethyl-linked phenyl reverse phase column with polar endcapping with an acetonitrile-water-formic acid gradient. Mass spectrometry was performed using a triple quadrupole mass spectrometer operating in positive electrospray ionization mode. The elution of PG (254.07-->169.99), CG (252.12-->195.02) and 4CPB (212.06-->153.06) was monitored using selected reaction monitoring. The three compounds and the internal standard (chloroproguanil) were well separated by HPLC and no interfering peaks were detected at the usual concentrations found in blood and plasma. The limit of quantification of PG and CG was 1 ng/mL and 5 ng/mL for 4CPB in rat blood and plasma. The extraction efficiency of PG, CG and 4CPB from rat blood and plasma was higher than 73%. The intra- and inter-assay variability of PG, CG and 4CPB were within 12% and the accuracy within +/-5%. This new assay offers higher sensitivity and a much shorter run time over earlier methods.

MT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib

PubMed Central

Yip, Cassandre; Foidart, Pierre; Somja, Joan; Truong, Alice; Lienard, Mehdi; Feyereisen, Emilie; Schroeder, Hélène; Gofflot, Stéphanie; Donneau, Anne-Françoise; Collignon, Joëlle; Delvenne, Philippe; Sounni, Nor Eddine; Jerusalem, Guy; Noël, Agnès

2017-01-01

Background: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC. Methods: We conducted a retrospective immunohistochemical analysis on human TNBC samples (n=81) and validated our findings in in vitro and in vivo assays. Results: Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro. In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours. Conclusions: We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs. PMID:28196064

Staying Well at Work.

ERIC Educational Resources Information Center

Blai, Boris, Jr.

Employee wellness directly affects business/industry operations and costs. When employees are helped and encouraged to stay well, this people-positive policy results in triple benefits: reduced worker absenteeism, increased employee productivity, and lower company expenditures for health costs. Health care programs at the worksite offer these…

Apheresis and intravenous immunoglobulins used in addition to conventional therapy to treat high-risk pregnant antiphospholipid antibody syndrome patients. A prospective study.

PubMed

Ruffatti, Amelia; Favaro, Maria; Hoxha, Ariela; Zambon, Alessandra; Marson, Piero; Del Ross, Teresa; Calligaro, Antonia; Tonello, Marta; Nardelli, Giovanni B

2016-06-01

Pregnant women with triple antibody positive antiphospholipid syndrome (APS) who have had thrombosis or a history of early, severe pregnancy complications are generally considered at high risk of pregnancy loss. The objectives of this study were to investigate the efficacy and safety of a relatively new treatment protocol used in addition to conventional therapy in high-risk pregnant patients affected with primary APS. The study's two inclusion criteria were: (1) the presence of triple antiphospholipid positivity, (2) previous thrombosis and/or a history of one or more early, severe pregnancy complications. Eighteen pregnancies occurring between 2002 and 2015 in 14 APS patients, (mean age 34.8±3.6 SD) were monitored. All 14 (100%) patients had triple antiphospholipid positivity. In addition, six of them (42.8%) had a history of thrombosis, four (28.6%) had one or more previous early and severe pregnancy complications, and four (30.8%) met both clinical study criteria. The study protocol included weekly plasmapheresis or immunoadsorption and fortnightly 1g/kg intravenous immunoglobulins. Seventeen of the pregnancies (94.4%) produced live neonates, all born between the 26th and 37th weeks of gestation (mean 33.1±3.5 SD). One female (5.5%), born prematurely at 24 weeks, died of sepsis a week after birth. There were two cases (11.1%) of severe pregnancy complications. No treatment side effects were registered. Given the high live birth rate and the safety associated to it, the study protocol described here could be taken into consideration by medical teams treating high-risk APS pregnant patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Detection of Gelatin Adulteration in Traditional Chinese Medicine: Analysis of Deer-Horn Glue by Rapid-Resolution Liquid Chromatography-Triple Quadrupole Mass Spectrometry

PubMed Central

Chen, Jia; Cheng, Xian-Long; Wei, Feng; Zhang, Qian-Qian; Li, Ming-Hua; Ma, Shuang-Cheng

2015-01-01

Simultaneous identification of donkey-hide gelatin and bovine-hide gelatin in deer-horn glue was established by rapid-resolution liquid chromatography-triple quadrupole mass spectrometry. Water containing 1% NH4HCO3 was used for sample dissolution and trypsin was used for hydrolysis of the gelatins. After separation by a SB-C18 reversed-phase analytical column, collagen marker peptides were detected by mass spectrometry in positive electrospray ionization mode with multiple reaction monitoring. The method was specific, precise and reliable, and suitable for detection of adulterants derived from donkey-hide gelatin and bovine-hide gelatin in deer-horn glue. PMID:26504613

Spin-dependent dwell times of electron tunneling through double- and triple-barrier structures

NASA Astrophysics Data System (ADS)

Erić, Marko; Radovanović, Jelena; Milanović, Vitomir; Ikonić, Zoran; Indjin, Dragan

2008-04-01

We have analyzed the influence of Dresselhaus and Rashba spin-orbit couplings (caused by the bulk inversion asymmetry and the structural asymmetry, respectively) on electron tunneling through a double- and triple-barrier structures, with and without an externally applied electric field. The results indicate that the degree of structural asymmetry and external electric field can greatly affect the dwell times of electrons with opposite spin orientation. This opens up the possibilities of obtaining efficient spin separation in the time domain. The material system of choice is AlxGa1-xSb, and the presented model takes into account the position dependence of material parameters, as well as the effects of band nonparabolicity.

Triple-axis common-pivot arm wrist device for manipulative applications

NASA Technical Reports Server (NTRS)

Kersten, L.; Johnston, J. D.

1980-01-01

A concept in manipulator development to overcome the 'weak wrist syndrome', a triple-axis common-pivot arm wrist (TACPAW), is presented. It contains torque motors for actuation, tachometers for measuring rate, and resolvers for position measurements. Furthermore, it provides three degrees of freedom, i.e., pitch, yaw, and roll, in a single manipulator joint. The advantages of this development are increased strength, compactness, and simplification of controls. Designed to be compatible with the protoflight manipulator arm, the joints of TACPAW are back-driveable with + or - 45 deg rotation in pitch, + or - 45 deg in yaw and continuous roll in either direction while delivering 20.5 N-m (15 ft-lb) torque in each of the three movements.

Age-Specific Incidence of Breast Cancer Subtypes: Understanding the Black–White Crossover

PubMed Central

2012-01-01

Background Breast cancer incidence is higher among black women than white women before age 40 years, but higher among white women than black women after age 40 years (black–white crossover). We used newly available population-based data to examine whether the age-specific incidences of breast cancer subtypes vary by race and ethnicity. Methods We classified 91908 invasive breast cancers diagnosed in California between January 1, 2006, and December 31, 2009, by subtype based on tumor expression of estrogen receptor (ER) and progesterone receptor (PR)—together referred to as hormone receptor (HR)—and human epidermal growth factor receptor 2 (HER2). Breast cancer subtypes were classified as ER or PR positive and HER2 negative (HR+/HER2−), ER or PR positive and HER2 positive (HR+/HER2+), ER and PR negative and HER2 positive (HR−/HER2+), and ER, PR, and HER2 negative (triple-negative). We calculated and compared age-specific incidence rates, incidence rate ratios, and 95% confidence intervals by subtype and race (black, white, Hispanic, and Asian). All P values are two-sided. Results We did not observe an age-related black–white crossover in incidence for any molecular subtype of breast cancer. Compared with white women, black women had statistically significantly higher rates of triple-negative breast cancer at all ages but statistically significantly lower rates of HR+/HER2− breast cancers after age 35 years (all P < .05). The age-specific incidence of HR+/HER2+ and HR−/HER2+ subtypes did not vary markedly between white and black women. Conclusions The black–white crossover in breast cancer incidence occurs only when all breast cancer subtypes are combined and relates largely to higher rates of triple-negative breast cancers and lower rates of HR+/HER2− breast cancers in black vs white women. PMID:22773826

Outcome Evidence for Structured Pediatric to Adult Health Care Transition Interventions: A Systematic Review.

PubMed

Gabriel, Phabinly; McManus, Margaret; Rogers, Katherine; White, Patience

2017-09-01

To identify statistically significant positive outcomes in pediatric-to-adult transition studies using the triple aim framework of population health, consumer experience, and utilization and costs of care. Studies published between January 1995 and April 2016 were identified using the CINAHL, Ovid MEDLINE, PubMed, Scopus, and Web of Science databases. Included studies evaluated pre-evaluation and postevaluation data, intervention and comparison groups, and randomized clinic trials. The methodological strength of each study was assessed using the Effective Public Health Practice Project Quality Assessment Tool. Out of a total of 3844 articles, 43 met our inclusion criteria. Statistically significant positive outcomes were found in 28 studies, most often related to population health (20 studies), followed by consumer experience (8 studies), and service utilization (9 studies). Among studies with moderate to strong quality assessment ratings, the most common positive outcomes were adherence to care and utilization of ambulatory care in adult settings. Structured transition interventions often resulted in positive outcomes. Future evaluations should consider aligning with professional transition guidance; incorporating detailed intervention descriptions about transition planning, transfer, and integration into adult care; and measuring the triple aims of population health, experience, and costs of care. Copyright © 2017 Elsevier Inc. All rights reserved.

The most important questions in cancer research and clinical oncology : Question 1. Could the vertical transmission of human papilloma virus (HPV) infection account for the cause, characteristics, and epidemiology of HPV-positive oropharyngeal carcinoma, non-smoking East Asian female lung adenocarcinoma, and/or East Asian triple-negative breast carcinoma?

PubMed

Wee, Joseph T S; Poh, Sharon Shuxian

2017-01-16

Specific research foci: (1) Mouse models of gamma-herpes virus-68 (γHV-68) and polyomavirus (PyV) infections during neonatal versus adult life. (2) For human papilloma virus (HPV)-positive oropharyngeal carcinoma (OPC)-(a) Asking the question: Is oral sex a powerful carcinogen? (b) Examining the evidence for the vertical transmission of HPV infection. (c) Examining the relationship between HPV and Epstein-Barr virus (EBV) infections and nasopharyngeal cancer (NPC) in West European, East European, and East Asian countries. (d) Examining the association between HPV-positive OPC and human leukocyte antigen (HLA). (3) For non-smoking East Asian female lung adenocarcinoma-(a) Examining the incidence trends of HPV-positive OPC and female lung adenocarcinoma according to birth cohorts. (b) Examining the association between female lung adenocarcinoma and HPV. (c) Examining the associations of lung adenocarcinoma with immune modulating factors. (4) For triple-negative breast carcinoma (TNBC) in East Asians-(a) Examining the association between TNBC and HPV. (b) Examining the unique epidemiological characteristics of patients with TNBC. A summary "epidemiological" model tying some of these findings together.

The combination of the error correction methods of GAFCHROMIC EBT3 film

PubMed Central

Li, Yinghui; Chen, Lixin; Zhu, Jinhan; Liu, Xiaowei

2017-01-01

Purpose The aim of this study was to combine a set of methods for use of radiochromic film dosimetry, including calibration, correction for lateral effects and a proposed triple-channel analysis. These methods can be applied to GAFCHROMIC EBT3 film dosimetry for radiation field analysis and verification of IMRT plans. Methods A single-film exposure was used to achieve dose calibration, and the accuracy was verified based on comparisons with the square-field calibration method. Before performing the dose analysis, the lateral effects on pixel values were corrected. The position dependence of the lateral effect was fitted by a parabolic function, and the curvature factors of different dose levels were obtained using a quadratic formula. After lateral effect correction, a triple-channel analysis was used to reduce disturbances and convert scanned images from films into dose maps. The dose profiles of open fields were measured using EBT3 films and compared with the data obtained using an ionization chamber. Eighteen IMRT plans with different field sizes were measured and verified with EBT3 films, applying our methods, and compared to TPS dose maps, to check correct implementation of film dosimetry proposed here. Results The uncertainty of lateral effects can be reduced to ±1 cGy. Compared with the results of Micke A et al., the residual disturbances of the proposed triple-channel method at 48, 176 and 415 cGy are 5.3%, 20.9% and 31.4% smaller, respectively. Compared with the ionization chamber results, the difference in the off-axis ratio and percentage depth dose are within 1% and 2%, respectively. For the application of IMRT verification, there were no difference between two triple-channel methods. Compared with only corrected by triple-channel method, the IMRT results of the combined method (include lateral effect correction and our present triple-channel method) show a 2% improvement for large IMRT fields with the criteria 3%/3 mm. PMID:28750023

Prenatal diagnosis of 47,XXX.

PubMed

Khoury-Collado, Fady; Wehbeh, Ammar N; Fisher, Allan J; Bombard, Allan T; Weiner, Zeev

2005-05-01

We report 2 cases of 47,XXX that were diagnosed prenatally and were screened positive for trisomy 21 by biochemical and ultrasound markers. These cases underline the importance of discussing the sex chromosome abnormalities during the genetic counseling after an abnormal triple screen test or ultrasound examination.

Classifying injury narratives of large administrative databases for surveillance-A practical approach combining machine learning ensembles and human review.

PubMed

Marucci-Wellman, Helen R; Corns, Helen L; Lehto, Mark R

2017-01-01

Injury narratives are now available real time and include useful information for injury surveillance and prevention. However, manual classification of the cause or events leading to injury found in large batches of narratives, such as workers compensation claims databases, can be prohibitive. In this study we compare the utility of four machine learning algorithms (Naïve Bayes, Single word and Bi-gram models, Support Vector Machine and Logistic Regression) for classifying narratives into Bureau of Labor Statistics Occupational Injury and Illness event leading to injury classifications for a large workers compensation database. These algorithms are known to do well classifying narrative text and are fairly easy to implement with off-the-shelf software packages such as Python. We propose human-machine learning ensemble approaches which maximize the power and accuracy of the algorithms for machine-assigned codes and allow for strategic filtering of rare, emerging or ambiguous narratives for manual review. We compare human-machine approaches based on filtering on the prediction strength of the classifier vs. agreement between algorithms. Regularized Logistic Regression (LR) was the best performing algorithm alone. Using this algorithm and filtering out the bottom 30% of predictions for manual review resulted in high accuracy (overall sensitivity/positive predictive value of 0.89) of the final machine-human coded dataset. The best pairings of algorithms included Naïve Bayes with Support Vector Machine whereby the triple ensemble NB SW =NB BI-GRAM =SVM had very high performance (0.93 overall sensitivity/positive predictive value and high accuracy (i.e. high sensitivity and positive predictive values)) across both large and small categories leaving 41% of the narratives for manual review. Integrating LR into this ensemble mix improved performance only slightly. For large administrative datasets we propose incorporation of methods based on human-machine pairings such as we have done here, utilizing readily-available off-the-shelf machine learning techniques and resulting in only a fraction of narratives that require manual review. Human-machine ensemble methods are likely to improve performance over total manual coding. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Triple-negative breast cancer: current state of the art.

PubMed

Rastelli, Francesca; Biancanelli, Sandra; Falzetta, Amalia; Martignetti, Angelo; Casi, Camilla; Bascioni, Romeo; Giustini, Lucio; Crispino, Sergio

2010-01-01

Triple-negative breast cancer, defined by a lack of expression of estrogen, progesterone and HER-2 receptors, accounts for 15% of all types of breast cancer. The subtype mainly includes a molecularly distinct subgroup, the basal-like subtype (accounting for 75% of all cases). We attempt to define triple-negative breast cancer and compare it with basal-like disease, review the molecular, pathologic and clinical features of triple-negative disease, provide an overview of a retrospective subset analysis of clinical trials, and outline ongoing therapeutic trials and possible paths for future research. We collected data regarding classification, molecular and clinical features and treatment, drawn from the existing literature, including abstracts and verbal accounts. By the term "basal-like", we defined all cases where gene expression array or more sophisticated immunophenotypes are used for identification. When the analysis is restricted to clinical assay (immunohistochemistry), we refer to "triple-negative". Basal-like breast cancer expresses genes characteristic of basal epithelial cells, which include high-molecular weight basal cytokeratins (CK5/6, CK14, CK17), vimentin, p-cadherin, alpha B crystalline, caveolins 1 and 2 and EGFR. The expression of basal markers (basal cytokeratins and EGFR) is related to a worse prognosis and identifies a clinically distinct subgroup within the triple-negative breast cancer. BRCA1 mutations are present in 11% of triple-negative tumors and even more rare is BRCA2 deficiency. BR-CA1-associated breast cancers types are typically characterized by a high rate of DNA aberrations and defective DNA repair pathways (the so-called "BRCAness"). The use of regimens based on DNA-damaging agents, such as anthracyclines, platinum derivatives and cyclophosphamide seems a sensible option for this breast cancer subtypes. Clinical data support a strong sensitivity to primary chemotherapy with pathologic response rates ranging from 27-45% (with anthracyclines and taxanes) to more than 60% with platinum-based triplets. However, based on retrospective data, major response to chemotherapy does not carry better survival ("triple-negative paradox"). There is no specific targeted therapy in the armamentarium: ongoing trials include anti-angiogenic agents, anti-EGFR and EGFR-TK inhibitors, epothilones and PARP inhibitors. A specific systemic regimen cannot yet be recommended. Moreover, only a few data are available on which treatment selection can be based. Use of the existing cytotoxic agents can be optimized for this patient subgroup by investigating the proliferative signals and the suitability of these signals as therapeutic targets, besides assessing the BRCA1-pathway in this subgroup as regards treatment. A greater understanding of the pathologic and molecular characteristics of this phenotype may lead to customized treatment for these patients.

Increased sensitivity of African American triple negative breast cancer cells to nitric oxide-induced mitochondria-mediated apoptosis.

PubMed

Martinez, Luis; Thames, Easter; Kim, Jinna; Chaudhuri, Gautam; Singh, Rajan; Pervin, Shehla

2016-07-29

Breast cancer is a complex heterogeneous disease where many distinct subtypes are found. Younger African American (AA) women often present themselves with aggressive form of breast cancer with unique biology which is very difficult to treat. Better understanding the biology of AA breast tumors could lead to development of effective treatment strategies. Our previous studies indicate that AA but not Caucasian (CA) triple negative (TN) breast cancer cells were sensitive to nitrosative stress-induced cell death. In this study, we elucidate possible mechanisms that contribute to nitric oxide (NO)-induced apoptosis in AA TN breast cancer cells. Breast cancer cells were treated with various concentrations of long-acting NO donor, DETA-NONOate and cell viability was determined by trypan blue exclusion assay. Apoptosis was determined by TUNEL and caspase 3 activity as well as changes in mitochondrial membrane potential. Caspase 3 and Bax cleavage, levels of Cu/Zn superoxide dismutase (SOD) and Mn SOD was assessed by immunoblot analysis. Inhibition of Bax cleavage by Calpain inhibitor, and levels of reactive oxygen species (ROS) as well as SOD activity was measured in NO-induced apoptosis. In vitro and in vivo effect of NO treatment on mammary cancer stem cells (MCSCs) was assessed. NO induced mitocondria-mediated apoptosis in all AA but not in CA TN breast cancer cells. We found significant TUNEL-positive cells, cleavage of Bax and caspase-3 activation as well as depolarization mitochondrial membrane potential only in AA TN breast cancer cells exposed to NO. Inhibition of Bax cleavage and quenching of ROS partially inhibited NO-induced apoptosis in AA TN cells. Increase in ROS coincided with reduction in SOD activity in AA TN breast cancer cells. Furthermore, NO treatment of AA TN breast cancer cells dramatically reduced aldehyde dehydrogenase1 (ALDH1) expressing MCSCs and xenograft formation but not in breast cancer cells from CA origin. Ethnic differences in breast tumors dictate a need for tailoring treatment options more suited to the unique biology of the disease.

Pulsed Multiple Reaction Monitoring Approach to Enhancing Sensitivity of a Tandem Quadrupole Mass Spectrometer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Belov, Mikhail E.; Prasad, Satendra; Prior, David C.

2011-02-23

Liquid chromatography (LC)-triple quadrupole mass spectrometers operating in a Multiple Reaction Monitoring (MRM) mode are increasingly used for quantitative analysis of low abundance analytes in highly complex biochemical matrices. After development and selection of optimum MRM transition, sensitivity and data quality limitations are largely related to mass spectral peak interferences from sample or matrix constituents and statistical limitations at low number of ions reaching the detector. Herein, we report a new approach to enhancing MRM sensitivity by converting the continuous stream of ions from the ion source into a pulsed ion beam through the use of an Ion Funnel Trapmore » (IFT). Evaluation of the pulsed MRM approach was performed with a tryptic digest of Shewanella oneidensis strain MR-1 spiked with several reference peptides. The sensitivity improvement observed with the IFT coupled to the triple quadrupole instrument is based on several unique features. First, ion accumulation in the radio frequency (RF) ion trap facilitates improved droplet desolvation, which is manifested in the reduced background ion noise at the detector. Second, signal amplitude for a given transition is enhanced because of an order-of-magnitude increase in the ion charge density per unit time compared to a continuous mode of operation. Third, signal detection at the full duty cycle is obtained, as the trap use eliminates dead times between transitions, which are inevitable with continuous ion streams. In comparison with the conventional approach, the pulsed MRM signals showed up to 5-fold enhanced peak amplitude and 2-3 fold reduced chemical background, resulting in an improvement in the limit of detection (LOD) by a factor of ~ 4 to ~ 8.« less

Investigations in the possibility of early detection of colorectal cancer by gas chromatography/triple-quadrupole mass spectrometry

PubMed Central

Kawana, Shuichi; Unno, Yumi; Sakai, Takero; Okamoto, Koji; Yamada, Yasuhide; Sudo, Kazuki; Yamaji, Taiki; Saito, Yutaka; Kanemitsu, Yukihide; Okita, Natsuko Tsuda; Saito, Hiroshi; Tsugane, Shoichiro; Azuma, Takeshi; Ojima, Noriyuki; Yoshida, Masaru

2017-01-01

In developed countries, the number of patients with colorectal cancer has been increasing, and colorectal cancer is one of the most common causes of cancer death. To improve the quality of life of colorectal cancer patients, it is necessary to establish novel screening methods that would allow early detection of colorectal cancer. We performed metabolome analysis of a plasma sample set from 282 stage 0/I/II colorectal cancer patients and 291 healthy volunteers using gas chromatography/triple-quadrupole mass spectrometry in an attempt to identify metabolite biomarkers of stage 0/I/II colorectal cancer. The colorectal cancer patients included patients with stage 0 (N=79), I (N=80), and II (N=123) in whom invasion and metastasis were absent. Our analytical system detected 64 metabolites in the plasma samples, and the levels of 29 metabolites differed significantly (Bonferroni-corrected p=0.000781) between the patients and healthy volunteers. Based on these results, a multiple logistic regression analysis of various metabolite biomarkers was carried out, and a stage 0/I/II colorectal cancer prediction model was established. The area under the curve, sensitivity, and specificity values of this model for detecting stage 0/I/II colorectal cancer were 0.996, 99.3%, and 93.8%, respectively. The model's sensitivity and specificity values for each disease stage were >90%, and surprisingly, its sensitivity for stage 0, specificity for stage 0, and sensitivity for stage II disease were all 100%. Our predictive model can aid early detection of colorectal cancer and has potential as a novel screening test for cases of colorectal cancer that do not involve lymph node or distant metastasis. PMID:28179577

A novel approach for in-office tooth bleaching with 6% H2O2/TiO_N and LED/laser system-a controlled, triple-blinded, randomized clinical trial.

PubMed

Bortolatto, Janaina Freitas; Trevisan, Tamara Carolina; Bernardi, Priscila Sadalla Ismael; Fernandez, Eduardo; Dovigo, Livia Nordi; Loguercio, Alessandro Dourado; Batista de Oliveira Junior, Osmir; Pretel, Hermes

2016-04-01

The purpose of this randomized, parallel, triple-blinded clinical trial was to compare efficacy and tooth sensitivity (TS) after use of an in-office bleaching agent of 6% hydrogen peroxide containing nanoparticles of nitrogen-doped titanium oxide (HP6) vs. 35% hydrogen peroxide (HP35). Forty-eight volunteers were randomly divided either a HP6 or HP35. Two clinical sessions were performed with an interval of 7 days between them for each group. In each session, two consecutive applications of each bleaching agent were performed and activated by a hybrid LED/laser light. Efficacy was determined by color alteration (ΔE), recorded with reflectance spectroscopy. It was assessed at baseline and after the first and second bleaching session. TS was characterized according to occurrence, intensity, duration, and type. Efficacy was analyzed by repeated measures analysis of variance (ANOVA) and post hoc Bonferroni test, and TS was analyzed by means of chi(2) test (α = 0.05). For HP35, highest and significant values of ΔE were found after bleaching when compared to HP6 (p = 0.002). However, HP35 showed a significantly higher occurrence of TS than HP6 (p = 0.008). Also, intensity and duration were higher in HP35. The majority of volunteers classified the type experienced in their sensitivity in the form of a "shock." The use of HP6 despite reducing efficacy when compared to an in-office bleaching in higher concentration (35%) produced less tooth sensitivity. In terms of tooth sensitivity, the use of lower concentrations of in-office bleaching should be the first choice, suggesting greater biocompatibility and safety compared to a conventional HP35.

Investigations in the possibility of early detection of colorectal cancer by gas chromatography/triple-quadrupole mass spectrometry.

PubMed

Nishiumi, Shin; Kobayashi, Takashi; Kawana, Shuichi; Unno, Yumi; Sakai, Takero; Okamoto, Koji; Yamada, Yasuhide; Sudo, Kazuki; Yamaji, Taiki; Saito, Yutaka; Kanemitsu, Yukihide; Okita, Natsuko Tsuda; Saito, Hiroshi; Tsugane, Shoichiro; Azuma, Takeshi; Ojima, Noriyuki; Yoshida, Masaru

2017-03-07

In developed countries, the number of patients with colorectal cancer has been increasing, and colorectal cancer is one of the most common causes of cancer death. To improve the quality of life of colorectal cancer patients, it is necessary to establish novel screening methods that would allow early detection of colorectal cancer. We performed metabolome analysis of a plasma sample set from 282 stage 0/I/II colorectal cancer patients and 291 healthy volunteers using gas chromatography/triple-quadrupole mass spectrometry in an attempt to identify metabolite biomarkers of stage 0/I/II colorectal cancer. The colorectal cancer patients included patients with stage 0 (N=79), I (N=80), and II (N=123) in whom invasion and metastasis were absent. Our analytical system detected 64 metabolites in the plasma samples, and the levels of 29 metabolites differed significantly (Bonferroni-corrected p=0.000781) between the patients and healthy volunteers. Based on these results, a multiple logistic regression analysis of various metabolite biomarkers was carried out, and a stage 0/I/II colorectal cancer prediction model was established. The area under the curve, sensitivity, and specificity values of this model for detecting stage 0/I/II colorectal cancer were 0.996, 99.3%, and 93.8%, respectively. The model's sensitivity and specificity values for each disease stage were >90%, and surprisingly, its sensitivity for stage 0, specificity for stage 0, and sensitivity for stage II disease were all 100%. Our predictive model can aid early detection of colorectal cancer and has potential as a novel screening test for cases of colorectal cancer that do not involve lymph node or distant metastasis.

Utility of contrast-enhanced computed tomography in the evaluation of canine insulinoma location.

PubMed

Buishand, Floryne O; Vilaplana Grosso, Federico R; Kirpensteijn, Jolle; van Nimwegen, Sebastiaan A

2018-06-05

To determine 1) the sensitivity of contrast-enhanced CT (CECT) for detection of primary canine insulinomas and metastases 2) the sensitivity of CECT to locate canine insulinomas within the pancreas and 3) the CECT attenuation pattern of canine insulinomas and post-contrast phase in which insulinomas have the best visibility. A retrospective review was performed of the medical records of 27 canine insulinoma patients. Simultaneous occurrence of blood glucose < 3.5 mmol/L (reference interval: 4.2-5.8 mmol/L) and plasma insulin > 10 mIU/L (reference interval: 1.4-24.5 mIU/L) were considered diagnostic for insulinoma. The dogs had a mean age of 9.0 ± 1.7 (SD) years and comprised 11 males and 17 females. Using CECT-scans, 26/27 insulinomas were successfully detected. However, CECT-scans predicted the correct location of insulinomas within the pancreas in only 14/27 dogs. In 9/13 inaccurately located insulinoma cases, the location error was major. There was no significant difference between triple, double and single-phase CECT-scans with location accuracies of 54%, 50% and 50%, respectively. Also, there was no specific post-contrast phase in which insulinomas could be visualised best. Detection of lymph node metastases with CECT-scans had a sensitivity of 67% (10/15 lymph node metastases). Detection of liver metastases had a sensitivity of 75% (6/8 liver metastases). This study highlights that major location errors mainly occurred if single- or double-phase CECT-scans were used (6/9 cases). It is suggested that triple-phase CECT-scans have superior outcome over single- or double-phase CECT-scans in pre-operative imaging of canine insulinomas.

Quantitative validation of sensory mapping in persistent postherniorrhaphy inguinal pain patients undergoing triple neurectomy.

PubMed

Bjurström, M F; Álvarez, R; Nicol, A L; Olmstead, R; Amid, P K; Chen, D C

2017-04-01

Neurectomy of the inguinal nerves may be considered for selected refractory cases of chronic postherniorrhaphy inguinal pain (CPIP). There is to date a paucity of easily applicable clinical tools to identify neuropathic pain and examine the neurosensory effects of remedial surgery. The present quantitative sensory testing (QST) pilot study evaluates a sensory mapping technique. Longitudinal (preoperative, immediate postoperative, and late postoperative) dermatomal sensory mapping and a comprehensive QST protocol were conducted in CPIP patients with unilateral, predominantly neuropathic inguinodynia presenting for triple neurectomy (n = 13). QST was conducted in four areas on the affected, painful side and in one contralateral comparison site. QST variables were compared according to sensory mapping outcomes: (o)/normal sensation, (+)/pain, and (-)/numbness. Diagnostic ability of the sensory mapping outcomes to detect QST-assessed allodynia or hypoesthesia was estimated through calculation of specificity and sensitivity values. Preoperatively, patients exhibited mechanical hypoesthesia and allodynia and pressure allodynia and hyperalgesia in painful areas mapped (+) (p < .05); sensory mapping outcome (+) demonstrated high ability to detect mechanical allodynia [sensitivity 0.74 (95% CI 0.61-0.86), specificity 0.94 (0.84-1.00)] and pressure allodynia [sensitivity 0.96 (0.89-1.00), specificity 1.00 (1.00-1.00)], but not thermal allodynia. Postoperatively, mapped areas of numbness (-) were associated with mechanical and thermal hypoesthesia (p < .05); (-) showed high sensitivity and specificity to detect mechanical and cold hypoesthesia. Sensory mapping provides an accurate clinical neuropathic assessment with strong correlation to QST findings of preoperative mechanical and pressure allodynia, and postoperative mechanical and thermal hypoesthesia in CPIP patients undergoing neurectomy.

Timing group delay and differential code bias corrections for BeiDou positioning

NASA Astrophysics Data System (ADS)

Guo, Fei; Zhang, Xiaohong; Wang, Jinling

2015-05-01

This article first clearly figures out the relationship between parameters of timing group delay (TGD) and differential code bias (DCB) for BDS, and demonstrates the equivalence of TGD and DCB correction models combining theory with practice. The TGD/DCB correction models have been extended to various occasions for BDS positioning, and such models have been evaluated by real triple-frequency datasets. To test the effectiveness of broadcast TGDs in the navigation message and DCBs provided by the Multi-GNSS Experiment (MGEX), both standard point positioning (SPP) and precise point positioning (PPP) tests are carried out for BDS signals with different schemes. Furthermore, the influence of differential code biases on BDS positioning estimates such as coordinates, receiver clock biases, tropospheric delays and carrier phase ambiguities is investigated comprehensively. Comparative analysis show that the unmodeled differential code biases degrade the performance of BDS SPP by a factor of two or more, whereas the estimates of PPP are subject to varying degrees of influences. For SPP, the accuracy of dual-frequency combinations is slightly worse than that of single-frequency, and they are much more sensitive to the differential code biases, particularly for the B2B3 combination. For PPP, the uncorrected differential code biases are mostly absorbed into the receiver clock bias and carrier phase ambiguities and thus resulting in a much longer convergence time. Even though the influence of the differential code biases could be mitigated over time and comparable positioning accuracy could be achieved after convergence, it is suggested to properly handle with the differential code biases since it is vital for PPP convergence and integer ambiguity resolution.

A temperature, pH and sugar triple-stimuli-responsive nanofluidic diode.

PubMed

Zheng, Yu-Bin; Zhao, Shuang; Cao, Shuo-Hui; Cai, Sheng-Lin; Cai, Xiu-Hong; Li, Yao-Qun

2017-01-07

In this article, we have demonstrated for the first time a triple stimuli-responsive nanofluidic diode that can rectify ionic current under multiple external stimuli including temperature, pH, and sugar. This diode was fabricated by immobilizing poly[2-(dimethylamino)ethyl methacrylate]-co-[4-vinyl phenylboronic acid] (P(DMAEMA-co-VPBA)) onto the wall of a single glass conical nanopore channel via surface-initiator atom transfer radical polymerization (SI-ATRP). The copolymer brushes contain functional groups sensitive to pH, temperature and sugar that can induce charge and configuration change to affect the status of the pore wall. The experimental results confirmed that the P(DMAEMA-co-VPBA) brush modified nanochannel regulated the ionic current rectification successfully under three different external stimuli. This biomimetically inspired research simulates the complex biological multi-functions of ion channels and promotes the development of "smart" biomimetic nanochannel systems for actuating and sensing applications.

Triple-negative breast cancer--current status and future directions.

PubMed

Gluz, O; Liedtke, C; Gottschalk, N; Pusztai, L; Nitz, U; Harbeck, N

2009-12-01

Triple-negative breast cancer (TNBC) is defined by a lack of expression of both estrogen and progesterone receptor as well as human epidermal growth factor receptor 2. It is characterized by distinct molecular, histological and clinical features including a particularly unfavorable prognosis despite increased sensitivity to standard cytotoxic chemotherapy regimens. TNBC is highly though not completely concordant with various definitions of basal-like breast cancer (BLBC) defined by high-throughput gene expression analyses. The lack in complete concordance may in part be explained by both BLBC and TNBC comprising entities that in themselves are heterogeneous. Numerous efforts are currently being undertaken to improve prognosis for patients with TNBC. They comprise both optimization of choice and scheduling of common cytotoxic agents (i.e. addition of platinum salts or dose intensification strategies) and introduction of novel agents (i.e. poly-ADP-ribose-polymerase-1 inhibitors, agents targeting the epidermal growth factor receptor, multityrosine kinase inhibitors or antiangiogenic agents).

High granularity tracker based on a Triple-GEM optically read by a CMOS-based camera

NASA Astrophysics Data System (ADS)

Marafini, M.; Patera, V.; Pinci, D.; Sarti, A.; Sciubba, A.; Spiriti, E.

2015-12-01

The detection of photons produced during the avalanche development in gas chambers has been the subject of detailed studies in the past. The great progresses achieved in last years in the performance of micro-pattern gas detectors on one side and of photo-sensors on the other provide the possibility of making high granularity and very sensitive particle trackers. In this paper, the results obtained with a triple-GEM structure read-out by a CMOS based sensor are described. The use of an He/CF4 (60/40) gas mixture and a detailed optimization of the electric fields made possible to obtain a very high GEM light yield. About 80 photons per primary electron were detected by the sensor resulting in a very good capability of tracking both muons from cosmic rays and electrons from natural radioactivity.

Searching for the doubly charged scalars in the Georgi-Machacek model via γγ collisions at the ILC

NASA Astrophysics Data System (ADS)

Cao, Jun; Li, Yu-Qi; Liu, Yao-Bei

2018-04-01

The Georgi-Machacek (GM) model predicts the existence of the doubly-charged scalars H5±±, which can be seen the typical particles in this model and their diboson decay channels are one of the most promising ways to discover such new doubly-charged scalars. Based on the constraints of the latest combined ATLAS and CMS Higgs boson diphoton signal strength data at 2σ confidence level, we focus on the study of the triple scalar production in γγ collisions at the future International Linear collider (ILC): γγ → hH5++H 5‑‑, where the production cross-sections are very sensitive to the triple scalar coupling parameter ghHH. Considering the typical same-sign diboson decay modes for the doubly-charged scalars, the possible final signals might be detected via this process at the future ILC experiments.

Indication of prenatal diagnosis in pregnancies complicated by undetectable second-trimester maternal serum estriol levels.

PubMed

Minsart, Anne-Frédérique; Van Onderbergen, Anne; Jacques, Francotte; Kurt, Crener; Gillerot, Yves

2008-07-01

Undetectable maternal serum unconjugated estriol levels in the second-trimester screening test have been associated with congenital pathology and an adverse pregnancy outcome. We reviewed outcomes of pregnancies with undetectable levels of estriol (<0.25 ng/ml) in the triple-marker screening test and assessed the clinical value of this finding. We studied estriol values in 6,018 pregnant patients who underwent a triple-marker screening test during a seven-year period. 26 women had estriol levels at or below the sensitivity of the assay. The most common explanations were dating errors, prematurity, growth restriction and X-linked ichthyosis. We also observed one fetal death at 16 weeks, one severe threatened fetal abortion, one case of multiple congenital anomalies and one case of isolated adrenocorticotropin hormone deficiency. There were 6 women remaining with unexplained undetectable estriol. Undetectable maternal estriol values may indicate a severe fetal pathology and should lead to further investigations.

A 700 V narrow channel nJFET with low pinch-off voltage and suppressed drain-induced barrier lowering effect

NASA Astrophysics Data System (ADS)

Mao, Kun; Qiao, Ming; Zhang, WenTong; Zhang, Bo; Li, Zhaoji

2014-11-01

This paper proposes a 700 V narrow channel region triple-RESURF (reduced surface field) n-type junction field-effect transistor (NCT-nJFET). Compared to traditional structures, low pinch-off voltage (VP) with unobvious drain-induced barrier lowering (DIBL) effect and large saturated current (IDsat) are achieved. This is because p-type buried layer (Pbury) and PWELL are introduced to shape narrow n-type channel in JFET channel region. DIBL sensitivity (SDIBL) is firstly introduced in this paper to analyze the DIBL effect of high-voltage long-channel JFET. Ultra-high breakdown voltage is obtained by triple RESURF technology. Experimental results show that proposed NCT-nJFET achieves 24-V VP, 3.5% SDIBL, 2.3-mA IDsat, 800-V OFF-state breakdown voltage (OFF-BV) and 650-V ON-state breakdown voltage when VGS equals 0 V (ON-BV).

A P300-based Brain-Computer Interface with Stimuli on Moving Objects: Four-Session Single-Trial and Triple-Trial Tests with a Game-Like Task Design

PubMed Central

Ganin, Ilya P.; Shishkin, Sergei L.; Kaplan, Alexander Y.

2013-01-01

Brain-computer interfaces (BCIs) are tools for controlling computers and other devices without using muscular activity, employing user-controlled variations in signals recorded from the user’s brain. One of the most efficient noninvasive BCIs is based on the P300 wave of the brain’s response to stimuli and is therefore referred to as the P300 BCI. Many modifications of this BCI have been proposed to further improve the BCI’s characteristics or to better adapt the BCI to various applications. However, in the original P300 BCI and in all of its modifications, the spatial positions of stimuli were fixed relative to each other, which can impose constraints on designing applications controlled by this BCI. We designed and tested a P300 BCI with stimuli presented on objects that were freely moving on a screen at a speed of 5.4°/s. Healthy participants practiced a game-like task with this BCI in either single-trial or triple-trial mode within four sessions. At each step, the participants were required to select one of nine moving objects. The mean online accuracy of BCI-based selection was 81% in the triple-trial mode and 65% in the single-trial mode. A relatively high P300 amplitude was observed in response to targets in most participants. Self-rated interest in the task was high and stable over the four sessions (the medians in the 1st/4th sessions were 79/84% and 76/71% in the groups practicing in the single-trial and triple-trial modes, respectively). We conclude that the movement of stimulus positions relative to each other may not prevent the efficient use of the P300 BCI by people controlling their gaze, e.g., in robotic devices and in video games. PMID:24302977

Pathway-Enriched Gene Signature Associated with 53BP1 Response to PARP Inhibition in Triple-Negative Breast Cancer.

PubMed

Hassan, Saima; Esch, Amanda; Liby, Tiera; Gray, Joe W; Heiser, Laura M

2017-12-01

Effective treatment of patients with triple-negative (ER-negative, PR-negative, HER2-negative) breast cancer remains a challenge. Although PARP inhibitors are being evaluated in clinical trials, biomarkers are needed to identify patients who will most benefit from anti-PARP therapy. We determined the responses of three PARP inhibitors (veliparib, olaparib, and talazoparib) in a panel of eight triple-negative breast cancer cell lines. Therapeutic responses and cellular phenotypes were elucidated using high-content imaging and quantitative immunofluorescence to assess markers of DNA damage (53BP1) and apoptosis (cleaved PARP). We determined the pharmacodynamic changes as percentage of cells positive for 53BP1, mean number of 53BP1 foci per cell, and percentage of cells positive for cleaved PARP. Inspired by traditional dose-response measures of cell viability, an EC 50 value was calculated for each cellular phenotype and each PARP inhibitor. The EC 50 values for both 53BP1 metrics strongly correlated with IC 50 values for each PARP inhibitor. Pathway enrichment analysis identified a set of DNA repair and cell cycle-associated genes that were associated with 53BP1 response following PARP inhibition. The overall accuracy of our 63 gene set in predicting response to olaparib in seven breast cancer patient-derived xenograft tumors was 86%. In triple-negative breast cancer patients who had not received anti-PARP therapy, the predicted response rate of our gene signature was 45%. These results indicate that 53BP1 is a biomarker of response to anti-PARP therapy in the laboratory, and our DNA damage response gene signature may be used to identify patients who are most likely to respond to PARP inhibition. Mol Cancer Ther; 16(12); 2892-901. ©2017 AACR . ©2017 American Association for Cancer Research.

Clinical value of R-spondins in triple-negative and metaplastic breast cancers.

PubMed

Coussy, F; Lallemand, F; Vacher, S; Schnitzler, A; Chemlali, W; Caly, M; Nicolas, A; Richon, S; Meseure, D; El Botty, R; De-Plater, L; Fuhrmann, L; Dubois, T; Roman-Roman, S; Dangles-Marie, V; Marangoni, E; Bièche, I

2017-06-06

RSPO ligands, activators of the Wnt/β-catenin pathway, are overexpressed in different cancers. The objective of this study was to investigate the role of RSPOs in breast cancer (BC). Expression of RSPO and markers of various cancer pathways were measured in breast tumours and cell lines by qRT-PCR. The effect of RSPO on the Wnt/β-catenin pathway activity was determined by luciferase assay, western blotting, and qRT-PCR. The effect of RSPO2 inhibition on proliferation was determined by using RSPO2 siRNAs. The effect of IWR-1, an inhibitor of the Wnt/β-catenin pathway, was examined on the growth of an RSPO2-positive patient-derived xenograft (PDX) model of metaplastic triple-negative BC. We detected RSPO2 and RSPO4 overexpression levels in BC, particularly in triple-negative BC (TNBC), metaplastic BC, and triple-negative cell lines. Various mechanisms could account for this overexpression: presence of fusion transcripts involving RSPO, and amplification or hypomethylation of RSPO genes. Patients with RSPO2-overexpressing tumours have a poorer metastasis-free survival (P=3.6 × 10 -4 ). RSPO2 and RSPO4 stimulate Wnt/β-catenin pathway activity. Inhibition of RSPO expression in a TN cell line inhibits cell growth, and IWR-1 significantly inhibits the growth of an RSPO2-overexpressing PDX. RSPO overexpression could therefore be a new prognostic biomarker and therapeutic target for TNBC.

Veliparib in Combination With Carboplatin and Paclitaxel in Treating Patients With Locally Advanced or Metastatic Solid Tumors

ClinicalTrials.gov

2015-05-22

Adult Solid Neoplasm; Estrogen Receptor Negative; Estrogen Receptor Positive; HER2/Neu Negative; Male Breast Carcinoma; Progesterone Receptor Negative; Recurrent Breast Carcinoma; Stage IIIB Breast Cancer; Stage IIIC Breast Cancer; Stage IV Breast Cancer; Triple-Negative Breast Carcinoma

Rapid and sensitive liquid chromatography-tandem mass spectrometric method for the quantitative determination of potentially harmful substance 5,5'-oxydimethylenebis (2-furfural) in traditional Chinese medicine injections.

PubMed

Zang, Qingce; Gao, Yang; Huang, Luojiao; He, Jiuming; Lin, Sheng; Jin, Hongtao; Zhang, Ruiping; Abliz, Zeper

2018-03-01

With the rapid development and wide application of traditional Chinese medicine injection (TCMI), a number of adverse events of some TCMIs have incessantly been reported and have drawn broad attention in recent years. Establishing effective and practical analytical methods for safety evaluation and quality control of TCMI can help to improve the safety of TCMIs in clinical applications. In this study, a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed and validated for the quantitative determination of potentially harmful substance 5,5'-oxydimethylenebis (2-furfural, OMBF) in TCMI samples. Chromatographic separation was performed on a C18 reversed-phase column (150 mm × 2.1 mm, 5 µm) by gradient elution, using methanol-water containing 0.1% formic acid as mobile phase at the flow rate of 0.3 mL/min. MS/MS detection was performed on a triple quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction-monitoring mode. The method was sensitive with a limit of quantification of 0.3 ng/mL and linear over the range of 0.3-30 ng/mL ( r =0.9998). Intra- and inter-day precision for analyte was <9.52% RSD with recoveries in the range 88.0-109.67% at three concentration levels. The validated method was successfully applied to quantitatively determine the compound OMBF in TCMIs and glucose injections. Our study indicates that this method is simple, sensitive, practicable and reliable, and could be applied for safety evaluation and quality control of TCMIs and glucose injections.

Cysteine residue 911 in C-terminal tail of human BK(Ca)α channel subunit is crucial for its activation by carbon monoxide.

PubMed

Telezhkin, Vsevolod; Brazier, Stephen P; Mears, Ruth; Müller, Carsten T; Riccardi, Daniela; Kemp, Paul J

2011-06-01

The large conductance, voltage- and calcium-activated potassium channel, BK(Ca), is a known target for the gasotransmitter, carbon monoxide (CO). Activation of BK(Ca) by CO modulates cellular excitability and contributes to the physiology of a diverse array of processes, including vascular tone and oxygen-sensing. Currently, there is no consensus regarding the molecular mechanisms underpinning reception of CO by the BK(Ca). Here, employing voltage-clamped, inside-out patches from HEK293 cells expressing single, double and triple cysteine mutations in the BK(Ca) α-subunit, we test the hypothesis that CO regulation is conferred upon the channel by interactions with cysteine residues within the RCK2 domain. In physiological [Ca(2+)](i), all mutants carrying a cysteine substitution at position 911 (C911G) demonstrated significantly reduced CO sensitivity; the C911G mutant did not express altered Ca(2+)-sensitivity. In contrast, histidine residues in RCK1 domain, previously shown to ablate CO activation in low [Ca(2+)](i), actually increased CO sensitivity when [Ca(2+)](i) was in the physiological range. Importantly, cyanide, employed here as a substituent for CO at potential metal centres, occluded activation by CO; this effect was freely reversible. Taken together, these data suggest that a specific cysteine residue in the C-terminal domain, which is close to the Ca(2+) bowl but which is not involved in Ca(2+) activation, confers significant CO sensitivity to BK(Ca) channels. The rapid reversibility of CO and cyanide binding, coupled to information garnered from other CO-binding proteins, suggests that C911 may be involved in formation of a transition metal cluster which can bind and, thereafter, activate BK(Ca).

Spinal afferent neurons projecting to the rat lung and pleura express acid sensitive channels

PubMed Central

Groth, Michael; Helbig, Tanja; Grau, Veronika; Kummer, Wolfgang; Haberberger, Rainer V

2006-01-01

Background The acid sensitive ion channels TRPV1 (transient receptor potential vanilloid receptor-1) and ASIC3 (acid sensing ion channel-3) respond to tissue acidification in the range that occurs during painful conditions such as inflammation and ischemia. Here, we investigated to which extent they are expressed by rat dorsal root ganglion neurons projecting to lung and pleura, respectively. Methods The tracer DiI was either injected into the left lung or applied to the costal pleura. Retrogradely labelled dorsal root ganglion neurons were subjected to triple-labelling immunohistochemistry using antisera against TRPV1, ASIC3 and neurofilament 68 (marker for myelinated neurons), and their soma diameter was measured. Results Whereas 22% of pulmonary spinal afferents contained neither channel-immunoreactivity, at least one is expressed by 97% of pleural afferents. TRPV1+/ASIC3- neurons with probably slow conduction velocity (small soma, neurofilament 68-negative) were significantly more frequent among pleural (35%) than pulmonary afferents (20%). TRPV1+/ASIC3+ neurons amounted to 14 and 10% respectively. TRPV1-/ASIC3+ neurons made up between 44% (lung) and 48% (pleura) of neurons, and half of them presumably conducted in the A-fibre range (larger soma, neurofilament 68-positive). Conclusion Rat pleural and pulmonary spinal afferents express at least two different acid-sensitive channels that make them suitable to monitor tissue acidification. Patterns of co-expression and structural markers define neuronal subgroups that can be inferred to subserve different functions and may initiate specific reflex responses. The higher prevalence of TRPV1+/ASIC3- neurons among pleural afferents probably reflects the high sensitivity of the parietal pleura to painful stimuli. PMID:16813657

Rational Design of a Triple Reporter Gene for Multimodality Molecular Imaging

PubMed Central

Hsieh, Ya-Ju; Ke, Chien-Chih; Yeh, Skye Hsin-Hsien; Lin, Chien-Feng; Chen, Fu-Du; Lin, Kang-Ping; Chen, Ran-Chou; Liu, Ren-Shyan

2014-01-01

Multimodality imaging using noncytotoxic triple fusion (TF) reporter genes is an important application for cell-based tracking, drug screening, and therapy. The firefly luciferase (fl), monomeric red fluorescence protein (mrfp), and truncated herpes simplex virus type 1 thymidine kinase SR39 mutant (ttksr39) were fused together to create TF reporter gene constructs with different order. The enzymatic activities of TF protein in vitro and in vivo were determined by luciferase reporter assay, H-FEAU cellular uptake experiment, bioluminescence imaging, and micropositron emission tomography (microPET). The TF construct expressed in H1299 cells possesses luciferase activity and red fluorescence. The tTKSR39 activity is preserved in TF protein and mediates high levels of H-FEAU accumulation and significant cell death from ganciclovir (GCV) prodrug activation. In living animals, the luciferase and tTKSR39 activities of TF protein have also been successfully validated by multimodality imaging systems. The red fluorescence signal is relatively weak for in vivo imaging but may expedite FACS-based selection of TF reporter expressing cells. We have developed an optimized triple fusion reporter construct DsRedm-fl-ttksr39 for more effective and sensitive in vivo animal imaging using fluorescence, bioluminescence, and PET imaging modalities, which may facilitate different fields of biomedical research and applications. PMID:24809057

Anti-proliferative and apoptosis-inducing activity of lycopene against three subtypes of human breast cancer cell lines

PubMed Central

Takeshima, Mikako; Ono, Misaki; Higuchi, Takako; Chen, Chen; Hara, Takayuki; Nakano, Shuji

2014-01-01

Although lycopene, a major carotenoid component of tomatoes, has been suggested to attenuate the risk of breast cancer, the underlying preventive mechanism remains to be determined. Moreover, it is not known whether there are any differences in lycopene activity among different subtypes of human breast cancer cells. Using ER/PR positive MCF-7, HER2-positive SK-BR-3 and triple-negative MDA-MB-468 cell lines, we investigated the cellular and molecular mechanism of the anticancer activity of lycopene. Lycopene treatment for 168 consecutive hours exhibited a time-dependent and dose-dependent anti-proliferative activity against these cell lines by arresting the cell cycle at the G0/G1 phase at physiologically achievable concentrations found in human plasma. The greatest growth inhibition was observed in MDA-MB-468 where the sub-G0/G1 apoptotic population was significantly increased, with demonstrable cleavage of PARP. Lycopene induced strong and sustained activation of the ERK1/2, with concomitant cyclin D1 suppression and p21 upregulation in these three cell lines. In triple negative cells, lycopene inhibited the phosphorylation of Akt and its downstream molecule mTOR, followed by subsequent upregulation of proapoptotic Bax without affecting anti-apoptotic Bcl-xL. Taken together, these data indicate that the predominant anticancer activity of lycopene in MDA-MB-468 cells suggests a potential role of lycopene for the prevention of triple negative breast cancer. PMID:24397737

Anti-E1E2 antibodies do predict response to triple therapy in treatment-experienced Hepatitis C Virus-cirrhosis cases.

PubMed

Petit, Marie-Anne; Berthillon, Pascale; Pradat, Pierre; Arnaud, Clémence; Bordes, Isabelle; Virlogeux, Victor; Maynard, Marianne; Bailly, François; Zoulim, Fabien; Chemin, Isabelle; Trépo, Christian

2015-12-01

We previously showed that pre-treatment serum anti-E1E2 predicted hepatitis C virus (HCV) RNA viral kinetics (VKs) and treatment outcome in patients with chronic hepatitis C receiving pegylated interferon/ribavirin (Peg-IFN/RBV) double therapy. Here, we determined whether baseline anti-E1E2 was correlated with the on-treatment VK and could predict virological outcome in treatment-experienced HCV-infected cirrhotic patients receiving protease inhibitor-based triple therapy. Sera from 19 patients with HCV genotype 1 infection and compensated cirrhosis who failed to respond to a prior course of Peg-IFN/RBV were selected at time 0 before starting triple therapy with boceprevir or telaprevir. We assessed patients with sustained viral response 12 weeks after the end of triple therapy (SVR12) by analyzing VKs at weeks 4, 12, 24, 36, 48 (end of treatment) and 60. Patients baseline characteristics were similar to the well-defined CUPIC cohort (age, HCV subtype, baseline viremia, and treatment history). Among the 19 patients, 11 achieved an SVR12. Fifteen patients were positive for pre-treatment anti-E1E2 and all of them achieved SVR12. Moreover, anti-E1E2 and SVR12 correlated with prior response to IFN/RBV therapy (relapse, partial or null response). Baseline anti-E1E2 could be considered as a new biomarker to predict SVR12 after triple therapy in this most difficult-to-treat population. These results warrant further validation on larger cohorts including patients receiving highly effective direct-acting antivirals to explore whether this test could help in better defining treatment duration for these very costly molecules. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

A pilot randomised controlled trial to evaluate the feasibility and acceptability of the Baby Triple P Positive Parenting Programme in mothers with postnatal depression

PubMed Central

Tsivos, Zoe-Lydia; Calam, Rachel; Sanders, Matthew R; Wittkowski, Anja

2015-01-01

Few interventions for Postnatal Depression (PND) have focused on parenting difficulties; the aim of this research was to investigate the feasibility and evaluate a parenting intervention (Baby Triple P) in women with PND. This was a pilot randomised controlled trial (RCT) to evaluate and determine the feasibility of the newly developed Baby Triple P compared with treatment as usual (TAU) in women with PND. In all, 27 female participants aged from 18 to 45 years (mean age = 28.4 years, standard deviation (SD) = 6.1), with a primary diagnosis of major depression and an infant under 12 months (mean age = 6.2 months, SD = 3.2 months), were recruited from primary care trusts in Greater Manchester, United Kingdom. Participants were randomly allocated to receive either eight Baby Triple P sessions in addition to TAU or TAU only. Outcomes were assessed at post-treatment (Time 2) and 3 months post-treatment (Time 3). Self-report outcomes were as follows: Beck Depression Inventory, Oxford Happiness Inventory, What Being the Parent of a New Baby is Like, Postpartum Bonding Questionnaire and the Brief Parenting Beliefs Scale–baby version. An assessor-rated observational measure of mother–infant interaction, the CARE Index and measure of intervention acceptability were also completed. Significant improvements from Time 1 to Time 2 and Time 1 to Time 3 were observed across both groups. Although women allocated to Baby Triple P showed more favourable improvements, the between-group differences were not significant. However, the intervention was highly acceptable to women with PND. A large-scale RCT is indicated. PMID:24778436

The diagnostic value of serum tumor markers CEA, CA19-9, CA125, CA15-3, and TPS in metastatic breast cancer.

PubMed

Wang, Weigang; Xu, Xiaoqin; Tian, Baoguo; Wang, Yan; Du, Lili; Sun, Ting; Shi, Yanchun; Zhao, Xianwen; Jing, Jiexian

2017-07-01

This study aims to understand the diagnostic value of serum tumor markers carcinoembryonic antigen (CEA), cancer antigen 19-9 (CA19-9), cancer antigen 125 (CA125), cancer antigen 15-3 (CA15-3), and tissue polypeptide-specific antigen (TPS) in metastatic breast cancer (MBC). A total of 164 metastatic breast cancer patients in Shanxi Cancer Hospital were recruited between February 2016 and July 2016. 200 breast cancer patients without metastasis in the same period were randomly selected as the control group. The general characteristics, immunohistochemical, and pathological results were investigated between the two groups, and tumor markers were determined. There were statistical differences in the concentration and the positive rates of CEA, CA19-9, CA125, CA15-3, and TPS between the MBC and control group (P<0.05). The highest sensitivity was in CEA and the highest specificity was in CA125 for the diagnosis of MBC when using a single tumor marker at 56.7% and 97.0%, respectively. In addition, two tumor markers were used for the diagnosis of MBC and the CEA and TPS combination had the highest diagnostic sensitivity with 78.7%, while the CA15-3 and CA125 combination had the highest specificity of 91.5%. Analysis of tumor markers of 164 MBC found that there were statistical differences in the positive rates of CEA and CA15-3 between bone metastases and other metastases (χ 2 =6.00, P=0.014; χ 2 =7.32, P=0.007, respectively). The sensitivity and specificity values of the CEA and CA15-3 combination in the diagnosis of bone metastases were 77.1% and 45.8%, respectively. The positive rate of TPS in the lung metastases group was lower than in other metastases (χ 2 =8.06, P=0.005).There were significant differences in the positive rates of CA15-3 and TPS between liver metastases and other metastases (χ 2 =15.42, P<0.001; χ 2 =9.72, P=0.002, respectively). The sensitivity and specificity of the CA15-3 and TPS combination in the diagnosis of liver metastases were 92.3% and 45.6%, respectively, and the positive rate of CEA in triple-negative metastatic breast cancer is lower than in other subtypes (χ 2 =4.80, P=0.028). Therefore, serum CEA, CA19-9, CA125, CA15-3, and TPS can be used in the diagnosis of MBC, and different combinations of tumor markers have varying diagnostic value. Copyright © 2017 Elsevier B.V. All rights reserved.

A fiber optic biosensor for fluorimetric detection of triple-helical DNA.

PubMed

Uddin, A H; Piunno, P A; Hudson, R H; Damha, M J; Krull, U J

1997-10-15

A fiber optic biosensor was used for the fluorimetric detection of T/AT triple-helical DNA formation. The surfaces of two sets of fused silica optical fibers were functionalized with hexaethylene oxide linkers from which decaadenylic acid oligonucleotides were grown in the 3'to 5'and 5'to 3'direction, respectively, using a DNA synthesizer. Fluorescence studies of hybridization showed unequivocal hybridization between oligomers immobilized on the fibers and complementary oligonucleotides from the solution phase, as detected by fluorescence from intercalated ethidium bromide. The complementary oligonucleotide, dT10, which was expected to Watson-Crick hybridize upon cooling the system below the duplex melting temperature ( T m), provided a fluorescence intensity with a negative temperature coefficient. Upon further cooling, to the point where the pyrimidine motif T*AT triple-helix formation occurred, a fluorescence intensity change with a positive temperature coefficient was observed. The reverse-Hoogsteen T.AT triplex, which is known to form with branched nucleic acids, provided a corresponding decrease in fluorescence intensity with decreasing temperature. Full analytical signal evolution was attainable in minutes.

Twenty-nine-gauge dual-chandelier retroillumination for the non-open-sky continuous curvilinear capsulorhexis in the penetrating keratoplasty triple procedure.

PubMed

Yokokura, Shunji; Hariya, Takehiro; Kobayashi, Wataru; Meguro, Yasuhiko; Nishida, Kohji; Nakazawa, Toru

2017-03-01

We describe a technique for the penetrating keratoplasty (PKP) triple procedure that uses 29-gauge dual-chandelier illumination during creation of a non-open-sky continuous curvilinear capsulorhexis (CCC). The chandeliers are inserted through the pars plana into the vitreous cavity through the bulbar conjunctiva at the 3 o'clock and 9 o'clock positions. We compared this approach with that of a core vitrectomy, in which a single 25-gauge port is inserted into the vitreous cavity transconjunctivally through the upper temporal pars plana. The area of halation around the corneal opacity was significantly smaller in the 29-gauge group than in the 25-gauge group. The reduction in halation improved visibility of the anterior capsule and enabled the surgeon to perform CCC with greater safety. The 29-gauge chandelier system was more suitable than the 25-gauge chandelier system for the non-open-sky CCC component of the PKP triple procedure. Copyright © 2017 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.

A 10 deg K triple-expansion Stirling-cycle cryocooler

NASA Technical Reports Server (NTRS)

Newman, W.; Keung, C. S.

1983-01-01

The design of a triple expansion closed cycle Stirling cryocooler optimized for a cooling load of 50 mW at 10 K is described. The cooler was designed with the objectives of low power, low weight, compactness, low mechanical motion, low electromagnetic noise, and low output temperature fluctuations. The design employs a direct drive linear motion piston motor and a triple expansion free displacer. Piston motion is controlled by feedback from an optical position transducer. Mechanical vibrations are attenuated with a passive resonant counterbalance. Electromagnetic noise is attenuated with layered high permeability magnetic shielding. The regenerators move with the displacer within a thin titanium cold finger. The piston and displacer oscillate at 8.33 Hz on bearings and seals of reinforced Teflon. The cooler is designed to provide the desired 50 mW of cooling at 10 K with a power input of less than 100 W. The piston can be driven at a greater stroke to produce up to 200 mW of cooling with an input power of 250 W. A lead and copper cold tip heat exchanger will limit temperature fluctuations to within 0.01 K.

Superconducting analog-to-digital converter with a triple-junction reversible flip-flop bidirectional counter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, G.S.

1993-07-13

A high-performance superconducting analog-to-digital converter is described, comprising: a bidirectional binary counter having n stages of triple-junction reversible flip-flops connected together in a cascade arrangement from the least significant bit (LSB) to the most significant bit (MSB) where n is the number of bits of the digital output, each triple-junction reversible flip-flop including first, second and third shunted Josephson tunnel junctions and a superconducting inductor connected in a bridge circuit, the Josephson junctions and the inductor forming upper and lower portions of the flip-flop, each reversible flip-flop being a bistable logic circuit in which the direction of the circulating currentmore » determines the state of the circuit; and means for applying an analog input current to the bidirectional counter; wherein the bidirectional counter algebraically counts incremental changes in the analog input current, increasing the binary count for positive incremental changes in the analog current and decreasing the binary count for negative incremental changes in the current, and wherein the counter does not require a gate bias, thus minimizing power dissipation.« less

Highly improved photo-induced bias stability of sandwiched triple layer structure in sol-gel processed fluorine-doped indium zinc oxide thin film transistor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Dongha; Park, Hyungjin; Bae, Byeong-Soo, E-mail: bsbae@kaist.ac.kr

In order to improve the reliability of TFT, an Al{sub 2}O{sub 3} insulating layer is inserted between active fluorine doped indium zinc oxide (IZO:F) thin films to form a sandwiched triple layer. All the thin films were fabricated via low-cost sol-gel process. Due to its large energy bandgap and high bonding energy with oxygen atoms, the Al{sub 2}O{sub 3} layer acts as a photo-induced positive charge blocking layer that effectively blocks the migration of both holes and V {sub o}{sup 2+} toward the interface between the gate insulator and the semiconductor. The inserted Al{sub 2}O{sub 3} triple layer exhibits amore » noticeably low turn on voltage shift of −0.7 V under NBIS as well as the good TFT performance with a mobility of 10.9 cm{sup 2}/V ⋅ s. We anticipate that this approach can be used to solve the stability issues such as NBIS, which is caused by inescapable oxygen vacancies.« less

Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial.

PubMed

Arribas, José R; Girard, Pierre-Marie; Landman, Roland; Pich, Judit; Mallolas, Josep; Martínez-Rebollar, María; Zamora, Francisco X; Estrada, Vicente; Crespo, Manuel; Podzamczer, Daniel; Portilla, Joaquín; Dronda, Fernando; Iribarren, José A; Domingo, Pere; Pulido, Federico; Montero, Marta; Knobel, Hernando; Cabié, André; Weiss, Laurence; Gatell, José M

2015-07-01

Our objective was to assess therapeutic non-inferiority of dual treatment with lopinavir-ritonavir and lamivudine to triple treatment with lopinavir-ritonavir plus two nucleos(t)ides for maintenance of HIV-1 viral suppression. In this randomised, open-label, non-inferiority trial, we recruited patients from 32 HIV units in hospitals in Spain and France. Eligible patients were HIV-infected adults (aged ≥18 years) with HIV-1 RNA of less than 50 copies per mL, for at least 6 months on triple treatment with lopinavir-ritonavir (twice daily) plus lamivudine or emtricitabine and a second nucleos(t)ide, with no resistance or virological failure to these drugs, and no positive hepatitis B serum surface antigen. Investigators at each centre randomly assigned patients (1:1; block size of four; stratified by time to suppression [<1 year or >1 year] and nadir CD4 cell count [<100 cells per μL or >100 cells per μL]; computer-generated random sequence) to continue triple treatment or switch to dual treatment (oral lopinavir 400 mg and oral ritonavir 100 mg twice daily plus oral lamivudine 300 mg once daily). The primary endpoint was response to treatment in the intention-to-treat population (all randomised patients) at 48 weeks. The non-inferiority margin was 12%. This study is registered with ClinicalTrials.gov, number NCT01471821. Between Oct 1, 2011, and April 1, 2013, we randomly assigned 250 participants to continue triple treatment (127 [51%] patients) or switch to dual treatment (123 [49%] patients). In the intention-to-treat population, 110 (86·6%) of 127 patients in the triple-treatment group responded to treatment versus 108 (87·8%) of 123 in the dual-treatment group (difference -1·2% [95% CI -9·6 to 7·3]; p=0·92), meeting the criteria for non-inferiority. Serious adverse events occurred in eight (7%) patients in the triple-treatment group and five (4%) in the dual-treatment group (p=0·515), and study drug discontinuations due to adverse events occurred in four (3%) in the triple-treatment group and one (1%) in the dual-treatment group (p=0·223). Dual treatment with lopinavir-ritonavir plus lamivudine has non-inferior therapeutic efficacy and is similarly tolerated to triple treatment. AbbVie and Red Temática Cooperativa de Investigación en Sida. Copyright © 2015 Elsevier Ltd. All rights reserved.

Data processing for soft X-ray diagnostics based on GEM detector measurements for fusion plasma imaging

NASA Astrophysics Data System (ADS)

Czarski, T.; Chernyshova, M.; Pozniak, K. T.; Kasprowicz, G.; Byszuk, A.; Juszczyk, B.; Wojenski, A.; Zabolotny, W.; Zienkiewicz, P.

2015-12-01

The measurement system based on GEM - Gas Electron Multiplier detector is developed for X-ray diagnostics of magnetic confinement fusion plasmas. The Triple Gas Electron Multiplier (T-GEM) is presented as soft X-ray (SXR) energy and position sensitive detector. The paper is focused on the measurement subject and describes the fundamental data processing to obtain reliable characteristics (histograms) useful for physicists. So, it is the software part of the project between the electronic hardware and physics applications. The project is original and it was developed by the paper authors. Multi-channel measurement system and essential data processing for X-ray energy and position recognition are considered. Several modes of data acquisition determined by hardware and software processing are introduced. Typical measuring issues are deliberated for the enhancement of data quality. The primary version based on 1-D GEM detector was applied for the high-resolution X-ray crystal spectrometer KX1 in the JET tokamak. The current version considers 2-D detector structures initially for the investigation purpose. Two detector structures with single-pixel sensors and multi-pixel (directional) sensors are considered for two-dimensional X-ray imaging. Fundamental output characteristics are presented for one and two dimensional detector structure. Representative results for reference source and tokamak plasma are demonstrated.

System and process for pulsed multiple reaction monitoring

DOEpatents

Belov, Mikhail E

2013-05-17

A new pulsed multiple reaction monitoring process and system are disclosed that uses a pulsed ion injection mode for use in conjunction with triple-quadrupole instruments. The pulsed injection mode approach reduces background ion noise at the detector, increases amplitude of the ion signal, and includes a unity duty cycle that provides a significant sensitivity increase for reliable quantitation of proteins/peptides present at attomole levels in highly complex biological mixtures.

Triple pulse shape discrimination and capture-gated spectroscopy in a composite heterogeneous scintillator

NASA Astrophysics Data System (ADS)

Sharma, M.; Nattress, J.; Wilhelm, K.; Jovanovic, I.

2017-06-01

We demonstrate an all-solid-state design for a composite heterogeneous scintillation detector sensitive to interactions with high-energy photons (gammas), fast neutrons, and thermal neutrons. The scintillator exhibits triple pulse shape discrimination, effectively separating electron recoils, fast neutron recoils, and neutron captures. This is accomplished by combining the properties of two distinct scintillators, whereby a 51-mm diameter, 51-mm tall cylinder of pulse shape discriminating plastic is wrapped by a 320-μm thick sheet of 6LiF:ZnS(Ag), optically coupling the scintillators to each other and to the photomultiplier tube. In this way, the sensitivity to neutron captures is achieved without the need to load the plastic scintillator with a capture agent. We demonstrate a figure of merit of up to 1.2 for fast neutrons/gammas and 5.7 for thermal neutrons/gammas. Intrinsic capture efficiency is found to be 0.46±0.05% and is in good agreement with simulation, while gamma rejection was 10-6 with respect to the capture region and 10-4 with respect to the recoil region using a 300 keVee threshold. Finally, we show an improvement in capture-gated neutron spectroscopy by rejecting accidental gamma coincidences using pulse shape discrimination in the plastic scintillator.

Single-indicator-based Multidimensional Sensing: Detection and Identification of Heavy Metal Ions and Understanding the Foundations from Experiment to Simulation

PubMed Central

Leng, Yumin; Qian, Sihua; Wang, Yuhui; Lu, Cheng; Ji, Xiaoxu; Lu, Zhiwen; Lin, Hengwei

2016-01-01

Multidimensional sensing offers advantages in accuracy, diversity and capability for the simultaneous detection and discrimination of multiple analytes, however, the previous reports usually require complicated synthesis/fabrication process and/or need a variety of techniques (or instruments) to acquire signals. Therefore, to take full advantages of this concept, simple designs are highly desirable. Herein, a novel concept is conceived to construct multidimensional sensing platforms based on a single indicator that has capability of showing diverse color/fluorescence responses with the addition of different analytes. Through extracting hidden information from these responses, such as red, green and blue (RGB) alterations, a triple-channel-based multidimensional sensing platform could consequently be fabricated, and the RGB alterations are further applicable to standard statistical methods. As a proof-of-concept study, a triple-channel sensing platform is fabricated solely using dithizone with assistance of cetyltrimethylammonium bromide (CTAB) for hyperchromicity and sensitization, which demonstrates superior capabilities in detection and identification of ten common heavy metal ions at their standard concentrations of wastewater-discharge of China. Moreover, this sensing platform exhibits promising applications in semi-quantitative and even quantitative analysis individuals of these heavy metal ions with high sensitivity as well. Finally, density functional theory calculations are performed to reveal the foundations for this analysis. PMID:27146105

Determination of mycotoxins in different food commodities by ultra-high-pressure liquid chromatography coupled to triple quadrupole mass spectrometry.

PubMed

Beltrán, Eduardo; Ibáñez, María; Sancho, Juan Vicente; Hernández, Félix

2009-06-01

A rapid multianalyte-multiclass method with little sample manipulation has been developed for the simultaneous determination of eleven mycotoxins in different food commodities by using ultra-high-pressure liquid chromatography coupled to triple quadrupole mass spectrometry (UHPLC/MS/MS). Toxins were extracted from the samples with acetonitrile/water (80:20, v/v) 0.1% HCOOH and, after a two-fold dilution with water, directly injected into the system. Thanks to the fast high-resolution separation of UHPLC, the eleven mycotoxins were separated by gradient elution in only 4 min. The method has been validated in three food matrices (maize kernels, dry pasta (wheat), and eight-multicereal babyfood (wheat, maize, rice, oat, barley, rye, sorghum, millet)) at four different concentration levels. Satisfactory recoveries were obtained (70-110%) and precision (expressed as relative standard deviation) was typically below 15% with very few exceptions. Quantification of samples was carried out with matrix-matched standards calibration. The lowest concentration successfully validated in sample was as low as 0.5 microg/kg for aflatoxins and ochratoxin A in babyfood, and 20 microg/kg for the rest of the selected mycotoxins in all matrices tested. Deoxynivalenol could be only validated at 200 microg/kg, due the poor sensitivity for this mycotoxin analysis. With only two exceptions (HT-2 and deoxynivalenol), the limits of detection (LODs), estimated for a signal-to-noise ratio of 3 from the chromatograms of samples spiked at the lowest level validated, varied between 0.1 and 1 microg/kg in the three food matrices tested. The method was applied to the analysis of different kinds of samples. Positive findings were confirmed by acquiring two transitions (Q quantification, q confirmation) and evaluating the Q/q ratio. Copyright (c) 2009 John Wiley & Sons, Ltd.

Comparison between triple quadrupole, time of flight and hybrid quadrupole time of flight analysers coupled to liquid chromatography for the detection of anabolic steroids in doping control analysis.

PubMed

Pozo, Oscar J; Van Eenoo, Peter; Deventer, Koen; Elbardissy, Hisham; Grimalt, Susana; Sancho, Juan V; Hernandez, Felix; Ventura, Rosa; Delbeke, Frans T

2011-01-17

Triple quadrupole (QqQ), time of flight (TOF) and quadrupole-time of flight (QTOF) analysers have been compared for the detection of anabolic steroids in human urine. Ten anabolic steroids were selected as model compounds based on their ionization and the presence of endogenous interferences. Both qualitative and quantitative analyses were evaluated. QqQ allowed for the detection of all analytes at the minimum required performance limit (MRPL) established by the World Anti-Doping Agency (between 2 and 10 ng mL(-1) in urine). TOF and QTOF approaches were not sensitive enough to detect some of the analytes (3'-hydroxy-stanozolol or the metabolites of boldenone and formebolone) at the established MRPL. Although a suitable accuracy was obtained, the precision was unsatisfactory (RSD typically higher than 20%) for quantitative purposes irrespective of the analyser used. The methods were applied to 30 real samples declared positives either for the misuse of boldenone, stanozolol and/or methandienone. Most of the compounds were detected by every technique, however QqQ was necessary for the detection of some metabolites in a few samples. Finally, the possibility to detect non-target steroids has been explored by the use of TOF and QTOF. The use of this approach revealed that the presence of boldenone and its metabolite in one sample was due to the intake of androsta-1,4,6-triene-3,17-dione. Additionally, the intake of methandienone was confirmed by the post-target detection of a long-term metabolite. Copyright © 2010 Elsevier B.V. All rights reserved.

The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer

PubMed Central

Kimler, Bruce F.; Sethi, Geetika; Petroff, Brian K.; Phillips, Teresa A.; Tawfik, Ossama W.; Godwin, Andrew K.; Jensen, Roy A.

2014-01-01

Introduction Methylation of the BRCA1 promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar to BRCA1-mutated tumors. BRCA1 mutation-associated cancers are more sensitive to DNA damaging agents as compared to conventional chemotherapy agents. It is not known if there is an interaction between the presence of BRCA1 promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance of BRCA1 PM in TNBC patients receiving standard chemotherapy. Methods Subjects with stage I-III TNBC treated with chemotherapy were identified and their formalin-fixed paraffin-embedded (FFPE) tumor specimens retrieved. Genomic DNA was isolated and subjected to methylation-specific PCR (MSPCR). Results DNA was isolated from primary tumor of 39 subjects. BRCA1 PM was detected in 30% of patients. Presence of BRCA1 PM was associated with lower BRCA1 transcript levels, suggesting epigenetic BRCA1 silencing. All patients received chemotherapy (anthracycline:90%, taxane:69%). At a median follow-up of 64 months, 46% of patients have recurred and 36% have died. On univariate analysis, African-American race, node positivity, stage, and BRCA1 PM were associated with worse RFS and OS. Five year OS was 36% for patients with BRCA1 PM vs. 77% for patients without BRCA1 PM (p=0.004). On multivariable analysis, BRCA1 PM was associated with significantly worse RFS and OS. Conclusions We show that BRCA1 PM is common in TNBC and has the potential to identify a significant fraction of TNBC patients who have suboptimal outcomes with standard chemotherapy. PMID:25177489

Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

PubMed

Riva, Francesca; Bidard, Francois-Clement; Houy, Alexandre; Saliou, Adrien; Madic, Jordan; Rampanou, Aurore; Hego, Caroline; Milder, Maud; Cottu, Paul; Sablin, Marie-Paule; Vincent-Salomon, Anne; Lantz, Olivier; Stern, Marc-Henri; Proudhon, Charlotte; Pierga, Jean-Yves

2017-03-01

In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery. Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 ( TP53 ) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS). Forty-six patients with nonmetastatic TNBC were enrolled. TP53 mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS ( r = 0.99), specificity (≥2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index ( P = 0.003), tumor grade ( P = 0.003), and stage ( P = 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free ( P < 0.001) and overall ( P = 0.006) survival. Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival. © 2016 American Association for Clinical Chemistry.

Identification of urinary metabolites of imperatorin with a single run on an LC/Triple TOF system based on multiple mass defect filter data acquisition and multiple data mining techniques.

PubMed

Qiao, Shi; Shi, Xiaowei; Shi, Rui; Liu, Man; Liu, Ting; Zhang, Kerong; Wang, Qiao; Yao, Meicun; Zhang, Lantong

2013-08-01

The detection of drug metabolites, especially for minor metabolites, continues to be a challenge because of the complexity of biological samples. Imperatorin (IMP) is an active natural furocoumarin component originating from many traditional Chinese herbal medicines and is expected to be pursued as a new vasorelaxant agent. In the present study, a generic and efficient approach was developed for the in vivo screening and identification of IMP metabolites using liquid chromatography-Triple TOF mass spectrometry. In this approach, a novel on-line data acquisition method mutiple mass defect filter (MMDF) combined with dynamic background subtraction was developed to trace all probable urinary metabolites of IMP. Comparing with the traditionally intensity-dependent data acquisition method, MMDF method could give the information of low-level metabolites masked by background noise and endogenous components. Thus, the minor metabolites in complex biological matrices could be detected. Then, the sensitive and specific multiple data-mining techniques extracted ion chromatography, mass defect filter, product ion filter, and neutral loss filter were used for the discovery of IMP metabolites. Based on the proposed strategy, 44 phase I and 7 phase II metabolites were identified in rat urine after oral administration of IMP. The results indicated that oxidization was the main metabolic pathway and that different oxidized substituent positions had a significant influence on the fragmentation of the metabolites. Two types of characteristic ions at m/z 203 and 219 can be observed in the MS/MS spectra. This is the first study of IMP metabolism in vivo. The interpretation of the MS/MS spectra of these metabolites and the proposed metabolite pathway provide essential data for further pharmacological studies of other linear-type furocoumarins.

Water vapor δ17O measurements using an off-axis integrated cavity output spectrometer and seasonal variation in 17O-excess of precipitation in the east-central United States

NASA Astrophysics Data System (ADS)

Tian, C.; Wang, L.; Novick, K. A.

2016-12-01

High-precision triple oxygen isotope analysis can be used to improve our understanding of multiple hydrological and meteorological processes. Recent studies focus on understanding 17O-excess variation of tropical storms, high-latitude snow and ice-core as well as spatial distribution of meteoric water (tap water). The temporal scale of 17O-excess variation in middle-latitude precipitation is needed to better understand which processes control on the 17O-excess variations. This study focused on assessing how the accuracy and precision of vapor δ17O laser spectroscopy measurements depend on vapor concentration, delta range, and averaging-time. Meanwhile, we presented 17O-excess data from two-year, event based precipitation sampling in the east-central United States. A Triple Water Vapor Isotope Analyzer (T-WVIA) was used to evaluate the accuracy and precision of δ2H, δ18O and δ17O measurements. GISP and SLAP2 from IAEA and four working standards were used to evaluate the sensitivity in the three factors. Overall, the accuracy and precision of all isotope measurements were sensitive to concentration, with higher accuracy and precision generally observed under moderate vapor concentrations (i.e., 10000-15000 ppm) for all isotopes. Precision was also sensitive to the range of delta values, though the effect was not as large when compared to the sensitivity to concentration. The precision was much less sensitive to averaging time when compared with concentration and delta range effects. The preliminary results showed that 17O-excess variation was lower in summer (23±17 per meg) than in winter (34±16 per meg), whereas spring values (30±21 per meg) was similar to fall (29±13 per meg). That means kinetic fractionation influences the isotopic composition and 17O-excess in different seasons.

[Diseases linked to Helicobacter pylori infection].

PubMed

Gisbert, Javier P

2014-09-01

Below is a summary of the main conclusions that came from reports presented at this year's Digestive Disease Week (2014) relating to Helicobacter pylori infection. Despite the undeniable decline of the infection's frequency, in the near future, developed countries--or at least some sub-populations--will continue to have a significant prevalence of the infection. Clarithromycin, metronidazole and quinolone resistance rates are considerably high in most countries and these rates are on the rise. The eradication of H. pylori improves symptoms of functional dyspepsia, although only in a minority of patients; adding antidepressants to eradication therapy could improve long-term response. In patients who were admitted with gastrointestinal bleeding from peptic ulcers, it is necessary to thoroughly study the presence of H. pylori infection and administer eradication therapy as early as possible. Eradication of H. pylori in patients undergoing endoscopic resection of early-stage gastric cancer reduces incidence of metachronous tumors. We have some diagnostic innovations, such as carrying out various techniques--a rapid urease test, culture or PCR--based on gastric samples obtained by scraping the mucosa. The effectiveness of conventional triple therapy is clearly insufficient and continues to decline. The superiority of sequential therapy over conventional triple therapies has not been definitively established. Concomitant therapy is simpler and more effective than sequential therapy. Optimized concomitant therapy (with high doses of proton-pump inhibitors [PPI] and over 14 days) is highly effective, more so than standard concomitant therapy. For patients who are allergic to penicillin, 2 treatment options were essentially described: PPI-clarithromycin-metronidazole (clarithromycin-sensitive strains) and quadruple therapy with bismuth (when the bacterial sensitivity is unknown). If conventional triple therapy fails, second-line therapy with levofloxacin is effective and is also easier and better tolerated than quadruple therapy with bismuth. Triple therapy with levofloxacin is also a promising alternative if sequential or concomitant therapy fails. New-generation quinolones, such as moxifloxacin, could be useful as part of rescue eradication therapy. Even after 3 eradication therapies have failed, a fourth empirical rescue therapy (with rifabutin) could be effective. The eradication of H. pylori can finally be obtained in the vast majority of patients by using a rescue strategy of up to 4 consecutive empirical therapies, without conducting bacterial cultures. Copyright © 2014 Elsevier España, S.L.U. All rights reserved.

Switching effect of the side chain on quantum walks on triple graphs

NASA Astrophysics Data System (ADS)

Du, Yi-Mu; Lu, Li-Hua; Li, You-Quan

2015-07-01

We consider a continuous-time quantum walk on a triple graph and investigate the influence of the side chain on propagation in the main chain. Calculating the interchange of the probabilities between the two parts of the main chain, we find that a switching effect appears if there is an odd number of points in the side chain when concrete conditions between the length of the main chain and the position of the side chain are satisfied. However, such an effect does not occur if there is an even number of points in the side chain. We also suggest two proposals for experiments to demonstrate this effect, which may be employed to design a new type of switching device.

Reconfigurable and Reprocessable Thermoset Shape Memory Polymer with Synergetic Triple Dynamic Covalent Bonds.

PubMed

Wang, Yongwei; Pan, Yi; Zheng, Zhaohui; Ding, Xiaobin

2018-04-20

Degradable shape memory polymers (SMPs), especially for polyurethane-based SMPs, have shown great potential for biomedical applications. How to reasonably fabricate SMPs with the ideal combination of degradability, shape reconfigurability, and reprocessability is a critical issue and remains a challenge for medical disposable materials. Herein, a shape memory poly(urethane-urea) with synergetic triple dynamic covalent bonds is reported via embedding polycaprolactone unit into poly(urethane-urea) with the hindered urea dynamic bond. The single polymer network is biodegradable, thermadapt, and reprocessable, without sacrificing the outstanding shape memory performance. Such a shape memory network with plasticity and reprocessability is expected to have significant and positive impact on the medical device industry. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cost-effectiveness analysis of triple therapy with protease inhibitors in treatment-naive hepatitis C patients.

PubMed

Blázquez-Pérez, Antonio; San Miguel, Ramón; Mar, Javier

2013-10-01

Chronic hepatitis C is the leading cause of chronic liver disease, representing a significant burden in terms of morbidity, mortality and costs. A new scenario of therapy for hepatitis C virus (HCV) genotype 1 infection is being established with the approval of two effective HCV protease inhibitors (PIs) in combination with the standard of care (SOC), peginterferon and ribavirin. Our objective was to estimate the cost effectiveness of combination therapy with new PIs (boceprevir and telaprevir) plus peginterferon and ribavirin versus SOC in treatment-naive patients with HCV genotype 1 according to data obtained from clinical trials (CTs). A Markov model simulating chronic HCV progression was used to estimate disease treatment costs and effects over patients' lifetimes, in the Spanish national public healthcare system. The target population was treatment-naive patients with chronic HCV genotype 1, demographic characteristics for whom were obtained from the published pivotal CTs SPRINT and ADVANCE. Three options were analysed for each PI based on results from the two CTs: universal triple therapy, interleukin (IL)-28B-guided therapy and dual therapy with peginterferon and ribavirin. A univariate sensitivity analysis was performed to evaluate the uncertainty of certain parameters: age at start of treatment, transition probabilities, drug costs, CT efficacy results and a higher hazard ratio for all-cause mortality for patients with chronic HCV. Probabilistic sensitivity analyses were also carried out. Incremental cost-effectiveness ratios (ICERs) of €2012 per quality-adjusted life-year (QALY) gained were used as outcome measures. According to the base-case analysis, using dual therapy as the comparator, the alternative IL28B-guided therapy presents a more favorable ICER (€18,079/QALY for boceprevir and €25,914/QALY for telaprevir) than the universal triple therapy option (€27,594/QALY for boceprevir and €33,751/QALY for telaprevir), with an ICER clearly below the efficiency threshold for medical interventions in the Spanish setting. Sensitivity analysis showed that age at the beginning of treatment was an important factor that influenced the ICER. A potential reduction in PI costs would also clearly improve the ICER, and transition probabilities influenced the results, but to a lesser extent. Probabilistic sensitivity analyses showed that 95 % of the simulations presented an ICER below €40,000/QALY. Post hoc estimations of sustained virological responses of the IL28B-guided therapeutic option represented a limitation of the study. The therapeutic options analysed for the base-case cohort can be considered cost-effective interventions for the Spanish healthcare framework. Sensitivity analysis estimated an acceptability threshold of the IL28B-guided strategy of patients younger than 60 years.

Handling the satellite inter-frequency biases in triple-frequency observations

NASA Astrophysics Data System (ADS)

Zhao, Lewen; Ye, Shirong; Song, Jia

2017-04-01

The new generation of GNSS satellites, including BDS, Galileo, modernized GPS, and GLONASS, transmit navigation sdata at more frequencies. Multi-frequency signals open new prospects for precise positioning, but satellite code and phase inter-frequency biases (IFB) induced by the third frequency need to be handled. Satellite code IFB can be corrected using products estimated by different strategies, the theoretical and numerical compatibility of these methods need to be proved. Furthermore, a new type of phase IFB, which changes with the relative sun-spacecraft-earth geometry, has been observed. It is necessary to investigate the cause and possible impacts of phase Time-variant IFB (TIFB). Therefore, we present systematic analysis to illustrate the relevancy between satellite clocks and phase TIFB, and compare the handling strategies of the code and phase IFB in triple-frequency positioning. First, the un-differenced L1/L2 satellite clock corrections considering the hardware delays are derived. And IFB induced by the dual-frequency satellite clocks to triple-frequency PPP model is detailed. The analysis shows that estimated satellite clocks actually contain the time-variant phase hardware delays, which can be compensated in L1/L2 ionosphere-free combinations. However, the time-variant hardware delays will lead to TIFB if the third frequency is used. Then, the methods used to correct the code and phase IFB are discussed. Standard point positioning (SPP) and precise point positioning (PPP) using BDS observations are carried out to validate the improvement of different IFB correction strategies. Experiments show that code IFB derived from DCB or geometry-free and ionosphere-free combination show an agreement of 0.3 ns for all satellites. Positioning results and error distribution with two different code IFB correcting strategies achieve similar tendency, which shows their substitutability. The original and wavelet filtered phase TIFB long-term series show significant periodical characteristic for most GEO and IGSO satellites, with the magnitude varies between - 5 cm and 5 cm. Finally, BDS L1/L3 kinematic PPP is conducted with code IFB corrected with DCB combinations, and TIFB corrected with filtered series. Results show that the IFB corrected L1/L3 PPP can achieve comparable convergence and positioning accuracy as L1/L2 combinations in static and kinematic mode.

A VLT/NACO survey for triple and quadruple systems among visual pre-main sequence binaries

NASA Astrophysics Data System (ADS)

Correia, S.; Zinnecker, H.; Ratzka, Th.; Sterzik, M. F.

2006-12-01

Aims.This paper describes a systematic search for high-order multiplicity among wide visual Pre-Main Sequence (PMS) binaries. Methods: .We conducted an Adaptive Optics survey of a sample of 58 PMS wide binaries from various star-forming regions, which include 52 T Tauri systems with mostly K- and M-type primaries, with the NIR instrument NACO at the VLT. Results: .Of these 52 systems, 7 are found to be triple (2 new) and 7 quadruple (1 new). The new close companions are most likely physically bound based on their probability of chance projection and, for some of them, on their position on a color-color diagram. The corresponding degree of multiplicity among wide binaries (number of triples and quadruples divided by the number of systems) is 26.9 ± 7.2% in the projected separation range ~0.07 arcsec -12'', with the largest contribution from the Taurus-Auriga cloud. We also found that this degree of multiplicity is twice in Taurus compared to Ophiuchus and Chamaeleon for which the same number of sources are present in our sample. Considering a restricted sample composed of systems at distance 140-190 pc, the degree of multiplicity is 26.8 ± 8.1%, in the separation range 10/14 AU-1700/2300 AU (30 binaries, 5 triples, 6 quadruples). The observed frequency agrees with results from previous multiplicity surveys within the uncertainties, although a significant overabundance of quadruple systems compared to triple systems is apparent. Tentatively including the spectroscopic pairs in our restricted sample and comparing the multiplicity fractions to those measured for solar-type main-sequence stars in the solar neighborhood leads to the conclusion that both the ratio of triples to binaries and the ratio of quadruples to triples seems to be in excess among young stars. Most of the current numerical simulations of multiple star formation, and especially smoothed particles hydrodynamics simulations, over-predict the fraction of high-order multiplicity when compared to our results. The circumstellar properties around the individual components of our high-order multiple systems tend to favor mixed systems (i.e. systems including components of wTTS and cTTS type), which is in general agreement with previous studies of disks in binaries, with the exception of Taurus, where we find a preponderance of similar type of components among the multiples studied.

Comparison of Multispot EIA with Western blot for confirmatory serodiagnosis of HIV.

PubMed

Torian, Lucia V; Forgione, Lisa A; Punsalang, Amado E; Pirillo, Robert E; Oleszko, William R

2011-12-01

Recent improvements in the sensitivity of immunoassays (IA) used for HIV screening, coupled with increasing recognition of the importance of rapid point-of-care testing, have led to proposals to adjust the algorithm for serodiagnosis of HIV so that screening and confirmation can be performed using a dual or triple IA sequence that does not require Western blotting for confirmation. One IA that has been proposed as a second or confirmatory test is the Bio-Rad Multispot(®) Rapid HIV-1/HIV-2 Test. This test would have the added advantage of differentiating between HIV-1 and HIV-2 antibodies. To compare the sensitivity and type-specificity of an algorithm combining a 3rd generation enzyme immunoassay (EIA) followed by a confirmatory Multispot with the conventional algorithm that combines a 3rd generation EIA (Bio-Rad GS HIV-1/HIV-2 Plus O EIA) followed by confirmatory Western blot (Bio-Rad GS HIV-1 WB). 8760 serum specimens submitted for HIV testing to the New York City Public Health Laboratory between May 22, 2007, and April 30, 2010, tested repeatedly positive on 3rd generation HIV-1-2+O EIA screening and received parallel confirmatory testing by WB and Multispot (MS). 8678/8760 (99.1%) specimens tested WB-positive; 82 (0.9%) tested WB-negative or indeterminate (IND). 8690/8760 specimens (99.2%) tested MS-positive, of which 14 (17.1%) had been classified as negative or IND by WB. Among the HIV-1 WB-positive specimens, MS classified 26 (0.29%) as HIV-2. Among the HIV-1 WB negative and IND, MS detected 12 HIV-2. MS detected an additional 14 HIV-1 infections among WB negative or IND specimens, differentiated 26 HIV-1 WB positives as HIV-2, and detected 12 additional HIV-2 infections among WB negative/IND. A dual 3rd generation EIA algorithm incorporating MS had equivalent HIV-1 sensitivity to the 3rd generation EIA-WB algorithm and had the added advantage of detecting 12 HIV-2 specimens that were not HIV-1 WB cross-reactors. In this series an algorithm using EIA followed by MS would have resulted in the expedited referral of 38 specimens for HIV-2 testing and 40 specimens for nucleic acid confirmation. Further testing using a combined gold standard of nucleic acid detection and WB is needed to calculate specificity and validate the substitution of MS for WB in the diagnostic algorithm used by a large public health laboratory. Copyright © 2011. Published by Elsevier B.V.

Analysis of a Triple Star System Occulted By Saturn’s Rings

NASA Astrophysics Data System (ADS)

Bratcher, Allison; Colwell, J. E.; Bolin, B.

2012-10-01

On January 4, 2012, the Ultraviolet Imaging Spectrograph aboard the Cassini Spacecraft observed Saturn’s rings as they occulted the triple star system, Iota Orionis. Remarkably, the brightest star was occulted by the moon Prometheus, and we provide the timing information of first and last contact for navigation purposes and a chord across the moon. The large separation of the individual stars projected in the ring plane makes it possible to measure the profiles of narrow features in the rings as they were occulted by each of the three stars. This occultation thus provides a unique opportunity to measure short-scale longitudinal variations in narrow ringlets with stellar occultation data that usually provide only a single longitudinal sample. Iota Orionis has a low elevation angle (B=1.4 degrees) above the plane of the rings, enhancing the sensitivity of the occultation (by a factor of 1/sin(B)=41) to the optically thin regions of the rings such as the C Ring and the Cassini Division as well as faint ringlets in the Encke gap. We distinguished the three signals by creating a model triple star signal using data from another occultation. We were able to identify several faint, narrow ringlets, including two in the Encke gap, occulted by two of the three stars and more prominent ringlets, such as the Huygens ringlet, in all three stellar light curves. We present the equivalent widths of these ringlets in the data from this triple star system and limits on ring variability over the azimuthal separation of the stars that ranges from 6000 km at the inner C ring to 200 km at the outer A ring.

Cost-effectiveness of treatment regimens for the eradication of Helicobacter pylori in duodenal ulcer.

PubMed

Vakil, N; Fennerty, M B

1996-02-01

Eradication of Helicobacter pylori with antimicrobials was recommended by a recent NIH consensus panel for all infected patients with peptic ulcer disease. The precise regimen that should be used for eradication of the infection remains uncertain because of the variety of regimens described, variable results with the regimens, and difficulties in predicting drug compliance outside clinical trials. A decision analysis tree was developed with three regimens that are widely used regimens for the eradication of H. pylori: 1) 2-wk triple drug therapy (metronidazole, bismuth, tetracycline with H2 receptor antagonist), 2) 2-wk omeprazole and amoxicillin, and 3) 2-wk omeprazole and clarithromycin. Traditional H2 receptor antagonist therapy was used for comparison. A 2-yr time period was chosen for study to allow sufficient time for relapse and to evaluate its effect on the treatment strategy. Probabilities for eradication, compliance, and metronidazole resistance were determined from published data, and assumptions were tested by sensitivity analysis. Standard 2-wk triple drug therapy was the least expensive strategy ($720), and conventional H2 receptor antagonist therapy was the most expensive ($1791). Costs with 2-wk therapy with omeprazole and clarithromycin ($768) were lower than with omeprazole and amoxicillin ($1028). Treatment to eradicate H. pylori in infected patients with duodenal ulcer is a less expensive strategy than traditional therapy with H2 receptor antagonists. Triple drug therapy is the optimal regimen in areas where metronidazole resistance rates are < 36% and compliance is > 53%. Omeprazole and amoxicillin is not cost-effective unless eradication rates are greater than 74%. Dual drug therapy with omeprazole and clarithromycin is effective in regions where metronidazole resistance is high or where it is anticipated that there would be poor compliance with the more complicated triple drug therapy regimen.

Proteomics as a Guide for Personalized Adjuvant Chemotherapy in Patients with Early Breast Cancer.

PubMed

Lumachi, Franco; Chiara, Giordano B; Foltran, Luisa; Basso, Stefano M M

2015-01-01

Proteomics allows for better understanding of the function and regulation of cancer cells mediated by intra- and extracellular signaling networks. Integrating such information with clinicopathological characteristics of the tumor may lead to either detection of disease biomarkers useful to differentiate high-from low-risk patients, or to identification of new drug targets. Adjuvant chemotherapy is currently a personalized treatment strategy, especially for breast cancer (BC) patients, and the risk assessment of each patient influences its use because the benefit strictly correlates with the level of risk. Luminal A BCs are endocrine therapy (ET)-sensitive but exhibit low sensitivity to chemotherapy, while luminal B cancers, according to the Ki-67 proliferation rate may require for chemotherapy in addition to ET, and HER2-positive tumors derive benefit from adjuvant chemotherapy containing an anthracycline, a taxane and trastuzumab for one year. Triple-negative BCs have a high degree of genomic instability exhibiting a more aggressive clinical course with respect to other types of BC, and the anthracycline-taxane regimen constitutes the standard approach. Studies considering the use of targeted approaches (drugs), including poly (ADP-ribose) polymerase (PARP-1), vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR) inhibitors, or EFGR and HER2 blockers, are still under evaluation. In the genomic era, promising new targeted-therapies are worthy of further investigation, and mTOR inhibitors have been used for patients with high-risk ER-positive and HER2-negative tumors. In the near future, genetic and molecular profiling of BC will help to better-categorize patients, determine the choice of chemotherapy in low-risk, or intensify the treatment in high-risk cancer patients, eventually revealing new targeted agents. Copyright© 2015, International Institute of Anticancer Research (Dr. John G. Delinasios), All rights reserved.

Prevalence of antifolate resistance mutations in Plasmodium falciparum isolates in Afghanistan

PubMed Central

2013-01-01

Background Artesunate plus sulphadoxine-pyrimethamine (AS+SP) is now first-line treatment for Plasmodium falciparum infection in several south Asian countries, including Afghanistan. Molecular studies provide a sensitive means to investigate the current state of drug susceptibility to the SP component, and can also provide information on the likely efficacy of other potential forms of artemisinin-combination therapy. Methods During the years 2007 to 2010, 120 blood spots from patients with P. falciparum malaria were obtained in four provinces of Afghanistan. PCR-based methods were used to detect drug-resistance mutations in dhfr, dhps, pfcrt and pfmdr1, as well as to determine copy number of pfmdr1. Results The majority (95.5%) of infections had a double mutation in the dhfr gene (C59R, S108N); no mutations at dhfr positions 16, 51 or 164 were seen. Most isolates were wild type across the dhps gene, but five isolates from the provinces of Kunar and Nangarhar in eastern Afghanistan had the triple mutation A437G / K540E / A581G; all five cases were successfully treated with three receiving AS+SP and two receiving dihydroartemisinin-piperaquine. All isolates showed the pfcrt SVNMT chloroquine resistance haplotype. Five of 79 isolates had the pfmdr1 N86Y mutation, while 52 had pfmdr1 Y184F; positions 1034, 1042 and 1246 were wild type in all isolates. The pfmdr1 gene was not amplified in any sample. Conclusions This study indicates that shortly after the adoption of AS+SP as first-line treatment in Afghanistan, most parasites had a double mutation haplotype in dhfr, and a small number of isolates from eastern Afghanistan harboured a triple mutation haplotype in dhps. The impact of these mutations on the efficacy of AS+SP remains to be assessed in significant numbers of patients, but these results are clearly concerning since they suggest a higher degree of SP resistance than previously detected. Further focused molecular and clinical studies in this region are urgently required. PMID:23497229

High Throughput Protein Quantitation using MRM Viewer Software and Dynamic MRM on a Triple Quadruple Mass Spectrometer

PubMed Central

Miller, C.; Waddell, K.; Tang, N.

2010-01-01

RP-122 Peptide quantitation using Multiple Reaction Monitoring (MRM) has been established as an important methodology for biomarker verification andvalidation.This requires high throughput combined with high sensitivity to analyze potentially thousands of target peptides in each sample.Dynamic MRM allows the system to only acquire the required MRMs of the peptide during a retention window corresponding to when each peptide is eluting. This reduces the number of concurrent MRM and therefore improves quantitation and sensitivity. MRM Selector allows the user to generate an MRM transition list with retention time information from discovery data obtained on a QTOF MS system.This list can be directly imported into the triple quadrupole acquisition software.However, situations can exist where a) the list of MRMs contain an excess of MRM transitions allowable under the ideal acquisition conditions chosen ( allowing for cycle time and chromatography conditions), or b) too many transitions in a certain retention time region which would result in an unacceptably low dwell time and cycle time.A new tool - MRM viewer has been developed to help users automatically generate multiple dynamic MRM methods from a single MRM list.In this study, a list of 3293 MRM transitions from a human plasma sample was compiled.A single dynamic MRM method with 3293 transitions results in a minimum dwell time of 2.18ms.Using MRM viewer we can generate three dynamic MRM methods with a minimum dwell time of 20ms which can give a better quality MRM quantitation.This tool facilitates both high throughput and high sensitivity for MRM quantitation.

A targeted strategy to identify untargeted metabolites from in vitro to in vivo: Rapid and sensitive metabolites profiling of licorice in rats using ultra-high performance liquid chromatography coupled with triple quadrupole-linear ion trap mass spectrometry.

PubMed

Huang, Meilin; Cheng, Zhongzhe; Wang, Lu; Feng, Yulin; Huang, Jiangeng; Du, Zhifeng; Jiang, Hongliang

2018-05-29

It is challenging to conduct in vivo metabolic study for traditional Chinese medicines (TCMs) because of complex components, unpredictable metabolic pathways and low metabolite concentrations. Herein, we proposed a sensitive strategy to characterize TCM metabolites in vivo at an orally clinical dose using ultra-high performance liquid chromatography-triple quadrupole-linear ion trap mass spectrometry (UHPLC-QTRAP-MS). Firstly, the metabolism of individual compounds in rat liver microsomes was studied to obtain the metabolic pathways and fragmentation patterns. The untargeted metabolites in vitro were detected by multiple ion monitoring-enhanced product ion (EPI) and neutral loss-EPI scans. Subsequently, a sensitive multiple reaction monitoring-EPI method was developed according to the in vitro results and predicted metabolites to profile the in vivo metabolites. Licorice as a model herb was used to evaluate and validate our strategy. A clinical dose of licorice water extract was orally administered to rats, then a total of 45 metabolites in urine, 21 metabolites in feces and 35 metabolites in plasma were detected. Among them, 18 minor metabolites have not been reported previously and 6 minor metabolites were first detected in vivo. Several isomeric metabolites were well separated and differentiated in our strategy. These results suggested that this new strategy could be widely used for the detection and characterization of in vivo metabolites of TCMs. Copyright © 2018. Published by Elsevier B.V.

The Correlation Between PARP1 and BRCA1 in AR Positive Triple-negative Breast Cancer.

PubMed

Luo, Jiayan; Jin, Juan; Yang, Fang; Sun, Zijia; Zhang, Wenwen; Shi, Yaqin; Xu, Jing; Guan, Xiaoxiang

2016-01-01

Triple-negative breast cancer (TNBC) lacks estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER-2) expression and thus cannot benefit from conventional hormonal or anti-HER2 targeted therapies. Anti-androgen therapy has shown a certain effect on androgen receptor (AR) positive TNBC. The emerging researches have proved that poly (ADP-ribose) polymerase (PARP) inhibitor is effective in BRCA1-deficient breast cancers. We demonstrated that combination of AR antagonist (bicalutamide) and PARP inhibitor (ABT-888) could inhibit cell viability and induce cell apoptosis significantly whatever in vitro or in vivo setting in AR-positive TNBC. Previous studies have proved that both BRCA1 and PARP1 have close connections with AR in prostate cancer. We explored the correlation among AR, PARP1 and BRCA1 in TNBC for the first time. After BRCA1 overexpression, the expression of AR and PARP1 were decreased in mRNA and protein levels. Additionally, AR positively regulated PARP1 while PARP1 also up-regulated AR expression in vitro. We also confirmed BRCA1 expression was negatively correlated with AR and PARP1 in TNBC patients using a tissue microarray with TNBC patient samples. These results suggest that the combination of bicalutamide and PARP inhibitor may be a potential strategy for TNBC patients and merits further evaluation.

Development and validation of a highly sensitive liquid chromatography/mass spectrometry method for simultaneous quantification of lenalidomide and flavopiridol in human plasma.

PubMed

Liu, Qing; Farley, Katherine L; Johnson, Amy J; Muthusamy, Natarajan; Hofmeister, Craig C; Blum, Kristie A; Schaaf, Larry J; Grever, Michael R; Byrd, John C; Dalton, James T; Phelps, Mitch A

2008-10-01

Lenalidomide, an immunomodulatory agent, and flavopiridol, a broad cyclin-dependent kinase inhibitor, are active therapies for clinical use in genomic high-risk chronic lymphocytic leukemia. A high-performance liquid chromatographic assay with tandem mass spectrometric detection has been developed to simultaneously quantify lenalidomide and flavopiridol in human and mouse plasma to facilitate their combined clinical development. Samples were prepared by liquid-liquid extraction with acetonitrile (ACN)-containing internal standard, genistein, followed by evaporation of solvent and reconstitution in 95/5 H2O/ACN. Lenalidomide and internal standard were separated by reversed-phase liquid chromatography on a C-18 column using a gradient of H2O and ACN, each with 0.1% formic acid. Atmospheric pressure chemical ionization in positive ion mode with single reaction monitoring on a triple quadrupole mass spectrometer was applied to detect transitions of lenalidomide (260.06 > 149.10) and flavopiridol (402.09 > 341.02). Lower limits of quantification of lenalidomide and flavopiridol were 1 and 0.3 nM, respectively. Recoveries of lenalidomide and flavopiridol from human plasma ranged from 99% to 116% throughout their linear ranges. Within- and between-run precision and accuracy of replicate samples were all less than 15%. This is the most sensitive analytical method reported to date for both lenalidomide and flavopiridol. This sensitivity will enable late terminal phase concentration measurements and accurate pharmacokinetic parameter estimation in a planned clinical trial with lenalidomide and flavopiridol in patients with chronic lymphocytic leukemia.

High-throughput autofluorescence flow cytometry of breast cancer metabolism (Conference Presentation)

NASA Astrophysics Data System (ADS)

Shah, Amy T.; Cannon, Taylor M.; Higginbotham, Jim N.; Skala, Melissa C.

2016-02-01

Tumor heterogeneity poses challenges for devising optimal treatment regimens for cancer patients. In particular, subpopulations of cells can escape treatment and cause relapse. There is a need for methods to characterize tumor heterogeneity of treatment response. Cell metabolism is altered in cancer (Warburg effect), and cells use the autofluorescent cofactor NADH in numerous metabolic reactions. Previous studies have shown that microscopy measurements of NADH autofluorescence are sensitive to treatment response in breast cancer, and these techniques typically assess hundreds of cells per group. An alternative approach is flow cytometry, which measures fluorescence on a single-cell level and is attractive for characterizing tumor heterogeneity because it achieves high-throughput analysis and cell sorting in millions of cells per group. Current applications for flow cytometry rely on staining with fluorophores. This study characterizes flow cytometry measurements of NADH autofluorescence in breast cancer cells. Preliminary results indicate flow cytometry of NADH is sensitive to cyanide perturbation, which inhibits oxidative phosphorylation, in nonmalignant MCF10A cells. Additionally, flow cytometry is sensitive to higher NADH intensity for HER2-positive SKBr3 cells compared with triple-negative MDA-MB-231 cells. These results agree with previous microscopy studies. Finally, a mixture of SKBr3 and MDA-MB-231 cells were sorted into each cell type using NADH intensity. Sorted cells were cultured, and microscopy validation showed the expected morphology for each cell type. Ultimately, flow cytometry could be applied to characterize tumor heterogeneity based on treatment response and sort cell subpopulations based on metabolic profile. These achievements could enable individualized treatment strategies and improved patient outcomes.

Family intervention in Indigenous communities: emergent issues in conducting outcome research.

PubMed

Turner, Karen; Sanders, Matthew

2007-01-01

Indigenous children and youth are at greater risk of emotional and behavioural problems than non-Indigenous youth, with family life stresses and parenting style identified as common risk factors. There is substantial evidence that parenting programs can improve family relationships and improve child outcomes, however little research has focused on Indigenous communities. Our team is conducting research to evaluate a culturally sensitive adaptation of a mainstream intervention, the Group Triple P---Positive Parenting Program, for Indigenous families. This paper shares some of the insights into research and clinical issues gained as non-Indigenous researchers working with urban, rural and remote Indigenous communities. The experience of the research team and feedback from practitioners and parents have been drawn on for this discussion. Parenting programs need to be sensitive to the political and cultural context in which parenting takes place, flexibly incorporate cultural practices and expectations, and develop an evidence base of outcomes for families in diverse communities. As research is needed to evaluate the acceptability and effectiveness of these programs, culturally sensitive research practices are also necessary and the value of program evaluation and its benefit to the community must be clear. Community acceptance of the research process and the intervention itself is vital and may be influenced by community perceptions, current priorities, and local issues. If our overall aim is to increase the skilled health and mental health workforce in Indigenous communities and their use of evidence-based interventions, ongoing collaborative relationships between research institutions and service providers will serve to further this aim.

Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy.

PubMed

Darb-Esfahani, Silvia; Denkert, Carsten; Stenzinger, Albrecht; Salat, Christoph; Sinn, Bruno; Schem, Christian; Endris, Volker; Klare, Peter; Schmitt, Wolfgang; Blohmer, Jens-Uwe; Weichert, Wilko; Möbs, Markus; Tesch, Hans; Kümmel, Sherko; Sinn, Peter; Jackisch, Christian; Dietel, Manfred; Reimer, Toralf; Loi, Sherene; Untch, Michael; von Minckwitz, Gunter; Nekljudova, Valentina; Loibl, Sibylle

2016-10-18

TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup. Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019). Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes.

Antimicrobial resistance of H. pylori to the outcome of 10-days vs. 7-days Moxifloxacin based therapy for the eradication: a randomized controlled trial

PubMed Central

2010-01-01

Introduction Antibiotic resistance decreases success of Helicobacter pylori (Hp) eradication. Recently published results show low rate of resistance and better compliance with moxifloxacin based regiments. Aims&methods Whether 7 days moxifloxacin with lansoprasole and amoxycillin can be compared with 10 days moxifloxacin with lansoprasole and amoxycillin according to moxifloxacin resistance. Patients with non-ulcer dyspepsia who had culture and histology positive Hp infection (n = 150) were randomly assigned into two groups. The first group (n = 75) received moxifloxacin 400 mg/d during 7 days and the other (n = 75) received moxifloxacin 400 mg/d during 10 days. All patients received amoxycillin 1 g twice daily, lansoprasole 30 mg twice daily. All Hp cultures were tested for sensitivity to moxifloxacin. Results 138 patients (92%) completed the study, 68 in the first group and 70 in the second. Eradication rates were 84% (57/68) and 76% (57/75) in the 7 days moxifloxacin group and 90% and 84% in the second group (63/70, 63/75) according to the PP and ITT analysis; p = n.s. Among 129 patients (86% of study group), 6% of strains were primary resistant to moxifloxacin. Eradication of moxifloxacin sensitive/resistant strains was 98%/66%, p < 0.05 Conclusion According to our results we recommend 7 days moxiflixacin based triple therapy. PMID:20398300

Determination of xylazine and 2,6-xylidine in animal tissues by liquid chromatography-tandem mass spectrometry.

PubMed

Zheng, Xiaochun; Mi, Xiaoxia; Li, Sicong; Chen, Gang

2013-06-01

Xylazine is a potent α2-adrenergic agonist used in veterinary medicine for sedation, analgesia, muscle relaxation, and so on. Its residue in animal-derived food may cause the food safety problem. Moreover, the metabolite 2,6-xylidine was reported to be a genotoxic and carcinogenic compound. Therefore, it is necessary to develop a high sensitive method for analyzing xylazine and metabolite residue in animal products. Here, we described a LC-MS/MS method for simultaneous determination of xylazine and 2,6-xylidine in 4 animal tissues: liver, meat, kidney, and fat. The samples were extracted by acetonitrile, and further clean up by hexane. The analysis was performed on a C18 reversed-phase column and API 5000 Triple Quadrupole mass spectrometry with positive electrospray ionization interface operating in the multiple-reaction monitoring mode. For all of the investigated sample matrix, the limit of detection (limit of quantitation) for xylazine and 2,6-xylidine were 0.06 (0.2) and 1.5 (5) μg/kg, respectively, the recoveries were between 63.5% and 90.8%. The precision was within the range of required criteria for method development. The presented method is sensitive and reproducible, and thus suitable for accurate quantification of xylazine and metabolite residue in animal-derived food products. © 2013 Institute of Food Technologists®

Efficacy of PPI, levofloxacin and amoxicillin in the eradication of Helicobacter pylori compared to conventional triple therapy at a Venezuelan hospital.

PubMed

Dib, Jacobo; Alvarez, Bethseidy; Mendez, Liskie; Cruz, Maria E

2013-09-01

Helicobacter pylori is the main cause of gastritis, gastroduodenal ulcers and gastric cancer. In the past two decades, the recommended treatment for its eradication as a first-line regimen is the standard triple therapy consisting of a proton pump inhibitor (PPI), amoxicillin and clarithromycin or metronidazole. However, the effectiveness of this traditional regime, which initially was 90%, progressively declined in many parts of the world and is currently 57-73%. The aim of this study was to evaluate whether the eradication rate with triple therapy with levofloxacin is superior as first-line therapy to that with treatment using clarithromycin in the population that attended as outpatients at the Hospital of Lídice. We designed a prospective study, with two groups of patients presenting dyspeptic symptoms, from October 2010 to October 2011, who underwent upper gastrointestinal endoscopy and whose biopsies were positive for infection with H. pylori. At the end, 81 patients were included in the order of biopsy result arrival to fill the quota of each group. The first group with 42 patients underwent triple therapy with clarithromycin and the second group with 39 patients underwent therapy with levofloxacin, amoxicillin and a PPI. The patients' age ranged between 23 and 76years, the average being 49.5. The predominant sex was female, at 72.84%. Both treatments lasted for 10days and the patients were clinically re-evaluated 15days after their conclusion and programmed for a second endoscopy to verify H. pylori eradication. Among the 42 patients in the control group, there were 14 eradication failures with 33.33% resistance to clarithromycin. Among the 39 patients in the experimental group, two eradication failures with 5.13% resistance to levofloxacin were observed. The χ(2) value was 6.96. Treatment with levofloxacin was more effective than conventional triple therapy. Triple therapy with levofloxacin can be implemented in populations where resistance to clarithromycin has been observed. Copyright © 2013 Arab Journal of Gastroenterology. Published by Elsevier Ltd. All rights reserved.

Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

ClinicalTrials.gov

2016-02-18

Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

Regulation of DM-20 mRNA expression and intracellular translocation of glutathione-S-transferase pi isoform during oligodendrocyte differentiation in the adult rat spinal cord.

PubMed

Kitada, Masaaki; Takeda, Kazuya; Dezawa, Mari

2016-07-01

We previously demonstrated that NG2-positive oligodendrocyte precursor cells (OPCs) do not express DM-20 mRNA and identified a distinct DM-20 mRNA-positive cell population expressing glutathione-S-transferase pi isoform (GST-pi) in the nucleus (GST-pi(Nuc)) of the adult rat spinal cord. As GST-pi intranuclear localization correlates with progenitor cell properties, we examined the differentiation status of this cell population under the intensive 5-bromo-2'-deoxyuridine (BrdU) administration method, consisting of intraperitoneal BrdU injections every 2 h for 48 h. We observed that a certain population of proliferating/proliferated cells expressed DM-20 mRNA, and sometimes two proliferating/proliferated cells were observed still attached to each other. We performed triple staining for BrdU, DM-20 mRNA, and NG2 and found pairs of neighboring BrdU-positive cells, which were considered to originate from the same progenitor cells and where both cells expressed DM-20 mRNA. Triple staining for BrdU, DM-20 mRNA, and GST-pi detected proliferating/proliferated cells exhibiting the GST-pi(Nuc)/DM-20 mRNA-positive expression pattern. These findings suggested the presence of a GST-pi(Nuc)/DM-20 mRNA-positive oligodendrocyte-lineage progenitor cell population in the adult rat spinal cord. However, we did not find any pair of neighboring BrdU-positive cells with this expression pattern. These observations collectively support the idea that GST-pi(Nuc)/DM-20 mRNA-expressing cells are the progeny of NG2-positive OPCs rather than a novel type of oligodendrocyte-lineage progenitor cells and that DM-20 mRNA expression is dynamically regulated during differentiation of OPCs into oligodendrocytes.

Breast cancer subtypes can be determinant in the decision making process to avoid surgical axillary staging: A retrospective cohort study.

PubMed

Marrazzo, Antonio; Boscaino, Giovanni; Marrazzo, Emilia; Taormina, Pietra; Toesca, Antonio

2015-09-01

The need for performing axillary lymph-node dissection in early breast cancer when the sentinel lymph node (SLN) is positive has been questioned in recent years. The purpose of this study was to identify a low-risk subgroup of early breast cancer patients in whom surgical axillary staging could be avoided, and to assess the probability of having a positive lymph-node (LN). We evaluated the cohort of 612 consecutive women affected by early breast cancer. We considered age, tumor size, histological grade, vascular invasion, lymphatic invasion and cancer subtype (Luminal A, Luminal B HER-2+, Luminal B HER-2-, HER-2+, and Triple Negative) as variables for univariate and multivariate analyses to assess probability of there being a positive SLN o nonsentinel lymph node (NSLN). Chi-square, Fisher's Exact test and Student's t tests were used to investigate the relationship between variables; whereas logit models were used to estimate and quantify the strength of the relationship among some covariates and SLN or the number of metastases. A significant positive effect of vascular invasion and lymphatic invasion (odds ratios are 4 and 6), and a negative effect of TN (odds ratios is 10) were noted. With respect to positive NSLN, size alone has a significant (positive) effect on tumor presence, but focusing on the number of metastases, also age has a (negative) significant effect. This work shows correlation between subtypes and the probability of having positive SLN. Patients not expressing vascular invasion, lymphatic invasion and, moreover, a triple-negative tumor subtype may be good candidates for breast conservative surgery without axillary surgical staging. Copyright © 2015 IJS Publishing Group Limited. Published by Elsevier Ltd. All rights reserved.

Liquid chromatography-tandem mass spectrometric assay for the simultaneous determination of the irreversible BTK inhibitor ibrutinib and its dihydrodiol-metabolite in plasma and its application in mouse pharmacokinetic studies.

PubMed

Rood, Johannes J M; van Hoppe, Stephanie; Schinkel, Alfred H; Schellens, Jan H M; Beijnen, Jos H; Sparidans, Rolf W

2016-01-25

A validated simple, fast and sensitive bio-analytical assay for ibrutinib and its dihydrodiol metabolite in human and mouse plasma was set up. Sample preparation was performed by protein precipitation, and addition of the respective deuterated internal standards, followed by LC-MS/MS analysis. Separation was performed on a 3.5 μm particle-size, bridged ethylene hybrid column with gradient elution by 0.1% v/v formic acid and acetonitrile. The full eluate was transferred to an electrospray interface in positive ionization mode, and subsequently analyzed by a triple quadrupole mass spectrometer by selected reaction monitoring. The assay was validated in a 5-5000 ng/ml calibration range. Both ibrutinib and dihydrodiol-ibrutinib were deemed stable under refrigerated or frozen storage conditions. At room temperature, ibrutinib showed a not earlier described instability, and revealed rapid degradation at 37 °C. Finally, the assay was used for a pharmacokinetic study of plasma levels in treated FVB mice. Copyright © 2015 Elsevier B.V. All rights reserved.

Prognostic value of androgen receptor in triple negative breast cancer: A meta-analysis.

PubMed

Wang, Changjun; Pan, Bo; Zhu, Hanjiang; Zhou, Yidong; Mao, Feng; Lin, Yan; Xu, Qianqian; Sun, Qiang

2016-07-19

Androgen receptor (AR) is a promising therapeutic target for breast cancer. However, its prognostic value remains controversial in triple negative breast cancer (TNBC). Here we present a meta-analysis to investigate the correlation between AR expression and TNBC prognosis. Thirteen relevant studies with 2826 TNBC patients were included. AR positive rate was 24.4%. AR+ patients tended to have lower tumor grade (p< 0.001), but more lymph node metastases (p < 0.01). AR positivity was associated with prolonged disease free survival (HR 0.809, 95% CI = 0.659-0.995, p < 0.05), but had no significant impact on overall survival (HR 1.270, 95% CI=0.904-1.782, p = 0.168). No difference in survival existed between subgroups using different AR or estrogen receptor cutoff values. Literature search was performed in Pubmed, Embase and Cochrane Central Register of Controlled Trials databases to identify relevant articles on AR and TNBC prognosis. Fixed- and random-effect meta-analyses were conducted based on the heterogeneity of included studies. Heterogeneity and impacts of covariates were further evaluated by subgroup analyses and meta-regression. AR positivity is associated with lower risk of disease recurrence in TNBC. Further clinical studies are warranted to clarify its prognostic role on TNBC recurrence and survival.

Advances in chemical pharmacotherapy to manage advanced breast cancer.

PubMed

Gombos, Andrea; Awada, Ahmad

2017-01-01

Advanced breast cancer is still incurable. However, patients diagnosed with this fatal disease live longer. The selection of systemic therapy is mainly based on molecular subtype. The aim of management in these patients is to not only improve outcome, but also to maintain quality of life. Areas covered: In this paper we focus on available treatments and drugs under late development in the three main subtypes of breast cancer: luminal (hormone receptor positive), HER2 positive and triple negative disease. Main advances during the last years have been made in the treatment of HER2 positive breast cancer with the approval of several new targeted agents. Luminal breast cancer is also a field of active clinical research. So far triple negative breast cancer remains the subtype with the worse prognosis, even though new discoveries have been made to better understand the huge heterogeneity of this type of breast cancer. Expert opinion: Several new treatment options have recently been established in metastatic breast cancer. Side effects are sometimes cumbersome for the patient and are difficult to manage easily. Thus, identification of patients who derive the most benefit is needed. In addition, collaborative efforts should integrate the genotypic fragmentation in the management and future clinical research strategies of metastatic breast cancer patients.

A triple quantum dot based nano-electromechanical memory device

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pozner, R.; Lifshitz, E.; Solid State Institute, Technion-Israel Institute of Technology, Haifa 32000

Colloidal quantum dots (CQDs) are free-standing nano-structures with chemically tunable electronic properties. This tunability offers intriguing possibilities for nano-electromechanical devices. In this work, we consider a nano-electromechanical nonvolatile memory (NVM) device incorporating a triple quantum dot (TQD) cluster. The device operation is based on a bias induced motion of a floating quantum dot (FQD) located between two bound quantum dots (BQDs). The mechanical motion is used for switching between two stable states, “ON” and “OFF” states, where ligand-mediated effective interdot forces between the BQDs and the FQD serve to hold the FQD in each stable position under zero bias. Consideringmore » realistic microscopic parameters, our quantum-classical theoretical treatment of the TQD reveals the characteristics of the NVM.« less

DOE Office of Scientific and Technical Information (OSTI.GOV)

Letsoalo, A.; Blignaut, J.; de Wet, T.

The South African government is exploring ways to address water scarcity problems by introducing a water resource management charge on the quantity of water used in sectors such as irrigated agriculture, mining, and forestry. It is expected that a more efficient water allocation, lower use, and a positive impact on poverty can be achieved. This paper reports on the validity of these claims by applying a computable general equilibrium model to analyze the triple dividend of water consumption charges in South Africa: reduced water use, more rapid economic growth, and a more equal income distribution. It is shown that anmore » appropriate budget-neutral combination of water charges, particularly on irrigated agriculture and coal mining, and reduced indirect taxes, particularly on food, would yield triple dividends, that is, less water use, more growth, and less poverty.« less

Unexpected variations in the triple oxygen isotope composition of stratospheric carbon dioxide

NASA Astrophysics Data System (ADS)

Wiegel, Aaron A.; Cole, Amanda S.; Hoag, Katherine J.; Atlas, Elliot L.; Schauffler, Sue M.; Boering, Kristie A.

2013-10-01

We report observations of stratospheric CO2 that reveal surprisingly large anomalous enrichments in 17O that vary systematically with latitude, altitude, and season. The triple isotope slopes reached 1.95 ± 0.05(1σ) in the middle stratosphere and 2.22 ± 0.07 in the Arctic vortex versus 1.71 ± 0.03 from previous observations and a remarkable factor of 4 larger than the mass-dependent value of 0.52. Kinetics modeling of laboratory measurements of photochemical ozone-CO2 isotope exchange demonstrates that non-mass-dependent isotope effects in ozone formation alone quantitatively account for the 17O anomaly in CO2 in the laboratory, resolving long-standing discrepancies between models and laboratory measurements. Model sensitivities to hypothetical mass-dependent isotope effects in reactions involving O3, O(1D), or CO2 and to an empirically derived temperature dependence of the anomalous kinetic isotope effects in ozone formation then provide a conceptual framework for understanding the differences in the isotopic composition and the triple isotope slopes between the laboratory and the stratosphere and between different regions of the stratosphere. This understanding in turn provides a firmer foundation for the diverse biogeochemical and paleoclimate applications of 17O anomalies in tropospheric CO2, O2, mineral sulfates, and fossil bones and teeth, which all derive from stratospheric CO2.

Lifeguard inhibition of Fas-mediated apoptosis: A possible mechanism for explaining the cisplatin resistance of triple-negative breast cancer cells.

PubMed

Radin, Daniel; Lippa, Arnold; Patel, Parth; Leonardi, Donna

2016-02-01

Triple-negative breast cancer does not express estrogen receptor-α, progesterone or the HER2 receptor making hormone or antibody therapy ineffective. Cisplatin may initiate p73-dependent apoptosis in p53 mutant cell lines through Fas trimerization and Caspase-8 activation and Bax up regulation and subsequent Caspase-9 activation. The triple-negative breast cancer, MDA-MB-231, overexpresses the protein Lifeguard, which inhibits Fas-mediated apoptosis by inhibiting Caspase-8 activation after Fas trimerization. The relationship between Fas, Lifeguard and cisplatin is investigated by down regulating Lifeguard via shRNA. Results demonstrate that cisplatin's efficacy increases when Lifeguard is down regulated. Lifeguard Knockdown MDA-MB-231 continue to decrease in cell viability from 24 to 48h after cisplatin treatment while no additional decrease in viability is observed in the Wild-Type MDA over the same period. Higher Caspase-8 activity in the Lifeguard knockdown MDA after cisplatin administration could explain the significant decrease in cell viability from 24 to 48h. This cell type is also more sensitive to Fas ligand-mediated reductions in cell viability, confirming Lifeguard's anti-apoptotic function through the Fas receptor. This research suggests that the efficacy of chemotherapy acting through the Fas pathway would increase if Lifeguard were not overexpressed to inhibit Fas-mediated apoptosis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Prognostic Value of Tumor-Infiltrating Lymphocyte Density Assessed Using a Standardized Method Based on Molecular Subtypes and Adjuvant Chemotherapy in Invasive Breast Cancer.

PubMed

Jang, Nuri; Kwon, Hee Jung; Park, Min Hui; Kang, Su Hwan; Bae, Young Kyung

2018-04-01

This study investigated the prognostic value of tumor-infiltrating lymphocyte (TIL) density as determined by molecular subtype and receipt of adjuvant chemotherapy in invasive breast cancer (IBC). Stromal TIL densities were evaluated in 1489 IBC samples using recommendations proposed by the International TILs Working Group. Cases were allocated to high- and low-TIL density groups using a cutoff of 10%. Of the 1489 IBC patients, 427 (28.7%) were assigned to the high-TIL group and 1062 (71.3%) to the low-TIL group. High TIL density was found to be significantly associated with large tumor size (p = 0.001), high histologic grade (p < 0.001), and high Ki-67 labeling index (p < 0.001). Triple-negative and human epidermal growth factor receptor 2 (HER2)-positive subtypes had significantly higher TIL densities than luminal A or B (HER2-negative) subtypes (p < 0.001). High TIL density was significantly associated with prolonged disease-free survival (DFS) by univariate (p < 0.001) and multivariate (p < 0.001) analyses. In the low-TIL-density group, the patients who did not receive adjuvant chemotherapy showed better DFS (p < 0.001), but no such survival difference was observed in the high-TIL group (p = 0.222). For the patients who received adjuvant anthracycline, high-TIL density was found to be an independent prognostic factor of favorable DFS in the luminal B (HER2-negative; p = 0.003), HER2-positive (p = 0.019), and triple-negative (p = 0.017) subtypes. Measurements of TIL density in routine clinical practice could give useful prognostic information for the triple-negative, HER2-positive, and luminal B (HER2-negative) IBC subtypes, especially for patients administered adjuvant anthracycline.

Astrometric Measurements of Triple Star System 15379+3006 STF 1963AB, STF 1963AC

NASA Astrophysics Data System (ADS)

Russell, Harker; Miller, Lindsey; Beltzer-Sweeney, Alexander; Shilts, Trey; Stojimirovic, Irena

2018-04-01

Research team PRSM reports astrometric measurements of the double star system WDS 15379+3006 (STF 1963AB, STF 1963AC) obtained using the iTelescope Network. By performing CCD astrometry, the team determined a position angle of 298.4° ± 0.1° with an angular separation of 05. 28" ± 0.1" for STF 1963AB, and a position angle of 116.1° ± 0.1° with an angular separation of 32.35" ± 0.1" for STF 1963AC. The angular separation and position angle have changed from previous measurements.

A Study of Neoadjuvant Paclitaxel in Combination With Bavituximab in Early- Stage Triple- Negative Breast Cancer

ClinicalTrials.gov

2017-03-08

Breast Cancer; Triple Negative Breast Neoplasms; Triple-Negative Breast Neoplasm; Triple-Negative Breast Cancer; Triple Negative Breast Cancer; ER-Negative PR-Negative HER2-Negative Breast Neoplasms; ER-Negative PR-Negative HER2-Negative Breast Cancer

Binding affinity and adhesion force of organophosphate hydrolase enzyme with soil particles related to the isoelectric point of the enzyme.

PubMed

Islam, Shah Md Asraful; Yeasmin, Shabina; Islam, Md Saiful; Islam, Md Shariful

2017-07-01

The binding affinity of organophosphate hydrolase enzyme (OphB) with soil particles in relation to the isoelectric point (pI) was studied. Immobilization of OphB with soil particles was observed by confocal microscopy, Fourier transform infrared spectroscopy (FT-IR), and Atomic force microscopy (AFM). The calculated pI of OphB enzyme was increased from 8.69 to 8.89, 9.04 and 9.16 by the single, double and triple mutant of OphB enzyme, respectively through the replacement of negatively charged aspartate with positively charged histidine. Practically, the binding affinity was increased to 5.30%, 11.50%, and 16.80% for single, double and triple mutants, respectively. In contrast, enzyme activity of OphB did not change by the mutation of the enzyme. On the other hand, adhesion forces were gradually increased for wild type OphB enzyme (90 pN) to 96, 100 and 104 pN for single, double and triple mutants of OphB enzyme, respectively. There was an increasing trend of binding affinity and adhesion force by the increase of isoelectric point (pI) of OphB enzyme. Copyright © 2017 Elsevier Inc. All rights reserved.

Predicting Sensitivity of Breast Tumors to Src-targeted Therapies Through Assessment of Cas/Src/BCAR3 Activity

DTIC Science & Technology

2017-10-01

expression is elevated in DCIS samples compared to normal mammary tissue, invasive ductal carcinoma (IDC) compared to normal mammary tissue, and DCIS... compared to IDC. (2) BCAR3 is significantly upregulated in triple negative breast cancer and normal tissue; (3) BCAR3 expression shows a modest...expression was seen to be elevated in DCIS samples compared to normal mammary tissue, invasive ductal carcinoma (IDC) compared to normal mammary tissue, and

The selective effect of glycyrrhizin and glycyrrhetinic acid on topoisomerase IIα and apoptosis in combination with etoposide on triple negative breast cancer MDA-MB-231 cells.

PubMed

Cai, Yun; Zhao, Boxin; Liang, Qianying; Zhang, Yunqi; Cai, Jieying; Li, Guofeng

2017-08-15

Triple negative breast cancer(TNBC) has generated growing interests due to its aggressive biologic behavior and absence of targeted therapy approach. Glycyrrhizin(GL) from licorice root and its metabolite, glycyrrhetinic acid(GA) have shown extensive bioactivities in clinic. Here, we demonstrate that GL and GA have contrary anti-cancer effect on TNBC MDA-MB-231 cells. Beside its inhibition of cell proliferation, GA at non-cytotoxic concentration showed synergistic effect in combination with anti-cancer drug, etoposide(VP-16). Specifically, GA enhanced cytotoxicity through regulating topoisomerase IIα(TOPO 2A) targeted by etoposide. GA sensitized the cells to etoposide through elevating TOPO 2A with a 2.4 fold rate at 12h. From 12 to 48h, GA halved the expression of TOPO 2A and stimulated apoptosis, which exhibited its antineoplastic effect. Our experiments showed that GSH depletion, modulation of MAPK and AKT pathways accounted for the regulation of topoisomerase IIα and apoptosis. However, GL showed protection and detoxication by decreasing reactive oxygen species generation, maintaining GSH and differentially modulating apoptosis, AKT pathway, ERK and JNK of MAPK pathway. Collectively, our results demonstrate that GA, instead of GL, is a better candidate for TNBC treatment because of its anti-cancer effect and sensitization of topoisomerase IIα inhibitor. Copyright © 2017 Elsevier B.V. All rights reserved.

Cost-effectiveness of chronic hepatitis C treatment with thymosin alpha-1.

PubMed

García-Contreras, Fernando; Nevárez-Sida, Armando; Constantino-Casas, Patricia; Abud-Bastida, Fernando; Garduño-Espinosa, Juan

2006-07-01

More than one million individuals in Mexico are infected with hepatitis C virus (HCV), and 80% are at risk for developing a chronic infection that could lead to hepatic cirrhosis and other complications that impact quality of life and institutional costs. The objective of the study was to determine the most cost-effective treatment against HCV among the following: peginterferon, peginterferon plus ribavirin, peginterferon plus ribavirin plus thymosin, and no treatment. We carried out cost-effectiveness analysis using the institutional perspective, including a 45-year time frame and a 3% discount rate for costs and effectiveness. We employed a Bayesian-focused decision tree and a Markov model. One- and two-way sensitivity analyses were performed, as well as threshold-oriented and probabilistic analyses, and we obtained acceptability curves and net health benefits. Triple therapy (peginterferon plus ribavirin plus thymosin alpha-1) was dominant with lower cost and higher utility in relationship with peginterferon + ribavirin option, peginterferon alone and no-treatment option. In triple therapy the cost per unit of success was of 1,908 [USD/quality-adjusted life years (QALY)] compared with peginterferon plus ribavirin 2,277/QALY, peginterferon alone 2,929/QALY, and no treatment 4,204/QALY. Sensitivity analyses confirmed the robustness of the base case. Peginterferon plus ribavirin plus thymosin alpha-1 option was dominant (lowest cost and highest effectiveness). Using no drug was the most expensive and least effective option.

Applying Triple-Matrix Masking for Privacy Preserving Data Collection and Sharing in HIV Studies.

PubMed

Pei, Qinglin; Chen, Shigang; Xiao, Yao; Wu, Samuel S

2016-01-01

Many HIV research projects are plagued by the high missing rate of selfreported information during data collection. Also, due to the sensitive nature of the HIV research data, privacy protection is always a concern for data sharing in HIV studies. This paper applies a data masking approach, called triple-matrix masking [1], to the context of HIV research for ensuring privacy protection during the process of data collection and data sharing. Using a set of generated HIV patient data, we show step by step how the data are randomly transformed (masked) before leaving the patients' individual data collection device (which ensures that nobody sees the actual data) and how the masked data are further transformed by a masking service provider and a data collector. We demonstrate that the masked data retain statistical utility of the original data, yielding the exactly same inference results in the planned logistic regression on the effect of age on the adherence to antiretroviral therapy and in the Cox proportional hazard model for the age effect on time to viral load suppression. Privacy-preserving data collection method may help resolve the privacy protection issue in HIV research. The individual sensitive data can be completely hidden while the same inference results can still be obtained from the masked data, with the use of common statistical analysis methods.

Efficient amplitude-modulated pulses for triple- to single-quantum coherence conversion in MQMAS NMR.

PubMed

Colaux, Henri; Dawson, Daniel M; Ashbrook, Sharon E

2014-08-07

The conversion between multiple- and single-quantum coherences is integral to many nuclear magnetic resonance (NMR) experiments of quadrupolar nuclei. This conversion is relatively inefficient when effected by a single pulse, and many composite pulse schemes have been developed to improve this efficiency. To provide the maximum improvement, such schemes typically require time-consuming experimental optimization. Here, we demonstrate an approach for generating amplitude-modulated pulses to enhance the efficiency of the triple- to single-quantum conversion. The optimization is performed using the SIMPSON and MATLAB packages and results in efficient pulses that can be used without experimental reoptimisation. Most significant signal enhancements are obtained when good estimates of the inherent radio-frequency nutation rate and the magnitude of the quadrupolar coupling are used as input to the optimization, but the pulses appear robust to reasonable variations in either parameter, producing significant enhancements compared to a single-pulse conversion, and also comparable or improved efficiency over other commonly used approaches. In all cases, the ease of implementation of our method is advantageous, particularly for cases with low sensitivity, where the improvement is most needed (e.g., low gyromagnetic ratio or high quadrupolar coupling). Our approach offers the potential to routinely improve the sensitivity of high-resolution NMR spectra of nuclei and systems that would, perhaps, otherwise be deemed "too challenging".

Efficient Amplitude-Modulated Pulses for Triple- to Single-Quantum Coherence Conversion in MQMAS NMR

PubMed Central

2014-01-01

The conversion between multiple- and single-quantum coherences is integral to many nuclear magnetic resonance (NMR) experiments of quadrupolar nuclei. This conversion is relatively inefficient when effected by a single pulse, and many composite pulse schemes have been developed to improve this efficiency. To provide the maximum improvement, such schemes typically require time-consuming experimental optimization. Here, we demonstrate an approach for generating amplitude-modulated pulses to enhance the efficiency of the triple- to single-quantum conversion. The optimization is performed using the SIMPSON and MATLAB packages and results in efficient pulses that can be used without experimental reoptimisation. Most significant signal enhancements are obtained when good estimates of the inherent radio-frequency nutation rate and the magnitude of the quadrupolar coupling are used as input to the optimization, but the pulses appear robust to reasonable variations in either parameter, producing significant enhancements compared to a single-pulse conversion, and also comparable or improved efficiency over other commonly used approaches. In all cases, the ease of implementation of our method is advantageous, particularly for cases with low sensitivity, where the improvement is most needed (e.g., low gyromagnetic ratio or high quadrupolar coupling). Our approach offers the potential to routinely improve the sensitivity of high-resolution NMR spectra of nuclei and systems that would, perhaps, otherwise be deemed “too challenging”. PMID:25047226

Pt NPs and DNAzyme functionalized polymer nanospheres as triple signal amplification strategy for highly sensitive electrochemical immunosensor of tumour marker.

PubMed

Chang, Honghong; Zhang, Haochun; Lv, Jia; Zhang, Bing; Wei, Wenlong; Guo, Jingang

2016-12-15

Highly sensitive determination of tumour markers is the key for early diagnosis of cancer. Herein, triple signal amplification strategy resulting from polymer nanospheres, Pt NPs, and DNAzyme was proposed in the developed electrochemical immunosensor. First, electroactive polymer nanospheres were synthesized by infinite coordination polymerization of ferrocenedicarboxylic acid, which could generate strong electrochemical signals due to plentiful ferrocene molecules. Further, the polymer nanospheres were functionalized by Pt NPs and DNAzyme (hemin/G-quadruplex) with the ability of catalyzing H2O2, which contributes to enhance the electrochemical signals. The prepared conjugations were characterized by transmission electron microscope (TEM) and energy dispersive X-ray spectroscopy (EDX). And the process of preparation was monitored by zeta potential. Based on the sandwich-type immunoassay, the electrochemical immunosensor was constructed employing the conjugations as signal tags. Under optimal conditions, the DPV peak increased with the increasing of alpha fetal protein (AFP) concentration, and the linear range was from 0.1pgmL(-1) to 100ngmL(-1) with low detection limit of 0.086pgmL(-1). Meanwhile, the designed immunosensor exhibited excellent selectivity and anti-interference property, good reproducibility and stability. More importantly, there were no significant differences in analyzing real clinical samples between designed immunosensor and commercial ELISA. Copyright © 2016 Elsevier B.V. All rights reserved.

Histone deacetylase inhibitor treatment induces ‘BRCAness’ and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells

PubMed Central

Ha, Kyungsoo; Bhaskara, Srividya; Cerchietti, Leandro; Devaraj, Santhana G. T.; Shah, Bhavin; Sharma, Sunil; Chang, Jenny C.; Melnick, Ari M.; Hiebert, Scott; Bhalla, Kapil N.

2014-01-01

There is an unmet need to develop new, more effective and safe therapies for the aggressive forms of triple negative breast cancers (TNBCs). While up to 20% of women under 50 years of age with TNBC harbor germline mutations in BRCA1, and these tumors are sensitive to treatment with poly(ADP) ribose polymerase inhibitors, a majority of TNBCs lack BRCA1 mutations or loss of expression. Findings presented here demonstrate that by attenuating the levels of DNA damage response and homologous recombination proteins, pan-histone deacetylase inhibitor (HDI) treatment induces ‘BRCAness’ and sensitizes TNBC cells lacking BRCA1 to lethal effects of PARP inhibitor or cisplatin. Treatment with HDI also induced hyperacetylation of nuclear hsp90. Similar effects were observed following shRNA-mediated depletion of HDAC3, confirming its role as the deacetylase for nuclear HSP90. Furthermore, cotreatment with HDI and ABT-888 induced significantly more DNA strand breaks than either agent alone, and synergistically induced apoptosis of TNBC cells. Notably, co-treatment with HDI and ABT-888 significantly reduced in vivo tumor growth and markedly improved the survival of mice bearing TNBC cell xenografts. These findings support the rationale to interrogate the clinical activity of this novel combination against human TNBC, irrespective of its expression of mutant BRCA1. PMID:25026298

First report on molecular breast cancer subtypes and their clinico-pathological characteristics in Eastern Morocco: series of 2260 cases.

PubMed

Elidrissi Errahhali, Manal; Elidrissi Errahhali, Mounia; Ouarzane, Meryem; El Harroudi, Tijani; Afqir, Said; Bellaoui, Mohammed

2017-01-09

Breast cancer is the most frequent malignancy among women in Eastern Morocco. In this paper, we provide the first report on molecular breast cancer subtypes in this region. This is the largest population-based study on breast cancer among Moroccan women. We analyzed 2260 breast cancer cases diagnosed at the Hassan II Regional Oncology Center between October 2005 and December 2012. Clinico-pathological and therapeutic features were studied. Molecular subtypes were determined and their associations with the clinico-pathological characteristics of the tumors were examined. The mean age at diagnosis was 48.7 years ±11.4. Invasive ductal carcinoma was the predominant histological type (77.1%), followed by lobular invasive carcinoma (15.3%). The mean size of breast tumors was 3.5 cm ± 1.96, and 84% of our patients are diagnosed with tumors of more than 2 cm. Histological grade II tumors were the most frequent (70.4%), followed by advanced histological grade (18%). Lymph node positive tumors were observed in 64.8% of cases and 29.3% of patients had distant metastasis. Most tumors were hormone receptor-positive (73%) and 28.6% were HER2 positive. 86.1% of patients with hormone receptor-positive breast cancer were given hormone therapy, while 68.9% of patients with HER2+ breast cancer received targeted therapy with Herceptin. Luminal A was the commonest molecular subtype, followed by Luminal B, Triple Negative and HER2. The highest prevalence of premenopausal patients was observed in Triple Negative subtype (72.2%), followed by HER2 (64.1%), Luminal B (62.2%), and Luminal A (55.1%). Luminal B subtype had a poorer prognosis than Luminal A. Compared with Triple Negative, HER2 subtype tend to spread more aggressively and is associated with poorer prognosis. Unlike Western countries, breast cancer occurs at an earlier age and is diagnosed at a more advanced stage in Eastern Morocco. In this region, hormone receptor-positive tumors are predominant and so the majority of breast cancer patients should benefit from hormone therapy. HER2 subtype presents an aggressive tendency, suggesting the importance of anti-HER2 therapy. This study will contribute in developing appropriate screening and cancer management strategies in Eastern Morocco.

Simultaneous determination of zearalenone and its derivatives in edible vegetable oil by gel permeation chromatography and gas chromatography-triple quadrupole mass spectrometry.

PubMed

Qian, Mingrong; Zhang, Hu; Wu, Liqin; Jin, Nuo; Wang, Jianmei; Jiang, Kezhi

2015-01-01

A sensitive gas chromatographic-triple quadrupole mass spectrometric (GC-QqQ MS) analytical method, for the determination of zearalenone and its five derivatives in edible vegetable oil, was developed. After the vegetable oil samples were prepared using gel permeation chromatography, the eluent was collected, evaporated and dried with nitrogen gas. The residue was silylated with N,O-bis-trimethylsilyltrifluoroacetamide, containing 1% trimethylchlorosilane. GC-QqQ MS was performed in the reaction-monitoring mode to confirm and quantify mycotoxins in vegetable oil. The limits of quantitation were 0.03-0.2 μg kg(-1) for the six mycotoxins. The average recoveries, measured at 2, 20 and 200 μg kg(-1), were in the range 80.3-96.5%. Zearalenone was detected in the range 5.2-184.6 μg kg(-1) in nine maize oils and at 40.7 μg kg(-1) in a rapeseed oil from the local market. Copyright © 2014 Elsevier Ltd. All rights reserved.

Triple-helix molecular switch-based aptasensors and DNA sensors.

PubMed

Bagheri, Elnaz; Abnous, Khalil; Alibolandi, Mona; Ramezani, Mohammad; Taghdisi, Seyed Mohammad

2018-07-15

Utilization of traditional analytical techniques is limited because they are generally time-consuming and require high consumption of reagents, complicated sample preparation and expensive equipment. Therefore, it is of great interest to achieve sensitive, rapid and simple detection methods. It is believed that nucleic acids assays, especially aptamers, are very important in modern life sciences for target detection and biological analysis. Aptamers and DNA-based sensors have been widely used for the design of various sensors owing to their unique features. In recent years, triple-helix molecular switch (THMS)-based aptasensors and DNA sensors have been broadly utilized for the detection and analysis of different targets. The THMS relies on the formation of DNA triplex via Watson-Crick and Hoogsteen base pairings under optimal conditions. This review focuses on recent progresses in the development and applications of electrochemical, colorimetric, fluorescence and SERS aptasensors and DNA sensors, which are based on THMS. Also, the advantages and drawbacks of these methods are discussed. Copyright © 2018 Elsevier B.V. All rights reserved.

Next-generation bidirectional Triple-play services using RSOA based WDM Radio on Free-Space Optics PON

NASA Astrophysics Data System (ADS)

Mandal, Gour Chandra; Mukherjee, Rahul; Das, Binoy; Patra, Ardhendu Sekhar

2018-03-01

An innovative low cost reflective semiconductor amplifier (RSOA) based bidirectional Triple-play services (TPS) using wavelength division multiplexed radio on free-space-optics passive optical network (WDM-RoFSO-PON) is proposed and experimentally demonstrated to transmit data, voice and video services simultaneously. In this paper, the TPS (10 Gb/s data/voice and 1.49 Gb/s HDTV signal) are successfully transmitted over a 500 m free-space link in downstream and RSOA is utilized at the receiving site to broadcast 1.25 Gb/s data/voice signal over same free-space link in upstream by reusing the carrier, that makes the system cost-effective. High receiver sensitivity and signal-to-noise ratio (SNR), low bit-error-rate (BER) and low error vector magnitude (EVM), and excellent eye-diagrams in our proposed network build the system more reliable and stable with acceptable performance. Therefore, proposed WDM-RoFSO-PON could be the viable solution for future ubiquitous multiservice wireless network in the scenario of TPS.

Ultrasensitive Sample Quantitation via Selected Reaction Monitoring Using CITP/CZE-ESI-Triple Quadrupole MS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Chenchen; Lee, Cheng S.; Smith, Richard D.

2012-11-10

We demonstrate the direct coupling of transient capillary isotachophoresis/ capillary zone electrophoresis (CITP/CZE) with a high sensitivity triple quadrupole mass spectrometer operating in selected reaction monitoring (SRM) mode for sample quantitation. The capability of CITP/CZE for in situ sample enrichment and separation has been shown to significantly improve the analytical figures of merit. A linear dynamic range spanning more than 4 orders of magnitude was observed. An average signal-to-noise ratio (S/N) of 49.6 was observed for 50 attomoles of targeted peptide in the presence of a complex and much more abundant bovine serum albumin (BSA) digest products. A correlation ofmore » variation (CV) less than 10 % for peak area was measured from triplicate sample analyses at 50 pM peptide concentration, showing good reproducibility of this online CITP/CZE-SRM mass spectrometry (MS) platform, and with limit of quantitation (LOQ) demonstrated to be well below 50 pM.« less

Symmetric operation of the resonant exchange qubit

NASA Astrophysics Data System (ADS)

Malinowski, Filip K.; Martins, Frederico; Nissen, Peter D.; Fallahi, Saeed; Gardner, Geoffrey C.; Manfra, Michael J.; Marcus, Charles M.; Kuemmeth, Ferdinand

2017-07-01

We operate a resonant exchange qubit in a highly symmetric triple-dot configuration using IQ-modulated rf pulses. We find that the qubit splitting is an order of magnitude less sensitive to all relevant control voltages, compared to the conventional operating point, but we observe no significant improvement in the quality of Rabi oscillations. For weak driving this is consistent with Overhauser field fluctuations modulating the qubit splitting. For strong driving we infer that effective voltage noise modulates the coupling strength between rf drive and the qubit, thereby quickening Rabi decay. Application of CPMG dynamical decoupling sequences consisting of up to 32 π pulses significantly prolongs qubit coherence, leading to marginally longer dephasing times in the symmetric configuration. This is consistent with dynamical decoupling from low frequency noise, but quantitatively cannot be explained by effective gate voltage noise and Overhauser field fluctuations alone. Our results inform recent strategies for the utilization of symmetric configurations in the operation of triple-dot qubits.

Rapid Quantification of Four Anthocyanins in Red Grape Wine by Hydrophilic Interaction Liquid Chromatography/Triple Quadrupole Linear Ion Trap Mass Spectrometry.

PubMed

Sun, Yongming; Xia, Biqi; Chen, Xiangzhun; Duanmu, Chuansong; Li, Denghao; Han, Chao

2015-01-01

The identification and quantification of four anthocyanins (cyanidin-3-O-glucoside, peonidin-3-O-glucoside, delphinidin-3-O-glucoside, and malvidin-3-O-glucoside) in red grape wine were carried out by hydrophilic interaction liquid chromatography/triple quadrupole linear ion trap MS (HILIC/QTrap-MS/MS). Samples were diluted directly and separated on a Merck ZIC HILIC column with 20 mM ammonium acetate solution-acetonitrile mobile phase. Quantitative data acquisition was carried out in the multiple reaction monitoring mode. Additional identification and confirmation of target compounds were performed using the enhanced product ion mode of the linear ion trap. The LOQs were in the range 0.05-1.0 ng/mL. The average recoveries were in the range 94.6 to 104.5%. The HILIC/QTrap-MS/MS platform offers the best sensitivity and specificity for characterization and quantitative determination of the four anthocyanins in red grape wines and fulfills the quality criteria for routine laboratory application.

Novel 2D Triple-Resonance NMR Experiments for Sequential Resonance Assignments of Proteins

NASA Astrophysics Data System (ADS)

Ding, Keyang; Gronenborn, Angela M.

2002-06-01

We present 2D versions of the popular triple resonance HN(CO) CACB, HN(COCA)CACB, HN(CO)CAHA, and HN(COCA) CAHA experiments, commonly used for sequential resonance assignments of proteins. These experiments provide information about correlations between amino proton and nitrogen chemical shifts and the α- and β-carbon and α-proton chemical shifts within and between amino acid residues. Using these 2D spectra, sequential resonance assignments of H N, N, C α, C β, and H α nuclei are easily achieved. The resolution of these spectra is identical to the well-resolved 2D 15N- 1H HSQC and H(NCO)CA spectra, with slightly reduced sensitivity compared to their 3D and 4D versions. These types of spectra are ideally suited for exploitation in automated assignment procedures and thereby constitute a fast and efficient means for NMR structural determination of small and medium-sized proteins in solution in structural genomics programs.

Examining Primary Healthcare Performance through a Triple Aim Lens.

PubMed

Ryan, Bridget L; Brown, Judith Belle; Glazier, Richard H; Hutchison, Brian

2016-02-01

This study sought to apply a Triple Aim framework to the measurement and evaluation of primary healthcare (PHC) team performance. Triple Aim components were populated with 10 dimensions derived from survey and health administrative data for 17 Family Health Teams (FHTs) in Ontario, Canada. Bivariate analyses and rankings of sites examined the relationships among dimensions and among Triple Aim components. Readily available measures to fully populate the Triple Aim framework were lacking in FHTs. Within sites, there was little consistency in performance across the Triple Aim components (health, patient experience and cost). More and better measures are needed that can be readily used to examine the Triple Aim performance in PHC teams. FHTs, in this study, are partially achieving Triple Aim goals; however, there was a lack of consistency in performance. It is essential to collect appropriate measures and attend to performance across all components of the Triple Aim. Copyright © 2016 Longwoods Publishing.

Examining Primary Healthcare Performance through a Triple Aim Lens

PubMed Central

Ryan, Bridget L.; Brown, Judith Belle; Glazier, Richard H.; Hutchison, Brian

2016-01-01

Purpose: This study sought to apply a Triple Aim framework to the measurement and evaluation of primary healthcare (PHC) team performance. Methods: Triple Aim components were populated with 10 dimensions derived from survey and health administrative data for 17 Family Health Teams (FHTs) in Ontario, Canada. Bivariate analyses and rankings of sites examined the relationships among dimensions and among Triple Aim components. Results: Readily available measures to fully populate the Triple Aim framework were lacking in FHTs. Within sites, there was little consistency in performance across the Triple Aim components (health, patient experience and cost). Conclusions: More and better measures are needed that can be readily used to examine the Triple Aim performance in PHC teams. FHTs, in this study, are partially achieving Triple Aim goals; however, there was a lack of consistency in performance. It is essential to collect appropriate measures and attend to performance across all components of the Triple Aim. PMID:27027790

Effect of young age, positive margins, and triple negative status on disease recurrence after breast conserving therapy

PubMed Central

Sakulchairungreung, Bundit; Chirappapha, Prakasit; Suvikapakornkul, Ronnarat; Wasuthit, Yodying; Sukarayothin, Thongchai; Leesombatpaiboon, Montchai; Kongdan, Youwanush

2016-01-01

Background To determine the risk factors for disease recurrence after breast conserving therapy (BCT) for breast cancer in a group of South-East Asian women. Methods Medical and pathological records of women who underwent BCT during the 10-year period from 2001 to 2010 were reviewed. Data collected included age ≤35 years defined as the young, type of operation, pathological data, hormonal receptor (HR) status, human epidermal growth factor receptor-2 (HER-2) expression status, and surgical margin status. Data on adjuvant therapy were also collected. Main outcomes were overall breast cancer recurrence, locoregional, and distant recurrence. Risk factors for each type of recurrence were identified using Cox proportional hazards regression models. Results There were 294 BCTs in 290 patients during the study period. The overwhelming majority (91%) had early stage (stages I-II) breast cancers. Young age patients constituted 9% of all patients, and triple negative cancers (HR negative and HER-2 negative) were seen in 19%. Involved margins on initial surgery were found in 9% of cases, and after reoperation, only 2% had involved margins. After a median follow-up of 50 months, and a maximum follow-up of 135 months, there were 30 recurrences and 6 deaths. Of the 30 recurrences, 19 included locoregional, 20 included distant, and 13 had in-breast recurrences. The disease-free survival at 10 years was 82.5% (95% CI: 74.8% to 88.1%), and the cumulative in-breast recurrence was 9.3% (95% CI: 4.9% to 17.2%) at 10 years. Multivariable Cox regression analysis revealed that young age, larger tumor size, involved margins, and no breast irradiation were associated with higher risk of locoregional recurrence. Triple negative status, larger tumor size, more positive nodes, and involved margins were associated with higher risk of distant recurrence. Conclusions We found young age to be a significant prognosticator of locoregional recurrence, and triple negative status of distant recurrence. Involved surgical margin status was associated with both recurrences. Tumor size was associated with both recurrences, and axillary lymph node metastasis was associated with distant recurrence. PMID:26855904

Glycemic Pentad.

PubMed

Forum, Glycemic Pentad

2017-07-01

Conventionally, diabetes management involved targeting the triad of FPG, PPG, and HbA1c. However, several studies have suggested the quintessential need for a paradigm shift to incorporate glycemic variability and quality of life in the holistic diabetes control regimen. To generate a consensus and ratify the position of Glycemic Variability (GV) and Quality of Life (QOL), along with the traditional triad, in diabetes management in India. To evaluate whether the triple fixed dose combination of metformin, glimepiride, and voglibose can accomplish the goals of glycemic pentad. Glycemic pentad forum was instituted comprising of 55 experts from different regions of India in the field of diabetology who discussed various evidences related to the topic and shared their experiences and expressed their opinion on the relevance of glycemic pentad in the present diabetes management and whether triple fixed dose combination of metformin, glimepiride, and voglibose is able to achieve glycemic pentad targets. Forum has come to a consensus that the conglomerate of quintuple elements - FPG, PPG, HbA1c, glycemic variability and quality of life to be termed as glycemic pentad and these milestones to be considered for any antidiabetic therapy. Experts opined that combination therapy is required to achieve the Glycemic Pentad, as monotherapy might not address all the five arms of Glycemic Pentad. Group also agreed that the diabetes management in Indians require separate attention due to their distinct dietary habits (high carbohydrate content) and socio-economic status (economically weak and poorly educated). Therefore, mild adjustments to the standard practices in the western countries are suggested. After evaluating various drugs in the current market to identify candidates that could regulate the elements of Glycemic Pentad, the forum assume that a triple fixed dose combination of metformin, glimepiride, and voglibose could be a better choice in Indians as the combination is safe, affordable and effective in attaining optimal glucose levels and reducing the complications. Glycemic pentad deserves a prominent position in the diabetes management in India. The triple fixed dose combination of metformin, glimepiride, and voglibose has essential commodities to achieve glycemic pentad targets.

19p13.1 is a triple negative-specific breast cancer susceptibility locus

PubMed Central

Stevens, Kristen N.; Fredericksen, Zachary; Vachon, Celine M.; Wang, Xianshu; Margolin, Sara; Lindblom, Annika; Nevanlinna, Heli; Greco, Dario; Aittomäki, Kristiina; Blomqvist, Carl; Chang-Claude, Jenny; Vrieling, Alina; Flesch-Janys, Dieter; Sinn, Hans-Peter; Wang-Gohrke, Shan; Nickels, Stefan; Brauch, Hiltrud; Ko, Yon-Dschun; Fischer, Hans-Peter; Schmutzler, Rita K.; Meindl, Alfons; Bartram, Claus R.; Schott, Sarah; Engel, Christof; Godwin, Andrew K.; Weaver, JoEllen; Pathak, Harsh B.; Sharma, Priyanka; Brenner, Hermann; Müller, Heiko; Arndt, Volker; Stegmaier, Christa; Miron, Penelope; Yannoukakos, Drakoulis; Stavropoulou, Alexandra; Fountzilas, George; Gogas, Helen J.; Swann, Ruth; Dwek, Miriam; Perkins, Annie; Milne, Roger L.; Benítez, Javier; Zamora, M Pilar; Pérez, José Ignacio Arias; Bojesen, Stig E.; Nielsen, Sune F.; Nordestgaard, Børge G; Flyger, Henrik; Guénel, Pascal; Truong, Thérèse; Menegaux, Florence; Cordina-Duverger, Emilie; Burwinkel, Barbara; Marmé, Frederick; Schneeweiss, Andreas; Sohn, Christof; Sawyer, Elinor; Tomlinson, Ian; Kerin, Michael J.; Peto, Julian; Johnson, Nichola; Fletcher, Olivia; Silva, Isabel dos Santos; Fasching, Peter A.; Beckmann, Matthias W.; Hartmann, Arndt; Ekici, Arif B.; Lophatananon, Artitaya; Muir, Kenneth; Puttawibul, Puttisak; Wiangnon, Surapon; Schmidt, Marjanka K; Broeks, Annegien; Braaf, Linde M; Rosenberg, Efraim H; Hopper, John L.; Apicella, Carmel; Park, Daniel J.; Southey, Melissa C.; Swerdlow, Anthony J.; Ashworth, Alan; Orr, Nicholas; Schoemaker, Minouk J.; Anton-Culver, Hoda; Ziogas, Argyrios; Bernstein, Leslie; Dur, Christina Clarke; Shen, Chen-Yang; Yu, Jyh-Cherng; Hsu, Huan-Ming; Hsiung, Chia-Ni; Hamann, Ute; Dünnebier, Thomas; Rüdiger, Thomas; Ulmer, Hans Ulrich; Pharoah, Paul P.; Dunning, Alison M; Humphreys, Manjeet K.; Wang, Qin; Cox, Angela; Cross, Simon S.; Reed, Malcom W.; Hall, Per; Czene, Kamila; Ambrosone, Christine B.; Ademuyiwa, Foluso; Hwang, Helena; Eccles, Diana M.; Garcia-Closas, Montserrat; Figueroa, Jonine D.; Sherman, Mark E.; Lissowska, Jolanta; Devilee, Peter; Seynaeve, Caroline; Tollenaar, R.A.E.M.; Hooning, Maartje J.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Mulligan, Anna Marie; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; John, Esther M.; Miron, Alexander; Alnæs, Grethe Grenaker; Kristensen, Vessela; Børresen-Dale, Anne-Lise; Giles, Graham G.; Baglietto, Laura; McLean, Catriona A; Severi, Gianluca; Kosel, Matthew L.; Pankratz, V.S.; Slager, Susan; Olson, Janet E.; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Barile, Monica; Lambrechts, Diether; Hatse, Sigrid; Dieudonne, Anne-Sophie; Christiaens, Marie-Rose; Chenevix-Trench, Georgia; Beesley, Jonathan; Chen, Xiaoqing; Mannermaa, Arto; Kosma, Veli-Matti; Hartikainen, Jaana M.; Soini, Ylermi; Easton, Douglas F.; Couch, Fergus J.

2012-01-01

The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 – 1.15, p=3.49 × 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 – 1.31, p=2.22 × 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 – 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 – 1.33, p=3.31 × 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways. PMID:22331459

On Pell, Pell-Lucas, and balancing numbers.

PubMed

Karadeniz Gözeri, Gül

2018-01-01

In this paper, we derive some identities on Pell, Pell-Lucas, and balancing numbers and the relationships between them. We also deduce some formulas on the sums, divisibility properties, perfect squares, Pythagorean triples involving these numbers. Moreover, we obtain the set of positive integer solutions of some specific Pell equations in terms of the integer sequences mentioned in the text.

Promoting Scientific Literacy by Using ICT in Science Teaching

ERIC Educational Resources Information Center

Al-Rsa'i, Mohammed Salameh

2013-01-01

This study aims to identify the way upon which ICT can be employed in science teaching to develop scientific literacy level. The study has conclude to design a triple learning model (PEA) based on ICT and constructive learning strategy in teaching science through a context which cares for building positive trends of searching for knowledge and…

Role of TP53 mutations in triple negative and HER2-positive breast cancer treated with neoadjuvant anthracycline/taxane-based chemotherapy

PubMed Central

Darb-Esfahani, Silvia; Denkert, Carsten; Stenzinger, Albrecht; Salat, Christoph; Sinn, Bruno; Schem, Christian; Endris, Volker; Klare, Peter; Schmitt, Wolfgang; Blohmer, Jens-Uwe; Weichert, Wilko; Möbs, Markus; Tesch, Hans; Kümmel, Sherko; Sinn, Peter; Jackisch, Christian; Dietel, Manfred; Reimer, Toralf; Loi, Sherene; Untch, Michael; von Minckwitz, Gunter; Nekljudova, Valentina; Loibl, Sibylle

2016-01-01

Background TP53 mutations are frequent in breast cancer, however their clinical relevance in terms of response to chemotherapy is controversial. Methods 450 pre-therapeutic, formalin-fixed, paraffin-embedded core biopsies from the phase II neoadjuvant GeparSixto trial that included HER2-positive and triple negative breast cancer (TNBC) were subjected to Sanger sequencing of exons 5-8 of the TP53 gene. TP53 status was correlated to response to neoadjuvant anthracycline/taxane-based chemotherapy with or without carboplatin and trastuzumab/lapatinib in HER2-positive and bevacizumab in TNBC. p53 protein expression was evaluated by immunohistochemistry in the TNBC subgroup. Results Of 450 breast cancer samples 297 (66.0%) were TP53 mutant. Mutations were significantly more frequent in TNBC (74.8%) compared to HER2-positive cancers (55.4%, P < 0.0001). Neither mutations nor different mutation types and effects were associated with pCR neither in the whole study group nor in molecular subtypes (P > 0.05 each). Missense mutations tended to be associated with a better survival compared to all other types of mutations in TNBC (P = 0.093) and in HER2-positive cancers (P = 0.071). In TNBC, missense mutations were also linked to higher numbers of tumor-infiltrating lymphocytes (TILs, P = 0.028). p53 protein overexpression was also linked with imporved survival (P = 0.019). Conclusions Our study confirms high TP53 mutation rates in TNBC and HER2-positive breast cancer. Mutations did not predict the response to an intense neoadjuvant chemotherapy in these two molecular breast cancer subtypes. PMID:27611952

Highly sensitive and label-free electrochemical detection of microRNAs based on triple signal amplification of multifunctional gold nanoparticles, enzymes and redox-cycling reaction.

PubMed

Liu, Lin; Xia, Ning; Liu, Huiping; Kang, Xiaojing; Liu, Xiaoshuan; Xue, Chan; He, Xiaoling

2014-03-15

MicroRNAs (miRNAs) are believed to be important for cancer diagnosis and prognosis, serving as reliable molecular biomarkers. In this work, we presented a label-free and highly sensitive electrochemical genosensor for miRNAs detection with the triple signal amplification of gold nanoparticles (AuNPs), alkaline phosphatase (ALP) and p-aminophenol (p-AP) redox cycling. The label-free strategy is based on the difference in the structures of RNA and DNA. Specifically, miRNAs were first captured by the pre-immobilized DNA probes on a gold electrode. Next, the cis-diol group of ribose sugar at the end of the miRNAs chain allowed 3-aminophenylboronic acid (APBA)/biotin-modified multifunctional AuNPs (denoted as APBA-biotin-AuNPs) to be attached through the formation of a boronate ester covalent bond, which facilitated the capture of streptavidin-conjugated alkaline phosphatase (SA-ALP) via the biotin-streptavidin interaction. After the addition of the 4-aminophenylphosphate (p-APP) substrate, the enzymatic conversion from p-APP to p-AP occurred. The resulting p-AP could be cycled by a chemical reducing reagent after its electro-oxidization on the electrode (known as p-AP redox cycling), thus enabling an increase in the anodic current. As a result, the current increased linearly with the miRNAs concentration over a range of 10 fM-5 pM, and a detection limit of 3 fM was achieved. We believe that this work will be valuable for the design of new types of label-free and sensitive electrochemical biosensors. © 2013 Published by Elsevier B.V.

NOTCH3 inactivation increases triple negative breast cancer sensitivity to gefitinib by promoting EGFR tyrosine dephosphorylation and its intracellular arrest.

PubMed

Diluvio, Giulia; Del Gaudio, Francesca; Giuli, Maria Valeria; Franciosa, Giulia; Giuliani, Eugenia; Palermo, Rocco; Besharat, Zein Mersini; Pignataro, Maria Gemma; Vacca, Alessandra; d'Amati, Giulia; Maroder, Marella; Talora, Claudio; Capalbo, Carlo; Bellavia, Diana; Checquolo, Saula

2018-05-25

Notch dysregulation has been implicated in numerous tumors, including triple-negative breast cancer (TNBC), which is the breast cancer subtype with the worst clinical outcome. However, the importance of individual receptors in TNBC and their specific mechanism of action remain to be elucidated, even if recent findings suggested a specific role of activated-Notch3 in a subset of TNBCs. Epidermal growth factor receptor (EGFR) is overexpressed in TNBCs but the use of anti-EGFR agents (including tyrosine kinase inhibitors, TKIs) has not been approved for the treatment of these patients, as clinical trials have shown disappointing results. Resistance to EGFR blockers is commonly reported. Here we show that Notch3-specific inhibition increases TNBC sensitivity to the TKI-gefitinib in TNBC-resistant cells. Mechanistically, we demonstrate that Notch3 is able to regulate the activated EGFR membrane localization into lipid rafts microdomains, as Notch3 inhibition, such as rafts depletion, induces the EGFR internalization and its intracellular arrest, without involving receptor degradation. Interestingly, these events are associated with the EGFR tyrosine dephosphorylation at Y1173 residue (but not at Y1068) by the protein tyrosine phosphatase H1 (PTPH1), thus suggesting its possible involvement in the observed Notch3-dependent TNBC sensitivity response to gefitinib. Consistent with this notion, a nuclear localization defect of phospho-EGFR is observed after combined blockade of EGFR and Notch3, which results in a decreased TNBC cell survival. Notably, we observed a significant correlation between EGFR and NOTCH3 expression levels by in silico gene expression and immunohistochemical analysis of human TNBC primary samples. Our findings strongly suggest that combined therapies of TKI-gefitinib with Notch3-specific suppression may be exploited as a drug combination advantage in TNBC treatment.

Rapid determination of eight bioactive alkaloids in Portulaca oleracea L. by the optimal microwave extraction combined with positive-negative conversion multiple reaction monitor (+/-MRM) technology.

PubMed

Liang, Xiao; Tian, Jinlong; Li, Lingzhi; Gao, Jun; Zhang, Qingyi; Gao, Pinyi; Song, Shaojiang

2014-03-01

A rapid and reliable microwave extraction and the triple quadrupole-linear ion trap mass spectrometry method was developed and validated for the determination of eight alkaloids in Portulaca oleracea L. The optimal microwave extraction (MWE) condition was performed at 60 °C for 12 min with ethanol-water (70:30, v/v) as the extracting solvent, and the solvent to solid ratio was 30:1. The alkaloids were first detected simultaneously by electrospray ionization tandem mass spectrometry under positive-negative conversion multiple reaction monitor ((+/-)MRM) technique. With investigating three different columns, samples were separated in only 8 min on a Waters ACQUITY UPLC HSS T3 (50 × 2.1 mm(2), 1.8 μm) column using acetonitrile and formic acid-water solution as a mobile phase with a flow rate at 0.2 mL/min. All calibration curves showed good linearity (r>0.999) within the test ranges. The method developed was validated with acceptable sensitivity, intra- and inter-day precision, reproducibility, and extraction recoveries. It was successfully applied to the determination of eight alkaloids in Portulaca oleracea L. from different sources and different harvest periods. The method also provide a reference for extraction and determination of alkaloids in other complex systems. © 2013 Elsevier B.V. All rights reserved.

Laser speckle strain and deformation sensor using linear array image cross-correlation method for specifically arranged triple-beam triple-camera configuration

NASA Technical Reports Server (NTRS)

Sarrafzadeh-Khoee, Adel K. (Inventor)

2000-01-01

The invention provides a method of triple-beam and triple-sensor in a laser speckle strain/deformation measurement system. The triple-beam/triple-camera configuration combined with sequential timing of laser beam shutters is capable of providing indications of surface strain and structure deformations. The strain and deformation quantities, the four variables of surface strain, in-plane displacement, out-of-plane displacement and tilt, are determined in closed form solutions.

Effectiveness of Vascular Markers (Immunohistochemical Stains) in Soft Tissue Sarcomas.

PubMed

Naeem, Namra; Mushtaq, Sajid; Akhter, Noreen; Hussain, Mudassar; Hassan, Usman

2018-05-01

To ascertain the effectiveness of IHC markers of vascular origin like CD31, CD34, FLI1 and ERG in vascular soft tissue sarcomas including angiosarcomas, Kaposi sarcomas, epithelioid hemangioendothelioma and a non-vascular soft tissue sarcoma (Epithelioid sarcoma). Descriptive study. Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, from 2011 to 2017. Diagnosed cases of angiosarcomas (n=48), epithelioid hemangioendothelioma (n=9), Kaposi sarcoma (n=9) and epithelioid sarcoma (n=20) were selected. Immunohistochemical staining as performed on formalin fixed paraffin embedded sections. The sections were stained for the following markers: CD34 (VENTANA clone Q Bend 10), CD31 (Leica clone 1 A 10), FLI1 (CELL MARQUE clone MRQ-1) and ERG (CELL MARQUE clone EP111). A complete panel of CD34, CD31 and ERG was applied on 8/48 cases of angiosarcomas with triple positivity in 6 cases. Eight cases showed positivity for only CD31 and ERG and 2 cases showed positivity for only ERG. A complete panel of CD34, CD31 and ERG was applied on 3/9 cases of epithelioid hemangioendothelioma with positivity for all markers in 2 cases. Combined positivity for ERG and CD34 was seen in 2 cases and on 4 cases only CD31 immunohistochemical was solely applied with 100% positivity. FLI1 was not applied on any case. Among 9 cases of Kaposi sarcoma, ERG, CD34 and CD31 in combination were applied on only 1 case with triple positivity. Remaining cases show positivity for either CD34, CD31 or FLI1. Majority of cases of epithelioid sarcomas were diagnosed on the basis of cytokeratin and CD34 positivity with loss of INI1. The other vascular markers showed negativity in all cases. Among these four markers, ERG immunohistochemical stain is highly effective for endothelial differentiation due to its specific nuclear staining pattern in normal blood vessel endothelial cells (internal control) as well as neoplastic cells of vascular tumors and lack of background staining.

A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study.

PubMed

Montaner, J S; Reiss, P; Cooper, D; Vella, S; Harris, M; Conway, B; Wainberg, M A; Smith, D; Robinson, P; Hall, D; Myers, M; Lange, J M

1998-03-25

Current guidelines recommend that individuals infected with the human immunodeficiency virus type 1 (HIV-1) be treated using combinations of antiretroviral agents to achieve sustained suppression of viral replication as measured by the plasma HIV-1 RNA assay, in the hopes of achieving prolonged remission of the disease. However, until recently, many drug combinations have not led to sustained suppression of HIV-1 RNA. To compare the virologic effects of various combinations of nevirapine, didanosine, and zidovudine. Double-blind, controlled, randomized trial. University-affiliated ambulatory research clinics in Italy, the Netherlands, Canada and Australia (INCAS). Antiretroviral therapy-naive adults free of the acquired immunodeficiency syndrome with CD4 cell counts between 0.20 and 0.60x10(9)/L (200-600/microL). Patients received zidovudine plus nevirapine (plus didanosine placebo), zidovudine plus didanosine (plus nevirapine placebo), or zidovudine plus didanosine plus nevirapine. Plasma HIV-1 RNA. Of the 153 enrolled patients, 151 were evaluable. At week 8, plasma HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.05). The proportions of patients with plasma HIV-1 RNA levels below 20 copies per milliliter at week 52 were 51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively (P<.001). Viral amplification was attempted in 59 patients at 6 months. Viral isolation was unsuccessful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups, respectively. Among patients from whom virus could be amplified, resistance to nevirapine was found in all 11 patients receiving zidovudine plus nevirapine and in all 5 patients receiving triple drug therapy. Rates of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51) for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple drug therapy groups, respectively (P=.08). Triple drug therapy with zidovudine, didanosine, and nevirapine led to a substantially greater and sustained decrease in plasma viral load than the 2-drug regimens studied. Our results also suggest that suppression of viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of quantitation of the most sensitive test available, may at least forestall the development of resistance.

Kinematic and Kinetic Analysis of the Single-Leg Triple Hop Test in Women With and Without Patellofemoral Pain.

PubMed

dos Reis, Amir Curcio; Correa, João Carlos Ferrari; Bley, André Serra; Rabelo, Nayra Deise dos Anjos; Fukuda, Thiago Yukio; Lucareli, Paulo Roberto Garcia

2015-10-01

Cross-sectional study. To compare the biomechanical strategies of the trunk and lower extremity during the transition period between the first and second hop of a single-leg triple hop test in women with and without patellofemoral pain (PFP). Recent literature has shown that PFP is associated with biomechanical impairments of the lower extremities. A number of studies have analyzed the position of the trunk and lower extremities for functional activities such as walking, squatting, jumping, and the step-down test. However, studies on more challenging activities, such as the single-leg triple hop test, may be more representative of sports requiring jumping movements. Women between 18 and 35 years of age (control group, n = 20; PFP group, n = 20) participated in the study. Three-dimensional kinematic and kinetic data were collected during the transition period between the first and second hops while participants performed the single-leg triple hop test. Compared to the control group, women with PFP exhibited greater (P<.05) anterior and ipsilateral trunk lean, contralateral pelvic drop, hip internal rotation and adduction, and ankle eversion, while exhibiting less hip and knee flexion. A significant difference (P<.05) in time to peak joint angle was also found between groups for all the variables analyzed, except anterior pelvic tilt and hip flexion. In addition, women with PFP exhibited greater (P<.05) hip and knee abductor internal moments. Compared to the control group, women with PFP exhibited altered trunk, pelvis, hip, knee, and ankle kinematics and kinetics.

STAT3/NF-κB-Regulated Lentiviral TK/GCV Suicide Gene Therapy for Cisplatin-Resistant Triple-Negative Breast Cancer

PubMed Central

Kuo, Wei-Ying; Hwu, Luen; Wu, Chun-Yi; Lee, Jhih-Shian; Chang, Chi-Wei; Liu, Ren-Shyan

2017-01-01

Triple-negative breast cancer (TNBC) represents approximately 20% of all breast cancers and appears resistance to conventional cytotoxic chemotherapy, demonstrating a particularly poor prognosis and a significantly worse clinical outcome than other types of cancer. Suicide gene therapy has been used for the in vivo treatment of various solid tumors in recent clinical trials. In tumor microenvironment, STAT3/NF-κB pathways are constitutively activated in stromal cells as well as in cancer stem cells (CSCs). In this study, we have cloned a novel STAT3/NF-κB-based reporter system to drive the expression of herpes simplex virus thymidine kinase (HSV-TK) against breast cancer. Lentiviral vector expressing HSV-TK under the regulation of STAT3/NF-κB fused response element was developed. In this setting, we exploited the constitutive STAT3/NF-κB activation in tumors to achieve higher transgene expression than that driven by a constitutively active CMV promotor in vivo. An orthotropic MDA-MB-231 triple negative breast cancer mouse model was used for evaluating the feasibility of STAT3-NF-κB-TK/GCV suicide gene therapy system. The basal promoter activity of Lenti-CMV-TK and Lenti-STAT3-NF-κB-TK in MDA-MB-231 cells was compared by 3H-FEAU uptake assay. The Lenti-CMV-TK showed ~5 fold higher 3H-FEAU uptake then Lenti -STAT3-NF-κB-TK. In clonogenic assay, cells expressing Lenti-CMV-TK were 2-fold more sensitive to GCV than Lenti-STAT3-NF-κB-TK transduced cells. In vitro effect of STAT3-NF-κB-induced transgene expression was determined by 10ng/mL TNF-α induction and confirmed by western blot analysis and DsRedm fluorescent microscopy. In vivo evaluation of therapeutic effect by bioluminescence and [18F]FHBG microPET imaging indicated that Lenti-STAT3-NF-κB-TK showed more tumor growth retardation than Lenti-CMV-TK when GCV (20 mg/kg) was administered. The invasiveness and expression of cancer stem cell markers were both decreased after STAT3/NF-κB-regulated HSV-TK/GCV therapy. Moreover, STAT3/NF-κB signaling targeting could further sensitize tumor cells to cisplatin. This study successfully established a theranositic approach to treat triple-negative breast cancer via STAT3-NF-κB responsive element-driven suicide gene therapy. This platform may also be an alternative strategy to handle with drug-resistant cancer cells. PMID:28255357

Quantitative Determination of Bioactive Constituents in Noni Juice by High-performance Liquid Chromatography with Electrospray Ionization Triple Quadrupole Mass Spectrometry.

PubMed

Yan, Yongqiu; Lu, Yu; Jiang, Shiping; Jiang, Yu; Tong, Yingpeng; Zuo, Limin; Yang, Jun; Gong, Feng; Zhang, Ling; Wang, Ping

2018-01-01

Noni juice has been extensively used as folk medicine for the treatment of arthritis, infections, analgesic, colds, cancers, and diabetes by Polynesians for many years. Due to the lack of standard scientific evaluation methods, various kinds of commercial Noni juice with different quality and price were available on the market. To establish a sensitive, reliable, and accurate high-performance liquid chromatography with electrospray ionization triple quadrupole mass spectrometry (HPLC-ESI-MS/MS) method for separation, identification, and simultaneous quantitative analysis of bioactive constituents in Noni juice. The analytes and eight batches of commercially available samples from different origins were separated and analyzed by the HPLC-ESI-MS/MS method on an Agilent ZORBAX SB-C 18 (150 mm × 4.6 mm i.d., 5 μm) column using a gradient elution of acetonitrile-methanol-0.05% glacial acetic acid in water (v/v) at a constant flow rate of 0.5 mL/min. Seven components were identification and all of the assay parameters were within the required limits. Components were within the correlation coefficient values ( R 2 ≥ 0.9993) at the concentration ranges tested. The precision of the assay method was <0.91% and the repeatability between 1.36% and 3.31%. The accuracy varied from 96.40% to 103.02% and the relative standard deviations of stability were <3.91%. Samples from the same origin showed similar content while different origins showed significant different result. The developed methods would provide a reliable basis and be useful in the establishment of a rational quality control standard of Noni juice. Separation, identification, and simultaneous quantitative analysis method of seven bioactive constituents in Noni juice is originally developed by high-performance liquid chromatography with electrospray ionization triple quadrupole mass spectrometryThe presented method was successfully applied to the quality control of eight batches of commercially available samples of Noni juiceThis method is simple, sensitive, reliable, accurate, and efficient method with strong specificity, good precision, and high recovery rate and provides a reliable basis for quality control of Noni juice. Abbreviations used: HPLC-ESI-MS/MS: High-performance liquid chromatography with electrospray ionization triple quadrupole mass spectrometry, LOD: Limit of detection, LOQ: Limit of quantitation, S/N: Signal-to-noise ratio, RSD: Relative standard deviations, DP: Declustering potential, CE: Collision energy, MRM: Multiple reaction monitoring, RT: Retention time.

Quantitative Determination of Bioactive Constituents in Noni Juice by High-performance Liquid Chromatography with Electrospray Ionization Triple Quadrupole Mass Spectrometry

PubMed Central

Yan, Yongqiu; Lu, Yu; Jiang, Shiping; Jiang, Yu; Tong, Yingpeng; Zuo, Limin; Yang, Jun; Gong, Feng; Zhang, Ling; Wang, Ping

2018-01-01

Background: Noni juice has been extensively used as folk medicine for the treatment of arthritis, infections, analgesic, colds, cancers, and diabetes by Polynesians for many years. Due to the lack of standard scientific evaluation methods, various kinds of commercial Noni juice with different quality and price were available on the market. Objective: To establish a sensitive, reliable, and accurate high-performance liquid chromatography with electrospray ionization triple quadrupole mass spectrometry (HPLC-ESI-MS/MS) method for separation, identification, and simultaneous quantitative analysis of bioactive constituents in Noni juice. Materials and Methods: The analytes and eight batches of commercially available samples from different origins were separated and analyzed by the HPLC-ESI-MS/MS method on an Agilent ZORBAX SB-C18 (150 mm × 4.6 mm i.d., 5 μm) column using a gradient elution of acetonitrile-methanol-0.05% glacial acetic acid in water (v/v) at a constant flow rate of 0.5 mL/min. Results: Seven components were identification and all of the assay parameters were within the required limits. Components were within the correlation coefficient values (R2 ≥ 0.9993) at the concentration ranges tested. The precision of the assay method was <0.91% and the repeatability between 1.36% and 3.31%. The accuracy varied from 96.40% to 103.02% and the relative standard deviations of stability were <3.91%. Samples from the same origin showed similar content while different origins showed significant different result. Conclusions: The developed methods would provide a reliable basis and be useful in the establishment of a rational quality control standard of Noni juice. SUMMARY Separation, identification, and simultaneous quantitative analysis method of seven bioactive constituents in Noni juice is originally developed by high-performance liquid chromatography with electrospray ionization triple quadrupole mass spectrometryThe presented method was successfully applied to the quality control of eight batches of commercially available samples of Noni juiceThis method is simple, sensitive, reliable, accurate, and efficient method with strong specificity, good precision, and high recovery rate and provides a reliable basis for quality control of Noni juice. Abbreviations used: HPLC-ESI-MS/MS: High-performance liquid chromatography with electrospray ionization triple quadrupole mass spectrometry, LOD: Limit of detection, LOQ: Limit of quantitation, S/N: Signal-to-noise ratio, RSD: Relative standard deviations, DP: Declustering potential, CE: Collision energy, MRM: Multiple reaction monitoring, RT: Retention time. PMID:29576704

Quantification of tamoxifen and three of its phase-I metabolites in human plasma by liquid chromatography/triple-quadrupole mass spectrometry.

PubMed

Binkhorst, Lisette; Mathijssen, Ron H J; Ghobadi Moghaddam-Helmantel, Inge M; de Bruijn, Peter; van Gelder, Teun; Wiemer, Erik A C; Loos, Walter J

2011-12-15

In view of future pharmacokinetic studies, a highly sensitive ultra performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method has been developed for the simultaneous quantification of tamoxifen and three of its main phase I metabolites in human lithium heparinized plasma. The analytical method has been thoroughly validated in agreement with FDA recommendations. Plasma samples of 200 μl were purified by liquid-liquid extraction with 1 ml n-hexane/isopropanol, after deproteination through addition of 50 μl acetone and 50 μl deuterated internal standards in acetonitrile. Tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen were chromatographically separated on an Acquity UPLC(®) BEH C18 1.7 μm 2.1 mm×100 mm column eluted at a flow-rate of 0.300 ml/min on a gradient of 0.2mM ammonium formate and acetonitrile, both acidified with 0.1% formic acid. The overall run time of the method was 10 min, with elution times of 2.9, 3.0, 4.1 and 4.2 min for endoxifen, 4-hydroxy-tamoxifen, N-desmethyl-tamoxifen and tamoxifen, respectively. Tamoxifen and its metabolites were quantified by triple-quadrupole mass spectrometry in the positive ion electrospray ionization mode. The multiple reaction monitoring transitions were set at 372>72 (m/z) for tamoxifen, 358>58 (m/z) for N-desmethyl-tamoxifen, 388>72 (m/z) for 4-hydroxy-tamoxifen and 374>58 (m/z) for endoxifen. The analytical method was highly sensitive with the lower limit of quantification validated at 5.00 nM for tamoxifen and N-desmethyl-tamoxifen and 0.500 nM for 4-hydroxy-tamoxifen and endoxifen, which is equivalent to 1.86, 1.78, 0.194 and 0.187 ng/ml for tamoxifen, N-desmethyl-tamoxifen, 4-hydroxy-tamoxifen and endoxifen, respectively. The method was also precise and accurate, with within-run and between-run precisions within 12.0% and accuracy ranging from 89.5 to 105.3%. The method has been applied to samples from a clinical study and cross-validated with a validated LC-MS/MS method in serum. Copyright © 2011 Elsevier B.V. All rights reserved.

Quantitative mass spectrometry methods for pharmaceutical analysis

PubMed Central

Loos, Glenn; Van Schepdael, Ann

2016-01-01

Quantitative pharmaceutical analysis is nowadays frequently executed using mass spectrometry. Electrospray ionization coupled to a (hybrid) triple quadrupole mass spectrometer is generally used in combination with solid-phase extraction and liquid chromatography. Furthermore, isotopically labelled standards are often used to correct for ion suppression. The challenges in producing sensitive but reliable quantitative data depend on the instrumentation, sample preparation and hyphenated techniques. In this contribution, different approaches to enhance the ionization efficiencies using modified source geometries and improved ion guidance are provided. Furthermore, possibilities to minimize, assess and correct for matrix interferences caused by co-eluting substances are described. With the focus on pharmaceuticals in the environment and bioanalysis, different separation techniques, trends in liquid chromatography and sample preparation methods to minimize matrix effects and increase sensitivity are discussed. Although highly sensitive methods are generally aimed for to provide automated multi-residue analysis, (less sensitive) miniaturized set-ups have a great potential due to their ability for in-field usage. This article is part of the themed issue ‘Quantitative mass spectrometry’. PMID:27644982

Divergent Synthesis of Chondroitin Sulfate Disaccharides and Identification of Sulfate Motifs that Inhibit Triple Negative Breast Cancer

NASA Astrophysics Data System (ADS)

Wei Poh, Zhong; Heng Gan, Chin; Lee, Eric J.; Guo, Suxian; Yip, George W.; Lam, Yulin

2015-09-01

Glycosaminoglycans (GAGs) regulate many important physiological processes. A pertinent issue to address is whether GAGs encode important functional information via introduction of position specific sulfate groups in the GAG structure. However, procurement of pure, homogenous GAG motifs to probe the “sulfation code” is a challenging task due to isolation difficulty and structural complexity. To this end, we devised a versatile synthetic strategy to obtain all the 16 theoretically possible sulfation patterns in the chondroitin sulfate (CS) repeating unit; these include rare but potentially important sulfated motifs which have not been isolated earlier. Biological evaluation indicated that CS sulfation patterns had differing effects for different breast cancer cell types, and the greatest inhibitory effect was observed for the most aggressive, triple negative breast cancer cell line MDA-MB-231.

Genetics Home Reference: triple X syndrome

MedlinePlus

... Twitter Home Health Conditions Triple X syndrome Triple X syndrome Printable PDF Open All Close All Enable ... to view the expand/collapse boxes. Description Triple X syndrome , also called trisomy X or 47,XXX, ...

Thermodynamics of a pure substance at the triple point

NASA Astrophysics Data System (ADS)

Velasco, S.; Fernández-Pineda, C.

2007-12-01

A thermodynamic study of a pure substance at the triple point is presented. In particular, we show that the mass fractions of the phases coexisting at the triple point obey lever rules in the specific entropy-specific volume diagram, and the relative changes in the mass fractions present in each phase along reversible isochoric and adiabatic processes of a pure substance at the triple point are governed by the relative sizes of the segments of the triple-point line in the pressure-specific volume diagram and in the temperature-specific entropy diagram. Applications to the ordinary triple point of water and to the triple point of Al2SiO5 polymorphs are presented.

Solid State Research.

DTIC Science & Technology

1984-02-15

Diode Lasers 10 - 3. MATERIALS RESEARCH 15 3.1 Role of Oxygen in Zone-Melting Recrystallization of Si Films on Si0 2 -Coated Si Substrates 15 3.2 Triple... Film that Has Been Etch-Delineated to Show Sub- ndaries. Upper Graphite Heater Was Scanned in Direction from top to Bottom of Micrograph. 15 3-2...Operation at 1060 nm with a 5-percent differential power efficiency has been obtained from a flashlamp-pumped laser rod of the sensitized garnet Nd:Cr:Gd 3Sc

Triple ionization chamber method for clinical dose monitoring with a Be-covered Li BNCT field.

PubMed

Nguyen, Thanh Tat; Kajimoto, Tsuyoshi; Tanaka, Kenichi; Nguyen, Chien Cong; Endo, Satoru

2016-11-01

Fast neutron, gamma-ray, and boron doses have different relative biological effectiveness (RBE). In boron neutron capture therapy (BNCT), the clinical dose is the total of these dose components multiplied by their RBE. Clinical dose monitoring is necessary for quality assurance of the irradiation profile; therefore, the fast neutron, gamma-ray, and boron doses should be separately monitored. To estimate these doses separately, and to monitor the boron dose without monitoring the thermal neutron fluence, the authors propose a triple ionization chamber method using graphite-walled carbon dioxide gas (C-CO 2 ), tissue-equivalent plastic-walled tissue-equivalent gas (TE-TE), and boron-loaded tissue-equivalent plastic-walled tissue-equivalent gas [TE(B)-TE] chambers. To use this method for dose monitoring for a neutron and gamma-ray field moderated by D 2 O from a Be-covered Li target (Be-covered Li BNCT field), the relative sensitivities of these ionization chambers are required. The relative sensitivities of the TE-TE, C-CO 2 , and TE(B)-TE chambers to fast neutron, gamma-ray, and boron doses are calculated with the particle and heavy-ion transport code system (PHITS). The relative sensitivity of the TE(B)-TE chamber is calculated with the same method as for the TE-TE and C-CO 2 chambers in the paired chamber method. In the Be-covered Li BNCT field, the relative sensitivities of the ionization chambers to fast neutron, gamma-ray, and boron doses are calculated from the kerma ratios, mass attenuation coefficient tissue-to-wall ratios, and W-values. The Be-covered Li BNCT field consists of neutrons and gamma-rays which are emitted from a Be-covered Li target, and this resultant field is simulated by using PHITS with the cross section library of ENDF-VII. The kerma ratios and mass attenuation coefficient tissue-to-wall ratios are determined from the energy spectra of neutrons and gamma-rays in the Be-covered Li BNCT field. The W-value is calculated from recoil charged particle spectra by the collision of neutrons and gamma-rays with the wall and gas materials of the ionization chambers in the gas cavities of TE-TE, C-CO 2 , and TE(B)-TE chambers ( 10 B concentrations of 10, 50, and 100 ppm in the TE-wall). The calculated relative sensitivity of the C-CO 2 chamber to the fast neutron dose in the Be-covered Li BNCT field is 0.029, and those of the TE-TE and TE(B)-TE chambers are both equal to 0.965. The relative sensitivities of the C-CO 2 , TE-TE, and TE(B)-TE chambers to the gamma-ray dose in the Be-covered Li BNCT field are all 1 within the 1% calculation uncertainty. The relative sensitivities of TE(B)-TE to boron dose with concentrations of 10, 50, and 100 ppm 10 B are calculated to be 0.865 times the ratio of the in-tumor to in-chamber wall boron concentration. The fast neutron, gamma-ray, and boron doses of a tumor in-air can be separately monitored by the triple ionization chamber method in the Be-covered Li BNCT field. The results show that these doses can be easily converted to the clinical dose with the depth correction factor in the body and the RBE.

Safety of first-line triple therapy with a potassium-competitive acid blocker for Helicobacter pylori eradication in children.

PubMed

Kusano, Chika; Gotoda, Takuji; Suzuki, Sho; Ikehara, Hisatomo; Moriyama, Mitsuhiko

2018-06-01

Helicobacter pylori infection is a risk factor for gastric cancer, and it has been reported that eradication of H. pylori is effective for preventing such cancer. Recently, H. pylori eradication has been performed in children as first-line therapy against gastric cancer. Here, we report use of triple therapy with a potassium-competitive acid blocker (P-CAB) for H. pylori eradication in children. H. pylori infection testing and eradication therapy began in fiscal year 2015 in junior high school students located in Yurihonjo city and Nikaho city, Akita prefecture, Japan. Urine-based immunochromatography, stool antigen enzyme-linked immunosorbent assay tests, and serum antibody tests were performed as the initial screening examination. Those who tested positive on one of the three examinations then underwent a urea breath test ( 13 C-UBT). Those who tested positive on 13 C-UBT and expressed the desire to undergo H. pylori eradication then received eradication therapy comprising 20 mg P-CAB, 750 mg amoxicillin, and 200 mg clarithromycin twice a day for 7 days. At least 8 weeks after treatment, eradication success was evaluated using 13 C-UBT. A total of 118 students received eradication therapy. Eradication rates were 81.3% (95% confidence interval: 74.3-88.4, 96/118) in ITT analysis and 85.7% (95% confidence interval: 79.1-92.9 96/112) in PP analysis. Adverse effects associated with eradication therapy were observed in 25 of 118 subjects (21.1%), seven of whom required hospital treatment (rash in five, vomiting in two). All seven subjects either discontinued therapy or were administered anti-allergy drugs, which resulted in swift alleviation of symptoms. First-line triple therapy with a P-CAB for H. pylori eradication in children was found to be safe.

"Multi Light and Drugs": a new technique to treat face photoaging. Comparative study with photorejuvenation.

PubMed

Mezzana, Paolo

2008-04-01

Nonablative skin rejuvenation using laser, intense pulsed lights (IPLs), or radiofrequency techniques are becoming increasingly popular. In this paper, a novel protocol that integrates IPL sessions, low intense light and vitamin C, low-weight hyaluronic acid, betaglucan dermal injection versus IPL photorejuvenation as monotherapy is compared. A group of 100 patients, all women, with ages ranging from 35 to 65 years old (median age 56.3) with different degrees of photodamage was considered. A blinded control study was done. The patients were divided not randomly into two groups. These groups are similar for ages, skin types, and degrees of photoaging distribution. A first group of 40 patients had monotherapy consisting of seven sessions of IPL only. A second group of 60 patients had triple therapy consisting of seven sessions of IPL as well as nine sessions of low intense diode light and also biostimulation by drugs. Considering only the improvement in hyperpigmentations and teleangectasias, the monotherapy and the triple therapy show good results with no significant statistical difference between the two groups. Considering the improvement in skin texture and firmness in the group treated only with monotherapy, 30% (12 patients) had positive results, and 70% (28 patients) had poor results. In the group treated with triple therapy, 70% (42 patients) had positive results, and 30% (18 patients) had poor results, with the main differences in skin silicone negative imprints. On the basis of the data presented, the new technique of IPL, low intensity diode light, and multidrugs biostimulation seems to be a safe and effective method for skin rejuvenation and upgrades the effects of IPL in the fibroblasts' stimulation.

THE HUNT FOR EXOMOONS WITH KEPLER (HEK). V. A SURVEY OF 41 PLANETARY CANDIDATES FOR EXOMOONS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kipping, D. M.; Huang, X.; Hartman, J.

We present a survey of 41 Kepler Objects of Interest (KOIs) for exomoons using Bayesian photodynamics, more than tripling the number of KOIs surveyed with this technique. We find no compelling evidence for exomoons although 13 KOIs yield spurious detections driven by instrumental artifacts, stellar activity, and/or perturbations from unseen bodies. Regarding the latter, we find seven KOIs exhibiting >5 σ evidence of transit timing variations, including the “mega-Earth” Kepler-10c, likely indicating an additional planet in that system. We exploit the moderately large sample of 57 unique KOIs surveyed to date to infer several useful statistics. For example, although theremore » is a diverse range in sensitivities, we find that we are sensitive to Pluto–Charon mass-ratio systems for ≃40% of KOIs studied and Earth–Moon mass-ratios for 1 in 8 cases. In terms of absolute mass, our limits probe down to 1.7 Ganymede masses, with a sensitivity to Earth-mass moons for 1 in 3 cases studied and to the smallest moons capable of sustaining an Earth-like atmosphere (0.3 M{sub ⨁}) for 1 in 4. Despite the lack of positive detections to date, we caution against drawing conclusions yet, since our most interesting objects remain under analysis. Finally, we point out that had we searched for the photometric transit signals of exomoons alone, rather than using photodynamics, we estimate that 1 in 4 KOIs would have erroneously been concluded to harbor exomoons due to residual time correlated noise in the Kepler data, posing a serious problem for alternative methods.« less

Quantification of Kryptofix 2.2.2 in [18F]fluorine-labelled radiopharmaceuticals by rapid-resolution liquid chromatography.

PubMed

Lao, Yexing; Yang, Cuiping; Zou, Wei; Gan, Manquan; Chen, Ping; Su, Weiwei

2012-05-01

The cryptand Kryptofix 2.2.2 is used extensively as a phase-transfer reagent in the preparation of [18F]fluoride-labelled radiopharmaceuticals. However, it has considerable acute toxicity. The aim of this study was to develop and validate a method for rapid (within 1 min), specific and sensitive quantification of Kryptofix 2.2.2 at trace levels. Chromatographic separations were carried out by rapid-resolution liquid chromatography (Agilent ZORBAX SB-C18 rapid-resolution column, 2.1 × 30 mm, 3.5 μm). Tandem mass spectra were acquired using a triple quadrupole mass spectrometer equipped with an electrospray ionization interface. Quantitative mass spectrometric analysis was conducted in positive ion mode and multiple reaction monitoring mode for the m/z 377.3 → 114.1 transition for Kryptofix 2.2.2. The external standard method was used for quantification. The method met the precision and efficiency requirements for PET radiopharmaceuticals, providing satisfactory results for specificity, matrix effect, stability, linearity (0.5-100 ng/ml, r(2)=0.9975), precision (coefficient of variation < 5%), accuracy (relative error < ± 3%), sensitivity (lower limit of quantification=0.5 ng) and detection time (<1 min). Fluorodeoxyglucose (n=6) was analysed, and the Kryptofix 2.2.2 content was found to be well below the maximum permissible levels approved by the US Food and Drug Administration. The developed method has a short analysis time (<1 min) and high sensitivity (lower limit of quantification=0.5 ng/ml) and can be successfully applied to rapid quantification of Kryptofix 2.2.2 at trace levels in fluorodeoxyglucose. This method could also be applied to other [18F]fluorine-labelled radiopharmaceuticals that use Kryptofix 2.2.2 as a phase-transfer reagent.

TM triple-mode microwave filter

NASA Astrophysics Data System (ADS)

Lai, S.-L.; Lin, W.-G.

1990-12-01

A novel realization of triple-mode six-pole microwave filters that use only TM modes is presented. The application involves TM triple degeneracies in cylindrical cavities using triple-mode elliptic function filter synthesis. Experimental results are reported.

Securing Sensitive Flight and Engine Simulation Data Using Smart Card Technology

NASA Technical Reports Server (NTRS)

Blaser, Tammy M.

2003-01-01

NASA Glenn Research Center has developed a smart card prototype capable of encrypting and decrypting disk files required to run a distributed aerospace propulsion simulation. Triple Data Encryption Standard (3DES) encryption is used to secure the sensitive intellectual property on disk pre, during, and post simulation execution. The prototype operates as a secure system and maintains its authorized state by safely storing and permanently retaining the encryption keys only on the smart card. The prototype is capable of authenticating a single smart card user and includes pre simulation and post simulation tools for analysis and training purposes. The prototype's design is highly generic and can be used to protect any sensitive disk files with growth capability to urn multiple simulations. The NASA computer engineer developed the prototype on an interoperable programming environment to enable porting to other Numerical Propulsion System Simulation (NPSS) capable operating system environments.

Sensitivity enhancements in MQ-MAS NMR of spin-5/2 nuclei using modulated rf mixing pulses

NASA Astrophysics Data System (ADS)

Vosegaard, Thomas; Massiot, Dominique; Grandinetti, Philip J.

2000-08-01

An X- overlineX pulse train with stepped modulation frequency was employed to enhance the multiple-quantum to single-quantum coherence transfer in the mixing period of the multiple-quantum magic-angle spinning (MQ-MAS) experiment for spin I=5/2 nuclei. Two MQ-MAS pulse sequences employing this mixing scheme for the triple-to-single and quintuple-to-single quantum coherence transfers have been designed and their performance is demonstrated for 27Al on samples of NaSi 3AlO 8 and 9Al 2O 3·2B 2O 3 . Compared to the standard single-pulse mixing sequences, the sensitivity is approximately doubled in the present experiments.

Direct two-photon excitation of Sm3+, Eu3+, Tb3+, Tb.DOTA-, and Tb.propargylDO3A in solution

NASA Astrophysics Data System (ADS)

Sørensen, Thomas Just; Blackburn, Octavia A.; Tropiano, Manuel; Faulkner, Stephen

2012-07-01

We have observed direct two-photon excitation of samarium, europium and terbium ions in solution upon near IR excitation using a tuneable pulsed light source, and have also studied two-photon processes in a pair of related terbium complexes, namely [Tb.DOTA]- and Tb.propargylDO3A. Direct two-photon excitation of lanthanides is observed in simple systems in the absence of sensitizing chromophores. Where even simple chromophores such as a triple bond are present in the complex, then single and two-photon excitation of chromophore excited states competes with direct two-photon excitation of the ions and is the dominant pathway for sensitizing formation of the lanthanide excited state.

CURCUMIN IN COMBINATION WITH TRIPLE THERAPY REGIMES AMELIORATES OXIDATIVE STRESS AND HISTOPATHOLOGIC CHANGES IN CHRONIC GASTRITIS-ASSOCIATED HELICOBACTER PYLORI INFECTION.

PubMed

Judaki, Arezu; Rahmani, Asghar; Feizi, Jalil; Asadollahi, Khairollah; Hafezi Ahmadi, Mohammad Reza

2017-01-01

Helicobacter pylori (H. pylori) gastric infection is a main cause of inflammatory changes and gastric cancers. The aim of this study was finding the effects of curcumin on oxidative stress and histological changes in chronic gastritis associated with H. pylori. In a randomized clinical trial, patients were divided into two groups: a standard triple therapy group and triple therapy with curcumin group. Endoscopic and histological examinations were measured for all patients before and after 8 weeks. Triple therapy with curcumin treatment group significantly decreased malondialdehyde markers, glutathione peroxides and increased total antioxidant capacity of the gastric mucosa at the end of study compared to baseline and triple regimen groups. In addition, the oxidative damage to DNA was significantly decreased in triple therapy with curcumin group at the end of study compared to baseline and compared to triple therapy (P<0.05 for both). Triple therapy group in combination with Curcumin significantly decreased all active, chronic and endoscopic inflammation scores of patients compared to the baseline and triple therapy group (P<0.05 for both). The eradication rate by triple therapy + curcumin was significantly increased compared to triple therapy alone (P<0.05). Curcumin can be a useful supplement to improve chronic inflammation and prevention of carcinogenic changes in patients with chronic gastritis associated by H. pylori.

Modeling Kepler Transit Light Curves as False Positives: Rejection of Blend Scenarios for Kepler-9, and Validation of Kepler-9 d, a Super-Earth-Size Planet in a Multiple System

DTIC Science & Technology

2011-01-20

of 2009, was de- signed to address the important question of the frequency of Earth -size planets around Sun -like stars, and to characterize ex...physically associated with the candidate (hierarchical triple systems) and in a long-period orbit around their common center of mass would often be spatially...positive scenar- ios that is complementary to other diagnostics, and should play an important role in the discovery of Earth -size planets around other

Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy in Patients With an Initial Diagnosis of Cytology-Proven Lymph Node-Positive Breast Cancer.

PubMed

Enokido, Katsutoshi; Watanabe, Chie; Nakamura, Seigo; Ogiya, Akiko; Osako, Tomo; Akiyama, Futoshi; Yoshimura, Akiyo; Iwata, Hiroji; Ohno, Shinji; Kojima, Yasuyuki; Tsugawa, Koichiro; Motomura, Kazuyoshi; Hayashi, Naoki; Yamauchi, Hideko; Sato, Nobuaki

2016-08-01

Sentinel lymph node biopsy (SNB) is the standard treatment of node-negative breast cancer; however, whether SNB should be performed for patients with node-positive disease before neoadjuvant chemotherapy (NAC) is controversial. We evaluated the accuracy of SNB after NAC in patients with breast cancer with nodal metastasis before chemotherapy to determine the false-negative rate (FNR) and detection rate for SNB. In the present multicenter prospective study performed from September 2011 to April 2013, 143 patients with breast cancer and positive axillary nodes, proved by fine needle aspiration cytology at the initial diagnosis (stage T1-T3N1M0), were enrolled. All patients underwent breast surgery with SNB and complete axillary lymph node dissection. After NAC, the pathologic complete nodal response rate was 52.4%. The sentinel lymph node could be identified in 130 cases (90.9%); the FNR was 16.0% (13 of 81). The FNR of each clinical subtype was 42.1% (8 of 19) for the estrogen receptor-positive and human epithelial growth factor 2 (HER2)-negative (luminal type), 16.7% (2 of 12) for ER-positive and HER2-positive (luminal-HER2 type), 3.2% (1 of 31) for HER2-positive (HER2-enriched type), and 10.5% (2 of 19) for ER-negative and HER2-negative (triple-negative breast cancer; P = .003). The FNR was significantly greater in the luminal than in the nonluminal type (odds ratio, 9.91; 95% confidence interval, 6.77-14.52). SNB after NAC in patients with initially node-positive breast cancer was technically feasible but should not be recommended for the luminal subtype. However, the tumor subtype can guide patient selection, and axillary lymph node dissection could be omitted for the luminal-HER2, HER2-enriched, and triple-negative breast cancer subtypes. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

A method for determining regioisomer abundances of polyunsaturated triacylglycerols in omega-3 enriched fish oils using reversed-phase liquid chromatography and triple-stage mass spectrometry.

PubMed

Cubero Herrera, Lisandra; Ramaley, Louis; Potvin, Michael A; Melanson, Jeremy E

2013-08-15

Reversed-phase high performance liquid chromatography (RP-HPLC), followed by post-column addition of lithium salts and electrospray ionisation triple-stage mass spectrometry (ESI-MS(3)) of lithiated TAG adducts, is shown to provide a useful method for the positional analysis of triacylglycerols (TAGs) in fish oils containing eicosapentaenoic (EPA, 20:5) and docosahexaenoic acids (DHA, 22:6). One prominent fragmentation pathway in the ESI-MS(3) of these adduct ions involves the loss of a fatty acid from the sn-1/3 position in the first step followed by the loss of an α,β-unsaturated fatty acid from the sn-2 position in the second. Regioisomeric TAGs of the type ABA and AAB produced abundant product ions - [ABA+Li-RACOOH-R'BCHCHCOOH](+) and [AAB+Li-RACOOH-R'ACHCHCOOH](+) - the relative intensities of which were dependent on the position of acyl substituents. Standard solutions of TAGs containing different ratios of the regioisomeric pairs MME/MEM, PPE/PEP, PPD/PDP, EEP/EPE and DDP/DPD (M=14:0, P=16:0, E=20:5, D=22:6) were analysed by ESI-MS(3) with a quadrupole linear ion trap instrument. Methodology developed on the standards was applied to quantifying the relative isomeric abundances of EPA and DHA in several fish oil samples. DHA was preferentially located at the sn-2 position in both DHA-containing TAGs studied, while EPA was either observed at near equal levels in all positions, or predominantly at the sn-1 and -3 positions in some cases. The analysis protocol allows for quantification of the designated regioisomers in one simple, rapid chromatographic procedure using a single column and has the advantage of specificity over other methods for the positional analysis of TAGs, since it eliminates interferences associated with co-eluting TAGs of the same molecular weight that yield isobaric diacylglycerol-like product ions. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Triple combination therapy and zeaxanthin for the treatment of neovascular age-related macular degeneration: an interventional comparative study and cost-effectiveness analysis.

PubMed

Olk, R Joseph; Peralta, Enrique; Gierhart, Dennis L; Brown, Gary C; Brown, Melissa M

2015-01-01

Reports of triple combination therapy for neovascular age-related macular degeneration (AMD) suggest a benefit, as do reports for zeaxanthin. An interventional comparative study was thus undertaken to evaluate the efficacy of triple combination therapy with and without zeaxanthin, as well as the economic viability of the therapies. The cases of 543 consecutive eyes of 424 patients with subfoveal choroidal neovascularization (CNV) secondary to AMD were reviewed. All eyes were treated with triple combination therapy (triple therapy) consisting of: (1) reduced-fluence photodynamic therapy with verteporfin, (2) intravitreal bevacizumab and (3) intravitreal dexamethasone. Therapy was repeated as necessary. One cohort of patients was also given supplementation with 20 mg of oral zeaxanthin (Zx) daily. The triple therapy group without Zx received a mean of 2.8 treatment cycles and 87 % of patients had stable or improved vision at 24 months. In the triple therapy group with Zx, the mean number of treatment cycles was 2.1, with 83 % of patients having stable or improved vision at 24 months. At 24 months, CNV developed in 12.5 % of fellow eyes treated with triple therapy alone; CNV developed in 6.25 % of eyes treated with triple therapy with Zx (p = 0.03). An average cost-utility analysis revealed that triple therapy was cost-effective with a cost-utility ratio of $26,574/QALY, while triple therapy with Zx was more cost-effective with an average cost-utility ratio of $19,962/QALY. The incremental cost-utility analysis assessing the addition of Zx to triple therapy disclosed Zx supplementation was very cost-effective at $5302/QALY. When it was assumed that triple therapy with Zx reduced fellow eye CNV development by 30.3 %, the incremental cost-utility dropped to (-$6332/QALY), indicating that adding Zx to triple therapy yielded greater patient value, and was also less expensive than using triple therapy alone. Triple therapy is comparatively effective and cost-effective. Considerably less treatment is needed than reported in monotherapy studies. The addition of oral Zx appears to further reduce the treatment cycles required, and possibly reduce the risk of CNV development in the fellow eye.

New halogenated constituents from Mangifera zeylanica Hook.f. and their potential anti-cancer effects in breast and ovarian cancer cells.

PubMed

Ediriweera, Meran Keshawa; Tennekoon, Kamani Hemamala; Adhikari, Achyut; Samarakoon, Sameera Ranganath; Thabrew, Ira; de Silva, E Dilip

2016-08-02

Mangifera zeylanica Hook.f. (Anacardiaceae) is a plant endemic to Sri Lanka. Its bark has been used in traditional and Ayurvedic medicine for the treatment of various diseases including some cancers. This study was planned to isolate and identify potentially cytotoxic compounds from the bark of M. zeylanica, which may have contributed to its ethno pharmacological use in the treatment of cancer. The chloroform extract of M. zeylanica bark which is cytotoxic to breast and ovarian cancer cells was fractionated using column chromatography and preparative reversed phase high performance liquid chromatography to isolate four compounds. Structures of the isolated compounds were elucidated by means of (1)H- and (13)C NMR spectroscopy, and mass spectrometric techniques. Cytotoxic potential of the isolated compounds was tested in MDA-MB-231 (triple negative breast cancer), MCF-7 (estrogen receptor positive breast cancer), SKOV-3 (ovarian epithelial cancer) and MCF-10A (normal mammary epithelial) cells by SRB assay. Human cancer drug target real-time PCR array was carried out to analyze regulation of possible cancer drug target genes in compound 2 treated triple negative breast cancer cells. DPPH radical scavenging and caspase 3 and 7 induction in response to isolated compounds were also studied. Two new halogenated compounds, bromomangiferic acid (1), and chloromangiferamide (2) along with two known compounds quercetin (3), and catechin (4), were isolated from the bark of Mangifera zeylanica for the first time. Interestingly, chloromangiferamide showed cytotoxicity only to triple negative breast cancer cells [IC50:73.19±0.87µM (24h), 56.29±0.86µM (48h)] with no cytotoxicity to other two cancer cell lines or to normal mammary epithelial cells. Quercetin and catechin were cytotoxic to all three cancer cell lines while bromomangiferic acid had no effect. Chloromangiferamide significantly regulated expression of genes associated with apoptosis, drug metabolism, cell cycle, receptor tyrosine kinase signaling, protein kinases, histone deacetylases, growth factors and receptors, topoisomerases, PI-3 kinases and phosphatases in triple negative breast cancer cells. Selective cytotoxic activity in triple negative breast cancer cells and regulation of some cancer drug target genes by chloromangiferamide indicate that it can be used to develop a potential chemotherapeutic agent for triple negative breast cancer cells. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Training in Parent Consultation Skills for Primary Care Practitioners in Early Intervention in the Pre-School Context.

ERIC Educational Resources Information Center

Crisante, Lea

2003-01-01

Describes the implementation of a brief behavioral intervention, based on the Triple P-Positive Parenting Program, by 13 pre-school practitioners with 39 parents. The results point to the role of primary care practitioners in providing services in settings that are easily accessed by parents, thus increasing the availability of support to parents…

"Every Family": A Population Approach to Reducing Behavioral and Emotional Problems in Children Making the Transition to School

ERIC Educational Resources Information Center

Sanders, Matthew R.; Ralph, Alan; Sofronoff, Kate; Gardiner, Paul; Thompson, Rachel; Dwyer, Sarah; Bidwell, Kerry

2008-01-01

A large-scale population trial using the Triple P-Positive Parenting Program (TPS) was evaluated. The target population was all parents of 4- to 7-year-old children residing in ten geographical catchment areas in Brisbane (intervention communities) and ten sociodemographically matched catchment areas from Sydney (5) and Melbourne (5), care as…

The Role of Practitioner Self-Efficacy, Training, Program and Workplace Factors on the Implementation of an Evidence-Based Parenting Intervention in Primary Care

ERIC Educational Resources Information Center

Turner, Karen M. T.; Nicholson, Jan M.; Sanders, Matthew R.

2011-01-01

This study examines factors affecting the implementation by primary care practitioners (nursing, education, allied health, and medical) of a brief parenting and family support intervention (the Primary Care Triple P--Positive Parenting Program) following professional training. It assesses the impact of prior experience, self-efficacy, program…

The Role of Novel Substituted Diindolyl Methane Analogues in the Treatment of Triple-Negative and ErbB2-Positive Breast Cancer

DTIC Science & Technology

2015-05-01

studies show differential expression of NR4A receptors [181,182] and studies on dopamine neurons showed that in the ventral tegmental area, haloperidol ...Blanchet, D. Levesque, Haloperidol -induced striatal Nur77 expression in a non-human primate model of tardive dyskinesia, Eur. J. Neurosci. 38 (2013

An Examination of Positive Coaching Alliance Triple Impact Competitor Workshops on the Moral Knowing of Secondary School Athletes

ERIC Educational Resources Information Center

Flynn, Michael R.

2017-01-01

A common belief in United States culture is that "...sports can provide opportunities for personal growth and social development." (Ewing, 1997). Unfortunately, more recent research has suggested there is a growing trend to the contrary. As a result, those whose work it is to develop an athlete's morality should seek out strategies that…

A comparison of online versus workbook delivery of a self-help positive parenting program.

PubMed

Sanders, Matthew R; Dittman, Cassandra K; Farruggia, Susan P; Keown, Louise J

2014-06-01

A noninferiority randomized trial design compared the efficacy of two self-help variants of the Triple P-Positive Parenting Program: an online version and a self-help workbook. We randomly assigned families of 193 children displaying early onset disruptive behavior difficulties to the online (N = 97) or workbook (N = 96) interventions. Parents completed questionnaire measures of child behavior, parenting, child maltreatment risk, personal adjustment and relationship quality at pre- and post-intervention and again at 6-month follow up. The short-term intervention effects of the Triple P Online program were not inferior to the workbook on the primary outcomes of disruptive child behavior and dysfunctional parenting as reported by both mothers and fathers. Both interventions were associated with significant and clinically meaningful declines from pre- to post-intervention in levels of disruptive child behavior, dysfunctional parenting styles, risk of child maltreatment, and inter-parental conflict on both mother and father report measures. Intervention effects were largely maintained at 6-month follow up, thus supporting the use of self-help parenting programs within a comprehensive population-based system of parenting support to reduce child maltreatment and behavioral problems in children.

FALDO: a semantic standard for describing the location of nucleotide and protein feature annotation.

PubMed

Bolleman, Jerven T; Mungall, Christopher J; Strozzi, Francesco; Baran, Joachim; Dumontier, Michel; Bonnal, Raoul J P; Buels, Robert; Hoehndorf, Robert; Fujisawa, Takatomo; Katayama, Toshiaki; Cock, Peter J A

2016-06-13

Nucleotide and protein sequence feature annotations are essential to understand biology on the genomic, transcriptomic, and proteomic level. Using Semantic Web technologies to query biological annotations, there was no standard that described this potentially complex location information as subject-predicate-object triples. We have developed an ontology, the Feature Annotation Location Description Ontology (FALDO), to describe the positions of annotated features on linear and circular sequences. FALDO can be used to describe nucleotide features in sequence records, protein annotations, and glycan binding sites, among other features in coordinate systems of the aforementioned "omics" areas. Using the same data format to represent sequence positions that are independent of file formats allows us to integrate sequence data from multiple sources and data types. The genome browser JBrowse is used to demonstrate accessing multiple SPARQL endpoints to display genomic feature annotations, as well as protein annotations from UniProt mapped to genomic locations. Our ontology allows users to uniformly describe - and potentially merge - sequence annotations from multiple sources. Data sources using FALDO can prospectively be retrieved using federalised SPARQL queries against public SPARQL endpoints and/or local private triple stores.

FALDO: a semantic standard for describing the location of nucleotide and protein feature annotation

DOE PAGES

Bolleman, Jerven T.; Mungall, Christopher J.; Strozzi, Francesco; ...

2016-06-13

Nucleotide and protein sequence feature annotations are essential to understand biology on the genomic, transcriptomic, and proteomic level. Using Semantic Web technologies to query biological annotations, there was no standard that described this potentially complex location information as subject-predicate-object triples. In this paper, we have developed an ontology, the Feature Annotation Location Description Ontology (FALDO), to describe the positions of annotated features on linear and circular sequences. FALDO can be used to describe nucleotide features in sequence records, protein annotations, and glycan binding sites, among other features in coordinate systems of the aforementioned “omics” areas. Using the same data formatmore » to represent sequence positions that are independent of file formats allows us to integrate sequence data from multiple sources and data types. The genome browser JBrowse is used to demonstrate accessing multiple SPARQL endpoints to display genomic feature annotations, as well as protein annotations from UniProt mapped to genomic locations. Our ontology allows users to uniformly describe – and potentially merge – sequence annotations from multiple sources. Finally, data sources using FALDO can prospectively be retrieved using federalised SPARQL queries against public SPARQL endpoints and/or local private triple stores.« less

De novo self-assembling collagen heterotrimers using explicit positive and negative design.

PubMed

Xu, Fei; Zhang, Lei; Koder, Ronald L; Nanda, Vikas

2010-03-23

We sought to computationally design model collagen peptides that specifically associate as heterotrimers. Computational design has been successfully applied to the creation of new protein folds and functions. Despite the high abundance of collagen and its key role in numerous biological processes, fibrous proteins have received little attention as computational design targets. Collagens are composed of three polypeptide chains that wind into triple helices. We developed a discrete computational model to design heterotrimer-forming collagen-like peptides. Stability and specificity of oligomerization were concurrently targeted using a combined positive and negative design approach. The sequences of three 30-residue peptides, A, B, and C, were optimized to favor charge-pair interactions in an ABC heterotrimer, while disfavoring the 26 competing oligomers (i.e., AAA, ABB, BCA). Peptides were synthesized and characterized for thermal stability and triple-helical structure by circular dichroism and NMR. A unique A:B:C-type species was not achieved. Negative design was partially successful, with only A + B and B + C competing mixtures formed. Analysis of computed versus experimental stabilities helps to clarify the role of electrostatics and secondary-structure propensities determining collagen stability and to provide important insight into how subsequent designs can be improved.

Changes in Lower Limb Strength and Function Following Lumbar Spinal Mobilization.

PubMed

Yuen, Tsoi Sze; Lam, Pui Yu; Lau, Mei Yan; Siu, Wai Lam; Yu, Ka Man; Lo, Chi Ngai; Ng, Joseph

2017-10-01

The purpose of this study was to investigate whether grade III passive lumbar rotational mobilization on L2-3 can improve hip flexor strength and performance in the single-leg triple-hop test in asymptomatic young adults. Twenty-four participants (12 men, 12 women) aged from 19 to 26 years who were positive in the hip flexor "break" test were recruited in this study. They were randomly allocated to the treatment group or sham group. Isometric hip flexor torque (N·m) and single-leg triple-hop distance (cm) were measured before and after a passive lumbar rotational mobilization or a sham intervention. After the intervention, both the treatment and sham groups exhibited a significant increase in longest hop distance (P = .040 and .044, respectively). The treatment group had a significantly higher (3.41 ± 5.44%) positive percentage change in torque than the sham group (-2.36 ± 5.81%) (P = .02). The study results indicated a potential effect of grade III passive lumbar rotational mobilization in improving hip flexor strength. However, whether the improvement in hopping performance was the result of a treatment effect or a learning effect could not be determined. Copyright © 2017. Published by Elsevier Inc.

Phenformin as prophylaxis and therapy in breast cancer xenografts.

PubMed

Appleyard, M V C L; Murray, K E; Coates, P J; Wullschleger, S; Bray, S E; Kernohan, N M; Fleming, S; Alessi, D R; Thompson, A M

2012-03-13

Observations that diabetics treated with biguanide drugs have a reduced risk of developing cancer have prompted an enthusiasm for these agents as anti-cancer therapies. We sought to determine the efficacy of the biguanide phenformin in the chemoprophylaxis and in the treatment of oestrogen receptor (ER)-positive MCF7 and receptor triple-negative MDAMB231 xenografts in immunocompromised mice. We also compared the efficacy of phenformin and metformin in the treatment of MDAMB231. Immunocompromised mice were divided into groups: (1) phenformin administered for 2 weeks prior to cell injection; (2) established tumours treated with phenformin; (3) established tumours treated with metformin (only for MDAMB231 tumours); (4) untreated controls. Post-treatment tumours, liver and spleen were harvested for further analysis. Phenformin significantly inhibited both the development and growth of MCF7 and MDAMB231 tumours, and for MDAMB231 at greater efficacy than metformin without murine toxicity. The number of mitotic figures was significantly fewer in xenografts treated with phenformin compared with controls. Results suggested that the mechanism of action of phenformin in vivo is consistent with AMPK activation. Phenformin has clinical potential as an antineoplastic agent and should be considered for clinical trials both in ER-positive and triple-negative breast cancer.

FALDO: a semantic standard for describing the location of nucleotide and protein feature annotation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bolleman, Jerven T.; Mungall, Christopher J.; Strozzi, Francesco

Nucleotide and protein sequence feature annotations are essential to understand biology on the genomic, transcriptomic, and proteomic level. Using Semantic Web technologies to query biological annotations, there was no standard that described this potentially complex location information as subject-predicate-object triples. In this paper, we have developed an ontology, the Feature Annotation Location Description Ontology (FALDO), to describe the positions of annotated features on linear and circular sequences. FALDO can be used to describe nucleotide features in sequence records, protein annotations, and glycan binding sites, among other features in coordinate systems of the aforementioned “omics” areas. Using the same data formatmore » to represent sequence positions that are independent of file formats allows us to integrate sequence data from multiple sources and data types. The genome browser JBrowse is used to demonstrate accessing multiple SPARQL endpoints to display genomic feature annotations, as well as protein annotations from UniProt mapped to genomic locations. Our ontology allows users to uniformly describe – and potentially merge – sequence annotations from multiple sources. Finally, data sources using FALDO can prospectively be retrieved using federalised SPARQL queries against public SPARQL endpoints and/or local private triple stores.« less

CXCR4 Protein Epitope Mimetic Antagonist POL5551 Disrupts Metastasis and Enhances Chemotherapy Effect in Triple-Negative Breast Cancer.

PubMed

Xiang, Jingyu; Hurchla, Michelle A; Fontana, Francesca; Su, Xinming; Amend, Sarah R; Esser, Alison K; Douglas, Garry J; Mudalagiriyappa, Chidananda; Luker, Kathryn E; Pluard, Timothy; Ademuyiwa, Foluso O; Romagnoli, Barbara; Tuffin, Gérald; Chevalier, Eric; Luker, Gary D; Bauer, Michael; Zimmermann, Johann; Aft, Rebecca L; Dembowsky, Klaus; Weilbaecher, Katherine N

2015-11-01

The SDF-1 receptor CXCR4 has been associated with early metastasis and poorer prognosis in breast cancers, especially the most aggressive triple-negative subtype. In line with previous reports, we found that tumoral CXCR4 expression in patients with locally advanced breast cancer was associated with increased metastases and rapid tumor progression. Moreover, high CXCR4 expression identified a group of bone marrow-disseminated tumor cells (DTC)-negative patients at high risk for metastasis and death. The protein epitope mimetic (PEM) POL5551, a novel CXCR4 antagonist, inhibited binding of SDF-1 to CXCR4, had no direct effects on tumor cell viability, but reduced migration of breast cancer cells in vitro. In two orthotopic models of triple-negative breast cancer, POL5551 had little inhibitory effect on primary tumor growth, but significantly reduced distant metastasis. When combined with eribulin, a chemotherapeutic microtubule inhibitor, POL5551 additively reduced metastasis and prolonged survival in mice after resection of the primary tumor compared with single-agent eribulin. Hypothesizing that POL5551 may mobilize tumor cells from their microenvironment and sensitize them to chemotherapy, we used a "chemotherapy framing" dosing strategy. When administered shortly before and after eribulin treatment, three doses of POL5551 with eribulin reduced bone and liver tumor burden more effectively than chemotherapy alone. These data suggest that sequenced administration of CXCR4 antagonists with cytotoxic chemotherapy synergize to reduce distant metastases. ©2015 American Association for Cancer Research.

Secular dynamics of the triple system harboring PSR J0337+1715 and implications for the origin of its orbital configuration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rafikov, Roman R., E-mail: rrr@astro.princeton.edu

2014-10-10

We explore secular dynamics of a recently discovered hierarchical triple system consisting of the radio pulsar PSR J0337+1715 and two white dwarfs (WDs). We show that three-body interactions endow the inner binary with a large forced eccentricity and suppress its apsidal precession, to about 24% of the rate due to the general relativity. However, precession rate is still quite sensitive to the non-Newtonian effects and may be used to constrain gravity theories if measured accurately. A small value of the free eccentricity of the inner binary e{sub i}{sup free}≈2.6×10{sup −5} and vanishing forced eccentricity of the outer, relatively eccentric binarymore » naturally result in their apsidal near-alignment. In addition, this triple system provides a unique opportunity to explore excitation of both eccentricity and inclination in neutron star-WD binaries, e.g., due to random torques caused by convective eddies in the WD progenitor. We show this process to be highly anisotropic and more effective at driving eccentricity rather than inclination. The outer binary eccentricity and e{sub i}{sup free} exceed by more than an order of magnitude the predictions of the eccentricity-period relation of Phinney, which is not uncommon. We also argue that the non-zero mutual inclination of the two binaries emerges at the end of the Roche lobe overflow of the outer (rather than the inner) binary.« less

β-cyclodextrin-ferrocene host-guest complex multifunctional labeling triple amplification strategy for electrochemical immunoassay of subgroup J of avian leukosis viruses.

PubMed

Shang, Kun; Wang, Xindong; Sun, Bing; Cheng, Ziqiang; Ai, Shiyun

2013-07-15

A novel sandwich-type electrochemical immunosensor was fabricated for ultrasensitive detection of subgroup J of avian leukosis virus (ALVs-J) by employing β-cyclodextrin-ferrocene (CD-Fc) host-guest complex multifunctional Fe3O4 nanospheres as labels and β-cyclodextrin functional graphene sheets (CD-GS) nanocomposite as sensor platform. The sensitivity was greatly improved based on the triple amplification strategy. Firstly, the CD-GS improved the electron transfer rate as well as increasing the surface area to capture a large amount of primary antibodies (Ab1). Secondly, the CD on the Fe3O4 surface with strong recognition capability could form stable CD-Fc host-guest inclusion complex and provided larger free room for the conjugation of secondary antibodies (Ab2) and glucose oxidase (GOD). Finally, the conjugated GOD exhibited extraordinary electrochemical biocatalysis towards the reduction reaction of Fc(+) by glucose. Under the optimized conditions, the electrochemical immunosensor exhibited a wide working range from 10(2.27)-10(3.50) TCID50/mL (TCID50: 50% tissue culture infective dose) with a low detection limit of 10(2.19) TCID50/mL (S/N=3). The selectivity, reproducibility, and stability are acceptable. The assay was evaluated for real avian serum sample, receiving satisfactory results. This new type of triple amplification strategy may provide potential applications for the clinic application. Copyright © 2013 Elsevier B.V. All rights reserved.

Audiometric asymmetry and tinnitus laterality.

PubMed

Tsai, Betty S; Sweetow, Robert W; Cheung, Steven W

2012-05-01

To identify an optimal audiometric asymmetry index for predicting tinnitus laterality. Retrospective medical record review. Data from adult tinnitus patients (80 men and 44 women) were extracted for demographic, audiometric, tinnitus laterality, and related information. The main measures were sensitivity, specificity, positive predictive value (PPV), and receiver operating characteristic (ROC) curves. Three audiometric asymmetry indices were constructed using one, two, or three frequency elements to compute the average interaural threshold difference (aITD). Tinnitus laterality predictive performance of a particular index was assessed by increasing the cutoff or minimum magnitude of the aITD from 10 to 35 dB in 5-dB steps to determine its ROC curve. Single frequency index performance was inferior to the other two (P < .05). Double and triple frequency indices were indistinguishable (P > .05). Two adjoining frequency elements with aITD ≥ 15 dB performed optimally for predicting tinnitus laterality (sensitivity = 0.59, specificity = 0.71, and PPV = 0.76). Absolute and relative magnitudes of hearing loss in the poorer ear were uncorrelated with tinnitus distress. An optimal audiometric asymmetry index to predict tinnitus laterality is one whereby 15 dB is the minimum aITD of two adjoining frequencies, inclusive of the maximal ITD. Tinnitus laterality dependency on magnitude of interaural asymmetry may inform design and interpretation of neuroimaging studies. Monaural acoustic tinnitus therapy may be an initial consideration for asymmetric hearing loss meeting the criterion of aITD ≥ 15 dB. Copyright © 2012 The American Laryngological, Rhinological, and Otological Society, Inc.

Quantitative determination of carfilzomib in mouse plasma by liquid chromatography-tandem mass spectrometry and its application to a pharmacokinetic study.

PubMed

Min, Jee Sun; Kim, Jiseon; Kim, Jung Ho; Kim, Doyun; Zheng, Yu Fen; Park, Ji Eun; Lee, Wooin; Bae, Soo Kyung

2017-11-30

A highly sensitive and rapid LC-MS/MS method was developed and validated to determine the levels of carfilzomib in mice plasma by using chlorpropamide as an internal standard. Carfilzomib and chlorpropamide were extracted from 5 μL of plasma after protein precipitation with acetonitrile. Chromatographic separation was performed on Phenomenex Luna C 18 column (50×2.0mm id, 3μm). The mobile phase consisted of 0.1% formic acid in acetonitrile -0.1% formic acid in water (1:1v/v) and the flow rate was 0.3mL/min. The total chromatographic run time was 2.5min. Detection was performed on a triple quadrupole mass spectrometer equipped with positive-ion electrospray ionization by selected reaction monitoring of the transitions at m/z 720.20>100.15 (for carfilzomib) and m/z 277.05>111.05 (for the internal standard). The lower limit of quantification was 0.075ng/mL and the linear range was 0.075-1250ng/mL (r≥0.9974). All validation data, including selectivity, precision, accuracy, matrix effect, recovery, dilution integrity, stability, and incurred sample reanalysis, were well within acceptance limits. This newly developed bioanalytical method was simple, highly sensitive, required only a small volume of plasma, and was suitable for application in pharmacokinetic studies in mice that used serial blood sampling. Copyright © 2017 Elsevier B.V. All rights reserved.

Simultaneous determination of 15 phenolic constituents of Chinese black rice wine by HPLC-MS/MS with SPE.

PubMed

Wang, Yutang; Liu, Yuanyuan; Xiao, Chunxia; Liu, Laping; Hao, Miao; Wang, Jianguo; Liu, Xuebo

2014-06-01

This study established a new method for quantitative and qualitative determination of certain components in black rice wine, a traditional Chinese brewed wine. Specifically, we combined solid-phase extraction and high-performance liquid chromatography (HPLC) with triple quadrupole mass spectrometry (MS/MS) to determine 8 phenolic acids, 3 flavonols, and 4 anthocyanins in black rice wine. First, we clean samples with OASIS HLB cartridges and optimized extraction parameters. Next, we performed separation on a SHIM-PACK XR-ODS column (I.D. 3.0 mm × 75 mm, 2.2 μm particle size) with a gradient elution of 50% aqueous acetonitrile (V/V) and water, both containing 0.2% formic acid. We used multiple-reaction monitoring scanning for quantification, with switching electrospray ion source polarity between positive and negative modes in a single chromatographic run. We detected 15 phenolic compounds properly within 38 min under optimized conditions. Limits of detection ranged from 0.008 to 0.030 mg/L, and average recoveries ranged from 60.8 to 103.1% with relative standard deviation ≤8.6%. We validated the method and found it to be sensitive and reliable for quantifying phenolic compounds in rice wine matrices. This study developed a new, reliable HPLC-MS/MS method for simultaneous determination of 15 bioactive components in black rice wine. This method was validated and found to be sensitive and reliable for quantifying phenolic compounds in rice wine. © 2014 Institute of Food Technologists®

Development and validation of a highly sensitive LC-MS/MS method for the determination of dexamethasone in nude mice plasma and its application to a pharmacokinetic study.

PubMed

Yuan, Yin; Zhou, Xuan; Li, Jian; Ye, Suofu; Ji, Xiwei; Li, Liang; Zhou, Tianyan; Lu, Wei

2015-04-01

In the current study, a simple, sensitive and rapid analytical method for the determination of dexamethasone was developed and applied to a pharmacokinetic study in nude mice. Using testosterone as an internal standard, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) approach after one-step precipitation with acetonitrile was validated and used to determine the concentrations of dexamethasone in nude mice plasma. The method utilized a simple isocratic reverse phase separation over a Dionex C18 column with a mobile phase composed of acetonitrile-water (40:60, v/v). The analyte was detected by a triple quadrupole tandem mass spectrometer via electrospray and multiple reaction monitoring was employed to select both dexamethasone at m/z 393.0/147.1 and testosterone at m/z 289.5/97.3 in the positive ion mode. The calibration curves were linear (r >0.99) ranging from 2.5 to 500 ng/mL with a lower limit of quantitation of 2.5 ng/mL. The relative standard deviation ranged from 1.69 to 9.22% while the relative error ranged from -1.92 to -8.46%. This method was successfully applied to a preclinical pharmacokinetic study of dexamethasone and its pharmacokinetics was characterized by a two-compartment model with first-order absorption in female nude mice. Copyright © 2014 John Wiley & Sons, Ltd.

Chiral Silver-Lanthanide Metal-Organic Frameworks Comprised of One-Dimensional Triple Right-Handed Helical Chains Based on [Ln7(μ3-OH)8]13+ Clusters.

PubMed

Guo, Yan; Zhang, Lijuan; Muhammad, Nadeem; Xu, Yan; Zhou, Yunshan; Tang, Fang; Yang, Shaowei

2018-02-05

Three new isostructural chiral silver-lanthanide heterometal-organic frameworks [Ag 3 Ln 7 (μ 3 -OH) 8 (bpdc) 6 (NO 3 ) 3 (H 2 O) 6 ](NO 3 )·2H 2 O [Ln = Eu (1), Tb (2, Sm (3); H 2 bpdc = 2,2'-bipyridine-3,3'-dicarboxylic acid] based on heptanuclear lanthanide clusters [Ln 7 (μ 3 -OH) 8 ] 13+ comprised of one-dimensional triple right-handed helical chains were hydrothermally synthesized. Various means such as UV-vis spectroscopy, IR spectroscopy, elemental analysis, powder X-ray diffraction, and thermogravimetric/differential thermal analysis were used to characterize the compounds, wherein compound 3 was crystallographically characterized. In the structure of compound 3, eight μ 3 -OH - groups link seven Sm 3+ ions, forming a heptanuclear cluster, [Sm 7 (μ 3 -OH) 8 ] 13+ , and the adjacent [Sm 7 (μ 3 -OH) 8 ] 13+ clusters are linked by the carboxylic groups of bpdc 2- ligands, leading to the formation of a one-dimensional triple right-handed helical chain. The adjacent triple right-handed helical chains are further joined together by coordinating the pyridyl N atoms of the bpdc 2- ligands with Ag + , resulting in a chiral three-dimensional silver(I)-lanthanide(III) heterometal-organic framework with one-dimensional channels wherein NO 3 - anions and crystal lattice H 2 O molecules are trapped. The compounds were studied systematically with respect to their photoluminescence properties and energy-transfer mechanism, and it was found that H 2 bpdc (the energy level for the triplet states of the ligand H 2 bpdc is 21505 cm -1 ) can sensitize Eu 3+ luminescence more effectively than Tb 3+ and Sm 3+ luminescence because of effective energy transfer from bpdc 2- to Eu 3+ under excitation in compound 1.

Quantitative calculations of fluorescence polarization and absorption anisotropy kinetics of double- and triple-chromophore complexes with energy transfer.

PubMed Central

Demidov, A A

1994-01-01

A new method is presented for calculation of the fluorescence depolarization and kinetics of absorption anisotropy for molecular complexes with a limited number of chromophores. The method considers absorption and emission of light by both chromophores, and also energy transfer between them, with regard to their mutual orientations. The chromophores in each individual complex are rigidly positioned. The complexes are randomly distributed and oriented in space, and there is no energy transfer between them. The new "practical" formula for absorption anisotropy and fluorescence depolarization kinetics, P(t) = [3B(t) - 1 + 2A(t)]/[3 + B(t) + 4A(t)], is derived both for double- and triple-chromophore complexes with delta-pulse excitation. The parameter B(t) is given by (a) B(t) = cos2(theta) for double-chromophore complexes, and (b) B(t) = q12(t)cos2(theta 12) + q13(t)-cos2(theta 13) + q23(t)cos2(theta 23) for triple-chromophore complexes, where q12(t) + q13(t) + q23(t) = 1. Here theta ij are the angles between the chromophore transition dipole moments in the individual molecular complex. The parameters qij(t) and A(t) are dependent on chromophore spectroscopic features and on the rates of energy transfer. PMID:7696461

Preparation, structure and some chemistry of FcC[identically equal to]CC[identically equal to]CC[identically equal to]CRu(dppe)Cp

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bruce, Michael I.; Humphrey, Paul A.; Jevric, Martyn

The synthesis of Fc(C{triple_bond}C){sub 3}Ru(dppe)Cp (2) from Fc(C{triple_bond}C){sub 3}SiMe{sub 3} and RuCl(dppe)Cp is described, together with its reactions with tcne to give the tetracyano-dienyl FcC{triple_bond}CC{triple_bond}C{l_brace}C[{triple_bond}C(CN){sub 2}]{r_brace}{sub 2}Ru(dppe)Cp (3) and -cyclobutenyl FcC{triple_bond}CC{triple_bond}C{l_brace}C{triple_bond}CC(CN){sub 2}C(CN){sub 2}{r_brace}Ru(dppe)Cp (4), with Co{sub 2}({mu}-dppm){sub n}(CO){sub 8-2n} (n = 0, 1) to give FcC{sub 2}{l_brace}Co{sub 2}(CO){sub 6}{r_brace}C{sub 2}{l_brace}Co{sub 2}(CO){sub 6}{r_brace}CCRu(dppe)Cp (5) and FcC{triple_bond}CC{triple_bond}CC{sub 2}{l_brace}Co{sub 2}({mu}-dppm)(CO){sub 4}{r_brace}Ru(dppe)Cp (6), respectively, and with Os{sub 3}(CO){sub 10}(NCMe){sub 2} to give Os{sub 3}{l_brace}{mu}{sub 3}-C{sub 2}C{triple_bond}CC{triple_bond}C[Ru(dppe)Cp]{r_brace}(CO){sub 10} (7). On standing in solution, the latter isomerises to the cyclo-metallated derivative Os{sub 3}({mu}-H){l_brace}{mu}{sub 3}-C[Ru(dppe)Cp]CCC[({eta}-C{sub 5}H{sub 3})FeCp]{r_brace}(CO){sub 8} (8). X-ray structural determinations of 1, 2, 6 andmore » 7 are reported.« less

Multiple Reaction Monitoring for Direct Quantitation of Intact Proteins Using a Triple Quadrupole Mass Spectrometer

NASA Astrophysics Data System (ADS)

Wang, Evelyn H.; Combe, Peter C.; Schug, Kevin A.

2016-05-01

Methods that can efficiently and effectively quantify proteins are needed to support increasing demand in many bioanalytical fields. Triple quadrupole mass spectrometry (QQQ-MS) is sensitive and specific, and it is routinely used to quantify small molecules. However, low resolution fragmentation-dependent MS detection can pose inherent difficulties for intact proteins. In this research, we investigated variables that affect protein and fragment ion signals to enable protein quantitation using QQQ-MS. Collision induced dissociation gas pressure and collision energy were found to be the most crucial variables for optimization. Multiple reaction monitoring (MRM) transitions for seven standard proteins, including lysozyme, ubiquitin, cytochrome c from both equine and bovine, lactalbumin, myoglobin, and prostate-specific antigen (PSA) were determined. Assuming the eventual goal of applying such methodology is to analyze protein in biological fluids, a liquid chromatography method was developed. Calibration curves of six standard proteins (excluding PSA) were obtained to show the feasibility of intact protein quantification using QQQ-MS. Linearity (2-3 orders), limits of detection (0.5-50 μg/mL), accuracy (<5% error), and precision (1%-12% CV) were determined for each model protein. Sensitivities for different proteins varied considerably. Biological fluids, including human urine, equine plasma, and bovine plasma were used to demonstrate the specificity of the approach. The purpose of this model study was to identify, study, and demonstrate the advantages and challenges for QQQ-MS-based intact protein quantitation, a largely underutilized approach to date.

Determinations of airborne synthetic musks by polyurethane foam coupled with triple quadrupole gas chromatography tandem mass spectrometer.

PubMed

Wang, I-Ting Ivy; Cheng, Shu-Fang; Tsai, Shih-Wei

2014-02-21

Synthetic musk is widely used in various scented consumer products. However, the exposure via inhalation is often ignored due to pleasant smells. In addition, the information regarding the distribution of synthetic musk in air is limited. Hence, this research is aimed to develop a highly sensitive and widely applicable method for the determination of airborne synthetic musk. In this study, polyurethane foam (PUF) and filter were employed for active air sampling. Microwave assisted extraction (MAE) and nitrogen evaporator were performed for sample preparation. A gas chromatography coupled with triple quadrupole tandem mass spectrometer (GC/MS-MS) with specific multiple reaction monitoring (MRM) transition pairs was applied for sample analysis. Compared with using selected ion monitoring (SIM) mode traditionally, the sensitivities were improved in this study about an order at least. In terms of air concentration, as low as 0.48ngm(-3) can be determined when sampling at 3.5Lmin(-1) for 8h. The method established was further applied to the analysis of synthetic musk compounds in air samples collected in a cosmetics plant. The results showed that the airborne concentrations of gaseous polycyclic musk, gaseous nitro-musk, and particle-phase polycyclic musk were 6.4×10(2), 4.0×10(1) and 3.1×10(2)ngm(-3), respectively. Meanwhile, Cashmeran, Celstolide, Galaxolide, and Tonalide were found as the dominant musk compounds in the factory investigated. Copyright © 2014 Elsevier B.V. All rights reserved.

Structural insights into the stabilization of MALAT1 noncoding RNA by a bipartite triple helix

PubMed Central

Brown, Jessica A.; Bulkley, David; Wang, Jimin; Valenstein, Max L.; Yario, Therese A.; Steitz, Thomas A.; Steitz, Joan A.

2014-01-01

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly-abundant nuclear long noncoding RNA that promotes malignancy. A 3′-stem-loop structure is predicted to confer stability by engaging a downstream A-rich tract in a triple helix, similar to the expression and nuclear retention element (ENE) from the KSHV polyadenylated nuclear RNA. The 3.1-Å resolution crystal structure of the human MALAT1 ENE and A-rich tract reveals a bipartite triple helix containing stacks of five and four U•A-U triples separated by a C+•G-C triplet and C-G doublet, extended by two A-minor interactions. In vivo decay assays indicate that this blunt-ended triple helix, with the 3′ nucleotide in a U•A-U triple, inhibits rapid nuclear RNA decay. Interruption of the triple helix by the C-G doublet induces a “helical reset” that explains why triple-helical stacks longer than six do not occur in nature. PMID:24952594

NIM Realization of the Gallium Triple Point

NASA Astrophysics Data System (ADS)

Xiaoke, Yan; Ping, Qiu; Yuning, Duan; Yongmei, Qu

2003-09-01

In the last three years (1999 to 2001), the gallium triple-point cell has been successfully developed, and much corresponding research has been carried out at the National Institute of Metrology (NIM), Beijing, China. This paper presents the cell design, apparatus and procedure for realizing the gallium triple point, and presents studies on the different freezing methods. The reproducibility is 0.03 mK, and the expanded uncertainty of realization of the gallium triple point is evaluated to be 0.17 mK (p=0.99, k=2.9). Also, the reproducibility of the gallium triple point was compared with that of the triple point of water.

Combinational Deletion of Three Membrane Protein-Encoding Genes Highly Attenuates Yersinia pestis while Retaining Immunogenicity in a Mouse Model of Pneumonic Plague

PubMed Central

Tiner, Bethany L.; Kirtley, Michelle L.; Erova, Tatiana E.; Popov, Vsevolod L.; Baze, Wallace B.; van Lier, Christina J.; Ponnusamy, Duraisamy; Andersson, Jourdan A.; Motin, Vladimir L.; Chauhan, Sadhana

2015-01-01

Previously, we showed that deletion of genes encoding Braun lipoprotein (Lpp) and MsbB attenuated Yersinia pestis CO92 in mouse and rat models of bubonic and pneumonic plague. While Lpp activates Toll-like receptor 2, the MsbB acyltransferase modifies lipopolysaccharide. Here, we deleted the ail gene (encoding the attachment-invasion locus) from wild-type (WT) strain CO92 or its lpp single and Δlpp ΔmsbB double mutants. While the Δail single mutant was minimally attenuated compared to the WT bacterium in a mouse model of pneumonic plague, the Δlpp Δail double mutant and the Δlpp ΔmsbB Δail triple mutant were increasingly attenuated, with the latter being unable to kill mice at a 50% lethal dose (LD50) equivalent to 6,800 LD50s of WT CO92. The mutant-infected animals developed balanced TH1- and TH2-based immune responses based on antibody isotyping. The triple mutant was cleared from mouse organs rapidly, with concurrent decreases in the production of various cytokines and histopathological lesions. When surviving animals infected with increasing doses of the triple mutant were subsequently challenged on day 24 with the bioluminescent WT CO92 strain (20 to 28 LD50s), 40 to 70% of the mice survived, with efficient clearing of the invading pathogen, as visualized in real time by in vivo imaging. The rapid clearance of the triple mutant, compared to that of WT CO92, from animals was related to the decreased adherence and invasion of human-derived HeLa and A549 alveolar epithelial cells and to its inability to survive intracellularly in these cells as well as in MH-S murine alveolar and primary human macrophages. An early burst of cytokine production in macrophages elicited by the triple mutant compared to WT CO92 and the mutant's sensitivity to the bactericidal effect of human serum would further augment bacterial clearance. Together, deletion of the ail gene from the Δlpp ΔmsbB double mutant severely attenuated Y. pestis CO92 to evoke pneumonic plague in a mouse model while retaining the required immunogenicity needed for subsequent protection against infection. PMID:25605764

Combinational deletion of three membrane protein-encoding genes highly attenuates yersinia pestis while retaining immunogenicity in a mouse model of pneumonic plague.

PubMed

Tiner, Bethany L; Sha, Jian; Kirtley, Michelle L; Erova, Tatiana E; Popov, Vsevolod L; Baze, Wallace B; van Lier, Christina J; Ponnusamy, Duraisamy; Andersson, Jourdan A; Motin, Vladimir L; Chauhan, Sadhana; Chopra, Ashok K

2015-04-01

Previously, we showed that deletion of genes encoding Braun lipoprotein (Lpp) and MsbB attenuated Yersinia pestis CO92 in mouse and rat models of bubonic and pneumonic plague. While Lpp activates Toll-like receptor 2, the MsbB acyltransferase modifies lipopolysaccharide. Here, we deleted the ail gene (encoding the attachment-invasion locus) from wild-type (WT) strain CO92 or its lpp single and Δlpp ΔmsbB double mutants. While the Δail single mutant was minimally attenuated compared to the WT bacterium in a mouse model of pneumonic plague, the Δlpp Δail double mutant and the Δlpp ΔmsbB Δail triple mutant were increasingly attenuated, with the latter being unable to kill mice at a 50% lethal dose (LD50) equivalent to 6,800 LD50s of WT CO92. The mutant-infected animals developed balanced TH1- and TH2-based immune responses based on antibody isotyping. The triple mutant was cleared from mouse organs rapidly, with concurrent decreases in the production of various cytokines and histopathological lesions. When surviving animals infected with increasing doses of the triple mutant were subsequently challenged on day 24 with the bioluminescent WT CO92 strain (20 to 28 LD50s), 40 to 70% of the mice survived, with efficient clearing of the invading pathogen, as visualized in real time by in vivo imaging. The rapid clearance of the triple mutant, compared to that of WT CO92, from animals was related to the decreased adherence and invasion of human-derived HeLa and A549 alveolar epithelial cells and to its inability to survive intracellularly in these cells as well as in MH-S murine alveolar and primary human macrophages. An early burst of cytokine production in macrophages elicited by the triple mutant compared to WT CO92 and the mutant's sensitivity to the bactericidal effect of human serum would further augment bacterial clearance. Together, deletion of the ail gene from the Δlpp ΔmsbB double mutant severely attenuated Y. pestis CO92 to evoke pneumonic plague in a mouse model while retaining the required immunogenicity needed for subsequent protection against infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

A Generalized Quantum Theory

NASA Astrophysics Data System (ADS)

Niestegge, Gerd

2014-09-01

In quantum mechanics, the selfadjoint Hilbert space operators play a triple role as observables, generators of the dynamical groups and statistical operators defining the mixed states. One might expect that this is typical of Hilbert space quantum mechanics, but it is not. The same triple role occurs for the elements of a certain ordered Banach space in a much more general theory based upon quantum logics and a conditional probability calculus (which is a quantum logical model of the Lueders-von Neumann measurement process). It is shown how positive groups, automorphism groups, Lie algebras and statistical operators emerge from one major postulate - the non-existence of third-order interference (third-order interference and its impossibility in quantum mechanics were discovered by R. Sorkin in 1994). This again underlines the power of the combination of the conditional probability calculus with the postulate that there is no third-order interference. In two earlier papers, its impact on contextuality and nonlocality had already been revealed.

Optimizing the triple-axis spectrometer PANDA at the MLZ for small samples and complex sample environment conditions

NASA Astrophysics Data System (ADS)

Utschick, C.; Skoulatos, M.; Schneidewind, A.; Böni, P.

2016-11-01

The cold-neutron triple-axis spectrometer PANDA at the neutron source FRM II has been serving an international user community studying condensed matter physics problems. We report on a new setup, improving the signal-to-noise ratio for small samples and pressure cell setups. Analytical and numerical Monte Carlo methods are used for the optimization of elliptic and parabolic focusing guides. They are placed between the monochromator and sample positions, and the flux at the sample is compared to the one achieved by standard monochromator focusing techniques. A 25 times smaller spot size is achieved, associated with a factor of 2 increased intensity, within the same divergence limits, ± 2 ° . This optional neutron focusing guide shall establish a top-class spectrometer for studying novel exotic properties of matter in combination with more stringent sample environment conditions such as extreme pressures associated with small sample sizes.

Collagenolytic Matrix Metalloproteinase Structure-Function Relationships: Insights From Molecular Dynamics Studies.

PubMed

Karabencheva-Christova, Tatyana G; Christov, Christo Z; Fields, Gregg B

2017-01-01

Several members of the zinc-dependent matrix metalloproteinase (MMP) family catalyze collagen degradation. Experimental data reveal a collaboration between different MMP domains in order to achieve efficient collagenolysis. Molecular dynamics (MD) simulations have been utilized to provide atomistic details of the collagenolytic process. The triple-helical structure of collagen exhibits local regions of flexibility, with modulation of interchain salt bridges and water bridges contributing to accessibility of individual chains by the enzyme. In turn, the hemopexin-like (HPX) domain of the MMP initially binds the triple helix and facilitates the presentation of individual strands to active site in the catalytic (CAT) domain. Extensive positive and negative correlated motions are observed between the CAT and HPX domains when collagen is bound. Ultimately, the MD simulation studies have complemented structural (NMR spectroscopy, X-ray crystallography) and kinetic analyses to provide a more detailed mechanistic view of MMP-catalyzed collagenolysis. © 2017 Elsevier Inc. All rights reserved.

A Triple Mutant in the Ω-loop of TEM-1 β-Lactamase Changes the Substrate Profile via a Large Conformational Change and an Altered General Base for Catalysis*

PubMed Central

Stojanoski, Vlatko; Chow, Dar-Chone; Hu, Liya; Sankaran, Banumathi; Gilbert, Hiram F.; Prasad, B. V. Venkataram; Palzkill, Timothy

2015-01-01

β-Lactamases are bacterial enzymes that hydrolyze β-lactam antibiotics. TEM-1 is a prevalent plasmid-encoded β-lactamase in Gram-negative bacteria that efficiently catalyzes the hydrolysis of penicillins and early cephalosporins but not oxyimino-cephalosporins. A previous random mutagenesis study identified a W165Y/E166Y/P167G triple mutant that displays greatly altered substrate specificity with increased activity for the oxyimino-cephalosporin, ceftazidime, and decreased activity toward all other β-lactams tested. Surprisingly, this mutant lacks the conserved Glu-166 residue critical for enzyme function. Ceftazidime contains a large, bulky side chain that does not fit optimally in the wild-type TEM-1 active site. Therefore, it was hypothesized that the substitutions in the mutant expand the binding site in the enzyme. To investigate structural changes and address whether there is an enlargement in the active site, the crystal structure of the triple mutant was solved to 1.44 Å. The structure reveals a large conformational change of the active site Ω-loop structure to create additional space for the ceftazidime side chain. The position of the hydroxyl group of Tyr-166 and an observed shift in the pH profile of the triple mutant suggests that Tyr-166 participates in the hydrolytic mechanism of the enzyme. These findings indicate that the highly conserved Glu-166 residue can be substituted in the mechanism of serine β-lactamases. The results reveal that the robustness of the overall β-lactamase fold coupled with the plasticity of an active site loop facilitates the evolution of enzyme specificity and mechanism. PMID:25713062

Myosins XI-K, XI-1, and XI-2 are required for development of pavement cells, trichomes, and stigmatic papillae in Arabidopsis

PubMed Central

2012-01-01

Background The positioning and dynamics of vesicles and organelles, and thus the growth of plant cells, is mediated by the acto-myosin system. In Arabidopsis there are 13 class XI myosins which mediate vesicle and organelle transport in different cell types. So far the involvement of five class XI myosins in cell expansion during the shoot and root development has been shown, three of which, XI-1, XI-2, and XI-K, are essential for organelle transport. Results Simultaneous depletion of Arabidopsis class XI myosins XI-K, XI-1, and XI-2 in double and triple mutant plants affected the growth of several types of epidermal cells. The size and shape of trichomes, leaf pavement cells and the elongation of the stigmatic papillae of double and triple mutant plants were affected to different extent. Reduced cell size led to significant size reduction of shoot organs in the case of triple mutant, affecting bolt formation, flowering time and fertility. Phenotype analysis revealed that the reduced fertility of triple mutant plants was caused by delayed or insufficient development of pistils. Conclusions We conclude that the class XI myosins XI-K, XI-1 and XI-2 have partially redundant roles in the growth of shoot epidermis. Myosin XI-K plays more important role whereas myosins XI-1 and XI-2 have minor roles in the determination of size and shape of epidermal cells, because the absence of these two myosins is compensated by XI-K. Co-operation between myosins XI-K and XI-2 appears to play an important role in these processes. PMID:22672737

A randomized controlled trial comparing mupirocin versus Polysporin Triple for the prevention of catheter-related infections in peritoneal dialysis patients (the MP3 study).

PubMed

Jassal, Sarbjit V; Lok, Charmaine E

2008-01-01

Peritonitis remains the most serious complication of peritoneal dialysis (PD). Gram-positive organisms are among the most common causes of PD peritonitis; however, recent trends show increasing rates of gram-negative and fungal infections. Strategies to prevent peritonitis include the use of prophylactic topical mupirocin at the site where the PD catheter exits from the abdominal wall; however, mupirocin does not afford protection against gram-negative or fungal infections. The aim of this study is to determine if the incidence of catheter-related infections (exit-site infection, tunnel infection, or peritonitis) is significantly reduced by the routine application of Polysporin Triple antibiotic ointment (Pfizer Canada, Markham, Ontario, Canada) in comparison to mupirocin ointment. The Mupirocin Versus Polysporin Triple Study (MP3) is a multicenter, randomized, double-blinded controlled study comparing Polysporin Triple (P3) against the current standard of care. The aim of the study is to recruit 200 patients being treated with or starting on PD and randomize them to receive either mupirocin or P3 at the catheter exit site. Patients will be followed for 18 months or until death or transfer from PD to an alternate treatment modality. The primary outcome will be the time to first catheter-related infection. Catheter-related infections will be strictly defined using current guidelines and categorized into exit-site infections, infective peritonitis, or tunnel infections. The primary analysis will be an intention-to-treat analysis. The results of this study will help determine if the use of P3 is superior to mupirocin ointment in the prevention of catheter-related infections and will help guide evidence-based best practices.

Relating the variation of secondary structure of gelatin at fish oil-water interface to adsorption kinetics, dynamic interfacial tension and emulsion stability.

PubMed

Liu, Huihua; Wang, Bo; Barrow, Colin J; Adhikari, Benu

2014-01-15

The objectives of this study were to quantify the relationship between secondary structure of gelatin and its adsorption at the fish-oil/water interface and to quantify the implication of the adsorption on the dynamic interfacial tension (DST) and emulsion stability. The surface hydrophobicity of the gelatin solutions decreased when the pH increased from 4.0 to 6.0, while opposite tend was observed in the viscosity of the solution. The DST values decreased as the pH increased from 4.0 to 6.0, indicating that higher positive charges (measured trough zeta potential) in the gelatin solution tended to result in higher DST values. The adsorption kinetics of the gelatin solution was examined through the calculated diffusion coefficients (Deff). The addition of acid promoted the random coil and β-turn structures at the expense of α-helical structure. The addition of NaOH decreased the β-turn and increased the α-helix and random coil. The decrease in the random coil and triple helix structures in the gelatin solution resulted into increased Deff values. The highest diffusion coefficients, the highest emulsion stability and the lowest amount of random coil and triple helix structures were observed at pH=4.8. The lowest amount of random coil and triple helix structures in the interfacial protein layer correlated with the highest stability of the emulsion (highest ESI value). The lower amount of random coil and triple helix structures allowed higher coverage of the oil-water interface by relatively highly ordered secondary structure of gelatin. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bifidobacterium lactis B94 plus inulin for Treatment of Helicobacter pylori infection in children: does it increase eradication rate and patient compliance?

PubMed

Islek, A; Sayar, E; Yilmaz, A; Artan, R

2015-01-01

The aim of this study is to investigate the effects of Bifidobacterium lactis B94 and inulin (synbiotic) treatment on eradication rate and patient compliance in subjects treated for symptomatic H. pylori infection. Patients with symptomatic H. pylori infection were divided into two groups. One group was treated with standard triple therapy (lansoprazole, amoxicillin, and clarithromycin) and B. lactis B94 (5 × 109 CFU/dose) plus inulin (900 mg) twice daily for seven days. The control group was treated with standard triple therapy and placebo. The side effects and eradication rates were evaluated at the end of the study. Ninety-three patients with H. pylori infection were treated with either synbiotic plus triple therapy (n = 47) or placebo plus triple therapy (n = 46). The infection eradication rates were not significantly different between the synbiotic and placebo groups [intent-to-treat (ITT), 80.8% and 67.3%, p = 0.13, respectively; per-protocol (PP), 86.3% and 81.5%, p = 0.55, respectively]. The drug side effects were significantly higher in the placebo group than in the synbiotic group (63% and 17%, respectively, p < 0.01). Although no intolerable adverse side effects were observed in the synbiotic group, intolerable adverse side effects were observed in 13% of the placebo group (p = 0.01). Our results suggest that twice daily 5 × 109 CFU/dose B. lactis B94 plus 900 mg inulin treatment did not have a direct positive effect on the H. pylori eradication rate. However, this treatment had significantly reduced side effects and indirectly increased eradication rates by increasing patient compliance. © Acta Gastro-Enterologica Belgica.

Efficacy, Safety, and Pharmacokinetics of Coadministered Diethylcarbamazine, Albendazole, and Ivermectin for Treatment of Bancroftian Filariasis.

PubMed

Thomsen, Edward K; Sanuku, Nelly; Baea, Manasseh; Satofan, Samson; Maki, Elit; Lombore, Bart; Schmidt, Mark S; Siba, Peter M; Weil, Gary J; Kazura, James W; Fleckenstein, Lawrence L; King, Christopher L

2016-02-01

Available treatments for lymphatic filariasis (LF) are limited in their longterm clearance of microfilaria from the blood. The safety and efficacy of a single-dose triple-drug therapy of the antifilarial drugs diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB) for LF are unknown. We performed a pilot study to test the efficacy, safety, and pharmacokinetics of single-dose DEC, IVM, and ALB in Wuchereria bancrofti-infected Papua New Guineans. Adults were randomized into 2 treatment arms, DEC 6 mg/kg + ALB 400 mg (N = 12) or DEC 6 mg/kg + ALB 400 mg + IVM 200 μg/kg (N = 12), and monitored for microfilaria, parasite antigenemia, adverse events (AEs), and serum drug levels. Triple-drug therapy induced >2-log reductions in microfilaria levels at 36 and 168 hours after treatment compared with approximately 1-log reduction with 2 drugs. All 12 individuals who received 3 drugs were microfilaria negative 1 year after treatment, whereas 11 of 12 individuals in the 2-drug regimen were microfilaria positive. In 6 participants followed 2 years after treatment, those who received 3 drugs remained microfilaria negative. AEs, particularly fever, myalgias, pruritus, and proteinuria/hematuria, occurred in 83% vs 50% of those receiving triple-drug compared to 2-drug treatment respectively (P = .021); all resolved within 7 days after treatment. No serious AEs were observed in either group. There was no significant effect of IVM on DEC or ALB drug levels. Triple-drug therapy is safe and more effective than DEC + ALB for Bancroftian filariasis and has the potential to accelerate elimination of lymphatic filariasis. NCT01975441. © The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Evaluation of the Unique and Specific Contributions of Dimensions of the Triple Vulnerability Model to the Prediction of DSM-IV Anxiety and Mood Disorder Constructs

PubMed Central

Brown, Timothy A.; Naragon-Gainey, Kristin

2013-01-01

The triple vulnerability model (Barlow, 2000, 2002) posits that three vulnerabilities contribute to the etiology of emotional disorders: (1) general biological vulnerability (i.e., dimensions of temperament such as neuroticism and extraversion); (2) general psychological vulnerability (i.e., perceived control over life stress and emotional states); (3) disorder-specific psychological vulnerability (e.g., thought-action fusion for obsessive-compulsive disorder, OCD). Despite the prominence of this model, a comprehensive empirical evaluation has not yet been undertaken. The current study used structural equation modeling to test the triple vulnerability model in a large clinical sample (N = 700), focusing on vulnerabilities for depression, social phobia, generalized anxiety disorder (GAD), and OCD. Specifically, we examined the incremental prediction of each level of the triple vulnerability model for each disorder, with the following putative disorder-specific psychological vulnerabilities: thought-action fusion (TAF) for OCD, the dysfunctional attitudes (DAS) for depression, and intolerance of uncertainty (IoU) for GAD. In the final model that included all three levels of vulnerabilities, neuroticism had significant direct effects on all four disorder constructs, and extraversion was inversely associated with depression and social phobia. However, perceived control was significantly associated with GAD and OCD only. Of the disorder-specific psychological vulnerabilities, TAF was significantly and specifically related to OCD. In contrast, DAS and IoU were not significant predictors of depression and GAD respectively, instead contributing to other disorders. The results are discussed in regard to structural models of the emotional disorders and the various roles of general and specific vulnerability dimensions in the onset, severity, and temporal course of psychopathology. PMID:23611077

An N-terminal glycine to cysteine mutation in the collagen COL1A1 gene produces moderately severe osteogenesis imperfecta

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wilcox, W.; Scott, L.; Cohn, D.

Osteogenesis imperfecta (OI) is usually due to mutations in the type I procollagen genes COL1A1 and COL1A2. Point mutations close to the N-terminus are generally milder than those near the C-terminus of the molecule (the gradient hypothesis of collagen mutations). We describe a patient with moderately severe OI due to a mutation in the N-terminal portion of the triple helical domain of the {alpha}1(I) chain. Electrophoretic analysis of collagen isolated from fibroblast cultures suggested the abnormal presence of a cysteine in the N-terminal portion of the {alpha}1(I) chain. Five overlapping DNA fragments amplified from fibroblast RNA were screened for mutationsmore » using single strand conformational polymorphism (SSCP) and heteroduplex analyses. Direct DNA sequence analysis of the single positive fragment demonstrated a G to T transversion, corresponding to a glycine to cysteine substitution at position 226 of the triple helical domain of the {alpha}1(I) chain. The mutation was confirmed by restriction enzyme analysis of amplified genomic DNA. The mutation was not present in fibroblasts from either phenotypically normal parent. Combining this mutation with other reported mutations, glycine to cysteine substitutions at positions 205, 211, 223, and 226 produce a moderately severe phenotype whereas flanking mutations at positions 175 and 382 produce a mild phenotype. This data supports a regional rather than a gradient model of the relationship between the nature and location of type I collagen mutations and OI phenotype.« less

Imaging features of breast cancers on digital breast tomosynthesis according to molecular subtype: association with breast cancer detection.

PubMed

Lee, Su Hyun; Chang, Jung Min; Shin, Sung Ui; Chu, A Jung; Yi, Ann; Cho, Nariya; Moon, Woo Kyung

2017-12-01

To evaluate imaging features of breast cancers on digital breast tomosynthesis (DBT) according to molecular subtype and to determine whether the molecular subtype affects breast cancer detection on DBT. This was an institutional review board--approved study with a waiver of informed consent. DBT findings of 288 invasive breast cancers were reviewed according to Breast Imaging Reporting and Data System lexicon. Detectability of breast cancer was quantified by the number of readers (0-3) who correctly detected the cancer in an independent blinded review. DBT features and the cancer detectability score according to molecular subtype were compared using Fisher's exact test and analysis of variance. Of 288 invasive cancers, 194 were hormone receptor (HR)-positive, 48 were human epidermal growth factor receptor 2 (HER2) positive and 46 were triple negative breast cancers. The most common DBT findings were irregular spiculated masses for HR-positive cancer, fine pleomorphic or linear branching calcifications for HER2 positive cancer and irregular masses with circumscribed margins for triple negative breast cancers (p < 0.001). Cancer detectability on DBT was not significantly different according to molecular subtype (p = 0.213) but rather affected by tumour size, breast density and presence of mass or calcifications. Breast cancers showed different imaging features according to molecular subtype; however, it did not affect the cancer detectability on DBT. Advances in knowledge: DBT showed characteristic imaging features of breast cancers according to molecular subtype. However, cancer detectability on DBT was not affected by molecular subtype of breast cancers.

Accurate inclusion mass screening: a bridge from unbiased discovery to targeted assay development for biomarker verification.

PubMed

Jaffe, Jacob D; Keshishian, Hasmik; Chang, Betty; Addona, Theresa A; Gillette, Michael A; Carr, Steven A

2008-10-01

Verification of candidate biomarker proteins in blood is typically done using multiple reaction monitoring (MRM) of peptides by LC-MS/MS on triple quadrupole MS systems. MRM assay development for each protein requires significant time and cost, much of which is likely to be of little value if the candidate biomarker is below the detection limit in blood or a false positive in the original discovery data. Here we present a new technology, accurate inclusion mass screening (AIMS), designed to provide a bridge from unbiased discovery to MS-based targeted assay development. Masses on the software inclusion list are monitored in each scan on the Orbitrap MS system, and MS/MS spectra for sequence confirmation are acquired only when a peptide from the list is detected with both the correct accurate mass and charge state. The AIMS experiment confirms that a given peptide (and thus the protein from which it is derived) is present in the plasma. Throughput of the method is sufficient to qualify up to a hundred proteins/week. The sensitivity of AIMS is similar to MRM on a triple quadrupole MS system using optimized sample preparation methods (low tens of ng/ml in plasma), and MS/MS data from the AIMS experiments on the Orbitrap can be directly used to configure MRM assays. The method was shown to be at least 4-fold more efficient at detecting peptides of interest than undirected LC-MS/MS experiments using the same instrumentation, and relative quantitation information can be obtained by AIMS in case versus control experiments. Detection by AIMS ensures that a quantitative MRM-based assay can be configured for that protein. The method has the potential to qualify large number of biomarker candidates based on their detection in plasma prior to committing to the time- and resource-intensive steps of establishing a quantitative assay.

A Targeted RNAi Screen of the Breast Cancer Genome Identifies KIF14 and TLN1 as Genes That Modulate Docetaxel Chemosensitivity in Triple-Negative Breast Cancer

PubMed Central

Singel, Stina Mui; Cornelius, Crystal; Batten, Kimberly; Fasciani, Gail; Wright, Woodring E.; Lum, Lawrence; Shay, Jerry W.

2015-01-01

Purpose To identify biomarkers within the breast cancer genome that may predict chemosensitivity in breast cancer. Experimental Design We conducted an RNA interference (RNAi) screen within the breast cancer genome for genes whose loss-of-function enhanced docetaxel chemosensitivity in an estrogen receptor–negative, progesterone receptor–negative, and Her2-negative (ER−, PR−, and Her2−, respectively) breast cancer cell line, MDA-MB-231. Top candidates were tested for their ability to modulate chemosensitivity in 8 breast cancer cell lines and to show in vivo chemosensitivity in a mouse xenograft model. Results From ranking chemosensitivity of 328 short hairpin RNA (shRNA) MDA-MB-231 cell lines (targeting 133 genes with known somatic mutations in breast cancer), we focused on the top two genes, kinesin family member 14 (KIF14) and talin 1 (TLN1). KIF14 and TLN1 loss-of-function significantly enhanced chemosensitivity in four triple-negative breast cancer (TNBC) cell lines (MDA-MB-231, HCC38, HCC1937, and Hs478T) but not in three hormone receptor–positive cell lines (MCF7, T47D, and HCC1428) or normal human mammary epithelial cells (HMEC). Decreased expression of KIF14, but not TLN1, also enhanced docetaxel sensitivity in a Her2-amplified breast cancer cell line, SUM190PT. Higher KIF14 and TLN1 expressions are found in TNBCs compared with the other clinical subtypes. Mammary fat pad xenografts of KIF14- and TLN1-deficient MDA-MB-231 cells revealed reduced tumor mass compared with control MDA-MB-231 cells after chemotherapy. KIF14 expression is also prognostic of relapse-free and overall survival in representative breast cancer expression arrays. Conclusion KIF14 and TLN1 are modulators of response to docetaxel and potential therapeutic targets in TNBC. PMID:23479679

Plasma Pharmacokinetic Determination of Canagliflozin and Its Metabolites in a Type 2 Diabetic Rat Model by UPLC-MS/MS.

PubMed

Dong, Song-Tao; Niu, Hui-Min; Wu, Yin; Jiang, Jia-Lei; Li, Ying; Jiang, Kun-Yu; Wang, Xin; Zhang, Mao-Fan; Han, Ming-Feng; Meng, Sheng-Nan

2018-05-20

Canagliflozin is a novel, orally selective inhibitor of sodium-dependent glucose co-transporter-2 (SGLT2) for the treatment of patients with type 2 diabetes mellitus. In this study, a sensitive and efficient UPLC-MS/MS method for the quantification of canagliflozin and its metabolites in rat plasma was established and applied to pharmacokinetics in a type 2 diabetic rat model. We firstly investigated the pharmacokinetic changes of canagliflozin and its metabolites in type 2 diabetic rats in order to use canagliflozin more safely, reasonably and effectively. We identified three types of O-glucuronide metabolites (M5, M7 and M17), two kinds of oxidation metabolites (M8 and M9) and one oxidation and glucuronide metabolite (M16) using API 5600 triple-TOF-MS/MS. Following liquid⁻liquid extraction by tert-butyl methyl ether, chromatographic separation of canagliflozin and its metabolites were performed on a Waters XBridge BEH C18 column (100 × 2.1 mm, 2.5 μm) using 0.1% acetonitrile⁻formic acid (75:15, v / v ) as the mobile phase at a flow rate of 0.7 mL/min. Selected ion monitoring transitions of m / z 462.00→191.10, 451.20→153.10, 638.10→191.10 and 478.00→267.00 were chosen to quantify canagliflozin, empagliflozin (IS), O-glucuronide metabolites (M5, M7 and M17), and oxidation metabolites (M9) using an API 5500-triple-MS/MS in the positive electrospray ionization mode. The validation of the method was found to be of sufficient specificity, accuracy and precision. The pathological condition of diabetes could result in altered pharmacokinetic behaviors of canagliflozin and its metabolites. The pharmacokinetic parameters (AUC 0⁻t , AUC 0⁻∞ , CL z /F, and V z /F) of canagliflozin were significantly different between the CTRL and DM group rats ( p < 0.05 or p < 0.01), which may subsequently cause different therapeutic effects.

Determination of Albendazole and Metabolites in Silkworm Bombyx mori Hemolymph by Ultrafast Liquid Chromatography Tandem Triple Quadrupole Mass Spectrometry

PubMed Central

Li, Li; Xing, Dong-Xu; Li, Qing-Rong; Xiao, Yang; Ye, Ming-Qiang; Yang, Qiong

2014-01-01

Albendazole is a broad-spectrum parasiticide with high effectiveness and low host toxicity. No method is currently available for measuring albendazole and its metabolites in silkworm hemolymph. This study describes a rapid, selective, sensitive, synchronous and reliable detection method for albendazole and its metabolites in silkworm hemolymph using ultrafast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-MS/MS). The method is liquid-liquid extraction followed by UFLC separation and quantification in an MS/MS system with positive electrospray ionization in multiple reaction monitoring mode. Precursor-to-product ion transitions were monitored at 266.100 to 234.100 for albendazole (ABZ), 282.200 to 208.100 for albendazole sulfoxide (ABZSO), 298.200 to 159.100 for albendazole sulfone (ABZSO2) and 240.200 to 133.100 for albendazole amino sulfone (ABZSO2-NH2). Calibration curves had good linearities with R2 of 0.9905–0.9972. Limits of quantitation (LOQs) were 1.32 ng/mL for ABZ, 16.67 ng/mL for ABZSO, 0.76 ng/mL for ABZSO2 and 5.94 ng/mL for ABZSO2-NH2. Recoveries were 93.12%–103.83% for ABZ, 66.51%–108.51% for ABZSO, 96.85%–105.6% for ABZSO2 and 96.46%–106.14% for ABZSO2-NH2, (RSDs <8%). Accuracy, precision and stability tests showed acceptable variation in quality control (QC) samples. This analytical method successfully determined albendazole and its metabolites in silkworm hemolymph in a pharmacokinetic study. The results of single-dose treatment suggested that the concentrations of ABZ, ABZSO and ABZSO2 increased and then fell, while ABZSO2-NH2 level was low without obvious change. Different trends were observed for multi-dose treatment, with concentrations of ABZSO and ABZSO2 rising over time. PMID:25255321

Determination of albendazole and metabolites in silkworm Bombyx mori hemolymph by ultrafast liquid chromatography tandem triple quadrupole mass spectrometry.

PubMed

Li, Li; Xing, Dong-Xu; Li, Qing-Rong; Xiao, Yang; Ye, Ming-Qiang; Yang, Qiong

2014-01-01

Albendazole is a broad-spectrum parasiticide with high effectiveness and low host toxicity. No method is currently available for measuring albendazole and its metabolites in silkworm hemolymph. This study describes a rapid, selective, sensitive, synchronous and reliable detection method for albendazole and its metabolites in silkworm hemolymph using ultrafast liquid chromatography tandem triple quadrupole mass spectrometry (UFLC-MS/MS). The method is liquid-liquid extraction followed by UFLC separation and quantification in an MS/MS system with positive electrospray ionization in multiple reaction monitoring mode. Precursor-to-product ion transitions were monitored at 266.100 to 234.100 for albendazole (ABZ), 282.200 to 208.100 for albendazole sulfoxide (ABZSO), 298.200 to 159.100 for albendazole sulfone (ABZSO2) and 240.200 to 133.100 for albendazole amino sulfone (ABZSO2-NH2). Calibration curves had good linearities with R2 of 0.9905-0.9972. Limits of quantitation (LOQs) were 1.32 ng/mL for ABZ, 16.67 ng/mL for ABZSO, 0.76 ng/mL for ABZSO2 and 5.94 ng/mL for ABZSO2-NH2. Recoveries were 93.12%-103.83% for ABZ, 66.51%-108.51% for ABZSO, 96.85%-105.6% for ABZSO2 and 96.46%-106.14% for ABZSO2-NH2, (RSDs <8%). Accuracy, precision and stability tests showed acceptable variation in quality control (QC) samples. This analytical method successfully determined albendazole and its metabolites in silkworm hemolymph in a pharmacokinetic study. The results of single-dose treatment suggested that the concentrations of ABZ, ABZSO and ABZSO2 increased and then fell, while ABZSO2-NH2 level was low without obvious change. Different trends were observed for multi-dose treatment, with concentrations of ABZSO and ABZSO2 rising over time.

Micro-pulverized extraction pretreatment for highly sensitive analysis of 11-nor-9-carboxy-Δ(9)-tetrahydrocannabinol in hair by liquid chromatography/tandem mass spectrometry.

PubMed

Kuwayama, Kenji; Miyaguchi, Hajime; Yamamuro, Tadashi; Tsujikawa, Kenji; Kanamori, Tatsuyuki; Iwata, Yuko T; Inoue, Hiroyuki

2015-11-30

A primary metabolite of Δ(9) -tetrahydrocannabinol, 11-nor-9-carboxytetrahydrocannabinol (THC-COOH), serves as an effective indicator for cannabis intake. According to the recommendations of the Society of Hair Testing, at least 0.2 pg/mg of THC-COOH (cut-off level) must be present in a hair sample to constitute a positive result in a drug test. Typically, hair is digested with an alkaline solution and is subjected to gas chromatography/tandem mass spectrometry (GC/MS/MS) with negative ion chemical ionization (NICI). It is difficult to quantify THC-COOH at the cut-off level using liquid chromatography/tandem mass spectrometry (LC/MS/MS) without acquisition of second-generation product ions in triple quadrupole-ion trap mass spectrometers, because large amounts of matrix components in the low-mass range produced by digestion interfere with the THC-COOH peak. Using the typical pretreatment method (alkaline dissolution) and micro-pulverized extraction (MPE) with a stainless bullet, we compared the quantification of THC-COOH using GC/MS/MS and LC/MS/MS. MPE reduced the amount of matrix components in the low-mass range and enabled the quantification of THC-COOH at 0.2 pg/mg using a conventional triple quadrupole liquid chromatograph coupled to a mass spectrometer. On the other hand, the MPE pretreatment was unsuitable for GC/MS/MS, probably due to matrix components in the high-mass range. The proper combination of pretreatments and instrumental analyses was shown to be important for detecting trace amounts of THC-COOH in hair. In MPE, samples can be prepared rapidly, and LC/MS/MS is readily available, unlike GC/MS/MS with NICI. The combination of MPE and LC/MS/MS might therefore be used in the initial screening for THC-COOH in hair prior to confirmatory analysis using GC/MS/MS with NICI. Copyright © 2015 John Wiley & Sons, Ltd.

Dysfunction in gastric myoelectric and motor activity in Helicobacter pylori positive gastritis patients with non-ulcer dyspesia.

PubMed

Thor, P; Lorens, K; Tabor, S; Herman, R; Konturek, J W; Konturek, S J

1996-09-01

Helicobacter pylori (Hp) infection has been shown to affect gastric acid secretion and the somatostatin-gastrin ratio but its effects on gastric motility have not been evaluated. This study was carried out in 12 patients (10 males and 2 females, mean age 33 +/- 6 yrs) who underwent endoscopy and Campylobacter-like Organism (CLO)-test. All patients were found initially to be Hp positive according to CLO-test. Gastric emptying was evaluated by measuring antral diameter with ultrasonography (Hitachi EUB 240) in fasted and fed patients. Electrogastrography (EGG) with antral manometry were done 5 h before and 4 h after a meal before the therapy and one month after the eradication with triple therapy (lanzoprazole 30 mg daily- 2 x 250 mg clarithromycin 500 mg t.i.d.-3 x 500 mg and metronidazole 500 mg b.i.d.-2 x 500 mg). In Hp positive patients before the triple therapy the mean fasted antral diameter was 4.3 cm2, initial EGG showed significant dysrhythmia of electrical control activity (ECA) with tachygastria up to 25% of recording time in 9 of 12 Hp positive patients without normal increase of the power of signal in any of tested subjects. In 7 Hp positive fasted antral manometry failed to exhibit gastric phases III of the migrating motor complex (MMC). Hp eradication was accomplished in 10 of 12 examined patients and this was followed by a decrease in tachygastria to 3 cpm rhythm with an increase of the ECA power after meal. Phase III of MMC was observed again in 7 Hp negative patients with a decrease of fasted antral diameter (p < 0.05). Fasted and fed antral motility pattern increased after eradication. Two patients remained Hp positive after standard therapy. We conclude that most symptomatic non ulcer dyspeptic Hp positive patients show changes in ECA and antral hypomotility that are associated with Hp infections.

Platinum(II) 1,10-phenanthroline complexes of acetylides containing redox-active groups.

PubMed

Siemeling, Ulrich; Bausch, Kirstin; Fink, Heinrich; Bruhn, Clemens; Baldus, Marc; Angerstein, Brigitta; Plessow, Regina; Brockhinke, Andreas

2005-07-21

The new diimine ligand 3,8-di-n-pentyl-4,7-di(phenylethynyl)-1,10-phenanthroline (1) was used for the synthesis of a range of Pt(II) complexes, viz.[Pt(1)Cl2], [Pt(1)(C triple bond C-Ph)2], [Pt(1)(C triple bond C-Fc)2] and [Pt(1)(C triple bond C-p-C6H4-C triple bond C-Fc)2](Fc = ferrocenyl). Crystal structure analyses were performed for [Pt(1)Cl2] and [Pt(1)(C triple bond C-Ph)2] and revealed that the di(acetylide)pi-tweezer of the latter binds a molecule of chloroform through C-H...pi hydrogen bonds. The redox and optical properties of 1 and its complexes were investigated by (spectro-)electrochemistry, UV-Vis and luminescence spectroscopy, and an energy level diagram was derived for [Pt(1)(C triple bond C-Fc)2] and related compounds on the basis of the data collected. The ferrocenyl-substituted Pt(II) complexes are donor-sensitiser assemblies. Intramolecular quenching of the photoexcited Pt(II) diimine unit leads to very short luminescence lifetimes for [Pt(1)(C triple bond C-p-C(6)H(4)-C triple bond C-Fc)2](2 ns) and [Pt(1)(C triple bond C-Fc)2](0.3 ns), as opposed to [Pt(1)(C triple bond C-Ph)2](0.7 micros). Excimer formation has been observed for [Pt(1)(C triple bond C-Ph)(2)] at room temperature in dichloromethane and at low temperatures in frozen glassy dichloromethane and 2-methyltetrahydrofuran solution, but not in the solid state.

Ligand-to-ligand charge-transfer transitions of platinum(II) complexes with arylacetylide ligands with different chain lengths: spectroscopic characterization, effect of molecular conformations, and density functional theory calculations.

PubMed

Tong, Glenna So Ming; Law, Yuen-Chi; Kui, Steven C F; Zhu, Nianyong; Leung, King Hong; Phillips, David Lee; Che, Chi-Ming

2010-06-11

The complexes [Pt(tBu(3)tpy){C[triple bond]C(C(6)H(4)C[triple bond]C)(n-1)R}](+) (n = 1: R = alkyl and aryl (Ar); n = 1-3: R = phenyl (Ph) or Ph-N(CH(3))(2)-4; n = 1 and 2, R = Ph-NH(2)-4; tBu(3)tpy = 4,4',4''-tri-tert-butyl-2,2':6',2''-terpyridine) and [Pt(Cl(3)tpy)(C[triple bond]CR)](+) (R = tert-butyl (tBu), Ph, 9,9'-dibutylfluorene, 9,9'-dibutyl-7-dimethyl-amine-fluorene; Cl(3)tpy = 4,4',4''-trichloro-2,2':6',2''-terpyridine) were prepared. The effects of substituent(s) on the terpyridine (tpy) and acetylide ligands and chain length of arylacetylide ligands on the absorption and emission spectra were examined. Resonance Raman (RR) spectra of [Pt(tBu(3)tpy)(C[triple bond]CR)](+) (R = n-butyl, Ph, and C(6)H(4)-OCH(3)-4) obtained in acetonitrile at 298 K reveal that the structural distortion of the C[triple bond]C bond in the electronic excited state obtained by 502.9 nm excitation is substantially larger than that obtained by 416 nm excitation. Density functional theory (DFT) and time-dependent DFT (TDDFT) calculations on [Pt(H(3)tpy)(C[triple bond]CR)](+) (R = n-propyl (nPr), 2-pyridyl (Py)), [Pt(H(3)tpy){C[triple bond]C(C(6)H(4)C[triple bond]C)(n-1)Ph}](+) (n = 1-3), and [Pt(H(3)tpy){C[triple bond]C(C(6)H(4)C[triple bond]C)(n-1)C(6)H(4)-N(CH(3))(2)-4}](+)/+H(+) (n = 1-3; H(3)tpy = nonsubstituted terpyridine) at two different conformations were performed, namely, with the phenyl rings of the arylacetylide ligands coplanar ("cop") with and perpendicular ("per") to the H(3)tpy ligand. Combining the experimental data and calculated results, the two lowest energy absorption peak maxima, lambda(1) and lambda(2), of [Pt(Y(3)tpy)(C[triple bond]CR)](+) (Y = tBu or Cl, R = aryl) are attributed to (1)[pi(C[triple bond]CR)-->pi*(Y(3)tpy)] in the "cop" conformation and mixed (1)[d(pi)(Pt)-->pi*(Y(3)tpy)]/(1)[pi(C[triple bond]CR)-->pi*(Y(3)tpy)] transitions in the "per" conformation. The lowest energy absorption peak lambda(1) for [Pt(tBu(3)tpy){C[triple bond]C(C(6)H(4)C[triple bond]C)(n-1)C(6)H(4)-H-4}](+) (n = 1-3) shows a redshift with increasing chain length. However, for [Pt(tBu(3)tpy){C[triple bond]C(C6H4C[triple bond]C)(n-1)C(6)H(4)-N(CH(3))(2)-4}](+) (n = 1-3), lambda(1) shows a blueshift with increasing chain length n, but shows a redshift after the addition of acid. The emissions of [Pt(Y(3)tpy)(C[triple bond]CR)](+) (Y = tBu or Cl) at 524-642 nm measured in dichloromethane at 298 K are assigned to the (3)[pi(C[triple bond]CAr)-->pi*(Y(3)tpy)] excited states and mixed (3)[d(pi)(Pt)-->pi*(Y(3)tpy)]/(3)[pi(C[triple bond]C)-->pi*(Y(3)tpy)] excited states for R = aryl and alkyl groups, respectively. [Pt(tBu(3)tpy){C[triple bond]C(C(6)H(4)C[triple bond]C)(n-1)C(6)H(4)-N(CH(3))(2)-4}](+) (n = 1 and 2) are nonemissive, and this is attributed to the small energy gap between the singlet ground state (S(0)) and the lowest triplet excited state (T(1)).

TU-G-204-09: The Effects of Reduced- Dose Lung Cancer Screening CT On Lung Nodule Detection Using a CAD Algorithm

DOE Office of Scientific and Technical Information (OSTI.GOV)

Young, S; Lo, P; Kim, G

2015-06-15

Purpose: While Lung Cancer Screening CT is being performed at low doses, the purpose of this study was to investigate the effects of further reducing dose on the performance of a CAD nodule-detection algorithm. Methods: We selected 50 cases from our local database of National Lung Screening Trial (NLST) patients for which we had both the image series and the raw CT data from the original scans. All scans were acquired with fixed mAs (25 for standard-sized patients, 40 for large patients) on a 64-slice scanner (Sensation 64, Siemens Healthcare). All images were reconstructed with 1-mm slice thickness, B50 kernel.more » 10 of the cases had at least one nodule reported on the NLST reader forms. Based on a previously-published technique, we added noise to the raw data to simulate reduced-dose versions of each case at 50% and 25% of the original NLST dose (i.e. approximately 1.0 and 0.5 mGy CTDIvol). For each case at each dose level, the CAD detection algorithm was run and nodules greater than 4 mm in diameter were reported. These CAD results were compared to “truth”, defined as the approximate nodule centroids from the NLST reports. Subject-level mean sensitivities and false-positive rates were calculated for each dose level. Results: The mean sensitivities of the CAD algorithm were 35% at the original dose, 20% at 50% dose, and 42.5% at 25% dose. The false-positive rates, in decreasing-dose order, were 3.7, 2.9, and 10 per case. In certain cases, particularly in larger patients, there were severe photon-starvation artifacts, especially in the apical region due to the high-attenuating shoulders. Conclusion: The detection task was challenging for the CAD algorithm at all dose levels, including the original NLST dose. However, the false-positive rate at 25% dose approximately tripled, suggesting a loss of CAD robustness somewhere between 0.5 and 1.0 mGy. NCI grant U01 CA181156 (Quantitative Imaging Network); Tobacco Related Disease Research Project grant 22RT-0131.« less

Rising School Attendance in Rural India: An Evaluation of the Effects of Major Educational Reforms

ERIC Educational Resources Information Center

Datta Gupta, Nabanita; Dubey, Amaresh; Simonsen, Marianne

2018-01-01

We evaluate the impact of educational reforms starting from the mid-1990s in India on the school attendance rate of low-income rural children aged 6-14 compared to ineligible rural children, employing NSSO data from 1983 to 2004/2005. We estimate a triple difference model allowing for differential (linear) trends and find a positive causal effect…

Treatment and prognosis of breast cancer patients with brain metastases according to intrinsic subtype.

PubMed

Kuba, Sayaka; Ishida, Mayumi; Nakamura, Yoshiaki; Yamanouchi, Kosho; Minami, Shigeki; Taguchi, Kenichi; Eguchi, Susumu; Ohno, Shinji

2014-11-01

How breast cancer subtypes should affect treatment decisions for breast cancer patients with brain metastases is unclear. We analyzed local brain metastases treatments and their outcomes according to subtype in patients with breast cancer and brain metastases. We reviewed records and database information for women treated at the National Kyushu Cancer Center between 2001 and 2010. Patients were divided into three breast cancer subtype groups: Luminal (estrogen receptor positive and/or progesterone receptor positive, but human epidermal growth factor receptor 2 negative); human epidermal growth factor receptor 2 positive and triple negative (estrogen receptor negative, progesterone receptor negative and human epidermal growth factor receptor 2 negative). Of 524 advanced breast cancer patients, we reviewed 65 (12%) with brain metastases and records showing estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status, as well as outcome data; there were 26 (40%) Luminal, 26 (40%) had human epidermal growth factor receptor 2 and 13 (20%) had triple negative subtypes. There was no statistical difference in the number of brain metastases among subtypes; however, rates of stereotactic radiosurgery or surgery for brain metastases differed significantly by subtype (human epidermal growth factor receptor 2: 81%, Luminal: 42% and triple negative: 47%; P = 0.03). Patients having the human epidermal growth factor receptor 2 subtype, a performance status of ≤1 and ≤4 brain metastases, who underwent systemic therapy after brain metastases and underwent stereotactic radiosurgery or surgery, were predicted to have longer overall survival after brain metastases. Multivariate analysis demonstrated that not having systemic therapy and not having the human epidermal growth factor receptor 2 subtype were independent factors associated with an increased risk of death (hazard ratio 2.4, 95% confidence interval 1.01-5.6; P = 0.05 and hazard ratio 2.9, 95% confidence interval 1.5-5.8; P = 0.003, respectively). Our study showed that local brain treatments and prognosis differed by subtype in breast cancer patients with brain metastases. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effects of novel triple-stage antimalarial ionic liquids on lipid membrane models.

PubMed

Ferraz, Ricardo; Pinheiro, Marina; Gomes, Ana; Teixeira, Cátia; Prudêncio, Cristina; Reis, Salette; Gomes, Paula

2017-09-01

Primaquine-based ionic liquids, obtained by acid-base reaction between parent primaquine and cinnamic acids, were recently found as triple-stage antimalarial hits. These ionic compounds displayed significant activity against both liver- and blood-stage Plasmodium parasites, as well as against stage V P. falciparum parasites. Remarkably, blood-stage activity of the ionic liquids against both chloroquine-sensitive (3D7) and resistant (Dd2) P. falciparum strains was clearly superior to those of the respective covalent (amide) analogues and of parent primaquine. Having hypothesized that such behaviour might be ascribed to an enhanced ability of the ionic compounds to permeate into Plasmodium-infected erythrocytes, we have carried out a differential scanning calorimetry-based study of the interactions between the ionic liquids and membrane models. Results provide evidence, at the molecular level, that the primaquine-derived ionic liquids may contribute to an increased permeation of the parent drug into malaria-infected erythrocytes, which has relevant implications towards novel antimalarial approaches based on ionic liquids. Copyright © 2017 Elsevier Ltd. All rights reserved.

Fast analysis of triterpenoids in Ganoderma lucidum spores by ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry.

PubMed

Yan, Zhou; Xia, Bing; Qiu, Ming Hua; Li Sheng, Ding; Xu, Hong Xi

2013-11-01

A rapid and reliable method was established for simultaneous determination of main triterpenoids in Ganoderma lucidum spores using ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-TQ-MS). The established method was validated in terms of linearity, sensitivity, precision, accuracy and stability, and was successfully applied to determine the contents of 10 main triterpenoids in different batches of G. lucidum spores. The analysis results showed that moderate levels of triterpenoids were found in G. lucidum spores. In addition, a MS full scan with a daughter ion scan experiment was performed to identify the potential derivatives of triterpenoids present in G. lucidum spores. As a result, a total of 22 triterpenoids from different G. lucidum spores were unequivocally or tentatively identified via comparisons with authentic standards and literatures. This method provides both qualitative and quantitative results without the need for repetitive UPLC-MS analyses, thereby increasing efficiency and productivity, making it suitable for high-throughput applications. Copyright © 2013 John Wiley & Sons, Ltd.

Development of high Tc (greater than 110K) Bi, Tl and Y-based materials as superconducting circuit elements

NASA Technical Reports Server (NTRS)

Haertling, Gene; Grabert, Gregory; Gilmour, Phillip

1991-01-01

Experimental work was continued on the development and characterization of bulk and hot pressed powders and tapecast materials in the Bi-Sr-Ca-Cu-O and Tl-Ba-Ca-Cu-O systems. A process for producing warp-free, sintered, superconducting tapes of Bi composition Bi1Sr2Ca2 Cu3O(x) was established. The procedure requires a triple calcination at 830 C for 24 hours and sintering at 845 C from 20 to 200 hours. Hot pressing the triple calcined powder at 845 C for 6 hours at 5000 psi yielded a dense material, which on further heat treatment at 845 C for 24 hours, exhibited a Tc of 108.2K. The Bi compositions were found to be much less oxygen sensitive than the Y compositions. This was especially noted in the case of the hot pressed materials which were superconducting as hot pressed, a condition that could not be achieved in the Y compositions. Safire-type grounding links are in the process of being fabricated from these materials.

Trastuzumab and survival of patients with metastatic breast cancer.

PubMed

Kast, Karin; Schoffer, Olaf; Link, Theresa; Forberger, Almuth; Petzold, Andrea; Niedostatek, Antje; Werner, Carmen; Klug, Stefanie J; Werner, Andreas; Gatzweiler, Axel; Richter, Barbara; Baretton, Gustavo; Wimberger, Pauline

2017-08-01

Prognosis of Her2-positive breast cancer has changed since the introduction of trastuzumab for treatment in metastatic and early breast cancer. It was described to be even better compared to prognosis of Her2-negative metastatic breast cancer. The purpose of this study was to evaluate the effect of trastuzumab in our cohort. Besides the effect of adjuvant pretreatment with trastuzumab on survival of patients with metastatic Her2-positive breast cancer was analyzed. All patients with primary breast cancer of the Regional Breast Cancer Center Dresden diagnosed during the years 2001-2013 were analyzed for treatment with or without trastuzumab in the adjuvant and in the metastatic treatment setting using Kaplan-Meier survival estimation and Cox regression. Age and tumor stage at time of first diagnosis of breast cancer as well as hormone receptor status, grading, time, and site of metastasis at first diagnosis of distant metastatic disease were analyzed. Of 4.481 female patients with primary breast cancer, 643 presented with metastatic disease. Her2-positive status was documented in 465 patients, including 116 patients with primary or secondary metastases. Median survival of patients with Her2-positive primary metastatic disease was 3.0 years (95% CI 2.3-4.0). After adjustment for other factors, survival was better in patients with Her2-positive breast cancer with trastuzumab therapy compared to Her2-negative metastatic disease (HR 2.10; 95% CI 1.58-2.79). Analysis of influence of adjuvant therapy with and without trastuzumab by Kaplan-Meier showed a trend for better survival in not pretreated patients. Median survival was highest in hormone receptor-positive Her2-positive (triple-positive) primary metastatic breast cancer patients with 3.3 years (95% CI 2.3-4.6). Prognosis of patients with Her2-positive metastatic breast cancer after trastuzumab treatment is more favorable than for Her2-negative breast cancer. The role of adjuvant chemotherapy with or without trastuzumab warrants further research. Survival is best in triple-positive metastatic breast cancer. This will effect counseling at the time of first diagnosis of metastatic breast cancer.

A reconstruction theorem for Connes-Landi deformations of commutative spectral triples

NASA Astrophysics Data System (ADS)

Ćaćić, Branimir

2015-12-01

We formulate and prove an extension of Connes's reconstruction theorem for commutative spectral triples to so-called Connes-Landi or isospectral deformations of commutative spectral triples along the action of a compact Abelian Lie group G, also known as toric noncommutative manifolds. In particular, we propose an abstract definition for such spectral triples, where noncommutativity is entirely governed by a deformation parameter sitting in the second group cohomology of the Pontryagin dual of G, and then show that such spectral triples are well-behaved under further Connes-Landi deformation, thereby allowing for both quantisation from and dequantisation to G-equivariant abstract commutative spectral triples. We then use a refinement of the Connes-Dubois-Violette splitting homomorphism to conclude that suitable Connes-Landi deformations of commutative spectral triples by a rational deformation parameter are almost-commutative in the general, topologically non-trivial sense.

Circular-polarization-sensitive metamaterial based on triple-quantum-dot molecules.

PubMed

Kotetes, Panagiotis; Jin, Pei-Qing; Marthaler, Michael; Schön, Gerd

2014-12-05

We propose a new type of chiral metamaterial based on an ensemble of artificial molecules formed by three identical quantum dots in a triangular arrangement. A static magnetic field oriented perpendicular to the plane breaks mirror symmetry, rendering the molecules sensitive to the circular polarization of light. By varying the orientation and magnitude of the magnetic field one can control the polarization and frequency of the emission spectrum. We identify a threshold frequency Ω, above which we find strong birefringence. In addition, Kerr rotation and circular-polarized lasing action can be implemented. We investigate the single-molecule lasing properties for different energy-level arrangements and demonstrate the possibility of circular-polarization conversion. Finally, we analyze the effect of weak stray electric fields or deviations from the equilateral triangular geometry.

Assessment of an RNA interference screen-derived mitotic and ceramide pathway metagene as a predictor of response to neoadjuvant paclitaxel for primary triple-negative breast cancer: a retrospective analysis of five clinical trials.

PubMed

Juul, Nicolai; Szallasi, Zoltan; Eklund, Aron C; Li, Qiyuan; Burrell, Rebecca A; Gerlinger, Marco; Valero, Vicente; Andreopoulou, Eleni; Esteva, Francisco J; Symmans, W Fraser; Desmedt, Christine; Haibe-Kains, Benjamin; Sotiriou, Christos; Pusztai, Lajos; Swanton, Charles

2010-04-01

Addition of taxanes to preoperative chemotherapy in breast cancer increases the proportion of patients who have a pathological complete response (pCR). However, a substantial proportion of patients do not respond, and the prognosis is particularly poor for patients with oestrogen-receptor (ER)/progesterone-receptor (PR)/human epidermal growth factor receptor 2 (HER2; ERBB2)-negative (triple-negative) disease who do not achieve a pCR. Reliable identification of such patients is the first step in determining who might benefit from alternative treatment regimens in clinical trials. We previously identified genes involved in mitosis or ceramide metabolism that influenced sensitivity to paclitaxel, with an RNA interference (RNAi) screen in three cancer cell lines, including a triple-negative breast-cancer cell line. Here, we assess these genes as a predictor of pCR to paclitaxel combination chemotherapy in triple-negative breast cancer. We derived a paclitaxel response metagene based on mitotic and ceramide genes identified by functional genomics studies. We used area under the curve (AUC) analysis and multivariate logistic regression to retrospectively assess the metagene in six cohorts of patients with triple-negative breast cancer treated with neoadjuvant chemotherapy; two cohorts treated with paclitaxel (n=27, 30) and four treated without paclitaxel (n=88, 28, 48, 39). The metagene was associated with pCR in paclitaxel-treated cohorts (AUC 0.79 [95% CI 0.53-0.93], 0.72 [0.48-0.90]) but not in non-paclitaxel treated cohorts (0.53 [0.31-0.77], 0.59 [0.22-0.82], 0.53 [0.36-0.71], 0.64 [0.43-0.81]). In multivariate logistic regression, the metagene was associated with pCR (OR 19.92, 2.62-151.57; p=0.0039) with paclitaxel-containing chemotherapy. The paclitaxel response metagene shows promise as a paclitaxel-specific predictor of pCR in patients with triple-negative breast cancer. The metagene is suitable for development into a reverse transcription-PCR assay, for which clinically relevant thresholds could be established in randomised clinical trials. These results highlight the potential for functional genomics to accelerate development of drug-specific predictive biomarkers without the need for training clinical trial cohorts. UK Medical Research Council; Cancer Research UK; the National Institute for Health Research (UK); the Danish Council for Independent Research-Medical Sciences (FSS); Breast Cancer Research Foundation (New York); Fondation Luxembourgeoise contre le Cancer; the Fonds National de la Recherche Scientifique; Brussels Region (IRSIB-IP, Life Sciences 2007) and Walloon Region (Biowin-Keymarker); Sally Pearson Breast Cancer Fund; and the European Commission. 2010 Elsevier Ltd. All rights reserved.

Defining Genomic Changes in Triple-Negative Breast Cancer in Women of African Descent

DTIC Science & Technology

2012-06-01

African and African - American breast cancer cases. Gene Expression Array Studies The 31 triple negative Kijabe samples were... American Adjacent Normal Breast Tissue PI: Pegram & Baumbach Defining Genomic Changes in Triple Negative Breast Cancer in Women of African ...Tissues from African - American and East African Patients with Triple Negative Breast

Prognostic and predictive value of tumor-infiltrating lymphocytes in two phase III randomized adjuvant breast cancer trials

PubMed Central

Dieci, M. V.; Mathieu, M. C.; Guarneri, V.; Conte, P.; Delaloge, S.; Andre, F.; Goubar, A.

2015-01-01

Background Tumor-infiltrating lymphocytes (TILs) are emerging as strong prognostic factor for early breast cancer patients, especially in the triple-negative subtype. Here, we aim to validate previous findings on the prognostic role of TIL in the context of two randomized adjuvant trials and to investigate whether lymphocyte infiltrates can predict benefit from adjuvant anthracyclines. Patients and methods A total of 816 patients enrolled and treated at the Gustave Roussy in the context of two multicentric randomized trials comparing adjuvant anthracyclines versus no chemotherapy were included in the present analysis. Primary end point was overall survival (OS). Hematoxilin and eosin slides of primary tumors were retrieved and evaluated for the percentage of intratumoral (It) and stromal (Str) TIL. Each case was also defined as high-TIL or low-TIL breast cancer adopting previously validated cutoffs. Results TIL were assessable for 781 of 816 cases. High-TIL cases were more likely grade 3 and estrogen receptor (ER)-negative (P < 0.001). In multivariate analysis, both continuous It-TIL and Str-TIL were strong prognostic factors for OS [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95 P = 0.003; HR 0.89, 95% CI 0.81–0.96, P = 0.005 for It-TIL and Str-TIL, respectively]. The prognostic effect of continuous TIL was limited to triple-negative and HER2-positive patients. Ten-year OS rates were: 89% and 68% for triple-negative high-TIL and low-TIL, respectively (HR 0.44, 95% CI 0.18–1.10, P = 0.07) and 78% and 57% for HER2-positive high-TIL versus low-TIL, respectively (HR 0.46, 95% CI 0.20–1.11, P = 0.08). Either continuous or binary TIL variables did not predict for the efficacy of anthracyclines. Test for interaction P value was not significant in the whole study population and in subgroups (ER+/HER2−, HER2+, ER−/HER2−). Conclusions We confirmed the prognostic role of TIL in triple-negative early breast cancer and suggested a prognostic impact in HER2+ patients as well. Basing on our data, TIL should not be used as a parameter to select patients for anthracyclines chemotherapy. PMID:25995301

Multicenter phase II study of apatinib in non-triple-negative metastatic breast cancer.

PubMed

Hu, Xichun; Cao, Jun; Hu, Wenwei; Wu, Changping; Pan, Yueyin; Cai, Li; Tong, Zhongsheng; Wang, Shusen; Li, Jin; Wang, Zhonghua; Wang, Biyun; Chen, Xiaoyu; Yu, Hao

2014-11-07

Apatinib is a tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). This study was conducted to assess the efficacy and safety of apatinib in patients with non-triple-negative metastatic breast cancer who had received prior chemotherapy for their metastatic disease. This multicenter, open-label, single arm study enrolled patients with non-triple-negative breast cancer, pretreated with anthracycline, taxanes and capecitabine, and who failed in the metastatic setting at least 1 and at most 4 prior chemotherapy regimens and at least one endocrine drug for hormone receptor-positive patients as well as at least one anti-Her2 drug for Her2-positive patients. The primary end point of this study was progression free survival (PFS). Secondary end points included objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity. Apatinib was administered as 500 mg daily on days 1 through 28 of each 4-week cycle. 38 patients were enrolled with a median age of 49 years (range, 35 to 62 years) and received apatinib for a median of 4 cycles (range from 0 to 10 cycles). 18 (47.4%) patients experienced dose reduction during treatment. The median relative dose intensity (relative to assigned dose for each cycle) was 82% (range, 45.0% to 100.0%). Median follow-up time was 10.1 months. Median PFS of all 38 patients was 4.0 months (95% confidence interval (CI), 2.8 m - 5.2 m). 36 patients were eligible for efficacy analysis. ORR was 16.7% (6/36). DCR was 66.7% (24/36). Median OS was 10.3 months (95% CI, 9.1 m - 11.6 m). The most common grade 3/4 treatment-related AEs were hypertension (20.5%), hand-foot syndrome (10.3%), and proteinuria (5.1%). Of three possibly drug-related SAEs recorded in the study, 2 (3.4%) deaths occurred within 28 days of last treatment and were both considered to be the result of disease progression. The other one was grade 2 diarrhea needing hospitalization. Apatinib exhibited objective efficacy in heavily pretreated, metastatic non-triple-negative breast cancer with manageable toxicity, and it might be better to be tested in breast cancer with high angiogenesis dependency. ClinicalTrials.gov: NCT01653561.

DESIGN OF MEDICAL RADIOMETER FRONT-END FOR IMPROVED PERFORMANCE

PubMed Central

Klemetsen, Ø.; Birkelund, Y.; Jacobsen, S. K.; Maccarini, P. F.; Stauffer, P. R.

2011-01-01

We have investigated the possibility of building a singleband Dicke radiometer that is inexpensive, small-sized, stable, highly sensitive, and which consists of readily available microwave components. The selected frequency band is at 3.25–3.75 GHz which provides a reasonable compromise between spatial resolution (antenna size) and sensing depth for radiometry applications in lossy tissue. Foreseen applications of the instrument are non-invasive temperature monitoring for breast cancer detection and temperature monitoring during heating. We have found off-the-shelf microwave components that are sufficiently small (< 5 mm × 5 mm) and which offer satisfactory overall sensitivity. Two different Dicke radiometers have been realized: one is a conventional design with the Dicke switch at the front-end to select either the antenna or noise reference channels for amplification. The second design places a matched pair of low noise amplifiers in front of the Dicke switch to reduce system noise figure. Numerical simulations were performed to test the design concepts before building prototype PCB front-end layouts of the radiometer. Both designs provide an overall power gain of approximately 50 dB over a 500 MHz bandwidth centered at 3.5 GHz. No stability problems were observed despite using triple-cascaded amplifier configurations to boost the thermal signals. The prototypes were tested for sensitivity after calibration in two different water baths. Experiments showed superior sensitivity (36% higher) when implementing the low noise amplifier before the Dicke switch (close to the antenna) compared to the other design with the Dicke switch in front. Radiometer performance was also tested in a multilayered phantom during alternating heating and radiometric reading. Empirical tests showed that for the configuration with Dicke switch first, the switch had to be locked in the reference position during application of microwave heating to avoid damage to the active components (amplifiers and power meter). For the configuration with a low noise amplifier up front, damage would occur to the active components of the radiometer if used in presence of the microwave heating antenna. Nevertheless, this design showed significantly improved sensitivity of measured temperatures and merits further investigation to determine methods of protecting the radiometer for amplifier first front ends. PMID:21779411