18F-FET PET prior to recurrent high-grade glioma re-irradiation-additional prognostic value of dynamic time-to-peak analysis and early static summation images?

PubMed

Fleischmann, Daniel F; Unterrainer, Marcus; Bartenstein, Peter; Belka, Claus; Albert, Nathalie L; Niyazi, Maximilian

2017-04-01

Most high-grade gliomas (HGG) recur after initial multimodal therapy and re-irradiation (Re-RT) has been shown to be a valuable re-treatment option in selected patients. We evaluated the prognostic value of dynamic time-to-peak analysis and early static summation images in O-(2- 18 F-fluoroethyl)-l-tyrosine ( 18 F-FET) PET for patients treated with Re-RT ± concomitant bevacizumab. We retrospectively analyzed 72 patients suffering from recurrent HGG with 18 F-FET PET prior to Re-RT. PET analysis revealed the maximal tumor-to-background-ratio (TBR max ), the biological tumor volume, the number of PET-foci and pattern of time-activity-curves (TACs; increasing vs. decreasing). Furthermore, the novel PET parameters early TBR max (at 5-15 min post-injection) and minimal time-to-peak (TTP min ) were evaluated. Additional analysis was performed for gender, age, KPS, O6-methylguanine-DNA methyltransferase methylation status, isocitrate dehydrogenase 1 mutational status, WHO grade and concomitant bevacizumab therapy. The influence of PET and clinical parameters on post-recurrence survival (PRS) was investigated. Shorter TTP min was related to shorter PRS after Re-RT with 6 months for TTP min  < 12.5 min, 7 months for TTP min 12.5-25 min and 11 months for TTP min >25 min (p = 0.027). TTP min had a significant impact on PRS both on univariate (p = 0.027; continuous) and multivariate analysis (p = 0.011; continuous). Other factors significantly related to PRS on multivariate analysis were increasing vs. decreasing TACs (p = 0.008) and Karnofsky Performance Score (p = 0.015; <70 vs. ≥70). Early TBR max as well as the other conventional PET parameters were not significantly related to PRS on univariate analysis. Dynamic 18 F-FET PET with TTP min provides a high prognostic value for recurrent HGG prior to Re-RT, whereas early TBR max does not. Dynamic 18 F-FET PET using TTP min might help to personalize Re-RT treatment regimens in future through voxelwise TTP min analysis for dose painting purposes and PET-guided dose escalation.

Predicting analysis time in events-driven clinical trials using accumulating time-to-event surrogate information.

PubMed

Wang, Jianming; Ke, Chunlei; Yu, Zhinuan; Fu, Lei; Dornseif, Bruce

2016-05-01

For clinical trials with time-to-event endpoints, predicting the accrual of the events of interest with precision is critical in determining the timing of interim and final analyses. For example, overall survival (OS) is often chosen as the primary efficacy endpoint in oncology studies, with planned interim and final analyses at a pre-specified number of deaths. Often, correlated surrogate information, such as time-to-progression (TTP) and progression-free survival, are also collected as secondary efficacy endpoints. It would be appealing to borrow strength from the surrogate information to improve the precision of the analysis time prediction. Currently available methods in the literature for predicting analysis timings do not consider utilizing the surrogate information. In this article, using OS and TTP as an example, a general parametric model for OS and TTP is proposed, with the assumption that disease progression could change the course of the overall survival. Progression-free survival, related both to OS and TTP, will be handled separately, as it can be derived from OS and TTP. The authors seek to develop a prediction procedure using a Bayesian method and provide detailed implementation strategies under certain assumptions. Simulations are performed to evaluate the performance of the proposed method. An application to a real study is also provided. Copyright © 2015 John Wiley & Sons, Ltd. Copyright © 2015 John Wiley & Sons, Ltd.

Time-to-positivity, type of culture media and oxidase test performed on positive blood culture vials to predict Pseudomonas aeruginosa in patients with Gram-negative bacilli bacteraemia.

PubMed

Cobos-Triguero, N; Zboromyrska, Y; Morata, L; Alejo, I; De La Calle, C; Vergara, A; Cardozo, C; Arcas, M P; Soriano, A; Marco, F; Mensa, J; Almela, M; Martínez, J A

2017-02-01

The aim of this study was to determine the usefulness of oxidase test and time-to-positivity (TTP) in aerobic and anaerobic blood culture vials to detect the presence of Pseudomonas aeruginosa in patients with Gram-negative bacilli (GNB) bacteraemia. TTP was recorded for each aerobic and anaerobic blood culture vial of monomicrobial bacteraemia due to GNB. Oxidase test was performed in a pellet of the centrifuged content of the positive blood culture. An algorithm was developed in order to perform the oxidase test efficiently taking into account TTP and type of vial. A total of 341 episodes of GNB bacteraemia were analysed. Sensitivity, specificity, positive predictive value and negative predictive value of the oxidase test performed on positive vials with GNB to predict P. aeruginosa were 95%, 99%, 91%, and 99%, respectively. When growth was first or exclusively detected in anaerobic vials, P. aeruginosa was never identified hence the performance of the oxidase test could be avoided. When growth was only or first detected in aerobic vials, a TTP≥8h predicted P. aeruginosa in 37% or cases (63 of 169), therefore oxidase test is highly recommended. Oxidase test performed onto positive blood culture vials previously selected by TTP and type of vials is an easy and inexpensive way to predict P. aeruginosa. In most cases, this can lead to optimization of treatment in less than 24 hours.

The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation

PubMed Central

Tiedje, Christopher; Diaz-Muñoz, Manuel D.; Trulley, Philipp; Ahlfors, Helena; Laaß, Kathrin; Blackshear, Perry J.; Turner, Martin; Gaestel, Matthias

2016-01-01

RNA-binding proteins (RBPs) facilitate post-transcriptional control of eukaryotic gene expression at multiple levels. The RBP tristetraprolin (TTP/Zfp36) is a signal-induced phosphorylated anti-inflammatory protein guiding unstable mRNAs of pro-inflammatory proteins for degradation and preventing translation. Using iCLIP, we have identified numerous mRNA targets bound by wild-type TTP and by a non-MK2-phosphorylatable TTP mutant (TTP-AA) in 1 h LPS-stimulated macrophages and correlated their interaction with TTP to changes at the level of mRNA abundance and translation in a transcriptome-wide manner. The close similarity of the transcriptomes of TTP-deficient and TTP-expressing macrophages upon short LPS stimulation suggested an effective inactivation of TTP by MK2, whereas retained RNA-binding capacity of TTP-AA to 3′UTRs caused profound changes in the transcriptome and translatome, altered NF-κB-activation and induced cell death. Increased TTP binding to the 3′UTR of feedback inhibitor mRNAs, such as Ier3, Dusp1 or Tnfaip3, in the absence of MK2-dependent TTP neutralization resulted in a strong reduction of their protein synthesis contributing to the deregulation of the NF-κB-signaling pathway. Taken together, our study uncovers a role of TTP as a suppressor of feedback inhibitors of inflammation and highlights the importance of fine-tuned TTP activity-regulation by MK2 in order to control the pro-inflammatory response. PMID:27220464

Thrombotic Thrombocytopenic Purpura in Black People: Impact of Ethnicity on Survival and Genetic Risk Factors.

PubMed

Martino, Suella; Jamme, Mathieu; Deligny, Christophe; Busson, Marc; Loiseau, Pascale; Azoulay, Elie; Galicier, Lionel; Pène, Frédéric; Provôt, François; Dossier, Antoine; Saheb, Samir; Veyradier, Agnès; Coppo, Paul

2016-01-01

Black people are at increased risk of thrombotic thrombocytopenic purpura (TTP). Whether clinical presentation of TTP in Black patients has specific features is unknown. We assessed here differences in TTP presentation and outcome between Black and White patients. Clinical presentation was comparable between both ethnic groups. However, prognosis differed with a lower death rate in Black patients than in White patients (2.7% versus 11.6%, respectively, P = .04). Ethnicity, increasing age and neurologic involvement were retained as risk factors for death in a multivariable model (P < .05 all). Sixty-day overall survival estimated by the Kaplan-Meier curves and compared with the Log-Rank test confirmed that Black patients had a better survival than White patients (P = .03). Salvage therapies were similarly performed between both groups, suggesting that disease severity was comparable. The comparison of HLA-DRB1*11, -DRB1*04 and -DQB1*03 allele frequencies between Black patients and healthy Black individuals revealed no significant difference. However, the protective allele against TTP, HLA-DRB1*04, was dramatically decreased in Black individuals in comparison with White individuals. Black people with TTP may have a better survival than White patients despite a comparable disease severity. A low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP in this population.

Thrombotic Thrombocytopenic Purpura in Black People: Impact of Ethnicity on Survival and Genetic Risk Factors

PubMed Central

Martino, Suella; Jamme, Mathieu; Deligny, Christophe; Busson, Marc; Loiseau, Pascale; Azoulay, Elie; Galicier, Lionel; Pène, Frédéric; Provôt, François; Dossier, Antoine; Saheb, Samir; Veyradier, Agnès; Coppo, Paul

2016-01-01

Black people are at increased risk of thrombotic thrombocytopenic purpura (TTP). Whether clinical presentation of TTP in Black patients has specific features is unknown. We assessed here differences in TTP presentation and outcome between Black and White patients. Clinical presentation was comparable between both ethnic groups. However, prognosis differed with a lower death rate in Black patients than in White patients (2.7% versus 11.6%, respectively, P = .04). Ethnicity, increasing age and neurologic involvement were retained as risk factors for death in a multivariable model (P < .05 all). Sixty-day overall survival estimated by the Kaplan-Meier curves and compared with the Log-Rank test confirmed that Black patients had a better survival than White patients (P = .03). Salvage therapies were similarly performed between both groups, suggesting that disease severity was comparable. The comparison of HLA-DRB1*11, -DRB1*04 and -DQB1*03 allele frequencies between Black patients and healthy Black individuals revealed no significant difference. However, the protective allele against TTP, HLA-DRB1*04, was dramatically decreased in Black individuals in comparison with White individuals. Black people with TTP may have a better survival than White patients despite a comparable disease severity. A low natural frequency of HLA-DRB1*04 in Black ethnicity may account for the greater risk of TTP in this population. PMID:27383202

Outcomes in the treatment of thrombotic thrombocytopenic purpura with splenectomy: a retrospective cohort study.

PubMed

Outschoorn, Ubaldo Martinez; Ferber, Andres

2006-12-01

The mainstay of treatment for thrombotic thrombocytopenic purpura (TTP) is plasma exchange (PE), but the role of splenectomy is still undefined. The records of all patients with TTP at a single center over a 20-year period were retrospectively reviewed. Response to plasma exchange was determined. The outcome of patients treated with splenectomy in the setting of TTP was evaluated. Sixty-one patients had been treated for TTP. Thirty-nine patients (64%) achieved complete remission (CR) with PE, nineteen (31%) of these achieving sustained CR and seventeen (28%) with relapsed TTP. Twenty patients (33%) had PE refractory TTP and two patients (3%) had PE dependent TTP. During this time period, 10 patients (16%) underwent splenectomy, four patients (7%) for PE dependent TTP, three (5%) for relapsed TTP, and three (5%) for refractory TTP. All of the patients achieved CR after splenectomy. Two patients who had undergone splenectomy had subsequent relapses, both with previously relapsed TTP. In relapsed patients the relapse rate after splenectomy was 0.27 events per patient year compared to 0.6 events per patient year before splenectomy. Median follow-up after splenectomy was 19 months (range 0.13-90 months). In conclusion, relapses in TTP can be managed successfully with additional PE or with splenectomy. PE dependent or refractory TTP can be successfully treated with splenectomy.

A comparative analysis of the dependences of the hemodynamic parameters on changes in ROI's position in perfusion CT scans

NASA Astrophysics Data System (ADS)

Choi, Yong-Seok; Cho, Jae-Hwan; Namgung, Jang-Sun; Kim, Hyo-Jin; Yoon, Dae-Young; Lee, Han-Joo

2013-05-01

This study performed a comparative analysis of cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT), and mean time-to-peak (TTP) obtained by changing the region of interest's (ROI) anatomical positions, during CT brain perfusion. We acquired axial source images of perfusion CT from 20 patients undergoing CT perfusion exams due to brain trauma. Subsequently, the CBV, CBF, MTT, and TTP values were calculated through data-processing of the perfusion CT images. The color scales for the CBV, CBF, MTT, and TTP maps were obtained using the image data. Anterior cerebral artery (ACA) was taken as the standard ROI for the calculations of the perfusion values. Differences in the hemodynamic average values were compared in a quantitative analysis by placing ROI and the dividing axial images into proximal, middle, and distal segments anatomically. By performing the qualitative analysis using a blind test, we observed changes in the sensory characteristics by using the color scales of the CBV, CBF, and MTT maps in the proximal, middle, and distal segments. According to the qualitative analysis, no differences were found in CBV, CBF, MTT, and TTP values of the proximal, middle, and distal segments and no changes were detected in the color scales of the the CBV, CBF, MTT, and TTP maps in the proximal, middle, and distal segments. We anticipate that the results of the study will useful in assessing brain trauma patients using by perfusion imaging.

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

Hoffmann, Ralf-T., E-mail: rthoffma@med.uni-muenchen.de; Paprottka, Philipp M., E-mail: philipp.paprottka@med.uni-muenchen.de; Schoen, Agnes

Introduction: In unresectable intrahepatic cholangiocarcinoma (ICC), systemic chemotherapy often is viewed as the only option, although efficacy is limited. Radioembolization (RE) using yttrium-90 ({sup 90}Y) microspheres is an accepted therapy for patients with hepatocellular-carcinoma or metastatic liver tumors. However, there are limited data on the value of RE in patients with ICC and few data on factors influencing prognosis. The purpose of our retrospective analysis was to establish which factors influenced time-to-progression (TTP) and overall survival (OS). Methods: Patients with unresectable ICC were treated with {sup 90}Y resin-microspheres and assessed at 3-monthly intervals. Radiologic response was evaluated by using Responsemore » Criteria in Solid Tumors (RECIST). Baseline characteristics, biochemical/clinical toxicities, and response were examined for impact on TTP and OS. Results: Thirty-four treatments were administered to 33 patients without major complications. By RECIST, 12 patients had a partial response, 17 had stable disease, and 5 had progressive disease after 3 months. The median OS was 22 months posttreatment and 43.7 months postdiagnosis. Median TTP was 9.8 months. Survival and TTP were significantly prolonged in patients with ECOG 0 (vs. ECOG 1 or 2; median OS: 29.4, 10, and 5.1 months; TTP: 17.5, 6.9, and 2.4 months), tumor burden {<=}25% (OS: 26.7 vs. 6 months; TTP: 17.5 vs. 2.3 months), or tumor response (PR or SD vs. PD; OS: 35.5, 17.7 vs. 5.7 months; TTP: 31.9, 9.8 vs. 2.5 months), respectively (P < 0.001). Conclusions: Radioembolization is an effective and safe option for patients with unresectable ICC. Predictors for prolonged survival are performance status, tumor burden, and RECIST response.« less

Millimeter wave sensor requirements for maritime small craft identification

NASA Astrophysics Data System (ADS)

Krapels, Keith; Driggers, Ronald G.; Garcia, Jose; Boettcher, Evelyn; Prather, Dennis; Schuetz, Chrisopher; Samluk, Jesse; Stein, Lee; Kiser, William; Visnansky, Andrew; Grata, Jeremy; Wikner, David; Harris, Russ

2009-09-01

Passive millimeter wave (mmW) imagers have improved in terms of resolution sensitivity and frame rate. Currently, the Office of Naval Research (ONR), along with the US Army Research, Development and Engineering Command, Communications Electronics Research Development and Engineering Center (RDECOM CERDEC) Night Vision and Electronic Sensor Directorate (NVESD), are investigating the current state-of-the-art of mmW imaging systems. The focus of this study was the performance of mmW imaging systems for the task of small watercraft / boat identification field performance. First mmW signatures were collected. This consisted of a set of eight small watercrafts; at 5 different aspects, during the daylight hours over a 48 hour period in the spring of 2008. Target characteristics were measured and characteristic dimension, signatures, and Root Sum Squared of Target's Temperature (RRSΔT) tabulated. Then an eight-alternative, forced choice (8AFC) human perception experiment was developed and conducted at NVESD. The ability of observers to discriminate between small watercraft was quantified. Next, the task difficulty criterion, V50, was quantified by applying this data to NVESD's target acquisition models using the Targeting Task Performance (TTP) metric. These parameters can be used to evaluate sensor field performance for Anti-Terrorism / Force Protection (AT/FP) and navigation tasks for the U.S. Navy, as well as for design and evaluation of imaging passive mmW sensors for both the U.S. Navy and U.S. Coast Guard.

2-(1,3-Dithiolan-2-ylidene)-5-(1,3-dithian-2-ylidene)-1,3,4,6- tetrathiapentalene(DHDA-TTP), a hybrid of BDH-TTP and BDA-TTP, and its metallic cation-radical salts.

PubMed

Yamada, Jun-ichi; Watanabe, Maki; Toita, Takashi; Akutsu, Hiroki; Nakatsuji, Shin'ichi; Nishikawa, Hiroyuki; Ikemoto, Isao; Kikuchi, Koichi

2002-05-21

The synthesis and electrochemical properties of the DHDA-TTP donor, a hybrid of 2,5-bis(1,3-dithiolan-2-ylidene)-1,3,4,6-tetrathiapentalene (BDH-TTP) and 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA-TTP), has been investigated, and its ability to form metallic cation-radical salts is elucidated.

Results of emergency surgery in patients with Moschowitz's disease refractory to hematological treatment: is splenectomy always advisable?

PubMed

Caronna, R; Cardi, M; Meloni, G; Mangioni, S; Spera, G; Benedetti, M; Frantellizzi, V; Layek, D; Catinelli, S; Schiratti, M; Chirletti, P

2005-01-01

Patients with thrombotic thrombocytopenic purpura (TTP), Moschowitz's disease, run a high risk of perioperative bleeding and need intensive hematologic support. In some patients, TTP is associated with cancer but the surgical role in these patients is still unclear. To illustrate the surgical problems and outcome we present the case histories of three patients with TTP observed in our emergency department. Two patients had TTP secondary to cancer and one patient with primary TTP (no evidence of neoplasia) had emergency operation for gastric hemorrhage, occlusion and TTP unresponsive to plasmapheresis. The first two patients who had not radical resection of cancer and no splenectomy, died for TTP complications. The third patient who underwent emergency splenectomy, had an uneventful postoperative course and TTP completely regressed. These case reports suggest that patients with TTP should be screened to rule out cancer. In patients with acute cancer-related complications emergency surgery should aim to resect the cancer. An associated splenectomy may increase the effectiveness of postoperative hematologic therapy.

Time-to-Passage Judgments in Nonconstant Optical Flow Fields

NASA Technical Reports Server (NTRS)

Kaiser, Mary K.; Hecht, Heiko

1995-01-01

The time until an approaching object will pass an observer (time to passage, or TTP) is optically specified by a global flow field even in the absence of local expansion or size cues. Kaiser and Mowafy have demonstrated that observers are in fact sensitive to this global flow information. The present studies investigate two factors that are usually ignored in work related to TTP: (1) non-constant motion functions and (2) concomitant eye rotation. Non-constant velocities violate an assumption of some TTP derivations, and eye rotations may complicate heading extraction. Such factors have practical significance, for example, in the case of a pilot accelerating an aircraft or executing a roll. In our studies, a flow field of constant-sized stars was presented monocularly on a large screen. TIP judgments had to be made on the basis of one target star. The flow field varied in its acceleration pattern and its roll component. Observers did not appear to utilize acceleration information. In particular, TTP with decelerating motion were consistently underestimated. TTP judgments were fairly robust with respect to roll, even when roll axis and track vector were decoupled. However, substantial decoupling between heading and track vector led to a decrement in performance, in both the presence and the absence of roll.

Pregnancy outcomes following recovery from acquired thrombotic thrombocytopenic purpura

PubMed Central

Jiang, Yang; McIntosh, Jennifer J.; Reese, Jessica A.; Deford, Cassandra C.; Kremer Hovinga, Johanna A.; Lämmle, Bernhard; Terrell, Deirdra R.; Vesely, Sara K.; Knudtson, Eric J.

2014-01-01

Pregnancy may precipitate acute episodes of thrombotic thrombocytopenic purpura (TTP), but pregnancy outcomes in women who have recovered from acquired TTP are not well documented. We analyzed pregnancy outcomes following recovery from TTP associated with acquired, severe ADAMTS13 deficiency (ADAMTS13 activity <10%) in women enrolled in the Oklahoma TTP-HUS Registry from 1995 to 2012. We also systematically searched for published reports on outcomes of pregnancies following recovery from TTP associated with acquired, severe ADAMTS13 deficiency. Ten women in the Oklahoma Registry had 16 subsequent pregnancies from 1999 to 2013. Two women had recurrent TTP, which occurred 9 and 29 days postpartum. Five of 16 pregnancies (31%, 95% confidence interval, 11%-59%) in 3 women were complicated by preeclampsia, a frequency greater than US population estimates (2.1%-3.2%). Thirteen (81%) pregnancies resulted in normal children. The literature search identified 382 articles. Only 6 articles reported pregnancies in women who had recovered from TTP associated with acquired, severe ADAMTS13 deficiency, describing 10 pregnancies in 8 women. TTP recurred in 6 pregnancies. Conclusions: With prospective complete follow-up, recurrent TTP complicating subsequent pregnancies in Oklahoma patients is uncommon, but the occurrence of preeclampsia may be increased. Most pregnancies following recovery from TTP in Oklahoma patients result in normal children. PMID:24398329

TOPICAL REVIEW: Tetrathiapentalene-based organic conductors

NASA Astrophysics Data System (ADS)

Misaki, Yohji

2009-04-01

The synthesis, structure and properties of tetrathiapentalene-based (TTP) organic conductors are reviewed. Among various TTP-type donors, bis-fused tetrathiafulvalene, 2,5-bis(1,3-dithiol-2-ylidene)-1,3,4,6-tetrathiapentalene (BDT-TTP) and its derivatives afford many metallic radical cation salts stable down to low temperatures, regardless of the size and shape of the counter anions. Most BDT-TTP conductors have a β-type donor arrangement with almost uniform stacks. Introduction of appropriate substituents results in molecular packing that differs from the β-type. A vinylogous TTP, 2-(1,3-dithiol-2-ylidene)-5-(2-ethanediylidene-1,3-dithiole)-1,3,4,6-tetrathiapentalene (DTEDT) has yielded an organic superconductor (DTEDT)3Au(CN)2 as well as metallic radical cation salts, regardless of the counter anions. (Thio)pyran analogs of TTP, namely (T)PDT-TTP and its derivatives produce molecular conductors with novel molecular arrangements. A TTP analog with reduced π-electron system 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA-TTP) has afforded several organic superconductors. Highly conducting molecular metals with unusual oxidation states (+1, +5/3 and neutral) have been developed on the basis of 2,5-bis(1,3-dithiol-2-ylidene)-1,3,4,6-tetrathiapentalene (BDT-TTP) derivatives and analogous metal derivatives M(dt)2 (M = Ni, Au).

Dose-finding designs using a novel quasi-continuous endpoint for multiple toxicities

PubMed Central

Ezzalfani, Monia; Zohar, Sarah; Qin, Rui; Mandrekar, Sumithra J; Deley, Marie-Cécile Le

2013-01-01

The aim of a phase I oncology trial is to identify a dose with an acceptable safety profile. Most phase I designs use the dose-limiting toxicity, a binary endpoint, to assess the unacceptable level of toxicity. The dose-limiting toxicity might be incomplete for investigating molecularly targeted therapies as much useful toxicity information is discarded. In this work, we propose a quasi-continuous toxicity score, the total toxicity profile (TTP), to measure quantitatively and comprehensively the overall severity of multiple toxicities. We define the TTP as the Euclidean norm of the weights of toxicities experienced by a patient, where the weights reflect the relative clinical importance of each grade and toxicity type. We propose a dose-finding design, the quasi-likelihood continual reassessment method (CRM), incorporating the TTP score into the CRM, with a logistic model for the dose–toxicity relationship in a frequentist framework. Using simulations, we compared our design with three existing designs for quasi-continuous toxicity score (the Bayesian quasi-CRM with an empiric model and two nonparametric designs), all using the TTP score, under eight different scenarios. All designs using the TTP score to identify the recommended dose had good performance characteristics for most scenarios, with good overdosing control. For a sample size of 36, the percentage of correct selection for the quasi-likelihood CRM ranged from 80% to 90%, with similar results for the quasi-CRM design. These designs with TTP score present an appealing alternative to the conventional dose-finding designs, especially in the context of molecularly targeted agents. PMID:23335156

Time to positivity of blood cultures in patients with bloodstream infections: A useful prognostic tool.

PubMed

Martín-Gutiérrez, Guillermo; Martín-Pérez, Carlos; Gutiérrez-Pizarraya, Antonio; Lepe, José A; Cisneros, José M; Aznar, Javier

2017-12-01

The time to positivity (TTP) of blood cultures in patients with bloodstream infections (BSIs) has been considered to be a possible prognostic tool for some bacterial species. However, notable differences have been found between sampling designs and statistical methods in published studies to date, which makes it difficult to compare results or to derive reliable conclusions. Our objective was to evaluate the clinical and microbiological implications of TTP among patients with BSI caused by the most common pathogens. A total of 361 episodes of BSI were reported for 332 patients. The survival of the entire cohort was measured from the time of blood culture sampling. In order to compare our results with those of previous studies, TTP was divided in three different groups based on log rank (short TTP <12h; medium TTP ≥12h to ≤27h, and long TTP >27h). Cox proportional hazard models were used to calculate crude and adjusted hazard ratios (HR). The Cox proportional hazard model revealed that TTP is an independent predictor of mortality (HR=1.00, p=0.031) in patients with BSIs. A higher mortality was found in the group of patients with the shortest TTP (<12h) (HR=2.100, p=0.047), as well as those with longest TTP (>27h) (HR=3.277, p=0.031). It seems that TTP may provide a useful prognostic tool associated with a higher risk of mortality, not only in patients with shorter TTP, but also in those with longer TTP. Copyright © 2016 Elsevier España, S.L.U. and Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica. All rights reserved.

Phosphorylation of human tristetraprolin in response to its interaction with the Cbl interacting protein CIN85.

PubMed

Kedar, Vishram P; Darby, Martyn K; Williams, Jason G; Blackshear, Perry J

2010-03-08

Tristetraprolin (TTP) is the prototype member of a family of CCCH tandem zinc finger proteins and is considered to be an anti-inflammatory protein in mammals. TTP plays a critical role in the decay of tumor necrosis factor alpha (TNF) mRNA, among others, by binding AU-rich RNA elements in the 3'-untranslated regions of this transcript and promoting its deadenylation and degradation. We used yeast two-hybrid analysis to identify potential protein binding partners for human TTP (hTTP). Various regions of hTTP recovered 31 proteins that fell into 12 categories based on sequence similarities. Among these, the interactions between hTTP and CIN85, cytoplasmic poly (A) binding protein (PABP), nucleolin and heat shock protein 70 were confirmed by co-immunoprecipitation experiments. CIN85 and hTTP co-localized in the cytoplasm of cells as determined by confocal microscopy. CIN85 contains three SH3 domains that specifically bind a unique proline-arginine motif (PXXXPR) found in several CIN85 effectors. We found that the SH3 domains of CIN85 bound to a PXXXPR motif located near the C-terminus of hTTP. Co-expression of CIN85 with hTTP resulted in the increased phosphorylation of hTTP at serine residues in positions 66 and 93, possibly due in part to the demonstrated association of mitogen-activated protein kinase kinase kinase 4 (MEKK4) to both proteins. The presence of CIN85 did not appear to alter hTTP's binding to RNA probes or its stimulated breakdown of TNF mRNA. These studies describe interactions between hTTP and nucleolin, cytoplasmic PABP, heat shock protein 70 and CIN85; these interactions were initially discovered by two-hybrid analysis, and confirmed by co-immunoprecipitation. We found that CIN85 binding to a C-terminal motif within hTTP led to the increased phosphorylation of hTTP, possibly through enhanced association with MEKK4. The functional consequences to each of the members of this putative complex remain to be determined.

Tristetraprolin: A novel target of diallyl disulfide that inhibits the progression of breast cancer.

PubMed

Xiong, Ting; Liu, Xiao-Wang; Huang, Xue-Long; Xu, Xiong-Feng; Xie, Wei-Quan; Zhang, Su-Jun; Tu, Jian

2018-05-01

Diallyl disulfide (DADS), a volatile component of garlic oil, has various biological properties, including antioxidant, antiangiogenic and anticancer effects. The present study aimed to explore novel targets of DADS that may slow or stop the progression of breast cancer. First, xenograft tumor models were created by subcutaneously injecting MCF-7 and MDA-MB-231 breast cancer cells into nude mice. Subsequently, western blot analysis was performed to investigate the expression of tristetraprolin (TTP), urokinase-type plasminogen activator (uPA) and matrix metalloproteinase-9 (MMP-9) in the xenograft tumors, and cell cultures. Tablet cloning, Transwell and wound healing assays revealed that DADS treatment significantly inhibited the proliferation, invasion and migration of breast cancer cells. In addition, DADS treatment led to significant downregulation of uPA and MMP-9 protein expression, but significantly upregulated TTP expression in vivo and in vitro . Knocking down TTP expression using small interfering RNA reversed the aforementioned effects of DADS, which suggests TTP is a key target of DADS in inhibiting the progression of breast cancer.

Diagnosis and management of acquired thrombotic thrombocytopenic purpura in southeast China: a single center experience of 60 cases.

PubMed

Zhou, Xinping; Ye, Xingnong; Ren, Yanling; Mei, Chen; Ma, Liya; Huang, Jiansong; Xu, Weilai; Wei, Juying; Ye, Li; Mai, Wenyuan; Qian, Wenbin; Meng, Haitao; Jin, Jie; Tong, Hongyan

2016-12-01

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening thrombotic microangiopathy. This study aimed to provide a profile of the diagnosis and management of patients with acquired TTP collected in 10 years in a single center in southeast China. A total of 60 patients diagnosed with acute acquired TTP from March 2005 to August 2015 were enrolled. Among the 60 patients, 52 patients presented with their first episodes, and eight patients had two or more episodes. The median age at presentation was 49 (range, 17 to 78) years with a female predominance (male:female ratio, 1:1.60). ADAMTS 13 activity were analyzed in 43 patients, among whom 33 (76.7%) patients had a baseline level of < 5%. Mortality was 30%. Plasma exchange (PEX) was performed in 62 of 69 (89.9%) episodes. Corticosteroids were administered in 54 of 69 (78.3%) episodes. Other immunosuppressants (e.g., vincristine, cyclosporine, and cyclosporin) were used in 7 of 69 (10.1%) episodes. Rituximab was documented in 4 patients with refractory/relapsed TTP for 5 episodes, showing encouraging results. In conclusion, the diagnosis of TTP depended on a comprehensive analysis of clinical data. Plasma ADAMTS13 activity assay helped confirm a diagnosis. PEX was the mainstay of the therapy, and rituximab can be used in relapsed/refractory disease.

Genetic Polymorphisms in RNA Binding Proteins Contribute to Breast Cancer Survival

PubMed Central

Upadhyay, Rohit; Sanduja, Sandhya; Kaza, Vimala; Dixon, Dan A.

2012-01-01

The RNA-binding proteins TTP and HuR control expression of numerous genes associated with breast cancer pathogenesis by regulating mRNA stability. However, the role of genetic variation in TTP (ZFP36) and HuR (ELAVL1) genes is unknown in breast cancer prognosis. A total of 251 breast cancer patients (170 Caucasians and 81 African-Americans) were enrolled and followed-up from 2001 to 2011 (or until death). Genotyping was performed for 10 SNPs in ZFP36 and 7 in ELAVL1 genes. On comparing both races with one another, significant differences were found for clinical and genetic variables. The influence of genetic polymorphisms on survival was analyzed by using Cox-regression, Kaplan-Meier analysis, and the log-rank test. Univariate (Kaplan-Meier/Cox-regression) and multivariate (Cox-regression) analysis showed that the TTP gene polymorphism ZFP36*2 A>G was significantly associated with poor prognosis of Caucasian patients (HR = 2.03; 95% CI = 1.09–3.76; P = 0.025; log-rank P = 0.022). None of the haplotypes, but presence of more than six risk genotypes in Caucasian patients, was significantly associated with poor prognosis (HR=2.42; 95% CI=1.17–4.99; P = 0.017; log-rank P = 0.007). The effect of ZFP36*2 A>G on gene expression was evaluated from patients' tissue samples. Both TTP mRNA and protein expression was significantly decreased in ZFP36*2 G allele carriers compared to A allele homozygotes. Conversely, upregulation of the TTP-target gene COX-2 was observed ZFP36*2 G allele carriers. Through its ability to attenuate TTP gene expression, the ZFP36*2 A>G gene polymorphism has appeared as a novel prognostic breast cancer marker in Caucasian patients. PMID:22907529

The RNA binding protein tristetraprolin down-regulates autophagy in lung adenocarcinoma cells.

PubMed

Dong, Fei; Li, Cen; Wang, Pu; Deng, Xiaoya; Luo, Qinli; Tang, Xiaokui; Xu, Li

2018-06-01

Tristetraprolin (TTP) is the most well-known member of RNA-binding zinc-finger protein that play a significant role in accelerating mRNA decay. Increasingly studies have reported that TTP was functioned as a tumor suppressor gene in several types of carcinomas, while its underlying mechanism is not clear yet. In the current study, we found that TTP overexpression decreased cell proliferation and increased cell death in lung adenocarcinoma cells, with the cell cycle arrest at the S phase. Remarkably, instead of inducing cell apoptosis directly, TTP overexpression alters cell autophagy. Our studies demonstrate that TTP overexpression has no effect on apoptosis related genes, but decreases the expression of autophagy-related genes, including Beclin 1 and LC3II. The level of autophagy flux assessed by infection with the mGFP-RFP-LC3 adenovirus construction has been blocked by TTP overexpression. Moreover, the autophagic vacuoles number detected by transmission electron microscopy decreased with TTP expression up-regulation. Our results indicate, for the first time, that TTP suppresses cell proliferation and increases cell death through cell autophagy pathway in lung cancer cells. Our study provides a new angle of view for TTP function as a tumor suppressor which could be targeted in tumor treatment. Copyright © 2018 Elsevier Inc. All rights reserved.

Regulation of sheep α-TTP by dietary vitamin E and preparation of monoclonal antibody for sheep α-TTP.

PubMed

Liu, Kun; Luo, Hai-Ling; Zuo, Zhao-Yun; Jia, Hui-Na; Zhang, Yu-Wei; Chang, Yan-Fei; Jiao, Li-Juan

2014-04-25

α-Tocopherol transfer protein (α-TTP) is a cytosolic protein that plays an important role in regulating concentrations of plasma α-tocopherol (the most bio-active form of vitamin E). Despite the central roles that α-TTP plays in maintaining vitamin E adequacy, we have only recently proved the existence of the α-TTP gene in sheep and, for the first time, cloned its full-length cDNA. However, the study of sheep α-TTP is still in its infancy. In the present study, thirty-five local male lambs of Tan sheep with similar initial body weight were randomly divided into five groups and fed with diets supplemented with 0 (control group), 20, 100, 200, 2000IU·sheep(-1)·d(-1) vitamin E for 120 days. At the end of the experiment, the plasma and liver vitamin E contents were analyzed first and then α-TTP mRNA and protein expression levels were determined by quantitative real-time PCR (qRT-PCR) and Western-blot analysis, respectively. In addition, as no sheep α-TTP antibody was available, a specific monoclonal antibody (McAb) against the ovine α-TTP protein was prepared. The effect of vitamin E supplementation was confirmed by the significant changes in the concentrations of vitamin E in the plasma and liver. As shown by qRT-PCR and Western-blot analysis, dietary vitamin E does not affect sheep α-TTP gene expression, except for high levels of vitamin E supplementation, which significantly increased expression at the protein level. Importantly, the specific sheep anti-α-TTP McAb we generated could provide optimal recognition in ELISA, Western-blot and immunohistochemistry assays, which will be a powerful tool in future studies of the biological functions of sheep α-TTP. Copyright © 2014 Elsevier B.V. All rights reserved.

Corona Enhancement and Mosaic Architecture for Prognosis and Selection Between of Liver Resection Versus Transcatheter Arterial Chemoembolization in Single Hepatocellular Carcinomas >5 cm Without Extrahepatic Metastases

PubMed Central

Li, Meng; Xin, Yongjie; Fu, Sirui; Liu, Zaiyi; Li, Yong; Hu, Baoshan; Chen, Shuting; Liang, Changhong; Lu, Ligong

2016-01-01

Abstract Corona enhancement and mosaic architecture are 2 radiologic features of hepatocellular carcinoma (HCC). However, neither their prognostic values nor their impacts on the selection of liver resection (LR) versus transcatheter arterial chemoembolization (TACE) as treatment modalities have been established. We retrospectively analyzed 275 patients with a single HCC lesion >5 cm without extrahepatic metastasis treated with LR or TACE. In LR patients, the overall survival (OS) and time to progression (TTP) were compared between corona enhancement negative (corona−) versus positive (corona+) and mosaic architecture negative (mosaic−) versus positive (mosaic+) patients. Furthermore, by the combination of corona and mosaic, LR patients were divided into negative for both corona and mosaic patterns (LR−/−), positive for only 1 feature (LR+/−), and positive for both (LR+/+); their OS and TTP were compared to those of the TACE group. Cox regression was performed to identify independent factors for OS. In the survival plots for LR, corona− had better OS and TTP than corona+, and mosaic− had better OS than mosaic+. There was no significant difference in TTP between the subgroups. On Cox regression analysis, corona enhancement, but not mosaic architecture, was a significant factor for OS, whereas neither were a significant factor for TTP. In TACE patients, neither corona nor mosaic patterns had significant correlations with OS or TTP. In the whole population, LR−/ and LR+/− subgroups had similar OS, which was better than the LR+/+ and TACE groups. Moreover, LR−/− and LR+/− patients had better TTP than TACE patients, but there were no differences between the LR−/− versus LR+/−, LR−/ versus LR+/+, LR+/− versus LR+/+, and LR+/+ versus TACE groups. On Cox regression analysis, the presence of corona/mosaic patterns was an independent prognostic factor for OS. Our results showed that, for patients with a single HCC >5 cm without extrahepatic metastasis, corona and mosaic patterns are indicators of limited LR efficacy. When both of the features are present, TACE can be used instead of LR with no negative influence on survival. PMID:26765441

Corona Enhancement and Mosaic Architecture for Prognosis and Selection Between of Liver Resection Versus Transcatheter Arterial Chemoembolization in Single Hepatocellular Carcinomas >5 cm Without Extrahepatic Metastases: An Imaging-Based Retrospective Study.

PubMed

Li, Meng; Xin, Yongjie; Fu, Sirui; Liu, Zaiyi; Li, Yong; Hu, Baoshan; Chen, Shuting; Liang, Changhong; Lu, Ligong

2016-01-01

Corona enhancement and mosaic architecture are 2 radiologic features of hepatocellular carcinoma (HCC). However, neither their prognostic values nor their impacts on the selection of liver resection (LR) versus transcatheter arterial chemoembolization (TACE) as treatment modalities have been established.We retrospectively analyzed 275 patients with a single HCC lesion >5 cm without extrahepatic metastasis treated with LR or TACE. In LR patients, the overall survival (OS) and time to progression (TTP) were compared between corona enhancement negative (corona-) versus positive (corona+) and mosaic architecture negative (mosaic-) versus positive (mosaic+) patients. Furthermore, by the combination of corona and mosaic, LR patients were divided into negative for both corona and mosaic patterns (LR-/-), positive for only 1 feature (LR+/-), and positive for both (LR+/+); their OS and TTP were compared to those of the TACE group. Cox regression was performed to identify independent factors for OS.In the survival plots for LR, corona- had better OS and TTP than corona+, and mosaic- had better OS than mosaic+. There was no significant difference in TTP between the subgroups. On Cox regression analysis, corona enhancement, but not mosaic architecture, was a significant factor for OS, whereas neither were a significant factor for TTP. In TACE patients, neither corona nor mosaic patterns had significant correlations with OS or TTP. In the whole population, LR-/ and LR+/- subgroups had similar OS, which was better than the LR+/+ and TACE groups. Moreover, LR-/- and LR+/- patients had better TTP than TACE patients, but there were no differences between the LR-/- versus LR+/-, LR-/ versus LR+/+, LR+/- versus LR+/+, and LR+/+ versus TACE groups. On Cox regression analysis, the presence of corona/mosaic patterns was an independent prognostic factor for OS.Our results showed that, for patients with a single HCC >5 cm without extrahepatic metastasis, corona and mosaic patterns are indicators of limited LR efficacy. When both of the features are present, TACE can be used instead of LR with no negative influence on survival.

Low incidence of ADAMTS13 missense mutation R1060W in adult Egyptian patients with thrombotic thrombocytopenic purpura.

PubMed

El Sissy, Maha H; El Hafez, A Abd; El Sissy, A H

2014-01-01

Thrombotic thrombocytopenic purpura (TTP) is an acute life-threatening disorder, characterized by thrombocytopenia, microangiopathic hemolytic anemia, widespread microvascular thrombi and consequent clinical sequelae due to ischemic organ damage. TTP is most commonly associated with deficiency or inhibition of von Willebrand factor-cleaving protease (ADAMTS13) activity. ADAMTS13 mutations and polymorphisms have been reported in childhood congenital TTP, but their significance in adult-onset TTP is still under investigation. Two mutations stand out: the single base insertion 4143insA in exon 29 and the missense mutation R1060W in exon 24 have both been observed in several unrelated families, mainly in adult-onset TTP, and over a wide geographic area. Our objective in this study is to identify the prevalence of R1060W missense mutation in exon 24 ADAMTS13 in a sample of adult Egyptian TTP patients. Thirty-one adult-onset TTP patients were included in this study, with a male/female ratio of 1:4. Twenty-six cases (84%) presented with acute idiopathic TTP, 2 cases were drug abusers and 3 cases were pregnant. None of the study cases provided a history of suspicious TTP symptoms during childhood (2 cases gave a history of episodes of thrombocytopenia during childhood). All cases showed statistically significant decreased ADAMTS13 activity compared to normal controls (p < 0.001). The study revealed a high statistical difference regarding the ADAMTS13 inhibitor level in primary versus secondary cases (p = 0.003). None of our Egyptian cases or of the healthy normal controls are positive for exon 24 missense mutation. Larger studies and regional and national TTP registries are recommended. © 2013 S. Karger AG, Basel.

Feature long axis size and local luminance contrast determine ship target acquisition performance: strong evidence for the TOD case

NASA Astrophysics Data System (ADS)

Bijl, Piet; Toet, Alexander; Kooi, Frank L.

2016-10-01

Visual images of a civilian target ship on a sea background were produced using a CAD model. The total set consisted of 264 images and included 3 different color schemes, 2 ship viewing aspects, 5 sun illumination conditions, 2 sea reflection values, 2 ship positions with respect to the horizon and 3 values of atmospheric contrast reduction. In a perception experiment, the images were presented on a display in a long darkened corridor. Observers were asked to indicate the range at which they were able to detect the ship and classify the following 5 ship elements: accommodation, funnel, hull, mast, and hat above the bridge. This resulted in a total of 1584 Target Acquisition (TA) range estimates for two observers. Next, the ship contour, ship elements and corresponding TA ranges were analyzed applying several feature size and contrast measures. Most data coincide on a contrast versus angular size plot using (1) the long axis as characteristic ship/ship feature size and (2) local Weber contrast as characteristic ship/ship feature contrast. Finally, the data were compared with a variety of visual performance functions assumed to be representative for Target Acquisition: the TOD (Triangle Orientation Discrimination), MRC (Minimum Resolvable Contrast), CTF (Contrast Threshold Function), TTP (Targeting Task Performance) metric and circular disc detection data for the unaided eye (Blackwell). The results provide strong evidence for the TOD case: both position and slope of the TOD curve match the ship detection and classification data without any free parameter. In contrast, the MRC and CTF are too steep, the TTP and disc detection curves are too shallow and all these curves need an overall scaling factor in order to coincide with the ship and ship feature recognition data.

Thrombotic thrombocytopenic purpura after prophylactic cefuroxime axetil administered in relation to a liposuction procedure.

PubMed

Eskazan, Ahmet Emre; Salihoglu, Ayse; Gulturk, Emine; Ongoren, Seniz; Soysal, Teoman

2012-04-01

Thrombotic thrombocytopenic purpura (TTP) or Moschcowitz's syndrome is characterized by platelet and von Willebrand factor (vWF) deposition in arterioles and capillaries throughout the body, which results in organ ischemia. The diagnostic pentad characterizing TTP consists of thrombocytopenia, microangiopathic hemolytic anemia (MAHA), fever, neurologic manifestations, and renal insufficiency. In terms of type, TTP can be either idiopathic or secondary. The causes of secondary TTP include pregnancy, infections, pancreatitis, collagen vascular disease, cancer, bone marrow transplantation, and drugs (including cephalosporins). Postoperative TTP has been reported after vascular surgery, renal and liver transplantations, and orthopedic, urologic, and abdominal surgical procedures. Therapeutic plasma exchange (TPE) therapy has reduced the mortality rates, but sometimes patients may have to receive immunosuppressive drugs including vincristine (VCR). This report describes a 42-year-old woman with TTP after prophylactic usage of cefuroxime axetil in relation to a liposuction procedure who was treated successfully with plasma exchange and VCR. The patient fully recovered after 17 TPEs and three doses of VCR. At this writing, her TTP still is in remission after 6 months of follow-up evaluation. To the authors' knowledge, this is the first report in the literature describing a patient with TTP after cefuroxime axetil administered in relation to a surgical procedure who was treated successfully with TPE and VCR.

Current insights into thrombotic microangiopathies: Thrombotic thrombocytopenic purpura and pregnancy.

PubMed

von Auer, Charis; von Krogh, Anne-Sophie; Kremer Hovinga, Johanna A; Lämmle, Bernhard

2015-02-01

The complex relation between thrombotic thrombocytopenic purpura (TTP) and pregnancy is concisely reviewed. Pregnancy is a very strong trigger for acute disease manifestation in patients with hereditary TTP caused by double heterozygous or homozygous mutations of ADAMTS13 (ADisintegrin And Metalloprotease with ThromboSpondin type 1 domains, no. 13). In several affected women disease onset during their first pregnancy leads to the diagnosis of hereditary TTP. Without plasma treatment mother and especially fetus are at high risk of dying. The relapse risk during a next pregnancy is almost 100% but regular plasma transfusion starting in early pregnancy will prevent acute TTP flare-up and may result in successful pregnancy outcome. Pregnancy may also constitute a mild risk factor for the onset of acute acquired TTP caused by autoantibody-mediated severe ADAMTS13 deficiency. Women having survived acute acquired TTP may not be at very high risk of TTP relapse during an ensuing next pregnancy but seem to have an elevated risk of preeclampsia. Monitoring of ADAMTS13 activity and inhibitor titre during pregnancy may help to guide management and to avoid disease recurrence. Finally, TTP needs to be distinguished from the much more frequent hypertensive pregnancy complications, preeclampsia and especially HELLP (Hemolysis, Elevated Liver Enzymes, Low Platelet count) syndrome. © 2015 Elsevier Ltd. All rights reserved.

Chloride permeability of rat brain membrane vesicles correlates with thiamine triphosphate content.

PubMed

Bettendorff, L; Hennuy, B; De Clerck, A; Wins, P

1994-07-25

Incubation of rat brain homogenates with thiamine or thiamine diphosphate (TDP) leads to a synthesis of thiamine triphosphate (TTP). In membrane vesicles subsequently prepared from the homogenates, increased TTP content correlates with increased 36Cl- uptake. A hyperbolic relationship was obtained with a K0.5 of 0.27 nmol TTP/mg protein. In crude mitochondrial fractions from the brains of animals previously treated with thiamine or sulbutiamine, a positive correlation between 36Cl- uptake and TTP content was found. These results, together with other results previously obtained with the patch-clamp technique, suggest that TTP is an activator of chloride channels having a large unit conductance.

Time From the Beginning of the Right Ventricle Isovolumetric Contraction to the Peak of the S Wave: A New TDI Indicator for the Non-Invasive Estimation of Pulmonary Hypertension.

PubMed

Parsaee, Mozhgan; Ghaderi, Fereshteh; Alizadehasl, Azin; Bakhshandeh, Hooman

2016-08-01

Echocardiography is a key screening tool in the diagnostic algorithm of pulmonary hypertension (PH). In addition, tissue doppler imaging (TDI) is a promising method for the noninvasive estimation of pulmonary artery pressure (PAP). The aim of this study was to validate the accuracy of measuring the time from the beginning of the right ventricular isovolumetric contraction time (RV IVRT) to the peak of the S wave in the TDI of the base of the RV free wall (time to peak or TTP), as an indicator for the non-invasive estimation of pulmonary hypertension. In this diagnostic test study, 60 consecutive patients referred for right heart catheterization (RHC) were enrolled. A pulse-wave TDI was performed before the cardiac catheterization, with a mean interval of 1 hour between the two measurements. The TDI variables, such as the RV IVRT, myocardial performance index (MPI), and the new "time to peak" parameter, were measured at the lateral basal RV free wall. The patients were divided into two sub-groups according to the RHC findings: no-PH (mean PAP < 25 mmHg) and PH (mean PAP ≥ 25 mmHg) groups. Then, we calculated the specificity and sensitivity of the TDI parameters (including the TTP) for the diagnosis of PH. In our study, the TTP showed a significant inverse relationship with the PAP. Based on our results, a TTP of less than 127 ms could be used to predict PH, with a sensitivity and specificity of about 70% (AUC = 0.746 ± 0.064). Based on the results of this study, we suggest the use of a novel "time from the beginning of isovolumetric contraction to the peak of the S wave" (TTP) parameter in the TDI of the base of the RV free wall to predict PH with acceptable accuracy in comparison with RHC.

Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial.

PubMed

Sanoff, Hanna K; Sargent, Daniel J; Green, Erin M; McLeod, Howard L; Goldberg, Richard M

2009-09-01

Racial disparities in colorectal cancer (CRC) survival are documented, but there are few data on comparative response to chemotherapy. A subgroup analysis of a multisite National Cancer Institute-sponsored trial (N9741) was performed comparing outcomes of black and white patients with metastatic CRC receiving uniform treatment. Adverse events (AEs), response rate (RR), time to progression (TTP), overall survival (OS), and dose-intensity were examined as a function of self-reported race in 1,412 patients treated with irinotecan/fluorouracil, fluorouracil/oxaliplatin, or irinotecan/oxaliplatin. Pharmacogenetic analysis was performed on 486 patients with blood available for germline DNA analysis. OS was 1.5 months shorter and TTP was 0.6 months shorter in black than white patients (OS: hazard ratio [HR] = 1.13; 95% CI, 0.90 to 1.42; TTP: HR = 0.91, 95% CI, 0.73 to 1.13); neither difference was statistically significant. RR was significantly higher in whites (41%) than blacks (28%; P = .008). Grade 3 or greater AEs were also higher in whites (48%) than blacks (34%; P = .004). These relationships were maintained in multivariate models adjusting for arm, age, sex, and performance status. There was no difference in dose-intensity of delivered therapy. Significant racial differences in prevalence of pharmacogenetic variants were observed, although small sample size precluded investigating the relationship between treatment, race, and genotype. OS and TTP are similar in black and white patients treated per protocol with standardized therapy for metastatic CRC. However, RR and AEs vary considerably by race. The marked racial differences in relevant pharmacogenetics, a potential explanation for differing RR and AEs, are worthy of future study.

Different motion cues are used to estimate time-to-arrival for frontoparallel and looming trajectories

PubMed Central

Calabro, Finnegan J.; Beardsley, Scott A.; Vaina, Lucia M.

2012-01-01

Estimation of time-to-arrival for moving objects is critical to obstacle interception and avoidance, as well as to timing actions such as reaching and grasping moving objects. The source of motion information that conveys arrival time varies with the trajectory of the object raising the question of whether multiple context-dependent mechanisms are involved in this computation. To address this question we conducted a series of psychophysical studies to measure observers’ performance on time-to-arrival estimation when object trajectory was specified by angular motion (“gap closure” trajectories in the frontoparallel plane), looming (colliding trajectories, TTC) or both (passage courses, TTP). We measured performance of time-to-arrival judgments in the presence of irrelevant motion, in which a perpendicular motion vector was added to the object trajectory. Data were compared to models of expected performance based on the use of different components of optical information. Our results demonstrate that for gap closure, performance depended only on the angular motion, whereas for TTC and TTP, both angular and looming motion affected performance. This dissociation of inputs suggests that gap closures are mediated by a separate mechanism than that used for the detection of time-to-collision and time-to-passage. We show that existing models of TTC and TTP estimation make systematic errors in predicting subject performance, and suggest that a model which weights motion cues by their relative time-to-arrival provides a better account of performance. PMID:22056519

Infrared and Raman spectroscopic study of BDA-TTP [2,5-bis(1,3-dithian-2-ylidene) 1,3,4,6-tetrathiapentalene] and its charge-transfer salts

NASA Astrophysics Data System (ADS)

Uruichi, Mikio; Nakano, Chikako; Tanaka, Masayuki; Yakushi, Kyuya; Kaihatsu, Takayuki; Yamada, Jun-ichi

2008-09-01

Infrared and Raman spectra in the frequency range of 1200-1600 cm -1 were observed using BDA-TTP and (BDA-TTP)CuCl 2 crystals. The C =C stretching and CH 2 bending modes in this frequency region were assigned based on quantum chemical calculation of the normal modes by the density functional theory (DFT) method. The three C =C stretching modes of BDA-TTP showed a significant low-frequency shift upon oxidation. One of the Raman-active C =C stretching modes is strongly coupled with the charge-transfer excited state. Vibrational analysis was applied to β-(BDA-TTP) 2I 3. The infrared-active C =C stretching mode strongly suggests that the insulating state of β-(BDA-TTP) 2I 3 is characterized as a dimer-Mott state below 150 K.

Utility of a blood culture time to positivity-incorporated scoring model in predicting vascular infections in adults with nontyphoid Salmonella bacteremia.

PubMed

Lin, Jr-Jiun; Weng, Tzu-Hua; Tseng, Wen-Pin; Chen, Shang-Yu; Fu, Chia-Ming; Lin, Hui-Wen; Liao, Chun-Hsing; Lee, Tai-Fen; Hsueh, Po-Ren; Chen, Shey-Ying

2018-02-21

Vascular infections (VI) are potentially catastrophic complications of nontyphoid Salmonella (NTS). We aimed to develop a scoring model incorporating information from blood culture time to positivity (TTP-NTSVI) and compared the prediction capability for VI among adults with NTS bacteremia between TTP-NTSVI and a previously published score (Chen-NTSVI). This retrospective cohort study enrolled 217 adults with NTS bacteremia ≧ 50 years old. We developed a TTP-NTSVI score by multiple logistic regression modeling to identify independent predictors for imaging-confirmed VI and assigned a point value weighting by the corresponding natural logarithm of the odds ratio for each model predictor. Chen-NTSVI score includes hypertension, male sex, serogroup C1, coronary arterial disease (CAD) as positive predictors, and malignancy and immunosuppressive therapy as negative predictors. The prediction capability of the two scores was compared by area under the receiver operating characteristic curve (AUC). The mean age was 68.3 ± 11.2 years-old. Serogroup D was the predominant isolate (155/217, 71.4%). Seventeen (7.8%) patients had VI. Four independent predictors for VI were identified: male sex (24.9 [2.59-239.60]; 6) (odds ratio [95% confidence interval]; assigned score point), peripheral arterial occlusive disease (9.41 [2.21-40.02]; 4), CAD (4.0 [1.16-13.86]; 3), and TTP <10 h (4.67 [1.42-15.39]; 3). Youden's index showed best cutoff value of ≧7 with 70.6% sensitivity and 82.5% specificity. TTP-NTSVI score had higher AUC than Chen-NTSVI (0.851 vs 0.741, P = 0.039). While the previously reported scoring model performed well, a TTP-incorporated scoring model was associated with improved capability in predicting NTSVI. Copyright © 2018. Published by Elsevier B.V.

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS): a 24-year clinical experience with 178 patients

PubMed Central

Levandovsky, Mark; Harvey, Danielle; Lara, Primo; Wun, Ted

2008-01-01

Background Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome (TTP-HUS) are related and uncommon disorders with a high fatality and complication rate if untreated. Plasma exchange therapy has been shown to produce high response rates and improve survival in patients with many forms of TTP-HUS. We performed a retrospective cohort study of 178 consecutively treated patients with TTP-HUS and analyzed whether clinical or laboratory characteristics could predict for important short- and long-term outcome measures. Results Overall 30-day mortality was 16% (n = 27). 171 patients (96%) received plasma exchange as the principal treatment, with a mean of 8 exchanges and a mean cumulative infused volume of 42 ± 71 L of fresh frozen plasma. The rate of complete response was 65% or 55% depending on whether this was defined by a platelet count of 100,000/μl or 150,000/μl, respectively. The rate of relapse was 18%. The Clinical Severity Score did not predict for 30-day mortality or relapse. The time to complete response did not predict for relapse. Renal insufficiency at presentation was associated with a decreased risk of relapse, with each unit increase in serum creatinine associated with a 40% decreased odds of relapse. 72% of our cohort had an idiopathic TTP-sporadic HUS, while 17% had an underlying cancer, received a solid organ transplant or were treated with a mitomycin-based therapy. The estimated overall 5-year survival was 55% and was significantly better in those without serious underlying conditions. Conclusion Plasma exchange therapy produced both high response and survival rates in this large cohort of patients with TTP-HUS. The Clinical Severity Score did not predict for 30-day mortality or relapse, contrary to our previous findings. Interestingly, the presence of renal insufficiency was associated with a decreased risk of relapse. The most important predictor of mortality was the presence or absence of a serious underlying disorder. PMID:19046460

The RNA-binding protein tristetraprolin schedules apoptosis of pathogen-engaged neutrophils during bacterial infection

PubMed Central

Ebner, Florian; Ivin, Masa; Kratochvill, Franz; Gratz, Nina; Villunger, Andreas; Sixt, Michael

2017-01-01

Protective responses against pathogens require a rapid mobilization of resting neutrophils and the timely removal of activated ones. Neutrophils are exceptionally short-lived leukocytes, yet it remains unclear whether the lifespan of pathogen-engaged neutrophils is regulated differently from that in the circulating steady-state pool. Here, we have found that under homeostatic conditions, the mRNA-destabilizing protein tristetraprolin (TTP) regulates apoptosis and the numbers of activated infiltrating murine neutrophils but not neutrophil cellularity. Activated TTP-deficient neutrophils exhibited decreased apoptosis and enhanced accumulation at the infection site. In the context of myeloid-specific deletion of Ttp, the potentiation of neutrophil deployment protected mice against lethal soft tissue infection with Streptococcus pyogenes and prevented bacterial dissemination. Neutrophil transcriptome analysis revealed that decreased apoptosis of TTP-deficient neutrophils was specifically associated with elevated expression of myeloid cell leukemia 1 (Mcl1) but not other antiapoptotic B cell leukemia/lymphoma 2 (Bcl2) family members. Higher Mcl1 expression resulted from stabilization of Mcl1 mRNA in the absence of TTP. The low apoptosis rate of infiltrating TTP-deficient neutrophils was comparable to that of transgenic Mcl1-overexpressing neutrophils. Our study demonstrates that posttranscriptional gene regulation by TTP schedules the termination of the antimicrobial engagement of neutrophils. The balancing role of TTP comes at the cost of an increased risk of bacterial infections. PMID:28504646

Engineering Tocopherol Selectivity in α-TTP: A Combined In Vitro/In Silico Study

PubMed Central

Helbling, Rachel E.; Aeschimann, Walter; Simona, Fabio; Stocker, Achim; Cascella, Michele

2012-01-01

We present a combined in vitro/in silico study to determine the molecular origin of the selectivity of -tocopherol transfer protein (-TTP) towards -tocopherol. Molecular dynamics simulations combined to free energy perturbation calculations predict a binding free energy for -tocopherol to -TTP 8.262.13 kcal mol lower than that of -tocopherol. Our calculations show that -tocopherol binds to -TTP in a significantly distorted geometry as compared to that of the natural ligand. Variations in the hydration of the binding pocket and in the protein structure are found as well. We propose a mutation, A156L, which significantly modifies the selectivity properties of -TTP towards the two tocopherols. In particular, our simulations predict that A156L binds preferentially to -tocopherol, with striking structural similarities to the wild-type--tocopherol complex. The affinity properties are confirmed by differential scanning fluorimetry as well as in vitro competitive binding assays. Our data indicate that residue A156 is at a critical position for determination of the selectivity of -TTP. The engineering of TTP mutants with modulating binding properties can have potential impact at industrial level for easier purification of single tocopherols from vitamin E mixtures coming from natural oils or synthetic processes. Moreover, the identification of a -tocopherol selective TTP offers the possibility to challenge the hypotheses for the evolutionary development of a mechanism for -tocopherol selection in omnivorous animals. PMID:23152872

Effects of AgRP Inhibition on Energy Balance and Metabolism in Rodent Models

PubMed Central

Dutia, Roxanne; Kim, Andrea J.; Modes, Matthew; Rothlein, Robert; Shen, Jane M.; Tian, Ye Edward; Ihbais, Jumana; Victory, Sam F.; Valcarce, Carmen; Wardlaw, Sharon L.

2013-01-01

Activation of brain melanocortin-4 receptors (MC4-R) by α-melanocyte-stimulating hormone (MSH) or inhibition by agouti-related protein (AgRP) regulates food intake and energy expenditure and can modulate neuroendocrine responses to changes in energy balance. To examine the effects of AgRP inhibition on energy balance, a small molecule, non-peptide compound, TTP2515, developed by TransTech Pharma, Inc., was studied in vitro and in rodent models in vivo. TTP2515 prevented AgRP from antagonizing α-MSH-induced increases in cAMP in HEK 293 cells overexpressing the human MC4-R. When administered to rats by oral gavage TTP2515 blocked icv AgRP-induced increases in food intake, weight gain and adiposity and suppression of T4 levels. In both diet-induced obese (DIO) and leptin-deficient mice, TTP2515 decreased food intake, weight gain, adiposity and respiratory quotient. TTP2515 potently suppressed food intake and weight gain in lean mice immediately after initiation of a high fat diet (HFD) but had no effect on these parameters in lean chow-fed mice. However, when tested in AgRP KO mice, TTP2515 also suppressed food intake and weight gain during HFD feeding. In several studies TTP2515 increased T4 but not T3 levels, however this was also observed in AgRP KO mice. TTP2515 also attenuated refeeding and weight gain after fasting, an effect not evident in AgRP KO mice when administered at moderate doses. This study shows that TTP2515 exerts many effects consistent with AgRP inhibition however experiments in AgRP KO mice indicate some off-target effects of this drug. TTP2515 was particularly effective during fasting and in mice with leptin deficiency, conditions in which AgRP is elevated, as well as during acute and chronic HFD feeding. Thus the usefulness of this drug in treating obesity deserves further exploration, to define the AgRP dependent and independent mechanisms by which TTP2515 exerts its effects on energy balance. PMID:23762342

CD(+)(4)CD(+)(25) Treg cells in thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus patients.

PubMed

Huang, Hongdong; Sun, Weiming; Liang, Yumei; Long, Xi-Dai; Peng, Youming; Liu, Zhihua; Wen, Xiaojun; Jia, Meng

2014-09-01

CD(+)(4)CD(+)(25) Treg cells are of critical importance for maintenance of tolerance. The purpose of the this study was to observe the number of CD(+)(4)CD(+)(25) Treg cells in the patients with thrombotic thrombocytopenic purpura (TTP) associated with systemic lupus erythematosus (SLE), and to study pathogenesis of TTP with SLE. Seven patients with TTP associated with SLE and seven healthy volunteers were studied. The CD(+)(4)CD(+)(25) Treg cells were examined by flow cytometry. Clinical and laboratory data, such as urinary protein, serum creatinine, endothelial markers and immunologic serologics, were obtained from each patient and healthy volunteer. Glomerular injury was assessed by histopathology. Serum IL-2, IL-4, IL-6 and anti-endothelial cell antibody were analyzed by ELISA and anti-ADAMTS13 antibody were detected by Western blotting. CD(+)(4)CD(+)(25) Treg cells significantly decreased in TTP with SLE patients compared with controls (p < 0.05). CD(+)(4)CD(+)(25) Treg cells are negatively correlated with blood urea nitrogen, serum uric acid, supernatant IL-4, and proteinuria, and positively with estimated glomerular filtration rate (eGFR) in TTP with SLE patients. [Formula: see text] Treg cells gradually decreased as the severity of renal histology increased. Serum IL-2, IL-6, supernatant IL-4, anti-endothelial cell antibody, and anti-ADAMTS13 antibody significantly increased in TTP with SLE patients compared to those of the control groups (all p < 0.05). In contrast, serum levels of C3 were significantly decreased in TTP with SLE patients compared to those of the control groups (p < 0.05). CD(+)(4)CD(+)(25) Treg cells are not only lower in TTP with SLE patients, but also are correlated with disease severity in TTP with SLE patients.CD(+)(4)CD(+)(25)Treg cells may play an important role in the pathogenesis of TTP with SLE.

Mineralogical conversion of asbestos containing materials

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

Pulsford, S.K.; Foltz, A.D.; Ek, R.B.

The principal objective of the Technical Task Plan (TTP) is to demonstrate a thermal-chemical mineralogical asbestos conversion unit at the Hanford Site, which converts non-radiological asbestos containing materials (ACMs) into an asbestos-free material. The permanent thermal-chemical mineralogical conversion of ACMs to a non-toxic, non-hazardous, potentially marketable end product should not only significantly reduce the waste stream volumes but terminate the {open_quotes}cradle to grave{close_quotes} ownership liabilities.

Tristetraprolin inhibits mitochondrial function through suppression of α-Synuclein expression in cancer cells

PubMed Central

Vo, Mai-Tram; Choi, Seong Hee; Lee, Ji-Heon; Hong, Chung Hwan; Kim, Jong Soo; Lee, Unn Hwa; Chung, Hyung-Min; Lee, Byung Ju; Park, Jeong Woo; Cho, Wha Ja

2017-01-01

Mitochondrial dynamics play critical roles in maintaining mitochondrial functions. Here, we report a novel mechanism for regulation of mitochondrial dynamics mediated by tristetraprolin (TTP), an AU-rich element (ARE)-binding protein. Overexpression of TTP resulted in elongated mitochondria, down-regulation of mitochondrial oxidative phosphorylation, reduced membrane potential, cytochrome c release, and increased apoptotic cell death in cancer cells. TTP overexpression inhibited the expression of α-Synuclein (α-Syn). TTP bound to the ARE within the mRNA 3′-untranslated regions (3′-UTRs) of α-Syn and enhanced the decay of α-Syn mRNA. Overexpression of α-Syn without the 3′-UTR restored TTP-induced defects in mitochondrial morphology, mitochondrial oxidative phosphorylation, membrane potential, and apoptotic cell death. Taken together, our data demonstrate that TTP acts as a regulator of mitochondrial dynamics through enhancing degradation of α-Syn mRNA in cancer cells. This finding will increase understanding of the molecular basis of mitochondrial dynamics. PMID:28410208

Comparison of the antiseptic efficacy of tissue-tolerable plasma and an octenidine hydrochloride-based wound antiseptic on human skin.

PubMed

Lademann, J; Richter, H; Schanzer, S; Patzelt, A; Thiede, G; Kramer, A; Weltmann, K-D; Hartmann, B; Lange-Asschenfeldt, B

2012-01-01

Colonization and infection of wounds represent a major reason for the impairment of tissue repair. Recently, it has been reported that tissue-tolerable plasma (TTP) is highly efficient in the reduction of the bacterial load of the skin. In the present study, the antiseptic efficacy of TTP was compared to that of octenidine hydrochloride with 2-phenoxyethanol. Both antiseptic methods proved to be highly efficient. Cutaneous treatment of the skin with octenidine hydrochloride and 2-phenoxyethanol leads to a 99% elimination of the bacteria, and 74% elimination is achieved by TTP treatment. Technical challenges with an early prototype TTP device could be held responsible for the slightly reduced antiseptic properties of TTP, compared to a standard antiseptic solution, since the manual treatment of the skin surface with a small beam of the TTP device might have led to an incomplete coverage of the treated area. Copyright © 2012 S. Karger AG, Basel.

Acquired thrombotic thrombocytopenic purpura: new therapeutic options and their optimal use.

PubMed

Cataland, S R; Wu, H M

2015-06-01

Advances in our understanding of the pathophysiology of both congenital and acquired thrombotic thrombocytopenic purpura (TTP) have led to both an increased understanding of the disease and novel approaches to therapy. The efficacy of rituximab in acquired TTP has led to consideration of rituximab as a prophylactic therapy to prevent relapse of TTP. Novel therapies that target the A1 domain of von Willebrand factor (VWF) to block the formation of microthrombotic disease have also entered clinical study and have demonstrated promise as potential therapeutic options. Additionally, a recombinant ADAMTS13 protease has been developed which may be an important therapeutic option for both congenital and acquired TTP. The development of these new therapeutic options for patients diagnosed with TTP has increased the importance of conducting prospective, randomized studies with these agents to both confirm their efficacy and more importantly understand their most appropriate role in the treatment of patients with TTP. © 2015 International Society on Thrombosis and Haemostasis.

Prospective study of serial 18F-FDG PET and 18F-fluoride (18F-NaF) PET to predict time to skeletal related events, time-to-progression, and survival in patients with bone-dominant metastatic breast cancer.

PubMed

Peterson, Lanell M; O'Sullivan, Janet; Wu, Qian Vicky; Novakova-Jiresova, Alena; Jenkins, Isaac; Lee, Jean H; Shields, Andrew; Montgomery, Susan; Linden, Hannah M; Gralow, Julie R; Gadi, Vijayakrishna K; Muzi, Mark; Kinahan, Paul E; Mankoff, David A; Specht, Jennifer M

2018-05-10

Assessing therapy response of breast cancer bone metastases is challenging. In retrospective studies, serial 18 F-FDG PET was predictive of time to skeletal related events (tSRE) and time-to-progression (TTP). 18 F-NaF PET improves bone metastasis detection compared to bone scans. We prospectively tested 18 F-FDG PET and 18 F-NaF PET to predict tSRE, TTP, and overall survival (OS) in patients with bone-dominant metastatic breast cancer (BD MBC). Methods: Patients with BD MBC were imaged with 18 F-FDG PET and 18 F-NaF PET prior to starting new therapy (scan1) and again at a range of times centered around approximately 4 months later (scan2). SUV max and SULpeak were recorded for a single index lesion and up to 5 most dominant lesions for each scan. tSRE, TTP, and OS were assessed exclusive of the PET images. Univariate Cox regression was performed to test the association between clinical endpoints and 18 F-FDG PET and 18 F-NaF PET measures. mPERCIST (Modified PET Response Criteria in Solid Tumors) criteria were also applied. Survival curves for mPERCIST compared response categories of Complete Response+Partial Response+Stable Disease versus Progressive Disease (CR+PR+SD vs PD) for tSRE, TTP, and OS. Results: Twenty-eight patients were evaluated. Higher FDG SULpeak at scan2 predicted shorter time to tSRE ( P = <0.001) and TTP ( P = 0.044). Higher FDG SUV max at scan2 predicted a shorter time to tSRE ( P = <0.001). A multivariable model using FDG SUV max of the index lesion at scan1 plus the difference in SUV max of up to 5 lesions between scans was predictive for tSRE and TTP. Among 24 patients evaluable by 18 F-FDG PET mPERCIST, tSRE and TTP were longer in responders (CR, PR, or stable) compared to non-responders (PD) ( P = 0.007, 0.028 respectively), with a trend toward improved survival ( P = 0.1). An increase in the uptake between scans of up to 5 lesions by 18 F-NaF PET was associated with longer OS ( P = 0.027). Conclusion: Changes in 18 F-FDG PET parameters during therapy are predictive of tSRE and TTP, but not OS. mPERCIST evaluation in bone lesions may be useful in assessing response to therapy and is worthy of evaluation in multicenter, prospective trials. Serial 18 F-NaF PET was associated with OS, but was not useful for predicting TTP or tSRE in BD MBC. Copyright © 2018 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

Low ADAMTS-13 in plavix induced thrombotic thrombocytopenic purpura.

PubMed

Cao, Long Bao; Jones, Christopher; Movahed, Assad

2013-04-16

Thrombotic thrombocytopenia purpura (TTP) was first described in 1924 as a "pathologic alteration of the microvasculature, with detachment or swelling of the endothelium, amorphous material in the sub-endothelial space, and luminal platelet aggregation leading to compromise of the microcirculation". Ticlopidine induced TTP has been highly associated with autoimmune induced reduction in ADAMTS-13 activity. These findings, to a lesser extent, have also been found in clopidogrel induced TTP. We report a case of clopidogrel associated TTP in a patient that presented with acute stroke, renal failure, and non-ST elevation myocardial infarction.

A new approach in the design of organic superconductors

NASA Astrophysics Data System (ADS)

Yamada, J.

2004-04-01

The preparation of charge-transfer (CT) salts of DODHT [(1,4-dioxane-2,3-diyldithio) dihydrotetrathia-fulvalene], BDH-TTP [2,5-bis(1,3-dithiolan-2-ylidene)-1,3,4,6-tetrathiapentalene] and BDA-TTP [2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene] has been investigated to develop new organic superconductors. The DODHT and BDA-TTP donors give organic superconductors (DODHT){2}BF{4}\\cdot H{2}O and (BDA-TTP){2}X (X = GaCl{4} and FeCl{4}) under applied pressures, whereas (BDH-TTP)Br{0.88} and (BDA-TTF){2}X (X = BF{4}, BF{4}\\cdot H{2}O and ClO{4}) fail to exhibit superconductivity at ambient pressure. Key words. Organic superconductor π -electron donor σ -bond framework loose donor packing motif.

Predicting Outcomes After Chemo-Embolization in Patients with Advanced-Stage Hepatocellular Carcinoma: An Evaluation of Different Radiologic Response Criteria

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

Gunn, Andrew J., E-mail: agunn@uabmc.edu; Sheth, Rahul A.; Luber, Brandon

2017-01-15

PurposeThe purpse of this study was to evaluate the ability of various radiologic response criteria to predict patient outcomes after trans-arterial chemo-embolization with drug-eluting beads (DEB-TACE) in patients with advanced-stage (BCLC C) hepatocellular carcinoma (HCC).Materials and methodsHospital records from 2005 to 2011 were retrospectively reviewed. Non-infiltrative lesions were measured at baseline and on follow-up scans after DEB-TACE according to various common radiologic response criteria, including guidelines of the World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), the European Association for the Study of the Liver (EASL), and modified RECIST (mRECIST). Statistical analysis was performed to see which,more » if any, of the response criteria could be used as a predictor of overall survival (OS) or time-to-progression (TTP).Results75 patients met inclusion criteria. Median OS and TTP were 22.6 months (95 % CI 11.6–24.8) and 9.8 months (95 % CI 7.1–21.6), respectively. Univariate and multivariate Cox analyses revealed that none of the evaluated criteria had the ability to be used as a predictor for OS or TTP. Analysis of the C index in both univariate and multivariate models showed that the evaluated criteria were not accurate predictors of either OS (C-statistic range: 0.51–0.58 in the univariate model; range: 0.54–0.58 in the multivariate model) or TTP (C-statistic range: 0.55–0.59 in the univariate model; range: 0.57–0.61 in the multivariate model).ConclusionCurrent response criteria are not accurate predictors of OS or TTP in patients with advanced-stage HCC after DEB-TACE.« less

Predicting Outcomes After Chemo-Embolization in Patients with Advanced-Stage Hepatocellular Carcinoma: An Evaluation of Different Radiologic Response Criteria.

PubMed

Gunn, Andrew J; Sheth, Rahul A; Luber, Brandon; Huynh, Minh-Huy; Rachamreddy, Niranjan R; Kalva, Sanjeeva P

2017-01-01

The purpse of this study was to evaluate the ability of various radiologic response criteria to predict patient outcomes after trans-arterial chemo-embolization with drug-eluting beads (DEB-TACE) in patients with advanced-stage (BCLC C) hepatocellular carcinoma (HCC). Hospital records from 2005 to 2011 were retrospectively reviewed. Non-infiltrative lesions were measured at baseline and on follow-up scans after DEB-TACE according to various common radiologic response criteria, including guidelines of the World Health Organization (WHO), Response Evaluation Criteria in Solid Tumors (RECIST), the European Association for the Study of the Liver (EASL), and modified RECIST (mRECIST). Statistical analysis was performed to see which, if any, of the response criteria could be used as a predictor of overall survival (OS) or time-to-progression (TTP). 75 patients met inclusion criteria. Median OS and TTP were 22.6 months (95 % CI 11.6-24.8) and 9.8 months (95 % CI 7.1-21.6), respectively. Univariate and multivariate Cox analyses revealed that none of the evaluated criteria had the ability to be used as a predictor for OS or TTP. Analysis of the C index in both univariate and multivariate models showed that the evaluated criteria were not accurate predictors of either OS (C-statistic range: 0.51-0.58 in the univariate model; range: 0.54-0.58 in the multivariate model) or TTP (C-statistic range: 0.55-0.59 in the univariate model; range: 0.57-0.61 in the multivariate model). Current response criteria are not accurate predictors of OS or TTP in patients with advanced-stage HCC after DEB-TACE.

A study on cerebral hemodynamic analysis of moyamoya disease by using perfusion MRI

NASA Astrophysics Data System (ADS)

Dong, Kyung-Rae; Goo, Eun-Hoe; Lee, Jae-Seung; Chung, Woon-Kwan

2013-10-01

This study examined the clinical applications of perfusion magnetic resonance imaging (MRI) in patients with moyamoya disease (MMD). Twenty-two patients with moyamoya disease (9 men and 13 women) with a mean age of 9.3 years (range: 4-22 years) were enrolled in this study. Perfusion MRI was performed by scanning the patients7.5 cm upward from the base of the cerebellum before their being process for post-treatment. The scan led to the acquisition of the following four map images: the cerebral blood volume (CBV), the cerebral blood flow (CBF), the mean transit time (MTT) for the contrast medium, and the time to peak (TTP) for the contrast medium. The lesions were assessed using the CBV, the CBF, the MTT and the TTP maps of perfusion MRI; the MTT and the TTP were measured in the lesion areas, as well as in the normal and the symmetric areas. Perfusion defects were recognizable in all four perfusion MRI maps, and the MTT and the TTP showed a conspicuous delay in the parts where perfusion defects were recognized. The MTT and the TTP images of perfusion MRI reflected a significant correlation between the degrees of stenosis and occlusion in the posterior cerebral artery (PCA), as well as the development of collateral vessels. The four perfusion MRI maps could be used to predict the degrees of stenosis and occlusion in the posterior circulation, as well as the development of the collateral vessels, which enabled a hemodynamic evaluation of the parts with perfusion defects. Overall, perfusion MRI is useful for the diagnosis and the treatment of moyamoya disease and can be applied to clinical practice.

Reducing Wait Time for Lung Cancer Diagnosis and Treatment: Impact of a Multidisciplinary, Centralized Referral Program.

PubMed

Common, Jessica L; Mariathas, Hensley H; Parsons, Kaylah; Greenland, Jonathan D; Harris, Scott; Bhatia, Rick; Byrne, SuzanneC

2018-06-04

A multidisciplinary, centralized referral program was established at our institution in 2014 to reduce delays in lung cancer diagnosis and treatment following diagnostic imaging observed with the traditional, primary care provider-led referral process. The main objectives of this retrospective cohort study were to determine if referral to a Thoracic Triage Panel (TTP): 1) expedites lung cancer diagnosis and treatment initiation; and 2) leads to more appropriate specialist consultation. Patients with a diagnosis of lung cancer and initial diagnostic imaging between March 1, 2015, and February 29, 2016, at a Memorial University-affiliated tertiary care centre in St John's, Newfoundland, were identified and grouped according to whether they were referred to the TTP or managed through a traditional referral process. Wait times (in days) from first abnormal imaging to biopsy and treatment initiation were recorded. Statistical analysis was performed using the Wilcoxon rank-sum test. A total of 133 patients who met inclusion criteria were identified. Seventy-nine patients were referred to the TTP and 54 were managed by traditional means. There was a statistically significant reduction in median wait times for patients referred to the TTP. Wait time from first abnormal imaging to biopsy decreased from 61.5 to 36.0 days (P < .0001). Wait time from first abnormal imaging to treatment initiation decreased from 118.0 to 80.0 days (P < .001). The percentage of specialist consultations that led to treatment was also greater for patients referred to the TTP. A collaborative, centralized intake and referral program helps to reduce wait time for diagnosis and treatment of lung cancer. Copyright © 2018 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.

Creep-rupture reliability analysis

NASA Technical Reports Server (NTRS)

Peralta-Duran, A.; Wirsching, P. H.

1984-01-01

A probabilistic approach to the correlation and extrapolation of creep-rupture data is presented. Time temperature parameters (TTP) are used to correlate the data, and an analytical expression for the master curve is developed. The expression provides a simple model for the statistical distribution of strength and fits neatly into a probabilistic design format. The analysis focuses on the Larson-Miller and on the Manson-Haferd parameters, but it can be applied to any of the TTP's. A method is developed for evaluating material dependent constants for TTP's. It is shown that optimized constants can provide a significant improvement in the correlation of the data, thereby reducing modelling error. Attempts were made to quantify the performance of the proposed method in predicting long term behavior. Uncertainty in predicting long term behavior from short term tests was derived for several sets of data. Examples are presented which illustrate the theory and demonstrate the application of state of the art reliability methods to the design of components under creep.

A new organic superconductor, beta-(BDA-TTP)2GaCl4 [BDA-TTP = 2,5-(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene].

PubMed

Yamada, Jun-ichi; Toita, Takashi; Akutsu, Hiroki; Nakatsuji, Shin'ichi; Nishikawa, Hiroyuki; Ikemoto, Isao; Kikuchi, Koichi; Choi, Eun S; Graf, David; Brooks, James S

2003-09-07

The preparation, crystal structure and physical properties of beta-(BDA-TTP)2GaCl4 has been investigated; the salt exhibits superconductivity at 3.1 K (onset) under a hydrostatic pressure of 7.6 kbar.

Correlation-based perfusion mapping using time-resolved MR angiography: A feasibility study for patients with suspicions of steno-occlusive craniocervical arteries.

PubMed

Nam, Yoonho; Jang, Jinhee; Park, Sonya Youngju; Choi, Hyun Seok; Jung, So-Lyung; Ahn, Kook-Jin; Kim, Bum-Soo

2018-05-22

To explore the feasibility of using correlation-based time-delay (CTD) maps produced from time-resolved MR angiography (TRMRA) to diagnose perfusion abnormalities in patients suspected to have steno-occlusive lesions in the craniocervical arteries. Twenty-seven patients who were suspected to have steno-occlusive lesions in the craniocervical arteries underwent both TRMRA and brain single-photon emission computed tomography (SPECT). TRMRA was performed on the supra-aortic area after intravenous injection of a 0.03 mmol/kg gadolinium-based contrast agent. Time-to-peak (TTP) maps and CTD maps of the brain were automatically generated from TRMRA data, and their quality was assessed. Detection of perfusion abnormalities was compared between CTD maps and the time-series maximal intensity projection (MIP) images from TRMRA and TTP maps. Correlation coefficients between quantitative changes in SPECT and parametric maps for the abnormal perfusion areas were calculated. The CTD maps were of significantly superior quality than TTP maps (p < 0.01). For perfusion abnormality detection, CTD maps (kappa 0.84, 95% confidence interval [CI] 0.67-1.00) showed better agreement with SPECT than TTP maps (0.66, 0.46-0.85). For perfusion deficit detection, CTD maps showed higher accuracy (85.2%, 95% CI 66.3-95.8) than MIP images (66.7%, 46-83.5), with marginal significance (p = 0.07). In abnormal perfusion areas, correlation coefficients between SPECT and CTD (r = 0.74, 95% CI 0.34-0.91) were higher than those between SPECT and TTP (r = 0.66, 0.20-0.88). CTD maps generated from TRMRA were of high quality and offered good diagnostic performance for detecting perfusion abnormalities associated with steno-occlusive arterial lesions in the craniocervical area. • Generation of perfusion parametric maps from time-resolved MR angiography is clinically useful. • Correlation-based delay maps can be used to detect perfusion abnormalities associated with steno-occlusive craniocervical arteries. • Estimation of correlation-based delay is robust for low signal-to-noise 4D MR data.

[Clopidogrel induced thrombotic thrombocytopenic purpura].

PubMed

Karkowski, L; Wolf, M; Lescampf, J; Coppérré, B; Veyradier, A; Ninet, J; Hot, A

2011-12-01

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder. Drug-induced TTP is uncommon and we report a TTP associated with the use of clopidogrel. We report a 50-year-old man who presented with acute myocardial infarction and received clopidogrel therapy. He developed acute TTP ten days after clopidogrel onset. Imputability of the drug was demonstrated during a reintroduction test. Deficiency of ADAMTS 13 was confirmed and autoantibodies against ADAMTS 13 were detected. Complete remission was obtained after 24 plasma exchange sessions and adjunction of corticosteroids. Drug-induced TTP are probably immunologic, as was demonstrated in our patient. Clinicians should be aware of this possible uncommon adverse effect of clopidogrel because prompt therapy is imperative for life saving. Copyright © 2011 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

3'UTR AU-Rich Elements (AREs) and the RNA-Binding Protein Tristetraprolin (TTP) Are Not Required for the LPS-Mediated Destabilization of Phospholipase-Cβ-2 mRNA in Murine Macrophages.

PubMed

Shukla, Smita; Elson, Genie; Blackshear, Perry J; Lutz, Carol S; Leibovich, S Joseph

2017-04-01

We have shown previously that bacterial lipopolysaccharide (LPS)-mediated suppression of phospholipase-Cβ-2 (PLCβ-2) expression is involved in M1 (inflammatory) to M2-like (wound healing) phenotypic switching of macrophages triggered by adenosine. This suppression is mediated post-transcriptionally by destabilization of PLCβ-2 mRNA (messenger ribonucleic acid). To investigate the mechanism of this LPS-mediated destabilization, we examined the roles of RNA-binding agents including microRNAs and RNA-binding proteins that are involved in regulating stability of mRNAs encoding growth factors, inflammatory mediators, and proto-oncogenes. Adenylate and uridylate (AU)-rich elements (AREs) in 3'UTRs are specific recognition sites for RNA-binding proteins including tristetraprolin (TTP), HuR, and AUF1 and for microRNAs that are involved in regulating mRNA stability. In this study, we investigated the role of TTP and AREs in regulating PLCβ-2 mRNA stability. The 3'UTR of the PLCβ-2 gene was inserted into the pLightswitch luciferase reporter plasmid and transfected into RAW264.7 cells. LPS suppressed luciferase expression from this reporter. Luciferase expression from mutant 3'UTR constructs lacking AREs was similarly downregulated, suggesting that these regions are not required for LPS-mediated suppression of PLCβ-2. TTP was rapidly upregulated in both primary murine macrophages and RAW264.7 cells in response to LPS. Suppression of PLCβ-2 by LPS was examined using macrophages from mice lacking TTP (TTP -/- ). LPS suppressed PLCβ-2 expression to the same extent in wild type (WT) and TTP -/- macrophages. Also, the rate of decay of PLCβ-2 mRNA in LPS-treated macrophages following transcriptional blockade was similar in WT and TTP -/- macrophages, clearly indicating that TTP is not involved in LPS-mediated destabilization of PLCβ-2 mRNA in macrophages.

Pretreatment chest x-ray severity and its relation to bacterial burden in smear positive pulmonary tuberculosis.

PubMed

Murthy, S E; Chatterjee, F; Crook, A; Dawson, R; Mendel, C; Murphy, M E; Murray, S R; Nunn, A J; Phillips, P P J; Singh, Kasha P; McHugh, T D; Gillespie, S H

2018-05-21

Chest radiographs are used for diagnosis and severity assessment in tuberculosis (TB). The extent of disease as determined by smear grade and cavitation as a binary measure can predict 2-month smear results, but little has been done to determine whether radiological severity reflects the bacterial burden at diagnosis. Pre-treatment chest x-rays from 1837 participants with smear-positive pulmonary TB enrolled into the REMoxTB trial (Gillespie et al., N Engl J Med 371:1577-87, 2014) were retrospectively reviewed. Two clinicians blinded to clinical details using the Ralph scoring system performed separate readings. An independent reader reviewed discrepant results for quality assessment and cavity presence. Cavitation presence was plotted against time to positivity (TTP) of sputum liquid cultures (MGIT 960). The Wilcoxon rank sum test was performed to calculate the difference in average TTP for these groups. The average lung field affected was compared to log 10 TTP by linear regression. Baseline markers of disease severity and patient characteristics were added in univariable regression analysis against radiological severity and a multivariable regression model was created to explore their relationship. For 1354 participants, the median TTP was 117 h (4.88 days), being 26 h longer (95% CI 16-30, p < 0.001) in patients without cavitation compared to those with cavitation. The median percentage of lung-field affected was 18.1% (IQR 11.3-28.8%). For every 10-fold increase in TTP, the area of lung field affected decreased by 11.4%. Multivariable models showed that serum albumin decreased significantly as the percentage of lung field area increased in both those with and without cavitation. In addition, BMI and logged TTP had a small but significant effect in those with cavitation and the number of severe TB symptoms in the non-cavitation group also had a small effect, whilst other factors found to be significant on univariable analysis lost this effect in the model. The radiological severity of disease on chest x-ray prior to treatment in smear positive pulmonary TB patients is weakly associated with the bacterial burden. When compared against other variables at diagnosis, this effect is lost in those without cavitation. Radiological severity does reflect the overall disease severity in smear positive pulmonary TB, but we suggest that clinicians should be cautious in over-interpreting the significance of radiological disease extent at diagnosis.

Early Stage Hepatocellular Carcinomas Not Feasible for Ultrasound-Guided Radiofrequency Ablation: Comparison of Transarterial Chemoembolization Alone and Combined Therapy with Transarterial Chemoembolization and Radiofrequency Ablation

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

Hyun, Dongho; Cho, Sung Ki, E-mail: chosk@skku.edu; Shin, Sung Wook

2016-03-15

PurposeTo report the results of combined therapy with transarterial chemoembolization (TACE) and radiofrequency ablation (RFA) for early stage hepatocellular carcinoma (HCC) considered infeasible for ultrasound (US)-guided RFA in comparison with those of TACE monotherapy.MethodsFrom January 2007 through December 2010, 91 patients with early or very early stage HCC infeasible for US-guided RFA received either TACE alone (TACE group; n = 54) or TACE immediately followed by RFA (TACE–RFA group; n = 37) as a first-line treatment. 1-month tumor response, time to progression (TTP), and overall survival (OS) rates were calculated. Univariate and multivariate analyses were performed to identify prognostic factors.ResultsTACE–RFA group showed a bettermore » 1-month tumor response than TACE group (P < .001). The mean TTP was 29.7 ± 3.4 months (95 % confidence intervals [CIs] 23.0–36.5) in TACE group and 34.9 ± 2.8 months (95 % CIs 29.4–40.4) in TACE–RFA group. TACE–RFA group had a significantly longer TTP (P = .014). Cumulative 1-, 2-, and 3-year OS rates in the TACE and TACE–RFA groups were 91, 79, and 71 % and 100, 97, and 93 %, respectively (P = .008). Initial treatment of TACE was found to be the only significant risk factor for tumor progression and OS in multivariate analysis.ConclusionTACE–RFA combination therapy appears superior to TACE monotherapy in terms of 1-month tumor response, TTP, and OS when performed for early stage HCC infeasible for US-guided RFA.« less

[Thrombotic microangiopathy in adults].

PubMed

Barrientos, Gonzalo J; Michelangelo, Hernán

2006-01-01

Thrombotic microangiopathic hemolytic anemias include thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and pregnancy associated thrombotic microangiopathy (TMA). Eight adult patients (four males and four females) with TMA who were treated between 2003 and 2004 at the Hospital Italiano de Buenos Aires were reviewed. The average age was 40. Clinical diagnosis of TMA was made on admission in four patients. During their stay in hospital, 4 patients developed HUS characteristics, three as TTP and one presented pregnancy associated TMA. All of them revealed thrombocytopenia and microangiophatic hemolytic anemia. Renal impairment was the third most frequent characteristic at presentation. The patients with TTP revealed the most severe condition. All patients received daily plasma exchange. Immunosuppressants were also used. Four patients recovered completely, 2 passed away, one remains with renal impairment and requires hemodialysis, and a colectomy was performed on one of them. The TMA syndromes are occlusive disorders associated to platelet microvascular thrombi. Systemic and renal circulations are primarily affected. TTP/HUS might represent an overlapping spectrum of idiopathic or secondary disease. Prompt recognition and treatment are vital, because high mortality occurs due to these disorders. Among the differential diagnosis of TMA we can refer to sepsis, neoplasms, systemic vasculitis, eclampsia and others. The mainstay treatments are daily plasma exchange and infusion with fresh frozen plasma. Improving the management of these diseases is required considering their high morbidity and mortality.

Plasmapheresis in thrombotic microangiopathy-associated syndromes: review of outcome data derived from clinical trials and open studies.

PubMed

von Baeyer, Hans

2002-08-01

Current reimbursement policy of health insurance for therapeutic plasmapheresis requires proof of efficacy using the concept of evidence-based medicine. The aim of this paper is to review the outcome of plasmapheresis used to treat thrombotic microangiopathy (TMA)-associated syndromes in the last decade to provide scientific evidence to back up reimbursement applications. The strength of evidence of each reviewed study was assessed using the five levels of evidence criteria as defined by the American Society of Hematology in 1996 for assessment of the treatment of immune thrombocytopenia. The level Experimental indication was added for situations where only case reports or small series supported by pathophysiological reasoning are available. The definitions of evidence used in this paper are as follows: Level I, randomized clinical trial with low rates of error (p < 0.01); Level II, randomized clinical trial with high rates of error (p < 0.05); Level III, nonrandomized studies with concurrent control group; Level IV, nonrandomized studies with historical control group; Level V, case series without a control group or expert opinion; and Experimental, case reports and pathophysiological reasoning. The results of this analysis based on the published data is summarized as follows: The indication of plasmapheresis is assigned to Level IV evidence for thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS); cancer/chemotherapy-associated TTP/HUS is assigned to Level V evidence; and TTP/HUS refractory to standard plasma exchange and post-bone marrow transplantation TTP/HUS are assigned to Experimental indication. For both subsets, protein A immunoadsorption is reportedly successful. The other TMA-associated syndromes, hemolysis elevated liver enzymes low platelets and HUS in early childhood, are no indication of plasmapheresis. Two randomized clinical trials were performed in order to demonstrate the superiority of plasma exchange/fresh frozen plasma (PEX/FFP) over plasma transfusion in the management of TTP/HUS. The results prove the greater clinical success of the latter type of plasma administration. Standard PEX/FFP has reduced the mortality of TTP/HUS from 94.5% to 13%.

Cardiac troponin-I on diagnosis predicts early death and refractoriness in acquired thrombotic thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies Reference Center.

PubMed

Benhamou, Y; Boelle, P-Y; Baudin, B; Ederhy, S; Gras, J; Galicier, L; Azoulay, E; Provôt, F; Maury, E; Pène, F; Mira, J-P; Wynckel, A; Presne, C; Poullin, P; Halimi, J-M; Delmas, Y; Kanouni, T; Seguin, A; Mousson, C; Servais, A; Bordessoule, D; Perez, P; Hamidou, M; Cohen, A; Veyradier, A; Coppo, P

2015-02-01

Cardiac involvement is a major cause of mortality in patients with thrombotic thrombocytopenic purpura (TTP). However, diagnosis remains underestimated and delayed, owing to subclinical injuries. Cardiac troponin-I measurement (cTnI) on admission could improve the early diagnosis of cardiac involvement and have prognostic value. To assess the predictive value of cTnI in patients with TTP for death or refractoriness. The study involved a prospective cohort of adult TTP patients with acquired severe ADAMTS-13 deficiency (< 10%) and included in the registry of the French Reference Center for Thrombotic Microangiopathies. Centralized cTnI measurements were performed on frozen serum on admission. Between January 2003 and December 2011, 133 patients with TTP (mean age, 48 ± 17 years) had available cTnI measurements on admission. Thirty-two patients (24%) had clinical and/or electrocardiogram features. Nineteen (14.3%) had cardiac symptoms, mainly congestive heart failure and myocardial infarction. Electrocardiogram changes, mainly repolarization disorders, were present in 13 cases. An increased cTnI level (> 0.1 μg L(-1) ) was present in 78 patients (59%), of whom 46 (59%) had no clinical cardiac involvement. The main outcomes were death (25%) and refractoriness (17%). Age (P = 0.02) and cTnI level (P = 0.002) showed the greatest impact on survival. A cTnI level of > 0.25 μg L(-1) was the only independent factor in predicting death (odds ratio [OR] 2.87; 95% confidence interval [CI] 1.13-7.22; P = 0.024) and/or refractoriness (OR 3.03; 95% CI 1.27-7.3; P = 0.01). A CTnI level of > 0.25 μg L(-1) at presentation in patients with TTP appears to be an independent factor associated with a three-fold increase in the risk of death or refractoriness. Therefore, cTnI level should be considered as a prognostic indicator in patients diagnosed with TTP. © 2014 International Society on Thrombosis and Haemostasis.

Regulation of p21/CIP1/WAF-1 mediated cell-cycle arrest by RNase L and tristetraprolin, and involvement of AU-rich elements

PubMed Central

Al-Haj, Latifa; Blackshear, Perry J.; Khabar, Khalid S.A.

2012-01-01

The p21Cip1/WAF1 plays an important role in cell-cycle arrest. Here, we find that RNase L regulates p21-mediated G1 growth arrest in AU-rich elements-dependent manner. We found a significant loss of p21 mRNA expression in RNASEL−/− MEFs and that the overexpression of RNase L in HeLa cells induces p21 mRNA expression. The p21 mRNA half-life significantly changes as a result of RNase L modulation, indicating a post-transcriptional effect. Indeed, we found that RNase L promotes tristetraprolin (TTP/ZFP36) mRNA decay. This activity was not seen with dimerization- and nuclease-deficient RNase L mutants. Deficiency in TTP led to increases in p21 mRNA and protein. With induced ablation of RNase L, TTP mRNA and protein expressions were higher, while p21 expression became reduced. We further establish that TTP, but not C124R TTP mutant, binds to, and accelerates the decay of p21 mRNA. The p21 mRNA half-life was prolonged in TTP−/− MEFs. The TTP regulation of p21 mRNA decay required functional AU-rich elements. Thus, we demonstrate a novel mechanism of regulating G1 growth arrest by an RNase L-TTP-p21 axis. PMID:22718976

Theme and Thematic Progression in English Writing Teaching

ERIC Educational Resources Information Center

Jing, Wei

2015-01-01

Theme and thematic progression (T/TP) is a major aspect of the way that speakers construct their messages in a way which makes them fit smoothly into the unfolding language event. While studies have illustrated the usefulness of observing T/TP to identify English learners' writing difficulties and suggested that T/TP should be included in English…

Heart Mitochondrial TTP Synthesis and the Compartmentalization of TMP*

PubMed Central

Kamath, Vasudeva G.; Hsiung, Chia-Heng; Lizenby, Zachary J.; McKee, Edward E.

2015-01-01

The primary pathway of TTP synthesis in the heart requires thymidine salvage by mitochondrial thymidine kinase 2 (TK2). However, the compartmentalization of this pathway and the transport of thymidine nucleotides are not well understood. We investigated the metabolism of [3H]thymidine or [3H]TMP as precursors of [3H]TTP in isolated intact or broken mitochondria from the rat heart. The results demonstrated that [3H]thymidine was readily metabolized by the mitochondrial salvage enzymes to TTP in intact mitochondria. The equivalent addition of [3H]TMP produced far less [3H]TTP than the amount observed with [3H]thymidine as the precursor. Using zidovudine to inhibit TK2, the synthesis of [3H]TTP from [3H]TMP was effectively blocked, demonstrating that synthesis of [3H]TTP from [3H]TMP arose solely from the dephosphorysynthase pathway that includes deoxyuridine triphosphatelation of [3H]TMP to [3H]thymidine. To determine the role of the membrane in TMP metabolism, mitochondrial membranes were disrupted by freezing and thawing. In broken mitochondria, [3H]thymidine was readily converted to [3H]TMP, but further phosphorylation was prevented even though the energy charge was well maintained by addition of oligomycin A, phosphocreatine, and creatine phosphokinase. The failure to synthesize TTP in broken mitochondria was not related to a loss of membrane potential or inhibition of the electron transport chain, as confirmed by addition of carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone and potassium cyanide, respectively, in intact mitochondria. In summary, these data, taken together, suggest that the thymidine salvage pathway is compartmentalized so that TMP kinase prefers TMP synthesized by TK2 over medium TMP and that this is disrupted in broken mitochondria. PMID:25505243

von Willebrand factor and its cleaving protease ADAMTS13 balance in coronary artery vessels: Lessons learned from thrombotic thrombocytopenic purpura. A narrative review.

PubMed

Morici, Nuccia; Cantoni, Silvia; Panzeri, Francesco; Sacco, Alice; Rusconi, Chiara; Stucchi, Miriam; Oliva, Fabrizio; Cattaneo, Marco

2017-07-01

Deficiency of the von Willebrand factor-cleaving protease ADAMTS13 is central to the pathophysiology of thrombotic thrombocytopenic purpura (TTP), a microangiopathic syndrome that presents as an acute medical emergency. In this review we will explore the evidence of a two-way relationship between TTP and ACS. Moreover, we will review the evidence emerged from epidemiological studies of an inverse relationship between the plasma levels of ADAMTS13 and the risk of ACS. Pubmed, MEDLINE and EMBASE, CINHAL, COCHRANE and Google Scholar databases were searched from inception to January 2017. The search yielded 43 studies representing 23 unique patient cases, 5 case series, 5 cohort studies and 10 case-control studies. Most ACS cases developing in the setting of TTP resolved with standard treatment of the underlying microangiopathy, with only a few requiring coronary invasive management. Antiplatelet therapy was not usually prescribed and all of the currently used P2Y 12 were felt to be a potential trigger for a TTP-like syndrome, although our review revealed that the occurrence of TTP in patients treated with new P2Y 12 antagonists is rare. Most studies confirmed the inverse association among ADAMTS13 levels and ACS. The heart is a definite target organ in TTP. The clinical spectrum of its involvement is probably influenced by local factors that add on to the systemic deficiency characteristic of TTP. It follows that patients with TTP should be carefully monitored for ACS events, especially when multiple risk factors for coronary disease exist. Copyright © 2017 Elsevier Ltd. All rights reserved.

Thrombotic thrombocytopenic purpura possibly triggered by Graves’ disease

PubMed Central

Chitnis, Saurabh D; Mene-Afejuku, Tuoyo O; Aujla, Amandeep; Shady, Ahmed; Gil, Gaby S; Cativo, Eder Hans; Popescu-Martinez, Andrea

2017-01-01

Abstract Thrombotic thrombocytopenic purpura (TTP) is a part of a spectrum of thrombotic microangiopathy syndromes which are mainly characterized by platelet aggregation causing microangiopathic hemolytic anemia, thrombocytopenia and microvascular occlusion. In literature, very few cases expressing a direct association between pre-existing Grave’s disease and TTP have been described. A 37-year-old African–American woman with past medical history of Grave’s disease and polysubstance abuse who presented with complaints of dyspnoea at rest and chest pain was diagnosed to have TTP on further evaluation. Patient also showed severely elevated thyroid hormones and suppressed thyroid stimulating hormone levels indicating severe thyrotoxicosis. Initiation of prompt management of TTP and thyrotoxicosis led to a favorable patient outcome. In conclusion, patients presenting with thyrotoxicosis, thrombocytopenia and microangioapthic hemolytic anemia without an alternative cause should be treated and screened for TTP due to the high fatality associated with untreated or untimely detection of this disease. PMID:29744115

75 FR 53732 - In the Matter of the Designation of Tehrik-e Taliban Pakistan (TTP) also known as Tehrik-I...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-01

... DEPARTMENT OF STATE [Public Notice 7141] In the Matter of the Designation of Tehrik-e Taliban Pakistan (TTP) also known as Tehrik-I-Taliban Pakistan also known as Tehrik-e- Taliban also known as.... 1189), exist with respect to Tehrik-e Taliban Pakistan (TTP), also known as Tehrik-I-Taliban Pakistan...

Familial acquired thrombotic thrombocytopenic purpura in siblings - no immunogenetic link with associated human leucocyte antigens.

PubMed

Gödel, Philipp; Fischer, Julia; Scheid, Christoph; Gathof, Birgit S; Wolf, Jürgen; Rybniker, Jan

2017-03-01

Acquired immunoglobulin G (IgG)-mediated thrombotic thrombocytopenic purpura (TTP) has not yet been described in non-twin siblings. We report two cases of acquired TTP in Caucasian sisters with inactive ADAMTS13 metalloprotease due to ADAMTS13 autoantibodies suggesting a role of genetic determinants in this life-threatening disease. However, human leucocyte antigen (HLA) class II types presumably associated with acquired TTP were not identified in the patients, indicating that HLA class II typing may not be useful in acquired TTP risk assessment of family members. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tristetraprolin Inhibits Ras-dependent Tumor Vascularization by Inducing Vascular Endothelial Growth Factor mRNA Degradation

PubMed Central

Essafi-Benkhadir, Khadija; Onesto, Cercina; Stebe, Emmanuelle; Moroni, Christoph

2007-01-01

Vascular endothelial growth factor (VEGF) is one of the most important regulators of physiological and pathological angiogenesis. Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway and overexpression of VEGF are common denominators of tumors from different origins. We have established a new link between these two fundamental observations converging on VEGF mRNA stability. In this complex phenomenon, tristetraprolin (TTP), an adenylate and uridylate-rich element-associated protein that binds to VEGF mRNA 3′-untranslated region, plays a key role by inducing VEGF mRNA degradation, thus maintaining basal VEGF mRNA amounts in normal cells. ERKs activation results in the accumulation of TTP mRNA. However, ERKs reduce the VEGF mRNA-destabilizing effect of TTP, leading to an increase in VEGF expression that favors the angiogenic switch. Moreover, TTP decreases RasVal12-dependent VEGF expression and development of vascularized tumors in nude mice. As a consequence, TTP might represent a novel antiangiogenic and antitumor agent acting through its destabilizing activity on VEGF mRNA. Determination of TTP and ERKs status would provide useful information for the evaluation of the angiogenic potential in human tumors. PMID:17855506

Unchanged thymidine triphosphate pools and thymidine metabolism in two lines of thymidine kinase 2-mutated fibroblasts.

PubMed

Frangini, Miriam; Rampazzo, Chiara; Franzolin, Elisa; Lara, Mari-Carmen; Vilà, Maya R; Martí, Ramon; Bianchi, Vera

2009-02-01

Mitochondrial thymidine kinase (TK2) catalyzes the phosphorylation of thymidine in mitochondria. Its function becomes essential for dTTP synthesis in noncycling cells, where cytosolic dTTP synthesis via R1/R2 ribonucleotide reductase and thymidine kinase 1 is turned down. Mutations in the nuclear gene for TK2 cause a fatal mtDNA depletion syndrome. Only selected cell types are affected, suggesting that the other cells compensate for the TK2 deficiency by adapting the enzyme network that regulates dTTP synthesis outside S-phase. Here we looked for such metabolic adaptation in quiescent cultures of fibroblasts from two TK2-deficient patients with a slow-progressing syndrome. In cell extracts, we measured the activities of TK2, deoxycytidine kinase, thymidine phosphorylase, deoxynucleotidases and the amounts of the three ribonucleotide reductase subunits. Patient cells contained 40% or 5% TK2 activity and unchanged activities of the other enzymes. However, their mitochondrial and cytosolic dTTP pools were unchanged, and also the overall composition of the dNTP pools was normal. TK2-dependent phosphorylation of [(3)H]thymidine in intact cells and the turnover of the dTTP pool showed that even the fibroblasts with 5% residual TK2 activity synthesized dTTP at an almost normal rate. Normal fibroblasts apparently contain more TK2 than needed to maintain dTTP during quiescence, which would explain why TK2-mutated fibroblasts do not manifest mtDNA depletion despite their reduced TK2 activity.

LARP4 Is Regulated by Tumor Necrosis Factor Alpha in a Tristetraprolin-Dependent Manner

PubMed Central

Mattijssen, Sandy

2015-01-01

LARP4 is a protein with unknown function that independently binds to poly(A) RNA, RACK1, and the poly(A)-binding protein (PABPC1). Here, we report on its regulation. We found a conserved AU-rich element (ARE) in the human LARP4 mRNA 3′ untranslated region (UTR). This ARE, but not its antisense version or a point-mutated version, significantly decreased the stability of β-globin reporter mRNA. We found that overexpression of tristetraprolin (TTP), but not its RNA binding mutant or the other ARE-binding proteins tested, decreased cellular LARP4 levels. RNA coimmunoprecipitation showed that TTP specifically associated with LARP4 mRNA in vivo. Consistent with this, mouse LARP4 accumulated to higher levels in TTP gene knockout (KO) cells than in control cells. Stimulation of WT cells with tumor necrosis factor alpha (TNF-α), which rapidly induces TTP, robustly decreased LARP4 with a coincident time course but had no such effect on LARP4B or La protein or on LARP4 in the TTP KO cells. The TNF-α-induced TTP pulse was followed by a transient decrease in LARP4 mRNA that was quickly followed by a subsequent transient decrease in LARP4 protein. Involvement of LARP4 as a target of TNF-α–TTP regulation provides a clue as to how its functional activity may be used in a physiologic pathway. PMID:26644407

75 FR 53732 - In the Matter of the Designation of Tehrik-e Taliban Pakistan (TTP) Also Known as Tehrik-I...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-09-01

... DEPARTMENT OF STATE [Public Notice 7142] In the Matter of the Designation of Tehrik-e Taliban Pakistan (TTP) Also Known as Tehrik-I-Taliban Pakistan Also Known as Tehrik-e- Taliban Also Known as... Tehrik-e Taliban Pakistan (TTP), also known as Tehrik-I-Taliban Pakistan, also known as Tehrik-e-Taliban...

Preclinical assessment of a new recombinant ADAMTS-13 drug product (BAX930) for the treatment of thrombotic thrombocytopenic purpura.

PubMed

Kopić, A; Benamara, K; Piskernik, C; Plaimauer, B; Horling, F; Höbarth, G; Ruthsatz, T; Dietrich, B; Muchitsch, E-M; Scheiflinger, F; Turecek, M; Höllriegl, W

2016-07-01

Essentials ADAMTS-13-deficiency is a cause of thrombotic thrombocytopenic purpura (TTP). Preclinical safety of recombinant human ADAMTS-13 (BAX930) was shown in animal models. Preclinical efficacy of BAX930 was shown in a mouse model of TTP. BAX930 showed advantageous efficacy over fresh frozen plasma, the current standard of care. Click to hear Dr Cataland and Prof. Lämmle present a seminar on Thrombotic Thrombocytopenic Purpura (TTP): new Insights in Pathogenesis and Treatment Modalities. Background Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder characterized by microthrombosis in small blood vessels of the body, resulting in a low platelet count. Baxalta has developed a new recombinant ADAMTS-13 (rADAMTS-13) product (BAX930) for on-demand and prophylactic treatment of patients with hereditary TTP (hTTP). Objectives To evaluate the pharmacokinetics, efficacy and safety of BAX930 in different species, by use of an extensive preclinical program. Methods The prophylactic and therapeutic efficacies of BAX930 were tested in a previously established TTP mouse model. Pharmacokinetics were evaluated after single intravenous bolus injection in mice and rats, and after repeated dosing in cynomolgus monkeys. Toxicity was assessed in rats and monkeys, safety pharmacology in monkeys, and local tolerance in rabbits. Results BAX930 was shown to be efficacious, as demonstrated by a stabilized platelet count in ADAMTS-13 knockout mice that were thrombocytopenic when treated. Prophylactic efficacy was dose-dependent and comparable with that achieved by treatment with fresh frozen plasma, the mainstay of hTTP treatment. Therapeutic efficacy was treatment interval-dependent. Safety pharmacology evaluation did not show any deleterious effects of BAX930 on cardiovascular and respiratory functions in monkeys. The compound's pharmacokinetics were similar and dose-proportional in mice, rats, and monkeys. BAX930 was well tolerated in rats, monkeys, and rabbits, even at the highest doses tested. Conclusions These results demonstrate that BAX930 has a favorable preclinical profile, and support the clinical development of rADAMTS-13 for the treatment of hTTP. © 2016 International Society on Thrombosis and Haemostasis.

2,2'-Bis(monoacylglycero) PO4 (BMP), but Not 3,1'-BMP, increases membrane curvature stress to enhance α-tocopherol transfer protein binding to membranes.

PubMed

Baptist, Matilda; Panagabko, Candace; Nickels, Jonathan D; Katsaras, John; Atkinson, Jeffrey

2015-03-01

Previous work revealed that α-tocopherol transfer protein (α-TTP) co-localizes with bis(monoacylglycero)phosphate (BMP) in late endosomes. BMP is a lipid unique to late endosomes and is believed to induce membrane curvature and support the multivesicular nature of this organelle. We examined the effect of BMP on α-TTP binding to membranes using dual polarization interferometry and vesicle-binding assay. α-TTP binding to membranes is increased by the curvature-inducing lipid BMP. α-TTP binds to membranes with greater affinity when they contain the 2,2'-BMP versus 3,1'-BMP isomers.

2,2'-Bis(monoacylglycero) PO 4 (BMP), but Not 3,1'-BMP, Increases Membrane Curvature Stress to Enhance α-Tocopherol Transfer Protein Binding to Membranes

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

Baptist, Matilda; Panagabko, Candace; Nickels, Jonathan D.

2015-01-21

Previous work revealed that α-tocopherol transfer protein (α-TTP) co-localizes with bis(monoacylglycero)phosphate (BMP) in late endosomes. BMP is a lipid unique to late endosomes and is believed to induce membrane curvature and support the multivesicular nature of this organelle. In this paper, we examined the effect of BMP on α-TTP binding to membranes using dual polarization interferometry and vesicle-binding assay. α-TTP binding to membranes is increased by the curvature-inducing lipid BMP. Finally, α-TTP binds to membranes with greater affinity when they contain the 2,2'-BMP versus 3,1'-BMP isomers.

Twice-daily therapeutical plasma exchange-based salvage therapy in severe autoimmune thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.

PubMed

Soucemarianadin, Myriam; Benhamou, Ygal; Delmas, Yahsou; Pichereau, Claire; Maury, Eric; Pène, Frédéric; Halimi, Jean-Michel; Presne, Claire; Thouret, Jean-Marc; Veyradier, Agnès; Coppo, Paul

2016-08-01

Daily therapeutic plasma exchange (TPE) and rituximab improved thrombotic thrombocytopenic purpura (TTP) prognosis. In the more severe cases, salvage therapies including twice-daily TPE and/or cyclophosphamide may be proposed and require evaluation. TTP was defined as a thrombotic microangiopathy (TMA) with severe (<10%) acquired ADAMTS13 deficiency. Among patients included in the French Reference Center for TMA registry, we considered those with a severe disease (i.e., unresponsive to daily TPE and rituximab) who received twice-daily TPE. Nineteen of 289 (6.6%) patients with TTP were treated by twice-daily TPE between 2008 and 2014. Twice-daily TPE was associated with rituximab in 16 cases. The median duration of twice-daily TPE treatment was 3 d (2-22 d). In 6 patients (31.6%), additional treatments (mainly pulses of cyclophosphamide) were performed because of a persistently refractory disease (4 cases) or an exacerbation (2 cases), despite twice-daily TPE. Only one patient (5.3%) died. The other 18 achieved a durable complete remission 25.5 d (13-68 d) after the first TPE. The median follow-up was 14.4 months (7 d-45 months). Twice-daily TPE may be an efficient strategy in the more severe TTP patients with a short-term life-threatening disease that could overcome their poor prognosis. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Dimensional Crossover and Its Interplay with In-Plane Anisotropy of Upper Critical Field in β-(BDA-TTP)2SbF6

NASA Astrophysics Data System (ADS)

Yasuzuka, Syuma; Koga, Hiroaki; Yamamura, Yasuhisa; Saito, Kazuya; Uji, Shinya; Terashima, Taichi; Akutsu, Hiroki; Yamada, Jun-ichi

2017-08-01

Resistance measurements have been performed to investigate the dimensionality and the in-plane anisotropy of the upper critical field (Hc2) for β-(BDA-TTP)2SbF6 in fields H up to 15 T and at temperatures T from 1.5 to 7.5 K, where BDA-TTP stands for 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene. The upper critical fields parallel and perpendicular to the conduction layer are determined and dimensional crossover from anisotropic three-dimensional behavior to two-dimensional behavior is found at around 6 K. When the direction of H is varied within the conducting layer at 6.0 K, Hc2 shows twofold symmetry: Hc2 along the minimum Fermi wave vector (maximum Fermi velocity) is larger than that along the maximum Fermi wave vector (minimum Fermi velocity). The normal-state magnetoresistance has twofold symmetry similar to Hc2 and shows a maximum when the magnetic field is nearly parallel to the maximum Fermi wave vector. This tendency is consistent with the Fermi surface anisotropy. At 3.5 K, we found clear fourfold symmetry of Hc2 despite the fact that the normal-state magnetoresistance shows twofold symmetry arising from the Fermi surface anisotropy. The origin of the fourfold symmetry of Hc2 is discussed in terms of the superconducting gap structure in β-(BDA-TTP)2SbF6.

Postpartum plasma exchange in a woman with suspected thrombotic thrombocytopenic purpura (TTP) vs. hemolysis, elevated liver enzymes, and low platelet syndrome (HELLP): a case study.

PubMed

Myers, Linda

2010-01-01

The occurrence of a hypercoagulable state and decreasing concentration of ADAMTS 13 in late pregnancy and during the postpartum period increases the risk for a woman to develop life-threatening thrombotic thrombocytopenic purpura (TTP). This is also the time of great risk for the more common obstetric complications of preeclampsia; eclampsia; and hemolysis, elevated liver functions tests, low platelets (HELLP) syndrome. These conditions are associated with high maternal and perinatal mortality. Differential diagnosis may be difficult due to the overlapping of clinical and laboratory findings, including thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, and renal insufficiency, making it difficult or impossible to distinguish them from TTP. Management of microangiopathic disorders encountered during pregnancy differ; therefore, an accurate diagnosis is required. Outcomes of TTP without plasma exchange therapy (TPE) are almost uniformly fatal. Early recognition and management of symptoms with prompt and aggressive TPE is essential when TTP is suspected.

Life after acquired thrombotic thrombocytopenic purpura: morbidity, mortality, and risks during pregnancy.

PubMed

Vesely, S K

2015-06-01

Patients who have recovered from their acute episode of acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura (TTP) were once thought to have complete recovery except for risk of relapse. Data from previous publications from the Oklahoma TTP-hemolytic uremic syndrome (HUS) Registry are summarized. Patients have decreased cognitive function and increased prevalence of hypertension, systemic lupus erythematosus, major depression, and albuminuria as compared to the expected values from the US population. The proportion of patients that died during the follow-up period was greater than expected based on the US population reference population. Among women who had a pregnancy following recovery from TTP, relapse during pregnancy or postpartum is uncommon, but the occurrence of preeclampsia may be increased. Thirteen of 16 pregnancies in these women resulted in healthy children. Increased morbidity and mortality in TTP patients following recovery suggest that TTP may be more of a chronic disorder than a disorder with acute episodes and complete recovery. © 2015 International Society on Thrombosis and Haemostasis.

A post-transcriptional mechanism pacing expression of neural genes with precursor cell differentiation status.

PubMed

Dai, Weijun; Li, Wencheng; Hoque, Mainul; Li, Zhuyun; Tian, Bin; Makeyev, Eugene V

2015-07-06

Nervous system (NS) development relies on coherent upregulation of extensive sets of genes in a precise spatiotemporal manner. How such transcriptome-wide effects are orchestrated at the molecular level remains an open question. Here we show that 3'-untranslated regions (3' UTRs) of multiple neural transcripts contain AU-rich cis-elements (AREs) recognized by tristetraprolin (TTP/Zfp36), an RNA-binding protein previously implicated in regulation of mRNA stability. We further demonstrate that the efficiency of ARE-dependent mRNA degradation declines in the neural lineage because of a decrease in the TTP protein expression mediated by the NS-enriched microRNA miR-9. Importantly, TTP downregulation in this context is essential for proper neuronal differentiation. On the other hand, inactivation of TTP in non-neuronal cells leads to dramatic upregulation of multiple NS-specific genes. We conclude that the newly identified miR-9/TTP circuitry limits unscheduled accumulation of neuronal mRNAs in non-neuronal cells and ensures coordinated upregulation of these transcripts in neurons.

Technology Transfer Program (TTP). Quality Assurance System. Volume 2. Appendices

DTIC Science & Technology

1980-03-03

LSCo Report No. - 2X23-5.1-4-I TECHNOLOGY TRANSFER PROGRAM (TTP) FINAL REPORT QUALITY ASSURANCE SYSTEM Appendix A Accuracy Control System QUALITY...4-1 TECHNOLOGY TRANSFER PROGRAM (TTP) FINAL REPORT QUALITY ASSURANCE SYSTEM Appendix A Accuracy Control System QUALITY ASSURANCE VOLUME 2 APPENDICES...prepared by: Livingston Shipbuilding Company Orange, Texas March 3, 1980 APPENDIX A ACCURACY CONTROL SYSTEM . IIII MARINE TECHNOLOGY. INC. HP-121

Tristetraprolin Represses Estrogen Receptor α Transactivation in Breast Cancer Cells*

PubMed Central

Barrios-García, Tonatiuh; Tecalco-Cruz, Angeles; Gómez-Romero, Vania; Reyes-Carmona, Sandra; Meneses-Morales, Iván; León-Del-Río, Alfonso

2014-01-01

Estrogen receptor α (ERα) mediates the effects of 17β-estradiol (E2) in normal mammary gland, and it is a key participant in breast cancer tumor development. ERα transactivation activity is mediated by the synergistic interaction of two domains designated AF1 and AF2. The function of AF2 is to recruit coactivator and corepressor proteins that allow ERα to oscillate between the roles of transcriptional activator and repressor. In contrast, the mechanism responsible for AF-1 transcriptional activity is not completely understood. In this study, we identified tristetraproline (TTP) as a novel ERα-associated protein. TTP expression in MCF7 cells repressed ERα transactivation and reduced MCF7 cell proliferation and the ability of the cells to form tumors in a mouse model. We show that TTP transcriptional activity is mediated through its recruitment to the promoter region of ERα target genes and its interaction with histone deacetylases, in particular with HDAC1. TTP expression attenuates the coactivating activity of SRC-1, suggesting that exchange between TTP and other coactivators may play an important role in fine-tuning ERα transactivation. These results indicate that TTP acts as a bona fide ERα corepressor and suggest that this protein may be a contributing factor in the development of E2-dependent tumors in breast cancer. PMID:24737323

Five-year data and prognostic factor analysis of oxaliplatin and irinotecan combinations for advanced colorectal cancer: N9741.

PubMed

Sanoff, Hanna K; Sargent, Daniel J; Campbell, Megan E; Morton, Roscoe F; Fuchs, Charles S; Ramanathan, Ramesh K; Williamson, Stephen K; Findlay, Brian P; Pitot, Henry C; Goldberg, Richard M

2008-12-10

In this report, we update survival (OS) and time-to-progression (TTP) data for the Intergroup trial N9741 after a median 5 years of follow-up by using risk-stratified and prognostic factor analyses to determine if treatment outcomes differ in specific patient subgroups. A total of 1,691 patients were randomly assigned to one of seven fluorouracil-, oxaliplatin-, and irinotecan-containing regimens. OS and TTP were calculated by treatment arm and baseline risk group (on the basis of WBC, performance status, number of sites of disease, and alkaline phosphatase). Multivariate prognostic factor analysis was used to assess clinical factors for their relationships to OS, TTP, response, and toxicity by using Cox and logistic regression models. The observed 5-year survival with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) of 9.8% was better than with irinotecan plus bolus fluorouracil and leucovorin (IFL; 3.7%; P = .04) or with bolus irinotecan/oxaliplatin (IROX; 5.1%; P = .128). OS and TTP were significantly longer for FOLFOX (20.2 months and 8.9 months, respectively) than for IFL (14.6 months and 6.1 months, respectively; P < .001 for both) or for IROX (17.3 months and 6.7 months, respectively; P < .001 for both). OS differed by risk group: 20.7 months for low risk, 17.4 months for intermediate risk, and 9.4 months for high risk (P < .001). FOLFOX treatment was superior in all risk groups and was the most powerful prognostic factor for OS, TTP, response rate, and toxicity. The 9.8% 5-year OS in patients with metastatic colorectal cancer who were treated with first-line FOLFOX sets a new benchmark. Neither baseline risk group nor any prognostic factor examined was predictive of treatment-specific outcome. However, treatment efficacy and patient longevity varied as a function of risk group.

Five-Year Data and Prognostic Factor Analysis of Oxaliplatin and Irinotecan Combinations for Advanced Colorectal Cancer: N9741

PubMed Central

Sanoff, Hanna K.; Sargent, Daniel J.; Campbell, Megan E.; Morton, Roscoe F.; Fuchs, Charles S.; Ramanathan, Ramesh K.; Williamson, Stephen K.; Findlay, Brian P.; Pitot, Henry C.; Goldberg, Richard M.

2008-01-01

Purpose In this report, we update survival (OS) and time-to-progression (TTP) data for the Intergroup trial N9741 after a median 5 years of follow-up by using risk-stratified and prognostic factor analyses to determine if treatment outcomes differ in specific patient subgroups. Patients and Methods A total of 1,691 patients were randomly assigned to one of seven fluorouracil-, oxaliplatin-, and irinotecan-containing regimens. OS and TTP were calculated by treatment arm and baseline risk group (on the basis of WBC, performance status, number of sites of disease, and alkaline phosphatase). Multivariate prognostic factor analysis was used to assess clinical factors for their relationships to OS, TTP, response, and toxicity by using Cox and logistic regression models. Results The observed 5-year survival with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) of 9.8% was better than with irinotecan plus bolus fluorouracil and leucovorin (IFL; 3.7%; P = .04) or with bolus irinotecan/oxaliplatin (IROX; 5.1%; P = .128). OS and TTP were significantly longer for FOLFOX (20.2 months and 8.9 months, respectively) than for IFL (14.6 months and 6.1 months, respectively; P < .001 for both) or for IROX (17.3 months and 6.7 months, respectively; P < .001 for both). OS differed by risk group: 20.7 months for low risk, 17.4 months for intermediate risk, and 9.4 months for high risk (P < .001). FOLFOX treatment was superior in all risk groups and was the most powerful prognostic factor for OS, TTP, response rate, and toxicity. Conclusion The 9.8% 5-year OS in patients with metastatic colorectal cancer who were treated with first-line FOLFOX sets a new benchmark. Neither baseline risk group nor any prognostic factor examined was predictive of treatment-specific outcome. However, treatment efficacy and patient longevity varied as a function of risk group. PMID:19001325

The pyrimidine nucleotide carrier PNC1 and mitochondrial trafficking of thymidine phosphates in cultured human cells

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

Franzolin, Elisa; Miazzi, Cristina; Frangini, Miriam

2012-10-15

In cycling cells cytosolic de novo synthesis of deoxynucleotides is the main source of precursors for mitochondrial (mt) DNA synthesis. The transfer of deoxynucleotides across the inner mt membrane requires protein carriers. PNC1, a SLC25 family member, exchanges pyrimidine nucleoside triphosphates in liposomes and its downregulation decreases mtUTP concentration in cultured cells. By an isotope-flow protocol we confirmed transport of uridine nucleotides by PNC1 in intact cultured cells and investigated PNC1 involvement in the mt trafficking of thymidine phosphates. Key features of our approach were the manipulation of PNC1 expression by RNA interference or inducible overexpression, the employment of cellsmore » proficient or deficient for cytosolic thymidine kinase (TK1) to distinguish the direction of flow of thymidine nucleotides across the mt membrane during short pulses with [{sup 3}H]-thymidine, the determination of mtdTTP specific radioactivity to quantitate the rate of mtdTTP export to the cytoplasm. Downregulation of PNC1 in TK1{sup -} cells increased labeled dTTP in mitochondria due to a reduced rate of export. Overexpression of PNC1 in TK1{sup +} cells increased mtdTTP pool size and radioactivity, suggesting an involvement in the import of thymidine phosphates. Thus PNC1 is a component of the network regulating the mtdTTP pool in human cells. -- Highlights: Black-Right-Pointing-Pointer Thymidine phosphates exchange between mitochondria and cytosol in mammalian cells. Black-Right-Pointing-Pointer siRNA-downregulation of PNC1 delays mitochondrial dTTP export in TK1{sup -} cells. Black-Right-Pointing-Pointer PNC1 overexpression accumulates dTTP in mitochondria of TK1{sup +} cells. Black-Right-Pointing-Pointer PNC1 exchanges thymidine nucleotides across the mitochondrial inner membrane. Black-Right-Pointing-Pointer PNC1 participates in the regulation of the mtdTTP pool supporting mtDNA synthesis.« less

Curva de aprendizaje en la colocación de tornillos pediculares percutáneos mínimamente invasivos

PubMed Central

Landriel, Federico; Hem, Santiago; Rasmussen, Jorge; Vecchi, Eduardo; Yampolsky, Claudio

2018-01-01

Resumen Objetivo: El objetivo de este estudio fue estimar la curva de aprendizaje necesaria para la correcta colocación de tornillos transpediculares percutáneos (TTP). Introducción: Los TTP son la forma de instrumentación más utilizada en el tratamiento quirúrgico de lesiones espinales que requieren estabilización. Métodos: Evaluamos retrospectivamente la inserción de 422 TTP (T5 a S1) en 75 pacientes operados entre 2013–2016, bajo guía fluoroscópica bidimensional. El cirujano 1 colocó siempre los tornillos del lado derecho y el cirujano 2, la totalidad del lado izquierdo. El posicionamiento y ruptura pedicular fue determinando con la clasificación tomográfica de Gertzbein. Se comparó la precisión en la colocación de TTP de nuestra serie con una tasa de ruptura de 8,08% (rango de 0,67-20,83%), valor de referencia obtenido de un meta-análisis propio. Resultados: De los 422 TTP, 395 fueron insertados en el pedículo sin violación de su cortical (Grado 1 = 93,6%), 27 (6,4%) rompieron la pared pedicular, de los cuales el 3,8% fue Grado 2, el 1,65% Grado 3 y sólo el 0,9% Grado 4. El Cirujano 1, presentó una tasa se ruptura global de 6,6%, alcanzando valores estándares de precisión al colocar 74 TTP; el Cirujano 2 presentó una tasa de ruptura de 6,1%, alcanzando valores de referencia a los 64 TTP; la diferencia entre ambos no fue estadísticamente significativa (P = 0,9009). Conclusión: En la serie evaluada se evidenció que se necesitan colocar aproximadamente 70 TTP para lograr resultados en términos de exactitud intrapedicular comparables con lo reportado por cirujanos experimentados en esta técnica mínimamente invasiva. PMID:29900033

A systematic review and meta-synthesis of the impact of becoming parents on the couple relationship.

PubMed

Delicate, Amy; Ayers, Susan; McMullen, Sarah

2018-06-01

the transition to parenthood (TTP) is associated with changes to a couple's relationship. Quantitative evidence shows the TTP is associated with reduced satisfaction and quality of a couples' relationships. Qualitative research provides information on the lived experience of couples in the TTP so can provide a more in-depth understanding of the impact. This review therefore aimed to synthesise qualitative research of the perceived impact of the TTP on a couple's relationship in contemporary Western society. a systematic search was conducted of nine databases and grey literature. Key author, citation and reference searches were also undertaken. Papers were included if they presented qualitative data of romantic partner relationships during the TTP with parents aged 18 or over. Studies were restricted to those conducted from 1996 in Western societies. Analysis was conducted using meta-ethnography. searches identified 5256 papers. After applying inclusion criteria 12 papers were included in the meta-synthesis. Six main themes were identified: (1) Adjustment Phase (a period of change in the relationship), (2) Focus on the Baby (with a sub-theme of feeling unprepared for the relationship impact), (3) Communication (shifts in communication patterns and importance), (4) Intimacy (changes to sexual relations, romance and closeness), (5) Strain on the Relationship (short-term or prolonged), and (6) Strengthened Relationships (deepening of connection and new affinity). Except for the themes of Strain on the Relationship and Strengthened Relationships, the findings showed the TTP had positive and negative impacts on couples' relationships. the review highlights a range of TTP relationship issues that couples experience and may require help with. Health care professionals working with parents in the TTP may be able to provide support through antenatal education that includes preparation for relationship changes, and provision of postnatal support to identify and overcome problems. Copyright © 2018 Elsevier Ltd. All rights reserved.

Structural basis for proficient incorporation of dTTP opposite O6-methylguanine by human DNA polymerase iota.

PubMed

Pence, Matthew G; Choi, Jeong-Yun; Egli, Martin; Guengerich, F Peter

2010-12-24

O(6)-methylguanine (O(6)-methylG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, even physiological ones (e.g. S-adenosylmethionine). The efficiency of a truncated, catalytic DNA polymerase ι core enzyme was determined for nucleoside triphosphate incorporation opposite O(6)-methylG, using steady-state kinetic analyses. The results presented here corroborate previous work from this laboratory using full-length pol ι, which showed that dTTP incorporation occurs with high efficiency opposite O(6)-methylG. Misincorporation of dTTP opposite O(6)-methylG occurred with ∼6-fold higher efficiency than incorporation of dCTP. Crystal structures of the truncated form of pol ι with O(6)-methylG as the template base and incoming dCTP or dTTP were solved and showed that O(6)-methylG is rotated into the syn conformation in the pol ι active site and that dTTP misincorporation by pol ι is the result of Hoogsteen base pairing with the adduct. Both dCTP and dTTP base paired with the Hoogsteen edge of O(6)-methylG. A single, short hydrogen bond formed between the N3 atom of dTTP and the N7 atom of O(6)-methylG. Protonation of the N3 atom of dCTP and bifurcation of the N3 hydrogen between the N7 and O(6) atoms of O(6)-methylG allow base pairing of the lesion with dCTP. We conclude that differences in the Hoogsteen hydrogen bonding between nucleotides is the main factor in the preferential selectivity of dTTP opposite O(6)-methylG by human pol ι, in contrast to the mispairing modes observed previously for O(6)-methylG in the structures of the model DNA polymerases Sulfolobus solfataricus Dpo4 and Bacillus stearothermophilus DNA polymerase I.

Magnetic properties of the new π -d organic superconductor β -(BDA-TTP){2}FeCl{4}

NASA Astrophysics Data System (ADS)

Tokumoto, M.; Ishii, K.; Tanaka, H.; Akutsu, H.; Yamada, J.; Choi, E. S.; Brooks, J. S.; Ishida, K.

2004-04-01

We have investigated complete anisotropy in the magnetic properties of the charge transfer salt β -(BDA-TTP){2}FeCl{4} [BDA-TTP = 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene] and revealed that the anisotropy in both the temperature and the field dependences of magnetization below TN show behaviours different from those for typical antiferromagnets. Key words. Antiferromagnet anisotropy Smagnetization.

Overweight individuals are at increased risk for thrombotic thrombocytopenic purpura.

PubMed

Nicol, Kathleen K; Shelton, Brent J; Knovich, Mary Ann; Owen, John

2003-11-01

Our understanding of the pathophysiology of thrombotic thrombocytopenic purpura, TTP, has increased dramatically in the past few years with the identification of the role of ADAMTS13. Nonetheless, risk factors for the development of acute TTP are few. Informally, obesity was felt to be common in patients with TTP and so a formal study was undertaken to further define this association. We report our data in 105 patients with classical TTP as defined by thrombocytopenia and microangiopathic hemolytic anemia. We found that marked obesity is a previously unrecognized risk factor with an associated odds ratio of 7.6. Interestingly, despite this increased risk, obesity might well be associated with lower mortality, although this did not reach statistical significance. Copyright 2003 Wiley-Liss, Inc.

Roles of spin fluctuation and frustration in the superconductivity of β-(BDA-TTP)2X (X=SbF6,AsF6) under uniaxial compression

NASA Astrophysics Data System (ADS)

Ito, Hiroshi; Ishihara, Tetsuo; Tanaka, Hisaaki; Kuroda, Shin-Ichi; Suzuki, Takeo; Onari, Seiichiro; Tanaka, Yukio; Yamada, Jun-Ichi; Kikuchi, Koichi

2008-11-01

β -type BDA-TTP [ BDA-TTP=2,5 -bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene] salts possess high transition temperatures TC reaching 7 K among organic superconductors. TC of β-(BDA-TTP)2X (X=SbF6,AsF6) is studied by resistive measurements under uniaxial compression. TC once increases and takes a maximum under compression parallel to the donor stack while it decreases under compression perpendicular to the donor stack. These results are in agreement with the half-filled Hubbard model on the triangular lattice in which the compression controls the spin fluctuation and frustration in the weak pressure region.

Pregnancy shortly after an acute episode of severe acquired thrombotic thrombocytopenic purpura.

PubMed

Panaitescu, Anca M; Stoia, Razvan; Ciobanu, Anca M; Demetrian, Mihaela; Peltecu, Gheorghe

2016-12-01

Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal condition. In women with a previous history of TTP there is increased risk of recurrence during pregnancy and the puerperium. There is some evidence that the risk of relapse during pregnancy is increased if the interval between the event and conception is short. We present a case in which pregnancy was achieved a few days after full recovery from an acute episode of severe acquired TTP (ADAMTS13 activity <0.1%) which was successfully treated with four courses of plasma exchange. There was no relapse of TTP during pregnancy and a healthy baby was delivered at term; the puerperium was uneventful. Copyright © 2016 Elsevier Ltd. All rights reserved.

Brain perfusion alterations in tick-borne encephalitis-preliminary report.

PubMed

Tyrakowska-Dadełło, Zuzanna; Tarasów, Eugeniusz; Janusek, Dariusz; Moniuszko-Malinowska, Anna; Zajkowska, Joanna; Pancewicz, Sławomir

2018-03-01

Magnetic resonance imaging (MRI) changes in tick-borne encephalitis (TBE) are non-specific and the pathophysiological mechanisms leading to their formation remain unclear. This study investigated brain perfusion in TBE patients using dynamic susceptibility-weighted contrast-enhanced magnetic resonance perfusion imaging (DSC-MRI perfusion). MRI scans were performed for 12 patients in the acute phase, 3-5days after the diagnosis of TBE. Conventional MRI and DSC-MRI perfusion studies were performed. Cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP) parametric maps were created. The bilateral frontal, parietal, and temporal subcortical regions and thalamus were selected as regions of interest. Perfusion parameters of TBE patients were compared to those of a control group. There was a slight increase in CBF and CBV, with significant prolongation of TTP in subcortical areas in the study subjects, while MTT values were comparable to those of the control group. A significant increase in thalamic CBF (p<0.001) and increased CBV (p<0.05) were observed. Increased TTP and a slight reduction in MTT were also observed within this area. The DSC-MRI perfusion study showed that TBE patients had brain perfusion disturbances, expressed mainly in the thalami. These results suggest that DSC-MRI perfusion may provide important information regarding the areas affected in TBE patients. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Rapid incorporation kinetics and improved fidelity of a novel class of 3'-OH unblocked reversible terminators.

PubMed

Gardner, Andrew F; Wang, Jinchun; Wu, Weidong; Karouby, Jennifer; Li, Hong; Stupi, Brian P; Jack, William E; Hersh, Megan N; Metzker, Michael L

2012-08-01

Recent developments of unique nucleotide probes have expanded our understanding of DNA polymerase function, providing many benefits to techniques involving next-generation sequencing (NGS) technologies. The cyclic reversible termination (CRT) method depends on efficient base-selective incorporation of reversible terminators by DNA polymerases. Most terminators are designed with 3'-O-blocking groups but are incorporated with low efficiency and fidelity. We have developed a novel class of 3'-OH unblocked nucleotides, called Lightning Terminators™, which have a terminating 2-nitrobenzyl moiety attached to hydroxymethylated nucleobases. A key structural feature of this photocleavable group displays a 'molecular tuning' effect with respect to single-base termination and improved nucleotide fidelity. Using Therminator DNA polymerase, we demonstrate that these 3'-OH unblocked terminators exhibit superior enzymatic performance compared to two other reversible terminators, 3'-O-amino-TTP and 3'-O-azidomethyl-TTP. Lightning Terminators show maximum incorporation rates (k(pol)) that range from 35 to 45 nt/s, comparable to the fastest NGS chemistries, yet with catalytic efficiencies (k(pol)/K(D)) comparable to natural nucleotides. Pre-steady-state kinetic studies of thymidine analogs revealed that the major determinant for improved nucleotide selectivity is a significant reduction in k(pol) by >1000-fold over TTP misincorporation. These studies highlight the importance of structure-function relationships of modified nucleotides in dictating polymerase performance.

Coagulase-negative staphylococcal bacteraemia in cancer patients. Time to positive culture can distinguish bacteraemia from contamination.

PubMed

Morioka, Shinichiro; Ichikawa, Mika; Mori, Keita; Kurai, Hanako

2018-03-16

Coagulase-negative staphylococci (CoNS) are the most common contaminants of blood cultures, however, we sometimes have difficulties in determining their clinical significance. It is still controversial that there is a significant difference between the contamination group and the true bacteraemia group in the time to positivity (TTP) of blood cultures. We validated the relationship between a TTP and the presence of CoNS bacteraemia in cancer patients by using an objective, non-judgmental definition for CoNS contamination. We retrospectively reviewed 175 sets of blood cultures drawn from 95 patients that yielded CoNS from October 2011 to March 2013. We considered as contamination if an isolate of CoNS was identified in one out of multiple sets of blood cultures. We investigated the TTP, the threshold values and corresponding likelihood ratios to distinguish CoNS bacteraemia from contamination. The median TTP in CoNS bacteraemia group was significantly shorter than that in contamination group (14 h 45 min and 20 h 31 min, respectively, p = .0157). A TTP of ≤16 h had a specificity of 83% for predicting CoNS bacteraemia, and that of >20 h had a sensitivity of 86% for predicting CoNS contamination. We validated that the median TTP in CoNS bacteraemia group was significantly shorter than that in their contamination group, and that a TTP of ≤16 h was associated with CoNS bacteraemia, while that of >20 h was associated with CoNS contamination, if evaluated with an objective, non-judgmental definition for CoNS contamination.

Feasibility of quantitative regional ventilation and perfusion mapping with phase-resolved functional lung (PREFUL) MRI in healthy volunteers and COPD, CTEPH, and CF patients.

PubMed

Voskrebenzev, Andreas; Gutberlet, Marcel; Klimeš, Filip; Kaireit, Till F; Schönfeld, Christian; Rotärmel, Alexander; Wacker, Frank; Vogel-Claussen, Jens

2018-04-01

In this feasibility study, a phase-resolved functional lung imaging postprocessing method for extraction of dynamic perfusion (Q) and ventilation (V) parameters using a conventional 1H lung MRI Fourier decomposition acquisition is introduced. Time series of coronal gradient-echo MR images with a temporal resolution of 288 to 324 ms of two healthy volunteers, one patient with chronic thromboembolic hypertension, one patient with cystic fibrosis, and one patient with chronic obstructive pulmonary disease were acquired at 1.5 T. Using a sine model to estimate cardiac and respiratory phases of each image, all images were sorted to reconstruct full cardiac and respiratory cycles. Time to peak (TTP), V/Q maps, and fractional ventilation flow-volume loops were calculated. For the volunteers, homogenous ventilation and perfusion TTP maps (V-TTP, Q-TTP) were obtained. The chronic thromboembolic hypertension patient showed increased perfusion TTP in hypoperfused regions in visual agreement with dynamic contrast-enhanced MRI, which improved postpulmonary endaterectomy surgery. Cystic fibrosis and chronic obstructive pulmonary disease patients showed a pattern of increased V-TTP and Q-TTP in regions of hypoventilation and decreased perfusion. Fractional ventilation flow-volume loops of the chronic obstructive pulmonary disease patient were smaller in comparison with the healthy volunteer, and showed regional differences in visual agreement with functional small airways disease and emphysema on CT. This study shows the feasibility of phase-resolved functional lung imaging to gain quantitative information regarding regional lung perfusion and ventilation without the need for ultrafast imaging, which will be advantageous for future clinical translation. Magn Reson Med 79:2306-2314, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

Structural Variations in β-(BDA-TTP)2FeCl4 at Low Temperature and under Pressure: Charge-Ordered State with a Two-Fold Crystal Structure

NASA Astrophysics Data System (ADS)

Sasamori, Kota; Takahashi, Kazuyuki; Kodama, Takeshi; Fujita, Wataru; Kikuchi, Koichi; Yamada, Jun-ichi

2013-05-01

The pressure-induced organic superconductor β-(BDA-TTP)2FeCl4 [BDA-TTP = 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene], which shows a metal--insulator (MI) transition at TMI = 113 K under ambient pressure, has been found by X-ray study to have a two-fold crystal structure along the c-axis in the insulating state at 10 K. In the donor layer, there are four independent BDA-TTP molecules, which are divided into two charge-poor ones and two charge-rich ones on the basis of the folding dihedral angles around the intramolecular sulfur-to-sulfur axes of two outer dithiane rings in BDA-TTP. The charge separation leads to the formation of two types of dimers: a dimer consisting of two charge-poor donors and a dimer consisting of two charge-rich ones. The tight-binding band calculation revealed a band gap of 5.3 meV in the energy dispersion. The MI transition can be therefore accounted for by the charge separation. In addition, we investigated the crystal and electronic structures of β-(BDA-TTP)2FeCl4 at different pressures up to 21 kbar, and found that the application of pressures causes variations in both the conformation of donor molecule and the donor arrangement, which are responsible for almost uniform interaction in the donor stacking and for an increase in bandwidth (W). As a result, the suppression of MI transition and subsequent occurrence of superconductivity in β-(BDA-TTP)2FeCl4 would be observed with increasing pressure.

Hemorrhagic Stroke in an Adolescent Female with HIV-Associated Thrombotic Thrombocytopenic Purpura

PubMed Central

Rakhmanina, Natella; Wong, Edward CC; Davis, Jeremiah C; Ray, Patricio E

2014-01-01

HIV-1 infection can trigger acute episodes of Idiopathic Thrombocytoponic Purpura (ITP), and Thrombotic Thrombocytopenic Purpura (TTP), particularly in populations with advanced disease and poor adherence to antiretroviral therapy (ART). These diseases should be distinguished because they respond to different treatments. Previous studies done in adults with HIV-TTP have recommended the prompt initiation or re-initiation of ART in parallel with plasma exchange therapy to improve the clinical outcome of these patients. Here, we describe a case of HIV-TTP resulting in an acute hemorrhagic stroke in a 16 year old female with perinatally acquired HIV infection and non-adherence to ART, who presented with severe thrombocytopenia, microangiopathic hemolytic anemia, and a past medical history of HIV-ITP. Both differential diagnosis and treatments for HIV-ITP and HIV-TTP were considered simultaneously. A decrease in plasma ADAMTS13 activity (<5%) without detectable inhibitory antibodies confirmed the diagnosis of HIV-TTP. Re-initiation of ART and plasma exchange resulted in a marked decrease in the HIV-RNA viral load, recovery of the platelet count, and complete recovery was achieved with sustained virologic suppression. PMID:25429351

Direct photoaffinity labeling of an allosteric site on subunit protein M1 of mouse ribonucleotide reductase by dTTP.

PubMed Central

Eriksson, S; Caras, I W; Martin, D W

1982-01-01

The protein M1 subunit of ribonucleotide reductase contains at least two allosteric nucleotide binding sites that control the capacity of the enzyme to reduce ribonucleotides to the deoxyribonucleotides required for DNA synthesis. Direct photoaffinity labeling of partially purified protein M1 from mouse T-lymphoma (S49) cells was observed after UV irradiation in the presence of dTTP at 0 degrees C. The relative molar incorporation of nucleotide per subunit was 4-8%. Competition experiments showed that the dTTP was bound to an allosteric domain genetically and kinetically defined as the substrate specificity site of the enzyme. An altered protein M1 isolated from a thymidine-resistant mutant cell line showed significantly decreased photoincorporation of dTTP, consistent with the fact that its CDP reductase activity is resistant to feedback inhibition by dTTP. Specific photolabeling of several other proteins with pyrimidine and purine nucleotides was also found, indicating the general usefulness of direct photoaffinity labeling in the study of enzymes involved in nucleotide and nucleic acid metabolism. Images PMID:7033963

A post-transcriptional mechanism pacing expression of neural genes with precursor cell differentiation status

PubMed Central

Dai, Weijun; Li, Wencheng; Hoque, Mainul; Li, Zhuyun; Tian, Bin; Makeyev, Eugene V.

2015-01-01

Nervous system (NS) development relies on coherent upregulation of extensive sets of genes in a precise spatiotemporal manner. How such transcriptome-wide effects are orchestrated at the molecular level remains an open question. Here we show that 3′-untranslated regions (3′ UTRs) of multiple neural transcripts contain AU-rich cis-elements (AREs) recognized by tristetraprolin (TTP/Zfp36), an RNA-binding protein previously implicated in regulation of mRNA stability. We further demonstrate that the efficiency of ARE-dependent mRNA degradation declines in the neural lineage because of a decrease in the TTP protein expression mediated by the NS-enriched microRNA miR-9. Importantly, TTP downregulation in this context is essential for proper neuronal differentiation. On the other hand, inactivation of TTP in non-neuronal cells leads to dramatic upregulation of multiple NS-specific genes. We conclude that the newly identified miR-9/TTP circuitry limits unscheduled accumulation of neuronal mRNAs in non-neuronal cells and ensures coordinated upregulation of these transcripts in neurons. PMID:26144867

A case report of uncompensated alkalosis induced by daily plasmapheresis in a patient with thrombotic thrombocytopenic purpura.

PubMed

Nagai, Yoshiko; Itabashi, Mitsuyo; Mizutani, Mayuko; Ogawa, Tetsuya; Yumura, Wako; Tsuchiya, Ken; Nitta, Kosaku

2008-02-01

Plasmapheresis (PP) is widely known as the standard therapy for thrombotic thrombocytopenic purpura (TTP). Citrate is used as an anticoagulant in fresh frozen plasma, and the large amount of citrate infused during PP induces metabolic alkalosis. A 29-year-old woman was diagnosed with TTP associated with systemic lupus erythematosus, and was treated by daily PP in addition to a steroid, an immunosuppressant, vincristine, and cyclophosphamide. Uncompensated alkalosis caused by a combination of metabolic and respiratory alkalosis developed after artificial ventilation was discontinued. Her metabolic status improved after controlling her respiratory status and the activity of the TTP. Metabolic alkalosis is a common complication in TTP patients treated by frequent PP, but several factors that affect metabolic status may aggravate the alkalosis and induce uncompensated alkalosis.

Structural Basis for Proficient Incorporation of dTTP Opposite O[superscript 6]-Methylguanine by Human DNA Polymerase [iota

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

Pence, Matthew G.; Choi, Jeong-Yun; Egli, Martin

2012-03-15

O{sup 6}-Methylguanine (O{sup 6}-methylG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, even physiological ones (e.g. S-adenosylmethionine). The efficiency of a truncated, catalytic DNA polymerase L core enzyme was determined for nucleoside triphosphate incorporation opposite O{sup 6}-methylG, using steady-state kinetic analyses. The results presented here corroborate previous work from this laboratory using full-length pol L, which showed that dTTP incorporation occurs with high efficiency opposite O{sup 6}-methylG. Misincorporation of dTTP opposite O{sup 6}-methylG occurred with {approx}6-fold higher efficiency than incorporation of dCTP. Crystal structures of the truncated form of pol L with O{sup 6}-methylG asmore » the template base and incoming dCTP or dTTP were solved and showed that O{sup 6}-methylG is rotated into the syn conformation in the pol L active site and that dTTP misincorporation by pol L is the result of Hoogsteen base pairing with the adduct. Both dCTP and dTTP base paired with the Hoogsteen edge of O{sup 6}-methylG. A single, short hydrogen bond formed between the N3 atom of dTTP and the N7 atom of O{sup 6}-methylG. Protonation of the N3 atom of dCTP and bifurcation of the N3 hydrogen between the N7 and O{sup 6} atoms of O{sup 6}-methylG allow base pairing of the lesion with dCTP. We conclude that differences in the Hoogsteen hydrogen bonding between nucleotides is the main factor in the preferential selectivity of dTTP opposite O{sup 6}-methylG by human pol L, in contrast to the mispairing modes observed previously for O{sup 6}-methylG in the structures of the model DNA polymerases Sulfolobus solfataricus Dpo4 and Bacillus stearothermophilus DNA polymerase I.« less

Distribution and clinical determinants of time-to-positivity of blood cultures in patients with neutropenia.

PubMed

Lambregts, Merel M C; Warreman, Eva B; Bernards, Alexandra T; Veelken, Hendrik; von dem Borne, Peter A; Dekkers, Olaf M; Visser, Leo G; de Boer, Mark G

2018-02-01

Blood cultures (BCs) are essential in the evaluation of neutropenic fever. Modern BC systems have significantly reduced the time-to-positivity (TTP) of BC. This study explores the probability of bacteraemia when BCs have remained negative for different periods of time. All adult patients with neutropenia and bacteraemia were included (January 2012-February 2016). Predictive clinical factors for short (≤16 hours) and long (>24 hours) TTP were determined. The residual probability of bacteraemia was estimated for the scenario of negative BC 24 hours after collection. The cohort consisted of 154 patients, accounting for 190 episodes of bacteraemia. Median age of 61 years, 60.5% were male. In 123 (64.7%) episodes, BC yielded a single Gram-positive micro-organism and in 49 (25.8%) a Gram-negative micro-organism (median TTP 16.7, 14.5 hours respectively, P < .01). TTP was ≤24 hours in 91.6% of episodes. Central line-associated bacteraemia was associated with long TTP. The probability of bacteraemia if BC had remained negative for 24 hours was 1%-3%. The expected TTP offers guidance in the management of patients with neutropenia and suspected bacteraemia. The knowledge of negative BC can support a change in working diagnosis, and impact clinical decisions as soon as 24 hours after BC collection. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease.

PubMed

Molle, Céline; Zhang, Tong; Ysebrant de Lendonck, Laure; Gueydan, Cyril; Andrianne, Mathieu; Sherer, Félicie; Van Simaeys, Gaetan; Blackshear, Perry J; Leo, Oberdan; Goriely, Stanislas

2013-08-26

Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine-rich element (ARE)-binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow-derived dendritic cells (BMDCs) from TTP(-/-) mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3' untranslated region. TTP(-/-) mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23-IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation.

Two approaches to the clinical dilemma of treating TTP with therapeutic plasma exchange in patients with a history of anaphylactic reactions to plasma.

PubMed

Sidhu, Davinder; Snyder, Edward L; Tormey, Christopher A

2017-06-01

Thrombotic thrombocytopenic purpura (TTP) is a rare but serious disease caused by autoantibody-mediated deficiency in von Willebrand factor (VWF) cleaving protease, ADAMTS-13. The primary acute treatment is therapeutic plasma exchange (TPE). However, some patients can develop allergic/anaphylactic reactions to the replacement (i.e., donor) plasma over time. Two potential treatment strategies for patients with TTP who demonstrate severe allergic reactions to plasma used for exchange were examined. Two patients with TTP exacerbations who developed severe allergic reactions to donor plasma were identified. One patient's TPE was re-initiated with Octaplas, a lot-batched solvent and detergent treated, type-specific, pooled donor plasma product. The other patient was exchanged with primarily albumin, followed by slow incremental exposures to donor plasma to mitigate exposures and allergic risks. Both patients were assessed for anaphylaxis. Both treatment strategies were successful in preventing any further clinically significant allergic/anaphylactic reactions and facilitated both patients' TTP remissions. Based on our experience with two similar patients with TTP exacerbations and history of anaphylactic reactions to plasma during TPE, we have identified two possible treatment protocols to achieve remission in this clinical dilemma. Substituting Octaplas for standard plasma or, alternatively, using albumin with slowly increasing amounts of standard plasma may help to mitigate the risk of further anaphylactic adverse events. J. Clin. Apheresis 32:158-162, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Group 4 Metalloporphyrin diolato Complexes and Catalytic Application of Metalloporphyrins and Related Transition Metal Complexes

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

Du, Guodong

In this work, the first examples of group 4 metalloporphyrin 1,2-diolato complexes were synthesized through a number of strategies. In general, treatment of imido metalloporphyrin complexes, (TTP)M=NR, (M = Ti, Zr, Hf), with vicinal diols led to the formation of a series of diolato complexes. Alternatively, the chelating pinacolate complexes could be prepared by metathesis of (TTP)MCl 2 (M = Ti, Hf) with disodium pinacolate. These complexes were found to undergo C-C cleavage reactions to produce organic carbonyl compounds. For titanium porphyrins, treatment of a titanium(II) alkyne adduct, (TTP)Ti(η 2-PhC≡CPh), with aromatic aldehydes or aryl ketones resulted in reductive couplingmore » of the carbonyl groups to produce the corresponding diolato complexes. Aliphatic aldehydes or ketones were not reactive towards (TTP)Ti(η 2-PhC≡CPh). However, these carbonyl compounds could be incorporated into a diolato complex on reaction with a reactive precursor, (TTP)Ti[O(Ph) 2C(Ph) 2O] to provide unsymmetrical diolato complexes via cross coupling reactions. In addition, an enediolato complex (TTP)Ti(OCPhCPhO) was obtained from the reaction of (TTP)Ti(η 2-PhC≡CPh) with benzoin. Titanium porphyrin diolato complexes were found to be intermediates in the (TTP)Ti=O-catalyzed cleavage reactions of vicinal diols, in which atmospheric oxygen was the oxidant. Furthermore, (TTP)Ti=O was capable of catalyzing the oxidation of benzyl alcohol and α-hydroxy ketones to benzaldehyde and α-diketones, respectively. Other high valent metalloporphyrin complexes also can catalyze the oxidative diol cleavage and the benzyl alcohol oxidation reactions with dioxygen. A comparison of Ti(IV) and Sn(IV) porphyrin chemistry was undertaken. While chelated diolato complexes were invariably obtained for titanium porphyrins on treatment with 1,2-diols, the reaction of vicinal diols with tin porphyrins gave a number of products, including mono-, bis-alkoxo, and chelating diolato complexes, depending on the identity of diols and the stoichiometry employed. It was also found that tin porphyrin complexes promoted the oxidative cleavage of vicinal diols and the oxidation of α-ketols to α-diketones with dioxygen. In extending the chemistry of metalloporphyrins and analogous complexes, a series of chiral tetraaza macrocyclic ligands and metal complexes were designed and synthesized. Examination of iron(II) complexes showed that they were efficient catalysts for the cyclopropanation of styrene by diazo reagents. Good yields and high diastereoselectivity were obtained with modest enantioselectivity. A rationalization of the stereoselectivity was presented on the basis of structural factors in a carbene intermediate.« less

Probing the communication of deoxythymidine triphosphate in HIV-1 reverse transcriptase by communication maps and interaction energy studies.

PubMed

Gnanasekaran, Ramachandran

2017-11-08

We calculate communication maps for HIV-1 Reverse Transcriptase (RT) to elucidate energy transfer pathways between deoxythymidine triphosphate (dTTP) and other parts of the protein. This approach locates energy transport channels from the dTTP to remote regions of the protein via residues and water molecules. We examine the water dynamics near the catalytic site of HIV-1 RT by molecular dynamics (MD) simulations. We find that, within the catalytic site, the relaxation of water molecules is similar to that of the hydration water molecules present in other proteins and the relaxation time scale is fast enough to transport energy and helps in communication between dTTP and other residues in the system. To quantify energy transfer, we also calculate the interaction energies of dTTP, 2Mg 2+ , doxy-guanosine nucleotide (DG22) with their surrounding residues by using the B3LYP-D3 method. The results, from classical vibrational energy diffusivity and QM interaction energy, are complementary to identify the important residues involved in the process of polymerization. The positive and negative interactions by dTTP with different types of residues in the catalytic region make the residues transfer energy through vibrational communication.

A case of severe thrombotic thrombocytopenic purpura with concomitant Legionella pneumonia: review of pathogenesis and treatment.

PubMed

Talebi, Tony; Fernandez-Castro, Gustavo; Montero, Alberto J; Stefanovic, Alexandra; Lian, Eric

2011-09-01

Thrombotic thrombocytopenia purpura (TTP) is a severe multisystem disorder characterized by fever, microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, and impaired renal function. Platelet counts are usually diminished, whereas the bone marrow shows a large number of megakaryocytes indicating peripheral destruction and consumption of platelets. Coagulation studies in patients with TTP are normal or slightly elevated, which helps differentiate this entity from disseminated intravascular coagulation. The peripheral smear shows an abundance of schistocytes, reticulocytes, and, at times, nucleated red blood cells. Serum lactate dehydrogenase and indirect bilirubin are elevated as a result of mechanical destruction of red blood cells. Legionella pneumophila has been identified as a relatively common cause of both community-acquired and hospital-acquired pneumonia. An association between Legionella and TTP has only been cited once in the literature. Here we present a case of severe TTP with concurrent Legionella infection. Our patient presented with the classic clinical findings of TTP and an ADAMTS13 level of less than 5% associated with an inhibitor. After a 3-week treatment course with plasma exchange, steroids, and antibiotics, he had complete clinical recovery and his ADAMTS13 level increased to greater than 75%. (C) 2011 Lippincott Williams & Wilkins, Inc.

Rapid Proteasomal Degradation of Posttranscriptional Regulators of the TIS11/Tristetraprolin Family Is Induced by an Intrinsically Unstructured Region Independently of Ubiquitination

PubMed Central

Ngoc, Long Vo; Wauquier, Corinne; Soin, Romuald; Bousbata, Sabrina; Twyffels, Laure; Kruys, Véronique

2014-01-01

The TIS11/tristetraprolin (TTP) CCCH tandem zinc finger proteins are major effectors in the destabilization of mRNAs bearing AU-rich elements (ARE) in their 3′ untranslated regions. In this report, we demonstrate that the Drosophila melanogaster dTIS11 protein is short-lived due to its rapid ubiquitin-independent degradation by the proteasome. Our data indicate that this mechanism is tightly associated with the intrinsically unstructured, disordered N- and C-terminal domains of the protein. Furthermore, we show that TTP, the mammalian TIS11/TTP protein prototype, shares the same three-dimensional characteristics and is degraded by the same proteolytic pathway as dTIS11, thereby indicating that this mechanism has been conserved across evolution. Finally, we observed a phosphorylation-dependent inhibition of dTIS11 and TTP degradation by the proteasome in vitro, raising the possibility that such modifications directly affect proteasomal recognition for these proteins. As a group, RNA-binding proteins (RNA-BPs) have been described as enriched in intrinsically disordered regions, thus raising the possibility that the mechanism that we uncovered for TIS11/TTP turnover is widespread among other RNA-BPs. PMID:25246635

Continued EGFR-TKI with concurrent radiotherapy to improve time to progression (TTP) in patients with locally progressive non-small cell lung cancer (NSCLC) after front-line EGFR-TKI treatment.

PubMed

Wang, Y; Li, Y; Xia, L; Niu, K; Chen, X; Lu, D; Kong, R; Chen, Z; Sun, J

2018-03-01

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the optimal treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, most patients developed systemic or local progression due to acquired EGFR-TKI resistance. This retrospective study aimed to evaluate the feasibility of continued EGFR-TKI with concurrent radiotherapy (CTCRT) in patients with local progression after front-line EGFR-TKI treatment. Advanced NSCLC patients with active EGFR mutation who received EGFR-TKI were treated with CTCRT after local progression. Medical data were analyzed for time to progression (TTP), progression-free survival (PFS), tumor response rate, overall survival (OS) and adverse events. A total of 50 irradiated lesions from 44 patients were included. Median TTP and PFS of measurable lesions (n = 31) were both significantly prolonged after local radiotherapy (TTP1 + TTP2 vs. TTP1: 21.7 vs. 16.0 months, P = 0.010; PFS1 + PFS2 vs. PFS1: 21.3 vs. 16.0 months, P = 0.027). For all lesions (n = 50), objective response rate (ORR) and local tumor control rate (LCR) were 54.0 and 84.0%, respectively. Median OS was 26.6 months. There were no serious adverse events before or after radiotherapy. The treatment modality of CTCRT is considerable and effective for EGFR-mutant NSCLC patients even with local failure from front-line EGFR-TKI treatment.

Thrombotic thrombocytopenic purpura misdiagnosed as autoimmune cytopenia: Causes of diagnostic errors and consequence on outcome. Experience of the French thrombotic microangiopathies reference centre.

PubMed

Grall, Maximilien; Azoulay, Elie; Galicier, Lionel; Provôt, François; Wynckel, Alain; Poullin, Pascale; Grange, Steven; Halimi, Jean-Michel; Lautrette, Alexandre; Delmas, Yahsou; Presne, Claire; Hamidou, Mohamed; Girault, Stéphane; Pène, Frédéric; Perez, Pierre; Kanouni, Tarik; Seguin, Amélie; Mousson, Christiane; Chauveau, Dominique; Ojeda-Uribe, Mario; Barbay, Virginie; Veyradier, Agnès; Coppo, Paul; Benhamou, Ygal

2017-04-01

Thrombotic thrombocytopenic purpura (TTP) has a devastating prognosis without adapted management. Sources of misdiagnosis need to be identified to avoid delayed treatment. We studied 84 patients with a final diagnosis of severe (<10%) acquired ADAMTS13 deficiency-associated TTP from our National database that included 423 patients, who had an initial misdiagnosis (20% of all TTP). Main diagnostic errors were attributed to autoimmune thrombocytopenia, associated (51%) or not (37%) with autoimmune hemolytic anemia. At admission, misdiagnosed patients were more frequently females (P = .034) with a history of autoimmune disorder (P = .017) and had organ involvement in 67% of cases; they had more frequently antinuclear antibodies (P = .035), a low/undetectable schistocyte count (P = .001), a less profound anemia (P = .008), and a positive direct antiglobulin test (DAT) (P = .008). In multivariate analysis, female gender (P = .022), hemoglobin level (P = .028), a positive DAT (P = .004), and a low schistocytes count on diagnosis (P < .001) were retained as risk factors of misdiagnosis. Platelet count recovery was significantly longer in the misdiagnosed group (P = .041) without consequence on mortality, exacerbation and relapse. However, patients in the misdiagnosed group had a less severe disease than those in the accurately diagnosed group, as evidenced by less organ involvement at TTP diagnosis (P = .006). TTP is frequently misdiagnosed with autoimmune cytopenias. A low schistocyte count and a positive DAT should not systematically rule out TTP, especially when associated with organ failure. © 2017 Wiley Periodicals, Inc.

Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.

PubMed

Weiss, Brian; Widemann, Brigitte C; Wolters, Pamela; Dombi, Eva; Vinks, Alexander; Cantor, Alan; Perentesis, John; Schorry, Elizabeth; Ullrich, Nicole; Gutmann, David H; Tonsgard, James; Viskochil, David; Korf, Bruce; Packer, Roger J; Fisher, Michael J

2015-04-01

Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway. We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging. The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI: 14.3-23.7 mo), which was significantly longer than 11.9 months (P < .001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria. This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way

PubMed Central

Deshpande, Devyani; Srivastava, Shashikant; Nuermberger, Eric; Pasipanodya, Jotam G.; Swaminathan, Soumya; Gumbo, Tawanda

2016-01-01

Background. The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination. Methods. We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic. First, we varied the percentage of time that faropenem persisted above minimum inhibitory concentration (TMIC) on the moxifloxacin-linezolid regimen. After choosing the best faropenem exposure, we performed experiments in which we varied the moxifloxacin and linezolid doses in the triple regimen. Finally, we performed longer-duration therapy validation experiments. Bacterial burden was quantified using both colony-forming units per milliliter (CFU/mL) and time to positivity (TTP). Kill slopes were modeled using exponential regression. Results. TTP was a more sensitive measure of bacterial burden than CFU/mL. A faropenem TMIC > 62% was associated with steepest microbial kill slope. Regimens of standard linezolid and moxifloxacin plus faropenem TMIC > 60%, as well as higher-dose moxifloxacin, achieved slopes equivalent to those of the standard regimen based by both TTP and CFU/mL over 28 days of treatment. Conclusions. We have developed an oral faropenem-linezolid-moxifloxacin (FLAME) regimen that is free of first-line drugs. The regimen could be effective against both multidrug-resistant and drug-susceptible tuberculosis in children. PMID:27742640

Systemic Lupus Erythematosus Presenting as Refractory Thrombotic Thrombocytopenic Purpura: A Diagnostic and Management Challenge. A Case Report and Concise Review of the Literature.

PubMed

Abu-Hishmeh, Mohammad; Sattar, Alamgir; Zarlasht, Fnu; Ramadan, Mohamed; Abdel-Rahman, Aisha; Hinson, Shante; Hwang, Caroline

2016-10-25

BACKGROUND Thrombotic thrombocytopenic purpura (TTP) is one of the thrombotic microangiopathic (TMA) syndromes, caused by severely reduced activity of the vWF-cleaving protease ADAMTS13. Systemic lupus erythematosus (SLE), on the other hand, is an autoimmune disease that affects various organs in the body, including the hematopoietic system. SLE can present with TMA, and differentiating between SLE and TTP in those cases can be very challenging, particularly in patients with no prior history of SLE. Furthermore, an association between these 2 diseases has been described in the literature, with most of the TTP cases occurring after the diagnosis of SLE. In rare cases, TTP may precede the diagnosis of SLE or occur concurrently. CASE REPORT We present a case of a previously healthy 34-year-old female who presented with dizziness and flu-like symptoms and was found to have thrombocytopenia, hemolytic anemia, and schistocytes in the peripheral smear. She was subsequently diagnosed with TTP and started on plasmapheresis and high-dose steroids, but without a sustained response. A diagnosis of refractory TTP was made, and she was transferred to our facility for further management. Initially, the patient was started on rituximab, but her condition continued to deteriorate, with worsening thrombocytopenia. Later, she also fulfilled the Systemic Lupus International Collaborating Clinics (SLICC) criteria for diagnosis of SLE. Treatment of TTP in SLE patients is generally similar to that in the general population, but in refractory cases there are few reports in the literature that show the efficacy of cyclophosphamide. We started our patient on cyclophosphamide and noticed a sustained improvement in the platelet count in the following weeks. CONCLUSIONS Thrombotic thrombocytopenic purpura is a life-threatening hematological emergency which must be diagnosed and treated in a timely manner. Refractory cases of TTP have been described in the literature, but without clear evidence-based guidelines for its management, and is solely based on expert opinion and previous case reports. Further studies are needed to establish guidelines for its management. We present this case to highlight the role that cyclophosphamide might carry in those cases and to be a foundation for these future studies.

Comparing masked target transform volume (MTTV) clutter metric to human observer evaluation of visual clutter

NASA Astrophysics Data System (ADS)

Camp, H. A.; Moyer, Steven; Moore, Richard K.

2010-04-01

The Night Vision and Electronic Sensors Directorate's current time-limited search (TLS) model, which makes use of the targeting task performance (TTP) metric to describe image quality, does not explicitly account for the effects of visual clutter on observer performance. The TLS model is currently based on empirical fits to describe human performance for a time of day, spectrum and environment. Incorporating a clutter metric into the TLS model may reduce the number of these empirical fits needed. The masked target transform volume (MTTV) clutter metric has been previously presented and compared to other clutter metrics. Using real infrared imagery of rural images with varying levels of clutter, NVESD is currently evaluating the appropriateness of the MTTV metric. NVESD had twenty subject matter experts (SME) rank the amount of clutter in each scene in a series of pair-wise comparisons. MTTV metric values were calculated and then compared to the SME observers rankings. The MTTV metric ranked the clutter in a similar manner to the SME evaluation, suggesting that the MTTV metric may emulate SME response. This paper is a first step in quantifying clutter and measuring the agreement to subjective human evaluation.

Laser scanning microscopy as a means to assess the augmentation of tissue repair by exposition of wounds to tissue tolerable plasma

NASA Astrophysics Data System (ADS)

Vandersee, Staffan; Richter, Heike; Lademann, Jürgen; Beyer, Marc; Kramer, Axel; Knorr, Fanny; Lange-Asschenfeldt, Bernhard

2014-11-01

Confocal laser scan microscopy (CLSM) has emerged as a tool for in vivo assessment of cutaneous conditions. In particular, its use in wound healing assessment has increasingly moved into focus. In this context, the application of tissue tolerable plasma (TTP) for wound treatment has recently become one of the most innovative therapeutic modalities. We analyzed wound healing parameters such as area decline and histomorphological characteristics of tissue repair in six subjects with vacuum-generated wounds on the forearm with a four-armed design: (A) no treatment, (B) treatment with TTP, (C) treatment with octenidine, and (D) sequential treatment with TTP and octenidine. Assessment of the wounds was conducted during six visits over the course of two weeks. The wounds were analyzed by photography and CLSM. TTP treatment led to a more rapid area decline that was statistically significant in comparison to other treatment groups. Besides mild pain, it was well tolerated. Morphologically, wound healing was found to initiate from the edges with the formation of dendritic structures consisting of keratinocytes. CLSM is a valuable tool for assessing the dynamics of wound healing. TTP, for reasons that still need to be investigated, can accelerate wound repair.

Evaluation of Plasma Platelet Microparticles in Thrombotic Thrombocytopenic Purpura.

PubMed

Tahmasbi, Leila; Karimi, Mehran; Kafiabadi, Sedigheh Amini; Nikougoftar, Mahin; Haghpanah, Sezaneh; Ranjbaran, Reza; Moghadam, Mohamad

2017-01-01

Platelet microparticles (PMPs) have a procoagulant activity about 50-100 times greater than active platelets due to high expression of negatively charged phospholipids on their surfaces. In this study, we evaluated microparticle immunophenotyping and also plasma PMPs level in patients with Thrombotic Thrombocytopenic Purpura (TTP) in Southern Iran. We had two study groups: 15 TTP patients and 15 healthy control group and PMPs from platelet concentrate (PC) at the 5 th day of storage. Microparticles were prepared in two steps, by low and high centrifugation followed by size confirmation via 'Dynamic Light Scattering (DLS)' Zetasizer. Immunophenotyping of PMPs was done via flow cytometry, using a FACS Calibur flow cytometer (BD, USA). PMPs counts were obtained using Partec-cyflow and Polysciences Microbeads (1 micron in diameter). Results were analyzed using FlowJo 7.6 (Treestar, USA) and Partec FlowMax software. Our results showed that the majority of microparticles in TTP patients and normal individuals were PMPs and also demonstrated that the plasma PMPs level in TTP patients was higher than the normal control group ( P -value<0.001). It seems that elevated PMPs level in TTP patients could be related to thrombotic events. Nevertheless, more studies are needed to confirm these results. © 2017 by the Association of Clinical Scientists, Inc.

Effect of 2',3'-dideoxythymidine-5'-triphosphate on HeLa cell in vitro DNA synthesis: evidence that DNA polymerase alpha is the only polymerase required for cellular DNA replication.

PubMed Central

Waqar, M A; Evans, M J; Huberman, J A

1978-01-01

We have studied the effects of the nucleotide analogue, 2',3'-dideoxythymidine-5'-triphosphate (ddTTP) on replicative DNA synthesis in HeLa cell lysates. As previously demonstrated (1), such lysates carry out extensive DNA synthesis in vitro, at rates and in a fashion similar to in vivo DNA replication. We report here that all aspects of DNA synthesis in such lysates (total dNTP incorporation, elongation of continuous nascent strands, and the initiation, elongation, and joining of Okazaki pieces) are only slightly inhibited by concentrations of ddTTP as high as 100-500 micrometer when the dTTP concentration is maintained at 10 micrometer. This finding is consistent with the report by Edenberg, Anderson, and DePamphilis (2) that all aspects of replicative in vitro simian virus 40 DNA synthesis are also resistant to ddTTP. We also find, in agreement with Edenberg, Anderson, and DePamphilis (2), that DNA synthesis catalyzed by DNA polymerases beta or gamma is easily inhibited by ddTTP, while synthesis catalyzed by DNA polymerase alpha is very resistant. These observations suggest that DNA polymerase alpha may be the only DNA polymerase required for all aspects of cellular DNA synthesis. PMID:673840

Treating TTP/HUS with plasma exchange: a single centre's 25-year experience.

PubMed

Forzley, Brian R; Sontrop, Jessica M; Macnab, Jennifer J; Chen, Salina; Clark, William F

2008-10-01

Thrombotic thrombocytopenic purpura/Haemolytic uremic syndrome (TTP/HUS) is a thrombotic microangiopathy with a 6-month mortality rate of 16-29%. The present study described the clinical features, treatment regime and 6-month all-cause mortality rate of TTP/HUS patients at the London Health Sciences Centre (LHSC), Canada. Data for this retrospective cohort study were obtained from inpatient and outpatient records for all patients referred for plasma exchange therapy at LHSC, Canada between 1981 and 2006. Patients (n = 110) were categorized as: idiopathic primary (38%) or relapsed (16%), and secondary responsive (30%) or non-responsive (16%). Mortality data were available for all but three patients. The all-cause 6-month mortality rate was 19% overall and was 12% and 26% among idiopathic and secondary TTP/HUS patients, respectively. No mortality events occurred among the 17 idiopathic patients who relapsed. Relapsed patients had the least severe presenting characteristics, the fastest response time, and experienced significant improvement in the severity of clinical features between the first and final presentation. These findings suggest an excellent outcome for relapsed TTP/HUS patients. Patient education, surveillance, and aggressive plasma exchange therapy are hypothesized to improve the likelihood of survival: these hypotheses should be tested in a randomized controlled trial.

Isothermal Time-Temperature-Precipitation Diagram for an Aluminum Alloy 6005A by In Situ DSC Experiments

PubMed Central

Milkereit, Benjamin; Giersberg, Lydia; Kessler, Olaf; Schick, Christoph

2014-01-01

Time-temperature-precipitation (TTP) diagrams deliver important material data, such as temperature and time ranges critical for precipitation during the quenching step of the age hardening procedure. Although the quenching step is continuous, isothermal TTP diagrams are often applied. Together with a so-called Quench Factor Analysis, they can be used to describe very different cooling paths. Typically, these diagrams are constructed based on mechanical properties or microstructures after an interrupted quenching, i.e., ex situ analyses. In recent years, an in situ calorimetric method to record continuous cooling precipitation diagrams of aluminum alloys has been developed to the application level by our group. This method has now been transferred to isothermal experiments, in which the whole heat treatment cycle was performed in a differential scanning calorimeter. The Al-Mg-Si-wrought alloy 6005A was investigated. Solution annealing at 540 °C and overcritical quenching to several temperatures between 450 °C and 250 °C were followed by isothermal soaking. Based on the heat flow curves during isothermal soaking, TTP diagrams were determined. An appropriate evaluation method has been developed. It was found that three different precipitation reactions in characteristic temperature intervals exist. Some of the low temperature reactions are not accessible in continuous cooling experiments and require isothermal studies. PMID:28788587

Isothermal Time-Temperature-Precipitation Diagram for an Aluminum Alloy 6005A by In Situ DSC Experiments.

PubMed

Milkereit, Benjamin; Giersberg, Lydia; Kessler, Olaf; Schick, Christoph

2014-03-28

Time-temperature-precipitation (TTP) diagrams deliver important material data, such as temperature and time ranges critical for precipitation during the quenching step of the age hardening procedure. Although the quenching step is continuous, isothermal TTP diagrams are often applied. Together with a so-called Quench Factor Analysis, they can be used to describe very different cooling paths. Typically, these diagrams are constructed based on mechanical properties or microstructures after an interrupted quenching, i.e ., ex situ analyses. In recent years, an in situ calorimetric method to record continuous cooling precipitation diagrams of aluminum alloys has been developed to the application level by our group. This method has now been transferred to isothermal experiments, in which the whole heat treatment cycle was performed in a differential scanning calorimeter. The Al-Mg-Si-wrought alloy 6005A was investigated. Solution annealing at 540 °C and overcritical quenching to several temperatures between 450 °C and 250 °C were followed by isothermal soaking. Based on the heat flow curves during isothermal soaking, TTP diagrams were determined. An appropriate evaluation method has been developed. It was found that three different precipitation reactions in characteristic temperature intervals exist. Some of the low temperature reactions are not accessible in continuous cooling experiments and require isothermal studies.

Ultrasound Guided Transversus Thoracic Plane block, Parasternal block and fascial planes hydrodissection for internal mammary post thoracotomy pain syndrome.

PubMed

Piraccini, E; Biondi, G; Byrne, H; Calli, M; Bellantonio, D; Musetti, G; Maitan, S

2018-05-16

Pectoral Nerves Block (PECS) and Serratus Plane Block (SPB) have been used to treat persistent post-surgical pain after breast and thoracic surgery; however, they cannot block the internal mammary region, so a residual pain may occur in that region. Parasternal block (PSB) and Thoracic Transversus Plane Block (TTP) anaesthetize the anterior branches of T2-6 intercostal nerves thus they can provide analgesia to the internal mammary region. We describe a 60-year-old man suffering from right post-thoracotomy pain syndrome with residual pain located in the internal mammary region after a successful treatment with PECS and SPB. We performed a PSB and TTP and hydrodissection of fascial planes with triamcinolone and Ropivacaine. Pain disappeared and the result was maintained 3 months later. This report suggests that PSB and TTP with local anaesthetic and corticosteroid with hydrodissection of fascial planes might be useful to treat a post thoracotomy pain syndrome located in the internal mammary region. The use of Transversus Thoracic Plane and Parasternal Blocks and fascial planes hydrodissection as a novel therapeutic approach to treat a residual post thoracotomy pain syndrome even when already treated with Pectoral Nerves Block and Serratus Plane Block. © 2018 European Pain Federation - EFIC®.

The role of human leukocyte antigen DRB1-DQB1 haplotypes in the susceptibility to acquired idiopathic thrombotic thrombocytopenic purpura.

PubMed

Sinkovits, György; Szilágyi, Ágnes; Farkas, Péter; Inotai, Dóra; Szilvási, Anikó; Tordai, Attila; Rázsó, Katalin; Réti, Marienn; Prohászka, Zoltán

2017-02-01

The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying ADAMTS13-deficiency is caused by inhibitory autoantibodies against the protease. Human leukocyte antigens (HLA), responsible for antigen presentation, play an important role in the development of antibodies. The loci coding HLA DR and DQ molecules are inherited in linkage as haplotypes. The c.1858C>T polymorphism of the PTPN22 gene, which codes a protein tyrosine phosphatase important in lymphocyte activation, predisposes to a number of autoimmune diseases. We determined the HLA-DRB1-DQB1 haplotypes and the PTPN22 c.1858C>T genotypes in 75 patients with acquired idiopathic TTP and in healthy controls, in order to assess the role of these genetic factors and their interactions in the susceptibility to TTP. We found that the carrier frequencies of the DRB1 ∗ 11-DQB1 ∗ 03 and DRB1 ∗ 15-DQB1 ∗ 06 haplotypes were higher, while those of the DRB1 ∗ 07-DQB1 ∗ 02 and DRB1 ∗ 13-DQB1 ∗ 06 haplotypes were lower in TTP patients. There was no difference in the overall frequency of the PTPN22 c.1858T allele between TTP patients and controls. In conclusion, we identified four HLA-DRB1-DQB1 haplotypes associated with an increased (DRB1 ∗ 11-DQB1 ∗ 03 and DRB1 ∗ 15-DQB1 ∗ 06) or a decreased (DRB1 ∗ 07-DQB1 ∗ 02 and DRB1 ∗ 13-DQB1 ∗ 06) susceptibility to acquired idiopathic TTP. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Effect of ADAMTS13 activity turnaround time on plasma utilization for suspected thrombotic thrombocytopenic purpura.

PubMed

Connell, Nathan T; Cheves, Tracey; Sweeney, Joseph D

2016-02-01

Thrombotic thrombocytopenic purpura (TTP) due to deficiency of the von Willebrand-cleaving protease ADAMTS13 is a hematologic emergency that requires prompt initiation of therapeutic plasma exchange (TPE). Long turnaround times (TATs) have precluded the use of pre-TPE measurement of ADAMTS13 activity for the initial diagnosis in most institutions. An in-house rapid TAT (r-TAT) assay for ADAMTS13 activity was implemented after 18 months of validation. In a quasi-experimental design using interrupted time series analysis, patterns of plasma utilization in patients with suspected TTP were assessed after implementation of this assay for ADAMTS13 activity and compared to utilization patterns for patients who received plasma exchange before r-TAT assay implementation designated the standard TAT period. In the 18 months after implementation of the r-TAT ADAMTS13 assay, there was a significant reduction in plasma utilization per patient suspected of having TTP (mean, 144.5 units vs. 63.3 units of plasma per patients suspected of having TTP; p = 0.002). The mean number of exchanges per patient and mean number of exchanges after achieving a platelet count of at least 150 × 10(9) /L were lower in the r-TAT cohort (p < 0.001 for both). There was no significant difference in 30-day mortality. Implementation of a rapid turnaround assay for ADAMTS13 resulted in a significant reduction in plasma utilization for patients with suspected TTP, without an increase in mortality. This study demonstrates that these data, provided in a timely fashion, can avoid unnecessary plasma exchange in patients who do not have TTP. © 2015 AABB.

Corticosteroid-Induced MKP-1 Represses Pro-Inflammatory Cytokine Secretion by Enhancing Activity of Tristetraprolin (TTP) in ASM Cells.

PubMed

Prabhala, Pavan; Bunge, Kristin; Ge, Qi; Ammit, Alaina J

2016-10-01

Exaggerated cytokine secretion drives pathogenesis of a number of chronic inflammatory diseases, including asthma. Anti-inflammatory pharmacotherapies, including corticosteroids, are front-line therapies and although they have proven clinical utility, the molecular mechanisms responsible for their actions are not fully understood. The corticosteroid-inducible gene, mitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1, DUSP1) has emerged as a key molecule responsible for the repressive effects of steroids. MKP-1 is known to deactivate p38 MAPK phosphorylation and can control the expression and activity of the mRNA destabilizing protein-tristetraprolin (TTP). But whether corticosteroid-induced MKP-1 acts via p38 MAPK-mediated modulation of TTP function in a pivotal airway cell type, airway smooth muscle (ASM), was unknown. While pretreatment of ASM cells with the corticosteroid dexamethasone (preventative protocol) is known to reduce ASM synthetic function in vitro, the impact of adding dexamethasone after stimulation (therapeutic protocol) had not been explored. Whether dexamethasone modulates TTP in a p38 MAPK-dependent manner in this cell type was also unknown. We address this herein and utilize an in vitro model of asthmatic inflammation where ASM cells were stimulated with the pro-asthmatic cytokine tumor necrosis factor (TNF) and the impact of adding dexamethasone 1 h after stimulation assessed. IL-6 mRNA expression and protein secretion was significantly repressed by dexamethasone acting in a temporally distinct manner to increase MKP-1, deactivate p38 MAPK, and modulate TTP phosphorylation status. In this way, dexamethasone-induced MKP-1 acts via p38 MAPK to switch on the mRNA destabilizing function of TTP to repress pro-inflammatory cytokine secretion from ASM cells. J. Cell. Physiol. 231: 2153-2158, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Perfluoroalkyl substances and time to pregnancy in couples from Greenland, Poland and Ukraine.

PubMed

Jørgensen, Kristian T; Specht, Ina O; Lenters, Virissa; Bach, Cathrine C; Rylander, Lars; Jönsson, Bo A G; Lindh, Christian H; Giwercman, Aleksander; Heederik, Dick; Toft, Gunnar; Bonde, Jens Peter

2014-12-22

Perfluoroalkyl substances (PFAS) are suggested to affect human fecundity through longer time to pregnancy (TTP). We studied the relationship between four abundant PFAS and TTP in pregnant women from Greenland, Poland and Ukraine representing varying PFAS exposures and pregnancy planning behaviors. We measured serum levels of perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexane sulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) in 938 women from Greenland (448 women), Poland (203 women) and Ukraine (287 women). PFAS exposure was assessed on a continuous logarithm transformed scale and in country-specific tertiles. We used Cox discrete-time models and logistic regression to estimate fecundability ratios (FRs) and infertility (TTP >13 months) odds ratios (ORs), respectively, and 95% confidence intervals (CI) according to PFAS levels. Adjusted analyses of the association between PFAS and TTP were done for each study population and in a pooled sample. Higher PFNA levels were associated with longer TTP in the pooled sample (log-scale FR = 0.80; 95% CI 0.69-0.94) and specifically in women from Greenland (log-scale FR = 0.72; 95% CI 0.58-0.89). ORs for infertility were also increased in the pooled sample (log-scale OR = 1.53; 95% CI 1.08-2.15) and in women from Greenland (log-scale OR = 1.97; 95% CI 1.22-3.19). However, in a sensitivity analysis of primiparous women these associations could not be replicated. Associations with PFNA were weaker for women from Poland and Ukraine. PFOS, PFOA and PFHxS were not consistently associated with TTP. Findings do not provide consistent evidence that environmental exposure to PFAS is impairing female fecundity by delaying time taken to conceive.

Time-Temperature-Precipitation Behavior in Al-Li Alloy 2195

NASA Technical Reports Server (NTRS)

Chen, P. S.; Bhat, B. N.

2002-01-01

Transmission electron microscopy was used to study time-temperature-precipitation (TTP) behavior in aluminum-lithium (Al-Li) 2195 alloy. Al-Li 2195 (nominally Al + 4 percent Cu + 1 percent Li + 0.3 percent Ag + 0.3 percent Mg + 0.1 percent Zr) was initially solutionized for 1 hr at 950 F and then stretched 3 percent. Heat treatments were conducted for up to 100 hr at temperatures ranging from 200 to 1,000 F. TTP diagrams were determined for both matrix and subgrain boundaries. Depending upon heat treatment conditions, precipitate phases (such as GP zone, theta'', theta', theta, delta', T1, TB, and T2) were found in the alloy. The TTP diagrams were applied as a guide to avoid T1 precipitation at subgrain boundaries, as part of an effort to improve the alloy's cryogenic fracture toughness (CFT). New understanding of TTP behavior was instrumental in the development of a two-step artificial aging treatment that significantly enhanced CFT in Al-Li 2195.

Value of blood culture time to positivity in identifying complicated nontyphoidal Salmonella bacteremia.

PubMed

Chen, Shang-Yu; Weng, Tzu-Hua; Tseng, Wen-Pin; Fu, Chia-Ming; Lin, Hui-Wen; Liao, Chun-Hsing; Lee, Tai-Fen; Hsueh, Po-Ren; Fang, Cheng-Chung; Chen, Shey-Ying

2018-02-13

Few studies analyzed the association between blood culture time to positivity (TTP) and risk of complicated nontyphoidal Salmonella (NTS) bacteremia. We conducted a retrospective study of 206 patients (aged 60.4 ± 17.4 years) with NTS bacteremia during a 30-month period. Complicated NTS bacteremia was defined as the presence of 30-day mortality, complicated infection requiring surgery or abscess drainage, or requirement of intensive care unit admission. Serogroup D (75.7%) was the predominant isolates. Malignancy (44.7%) was the most prevalent comorbidity. Patients with rapid TTP (<10 h) were more likely to have thrombocytopenia, septic shock, persistent bacteremia, complicated infection, and a higher intensive care unit admission rate. In multivariate logistic regression model, a TTP <10 h was an independent predictor for complicated NTS bacteremia (adjusted odd ratio, 5.683, 95% confidence interval, 2.396-13.482). Our study showed that blood culture TTP provides important diagnostic and prognostic information in the treatment of NTS bacteremia patients. Copyright © 2018. Published by Elsevier Inc.

Clinical use of a rapid collagen binding assay for von Willebrand factor cleaving protease in patients with thrombotic thrombocytopenic purpura.

PubMed

Rick, Margaret E; Moll, Stephan; Taylor, Mark A; Krizek, Dennis M; White, Gilbert C; Aronson, David L

2002-10-01

A simple collagen binding assay (CBA) for measuring activity of the von Willebrand factor cleaving protease in clinical samples is described, and results of fifty masked plasmapheresis samples rom patients with TTP/HUS and other diseases are presented. There was 97.5% concordance between the CBA and a multimer gel assay. The CBA identified low protease activity in 78% of patients who had a clinical syndrome consistent with TTP/HUS and in 2 of 10 sick controls, giving it a positive predictive value of 0.94. The heterogeneity regarding the presence or absence of vWF protease activity in patients with TTP/HUS was confirmed by finding a low negative predictive value of 0.50 with the CBA. The CBA detected inhibitors of the protease in 26 of 29 patients (90%) with TTP/HUS and low protease activity levels. The CBA is a useful clinical assay for examining von Willebrand factor protease activity and detecting inhibitors against the protease.

Caplacizumab reduces the frequency of major thromboembolic events, exacerbations and death in patients with acquired thrombotic thrombocytopenic purpura.

PubMed

Peyvandi, F; Scully, M; Kremer Hovinga, J A; Knöbl, P; Cataland, S; De Beuf, K; Callewaert, F; De Winter, H; Zeldin, R K

2017-07-01

Essentials Acquired thrombotic thrombocytopenic purpura (aTTP) is linked with significant morbidity/mortality. Caplacizumab's effect on major thromboembolic (TE) events, exacerbations and death was studied. Fewer caplacizumab-treated patients had a major TE event, an exacerbation, or died versus placebo. Caplacizumab has the potential to reduce the acute morbidity and mortality associated with aTTP. Background Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations, and death. In the phase II TITAN study, treatment with caplacizumab, an anti-von Willebrand factor Nanobody ® was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment. Objective The clinical benefit of caplacizumab was further investigated in a post hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and thrombotic thrombocytopenic purpura-related death during the study. Methods The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) for 'embolic and thrombotic events' was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients, of whom 35 received caplacizumab and 37 received placebo. Results Four events (one pulmonary embolism and three aTTP exacerbations) were reported in four patients in the caplacizumab group, and 20 such events were reported in 14 patients in the placebo group (two acute myocardial infarctions, one ischemic stroke, one hemorrhagic stroke, one pulmonary embolism, one deep vein thrombosis, one venous thrombosis, and 13 aTTP exacerbations). Two of the placebo-treated patients died from aTTP during the study. Conclusion In total, 11.4% of caplacizumab-treated patients and 43.2% of placebo-treated patients experienced one or more major thromboembolic events, experienced an exacerbation, or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP. © 2017 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Systemic lupus erythematosus and thrombotic thrombocytopenia purpura: a refractory case without lupus activity.

PubMed

Garcia Boyero, Raimundo; Mas Esteve, Eva; Mas Esteve, Maria; Millá Perseguer, M Magdalena; Marco Buades, Josefa; Beltran Fabregat, Juan; Cañigral Ferrando, Guillermo; Belmonte Serrano, Miguel Angel

2013-01-01

The association between systemic lupus erythematosus (SLE) and thrombotic thrombocytopenic purpura (TTP) has been infrequently reported. Usually, patients with TTP have more SLE activity and frequent renal involvement. Here we present a case of TTP associated to low-activity SLE. The absence of renal and major organ involvement increased the difficulty in making the initial diagnosis. ADAMTS13 activity in plasma in this patient was very low, as seen in other similar cases. The evolution of the patient was poor, needing plasma exchanges and immunosuppressive therapy, including the use of rituximab. Copyright © 2012 Elsevier España, S.L. All rights reserved.

Cobalt porphyrin-based material as methanol tolerant cathode in single chamber microbial fuel cells (SCMFCs)

NASA Astrophysics Data System (ADS)

Liu, Bingchuan; Brückner, Cristian; Lei, Yu; Cheng, Yue; Santoro, Carlo; Li, Baikun

2014-07-01

This study focused on the development of novel cathode material based on the pyrolysis of [meso-tetrakis(2-thienyl)porphyrinato]Co(II) (CoTTP) for use in single chamber microbial fuel cells (SCMFCs) to treat wastewater containing methanol. The cathodes produced at two loadings (0.5 and 1.0 mg cm-2) were examined in batch mode SCMFCs treating methanol of different concentrations (ranging from 0.005 to 0.04 M) over a 900 h operational period. Methanol was completely removed in SCMFCs, and the cycle duration was prolonged at high methanol concentrations, indicating methanol was used as fuel in SCMFCs. Methanol had more poisoning effects to the traditional platinum (Pt) cathodes than to the CoTTP cathodes. Specifically, power generations from SCMFCs with Pt cathodes gradually decreased over time, while the ones with CoTTP cathodes remained stable, even at the highest methanol concentration (0.04 M). Cathode linear sweep voltammetry (LSVs) indicated that the electrocatalytic activity of the Pt cathode was suppressed by methanol. Higher CoTTP loadings had similar open circuit potential (OCP) but higher electrocatalytic activity than lower loadings. This study demonstrated that methanol can be co-digested with wastewater and converted to power in MFCs, and a novel cathode CoTTP catalyst exhibits higher tolerance towards methanol compared with traditional Pt catalyst.

Consensus on the standardization of terminology in thrombotic thrombocytopenic purpura and related thrombotic microangiopathies.

PubMed

Scully, M; Cataland, S; Coppo, P; de la Rubia, J; Friedman, K D; Kremer Hovinga, J; Lämmle, B; Matsumoto, M; Pavenski, K; Sadler, E; Sarode, R; Wu, H

2017-02-01

Essentials An international collaboration provides a consensus for clinical definitions. This concerns thrombotic microangiopathies and thrombotic thrombocytopenic purpura (TTP). The consensus defines diagnosis, disease monitoring and response to treatment. Requirements for ADAMTS-13 are given. Background Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) are two important acute conditions to diagnose. Thrombotic microangiopathy (TMA) is a broad pathophysiologic process that leads to microangiopathic hemolytic anemia and thrombocytopenia, and involves capillary and small-vessel platelet aggregates. The most common cause is disseminated intravascular coagulation, which may be differentiated by abnormal coagulation. Clinically, a number of conditions present with microangiopathic hemolytic anemia and thrombocytopenia, including cancer, infection, transplantation, drug use, autoimmune disease, and pre-eclampsia and hemolysis, elevated liver enzymes and low platelet count syndrome in pregnancy. Despite overlapping clinical presentations, TTP and HUS have distinct pathophysiologies and treatment pathways. Objectives To present a consensus document from an International Working Group on TTP and associated thrombotic microangiopathies (TMAs). Methods The International Working Group has proposed definitions and terminology based on published information and consensus-based recommendations. Conclusion The consensus aims to aid clinical decisions, but also future studies and trials, utilizing standardized definitions. It presents a classification of the causes of TMA, and criteria for clinical response, remission and relapse of congenital and immune-mediated TTP. © 2016 International Society on Thrombosis and Haemostasis.

Anticipating the effects of visual gravity during simulated self-motion: estimates of time-to-passage along vertical and horizontal paths.

PubMed

Indovina, Iole; Maffei, Vincenzo; Lacquaniti, Francesco

2013-09-01

By simulating self-motion on a virtual rollercoaster, we investigated whether acceleration cued by the optic flow affected the estimate of time-to-passage (TTP) to a target. In particular, we studied the role of a visual acceleration (1 g = 9.8 m/s(2)) simulating the effects of gravity in the scene, by manipulating motion law (accelerated or decelerated at 1 g, constant speed) and motion orientation (vertical, horizontal). Thus, 1-g-accelerated motion in the downward direction or decelerated motion in the upward direction was congruent with the effects of visual gravity. We found that acceleration (positive or negative) is taken into account but is overestimated in module in the calculation of TTP, independently of orientation. In addition, participants signaled TTP earlier when the rollercoaster accelerated downward at 1 g (as during free fall), with respect to when the same acceleration occurred along the horizontal orientation. This time shift indicates an influence of the orientation relative to visual gravity on response timing that could be attributed to the anticipation of the effects of visual gravity on self-motion along the vertical, but not the horizontal orientation. Finally, precision in TTP estimates was higher during vertical fall than when traveling at constant speed along the vertical orientation, consistent with a higher noise in TTP estimates when the motion violates gravity constraints.

Hemodynamic response function in patients with stroke-induced aphasia: Implications for fMRI data analysis

PubMed Central

Bonakdarpour, B.; Parrish, T.B.; Thompson, C.K.

2007-01-01

Functional MRI is based on changes in cerebral microvasculature triggered by increased neuronal oxidative metabolism. This change in blood flow follows a pattern known as the hemodynamic response function (HRF), which typically peaks 4–6 s following stimulus delivery. However, in the presence of cerebrovascular disease the HRF may not follow this normal pattern, due to either the temporal signal to noise (tSNR) ratio or delays in the HRF, which may result in misinterpretation or underestimation of fMRI signal. The present study examined the HRF and SNR in five individuals with aphasia resulting from stroke and four unimpaired participants using a lexical decision task and a long trial event-related design. T1-weighted images were acquired using an MP-RAGE sequence and BOLD T2*-weighted images were acquired using Echo Planar Imaging to measure time to peak (TTP) in the HRF. Data were analyzed using Brain Voyager in four anatomic regions known to be involved in language processing: Broca’s area and the posterior perisylvian network (PPN) (including Wernicke’s area, the angular and supramarginal gyri) and right hemisphere homologues of these regions. The occipital area also was examined as a control region. Analyses showed that the TTP in three out of five patients in the left perisylvian area was increased significantly as compared to normal individuals and the left primary visual cortex in the same patients. In two other patients no significant delays were detected. We also found that the SNR for BOLD signal detection may by insufficient in damaged areas. These findings indicate that obtaining physiologic (TTP) and quality assurance (tSNR) information is essential for studying activation patterns in brain-damaged patients in order to avoid errors in interpretation of the data. An example of one such misinterpretation and the need for alternative data analysis strategies is discussed. PMID:17467297

Hemodynamic response function in patients with stroke-induced aphasia: implications for fMRI data analysis.

PubMed

Bonakdarpour, B; Parrish, T B; Thompson, C K

2007-06-01

Functional MRI is based on changes in cerebral microvasculature triggered by increased neuronal oxidative metabolism. This change in blood flow follows a pattern known as the hemodynamic response function (HRF), which typically peaks 4-6 s following stimulus delivery. However, in the presence of cerebrovascular disease the HRF may not follow this normal pattern, due to either the temporal signal to noise (tSNR) ratio or delays in the HRF, which may result in misinterpretation or underestimation of fMRI signal. The present study examined the HRF and SNR in five individuals with aphasia resulting from stroke and four unimpaired participants using a lexical decision task and a long trial event-related design. T1-weighted images were acquired using an MP-RAGE sequence and BOLD T2*-weighted images were acquired using Echo Planar Imaging to measure time to peak (TTP) in the HRF. Data were analyzed using Brain Voyager in four anatomic regions known to be involved in language processing: Broca's area and the posterior perisylvian network (PPN) (including Wernicke's area, the angular and supramarginal gyri) and right hemisphere homologues of these regions. The occipital area also was examined as a control region. Analyses showed that the TTP in three out of five patients in the left perisylvian area was increased significantly as compared to normal individuals and the left primary visual cortex in the same patients. In two other patients no significant delays were detected. We also found that the SNR for BOLD signal detection may by insufficient in damaged areas. These findings indicate that obtaining physiologic (TTP) and quality assurance (tSNR) information is essential for studying activation patterns in brain-damaged patients in order to avoid errors in interpretation of the data. An example of one such misinterpretation and the need for alternative data analysis strategies is discussed.

Pressure effect on the electrical conductivity and superconductivity of beta-(BDA-TTP)2I3.

PubMed

Yamada, Jun-Ichi; Fujimoto, Kazuya; Akutsu, Hiroki; Nakatsuji, Shin'ichi; Miyazaki, Akira; Aimatsu, Masashi; Kudo, Satoshi; Enoki, Toshiaki; Kikuchi, Koichi

2006-03-28

The pressure-induced electrical conductivity properties of beta-(BDA-TTP)2I3 have been investigated; the salt exhibits a dramatic change in the conductivity behaviour above ca. 10 kbar and undergoes a superconducting transition with an onset near 10 K.

A novel glucose oxidase biosensor based on poly([2,2';5',2″]-terthiophene-3'-carbaldehyde) modified electrode.

PubMed

Guler, Muhammet; Turkoglu, Vedat; Kivrak, Arif

2015-08-01

In the study, the electrochemical behavior of glucose oxidase (GOx) immobilized on poly([2,2';5',2″]-terthiophene-3'-carbaldehyde) (poly(TTP)) modified glassy carbon electrode (GCE) was investigated. The biosensor (poly(TTP)/GOx/GCE) showed a pair of redox peaks in 0.1 M phosphate buffer (pH 7.4) solution in the absence of oxygen the co-substrate of GOx. In here, Poly(TTP)/GOx/GCE biosensor acts as the co-substrate instead of oxygen. Upon the addition of glucose, the reduction and oxidation peak currents increased until the active site of GOx was fully saturated with glucose. The apparent m was estimated 26.13 mM from Lineweaver-Burk graph. The biosensor displayed a good stability and bioactivity. The biosensor showed a high sensitivity (56.1 nA/mM), a linear range (from 0.5 to 20.15 mM), and a good reproducibility with 3.6% of relative standard deviation. In addition, the interference currents of glycin, ascorbic acid, histidine, uric acid, dopamine, arginine, and fructose on GOx biosensor were investigated. All that substances exhibited an interference current under 10%. It was not shown a marked difference between GOx biosensor and spectrophotometric measurement of glucose in serum examples. UV-visible spectroscopy and scanning electron microscopy (SEM) experiments of the biosensor were also performed. Copyright © 2015 Elsevier B.V. All rights reserved.

Overview of the Telescience Testbed Program

NASA Technical Reports Server (NTRS)

Rasmussen, Daryl N.; Mian, Arshad; Leiner, Barry M.

1991-01-01

The NASA's Telescience Testbed Program (TTP) conducted by the Ames Research Center is described with particular attention to the objectives, the approach used to achieve these objectives, and the expected benefits of the program. The goal of the TTP is to gain operational experience for the Space Station Freedom and the Earth Observing System programs, using ground testbeds, and to define the information and communication systems requirements for the development and operation of these programs. The results of TTP are expected to include the requirements for the remote coaching, command and control, monitoring and maintenance, payload design, and operations management. In addition, requirements for technologies such as workstations, software, video, automation, data management, and networking will be defined.

A Case of Systemic Lupus Erythematosus developing Two years after Remission of Thrombotic Thrombocytopenic Purpura

PubMed Central

Myung, Seung-Jae; Yoo, Bin; Lee, Kyoo-Hyung; Yoo, Mi-Ran; Choi, Seung-Won; Yoo, Eun-Sil; Chi, Hyun-Sook; Moon, Hee-Bom

1996-01-01

We describe a 17-year-old male who presented with thrombotic thrombocytopenic purpura (TTP) and 2 years thereafter developed central nervous system lupus and nephritis. The association of TTP and systemic lupus erythematosus has been described, but the unusual sequence and chronological separation is very rare. PMID:8854658

Paternal work stress and prolonged time to pregnancy.

PubMed

Lee, Mi-Sun; Paek, Domyung; Eum, Ki-Do; Siegrist, Johannes; Li, Jian; Lee, Hye-Eun; Cho, Sung-Il

2009-01-01

The aim of this study was to explore an association between psychosocial stress at work in married men and their spouses' prolonged time to pregnancy (TTP). All married male workers of a large Korean petrochemical enterprise and their wives fulfilling the selection criteria were included. Main selection criteria were lack of use of contraceptives and experienced pregnancy in recent past. Data were available from 322 couples. Psychosocial stress at work was measured by the effort-reward imbalance questionnaire. Prolonged TTP was measured by the "TTP questionnaire". After adjustment for confounding effects of demographic and life-style characteristics and benzene exposure, delayed TTP, defined by frequency of first-cycle pregnancy, was associated with one standard deviation (SD) increase of the effort-reward ratio in the chronically stressed group of married men (OR = 0.47; 95% CI = 0.22-0.99) in logistic regression analysis. A similar, but somewhat weaker effect, was found for the overall group (OR = 0.67; 95% CI = 0.47-0.94). Paternal stress at work, as measured by effort-reward imbalance, seemed to be associated with a decreased number of conceptions in the first menstrual cycle.

Severe Vitamin E deficiency modulates airway allergic inflammatory responses in the murine asthma model

PubMed Central

LIM, YUNSOOK; VASU, VIHAS T.; VALACCHI, GIUSEPPE; LEONARD, SCOTT; AUNG, HNIN HNIN; SCHOCK, BETTINA C.; KENYON, NICHOLAS J.; LI, CHIN-SHANG; TRABER, MARET G.; CROSS, CARROLL E.

2009-01-01

Allergic asthma is a complex immunologically mediated disease associated with increased oxidative stress and altered antioxidant defenses. It was hypothesized that α-tocopherol (α-T) decreases oxidative stress and therefore its absence may influence allergic inflammatory process, a pathobiology known to be accompanied by oxidative stress. Therefore, selected parameters of allergic asthma sensitization and inflammation were evaluated following ovalbumin sensitization and re-challenge of α-T transfer protein (TTP) knock-out mice (TTP–/–) that have greatly reduced lung α-T levels (e.g. < 5%) compared to their litter mate controls (TTP+/+). Results showed that severe α-T deficiency result in a blunted lung expression of IL-5 mRNA and IL-5 protein and plasma IgE levels compared with TTP+/+ mice following immune sensitization and rechallenge, although lung lavage eosinophil levels were comparable in both genomic strains. It is concluded that the initial stimulation of immune responses by the TTP–/– mice were generally blunted compared to the TTP+/+ mice, thus diminishing some aspects of subsequent allergic inflammatory processes. PMID:18404538

Single-molecule fluorescence reveals the unwinding stepping mechanism of replicative helicase.

PubMed

Syed, Salman; Pandey, Manjula; Patel, Smita S; Ha, Taekjip

2014-03-27

Bacteriophage T7 gp4 serves as a model protein for replicative helicases that couples deoxythymidine triphosphate (dTTP) hydrolysis to directional movement and DNA strand separation. We employed single-molecule fluorescence resonance energy transfer methods to resolve steps during DNA unwinding by T7 helicase. We confirm that the unwinding rate of T7 helicase decreases with increasing base pair stability. For duplexes containing >35% guanine-cytosine (GC) base pairs, we observed stochastic pauses every 2-3 bp during unwinding. The dwells on each pause were distributed nonexponentially, consistent with two or three rounds of dTTP hydrolysis before each unwinding step. Moreover, we observed backward movements of the enzyme on GC-rich DNAs at low dTTP concentrations. Our data suggest a coupling ratio of 1:1 between base pairs unwound and dTTP hydrolysis, and they further support the concept that nucleic acid motors can have a hierarchy of different-sized steps or can accumulate elastic energy before transitioning to a subsequent phase. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

New organic superconductors beta-(BDA-TTP)2X [BDA-TTP + 2,5-bis(1,3-dithian-2ylidene)-1,3,4,6-tetrathiapentalene; X(-) = SbF6(-), AsF6(-), and PF6(-)].

PubMed

Yamada, J; Watanabe, M; Akutsu, H; Nakatsuji, S; Nishikawa, H; Ikemoto, I; Kikuchi, K

2001-05-09

The synthesis, electrochemical properties, and molecular structure of a new pi-electron donor, 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene (BDA-TTP), is described. In contrast to the hitherto-known tetrachalcogenafulvalene pi-donors providing organic superconductors, this donor contains only the bis-fused 1,3-dithiole-2-ylidene unit as a pi-electron system, yet produces a series of ambient-pressure superconductors beta-(BDA-TTP)2X [X = SbF6 (magnetic T(c) = 6.9 K, resistive T(c) = 7.5 K), AsF6 (magnetic T(c) = 5.9 K, resistive T(c) = 5.8 K), and PF6 (magnetic T(c) = 5.9 K)], which are isostructural. The values of the intermolecular overlap integrals calculated on the donor layers of these superconductors suggest a two-dimensional (2D) electronic structure with loose donor packing. Tight-binding band calculations also indicate that these superconductors have the 2D band dispersion relations and closed Fermi surfaces.

Differentiation of pernicious anemia from thrombotic thrombocytopenic purpura: The clinical value of subtle pathologic findings.

PubMed

Abbott, Daniel W; Friedman, Kenneth D; Karafin, Matthew S

2016-12-01

Thrombotic thrombocytopenic purpura (TTP) is a microangiopathic hemolytic anemia that requires emergent treatment with plasma exchange and is one of the most important conditions for which apheresis service professionals are consulted. Careful interpretation of initial laboratory values and the peripheral blood smear is a critical first step to determining the need for plasma exchange because other conditions can show deceptively similar red cell morphology, and ADAMTS13 levels are often not rapidly available. We report a case of a patient who was initially diagnosed with TTP and treated with plasma exchange based on preliminary laboratory data and a peripheral blood smear that contained bizarre microcytic red blood cells presumed to be schistocytes. The peripheral blood smear was later interpreted by the hematopathologist to be inconsistent with TTP, and further workup led to a diagnosis of severe vitamin B12 deficiency secondary to pernicious anemia. This case highlights the diagnostic complexity of thrombotic microangiopathies and the importance of a critical evaluation of the blood smear and presenting laboratory data when there is a concern for TTP. Copyright © 2016 Elsevier Ltd. All rights reserved.

The impact of a chest tube management protocol on the outcome of trauma patients with tube thoracostomy.

PubMed

de Abreu, Emanuelle Maria Sávio; Machado, Carla Jorge; Pastore Neto, Mario; de Rezende Neto, João Baptista; Sanches, Marcelo Dias

2015-01-01

to investigate the effect of standardized interventions in the management of tube thoracostomy patients and to assess the independent effect of each intervention. A chest tube management protocol was assessed in a retrospective cohort study. The tube thoracostomy protocol (TTP) was implemented in August 2012, and consisted of: antimicrobial prophylaxis, chest tube insertion in the operating room (OR), admission post chest tube thoracostomy (CTT) in a hospital floor separate from the emergency department (ED), and daily respiratory therapy (RT) sessions post-CTT. The inclusion criteria were, hemodynamic stability, patients between the ages of 15 and 59 years, and injury severity score (ISS) < 17. All patients had isolated injuries to the chest wall, lung, and pleura. During the study period 92 patients were managed according to the standardized protocol. The outcomes of those patients were compared to 99 patients treated before the TTP. Multivariate logistic regression analysis was performed to assess the independent effect of each variable of the protocol on selected outcomes. Demographics, injury severity, and trauma mechanisms were similar among the groups. As expected, protocol compliance increased after the implementation of the TTP. There was a significant reduction (p<0.05) in the incidence of retained hemothoraces, empyemas, pneumonias, surgical site infections, post-procedural complications, hospital length of stay, and number of chest tube days. Respiratory therapy was independently linked to significant reduction (p<0.05) in the incidence of seven out of eight undesired outcomes after CTT. Antimicrobial prophylaxis was linked to a significant decrease (p<0.05) in retained hemothoraces, despite no significant (p<0.10) reductions in empyema and surgical site infections. Conversely, OR chest tube insertion was associated with significant (p<0.05) reduction of both complications, and also significantly decreased the incidence of pneumonias. Implementation of a TTP effectively reduced complications after CTT in trauma patients.

Efficacy and Factors Affecting Outcome of Gemcitabine Concurrent Chemoradiotherapy in Patients With Locally Advanced Pancreatic Cancer

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

Huang, P.-I.; National Yang-Ming University School of Medicine, Taipei, Taiwan; Chao, Yee

Purpose: To evaluate the efficacy and prognostic factors of gemcitabine (GEM) concurrent chemoradiotherapy (CCRT) in patients with locally advanced pancreatic cancer. Methods and Materials: Between January 2002 and December 2005, 55 patients with locally advanced pancreatic cancer treated with GEM (400 mg/m{sup 2}/wk) concurrently with radiotherapy (median dose, 50.4 Gy; range, 26-61.2) at Taipei Veterans General Hospital were enrolled. GEM (1,000 mg/m{sup 2}) was continued after CCRT as maintenance therapy once weekly for 3 weeks and repeated every 4 weeks. The response, survival, toxicity, and prognostic factors were evaluated. Results: With a median follow-up of 10.8 months, the 1- andmore » 2-year survival rate was 52% and 19%, respectively. The median overall survival (OS) and median time to progression (TTP) was 12.4 and 5.9 months, respectively. The response rate was 42% (2 complete responses and 21 partial responses). The major Grade 3-4 toxicities were neutropenia (22%) and anorexia (19%). The median OS and TTP was 15.8 and 9.5 months in the GEM CCRT responders compared with 7.5 and 3.5 months in the nonresponders, respectively (both p < 0.001). The responders had a better Karnofsky performance status (KPS) (86 {+-} 2 vs. 77 {+-} 2, p = 0.002) and had received a greater GEM dose intensity (347 {+-} 13 mg/m{sup 2}/wk vs. 296 {+-} 15 mg/m{sup 2}/wk, p = 0.02) than the nonresponders. KPS and serum carbohydrate antigen 19-9 were the most significant prognostic factors of OS and TTP. Conclusion: The results of our study have shown that GEM CCRT is effective and tolerable for patients with locally advanced pancreatic cancer. The KPS and GEM dose correlated with response. Also, the KPS and CA 19-9 level were the most important factors affecting OS and TTP.« less

[Thrombotic thrombocytopenia purpura in Martinique: Retrospective study between 2008 and 2015].

PubMed

Patient, M; Fuseau, P; Deligny, C

2017-08-01

Some studies suggest that thrombotic thrombocytopenic purpura (TTP) occurs more often in African Americans. However there is low evidence for this in the literature. The aim of our study was to describe the clinical and biological characteristics of TTP in the Afro-Caribbean population of Martinique. We retrospectively analysed all patients with TTP diagnosed at the Fort-de-France hospital between 2008, January 1st and 2015, December 31st. Diagnosis was confirmed if ADAMTS-13 activity was<10 %. Ten patients were included, corresponding to an average annual incidence of 3.2 cases/year/million individuals. None of the patient presented with the association of the five characteristic features of TTP. Microangiopathic haemolytic anaemia and severe peripheral thrombocytopenia (median: 13G/L) was the main presentation leading to diagnosis. There was no kidney involvement in 90 % of all patients, but severe neurological manifestations occurred in 70 %. Classical management including corticosteroids and plasma exchanges allowed clinical remission in 6 out of the 10 cases. If necessary, rituximab or cyclophosphamide was used. The overall survival rate was 90 %. In Martinique, the incidence of TTP is twice that reported in similar studies in France. Clinical manifestations seem to differ by more common and more severe neurological involvement. Mortality is low, in part, due to optimal care. Copyright © 2017 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Ultrasonic contrast agents in transcranial perfusion sonography (TPS) for follow-up of patients with high grade gliomas.

PubMed

Ickenstein, G W; Valaikiene, J; Koch, H; Hau, P; Erban, P; Schlachetzki, F

2008-04-01

The aim of this study was to evaluate brain perfusion differences in patients with high grade gliomas after partial tumor resection and irradiation/chemotherapy between tumor and non-tumor hemisphere by transcranial perfusion sonography (TPS) employing a contrast burst imaging (CBI) technique. Six patients with glioblastoma (WHO Grade IV) in the temporoparietal region within the defined axial diencephalic scanning plane were examined by TPS during follow-up. All subjects had an adequate acoustic temporal bone window. Transtemporal insonation on brain tumor and non-tumor hemisphere was performed with a bolus-injection of sulphur hexafluoride-based contrast agent (10 mg i.v., 5mg/ml--SonoVue, Bracco, Altana, Switzerland). Recorded images were analysed off-line by Quanticon Software (3D-Echotech, Munich, Germany) and time intensity curve parameters [area under the curve (AUC, dB s), peak intensity (PI, dB), time to peak (TTP, s)] in five regions of interest (ROI) [thalamus anterior, thalamus posterior, nucleus lentiformis, white matter, whole hemisphere] were evaluated. Statistical analyses were performed. Perfusion differences between brain tumor and non-tumor hemispheres were detected with contrast burst imaging (CBI) technique with a significantly greater mean AUC (5343.69 dB s vs. 4625.04 dB s, p<0.028) and a significantly prolonged TTP (32.72 s vs. 28.91 s, p<0.046) in the tumor hemisphere. Within our study population, TTP and AUC seem to be the most robust parameters for the evaluation of cerebral perfusion differences assessed by transcranial perfusion sonography with CBI technique. We hypothesize that these results correlate with microvascular changes due to treatment regimens, such as microvessel necrosis after irradiation and chemotherapy. Above that, TPS may be of value for the long-term follow-up of brain tumor therapy concept.

The value of surrogate endpoints for predicting real-world survival across five cancer types.

PubMed

Shafrin, Jason; Brookmeyer, Ron; Peneva, Desi; Park, Jinhee; Zhang, Jie; Figlin, Robert A; Lakdawalla, Darius N

2016-01-01

It is unclear how well different outcome measures in randomized controlled trials (RCTs) perform in predicting real-world cancer survival. We assess the ability of RCT overall survival (OS) and surrogate endpoints - progression-free survival (PFS) and time to progression (TTP) - to predict real-world OS across five cancers. We identified 20 treatments and 31 indications for breast, colorectal, lung, ovarian, and pancreatic cancer that had a phase III RCT reporting median OS and median PFS or TTP. Median real-world OS was determined using a Kaplan-Meier estimator applied to patients in the Surveillance and Epidemiology End Results (SEER)-Medicare database (1991-2010). Performance of RCT OS and PFS/TTP in predicting real-world OS was measured using t-tests, median absolute prediction error, and R(2) from linear regressions. Among 72,600 SEER-Medicare patients similar to RCT participants, median survival was 5.9 months for trial surrogates, 14.1 months for trial OS, and 13.4 months for real-world OS. For this sample, regression models using clinical trial OS and trial surrogates as independent variables predicted real-world OS significantly better than models using surrogates alone (P = 0.026). Among all real-world patients using sample treatments (N = 309,182), however, adding trial OS did not improve predictive power over predictions based on surrogates alone (P = 0.194). Results were qualitatively similar using median absolute prediction error and R(2) metrics. Among the five tumor types investigated, trial OS and surrogates were each independently valuable in predicting real-world OS outcomes for patients similar to trial participants. In broader real-world populations, however, trial OS added little incremental value over surrogates alone.

3′UTR AU-rich elements (AREs) and the RNA-binding protein Tristetraprolin (TTP) are not required for the LPS-mediated destabilization of phospholipase-Cβ-2 mRNA in murine macrophages

PubMed Central

Shukla, Smita; Elson, Genie; Blackshear, Perry J.; Lutz, Carol S.; Leibovich, S. Joseph

2017-01-01

We have shown previously that bacterial lipopolysaccharide (LPS)-mediated suppression of Phospholipase-Cβ-2 (PLCβ-2) expression is involved in M1 (inflammatory) to M2-like (wound healing) phenotypic switching of macrophages triggered by adenosine. This suppression is mediated post-transcriptionally by destabilization of PLCβ-2 mRNA. To investigate the mechanism of this LPS-mediated destabilization, we examined the roles of RNA-binding agents including microRNAs and RNA-binding proteins that are involved in regulating stability of mRNAs encoding growth factors, inflammatory mediators and proto-oncogenes. Adenylate and Uridylate (AU)-rich elements (AREs) in 3′UTRs are specific recognition sites for RNA-binding proteins including Tristetraprolin (TTP), HuR and AUF1, and for microRNAs that are involved in regulating mRNA stability. In this study, we investigated the role of TTP and AREs in regulating PLCβ-2 mRNA stability. The 3′UTR of the PLCβ-2 gene was inserted into the pLightswitch luciferase reporter plasmid and transfected into RAW264.7 cells. LPS suppressed Luciferase expression from this reporter. Luciferase expression from mutant 3′UTR constructs lacking AREs was similarly down-regulated, suggesting that these regions are not required for LPS-mediated suppression of PLCβ-2. TTP was rapidly upregulated in both primary murine macrophages and RAW264.7 cells in response to LPS. Suppression of PLCβ-2 by LPS was examined using macrophages from mice lacking TTP. LPS suppressed PLCβ-2 expression to the same extent in wild type and TTP−/− macrophages. Also, the rate of decay of PLCβ-2 mRNA in LPS-treated macrophages following transcriptional blockade was similar in wild type and TTP−/− macrophages, clearly indicating that TTP is not involved in LPS-mediated destabilization of PLCβ-2 mRNA in macrophages. PMID:28124257

Error-prone bypass of O6-methylguanine by DNA polymerase of Pseudomonas aeruginosa phage PaP1.

PubMed

Gu, Shiling; Xiong, Jingyuan; Shi, Ying; You, Jia; Zou, Zhenyu; Liu, Xiaoying; Zhang, Huidong

2017-09-01

O 6 -Methylguanine (O 6 -MeG) is highly mutagenic and is commonly found in DNA exposed to methylating agents, generally leads to G:C to A:T mutagenesis. To study DNA replication encountering O 6 -MeG by the DNA polymerase (gp90) of P. aeruginosa phage PaP1, we analyzed steady-state and pre-steady-state kinetics of nucleotide incorporation opposite O 6 -MeG by gp90 exo - . O 6 -MeG partially inhibited full-length extension by gp90 exo - . O 6 -MeG greatly reduces dNTP incorporation efficiency, resulting in 67-fold preferential error-prone incorporation of dTTP than dCTP. Gp90 exo - extends beyond T:O 6 -MeG 2-fold more efficiently than C:O 6 -MeG. Incorporation of dCTP opposite G and incorporation of dCTP or dTTP opposite O 6 -MeG show fast burst phases. The pre-steady-state incorporation efficiency (k pol /K d,dNTP ) is decreased in the order of dCTP:G>dTTP:O 6 -MeG>dCTP:O 6 -MeG. The presence of O 6 -MeG at template does not affect the binding affinity of polymerase to DNA but it weakened their binding in the presence of dCTP and Mg 2+ . Misincorporation of dTTP opposite O 6 -MeG further weakens the binding affinity of polymerase to DNA. The priority of dTTP incorporation opposite O 6 -MeG is originated from the fact that dTTP can induce a faster conformational change step and a faster chemical step than dCTP. This study reveals that gp90 bypasses O 6 -MeG in an error-prone manner and provides further understanding in DNA replication encountering mutagenic alkylation DNA damage for P. aeruginosa phage PaP1. Copyright © 2017 Elsevier B.V. All rights reserved.

Associations between fatty acid oxidation, hepatic mitochondrial function, and plasma acylcarnitine levels in mice.

PubMed

Bjørndal, Bodil; Alterås, Eva Katrine; Lindquist, Carine; Svardal, Asbjørn; Skorve, Jon; Berge, Rolf K

2018-01-01

The 4-thia fatty acid tetradecylthiopropionic acid (TTP) is known to inhibit mitochondrial β-oxidation, and can be used as chemically induced hepatic steatosis-model in rodents, while 3-thia fatty acid tetradecylthioacetic acid (TTA) stimulates fatty acid oxidation through activation of peroxisome proliferator activated receptor alpha (PPARα). We wished to determine how these two compounds affected in vivo respiration and mitochondrial efficiency, with an additional goal to elucidate whether mitochondrial function is reflected in plasma acylcarnitine levels. C57BL/6 mice were divided in 4 groups of 10 mice and fed a control low-fat diet, low-fat diets with 0.4% ( w /w) TTP, 0.4% TTA or a combination of these two fatty acids for three weeks ( n  = 10). At sacrifice, β-oxidation and oxidative phosphorylation (OXPHOS) capacity was analysed in fresh liver samples. Hepatic mitochondria were studied using transmission electron microscopy. Lipid classes were measured in plasma, heart and liver, acylcarnitines were measured in plasma, and gene expression was measured in liver. The TTP diet resulted in hepatic lipid accumulation, plasma L-carnitine and acetylcarnitine depletion and elevated palmitoylcarnitine and non-esterified fatty acid levels. No significant lipid accumulation was observed in heart. The TTA supplement resulted in enhanced hepatic β-oxidation, accompanied by an increased level of acetylcarnitine and palmitoylcarnitine in plasma. Analysis of mitochondrial respiration showed that TTP reduced oxidative phosphorylation, while TTA increased the maximum respiratory capacity of the electron transport system. Combined treatment with TTP and TTA resulted in a profound stimulation of genes involved in the PPAR-response and L-carnitine metabolism, and partly prevented triacylglycerol accumulation in the liver concomitant with increased peroxisomal β-oxidation and depletion of plasma acetylcarnitines. Despite an increased number of mitochondria in the liver of TTA + TTP fed mice, the OXPHOS capacity was significantly reduced. This study indicates that fatty acid β-oxidation directly affects mitochondrial respiratory capacity in liver. As plasma acylcarnitines reflected the reduced mitochondrial β-oxidation in TTP-fed mice, they could be useful tools to monitor mitochondrial function. As mitochondrial dysfunction is a major determinant of metabolic disease, this supports their use as plasma markers of cardiovascular risk in humans. Results however indicate that high PPAR activation obscures the interpretation of plasma acylcarnitine levels.

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

Yan, Yushan

In this work, multiple polymer backbones were screened for oxidation resistance and multiple chemistries were explored for tethering tris(2,4,6-trimethylphenyl)phosphonium (9MeTTP +) to the selected polymer backbones. A new tethering strategy through brominated 9MeTTP+ cation was developed and used to obtain the desired 9MeTTP +-functionalized polysulfone (PSf) and hexafluoro polybenzimidazole (F 6PBI) polymer. The crosslinked 9MeTTP+-functionalized hexafluoro polybenzimidazole (9MeTTP-F 6PBI) polymer demonstrated excellent oxidation stability that met the go-no-go milestone of the first year. However, large-scale bromination inevitably involved multi-bromination products, which led to polymer crosslinking in the next tethering. A new synthesis strategy with diiodobutane as linker was developed tomore » overcome the crosslinking problem. The prepared 9MeTTP +-F 6PBI membrane without crosslinking showed only 3.58% water uptake and less than 1 mS/cm OH - conductivity in water at 20°C, possibly due to the hydrophobic 9MeTTP + cation. In order to improve the conductivity, hydrophilic tris(2,4,6-trimethoxylphenyl)phosphonium (9MeOTTP+) cation was tethered to an F 6PBI backbone, and a 9MeOTTP +-F 6PBI PTFE reinforced membrane was prepared with 17.4% water uptake to increase the mechanical strength and durability in cerium (IV) solution. A 9MeOTTP+-F 6PBI PTFE reinforced membrane had less than 20% conductivity loss during an accelerated stability test in 0.5 M cerium (IV) and 1.3 M HClO 4 at 55°C for 100 hours. Moreover, a 9MeOTTP +-F 6PBI PTFE reinforced membrane had more than double the lifetime of commercial FAS-30 and FAB-PK-130 AEMs during an accelerated stability test in 0.5 M cerium (IV) and 1.3 M HClO 4 at 55°C. Low area specific resistance (ASR) of a 9MeOTTP +-F 6PBI PTFE reinforced membrane in the sulfuric acid system was also achieved due to the high acid doping ability of the polymer structure. The cationic 9MeOTTP +-F 6PBI PTFE reinforced membrane shows a cerium (IV) permeability that is 27-fold lower than that of Nafion 212. Excellent voltage and energy efficiencies with a 9MeOTTP +-F 6PBI PTFE reinforced membrane were demonstrated in an all-vanadium redox flow battery (VRFB).« less

Secure Multi-party Computation Protocol for Defense Applications in Military Operations Using Virtual Cryptography

NASA Astrophysics Data System (ADS)

Pathak, Rohit; Joshi, Satyadhar

With the advent into the 20th century whole world has been facing the common dilemma of Terrorism. The suicide attacks on US twin towers 11 Sept. 2001, Train bombings in Madrid Spain 11 Mar. 2004, London bombings 7 Jul. 2005 and Mumbai attack 26 Nov. 2008 were some of the most disturbing, destructive and evil acts by terrorists in the last decade which has clearly shown their evil intent that they can go to any extent to accomplish their goals. Many terrorist organizations such as al Quaida, Harakat ul-Mujahidin, Hezbollah, Jaish-e-Mohammed, Lashkar-e-Toiba, etc. are carrying out training camps and terrorist operations which are accompanied with latest technology and high tech arsenal. To counter such terrorism our military is in need of advanced defense technology. One of the major issues of concern is secure communication. It has to be made sure that communication between different military forces is secure so that critical information is not leaked to the adversary. Military forces need secure communication to shield their confidential data from terrorist forces. Leakage of concerned data can prove hazardous, thus preservation and security is of prime importance. There may be a need to perform computations that require data from many military forces, but in some cases the associated forces would not want to reveal their data to other forces. In such situations Secure Multi-party Computations find their application. In this paper, we propose a new highly scalable Secure Multi-party Computation (SMC) protocol and algorithm for Defense applications which can be used to perform computation on encrypted data. Every party encrypts their data in accordance with a particular scheme. This encrypted data is distributed among some created virtual parties. These Virtual parties send their data to the TTP through an Anonymizer layer. TTP performs computation on encrypted data and announces the result. As the data sent was encrypted its actual value can’t be known by TTP and with the use of Anonymizers we have covered the identity of true source of data. Modifier tokens are generated along encryption of data which are distributed among virtual parties, then sent to TTP and finally used in the computation. Thus without revealing the data, right result can be computed and privacy of the parties is maintained. We have also given a probabilistic security analysis of hacking the protocol and shown how zero hacking security can be achieved.

Urinary paracetamol and time-to-pregnancy

PubMed Central

Smarr, Melissa M.; Grantz, Katherine L.; Sundaram, Rajeshwari; Maisog, José M.; Honda, Masato; Kannan, Kurunthachalam; Buck Louis, Germaine M.

2016-01-01

STUDY QUESTION Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)? SUMMARY ANSWER Higher urinary paracetamol concentrations among male partners were associated with a longer TTP. WHAT IS KNOWN ALREADY Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking. STUDY DESIGN, SIZE, DURATION This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005–2009 and residing in Michigan or Texas, USA. PARTICIPANTS/MATERIALS, SETTING, METHODS Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other. MAIN RESULTS AND THE ROLE OF CHANCE Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously. LIMITATIONS, REASONS FOR CAUTION Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders. WIDER IMPLICATIONS OF THE FINDINGS If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment. STUDY FUNDING/COMPETING INTEREST(S) This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare. PMID:27412248

Urinary paracetamol and time-to-pregnancy.

PubMed

Smarr, Melissa M; Grantz, Katherine L; Sundaram, Rajeshwari; Maisog, José M; Honda, Masato; Kannan, Kurunthachalam; Buck Louis, Germaine M

2016-09-01

Is preconception urinary paracetamol (acetaminophen) associated with time-to-pregnancy (TTP)? Higher urinary paracetamol concentrations among male partners were associated with a longer TTP. Paracetamol is a commonly used analgesic among women and men of all ages. As metabolites of select chemicals used in the manufacturing of polyurethane foam, dyes and various industrial products, as well as a common medicinal product, paracetamol and its primary metabolite p-aminophenol, are ubiquitous in the environment. Studies investigating the relationship between adult urinary concentrations of paracetamol and TTP are lacking. This prospective cohort included 501 couples discontinuing contraception for the purposes of attempting conception during the years 2005-2009 and residing in Michigan or Texas, USA. Total urinary paracetamol, its metabolite para-aminophenol (p-aminophenol), and a summary measure of both urinary biomarkers were quantified by ultra-performance liquid chromatography coupled with an electrospray triple quadrupole mass spectrometry (UPLC-ESI-MS/MS). Female partners used the Clearblue® digital home test to confirm pregnancy. Cox's proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs), adjusting for age, body mass index (BMI), urinary creatinine, preconception smoking status, race/ethnicity and household income. Models were further adjusted for hypothyroidism and hypertension as an attempt to account for possible indications of paracetamol medication use. FOR estimates <1.0 denote a longer TTP (diminished fecundity). Models were performed to examine urinary concentrations of paracetamol as a continuous and variable or categorized into quartiles. In light of TTP being a couple-dependent outcome, models were first performed for females and males, modeled separately, and then modeled for couples with each partner's concentrations being adjusted for the other. Among the 501 enrolled couples, 347 (69%) had an human chorionic gonadotrophin confirmed pregnancy. Urinary concentrations of paracetamol were lowest among females and males who achieved pregnancy and p-aminophenol concentrations were lowest among those not achieving pregnancy. Urinary paracetamol concentrations were higher among female than male partners (Median = 26.6 and 13.2 ng/ml, respectively; P < 0.0001). After adjustment for age, BMI, urinary creatinine, preconception smoking status, race/ethnicity and household income, the highest quartile of male urinary paracetamol was associated with a longer TTP [FOR = 0.67; 95% CI = (0.47, 0.95)]. This association remained after adjustment for chronic health conditions, hypothyroidism and hypertension and female partner's urinary paracetamol concentration [FOR = 0.65; 95% CI = (0.45, 0.94)]. No associations were observed between female or male partners' urinary concentrations of paracetamol or of its metabolite p-aminophenol when urinary concentrations were modeled continuously. Only a single spot urine was available for analysis despite the short-lived nature of paracetamol. Additionally, participants were not asked to provide information on indication of use for paracetamol medications; any underlying conditions for the paracetamol use would have been potential confounders. If corroborated with more robust studies, findings from our exploratory analysis may have both clinical and public health relevance among reproductive aged individuals, including those trying for pregnancy, given the prevalent use of paracetamol/acetaminophen medications and the ubiquitous nature of paracetamol in the environment. This research was supported by the National Institutes of Health, Intramural Research Program, and Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts N01-HD-3-3355; N01-HD-3-3356; NOH-HD-3-3358; HHSN27500001/HHSN27500001). None of the authors have any conflicts to declare. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Influenza-associated thrombotic microangiopathies.

PubMed

Bitzan, Martin; Zieg, Jakub

2017-09-07

Thrombotic microangiopathy (TMA) refers to phenotypically similar disorders, including hemolytic uremic syndromes (HUS) and thrombotic thrombocytopenic purpura (TTP). This review explores the role of the influenza virus as trigger of HUS or TTP. We conducted a literature survey in PubMed and Google Scholar using HUS, TTP, TMA, and influenza as keywords, and extracted and analyzed reported epidemiological and clinical data. We identified 25 cases of influenza-associated TMA. Five additional cases were linked to influenza vaccination and analyzed separately. Influenza A was found in 83%, 10 out of 25 during the 2009 A(H1N1) pandemic. Two patients had bona fide TTP with ADAMTS13 activity <10%. Median age was 15 years (range 0.5-68 years), two thirds were male. Oligoanuria was documented in 81% and neurological involvement in 40% of patients. Serum C3 was reduced in 5 out of 14 patients (36%); Coombs test was negative in 7 out of 7 and elevated fibrin/fibrinogen degradation products were documented in 6 out of 8 patients. Pathogenic complement gene mutations were found in 7 out of 8 patients tested (C3, MCP, or MCP combined with CFB or clusterin). Twenty out of 24 patients recovered completely, but 3 died (12%). Ten of the surviving patients underwent plasma exchange (PLEX) therapy, 5 plasma infusions. Influenza-mediated HUS or TTP is rare. A sizable proportion of tested patients demonstrated mutations associated with alternative pathway of complement dysregulation that was uncovered by this infection. Further research is warranted targeting the roles of viral neuraminidase, enhanced virus-induced complement activation and/or ADAMTS13 antibodies, and rational treatment approaches.

Time Triggered Protocol (TTP) for Integrated Modular Avionics

NASA Technical Reports Server (NTRS)

Motzet, Guenter; Gwaltney, David A.; Bauer, Guenther; Jakovljevic, Mirko; Gagea, Leonard

2006-01-01

Traditional avionics computing systems are federated, with each system provided on a number of dedicated hardware units. Federated applications are physically separated from one another and analysis of the systems is undertaken individually. Integrated Modular Avionics (IMA) takes these federated functions and integrates them on a common computing platform in a tightly deterministic distributed real-time network of computing modules in which the different applications can run. IMA supports different levels of criticality in the same computing resource and provides a platform for implementation of fault tolerance through hardware and application redundancy. Modular implementation has distinct benefits in design, testing and system maintainability. This paper covers the requirements for fault tolerant bus systems used to provide reliable communication between IMA computing modules. An overview of the Time Triggered Protocol (TTP) specification and implementation as a reliable solution for IMA systems is presented. Application examples in aircraft avionics and a development system for future space application are covered. The commercially available TTP controller can be also be implemented in an FPGA and the results from implementation studies are covered. Finally future direction for the application of TTP and related development activities are presented.

Association between a variant of the sigma-1 receptor gene and Alzheimer's disease.

PubMed

Fehér, Ágnes; Juhász, Anna; László, Anna; Kálmán, János; Pákáski, Magdolna; Kálmán, János; Janka, Zoltán

2012-05-31

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with complex etiology and strong genetic predisposition. A number of investigations support the possible involvement of sigma non-opioid intracellular receptor 1 (SIGMAR1) in the pathophysiology of AD. We aimed to investigate the association between SIGMAR1 polymorphisms and late-onset AD, therefore we genotyped rs1799729 (GC-241-240TT) and rs1800866 (Q2P) in 322 Hungarian late-onset AD patients and 250 ethnically matched, elderly control individuals. The investigated polymorphisms were in nearly complete linkage disequilibrium resulting in the GC-Q and TT-P predominant haplotypes that were subjected to the statistical analyses. Our data demonstrates an association between the SIGMAR1 TT-P variant and the risk for developing AD (p=0.019), and a potential modest interaction effect (p=0.058) of the co-presence of the TT-P haplotype with apolipoprotein E4 allele on the risk for AD. Based on this mild significance, we could not fully support the hypothesis that TT-P haplotype in interaction with APOE E4 allele confers risk for developing AD. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Metabolic Recruitment and Directed Evolution of Nucleoside Triphosphate Uptake in Escherichia coli.

PubMed

Pezo, Valérie; Hassan, Camille; Louis, Dominique; Sargueil, Bruno; Herdewijn, Piet; Marlière, Philippe

2018-05-18

We report the design and elaboration of a selection protocol for importing a canonical substrate of DNA polymerase, thymidine triphosphate (dTTP) in Escherichia coli. Bacterial strains whose growth depend on dTTP uptake, through the action of an algal plastid transporter expressed from a synthetic gene inserted in the chromosome, were constructed and shown to withstand the simultaneous loss of thymidylate synthase and thymidine kinase. Such thyA tdk dual deletant strains provide an experimental model of tight nutritional containment for preventing dissemination of microbial GMOs. Our strains transported the four canonical dNTPs, in the following order of preference: dCTP > dATP ≥ dGTP > dTTP. Prolonged cultivation under limitation of exogenous dTTP led to the enhancement of dNTP transport by adaptive evolution. We investigated the uptake of dCTP analogues with altered sugar or nucleobase moieties, which were found to cause a loss of cell viability and an increase of mutant frequency, respectively. E. coli strains equipped with nucleoside triphosphate transporters should be instrumental for evolving organisms whose DNA genome is morphed chemically by fully substituting its canonical nucleotide components.

Determinants of PCR performance (Xpert MTB/RIF), including bacterial load and inhibition, for TB diagnosis using specimens from different body compartments

PubMed Central

Theron, Grant; Peter, Jonny; Calligaro, Greg; Meldau, Richard; Hanrahan, Colleen; Khalfey, Hoosain; Matinyenya, Brian; Muchinga, Tapuwa; Smith, Liezel; Pandie, Shaheen; Lenders, Laura; Patel, Vinod; Mayosi, Bongani M.; Dheda, Keertan

2014-01-01

The determinants of Xpert MTB/RIF sensitivity, a widely used PCR test for the diagnosis of tuberculosis (TB) are poorly understood. We compared culture time-to-positivity (TTP; a surrogate of bacterial load), MTB/RIF TB-specific and internal positive control (IPC)-specific CT values, and clinical characteristics in patients with suspected TB who provided expectorated (n = 438) or induced sputum (n = 128), tracheal aspirates (n = 71), bronchoalveolar lavage fluid (n = 152), pleural fluid (n = 76), cerebral spinal fluid (CSF; n = 152), pericardial fluid (n = 131), or urine (n = 173) specimens. Median bacterial load (TTP in days) was the strongest associate of MTB/RIF positivity in each fluid. TTP correlated with CT values in pulmonary specimens but not extrapulmonary specimens (Spearman's coefficient 0.5043 versus 0.1437; p = 0.030). Inhibition affected a greater proportion of pulmonary specimens than extrapulmonary specimens (IPC CT > 34: 6% (47/731) versus 1% (4/381; p < 0.0001). Pulmonary specimens had greater load than extrapulmonary specimens [TTPs (interquartile range) of 11 (7–16) versus 22 (18–33.5) days; p < 0.0001]. HIV-infection was associated with a decreased likelihood of MTB/RIF-positivity in pulmonary specimens but an increased likelihood in extrapulmonary specimens. Mycobacterial load, which displays significant variation across different body compartments, is the main determinant of MTB/RIF-positivity rather than PCR inhibition. MTB/RIF CT is a poor surrogate of load in extrapulmonary specimens. PMID:25014250

Performance specifications for the extra-analytical phases of laboratory testing: Why and how.

PubMed

Plebani, Mario

2017-07-01

An important priority in the current healthcare scenario should be to address errors in laboratory testing, which account for a significant proportion of diagnostic errors. Efforts made in laboratory medicine to enhance the diagnostic process have been directed toward improving technology, greater volumes and more accurate laboratory tests being achieved, but data collected in the last few years highlight the need to re-evaluate the total testing process (TTP) as the unique framework for improving quality and patient safety. Valuable quality indicators (QIs) and extra-analytical performance specifications are required for guidance in improving all TTP steps. Yet in literature no data are available on extra-analytical performance specifications based on outcomes, and nor is it possible to set any specification using calculations involving biological variability. The collection of data representing the state-of-the-art based on quality indicators is, therefore, underway. The adoption of a harmonized set of QIs, a common data collection and standardised reporting method is mandatory as it will not only allow the accreditation of clinical laboratories according to the International Standard, but also assure guidance for promoting improvement processes and guaranteeing quality care to patients. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Quantitative contrast-enhanced ultrasonography for the differential diagnosis of endometrial hyperplasia and endometrial neoplasms

PubMed Central

Liu, Ying; Xu, Yi; Cheng, Wen; Liu, Xinghan

2016-01-01

The present study aimed to investigate the feasibility of applying contrast-enhanced ultrasonography (CEUS) imaging technology for distinguishing between benign and malignant endometrial lesions, and to screen markers that could be correlated with the pathological results. In this study, endometrial diseases were diagnosed by biopsy under hysteroscopy and CEUS examinations. The intensity and time parameters of the time-intensity curve (TIC) were analyzed. The mean arrival time (AT), time-to-peak (TTP), rise time (RT), washout half-time and clearance half-time of malignant lesions were shorter than those of benign lesions (P<0.05), whereas the average peak intensity (PI) and enhancement intensity (EI) of malignant lesions were higher than those of benign lesions (P<0.05). The receiver operating characteristic curve showed the following cut-off values: PI, 29.2 dB; EI, 21.35 dB; AT, 12.75 sec; TTP, 26.75 sec; RT, 13.2 sec; clearance half-time, 89.3 sec; and washout half-time, 75.45 sec. The lesions with PI, an EI higher than that of the cut-off and lesions with an AT, TTP, RT, half clearing time and washout half-time shorter than the cut-off were considered malignant. The TTP, RT and half clearing time were negatively correlated with microvessel density (MVD), i.e., MVD was higher when the TTP, RT and half clearing time were shorter. Overall, changes in the enhancement and clearing of lesions could be quantitatively analyzed by CEUS TIC and further discriminate benign from malignant lesions. In the present study, CEUS appeared to indirectly reflect blood vessel changes inside the lesions and provided a pre-operative non-invasive fast imaging method for the diagnosis of endometrial disease. PMID:27895728

Ultraearly assessed reperfusion status after middle cerebral artery recanalization predicting clinical outcome.

PubMed

Gölitz, P; Muehlen, I; Gerner, S T; Knossalla, F; Doerfler, A

2018-06-01

Mechanical thrombectomy has high evidence in stroke therapy; however, successful recanalization guarantees not a favorable clinical outcome. We aimed to quantitatively assess the reperfusion status ultraearly after successful middle cerebral artery (MCA) recanalization to identify flow parameters that potentially allow predicting clinical outcome. Sixty-seven stroke patients with acute MCA occlusion, undergoing recanalization, were enrolled. Using parametric color coding, a post-processing algorithm, pre-, and post-interventional digital subtraction angiography series were evaluated concerning the following parameters: pre- and post-procedural cortical relative time to peak (rTTP) of MCA territory, reperfusion time, and index. Functional long-term outcome was assessed by the 90-day modified Rankin Scale score (mRS; favorable: 0-2). Cortical rTTP was significantly shorter before (3.33 ± 1.36 seconds; P = .03) and after intervention (2.05 ± 0.70 seconds; P = .003) in patients with favorable clinical outcome. Additionally, age (P = .005) and initial National Institutes of Health Stroke Scale score (P = .02) were significantly different between the patients, whereas reperfusion index and time as well as initially estimated infarct size were not. In multivariate analysis, only post-procedural rTTP (P = .005) was independently associated with favorable clinical outcome. 2.29 seconds for post-procedural rTTP might be a threshold to predict favorable clinical outcome. Ultraearly quantitative assessment of reperfusion status after successful MCA recanalization reveals post-procedural cortical rTTP as possible independent prognostic value in predicting favorable clinical outcome, even determining a threshold value might be possible. In consequence, focusing stroke therapy on microcirculatory patency could be valuable to improve outcome. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Uniaxial strain orientation dependence of superconducting transition temperature (Tc) and critical superconducting pressure (Pc) in β-(BDA-TTP)2I3.

PubMed

Kikuchi, Koichi; Isono, Takayuki; Kojima, Masayuki; Yoshimoto, Haruo; Kodama, Takeshi; Fujita, Wataru; Yokogawa, Keiichi; Yoshino, Harukazu; Murata, Keizo; Kaihatsu, Takayuki; Akutsu, Hiroki; Yamada, Jun-ichi

2011-12-14

Dependence of the superconducting transition temperature (T(c)) and critial superconducting pressure (P(c)) of the pressure-induced superconductor β-(BDA-TTP)(2)I(3) [BDA-TTP = 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene] on the orientation of uniaxial strain has been investigated. On the basis of the overlap between the upper and lower bands in the energy dispersion curve, the pressure orientation is thought to change the half-filled band to the quarter-filled one. The observed variations in T(c) and P(c) are explained by considering the degree of application of the pressure and the degree of contribution of the effective electronic correlation at uniaxial strains with different orientations parallel to the conducting donor layer. © 2011 American Chemical Society

Erlotinib in African Americans with Advanced Non-Small Cell Lung Cancer: A Prospective Randomized Study with Genetic and Pharmacokinetic Analysis

PubMed Central

Phelps, Mitch A.; Stinchcombe, Thomas E.; Blachly, James S.; Zhao, Weiqiang; Schaaf, Larry J.; Starrett, Sherri L.; Wei, Lai; Poi, Ming; Wang, Danxin; Papp, Audrey; Aimiuwu, Josephine; Gao, Yue; Li, Junan; Otterson, Gregory A.; Hicks, William J.; Socinski, Mark A.; Villalona-Calero, Miguel A.

2014-01-01

Prospective studies focusing on EGFR inhibitors in African Americans with NSCLC have not been previously performed. In this phase II randomized study, 55 African Americans with NSCLC received erlotinib 150mg/day or a body weight adjusted dose with subsequent escalations to the maximum allowable, 200mg/day, to achieve rash. Erlotinib and OSI-420 exposures were lower compared to previous reports, consistent with CYP3A pharmacogenetics implying higher metabolic activity. Tumor genetics revealed only two EGFR mutations, EGFR amplification in 17/47 samples, 8 KRAS mutations and 5 EML4-ALK translocations. Although absence of rash was associated with shorter time to progression (TTP), disease control rate, TTP, and 1-year survival were not different between the two dose groups, indicating the dose-to-rash strategy failed to increase clinical benefit. Observed low incidence of toxicity and low erlotinib exposure suggest standardized and maximum allowable dosing may be suboptimal in African Americans. PMID:24781527

Pegylated bovine carboxyhaemoglobin utilisation in a thrombotic thrombocytopenic purpura patient.

PubMed

Sam, C; Desai, P; Laber, D; Patel, A; Visweshwar, N; Jaglal, M

2017-08-01

To determine if pegylated bovine carboxyhaemoglobin can be utilised in a thrombotic thrombocytopenic purpura (TTP) patient. TTP is a condition characterized by thrombotic microangiopathy and has a high mortality rate when left untreated. Therapeutic plasma exchange is well established as the most effective and evidence-based treatment of TTP. The ability to administer plasma exchange therapy is limited in Jehovah's Witnesses who decline blood products due to religious beliefs. Pegylated bovine carboxyhaemoglobin is a novel oxygen transfer agent in development for the management of complications of ischaemia due to acute anaemia. Treatment was well tolerated, with grade 1 paresthesia of the right face and arm 1 h after the first infusion of Sanguinate, which spontaneously resolved and did not recur, and grade 1 cardiac troponin elevation after receiving the medication (with peak at 0·079 ng mL -1 ), but further workup with electrocardiogram and echocardiogram was unremarkable. By discharge on day 19, the patient's haemoglobin increased to 8·8 g dL -1 and platelet count to 221 000. We report the first case of TTP in a Jehovah's Witness that was successfully managed with the use of pegylated bovine carboxyhaemoglobin as an adjunct medication. © 2017 British Blood Transfusion Society.

Acquired Thrombotic Thrombocytopenic Purpura in a Patient with Pernicious Anemia.

PubMed

Pandey, Ramesh Kumar; Dahal, Sumit; Fadlalla, Kamal Fadlalla El Jack; Bhagat, Shambhu; Bhattarai, Bikash

2017-01-01

Introduction . Acquired thrombotic thrombocytopenic purpura (TTP) has been associated with different autoimmune disorders. However, its association with pernicious anemia is rarely reported. Case Report . A 46-year-old male presented with blood in sputum and urine for one day. The vitals were stable. The physical examination was significant for icterus. Lab tests' results revealed leukocytosis, macrocytic anemia, severe thrombocytopenia, renal dysfunction, and unconjugated hyperbilirubinemia. He had an elevated LDH, low haptoglobin levels with many schistocytes, nucleated RBCs, and reticulocytes on peripheral smear. Low ADAMTS13 activity (<10%) with elevated ADAMTS13 antibody clinched the diagnosis of severe acquired TTP, and plasmapheresis was started. There was an initial improvement in his hematological markers, which were however not sustained on discontinuation of plasmapheresis. For his refractory TTP, he was resumed on daily plasmapheresis and Rituximab was started. Furthermore, the initial serum Vitamin B12 and reticulocyte index were low in the presence of anti-intrinsic factor antibody. So with the concomitant diagnosis of pernicious anemia, Vitamin B12 was supplemented. The rest of the immunological workups were negative. Subsequently, his symptoms resolved and his hematological parameters improved. Discussion . While pernicious anemia can masquerade as TTP, an actual association between the two can also occur and needs further evaluation and characterization.

Acquired Thrombotic Thrombocytopenic Purpura in a Patient with Pernicious Anemia

PubMed Central

Bhagat, Shambhu

2017-01-01

Introduction. Acquired thrombotic thrombocytopenic purpura (TTP) has been associated with different autoimmune disorders. However, its association with pernicious anemia is rarely reported. Case Report. A 46-year-old male presented with blood in sputum and urine for one day. The vitals were stable. The physical examination was significant for icterus. Lab tests' results revealed leukocytosis, macrocytic anemia, severe thrombocytopenia, renal dysfunction, and unconjugated hyperbilirubinemia. He had an elevated LDH, low haptoglobin levels with many schistocytes, nucleated RBCs, and reticulocytes on peripheral smear. Low ADAMTS13 activity (<10%) with elevated ADAMTS13 antibody clinched the diagnosis of severe acquired TTP, and plasmapheresis was started. There was an initial improvement in his hematological markers, which were however not sustained on discontinuation of plasmapheresis. For his refractory TTP, he was resumed on daily plasmapheresis and Rituximab was started. Furthermore, the initial serum Vitamin B12 and reticulocyte index were low in the presence of anti-intrinsic factor antibody. So with the concomitant diagnosis of pernicious anemia, Vitamin B12 was supplemented. The rest of the immunological workups were negative. Subsequently, his symptoms resolved and his hematological parameters improved. Discussion. While pernicious anemia can masquerade as TTP, an actual association between the two can also occur and needs further evaluation and characterization. PMID:28473932

Correlation of Hypertension and Proteinuria with Outcome in Elderly Bevacizumab-Treated Patients with Metastatic Colorectal Cancer

PubMed Central

Feliu, Jaime; Salud, Antonieta; Safont, Maria J.; García-Girón, Carlos; Aparicio, Jorge; Losa, Ferran; Bosch, Carlos; Escudero, Pilar; Casado, Enrique; Jorge, Monica; Bohn, Uriel; Pérez-Carrión, Ramon; Carmona, Alberto; Custodio, Ana B.; Maurel, Joan

2015-01-01

Background Studies suggest a relationship between hypertension and outcome in bevacizumab-treated patients with metastatic colorectal cancer (mCRC). We performed a retrospective analysis of two phase II studies (BECA and BECOX) to determine if hypertension and proteinuria predict outcome in elderly patients with mCRC treated with bevacizumab. Patients and Methods Patients ≥70 years of age received either capecitabine 1250 mg/m2 bid days 1–14 + bevacizumab 7.5 mg/kg day 1 every 21 days (BECA study) or capecitabine 1000 mg/m2 bid days 1–14 with bevacizumab 7.5 mg/kg and oxaliplatin 130 mg/m2 day 1 (BECOX study). The primary objective was to correlate hypertension and proteinuria with overall response rate (ORR), time to progression (TTP) and overall survival (OS). Secondary objectives included identification of risk factors associated with the development of hypertension and proteinuria and determining whether development of hypertension or proteinuria in the first 2 cycles was related to ORR, disease-control rate (DCR), TTP or OS. Results In total, 127 patients (median age 75.5 years) were included in the study. Hypertension correlated with DCR and OS; proteinuria correlated with ORR and DCR. Proteinuria or hypertension in the first 2 cycles did not correlate with efficacy. Risk factors for hypertension were female gender (odds ratio [OR] 0.241; P = 0.011) and more bevacizumab cycles (OR 1.112; P = 0.002); risk factors for proteinuria were diabetes (OR 3.869; P = 0.006) and more bevacizumab cycles (OR 1.181; P<0.0001). Multivariate analysis identified as having prognostic value: baseline lactate dehydrogenase, haemoglobin, number of metastatic lesions and DCR. Conclusion This analysis of two phase II studies suggests that hypertension is significantly correlated with OS but not with ORR and TTP, whereas proteinuria is correlated with ORR but not with OS and TTP. Both hypertension and proteinuria are associated with the duration of bevacizumab treatment and do not represent an independent prognostic factor. PMID:25602286

Cumulative Review of Thrombotic Microangiopathy, Thrombotic Thrombocytopenic Purpura, and Hemolytic Uremic Syndrome Reports with Subcutaneous Interferon β-1a.

PubMed

Ben-Amor, Ali-Frédéric; Trochanov, Anton; Fischer, Tanya Z

2015-05-01

Rare cases of thrombotic microangiopathy (TMA), manifested as thrombotic thrombocytopenic purpura (TTP) or hemolytic uremic syndrome (HUS), have been reported with interferon β products. We performed a cumulative review of TMA cases recorded in a Global Safety Database for patients with multiple sclerosis who received subcutaneous interferon β-1a treatment. Search criteria were: all reported cases, serious and non-serious, from all sources (including non-health care professionals and clinical trial reports), regardless of event ranking and causality assessment by reporter or company. Data lock was May 3, 2014, with additional analysis of cases reported between August 1, 2014-November 30, 2014. Ninety-one patient cases (76.9% female) with 105 events were retrieved. Time to onset varied from 2 months to 14 years, and in 31.9% of patients the event occurred within 2 years of treatment initiation. Seven patients had a fatal outcome (five were secondary to other causes and two reported insufficient information). Forty-four patients recovered, 32 patients had not recovered at the time of the report, and in eight cases outcome was either not reported or unknown. Treatment was discontinued in 84.6% (77/91) of patients. In 67% (61/91) of patients, the reporter suspected a causal association between treatment and TMA/TTP-HUS. Risk factors and/or confounding factors were present in 45.1% (41/91) of patients. Early prodromal syndrome or specific patterns were not detected, although 54.9% (50/91) of cases contained insufficient information. Overall reporting rate of TMA/TTP-HUS was estimated as 7.2 per 100,000 patient-years. Reporting rates for human serum album (HSA)-containing and HSA-free formulations were 5.72 and 7.68 per 100,000 patient-years, respectively. No new signal relating specifically to increased frequency of TMA/TTP-HUS with HSA-free subcutaneous interferon β-1a was detected and no additional risk mitigation measures are required regarding the different formulations. The benefit-risk balance of subcutaneous interferon β-1a remains positive, and routine pharmacovigilance monitoring is appropriate. Ares Trading SA, Aubonne, Switzerland, a subsidiary of Merck Serono SA.

Review of sensors for the in situ chemical characterization of the Hanford underground storage tanks

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

Kyle, K.R.; Mayes, E.L.

1994-07-29

Lawrence Livermore National Laboratory (LLNL), in the Technical Task Plan (TTP) SF-2112-03 subtask 2, is responsible for the conceptual design of a Raman probe for inclusion in the in-tank cone penetrometer. As part of this task, LLNL is assigned the further responsibility of generating a report describing a review of sensor technologies other than Raman that can be incorporated in the in-tank cone penetrometer for the chemical analysis of the tank environment. These sensors would complement the capabilities of the Raman probe, and would give information on gaseous, liquid, and solid state species that are insensitive to Raman interrogation. Thismore » work is part of a joint effort involving several DOE laboratories for the design and development of in-tank cone penetrometer deployable systems for direct UST waste characterization at Westinghouse Hanford Company (WHC) under the auspices of the U.S. Department of Energy (DOE) Underground Storage Tank Integrated Demonstration (UST-ID).« less

Static and dynamic 18F-FET PET for the characterization of gliomas defined by IDH and 1p/19q status.

PubMed

Verger, Antoine; Stoffels, Gabriele; Bauer, Elena K; Lohmann, Philipp; Blau, Tobias; Fink, Gereon R; Neumaier, Bernd; Shah, Nadim J; Langen, Karl-Josef; Galldiks, Norbert

2018-03-01

The molecular features isocitrate dehydrogenase (IDH) mutation and 1p/19q co-deletion have gained major importance for both glioma typing and prognosis and have, therefore, been integrated in the World Health Organization (WHO) classification in 2016. The aim of this study was to characterize static and dynamic O-(2- 18 F-fluoroethyl)-L-tyrosine ( 18 F-FET) PET parameters in gliomas with or without IDH mutation or 1p/19q co-deletion. Ninety patients with newly diagnosed and untreated gliomas with a static and dynamic 18 F-FET PET scan prior to evaluation of tumor tissue according to the 2016 WHO classification were identified retrospectively. Mean and maximum tumor-to-brain ratios (TBR mean/max ), as well as dynamic parameters (time-to-peak and slope) of 18 F-FET uptake were calculated. Sixteen (18%) oligodendrogliomas (IDH mutated, 1p/19q co-deleted), 27 (30%) astrocytomas (IDH mutated only), and 47 (52%) glioblastomas (IDH wild type only) were identified. TBR mean , TBR max , TTP and slope discriminated between IDH mutated astrocytomas and IDH wild type glioblastomas (P < 0.01). TBR mean showed the best diagnostic performance (cut-off 1.95; sensitivity, 89%; specificity, 67%; accuracy, 81%). None of the parameters discriminated between oligodendrogliomas (IDH mutated, 1p/19q co-deleted) and glioblastomas or astrocytomas. Furthermore, TBR mean , TBR max , TTP, and slope discriminated between gliomas with and without IDH mutation (p < 0.01). The best diagnostic performance was obtained for the combination of TTP with TBR max or slope (accuracy, 73%). Data suggest that static and dynamic 18 F-FET PET parameters may allow determining non-invasively the IDH mutation status. However, IDH mutated and 1p/19q co-deleted oligodendrogliomas cannot be differentiated from glioblastomas and astrocytomas by 18 F-FET PET.

Tri-Service Thermal Flash Test Facility. Summary Report.

DTIC Science & Technology

1980-01-15

degradation of materials exposed to the radiant heating generated by a nuclear blast can very enormously. The intense radiation needed to simulate a...Photography - Motion picture photo- graphy of surface degradation would be an asset to data analysis. Although this procedure is relatively straightforward...Polyvinylchloride 68 Rubber 69 Army Systems Camouflage MIL-E-52798A over TTP-636 primer 70 Army Systems Camouflage MIL-E-52835A over TTP-636 primer 71 Army

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

Xia, Shuangluo; Konigsberg, William H.; Wang, Jimin

Results obtained using 2,4-difluorotoluene nucleobase (dF) as a nonpolar thymine isostere by Kool and colleagues challenged the Watson-Crick dogma that hydrogen bonds between complementary bases are an absolute requirement for accurate DNA replication. Here, we report crystal structure of an RB69 DNA polymerase L561A/S565G/Y567A triple mutant ternary complex with a templating dF opposite dTTP at 1.8 {angstrom}-resolution. In this structure, direct hydrogen bonds were observed between: (i) dF and the incoming dTTP, (ii) dF and residue G568 of the polymerase, and (iii) dF and ordered water molecules surrounding the nascent base pair. Therefore, this structure provides evidence that a templatingmore » dF can form novel hydrogen bonds with the incoming dTTP and with the enzyme that differ from those formed with a templating dT.« less

Pressure-dependent ground states and fermiology in β- ( BDA-TTP ) 2 M Cl4 ( M=Fe,Ga )

NASA Astrophysics Data System (ADS)

Choi, E. S.; Graf, D.; Brooks, J. S.; Yamada, J.; Akutsu, H.; Kikuchi, K.; Tokumoto, M.

2004-07-01

We have investigated pressure- and magnetic-field-dependent electrical transport properties in the charge transfer salts β-(BDA-TTP)2MCl4(M=Fe,Ga) , both of which show a metal-insulator (MI) transition around 120K at ambient pressure. The zero field temperature-pressure phase diagrams of the two compounds are quite similar; the MI transition temperature decreases with pressure, and superconductivity is observed in both the magnetic and non-magnetic compounds above ˜4.5kbar . Likewise, Shubnikov-de Haas effect measurements show nearly identical Fermi surfaces. These similarities suggest that the magnetic interaction J between the conduction electrons and the magnetic moments in β-(BDA-TTP)2FeCl4 is small. Nevertheless, magnetoresistance measurements show remarkable differences and reveal that magnetic interactions with the conduction electrons are still effective in M=Fe compounds.

Association of acquired thrombotic thrombocytopaenic purpura in a patient with pernicious anaemia

PubMed Central

Podder, Sidhertha; Cervates, Jose; Dey, Bimalangshu R

2015-01-01

Pernicious anaemia is an autoimmune disease caused by intrinsic factor antibody; it leads to vitamin B12 deficiency and is marked by ineffective erythropoiesis. Haematological features reveal macrocytosis, hyperchromasia and hypersegmented neutrophils. Schistocytes are typically seen in microangiopathy, such as in thrombotic thrombocytopaenic purpura (TTP)/haemolytic uraemic syndrome or disseminated intravascular haemolysis (DIC). We report a case of a patient with severe anaemia who presented to the emergency room. Peripheral smear revealed macrocytosis, hypersegmented neutrophils and marked schistocytosis. The patient also had high reticulocyte count with high serum lactate dehydrogenase, elevated D-dimer, low fibrinogen and low haptoglobin. Vitamin B12 level came back low and the presence of intrinsic factor antibody confirmed pernicious anaemia. ADAMTS13 level was noted to be mildly reduced, which raised the suspicion of the association of acquired TTP with pernicious anaemia. Acquired TTP is another autoimmune disorder and its association with pernicious anaemia needs further evaluation. PMID:26464409

Calcination/dissolution chemistry development Fiscal year 1995

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

Delegard, C.H.

1995-09-01

The task {open_quotes}IPC Liaison and Chemistry of Thermal Reconstitution{close_quotes} is a $300,000 program that was conducted in Fiscal Year (FY) 1995 with U.S. Department of Energy (DOE) Office of Research and Development (EM-53) Efficient Separations and Processing Crosscutting Program supported under technical task plan (TTP) RL4-3-20-04. The principal investigator was Cal Delegard of the Westinghouse Hanford Company (WHC). The task encompassed the following two subtasks related to the chemistry of alkaline Hanford Site tank waste: (1) Technical Liaison with the Institute of Physical Chemistry of the Russian Academy of Science (IPC/RAS) and its research into the chemistry of transuranic elementsmore » (TRU) and technetium (Tc) in alkaline media. (2) Laboratory investigation of the chemistry of calcination/dissolution (C/D) (or thermal reconstitution) as an alternative to the present reference Hanford Site tank waste pretreatment flowsheet, Enhanced Sludge Washing (ESW). This report fulfills the milestone for the C/D subtask to {open_quotes}Provide End-of-Year Report on C/D Laboratory Test Results{close_quotes} due 30 September 1995. A companion report, fulfilling the milestone to provide an end-of-year report on the IPC/RAS liaison, also has been prepared.« less

Heterobimetallic Nitrido Complexes of Group 8 Metalloporphyrins.

PubMed

Cheung, Wai-Man; Chiu, Wai-Hang; de Vere-Tucker, Matthew; Sung, Herman H-Y; Williams, Ian D; Leung, Wa-Hung

2017-05-15

Heterobimetallic nitrido porphyrin complexes with the [(L)(por)M-N-M'(L OEt )Cl 2 ] formula {por 2- = 5,10,15,20-tetraphenylporphyrin (TPP 2- ) or 5,10,15,20-tetra(p-tolyl)porphyrin (TTP 2- ) dianion; L OEt - = [Co(η 5 -C 5 H 5 ){P(O)(OEt) 2 } 3 ] - ; M = Fe, Ru, or Os; M' = Ru or Os; L = H 2 O or pyridine} have been synthesized, and their electrochemistry has been studied. Treatment of trans-[Fe(TPP)(py) 2 ] (py = pyridine) with Ru(VI) nitride [Ru(L OEt )(N)Cl 2 ] (1) afforded Fe/Ru μ-nitrido complex [(py)(TPP)Fe(μ-N)Ru(L OEt )Cl 2 ] (2). Similarly, Fe/Os analogue [(py)(TPP)Fe(μ-N)Os(L OEt )Cl 2 ] (3) was obtained from trans-[Fe(TPP)(py) 2 ] and [Os(L OEt )(N)Cl 2 ]. However, no reaction was found between trans-[Fe(TPP)(py) 2 ] and [Re(L OEt )(N)Cl(PPh 3 )]. Treatment of trans-[M(TPP)(CO)(EtOH)] with 1 afforded μ-nitrido complexes [(H 2 O)(TPP)M(μ-N)Ru(L OEt )Cl 2 ] [M = Ru (4a) or Os (5)]. TTP analogue [(H 2 O)(TTP)Ru(μ-N)Ru(L OEt )Cl 2 ] (4b) was prepared similarly from trans-[Ru(TTP)(CO)(EtOH)] and 1. Reaction of [(H 2 O)(por)M(μ-N)M(L OEt )Cl 2 ] with pyridine gave adducts [(py)(por)M(μ-N)Ru(L OEt )Cl 2 ] [por = TTP, and M = Ru (6); por = TPP, and M = Os (7)]. The diamagnetism and short (por)M-N(nitride) distances in 2 [Fe-N, 1.683(3) Å] and 4b [Ru-N, 1.743(3) Å] are indicative of the M IV ═N═M' IV bonding description. The cyclic voltammograms of the Fe/Ru (2) and Ru/Ru (4b) complexes in CH 2 Cl 2 displayed oxidation couples at approximately +0.29 and +0.35 V versus Fc +/0 (Fc = ferrocene) that are tentatively ascribed to the oxidation of the {L OEt Ru} and {Ru(TTP)} moieties, respectively, whereas the Fe/Os (3) and Os/Ru (5) complexes exhibited Os-centered oxidation at approximately -0.06 and +0.05 V versus Fc +/0 , respectively. The crystal structures of 2 and 4b have been determined.

A Durable Airfield Marking System.

DTIC Science & Technology

1985-06-01

Resin is Mixed with the Black Curing Agent to Form the Epoxy Adhesive ..... ........... 17 14 The Gray Adhesive (White Resin Mixed with Black Curing...rubber 100 0 Polyester (peroxide-catalyzed) 100 0 Urethane 100 0 Epoxy polyamide 100 0 Acrylic latex (TT-P-1952) 100 0 Thermoplastic Tapes Type 1 100 0...suzmarrizes cost data co1parisons for traffic marking tapes, CAS tiles, fluorocarbon composites (Teflon ),and acrylic latex paint TT-P-1952. 8 -p °’. TABLE 2

Major pathogen microorganisms except yeasts can be detected from blood cultures within the first three days of incubation: A two-year study from a University Hospital.

PubMed

Moustos, Emmanuel; Staphylaki, Dimitra; Christidou, Athanasia; Spandidos, Demetrios A; Neonakis, Ioannis K

2017-12-01

The knowledge of the expected time-to-positivity (TTP) of blood cultures by major pathogens is essential both clinically and economically. To this end, we conducted the present two-year study in our Institution, aiming to assess the TTP of all the major microorganisms including Enterobacteriaceae, Pseudomonas aeruginosa , Acinetoacter baumannii , Enterococcii spp, Staphylococcus aureus and yeasts, to determine whether a 3-day interval is sufficient for their detection. The TTP for each case of strain isolation per patient was determined as the TTP of the first bottle among a set of bottles collected within the same period of time to be flagged as positive per patient. Based on our results, almost all major Gram-negative (99.30%), Gram-positive microbia (99.01%) and yeasts (98.85%) were detected within the first 5-days of incubation, leading to the solid conclusion that a 5-day period of incubation is adequate to detect almost all the major routine pathogens. By contrast, when a 3-day period was examined acceptable results were only found for Gram-negative (98.33%) and Gram-positive (98.51%) microbia. A significant proportion of yeasts (8.05%) could not be detected within this time frame. Therefore, regarding the yeasts, a 3-day incubation period cannot be considered as adequate and is not advocated.

SLCO2B1 and SLCO1B3 May Determine Time to Progression for Patients Receiving Androgen Deprivation Therapy for Prostate Cancer

PubMed Central

Yang, Ming; Xie, Wanling; Mostaghel, Elahe; Nakabayashi, Mari; Werner, Lillian; Sun, Tong; Pomerantz, Mark; Freedman, Matthew; Ross, Robert; Regan, Meredith; Sharifi, Nima; Figg, William Douglas; Balk, Steven; Brown, Myles; Taplin, Mary-Ellen; Oh, William K.; Lee, Gwo-Shu Mary; Kantoff, Philip W.

2011-01-01

Purpose Androgen deprivation therapy (ADT), an important treatment for advanced prostate cancer, is highly variable in its effectiveness. We hypothesized that genetic variants of androgen transporter genes, SLCO2B1 and SLCO1B3, may determine time to progression on ADT. Patients and Methods A cohort of 538 patients with prostate cancer treated with ADT was genotyped for SLCO2B1 and SLCO1B3 single nucleotide polymorphisms (SNP). The biologic function of a SLCO2B1 coding SNP in transporting androgen was examined through biochemical assays. Results Three SNPs in SLCO2B1 were associated with time to progression (TTP) on ADT (P < .05). The differences in median TTP for each of these polymorphisms were about 10 months. The SLCO2B1 genotype, which allows more efficient import of androgen, enhances cell growth and is associated with a shorter TTP on ADT. Patients carrying both SLCO2B1 and SLCO1B3 genotypes, which import androgens more efficiently, exhibited a median 2-year shorter TTP on ADT, demonstrating a gene-gene interaction (Pinteraction = .041). Conclusion Genetic variants of SLCO2B1 and SLCO1B3 may function as pharmacogenomic determinants of resistance to ADT in prostate cancer. PMID:21606417

Possible mechanism to enhance spin-fluctuation-mediated superconductivity in two-dimensional organic conductor

NASA Astrophysics Data System (ADS)

Nonoyama, Yoshito; Maekawa, Yukiko; Kobayashi, Akito; Suzumura, Yoshikazu; Yamada, Jun-ichi

2008-10-01

Mechanisms of superconductivity in quasi-two-dimensional organic conductors have been investigated using an extended Hubbard model by using the transfer energies between BDA-TTP molecules for β-(BDA-TTP)2I3 based on the X-ray experiment data and the extended Hückel calculation. We obtain several mean-field solutions with charge orderings which may represent short-range orderings or low-energy fluctuations in the low-dimensional electronic system. In the pressure-temperature phase diagram, a charge ordered metal state almost degenerates with a normal metal state between an insulating phase with charge ordering and the normal metal phase. Using the random phase approximation (RPA) and the linearized gap equation, the transition temperature of the superconducting state is estimated for the charge-ordered metal state and the normal metal state. It is found that transition temperature of the superconductivity induced by spin fluctuations in the charge-ordered metal state is much higher than that of the normal metal state and that the superconductivity in the charge-ordered metal state is the gapless d-wave. This suggests that the short range charge ordering may also contribute to an enhancement of spin-fluctuation-mediated superconductivity. The difference in the superconducting states between β-(BDA-TTP)2I3 and β-(BDA-TTP)2SbF6 are briefly discussed.

Local pressure and matrix component effects on verteporfin distribution in pancreatic tumors (Conference Presentation)

NASA Astrophysics Data System (ADS)

Nieskoski, Michael D.; Marra, Kayla; Gunn, Jason R.; Doyley, Marvin; Samkoe, Kimberly S.; Pereira, Stephen P.; Trembly, B. Stuart; Pogue, Brian W.

2017-02-01

Pancreatic tumors are characterized by large interstitial hypertension from enhanced deposition of extracellular matrix components, resulting in widespread vascular collapse and reduced molecular uptake of systemically delivered therapies. Although the origins of hypoperfusion is debated amongst researchers, spatial distribution of collagen density and hyaluronic acid content have shown to be a key metric in understanding the lack of efficacy for both acute and chronic therapies in these tumors. In this study, the AsPC-1 tumor model was used both subcutaneously and orthotopically to study the measurable factors which are related to this. A conventional piezoelectric pressure catheter was used to measure total tissue pressure (TTP), defined as a combination of solid stress (SS) and interstitial fluid pressure (IFP), TTP = SS + IFP, in multiple locations within the tumor interstitium. Matrix components such as collagen and hyaluronic acid were scored using masson's trichrome stain and hyaluronic acid binding protein (HABP), respectively, and co-registered with values of TTP. The results show that these key measurements are related to the spatial distribution of verteporfin in the same tumors. Photodynamic treatment with verteporfin is known to ablate large regions of tumor tissue and also allow better permeability for chemotherapies. The study of spatial distribution of verteporfin in relation to stromal content and TTP will help us better control these types of combination therapies.

Direct comparison of Xpert MTB/RIF assay with liquid and solid mycobacterial culture for quantification of early bactericidal activity.

PubMed

Kayigire, Xavier A; Friedrich, Sven O; Venter, Amour; Dawson, Rodney; Gillespie, Stephen H; Boeree, Martin J; Heinrich, Norbert; Hoelscher, Michael; Diacon, Andreas H

2013-06-01

The early bactericidal activity of antituberculosis agents is usually determined by measuring the reduction of the sputum mycobacterial load over time on solid agar medium or in liquid culture. This study investigated the value of a quantitative PCR assay for early bactericidal activity determination. Groups of 15 patients were treated with 6 different antituberculosis agents or regimens. Patients collected sputum for 16 h overnight at baseline and at days 7 and 14 after treatment initiation. We determined the sputum bacterial load by CFU counting (log CFU/ml sputum, reported as mean ± standard deviation [SD]), time to culture positivity (TTP, in hours [mean ± SD]) in liquid culture, and Xpert MTB/RIF cycle thresholds (C(T), n [mean ± SD]). The ability to discriminate treatment effects between groups was analyzed with one-way analysis of variance (ANOVA). All measurements showed a decrease in bacterial load from mean baseline (log CFU, 5.72 ± 1.00; TTP, 116.0 ± 47.6; C(T), 19.3 ± 3.88) to day 7 (log CFU, -0.26 ± 1.23, P = 0.2112; TTP, 35.5 ± 59.3, P = 0.0002; C(T), 0.55 ± 3.07, P = 0.6030) and day 14 (log CFU, -0.55 ± 1.24, P = 0.0006; TTP, 54.8 ± 86.8, P < 0.0001; C(T), 2.06 ± 4.37, P = 0.0020). The best discrimination between group effects was found with TTP at day 7 and day 14 (F = 9.012, P < 0.0001, and F = 11.580, P < 0.0001), followed by log CFU (F = 4.135, P = 0.0024, and F = 7.277, P < 0.0001). C(T) was not significantly discriminative (F = 1.995, P = 0.091, and F = 1.203, P = 0.316, respectively). Culture-based methods are superior to PCR for the quantification of early antituberculosis treatment effects in sputum.

Quantitative cerebral perfusion assessment using microscope-integrated analysis of intraoperative indocyanine green fluorescence angiography versus positron emission tomography in superficial temporal artery to middle cerebral artery anastomosis.

PubMed

Kobayashi, Shinya; Ishikawa, Tatsuya; Tanabe, Jun; Moroi, Junta; Suzuki, Akifumi

2014-01-01

Intraoperative qualitative indocyanine green (ICG) angiography has been used in cerebrovascular surgery. Hyperperfusion may lead to neurological complications after superficial temporal artery to middle cerebral artery (STA-MCA) anastomosis. The purpose of this study is to quantitatively evaluate intraoperative cerebral perfusion using microscope-integrated dynamic ICG fluorescence analysis, and to assess whether this value predicts hyperperfusion syndrome (HPS) after STA-MCA anastomosis. Ten patients undergoing STA-MCA anastomosis due to unilateral major cerebral artery occlusive disease were included. Ten patients with normal cerebral perfusion served as controls. The ICG transit curve from six regions of interest (ROIs) on the cortex, corresponding to ROIs on positron emission tomography (PET) study, was recorded. Maximum intensity (IMAX), cerebral blood flow index (CBFi), rise time (RT), and time to peak (TTP) were evaluated. RT/TTP, but not IMAX or CBFi, could differentiate between control and study subjects. RT/TTP correlated (|r| = 0.534-0.807; P < 0.01) with mean transit time (MTT)/MTT ratio in the ipsilateral to contralateral hemisphere by PET study. Bland-Altman analysis showed a wide limit of agreement between RT and MTT and between TTP and MTT. The ratio of RT before and after bypass procedures was significantly lower in patients with postoperative HPS than in patients without postoperative HPS (0.60 ± 0.032 and 0.80 ± 0.056, respectively; P = 0.017). The ratio of TTP was also significantly lower in patients with postoperative HPS than in patients without postoperative HPS (0.64 ± 0.081 and 0.85 ± 0.095, respectively; P = 0.017). Time-dependent intraoperative parameters from the ICG transit curve provide quantitative information regarding cerebral circulation time with quality and utility comparable to information obtained by PET. These parameters may help predict the occurrence of postoperative HPS.

A cohort study evaluation of maternal PCB exposure related to time to pregnancy in daughters.

PubMed

Gennings, Chris; Carrico, Caroline; Factor-Litvak, Pam; Krigbaum, Nickilou; Cirillo, Piera M; Cohn, Barbara A

2013-08-20

Polychlorinated biphenyls (PCBs) remain ubiquitous environmental contaminants. Developmental exposures are suspected to impact reproduction. Analysis of mixtures of PCBs may be problematic as components have a complex correlation structure, and along with limited sample sizes, standard regression strategies are problematic. We compared the results of a novel, empirical method to those based on categorization of PCB compounds by (1) hypothesized biological activity previously proposed and widely applied, and (2) degree of ortho- substitution (mono, di, tri), in a study of the relation of maternal serum PCBs and daughter's time to pregnancy. We measured PCBs in maternal serum samples collected in the early postpartum in 289 daughters in the Child Health and Development Studies birth cohort. We queried time to pregnancy in these daughters 28-31 years later. We applied a novel weighted quantile sum approach to find the bad-actor compounds in the PCB mixture found in maternal serum. The approach includes empirical estimation of the weights through a bootstrap step which accounts for the variation in the estimated weights. Bootstrap analyses indicated the dominant functionality groups associated with longer TTP were the dioxin-like, anti-estrogenic group (average weight, 22%) and PCBs not previously classified by biological activity (54%). In contrast, the unclassified PCBs were not important in the association with shorter TTP, where the anti-estrogenic groups and the PB-inducers group played a more important role (60% and 23%, respectively). The highly chlorinated PCBs (average weight, 89%) were mostly associated with longer TTP; in contrast, the degree of chlorination was less discriminating for shorter TTP. Finally, PCB 56 was associated with the strongest relationship with TTP with a weight of 47%. Our empirical approach found some associations previously identified by two classification schemes, but also identified other bad actors. This empirical method can generate hypotheses about mixture effects and mechanisms and overcomes some of the limitations of standard regression techniques.

Basis of Miscoding of the DNA Adduct N2,3-Ethenoguanine by Human Y-family DNA Polymerases*

PubMed Central

Zhao, Linlin; Pence, Matthew G.; Christov, Plamen P.; Wawrzak, Zdzislaw; Choi, Jeong-Yun; Rizzo, Carmelo J.; Egli, Martin; Guengerich, F. Peter

2012-01-01

N2,3-Ethenoguanine (N2,3-ϵG) is one of the exocyclic DNA adducts produced by endogenous processes (e.g. lipid peroxidation) and exposure to bioactivated vinyl monomers such as vinyl chloride, which is a known human carcinogen. Existing studies exploring the miscoding potential of this lesion are quite indirect because of the lability of the glycosidic bond. We utilized a 2′-fluoro isostere approach to stabilize this lesion and synthesized oligonucleotides containing 2′-fluoro-N2,3-ϵ-2′-deoxyarabinoguanosine to investigate the miscoding potential of N2,3-ϵG by Y-family human DNA polymerases (pols). In primer extension assays, pol η and pol κ replicated through N2,3-ϵG, whereas pol ι and REV1 yielded only 1-base incorporation. Steady-state kinetics revealed that dCTP incorporation is preferred opposite N2,3-ϵG with relative efficiencies in the order of pol κ > REV1 > pol η ≈ pol ι, and dTTP misincorporation is the major miscoding event by all four Y-family human DNA pols. Pol ι had the highest dTTP misincorporation frequency (0.71) followed by pol η (0.63). REV1 misincorporated dTTP and dGTP with much lower frequencies. Crystal structures of pol ι with N2,3-ϵG paired to dCTP and dTTP revealed Hoogsteen-like base pairing mechanisms. Two hydrogen bonds were observed in the N2,3-ϵG:dCTP base pair, whereas only one appears to be present in the case of the N2,3-ϵG:dTTP pair. Base pairing mechanisms derived from the crystal structures explain the slightly favored dCTP insertion for pol ι in steady-state kinetic analysis. Taken together, these results provide a basis for the mutagenic potential of N2,3-ϵG. PMID:22910910

Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

PubMed Central

Piskorz, Anna M.; Biggs, Heather; Addley, Helen; Freeman, Sue; Moyle, Penelope; Sala, Evis; Sayal, Karen; Hosking, Karen; Gounaris, Ioannis; Earl, Helena M.; Rosenfeld, Nitzan; Brenton, James D.

2016-01-01

Background Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). Methods and Findings We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%–22%) compared to 0.7% (IQR 0.3%–2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28–54) compared with a median time to nadir of 84 d (IQR 42–116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07–0.67, p = 0.008). Conversely, a decrease in TP53MAF of ≤60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%–92%) and 88% specificity (95% CI 64%–99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort. Conclusions In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment. PMID:27997533

Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study.

PubMed

Parkinson, Christine A; Gale, Davina; Piskorz, Anna M; Biggs, Heather; Hodgkin, Charlotte; Addley, Helen; Freeman, Sue; Moyle, Penelope; Sala, Evis; Sayal, Karen; Hosking, Karen; Gounaris, Ioannis; Jimenez-Linan, Mercedes; Earl, Helena M; Qian, Wendi; Rosenfeld, Nitzan; Brenton, James D

2016-12-01

Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%-22%) compared to 0.7% (IQR 0.3%-2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to chemotherapy was seen earlier with ctDNA, with a median time to nadir of 37 d (IQR 28-54) compared with a median time to nadir of 84 d (IQR 42-116) for CA-125. In 32 relapsed treatment courses evaluable for response after one cycle of chemotherapy, a decrease in TP53MAF of >60% was an independent predictor of TTP in multivariable analysis (hazard ratio 0.22, 95% CI 0.07-0.67, p = 0.008). Conversely, a decrease in TP53MAF of ≤60% was associated with poor response and identified cases with TTP < 6 mo with 71% sensitivity (95% CI 42%-92%) and 88% specificity (95% CI 64%-99%). Specificity was improved when patients with recent drainage of ascites were excluded. Ascites drainage led to a reduction of TP53MAF concentration. The limitations of this study include retrospective design, small sample size, and heterogeneity of treatment within the cohort. In this retrospective study, we demonstrated that ctDNA is correlated with volume of disease at the start of treatment in women with HGSOC and that a decrease of ≤60% in TP53MAF after one cycle of chemotherapy was associated with shorter TTP. These results provide evidence that ctDNA has the potential to be a highly specific early molecular response marker in HGSOC and warrants further investigation in larger cohorts receiving uniform treatment.

Evaluation of brain perfusion in Alzheimer disease with perfusion computed tomography and comparison to elderly patient without dementia.

PubMed

Yildirim, Tülin; Karakurum Göksel, Başak; Demir, Şenay; Tokmak, Naime; Tan, Meliha

2016-04-19

The aim of this study was to evaluate perfusion computed tomography (PCT) findings in patients with Alzheimer disease and to compare them with those of patients without dementia. PCT was performed in 35 patients: 20 with Alzheimer disease (mean age, 69.7 ± 5.5 years) and 15 control subjects (mean age, 67.5 ± 3.5 years). Control subjects were elderly individuals with no cognitive problems who were admitted with headaches. All PCT examinations were performed on a 4-slice CT unit. The PCT analysis software program was used to calculate regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), regional time-to-peak (rTTP) values in the bilateral frontal, temporal, and occipital cortices, and bilateral lentiform nucleus. rCBF values in the bilateral frontal and temporal cortices and bilateral lentiform nucleus were significantly lower in the patients with Alzheimer disease than in the control subjects. There were no significant differences in rCBV values between Alzheimer disease and the control group. rTTP values in all cortical areas and bilateral lentiform nucleus were significantly higher in the patients with Alzheimer disease than in the control subjects. PCT is a rapid and reliable imaging modality for evaluating brain perfusion in Alzheimer disease.

Pre-pregnancy fast food and fruit intake is associated with time to pregnancy.

PubMed

Grieger, Jessica A; Grzeskowiak, Luke E; Bianco-Miotto, Tina; Jankovic-Karasoulos, Tanja; Moran, Lisa J; Wilson, Rebecca L; Leemaqz, Shalem Y; Poston, Lucilla; McCowan, Lesley; Kenny, Louise C; Myers, Jenny; Walker, James J; Norman, Robert J; Dekker, Gus A; Roberts, Claire T

2018-06-01

Is preconception dietary intake associated with reduced fecundity as measured by a longer time to pregnancy (TTP)? Lower intake of fruit and higher intake of fast food in the preconception period were both associated with a longer TTP. Several lifestyle factors, such as smoking and obesity, have consistently been associated with a longer TTP or infertility, but the role of preconception diet in women remains poorly studied. Healthier foods or dietary patterns have been associated with improved fertility, however, these studies focused on women already diagnosed with or receiving treatments for infertility, rather than in the general population. This was a multi-center pregnancy-based cohort study of 5628 nulliparous women with low-risk singleton pregnancies who participated in the Screening for Pregnancy Endpoints (SCOPE) study. A total of 5598 women were included. Data on retrospectively reported TTP and preconception dietary intake were collected during the first antenatal study visit (14-16 weeks' gestation). Dietary information for the 1 month prior to conception was obtained from food frequency questions for fruit, green leafy vegetables, fish and fast foods, by a research midwife. Use of any fertility treatments associated with the current pregnancy was documented (yes, n = 340, no, n = 5258). Accelerated failure time models with log normal distribution were conducted to estimate time ratios (TR) and 95% CIs. The impact of differences in dietary intake on infertility (TTP >12 months) was compared using a generalized linear model (Poisson distribution) with robust variance estimates, with resulting relative risks (RR) and 95% CIs. All analyses were controlled for a range of maternal and paternal confounders. Sensitivity analyses were conducted to explore potential biases common to TTP studies. Lower intakes of fruit and higher intakes of fast food were both associated with modest increases in TTP and infertility. Absolute differences between the lowest and highest categories of intake for fruit and fast food were in the order of 0.6-0.9 months for TTP and 4-8% for infertility. Compared with women who consumed fruit ≥3 times/day, the adjusted effects of consuming fruit ≥1-<3 times/day (TR = 1.06, 95% CI: 0.97-1.15), 1-6 times/week (TR = 1.11, 95% CI: 1.01-1.22) or <1-3 times/month (TR = 1.19, 95% CI: 1.03-1.36), corresponded to 6, 11 and 19% increases in the median TTP (Ptrend = 0.007). Similarly, compared with women who consumed fast food ≥4 times/week, the adjusted effects of consuming fast food ≥2-<4 times/week (TR = 0.89, 95% CI: 0.81-0.98), >0-<2 times/week (TR 0.79, 95% CI 0.69-0.89) or no fast food (TR = 0.76, 95% CI: 0.61-0.95), corresponded to an 11, 21 and 24% reduction in the median TTP (Ptrend <0.001). For infertility, compared with women who consumed fruit ≥3 times/day, the adjusted effects of consuming fruit ≥1-<3 times/day, 1-6 times/week or <1-3 times/month corresponded to a 7, 18 and 29% increase in risk of infertility (Ptrend = 0.043). Similarly, compared with women who consumed fast food ≥4 times/week, the adjusted effects of consuming fast food ≥2-<4 times/week, >0-<2 times/week, or no fast food, corresponded to an 18, 34 and 41% reduced risk of infertility (Ptrend <0.001). Pre-pregnancy intake of green leafy vegetables or fish were not associated with TTP or infertility. Estimates remained stable across a range of sensitivity analyses. Collection of dietary data relied on retrospective recall and evaluated a limited range of foods. Paternal dietary data was not collected and the potential for residual confounding cannot be eliminated. Compared to prospective TTP studies, retrospective TTP studies are prone to a number of potential sources of bias. These findings underscore the importance of considering preconception diet for fecundity outcomes and preconception guidance. Further research is needed assessing a broader range of foods and food groups in the preconception period. The SCOPE database is provided and maintained by MedSciNet AB (http://medscinet.com). The Australian SCOPE study was funded by the Premier's Science and Research Fund, South Australian Government (http://www.dfeest.sa.gov.au/science-research/premiers-research-and-industry-fund). The New Zealand SCOPE study was funded by the New Enterprise Research Fund, Foundation for Research Science and Technology; Health Research Council (04/198); Evelyn Bond Fund, Auckland District Health Board Charitable Trust. The Irish SCOPE study was funded by the Health Research Board of Ireland (CSA/2007/2; http://www.hrb.ie). The UK SCOPE study was funded by National Health Service NEAT Grant (Neat Grant FSD025), Biotechnology and Biological Sciences Research council (www.bbsrc.ac.uk/funding; GT084) and University of Manchester Proof of Concept Funding (University of Manchester); Guy's and St. Thomas' Charity (King's College London) and Tommy's charity (http://www.tommys.org/; King's College London and University of Manchester); and Cerebra UK (www.cerebra.org.uk; University of Leeds). L.E.G. is supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship (ID 1070421). L.J.M. is supported by a SACVRDP Fellowship; a program collaboratively funded by the National Heart Foundation, the South Australian Department of Health and the South Australian Health and Medical Research Institute. L.C.K. is supported by a Science Foundation Ireland Program Grant for INFANT (12/RC/2272). C.T.R. was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship (GNT1020749). There are no conflicts of interest to declare. Not applicable.

Employment of Direct Fire Systems during Offensive Operations

DTIC Science & Technology

1990-06-01

problems, this criteria suffers from a lack of offensive direct fire planning as part 115 of the scheme of maneuver. Limited TTP discussion in the...these specific occurrences. Doctrine writers could develop TTP to do so. This problem could involve unit training practices. If units differentiate ...10 0 0 0 5 PURPOSE) 4. - IDENTIFIES DIRECT FIRE I 76 15 20 130 21 15 115 R&S PRIORITY (PIR/IR) 5. - IDENTIFIES ENGAGEMENT 1 5 10 0 25 16 0 0 PRIORITY

Everolimus in Combination with Octreotide Long-Acting Repeatable in a First-Line Setting for Patients with Neuroendocrine Tumors: A 5-Year Update.

PubMed

Bajetta, Emilio; Catena, Laura; Pusceddu, Sara; Spada, Francesca; Iannacone, Claudio; Sarno, Italo; Di Menna, Giandomenico; Dottorini, Lorenzo; Marte, Anna Maria

2018-01-01

We previously presented data of this multicentric, phase II study showing that everolimus plus octreotide long-acting repeatable (LAR) for advanced neuroendocrine neoplasms (NENs), in the first line setting, is an active and safe treatment. We now present updated data at 5 years. Patients with advanced well-differentiated, previously untreated neuroendocrine tumors of the gastroenteropancreatic tract and of the lung received octreotide LAR 30 mg plus everolimus 10 mg/day. The primary endpoint was the objective response rate (ORR). We performed an analysis of "long responder" patients and of time to progression (TTP) and overall survival (OS) at 5 years. Fifty patients were enrolled; the primary tumor site was: pancreas (14 patients), lung (11 patients), ileum (9 patients), jejunum/duodenum (2 patients), and unknown (14 patients). Seventeen (34%) of these patients have received treatment for more than 2 years. The median exposure to study drugs was 519.5 days (range 48-2,024). Currently 3 patients are still in treatment. The ORR (partial response + complete response) was 18% (95% confidence interval [CI] 7.4-28.6): complete response 1 patient (2%), partial response 8 patients (16%), stable disease 37 patients (74%). The median TTP was 33.6 months (95% CI 18.7-41.2) and the median OS was 61.0 months (95% CI 49.8-not reached). In this update of clinical outcome at 5-year follow-up, everolimus plus octreotide has been shown to be active in advanced NENs. The current analysis showed a further prolongation of TTP and a long exposure to the study drug without major side effects in the long term. © 2017 S. Karger AG, Basel.

Annexin-A1 and caldesmon are associated with resistance to tamoxifen in estrogen receptor positive recurrent breast cancer.

PubMed

De Marchi, Tommaso; Timmermans, Anne M; Smid, Marcel; Look, Maxime P; Stingl, Christoph; Opdam, Mark; Linn, Sabine C; Sweep, Fred C G J; Span, Paul N; Kliffen, Mike; van Deurzen, Carolien H M; Luider, Theo M; Foekens, John A; Martens, John W; Umar, Arzu

2016-01-19

Tamoxifen therapy resistance constitutes a major cause of death in patients with recurrent estrogen receptor (ER) positive breast cancer. Through high resolution mass spectrometry (MS), we previously generated a 4-protein predictive signature for tamoxifen therapy outcome in recurrent breast cancer. ANXA1 and CALD1, which were not included in the classifier, were however the most differentially expressed proteins. We first evaluated the clinical relevance of these markers in our MS cohort, followed by immunohistochemical (IHC) staining on an independent set of tumors incorporated in a tissue microarray (TMA) and regression analysis in relation to time to progression (TTP), clinical benefit and objective response. In order to assess which mechanisms ANXA1 and CALD1 might been involved in, we performed Ingenuity pathway analysis (IPA) on ANXA1 and CALD1 correlated proteins in our MS cohort. ANXA1 (Hazard ratio [HR] = 1.83; 95% confidence interval [CI]: 1.22-2.75; P = 0.003) and CALD1 (HR = 1.57; 95% CI: 1.04-2.36; P = 0.039) based patient stratification showed significant association to TTP, while IHC staining on TMA showed that both ANXA1 (HR = 1.82; 95% CI: 1.12-3.00; P = 0.016) and CALD1 (HR = 2.29; 95% CI: 1.40-3.75; P = 0.001) expression was associated with shorter TTP independently of traditional predictive factors. Pearson correlation analysis showed that the majority of proteins correlated to ANXA1 also correlated with CALD1. IPA indicated that ANXA1 and CALD1 were associated with ER-downregulation and NFκB signaling. We hereby report that ANXA1 and CALD1 proteins are independent markers for tamoxifen therapy outcome and are associated to fast tumor progression.

Randomized, phase II trial of pemetrexed and carboplatin with or without enzastaurin versus docetaxel and carboplatin as first-line treatment of patients with stage IIIB/IV non-small cell lung cancer.

PubMed

Socinski, Mark A; Raju, Robert N; Stinchcombe, Thomas; Kocs, Darren M; Couch, Linda S; Barrera, David; Rousey, Steven R; Choksi, Janak K; Jotte, Robert; Patt, Debra A; Periman, Phillip O; Schlossberg, Howard R; Weissman, Charles H; Wang, Yunfei; Asmar, Lina; Pritchard, Sharon; Bromund, Jane; Peng, Guangbin; Treat, Joseph; Obasaju, Coleman K

2010-12-01

Enzastaurin is an oral serine/threonine kinase inhibitor that targets protein kinase C-beta (PKC-β) and the phosphatidylinositol-3-kinase/AKT pathway. This trial assessed pemetrexed-carboplatin ± enzastaurin to docetaxel-carboplatin in advanced non-small cell lung cancer. Patients with stage IIIB (with pleural effusion) or IV non-small cell lung cancer and performance status 0 or 1 were randomized to one of the three arms: (A) pemetrexed 500 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to 6 cycles with a loading dose of enzastaurin 1125 or 1200 mg followed by 500 mg daily until disease progression, (B) the same regimen of pemetrexed-carboplatin without enzastaurin, or (C) docetaxel 75 mg/m and carboplatin area under the curve 6 once every 3 weeks for up to six cycles. The primary end point was time to disease progression (TTP). Between March 2006 and May 2008, 218 patients were randomized. Median TTP was 4.6 months for pemetrexed-carboplatin-enzastaurin, 6.0 months for pemetrexed-carboplatin, and 4.1 months for docetaxel-carboplatin (differences not significant). Median survival was 7.2 months for pemetrexed-carboplatin-enzastaurin, 12.7 months for pemetrexed-carboplatin, and 9.2 months for docetaxel-carboplatin (log-rank p = 0.05). Compared with the other arms, docetaxel-carboplatin was associated with lower rates of grade 3 thrombocytopenia and anemia but a higher rate of grade 3 or 4 febrile neutropenia. There was no difference in TTP between the three arms, but survival was longer with pemetrexed-carboplatin compared with docetaxel-carboplatin. Enzastaurin did not add to the activity of pemetrexed-carboplatin.

Transcatheter arterial chemoembolisation (TACE) plus S-1 for the treatment of BCLC stage B hepatocellular carcinoma refractory to TACE.

PubMed

Huang, Wu-Kui; Yang, Shu-Fa; You, Li-Na; Liu, Mo; Liu, Deng-Yao; Gu, Peng; Fan, Xi-Wen

2016-01-01

To assess the efficacy and safety of transcatheter arterial chemoembolization (TACE) plus S-1 for the treatment of Barcelona Clinic Liver Cancer (BCLC) Stage B HCC refractory to TACE. 26 patients meeting the eligibility criteria were enrolled. TACE was given on day 1, and S-1 on days 2-15. Tumor assessment was performed one month later according to mRECIST. The primary endpoints were TTP and OS. Twenty-six patients received 176 TACE interventions in all. Fifteen patients of TACE plus S-1 received a total of 55 cycles of treatment of S-1, with a median of 4 cycles (range, 2-6). The total dose of S-1 was 6165 mg per day, while average was 120 mg (range, 100-125 mg) for 15 patients of TACE plus S-1. Median TTP and OS of TACE plus S-1 were 6 months (95% CI: 4.7-7.3) and 18 months (95% CI: 15.3-24.7), respectively, while TACE monotherapy was 4 months (95% CI: 2.4-5.6) and 13 months (95% CI: 9.8-16.2), respectively, and significant differences were detected. Though there were higher DCRs in patients of TACE plus S-1, no significant differences were detected. A total of 612 adverse events occurred during the course of the treatment, 367 in TACE plus S-1 and 245 in TACE mono-therapy. There were significant differences to anorexia and nausea, but they were tolerable. TACE plus S-1 in the present analysis was tolerable and associated with an interesting TTP and OS. TACE plus S-1 may be used as a new treatment method to BCLC Stage B HCC refractory to TACE.

Structural Consequences of Mutations to the α-Tocopherol Transfer Protein Associated with the Neurodegenerative Disease Ataxia with Vitamin E Deficiency

PubMed Central

Bromley, Dennis; Anderson, Peter C.; Daggett, Valerie

2013-01-01

The α-tocopherol transfer protein (α-TTP) is a liver protein that transfers α-tocopherol (vitamin E) to very-low-density lipoproteins (VLDLs). These VLDLs are then circulated throughout the body to maintain blood α-tocopherol levels. Mutations to the α-TTP gene are associated with ataxia with vitamin E deficiency (AVED), a disease characterized by peripheral nerve degeneration. In this study, molecular dynamics simulations of the E141K and R59W disease-associated mutants were performed. The mutants displayed disruptions in and around the ligand-binding pocket. Structural analysis and ligand docking to the mutant structures predicted a decreased affinity for α-tocopherol. To determine the detailed mechanism of the mutation-related changes, we developed a new tool called ContactWalker that analyzes contact differences between mutant and wild-type proteins and highlights pathways of altered contacts within the mutant proteins. Taken together, our findings are in agreement with experiment and suggest structural explanations for the reduced ability of the mutants to bind and carry α-tocopherol. PMID:23713716

Analytical Comparison of In Vitro-Spiked Human Serum and Plasma for PCR-Based Detection of Aspergillus fumigatus DNA: a Study by the European Aspergillus PCR Initiative

PubMed Central

Mengoli, Carlo; Springer, Jan; Bretagne, Stéphane; Cuenca-Estrella, Manuel; Klingspor, Lena; Lagrou, Katrien; Melchers, Willem J. G.; Morton, C. Oliver; Barnes, Rosemary A.; Donnelly, J. Peter; White, P. Lewis

2015-01-01

The use of serum or plasma for Aspergillus PCR testing facilitates automated and standardized technology. Recommendations for serum testing are available, and while serum and plasma are regularly considered interchangeable for use in fungal diagnostics, differences in galactomannan enzyme immunoassay (GM-EIA) performance have been reported and are attributed to clot formation. Therefore, it is important to assess plasma PCR testing to determine if previous recommendations for serum are applicable and also to compare analytical performance with that of serum PCR. Molecular methods testing serum and plasma were compared through multicenter distribution of quality control panels, with additional studies to investigate the effect of clot formation and blood fractionation on DNA availability. Analytical sensitivity and time to positivity (TTP) were compared, and a regression analysis was performed to identify variables that enhanced plasma PCR performance. When testing plasma, sample volume, preextraction-to-postextraction volume ratio, PCR volume, duplicate testing, and the use of an internal control for PCR were positively associated with performance. When whole-blood samples were spiked and then fractionated, the analytical sensitivity and TTP were superior when testing plasma. Centrifugation had no effect on DNA availability, whereas the presence of clot material significantly lowered the concentration (P = 0.028). Technically, there are no major differences in the molecular processing of serum and plasma, but the formation of clot material potentially reduces available DNA in serum. During disease, Aspergillus DNA burdens in blood are often at the limits of PCR performance. Using plasma might improve performance while maintaining the methodological simplicity of serum testing. PMID:26085614

Analytical Comparison of In Vitro-Spiked Human Serum and Plasma for PCR-Based Detection of Aspergillus fumigatus DNA: a Study by the European Aspergillus PCR Initiative.

PubMed

Loeffler, Juergen; Mengoli, Carlo; Springer, Jan; Bretagne, Stéphane; Cuenca-Estrella, Manuel; Klingspor, Lena; Lagrou, Katrien; Melchers, Willem J G; Morton, C Oliver; Barnes, Rosemary A; Donnelly, J Peter; White, P Lewis

2015-09-01

The use of serum or plasma for Aspergillus PCR testing facilitates automated and standardized technology. Recommendations for serum testing are available, and while serum and plasma are regularly considered interchangeable for use in fungal diagnostics, differences in galactomannan enzyme immunoassay (GM-EIA) performance have been reported and are attributed to clot formation. Therefore, it is important to assess plasma PCR testing to determine if previous recommendations for serum are applicable and also to compare analytical performance with that of serum PCR. Molecular methods testing serum and plasma were compared through multicenter distribution of quality control panels, with additional studies to investigate the effect of clot formation and blood fractionation on DNA availability. Analytical sensitivity and time to positivity (TTP) were compared, and a regression analysis was performed to identify variables that enhanced plasma PCR performance. When testing plasma, sample volume, preextraction-to-postextraction volume ratio, PCR volume, duplicate testing, and the use of an internal control for PCR were positively associated with performance. When whole-blood samples were spiked and then fractionated, the analytical sensitivity and TTP were superior when testing plasma. Centrifugation had no effect on DNA availability, whereas the presence of clot material significantly lowered the concentration (P = 0.028). Technically, there are no major differences in the molecular processing of serum and plasma, but the formation of clot material potentially reduces available DNA in serum. During disease, Aspergillus DNA burdens in blood are often at the limits of PCR performance. Using plasma might improve performance while maintaining the methodological simplicity of serum testing. Copyright © 2015 Loeffler et al.

Stroke in thrombotic thrombocytopenic purpura induced by thyrotoxicosis: a case report.

PubMed

Bellante, Flavio; Redondo Saez, Patricia; Springael, Cecile; Dethy, Sophie

2014-07-01

Thrombotic thrombocytopenic purpura (TTP) is a hematologic disease involving the platelet aggregation and resulting in hemolytic anemia, thrombocytopenia, and microvascular occlusion. Although frequent neurologic features are headache and confusion, focal deficit is described in 30% of the cases. There are a lot of causes inducing thrombotic thrombocytopenic, but reports are lacking when associated with Grave disease. We describe the case of a 51-year-old Caucasian woman presenting a 24-hour story of sudden onset of dysarthria and left superior limb palsy. Four months before, she developed severe hyperthyroidism associated with petechiae, hemolytic anemia, thrombocytopenia, and schistocytes at blood film examination. Relapse of TTP in association with Grave disease was diagnosed. There are few reports describing association between Grave disease and TTP with only mild neurologic involvement. We described, to our knowledge, the first case of acute ischemic stroke secondary to thrombotic thrombocytopenic induced by thyrotoxicosis. Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Mechanism of Superconductivity in Quasi-Two-Dimensional Organic Conductor β-(BDA-TTP) Salts

NASA Astrophysics Data System (ADS)

Nonoyama, Yoshito; Maekawa, Yukiko; Kobayashi, Akito; Suzumura, Yoshikazu; Ito, Hiroshi

2008-09-01

We investigate theoretically the superconductivity of two-dimensional organic conductors, β-(BDA-TTP)2SbF6 and β-(BDA-TTP)2AsF6, to understand the role of the spin and charge fluctuations. The transition temperature is estimated by applying random phase approximation to an extended Hubbard model wherein realistic transfer energies are estimated by extended Hückel calculation. We find a gapless superconducting state with a dxy-like symmetry, which is consistent with the experimental results obtained by specific heat and scanning tunneling microscope. In the present model with an effectively half-filled triangular lattice, spin fluctuation competes with charge fluctuation as a mechanism of pairing interaction since both fluctuations have the same characteristic momentum q=(π,0) for V being smaller than U. This is in contrast to a model with a quarter-filled square lattice, wherein both fluctuations contribute cooperatively to pairing interaction due to fluctuations having different characteristic momenta. The resultant difference in the superconductivity of these two materials is also discussed.

mTOR Regulates Cellular Iron Homeostasis through Tristetraprolin

PubMed Central

Bayeva, Marina; Khechaduri, Arineh; Puig, Sergi; Chang, Hsiang-Chun; Patial, Sonika; Blackshear, Perry J.; Ardehali, Hossein

2013-01-01

SUMMARY Iron is an essential cofactor with unique redox properties. Iron regulatory proteins 1 and 2 (IRP1/2) have been established as important regulators of cellular iron homeostasis, but little is known about the role of other pathways in this process. Here we report that the mammalian target of rapamycin (mTOR) regulates iron homeostasis by modulating transferrin receptor 1 (TfR1) stability and altering cellular iron flux. Mechanistic studies identify tristetraprolin (TTP), a protein involved in anti-inflammatory response, as the downstream target of mTOR that binds to and enhances degradation of TfR1 mRNA. We also show that TTP is strongly induced by iron chelation, promotes downregulation of iron-requiring genes in both mammalian and yeast cells, and modulates survival in low-iron states. Taken together, our data uncover a link between metabolic, inflammatory, and iron regulatory pathways, and point towards the existence of a yeast-like TTP-mediated iron conservation program in mammals. PMID:23102618

Association of acquired thrombotic thrombocytopaenic purpura in a patient with pernicious anaemia.

PubMed

Podder, Sidhertha; Cervates, Jose; Dey, Bimalangshu R

2015-10-13

Pernicious anaemia is an autoimmune disease caused by intrinsic factor antibody; it leads to vitamin B12 deficiency and is marked by ineffective erythropoiesis. Haematological features reveal macrocytosis, hyperchromasia and hypersegmented neutrophils. Schistocytes are typically seen in microangiopathy, such as in thrombotic thrombocytopaenic purpura (TTP)/haemolytic uraemic syndrome or disseminated intravascular haemolysis (DIC). We report a case of a patient with severe anaemia who presented to the emergency room. Peripheral smear revealed macrocytosis, hypersegmented neutrophils and marked schistocytosis. The patient also had high reticulocyte count with high serum lactate dehydrogenase, elevated D-dimer, low fibrinogen and low haptoglobin. Vitamin B12 level came back low and the presence of intrinsic factor antibody confirmed pernicious anaemia. ADAMTS13 level was noted to be mildly reduced, which raised the suspicion of the association of acquired TTP with pernicious anaemia. Acquired TTP is another autoimmune disorder and its association with pernicious anaemia needs further evaluation. 2015 BMJ Publishing Group Ltd.

miRNA signature associated with outcome of gastric cancer patients following chemotherapy

PubMed Central

2011-01-01

Background Identification of patients who likely will or will not benefit from cytotoxic chemotherapy through the use of biomarkers could greatly improve clinical management by better defining appropriate treatment options for patients. microRNAs may be potentially useful biomarkers that help guide individualized therapy for cancer because microRNA expression is dysregulated in cancer. In order to identify miRNA signatures for gastric cancer and for predicting clinical resistance to cisplatin/fluorouracil (CF) chemotherapy, a comprehensive miRNA microarray analysis was performed using endoscopic biopsy samples. Methods Biopsy samples were collected prior to chemotherapy from 90 gastric cancer patients treated with CF and from 34 healthy volunteers. At the time of disease progression, post-treatment samples were additionally collected from 8 clinical responders. miRNA expression was determined using a custom-designed Agilent microarray. In order to identify a miRNA signature for chemotherapy resistance, we correlated miRNA expression levels with the time to progression (TTP) of disease after CF therapy. Results A miRNA signature distinguishing gastric cancer from normal stomach epithelium was identified. 30 miRNAs were significantly inversely correlated with TTP whereas 28 miRNAs were significantly positively correlated with TTP of 82 cancer patients (P<0.05). Prominent among the upregulated miRNAs associated with chemosensitivity were miRNAs known to regulate apoptosis, including let-7g, miR-342, miR-16, miR-181, miR-1, and miR-34. When this 58-miRNA predictor was applied to a separate set of pre- and post-treatment tumor samples from the 8 clinical responders, all of the 8 pre-treatment samples were correctly predicted as low-risk, whereas samples from the post-treatment tumors that developed chemoresistance were predicted to be in the high-risk category by the 58 miRNA signature, suggesting that selection for the expression of these miRNAs occurred as chemoresistance arose. Conclusions We have identified 1) a miRNA expression signature that distinguishes gastric cancer from normal stomach epithelium from healthy volunteers, and 2) a chemoreresistance miRNA expression signature that is correlated with TTP after CF therapy. The chemoresistance miRNA expression signature includes several miRNAs previously shown to regulate apoptosis in vitro, and warrants further validation. PMID:22112324

Toward fully automated processing of dynamic susceptibility contrast perfusion MRI for acute ischemic cerebral stroke.

PubMed

Kim, Jinsuh; Leira, Enrique C; Callison, Richard C; Ludwig, Bryan; Moritani, Toshio; Magnotta, Vincent A; Madsen, Mark T

2010-05-01

We developed fully automated software for dynamic susceptibility contrast (DSC) MR perfusion-weighted imaging (PWI) to efficiently and reliably derive critical hemodynamic information for acute stroke treatment decisions. Brain MR PWI was performed in 80 consecutive patients with acute nonlacunar ischemic stroke within 24h after onset of symptom from January 2008 to August 2009. These studies were automatically processed to generate hemodynamic parameters that included cerebral blood flow and cerebral blood volume, and the mean transit time (MTT). To develop reliable software for PWI analysis, we used computationally robust algorithms including the piecewise continuous regression method to determine bolus arrival time (BAT), log-linear curve fitting, arrival time independent deconvolution method and sophisticated motion correction methods. An optimal arterial input function (AIF) search algorithm using a new artery-likelihood metric was also developed. Anatomical locations of the automatically determined AIF were reviewed and validated. The automatically computed BAT values were statistically compared with estimated BAT by a single observer. In addition, gamma-variate curve-fitting errors of AIF and inter-subject variability of AIFs were analyzed. Lastly, two observes independently assessed the quality and area of hypoperfusion mismatched with restricted diffusion area from motion corrected MTT maps and compared that with time-to-peak (TTP) maps using the standard approach. The AIF was identified within an arterial branch and enhanced areas of perfusion deficit were visualized in all evaluated cases. Total processing time was 10.9+/-2.5s (mean+/-s.d.) without motion correction and 267+/-80s (mean+/-s.d.) with motion correction on a standard personal computer. The MTT map produced with our software adequately estimated brain areas with perfusion deficit and was significantly less affected by random noise of the PWI when compared with the TTP map. Results of image quality assessment by two observers revealed that the MTT maps exhibited superior quality over the TTP maps (88% good rating of MTT as compared to 68% of TTP). Our software allowed fully automated deconvolution analysis of DSC PWI using proven efficient algorithms that can be applied to acute stroke treatment decisions. Our streamlined method also offers promise for further development of automated quantitative analysis of the ischemic penumbra. Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.

First-line therapy with moderate dose capecitabine in metastatic breast cancer is safe and active: results of the MONICA trial.

PubMed

Kaufmann, M; Maass, N; Costa, S D; Schneeweiss, A; Loibl, S; Sütterlin, M W; Schrader, I; Gerber, B; Bauer, W; Wiest, W; Tomé, O; Distelrath, A; Hagen, V; Kleine-Tebbe, A; Ruckhaeberle, E; Mehta, K; von Minckwitz, G

2010-12-01

To determine activity and safety of capecitabine at a moderate dose of 2000 mg/m(2) as first-line therapy for metastatic breast cancer. In this prospective phase II trial, patients with HER2-negative metastatic breast cancer received first-line capecitabine 2000 mg/m(2) on days 1-14 every 3 weeks. The primary aim was to exclude a time to progression (TTP) <6 months. Secondary end-points were overall response rate, overall survival (OS), toxicity and quality of life. Median age of the 161 included patients was 65 years. Median TTP and OS were 7.3 months [95% (confidence interval) CI: 6.2-8.4] and 17.1 months (95% CI: 14.0-20.3), respectively. An overall response rate of 26.1%, including 13 complete remissions was observed. Patients developing grade I-III hand-foot syndrome had a significantly longer TTP and OS and patients >65 years also achieved a significantly longer TTP. Haematological grade I-IV toxicities were leucopenia (64.0%), anaemia (50.9%) and thrombocytopenia (28.0%). Relevant non-haematological toxicities were hand-food-syndrome (37.3%), fatigue (34.2%), nausea (29.8%) and diarrhoea (20.5%). Quality of life assessment revealed an improved emotional function, but worsening of nausea and vomiting from cycle 1-10. Capecitabine at a dose of 2000 mg/m(2) is active and safe as first-line treatment of patients with metastatic breast cancer. Copyright © 2010 Elsevier Ltd. All rights reserved.

Increased variability of watershed areas in patients with high-grade carotid stenosis.

PubMed

Kaczmarz, Stephan; Griese, Vanessa; Preibisch, Christine; Kallmayer, Michael; Helle, Michael; Wustrow, Isabel; Petersen, Esben Thade; Eckstein, Hans-Henning; Zimmer, Claus; Sorg, Christian; Göttler, Jens

2018-03-01

Watershed areas (WSAs) of the brain are most susceptible to acute hypoperfusion due to their peripheral location between vascular territories. Additionally, chronic WSA-related vascular processes underlie cognitive decline especially in patients with cerebral hemodynamic compromise. Despite of high relevance for both clinical diagnostics and research, individual in vivo WSA definition is fairly limited to date. Thus, this study proposes a standardized segmentation approach to delineate individual WSAs by use of time-to-peak (TTP) maps and investigates spatial variability of individual WSAs. We defined individual watershed masks based on relative TTP increases in 30 healthy elderly persons and 28 patients with unilateral, high-grade carotid stenosis, being at risk for watershed-related hemodynamic impairment. Determined WSA location was confirmed by an arterial transit time atlas and individual super-selective arterial spin labeling. We compared spatial variability of WSA probability maps between groups and assessed TTP differences between hemispheres in individual and group-average watershed locations. Patients showed significantly higher spatial variability of WSAs than healthy controls. Perfusion on the side of the stenosis was delayed within individual watershed masks as compared to a watershed template derived from controls, being independent from the grade of the stenosis and collateralization status of the circle of Willis. Results demonstrate feasibility of individual WSA delineation by TTP maps in healthy elderly and carotid stenosis patients. Data indicate necessity of individual segmentation approaches especially in patients with hemodynamic compromise to detect critical regions of impaired hemodynamics.

Genetic requirements for sensitivity of bacteriophage t7 to dideoxythymidine.

PubMed

Tran, Ngoc Q; Tabor, Stanley; Richardson, Charles C

2014-08-01

We previously reported that the presence of dideoxythymidine (ddT) in the growth medium selectively inhibits the ability of bacteriophage T7 to infect Escherichia coli by inhibiting phage DNA synthese (N. Q. Tran, L. F. Rezende, U. Qimron, C. C. Richardson, and S. Tabor, Proc. Natl. Acad. Sci. U. S. A. 105:9373-9378, 2008, doi:10.1073/pnas.0804164105). In the presence of T7 gene 1.7 protein, ddT is taken up into the E. coli cell and converted to ddTTP. ddTTP is incorporated into DNA as ddTMP by the T7 DNA polymerase, resulting in chain termination. We have identified the pathway by which exogenous ddT is converted to ddTTP. The pathway consists of ddT transport by host nucleoside permeases and phosphorylation to ddTMP by the host thymidine kinase. T7 gene 1.7 protein phosphorylates ddTMP and ddTDP, resulting in ddTTP. A 74-residue peptide of the gene 1.7 protein confers ddT sensitivity to the same extent as the 196-residue wild-type gene 1.7 protein. We also show that cleavage of thymidine to thymine and deoxyribose-1-phosphate by the host thymidine phosphorylase greatly increases the sensitivity of phage T7 to ddT. Finally, a mutation in T7 DNA polymerase that leads to discrimination against the incorporation of ddTMP eliminates ddT sensitivity. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Improved shear wave group velocity estimation method based on spatiotemporal peak and thresholding motion search

PubMed Central

Amador, Carolina; Chen, Shigao; Manduca, Armando; Greenleaf, James F.; Urban, Matthew W.

2017-01-01

Quantitative ultrasound elastography is increasingly being used in the assessment of chronic liver disease. Many studies have reported ranges of liver shear wave velocities values for healthy individuals and patients with different stages of liver fibrosis. Nonetheless, ongoing efforts exist to stabilize quantitative ultrasound elastography measurements by assessing factors that influence tissue shear wave velocity values, such as food intake, body mass index (BMI), ultrasound scanners, scanning protocols, ultrasound image quality, etc. Time-to-peak (TTP) methods have been routinely used to measure the shear wave velocity. However, there is still a need for methods that can provide robust shear wave velocity estimation in the presence of noisy motion data. The conventional TTP algorithm is limited to searching for the maximum motion in time profiles at different spatial locations. In this study, two modified shear wave speed estimation algorithms are proposed. The first method searches for the maximum motion in both space and time (spatiotemporal peak, STP); the second method applies an amplitude filter (spatiotemporal thresholding, STTH) to select points with motion amplitude higher than a threshold for shear wave group velocity estimation. The two proposed methods (STP and STTH) showed higher precision in shear wave velocity estimates compared to TTP in phantom. Moreover, in a cohort of 14 healthy subjects STP and STTH methods improved both the shear wave velocity measurement precision and the success rate of the measurement compared to conventional TTP. PMID:28092532

Improved Shear Wave Group Velocity Estimation Method Based on Spatiotemporal Peak and Thresholding Motion Search.

PubMed

Amador Carrascal, Carolina; Chen, Shigao; Manduca, Armando; Greenleaf, James F; Urban, Matthew W

2017-04-01

Quantitative ultrasound elastography is increasingly being used in the assessment of chronic liver disease. Many studies have reported ranges of liver shear wave velocity values for healthy individuals and patients with different stages of liver fibrosis. Nonetheless, ongoing efforts exist to stabilize quantitative ultrasound elastography measurements by assessing factors that influence tissue shear wave velocity values, such as food intake, body mass index, ultrasound scanners, scanning protocols, and ultrasound image quality. Time-to-peak (TTP) methods have been routinely used to measure the shear wave velocity. However, there is still a need for methods that can provide robust shear wave velocity estimation in the presence of noisy motion data. The conventional TTP algorithm is limited to searching for the maximum motion in time profiles at different spatial locations. In this paper, two modified shear wave speed estimation algorithms are proposed. The first method searches for the maximum motion in both space and time [spatiotemporal peak (STP)]; the second method applies an amplitude filter [spatiotemporal thresholding (STTH)] to select points with motion amplitude higher than a threshold for shear wave group velocity estimation. The two proposed methods (STP and STTH) showed higher precision in shear wave velocity estimates compared with TTP in phantom. Moreover, in a cohort of 14 healthy subjects, STP and STTH methods improved both the shear wave velocity measurement precision and the success rate of the measurement compared with conventional TTP.

Genetic Requirements for Sensitivity of Bacteriophage T7 to Dideoxythymidine

PubMed Central

Tran, Ngoc Q.; Tabor, Stanley

2014-01-01

We previously reported that the presence of dideoxythymidine (ddT) in the growth medium selectively inhibits the ability of bacteriophage T7 to infect Escherichia coli by inhibiting phage DNA synthese (N. Q. Tran, L. F. Rezende, U. Qimron, C. C. Richardson, and S. Tabor, Proc. Natl. Acad. Sci. U. S. A. 105:9373–9378, 2008, doi:10.1073/pnas.0804164105). In the presence of T7 gene 1.7 protein, ddT is taken up into the E. coli cell and converted to ddTTP. ddTTP is incorporated into DNA as ddTMP by the T7 DNA polymerase, resulting in chain termination. We have identified the pathway by which exogenous ddT is converted to ddTTP. The pathway consists of ddT transport by host nucleoside permeases and phosphorylation to ddTMP by the host thymidine kinase. T7 gene 1.7 protein phosphorylates ddTMP and ddTDP, resulting in ddTTP. A 74-residue peptide of the gene 1.7 protein confers ddT sensitivity to the same extent as the 196-residue wild-type gene 1.7 protein. We also show that cleavage of thymidine to thymine and deoxyribose-1-phosphate by the host thymidine phosphorylase greatly increases the sensitivity of phage T7 to ddT. Finally, a mutation in T7 DNA polymerase that leads to discrimination against the incorporation of ddTMP eliminates ddT sensitivity. PMID:24858186

Serum Phthalate Levels and Time to Pregnancy in Couples from Greenland, Poland and Ukraine

PubMed Central

Specht, Ina Olmer; Bonde, Jens Peter; Toft, Gunnar; Lindh, Christian H.; Jönsson, Bo A. G.; Jørgensen, Kristian T.

2015-01-01

Phthalates are ubiquitous industrial chemicals that have been associated with altered reproductive function in rodents. Several human studies have reported an inverse association between male testosterone and phthalate levels. Our aim was to investigate time to pregnancy (TTP) according to serum levels of diethylhexyl phthalate (DEHP) and diisononyl phthalate (DiNP) metabolites in both partners. In 2002-2004 we enrolled 938 pregnant women and 401 male spouses from Greenland, Poland and Ukraine. Six oxidized metabolites of DEHP and DiNP were summarized for each of the two parent compounds to provide proxies of the internal exposure. We used Cox discrete-time models to estimate fecundability ratios (FR) and 95% confidence intervals (95% CIs) for men and women according to their proxy-DEHP or -DiNP serum levels adjusted for a fixed set of covariates. The FR was slightly elevated among women with high levels of DEHP (FR=1.14, 95% CI 1.00;1.30) suggesting a shorter TTP in these women. The FR was unrelated to DiNP in women, whereas the results for men were inconsistent pointing in opposite directions. First-time pregnant women from Greenland with high serum DiNP levels had a longer TTP. This study spanning large contrast in environmental exposure does not indicate adverse effects of phthalates on couple fecundity. The shorter TTP in women with high levels of DEHP metabolites is unexplained and needs further investigation. PMID:25786246

Investigation of anti-Müllerian hormone concentrations in relation to natural conception rate and time to pregnancy.

PubMed

Korsholm, Anne-Sofie; Petersen, Kathrine Birch; Bentzen, Janne Gasseholm; Hilsted, Linda Maria; Andersen, Anders Nyboe; Hvidman, Helene Westring

2018-05-01

The objectives of this study were to investigate whether anti-Müllerian hormone (AMH) concentrations can predict pregnancy rates and time to pregnancy (TTP) in women attempting to conceive naturally/having an unplanned conception, and whether there is a lower AMH threshold compatible with natural conception. This prospective cohort study included 260 women aged 25-42 years in two subcohorts: (A) healthcare workers at Rigshospitalet (2008-2010), and (B) women consulting the Fertility Assessment and Counselling Clinic (2011-2014), Rigshospitalet, Denmark. Pregnancy rates and TTP at 2-year follow-up were stratified into AMH groups: low: < 9.5 pmol/l, intermediate: 9.5-33 pmol/l, high: > 33 pmol/l. Pregnancy rates increased with increasing AMH: 60.1% (low) versus 70.0% (intermediate) versus 78.3% (high) (P = 0.03). The highest pregnancy rate (84.1%) was seen in regular cycling women with high AMH. TTP was reduced in women with high AMH compared with intermediate or low AMH (stepwise trend test P = 0.01). Natural conceptions were observed with AMH concentrations down to 1.2 pmol/l. In conclusion, high AMH, especially in ovulatory women, was associated with higher pregnancy rates. Nonetheless, TTP reflected a large variation in fecundity within similar AMH concentrations and natural conceptions occurred with AMH down to 1.2 pmol/l. Copyright © 2018 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease

PubMed Central

Molle, Céline; Zhang, Tong; Ysebrant de Lendonck, Laure; Gueydan, Cyril; Andrianne, Mathieu; Sherer, Félicie; Van Simaeys, Gaetan; Blackshear, Perry J.; Leo, Oberdan

2013-01-01

Interleukin (IL) 12 and IL23 are two related heterodimeric cytokines produced by antigen-presenting cells. The balance between these two cytokines plays a crucial role in the control of Th1/Th17 responses and autoimmune inflammation. Most studies focused on their transcriptional regulation. Herein, we explored the role of the adenine and uridine–rich element (ARE)–binding protein tristetraprolin (TTP) in influencing mRNA stability of IL12p35, IL12/23p40, and IL23p19 subunits. LPS-stimulated bone marrow–derived dendritic cells (BMDCs) from TTP−/− mice produced normal levels of IL12/23p40. Production of IL12p70 was modestly increased in these conditions. In contrast, we observed a strong impact of TTP on IL23 production and IL23p19 mRNA stability through several AREs in the 3′ untranslated region. TTP−/− mice spontaneously develop an inflammatory syndrome characterized by cachexia, myeloid hyperplasia, dermatitis, and erosive arthritis. We observed IL23p19 expression within skin lesions associated with exacerbated IL17A and IL22 production by infiltrating γδ T cells and draining lymph node CD4 T cells. We demonstrate that the clinical and immunological parameters associated with TTP deficiency were completely dependent on the IL23–IL17A axis. We conclude that tight control of IL23 mRNA stability by TTP is critical to avoid severe inflammation. PMID:23940256

Ship Underwater Threat Response System (SUTRS): A Feasibility Study of Organic Mine Point-Defense

DTIC Science & Technology

2012-09-01

by implementing and testing the design until a final product has been established that addresses (and has been traced throughout to) the...The assumptions used to evaluate those TPMs are as follows: • The threshold Probability of Success for the total system should be 90% survival...Threat Response System xviii TOA Table of Allowance TPM Technical Performance Measures TTP Tactics Techniques and Procedures U.S. United

Cerebral Hemodynamics in Patients with Hemolytic Uremic Syndrome Assessed by Susceptibility Weighted Imaging and Four-Dimensional Non-Contrast MR Angiography.

PubMed

Löbel, Ulrike; Forkert, Nils Daniel; Schmitt, Peter; Dohrmann, Thorsten; Schroeder, Maria; Magnus, Tim; Kluge, Stefan; Weiler-Normann, Christina; Bi, Xiaoming; Fiehler, Jens; Sedlacik, Jan

2016-01-01

Conventional magnetic resonance imaging (MRI) of patients with hemolytic uremic syndrome (HUS) and neurological symptoms performed during an epidemic outbreak of Escherichia coli O104:H4 in Northern Europe has previously shown pathological changes in only approximately 50% of patients. In contrast, susceptibility-weighted imaging (SWI) revealed a loss of venous contrast in a large number of patients. We hypothesized that this observation may be due to an increase in cerebral blood flow (CBF) and aimed to identify a plausible cause. Baseline 1.5T MRI scans of 36 patients (female, 26; male, 10; mean age, 38.2±19.3 years) were evaluated. Venous contrast was rated on standard SWI minimum intensity projections. A prototype four-dimensional (time resolved) magnetic resonance angiography (4D MRA) assessed cerebral hemodynamics by global time-to-peak (TTP), as a surrogate marker for CBF. Clinical parameters studied were hemoglobin, hematocrit, creatinine, urea levels, blood pressure, heart rate, and end-tidal CO2. SWI venous contrast was abnormally low in 33 of 36 patients. TTP ranged from 3.7 to 10.2 frames (mean, 7.9 ± 1.4). Hemoglobin at the time of MRI (n = 35) was decreased in all patients (range, 5.0 to 12.6 g/dL; mean, 8.2 ± 1.4); hematocrit (n = 33) was abnormally low in all but a single patient (range, 14.3 to 37.2%; mean, 23.7 ± 4.2). Creatinine was abnormally high in 30 of 36 patients (83%) (range, 0.8 to 9.7; mean, 3.7 ± 2.2). SWI venous contrast correlated significantly with hemoglobin (r = 0.52, P = 0.0015), hematocrit (r = 0.65, P < 0.001), and TTP (r = 0.35, P = 0.036). No correlation of SWI with blood pressure, heart rate, end-tidal CO2, creatinine, and urea level was observed. Findings suggest that the loss of venous contrast is related to an increase in CBF secondary to severe anemia related to HUS. SWI contrast of patients with pathological conventional MRI findings was significantly lower compared to patients with normal MRI (mean SWI score, 1.41 and 2.05, respectively; P = 0.04). In patients with abnormal conventional MRI, mean TTP (7.45), mean hemoglobin (7.65), and mean hematocrit (22.0) were lower compared to patients with normal conventional MRI scans (mean TTP = 8.28, mean hemoglobin = 8.63, mean hematocrit = 25.23). In contrast to conventional MRI, almost all patients showed pathological changes in cerebral hemodynamics assessed by SWI and 4D MRA. Loss of venous contrast on SWI is most likely the result of an increase in CBF and may be related to the acute onset of anemia. Future studies will be needed to assess a possible therapeutic effect of blood transfusions in patients with HUS and neurological symptoms.

Superconductivity under uniaxial compression in β-(BDA-TTP) salts

NASA Astrophysics Data System (ADS)

Suzuki, T.; Onari, S.; Ito, H.; Tanaka, Y.

2009-10-01

In order to clarify the mechanism of organic superconductor β-(BDA-TTP) salts. We study the superconductivity under uniaxial compression with non-dimerized two-band Hubbard model. We have calculated the uniaxial compression dependence of T c by solving the Eliashberg’s equation using the fluctuation exchange (FLEX) approximation. The transfer integral under the uniaxial compression was estimated by the extended Huckel method. We have found that non-monotonic behaviors of T c in experimental results under uniaxial compression are understood taking the spin frustration and spin fluctuation into account.

Accurate Methods for Large Molecular Systems (Postprint)

DTIC Science & Technology

2009-01-06

D S A FB , C A o n Se pt em be r 23 , 2 00 9 | h ttp :// pu bs .a cs .o rg P ub lic at io n D at e (W eb ): A pr il 15 , 2 00 9 | d oi...r 23 , 2 00 9 | h ttp :// pu bs .a cs .o rg P ub lic at io n D at e (W eb ): A pr il 15 , 2 00 9 | d oi : 1 0. 10 21 /jp 81 15 19 x As noted...basis set is 6-31++G( d ,

Couples' body composition and time-to-pregnancy.

PubMed

Sundaram, Rajeshwari; Mumford, Sunni L; Buck Louis, Germaine M

2017-03-01

Is couples' body compositions associated with reduced fecundity as measured by a longer time-to-pregnancy (TTP)? Couples whose BMI are within obese class II (≥35 kg/m2) have a longer TTP in comparison to leaner (BMI < 25 kg/m2) couples, observed only when both partner's BMI was jointly modeled. Extremes of BMI have been associated with a longer TTP and with less successful assisted reproductive technology (ART) outcomes. To our knowledge, the association between measured adiposity in both partners of the couple and prospectively measured TTP has not been investigated despite pregnancy being a couple-dependent outcome. Prospective cohort with preconception recruitment of 501 couples trying for pregnancy and recruited from 16 counties in Michigan and Texas between 2005 and 2009. Couples were followed daily for up to a year of trying or until a hCG pregnancy. In-home standardized anthropometric assessment of couples upon enrollment included measured height and weight using calibrated stadiometers and scales, and measured waist and hip circumferences. Discrete-time Cox regression was used to estimate fecundability odds ratios (FORs) and 95% CIs, controlling for potential confounders including age, number of days of vigorous physical activity, serum cotinine concentration, race, education, free cholesterol levels for each partner in partner-specific models and for both partners in couple-based models as well as average acts of intercourse per menstrual cycle and menstrual cycle regularity. Neither male nor female partner's BMI was associated with TTP when modeled individually. However, obese class II (BMIs ≥ 35.0 kg/m2) couples experienced a reduction in fecundability in both unadjusted (FOR = 0.45; 95% CI: 0.23, 0.89) and adjusted analyses (aFOR = 0.41; 95% CI: 0.17, 0.98) resulting in a longer TTP in comparison to couples with normal BMI (<25 kg/m2). Female partners' waist circumference ≥88.6 cm was associated with a significant reduction in fecundability in the unadjusted model (FOR = 0.64; 95% CI: 0.48, 0.86) but not in the adjusted model (aFOR = 0.77; 95% CI: 0.55, 1.08) in comparison to females with a smaller (<80 cm) circumference. BMI and waist circumference are proxy measures of body composition and residual confounding cannot be eliminated. Findings may not be generalizable to clinical populations. This is the first cohort study known to us with preconception enrollment of couples who underwent standardized anthropometric assessment and for whom TTP was prospectively measured. The findings underscore the importance of considering both partners' body composition for fecundity outcomes and preconception guidance. Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contracts #N01-HD-3-3355, N01-HD-3-3356 and N01-HD-3-3358). The authors have no competing interests. N/A. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2017. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Procalcitonin reflects bacteremia and bacterial load in urosepsis syndrome: a prospective observational study

PubMed Central

2010-01-01

Introduction Guidelines recommend that two blood cultures be performed in patients with febrile urinary tract infection (UTI), to detect bacteremia and help diagnose urosepsis. The usefulness and cost-effectiveness of this practice have been criticized. This study aimed to evaluate clinical characteristics and the biomarker procalcitonin (PCT) as an aid in predicting bacteremia. Methods A prospective observational multicenter cohort study included consecutive adults with febrile UTI in 35 primary care units and 8 emergency departments of 7 regional hospitals. Clinical and microbiological data were collected and PCT and time to positivity (TTP) of blood culture were measured. Results Of 581 evaluable patients, 136 (23%) had bacteremia. The median age was 66 years (interquartile range 46 to 78 years) and 219 (38%) were male. We evaluated three different models: a clinical model including seven bed-side characteristics, the clinical model plus PCT, and a PCT only model. The diagnostic abilities of these models as reflected by area under the curve of the receiver operating characteristic were 0.71 (95% confidence interval (CI): 0.66 to 0.76), 0.79 (95% CI: 0.75 to 0.83) and 0.73 (95% CI: 0.68 to 0.77) respectively. Calculating corresponding sensitivity and specificity for the presence of bacteremia after each step of adding a significant predictor in the model yielded that the PCT > 0.25 μg/l only model had the best diagnostic performance (sensitivity 0.95; 95% CI: 0.89 to 0.98, specificity 0.50; 95% CI: 0.46 to 0.55). Using PCT as a single decision tool, this would result in 40% fewer blood cultures being taken, while still identifying 94 to 99% of patients with bacteremia. The TTP of E. coli positive blood cultures was linearly correlated with the PCT log value; the higher the PCT the shorter the TTP (R2 = 0.278, P = 0.007). Conclusions PCT accurately predicts the presence of bacteremia and bacterial load in patients with febrile UTI. This may be a helpful biomarker to limit use of blood culture resources. PMID:21083886

Capnocytophaga canimorsus infection presenting with complete splenic infarction and thrombotic thrombocytopenic purpura: a case report.

PubMed

Brichacek, Michal; Blake, Peter; Kao, Raymond

2012-12-26

Animal bites are typically harmless, but in rare cases infections introduced by such bites can be fatal. Capnocytophaga canimorsus, found in the normal oral flora of dogs, has the potential to cause conditions ranging from minor cellulitis to fatal sepsis. The tendency of C. canimorsus infections to present with varied symptoms, the organism's fastidious nature, and difficulty of culturing make this a challenging diagnosis. Rarely, bacterial cytotoxins such as those produced by C. canimorsus may act as causative agents of TTP, further complicating the diagnosis. Early recognition is crucial for survival, and the variability of presentation must be appreciated. We present the first known case of C. canimorsus infection resulting in TTP that initially presented as splenic infarction. 72-year-old Caucasian male presented with a four-day history of abdominal pain, nausea, vomiting, diarrhea, and intermittent confusion. On presentation, vital signs were stable and the patient was afebrile. Physical examination was unremarkable apart from petechiae on the inner left thigh, and extreme diffuse abdominal pain to palpation and percussion along with positive rebound tenderness. Initial investigations revealed leukocytosis with left shift and thrombocytopenia, but normal liver enzymes, cardiac enzymes, lipase, INR and PTT. Abdominal CT demonstrated a non-enhancing spleen and hemoperitoneum, suggesting complete splenic infarction. Although the patient remained afebrile, he continued deteriorating over the next two days with worsening thrombocytopenia. After becoming febrile, he developed microangiopathic hemolytic anemia and hemodynamic instability, and soon after was intubated due to hypoxic respiratory failure and decreased consciousness. Plasma exchange was initiated but subsequently stopped when positive blood cultures grew a gram-negative organism. The patient progressively improved following therapy with piperacillin-tazobactam, which was switched to imipenem, then meropenem when Capnocytophaga was identified. There is a common misconception amongst practitioners that the presence of systemic infection excludes the possibility of TTP and vice versa. This case emphasizes that TTP may occur secondary to a systemic infection, thereby allowing the two processes to coexist. It is important to maintain a wide differential when considering the diagnosis of either TTP or C. canimorsus infection since delays in treatment may have fatal consequences.

Prognostic Impact of 21-Gene Recurrence Score in Patients With Stage IV Breast Cancer: TBCRC 013

PubMed Central

Lyman, Jaclyn P.; Gonen, Mithat; Voci, Amy; De Brot, Marina; Boafo, Camilla; Sing, Amy Pratt; Hwang, E. Shelley; Alvarado, Michael D.; Liu, Minetta C.; Boughey, Judy C.; McGuire, Kandace P.; Van Poznak, Catherine H.; Jacobs, Lisa K.; Meszoely, Ingrid M.; Krontiras, Helen; Babiera, Gildy V.; Norton, Larry; Morrow, Monica; Hudis, Clifford A.

2016-01-01

Purpose The objective of this study was to determine whether the 21-gene Recurrence Score (RS) provides clinically meaningful information in patients with de novo stage IV breast cancer enrolled in the Translational Breast Cancer Research Consortium (TBCRC) 013. Patients and Methods TBCRC 013 was a multicenter prospective registry that evaluated the role of surgery of the primary tumor in patients with de novo stage IV breast cancer. From July 2009 to April 2012, 127 patients from 14 sites were enrolled; 109 (86%) patients had pretreatment primary tumor samples suitable for 21-gene RS analysis. Clinical variables, time to first progression (TTP), and 2-year overall survival (OS) were correlated with the 21-gene RS by using log-rank, Kaplan-Meier, and Cox regression. Results Median patient age was 52 years (21 to 79 years); the majority had hormone receptor–positive/human epidermal growth factor receptor 2 (HER2)–negative (72 [66%]) or hormone receptor–positive/HER2-positive (20 [18%]) breast cancer. At a median follow-up of 29 months, median TTP was 20 months (95% CI, 16 to 26 months), and median survival was 49 months (95% CI, 40 months to not reached). An RS was generated for 101 (93%) primary tumor samples: 22 (23%) low risk (< 18), 29 (28%) intermediate risk (18 to 30); and 50 (49%) high risk (≥ 31). For all patients, RS was associated with TTP (P = .01) and 2-year OS (P = .04). In multivariable Cox regression models among 69 patients with estrogen receptor (ER)–positive/HER2-negative cancer, RS was independently prognostic for TTP (hazard ratio, 1.40; 95% CI, 1.05 to 1.86; P = .02) and 2-year OS (hazard ratio, 1.83; 95% CI, 1.14 to 2.95; P = .013). Conclusion The 21-gene RS is independently prognostic for both TTP and 2-year OS in ER–positive/HER2-negative de novo stage IV breast cancer. Prospective validation is needed to determine the potential role for this assay in the clinical management of this patient subset. PMID:27001590

Prognostic Impact of 21-Gene Recurrence Score in Patients With Stage IV Breast Cancer: TBCRC 013.

PubMed

King, Tari A; Lyman, Jaclyn P; Gonen, Mithat; Voci, Amy; De Brot, Marina; Boafo, Camilla; Sing, Amy Pratt; Hwang, E Shelley; Alvarado, Michael D; Liu, Minetta C; Boughey, Judy C; McGuire, Kandace P; Van Poznak, Catherine H; Jacobs, Lisa K; Meszoely, Ingrid M; Krontiras, Helen; Babiera, Gildy V; Norton, Larry; Morrow, Monica; Hudis, Clifford A

2016-07-10

The objective of this study was to determine whether the 21-gene Recurrence Score (RS) provides clinically meaningful information in patients with de novo stage IV breast cancer enrolled in the Translational Breast Cancer Research Consortium (TBCRC) 013. TBCRC 013 was a multicenter prospective registry that evaluated the role of surgery of the primary tumor in patients with de novo stage IV breast cancer. From July 2009 to April 2012, 127 patients from 14 sites were enrolled; 109 (86%) patients had pretreatment primary tumor samples suitable for 21-gene RS analysis. Clinical variables, time to first progression (TTP), and 2-year overall survival (OS) were correlated with the 21-gene RS by using log-rank, Kaplan-Meier, and Cox regression. Median patient age was 52 years (21 to 79 years); the majority had hormone receptor-positive/human epidermal growth factor receptor 2 (HER2)-negative (72 [66%]) or hormone receptor-positive/HER2-positive (20 [18%]) breast cancer. At a median follow-up of 29 months, median TTP was 20 months (95% CI, 16 to 26 months), and median survival was 49 months (95% CI, 40 months to not reached). An RS was generated for 101 (93%) primary tumor samples: 22 (23%) low risk (< 18), 29 (28%) intermediate risk (18 to 30); and 50 (49%) high risk (≥ 31). For all patients, RS was associated with TTP (P = .01) and 2-year OS (P = .04). In multivariable Cox regression models among 69 patients with estrogen receptor (ER)-positive/HER2-negative cancer, RS was independently prognostic for TTP (hazard ratio, 1.40; 95% CI, 1.05 to 1.86; P = .02) and 2-year OS (hazard ratio, 1.83; 95% CI, 1.14 to 2.95; P = .013). The 21-gene RS is independently prognostic for both TTP and 2-year OS in ER-positive/HER2-negative de novo stage IV breast cancer. Prospective validation is needed to determine the potential role for this assay in the clinical management of this patient subset. © 2016 by American Society of Clinical Oncology.

The spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β

PubMed Central

Koag, Myong-Chul; Nam, Kwangho; Lee, Seongmin

2014-01-01

To provide molecular-level insights into the spontaneous replication error and the mismatch discrimination mechanisms of human DNA polymerase β (polβ), we report four crystal structures of polβ complexed with dG•dTTP and dA•dCTP mismatches in the presence of Mg2+ or Mn2+. The Mg2+-bound ground-state structures show that the dA•dCTP-Mg2+ complex adopts an ‘intermediate’ protein conformation while the dG•dTTP-Mg2+ complex adopts an open protein conformation. The Mn2+-bound ‘pre-chemistry-state’ structures show that the dA•dCTP-Mn2+ complex is structurally very similar to the dA•dCTP-Mg2+ complex, whereas the dG•dTTP-Mn2+ complex undergoes a large-scale conformational change to adopt a Watson–Crick-like dG•dTTP base pair and a closed protein conformation. These structural differences, together with our molecular dynamics simulation studies, suggest that polβ increases replication fidelity via a two-stage mismatch discrimination mechanism, where one is in the ground state and the other in the closed conformation state. In the closed conformation state, polβ appears to allow only a Watson–Crick-like conformation for purine•pyrimidine base pairs, thereby discriminating the mismatched base pairs based on their ability to form the Watson–Crick-like conformation. Overall, the present studies provide new insights into the spontaneous replication error and the replication fidelity mechanisms of polβ. PMID:25200079

Detection of small subendocardial infarction using speckle tracking echocardiography in a rat model.

PubMed

Bachner-Hinenzon, Noa; Shlomo, Liron; Khamis, Hanan; Ertracht, Offir; Vered, Zvi; Malka, Assaf; Binah, Ofer; Adam, Dan

2016-10-01

It is challenging to detect small nontransmural infarcts visually or automatically. As it is important to detect myocardial infarction (MI) at early stages, we tested the hypothesis that small nontransmural MI can be detected using speckle tracking echocardiography (STE) at the acute stage. Minimal nontransmural infarcts were induced in 18 rats by causing recurrent ischemia-reperfusion of the left anterior descending (LAD) coronary artery, followed by a 30-min ligation and by reperfusion. A week later, the scar size was measured by histological analysis. Each rat underwent three echocardiography measurements: at baseline, 1 day post-MI, and 1 week post-MI. To measure the peak circumferential strain (CS), peak systolic CS, radial strain (RS), and time-to-peak (TTP) of the CS, short-axis view of the apex was analyzed by a STE program. The TTP was normalized by the duration of the heart cycle to create percent change of heart cycle. Histological analysis after 1 week showed scar size of 4±6% at the anterior wall. At 24 h post-MI, the peak CS, peak systolic CS, and RS were reduced compared to baseline at the anterior wall due to the MI, and at the adjacent segments-the anterior septum and lateral wall, due to stunning (P<.05). However, only the anterior wall, the genuine damaged segment, showed prolonged TTP vs baseline (baseline 36%, 24 h 48%, P<.05). The TTP of the CS can distinguish between regions adjacent to MI (stunned or tethered) and MI, even in small nontransmural infarcts. © 2016, Wiley Periodicals, Inc.

Predicting stroke outcome using DCE-CT measured blood velocity

NASA Astrophysics Data System (ADS)

Oosterbroek, Jaap; Bennink, Edwin; Dankbaar, Jan Willem; Horsch, Alexander D.; Viergever, Max A.; Velthuis, Birgitta K.; de Jong, Hugo W. A. M.

2015-03-01

CT plays an important role in the diagnosis of acute stroke patients. Dynamic contrast enhanced CT (DCE-CT) can estimate local tissue perfusion and extent of ischemia. However, hemodynamic information of the large intracranial vessels may also be obtained from DCE-CT data and may contain valuable diagnostic information. We describe a novel method to estimate intravascular blood velocity (IBV) in large cerebral vessels using DCE-CT data, which may be useful to help predict stroke outcome. DCE-CT scans from 34 patients with isolated M1 occlusions were included from a large prospective multi-center cohort study of patients with acute ischemic stroke. Gaussians fitted to the intravascular data yielded the time-to-peak (TTP) and cerebral-blood-volume (CBV). IBV was computed by taking the inverse of the TTP gradient magnitude. Voxels with a CBV of at least 10% of the CBV found in the arterial input function were considered part of a vessel. Mid-sagittal planes were drawn manually and averages of the IBV over all vessel-voxels (arterial and venous) were computed for each hemisphere. Mean-hemisphere IBV differences, mean-hemisphere TTP differences, and hemisphere vessel volume differences were used to differentiate between patients with good and bad outcome (modified Rankin Scale score <3 versus ≥3 at 90 days) using ROC analysis. AUCs from the ROC for IBV, TTP, and vessel volume were 0.80, 0.67 and 0.62 respectively. In conclusion, IBV was found to be a better predictor of patient outcome than the parameters used to compute it and may be a promising new parameter for stroke outcome prediction.

Perfluoroalkyl and polyfluoroalkyl substances and measures of human fertility: a systematic review.

PubMed

Bach, Cathrine Carlsen; Vested, Anne; Jørgensen, Kristian Tore; Bonde, Jens Peter Ellekilde; Henriksen, Tine Brink; Toft, Gunnar

2016-10-01

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are found widespread in the environment and humans. The relation of PFASs to fertility has now been examined in a relatively large number of epidemiologic studies and a synthesis is in order. The aim of this study was to assess the current human epidemiologic evidence on the association between exposure to PFASs and measures of human fertility, with particular emphasis on perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA). Systematic literature searches were initially conducted in MEDLINE and EMBASE and subsequently in references and citations of included papers. Studies were included if they assessed exposure to PFASs in biological samples in relation to reproductive hormones, semen characteristics, or time to pregnancy (TTP). Study characteristics and results were abstracted to predefined forms, and the studies were assessed for the risk of bias and confounding. Sixteen studies investigated the association between PFAS exposure in men and semen parameters, reproductive hormone levels, or TTP. There was a lack of consistent results among the numerous investigated exposure-outcome combinations. However, subtle associations between higher PFOS and lower testosterone or abnormal semen morphology cannot be excluded. Eleven studies assessed the association between PFAS exposure in women and TTP or reproductive hormones levels. Four of eight studies found prolonged TTP with higher PFOS or PFOA, but only one study found an association when restricting to nulliparous women. In men, there is little evidence of an association between PFAS exposure and semen quality or levels of reproductive hormones. For PFOS and PFOA, the literature indicates an association with female fecundability in parous women, which is most likely not causal.

Women's Reproductive History Before the Diagnosis of Incident Endometriosis

PubMed Central

Backonja, Uba; Schliep, Karen C.; Sun, Liping; Peterson, C. Matthew; Chen, Zhen

2016-01-01

Abstract Background: Endometriosis is a gynecologic disease reported to be associated with infertility and, possibly, adverse pregnancy outcomes. While considerable research focuses on pregnancy outcomes following diagnosis and/or treatment, few data actually describe women's reproductive history before diagnosis for a more complete understanding of endometriosis and reproduction. Materials and Methods: The study sample comprised 473 women (aged 18–44 years) undergoing laparoscopies or laparotomies, irrespective of surgical indication at 14 clinical sites, during the period 2007–2009. Upon enrollment and before surgery, women were queried about pregnancy intentions and the time required to become pregnant for planned pregnancies. Endometriosis was defined as surgically visualized disease. Using discrete time survival analysis, we estimated fecundability odds ratios (FORs) and 95% confidence intervals (CIs) to assess time to pregnancy (TTP) after adjusting for potential confounders (age, body composition, cigarette smoking, site). Generalized estimating equations accounted for multiple pregnancy attempts per woman. FORs <1.0 denote a longer TTP or diminished fecundity. Results: Approximately 66% and 69% of women with and without endometriosis, respectively, reported having a planned pregnancy before surgery, respectively. After adjustment, an endometriosis diagnosis was associated with ≈29% reduction in fecundity or a longer TTP across all pregnancy-trying attempts (adjusted FOR = 0.71; 95% CI 0.46–1.10). While FORs were consistently <1.0, irrespective of endometriosis staging, CIs included 1. Conclusions: Women with endometriosis had a longer TTP than unaffected women, irrespective of disease severity, although the findings did not achieve significance. Prior reproductive history may be informative for predicting fecundity and pregnancy outcomes following diagnosis/treatment. PMID:27379997

Evolving Postmortems as Teams Evolve Through TxP

DTIC Science & Technology

2014-12-01

Instead of waiting for SEI to compile enough data to repeat this kind of analysis for the system integration test domain , a system integration test team...and stand up their Team Test Process (TTP). Some abilities, like planning on how many mistakes will be made by the team in producing a test procedure...can only be performed after the team has determined a) which mistakes count in the domain of system integration testing, b) what units to use to

Three year evaluation of Xpert MTB/RIF in a low prevalence tuberculosis setting: A Scottish perspective.

PubMed

Parcell, Benjamin J; Jarchow-MacDonald, Anna A; Seagar, Amie-Louise; Laurenson, Ian F; Prescott, Gordon J; Lockhart, Michael

2017-05-01

Xpert MTB/RIF (Cepheid) is a rapid molecular assay shown to be sensitive and specific for pulmonary tuberculosis (TB) diagnosis in highly endemic countries. We evaluated its diagnostic performance in a low TB prevalence setting, examined rifampicin resistance detection and quantitative capabilities predicting graded auramine microscopy and time to positivity (TTP) of culture. Xpert MTB/RIF was used to test respiratory samples over a 3 year period. Samples underwent graded auramine microscopy, solid/liquid culture, in-house IS6110 real-time PCR, and GenoType MTBDRplus (HAIN Lifescience) to determine rifampicin and/or isoniazid resistance. A total of 2103 Xpert MTB/RIF tests were performed. Compared to culture sensitivity was 95.8%, specificity 99.5%, positive predictive value (PPV) 82.1%, and negative predictive value (NPV) 99.9%. A positive correlation was found between auramine microscopy grade and Xpert MTB/RIF assay load. We found a clear reduction in the median TTP as Xpert MTB/RIF assay load increased. Rifampicin resistance was detected. Xpert MTB/RIF was rapid and accurate in diagnosing pulmonary TB in a low prevalence area. Rapid results will influence infection prevention and control and treatment measures. The excellent NPV obtained suggests further work should be carried out to assess its role in replacing microscopy. Copyright © 2017 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Application of infrared uncooled cameras in surveillance systems

NASA Astrophysics Data System (ADS)

Dulski, R.; Bareła, J.; Trzaskawka, P.; PiÄ tkowski, T.

2013-10-01

The recent necessity to protect military bases, convoys and patrols gave serious impact to the development of multisensor security systems for perimeter protection. One of the most important devices used in such systems are IR cameras. The paper discusses technical possibilities and limitations to use uncooled IR camera in a multi-sensor surveillance system for perimeter protection. Effective ranges of detection depend on the class of the sensor used and the observed scene itself. Application of IR camera increases the probability of intruder detection regardless of the time of day or weather conditions. It also simultaneously decreased the false alarm rate produced by the surveillance system. The role of IR cameras in the system was discussed as well as technical possibilities to detect human being. Comparison of commercially available IR cameras, capable to achieve desired ranges was done. The required spatial resolution for detection, recognition and identification was calculated. The simulation of detection ranges was done using a new model for predicting target acquisition performance which uses the Targeting Task Performance (TTP) metric. Like its predecessor, the Johnson criteria, the new model bounds the range performance with image quality. The scope of presented analysis is limited to the estimation of detection, recognition and identification ranges for typical thermal cameras with uncooled microbolometer focal plane arrays. This type of cameras is most widely used in security systems because of competitive price to performance ratio. Detection, recognition and identification range calculations were made, and the appropriate results for the devices with selected technical specifications were compared and discussed.

Outcome prediction in plasmacytoma of bone: a risk model utilizing bone marrow flow cytometry and light-chain analysis.

PubMed

Hill, Quentin A; Rawstron, Andy C; de Tute, Ruth M; Owen, Roger G

2014-08-21

The purpose of this study was to use multiparameter flow cytometry to detect occult marrow disease (OMD) in patients with solitary plasmacytoma of bone and assess its value in predicting outcome. Aberrant phenotype plasma cells were demonstrable in 34 of 50 (68%) patients and comprised a median of 0.52% of bone marrow leukocytes. With a median follow-up of 3.7 years, 28 of 50 patients have progressed with a median time to progression (TTP) of 18 months. Progression was documented in 72% of patients with OMD vs 12.5% without (median TTP, 26 months vs not reached; P = .003). Monoclonal urinary light chains (ULC) were similarly predictive of outcome because progression was documented in 91% vs 44% without (median TTP, 16 vs 82 months; P < .001). By using both parameters, it was possible to define patients with an excellent outcome (lacking both OMD and ULC, 7.7% progression) and high-risk patients (OMD and/or ULC, 75% progression; P = .001). Trials of systemic therapy are warranted in high-risk patients. © 2014 by The American Society of Hematology.

Uniaxial compression on the superconductivity of β-BDA-TTP salts

NASA Astrophysics Data System (ADS)

Ito, Hiroshi; Ishihara, Tetsuo; Tanaka, Hisaaki; Kuroda, Shin-ichi; Yamada, Jun-ichi

2008-10-01

The β-type BDA-TTP superconductors attract attention due to the high transition temperature Tc at ambient pressure for organic superconductors. In order to get insight into the superconductivity in terms of the dimerized anisotropic triangular lattice model, Tc of β-(BDA-TTP)2X [X = SbF6, X = AsF6] is studied under uniaxial compression by resistivity measurements. Under compression parallel to the donor stack, Tc increases gradually up to 3 (X = SbF6), 5 (X = AsF6) kbar, and decreases under further piston pressure. Under compression perpendicular to the donor stack, Tc decreases gradually up to 2.5 (X = SbF6), 4 (X = AsF6) kbar and then decreases rapidly under further pressure. Only for X = AsF6, a Tc minimum at 3 kbar is found for both direction. These trends in Tc are understood as an interplay between the enhancement of antiferromagnetic spin fluctuation and frustration on the triangular lattice. By the interplane compression, Tc increased by 0.5 K up to 2 kbar for both salts, demonstrating the importance of the interlayer interaction.

A review of heat transfer in human tooth--experimental characterization and mathematical modeling.

PubMed

Lin, Min; Xu, Feng; Lu, Tian Jian; Bai, Bo Feng

2010-06-01

With rapid advances in modern dentistry, high-energy output instruments (e.g., dental lasers and light polymerizing units) are increasingly employed in dental surgery for applications such as laser assisted tooth ablation, bleaching, hypersensitivity treatment and polymerization of dental restorative materials. Extreme high temperature occurs within the tooth during these treatments, which may induce tooth thermal pain (TTP) sensation. Despite the wide application of these dental treatments, the underlying mechanisms are far from clear. Therefore, there is an urgent need to better understand heat transfer (HT) process in tooth, thermally induced damage of tooth, and the corresponding TTP. This will enhance the design and optimization of clinical treatment strategies. This paper presents the state-of-the-art of the current understanding on HT in tooth, with both experimental study and mathematical modeling reviewed. Limitations of the current experimental and mathematical methodologies are discussed and potential solutions are suggested. Interpretation of TTP in terms of thermally stimulated dentinal fluid flow is also discussed. Copyright (c) 2010 Academy of Dental Materials. All rights reserved.

Improvements in Diagnostic Accuracy with Quantitative Dynamic Contrast-Enhanced MRI

DTIC Science & Technology

2013-12-01

11), and time to peak enhancement (TTP) were also determined for each lesion. TTP was calculated from the EMM parameters – i.e. the time at which...rate (α) (min-1) 0.54 ± 0.45 0.62 ± 0.64 14%±76% 51% ± 55% Washout rate (β) (min-1) 0.06 ± 0.03 0.03 ± 0.03 -11%±84% 67% ± 46% Time to peak ...radiofrequency field. Magn. Reson. Med. 2007;57:192– 200. doi: 10.1002/ mrm .21120. 7. Nehrke K. On the steady-state properties of actual flip angle imaging (AFI

Mitochondrial deoxyribonucleoside triphosphate pools in thymidine kinase 2 deficiency.

PubMed

Saada, Ann; Ben-Shalom, Efrat; Zyslin, Rivka; Miller, Chaya; Mandel, Hanna; Elpeleg, Orly

2003-10-24

Deficiency of mitochondrial thymidine kinase (TK2) is associated with mitochondrial DNA (mtDNA) depletion and manifests by severe skeletal myopathy in infancy. In order to elucidate the pathophysiology of this condition, mitochondrial deoxyribonucleoside triphosphate (dNTP) pools were determined in patients' fibroblasts. Despite normal mtDNA content and cytochrome c oxidase (COX) activity, mitochondrial dNTP pools were imbalanced. Specifically, deoxythymidine triphosphate (dTTP) content was markedly decreased, resulting in reduced dTTP:deoxycytidine triphosphate ratio. These findings underline the importance of balanced mitochondrial dNTP pools for mtDNA synthesis and may serve as the basis for future therapeutic interventions.

Accelerated molecular dynamics simulations of ligand binding to a muscarinic G-protein-coupled receptor.

PubMed

Kappel, Kalli; Miao, Yinglong; McCammon, J Andrew

2015-11-01

Elucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein-ligand binding, especially the drug recognition of GPCRs.

Association of testosterone and antimüllerian hormone with time to pregnancy and pregnancy loss in fecund women attempting pregnancy.

PubMed

Sjaarda, Lindsey A; Mumford, Sunni L; Kuhr, Daniel L; Holland, Tiffany L; Silver, Robert M; Plowden, Torie C; Perkins, Neil J; Schisterman, Enrique F

2018-03-01

To examine whether higher T and/or antimüllerian hormone (AMH) was associated with anovulation, time to pregnancy (TTP), or pregnancy loss risk among healthy, fecund women without diagnosed polycystic ovary syndrome. Prospective cohort study conducted as a secondary analysis from the Effects of Aspirin in Gestation and Reproduction randomized trial. University medical centers. A total of 1,198 healthy, eumenorrheic women aged 18-40 years attempting spontaneous pregnancy with one to two prior pregnancy losses were included. Women were categorized by baseline antimüllerian hormone (AMH), as a surrogate marker of antral follicle count, and T concentrations; the highest quartile for each was "high," and below the top quartile (i.e., lower 75% of values) was "norm," forming four groups: norm T/norm AMH (n = 742), norm T/high AMH (n = 156), high T/norm AMH (n = 157), and high T/high AMH (n = 143). Not applicable. Anovulation, pregnancy incidence, TTP, and pregnancy loss incidence. Women with high T/high AMH had a greater anovulation risk (risk ratio 1.58, 95% confidence interval 1.13-2.22) compared with women with norm T/norm AMH, but with imprecise differences in incidence of pregnancy, TTP, or pregnancy loss. Women with higher T and AMH had more frequent anovulatory cycles but with marginal impacts on TTP or pregnancy loss. A continuum of mild inefficiency in reproductive function may be related to higher T and AMH, including in fecund women with normal menstrual cycles and no clinical diagnosis of polycystic ovary syndrome, but with unclear effects on fecundability and pregnancy loss. NCT00467363. Published by Elsevier Inc.

Regional differences in time to pregnancy among fertile women from five Colombian regions with different use of glyphosate.

PubMed

Sanin, Luz-Helena; Carrasquilla, Gabriel; Solomon, Keith R; Cole, Donald C; Marshall, E J P

2009-01-01

The objective of this study was to test whether there was an association between the use of glyphosate when applied by aerial spray for the eradication of illicit crops (cocaine and poppy) and time to pregnancy (TTP) among fertile women. A retrospective cohort study (with an ecological exposure index) of first pregnancies was undertaken in 2592 fertile Colombian women from 5 regions with different uses of glyphosate. Women were interviewed regarding potential reproductive, lifestyle, and work history predictors of TTP, which was measured in months. Fecundability odds ratios (fOR) were estimated using a discrete time analogue of Cox's proportional hazard model. There were differences in TTP between regions. In the final multivariate model, the main predictor was the region adjusted by irregular relationship with partner, maternal age at first pregnancy, and, marginally, coffee consumption and self-perception of water pollution. Boyaca, a region with traditional crops and. recently, illicit crops without glyphosate eradication spraying (manual eradication), displayed minimal risk and was the reference region. Other regions, including Sierra Nevada (control area, organic agriculture), Putumayo and Narino (illicit crops and intensive eradication spray program), and Valle del Cauca, demonstrated greater risk of longer TTP, with the highest risk for Valle del Cauca (fOR 0.15, 95% CI 0.12, 0.18), a sugar-cane region with a history of use of glyphosate and others chemicals for more than 30 yr. The reduced fecundability in some regions was not associated with the use of glyphosate for eradication spraying. The observed ecological differences remain unexplained and may be produced by varying exposures to environmental factors, history of contraceptive programs in the region, or psychological distress. Future studies examining these or other possible causes are needed.

Carotid Artery Stenting and Blood-Brain Barrier Permeability in Subjects with Chronic Carotid Artery Stenosis.

PubMed

Szarmach, Arkadiusz; Halena, Grzegorz; Kaszubowski, Mariusz; Piskunowicz, Maciej; Studniarek, Michal; Lass, Piotr; Szurowska, Edyta; Winklewski, Pawel J

2017-05-08

Failure of the blood-brain barrier (BBB) is a critical event in the development and progression of diseases such as acute ischemic stroke, chronic ischemia or small vessels disease that affect the central nervous system. It is not known whether BBB breakdown in subjects with chronic carotid artery stenosis can be restrained with postoperative recovery of cerebral perfusion. The aim of the study was to assess the short-term effect of internal carotid artery stenting on basic perfusion parameters and permeability surface area-product (PS) in such a population. Forty subjects (23 males) with stenosis of >70% within a single internal carotid artery and neurological symptoms who underwent a carotid artery stenting procedure were investigated. Differences in the following computed tomography perfusion (CTP) parameters were compared before and after surgery: global cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), time to peak (TTP) and PS. PS acquired by CTP is used to measure the permeability of the BBB to contrast material. In all baseline cases, the CBF and CBV values were low, while MTT and TTP were high on both the ipsi- and contralateral sides compared to reference values. PS was approximately twice the normal value. CBF was higher (+6.14%), while MTT was lower (-9.34%) on the contralateral than on the ipsilateral side. All perfusion parameters improved after stenting on both the ipsilateral (CBF +22.66%; CBV +18.98%; MTT -16.09%, TTP -7.62%) and contralateral (CBF +22.27%, CBV +19.72%, MTT -14.65%, TTP -7.46%) sides. PS decreased by almost half: ipsilateral -48.11%, contralateral -45.19%. The decline in BBB permeability was symmetrical on the ipsi- and contralateral sides to the stenosis. Augmented BBB permeability can be controlled by surgical intervention in humans.

Application of CT perfusion to assess hemodynamics in symptomatic Moyamoya syndrome: focus on affected side and parameter characteristic.

PubMed

Huang, Shuran; Gao, Lingyun; Chen, Yueqin; Guo, Xiang; Liu, Deguo; Wang, Jiehuan; Shi, Zhitao; Sun, Zhanguo; Jin, Feng; Chen, Weijian; Yang, Yunjun

2018-01-27

Vascular and hemodynamic changes were not consistent in symptomatic and non-symptomatic cerebral hemisphere in patients with symptomatic moyamoya syndrome (MMS). Thus, the purpose of this study is to evaluate the hemodynamic difference between symptomatic and non-symptomatic cerebral hemisphere in patients with symptomatic MMS. Patients who were diagnosed with symptomatic MMS were retrospectively collected. All cases underwent CTP examination. Regions of interest (ROIs) were chosen in the mirroring bilateral frontal lobes, temporal lobes, the basal ganglia, and the brainstem as control region. The relative perfusion parameter values of symptomatic side were compared with non-symptomatic side. Of the 40 patients, 33 patients were taken into assessment. In all cases (n = 33), rCBF, rMTT, and rTTP in all regions of interest (ROIs) of the symptomatic side were significantly different from those of contralateral side. In unilateral MMS patients (n = 7), rCBF values were not significantly different between two sides in the temporal lobe and basal ganglia area; rTTP values were significantly higher in the symptomatic side. rMTT values were significantly higher only in the temporal lobe of symptomatic side. In bilateral MMS patients (n = 26), rCBF and rMTT in all ROIs of the symptomatic side were significantly different from those of contralateral side. However, there were no significant differences between two sides in all ROIs on rTTP values. This study demonstrates that rCBF and rMTT were more sensitive than rTTP for evaluating hemodynamic changes in patients with symptomatic bilateral MMS. Furthermore, patients with unilateral MMS may have a preserved rCBF compared to those with bilateral disease.

Correlating Surrogate Endpoints with Overall Survival at the Individual Patient Level in BRAFV600E-Mutated Metastatic Melanoma Patients Treated with Vemurafenib.

PubMed

Zabor, Emily C; Heller, Glenn; Schwartz, Lawrence H; Chapman, Paul B

2016-03-15

Surrogate endpoints are needed that correlate with overall survival (OS). We analyzed individual patient tumor data from a phase III trial of vemurafenib versus dacarbazine (BRIM3) to identify criteria for tumor measures that correlated with OS. Correlates were validated using a separate data set from a phase II trial of vemurafenib (BRIM2). Deidentified tumor measurements and OS data from BRIM3 and from BRIM2 were analyzed. Target tumor measurement data and nontarget tumor data were available from pretreatment, weeks 6,12, and every 9 weeks thereafter. In the BRIM3 data set, associations of OS with both early tumor response (first 12 weeks) and time to progression (TTP) were assessed. Different definitions of response and progression were explored. Findings were validated using the BRIM2 data set. Thresholds of early response were explored ranging from any degree of tumor shrinkage to 100% tumor shrinkage. Correlation was weak at all thresholds tested. TTP, however, was more strongly correlated with OS. The strongest correlation was seen when progression was defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors. This was confirmed by similar analyses in the BRIM2 cohort. TTP defined as ≥50% increase in the sum of tumor diameters or appearance of new tumors was more strongly associated with OS than early tumor shrinkage in melanoma patients treated with RAF inhibitor. In future trials, consideration should be given to replacing response rate with TTP or PFS as preferable clinical endpoints in early-phase studies. ©2015 American Association for Cancer Research.

Haematological manifestations of lupus

PubMed Central

Fayyaz, Anum; Igoe, Ann; Kurien, Biji T; Danda, Debashish; James, Judith A; Stafford, Haraldine A; Scofield, R Hal

2015-01-01

Our purpose was to compile information on the haematological manifestations of systemic lupus erythematosus (SLE), namely leucopenia, lymphopenia, thrombocytopenia, autoimmune haemolytic anaemia (AIHA), thrombotic thrombocytopenic purpura (TTP) and myelofibrosis. During our search of the English-language MEDLINE sources, we did not place a date-of-publication constraint. Hence, we have reviewed previous as well as most recent studies with the subject heading SLE in combination with each manifestation. Neutropenia can lead to morbidity and mortality from increased susceptibility to infection. Severe neutropenia can be successfully treated with granulocyte colony-stimulating factor. While related to disease activity, there is no specific therapy for lymphopenia. Severe lymphopenia may require the use of prophylactic therapy to prevent select opportunistic infections. Isolated idiopathic thrombocytopenic purpura maybe the first manifestation of SLE by months or even years. Some manifestations of lupus occur more frequently in association with low platelet count in these patients, for example, neuropsychiatric manifestation, haemolytic anaemia, the antiphospholipid syndrome and renal disease. Thrombocytopenia can be regarded as an important prognostic indicator of survival in patients with SLE. Medical, surgical and biological treatment modalities are reviewed for this manifestation. First-line therapy remains glucocorticoids. Through our review, we conclude glucocorticoids do produce a response in majority of patients initially, but sustained response to therapy is unlikely. Glucocorticoids are used as first-line therapy in patients with SLE with AIHA, but there is no conclusive evidence to guide second-line therapy. Rituximab is promising in refractory and non-responding AIHA. TTP is not recognised as a criteria for classification of SLE, but there is a considerable overlap between the presenting features of TTP and SLE, and a few patients with SLE have concurrent TTP. Myelofibrosis is an uncommon yet well-documented manifestation of SLE. We have compiled the cases that were reported in MEDLINE sources. PMID:25861458

Temporal similarity perfusion mapping: A standardized and model-free method for detecting perfusion deficits in stroke

PubMed Central

Song, Sunbin; Luby, Marie; Edwardson, Matthew A.; Brown, Tyler; Shah, Shreyansh; Cox, Robert W.; Saad, Ziad S.; Reynolds, Richard C.; Glen, Daniel R.; Cohen, Leonardo G.; Latour, Lawrence L.

2017-01-01

Introduction Interpretation of the extent of perfusion deficits in stroke MRI is highly dependent on the method used for analyzing the perfusion-weighted signal intensity time-series after gadolinium injection. In this study, we introduce a new model-free standardized method of temporal similarity perfusion (TSP) mapping for perfusion deficit detection and test its ability and reliability in acute ischemia. Materials and methods Forty patients with an ischemic stroke or transient ischemic attack were included. Two blinded readers compared real-time generated interactive maps and automatically generated TSP maps to traditional TTP/MTT maps for presence of perfusion deficits. Lesion volumes were compared for volumetric inter-rater reliability, spatial concordance between perfusion deficits and healthy tissue and contrast-to-noise ratio (CNR). Results Perfusion deficits were correctly detected in all patients with acute ischemia. Inter-rater reliability was higher for TSP when compared to TTP/MTT maps and there was a high similarity between the lesion volumes depicted on TSP and TTP/MTT (r(18) = 0.73). The Pearson's correlation between lesions calculated on TSP and traditional maps was high (r(18) = 0.73, p<0.0003), however the effective CNR was greater for TSP compared to TTP (352.3 vs 283.5, t(19) = 2.6, p<0.03.) and MTT (228.3, t(19) = 2.8, p<0.03). Discussion TSP maps provide a reliable and robust model-free method for accurate perfusion deficit detection and improve lesion delineation compared to traditional methods. This simple method is also computationally faster and more easily automated than model-based methods. This method can potentially improve the speed and accuracy in perfusion deficit detection for acute stroke treatment and clinical trial inclusion decision-making. PMID:28973000

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

PubMed

Fox, Lucy C; Cohney, Solomon J; Kausman, Joshua Y; Shortt, Jake; Hughes, Peter D; Wood, Erica M; Isbel, Nicole M; de Malmanche, Theo; Durkan, Anne; Hissaria, Pravin; Blombery, Piers; Barbour, Thomas D

2018-06-01

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA. © 2018 Asian Pacific Society of Nephrology.

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

PubMed

Fox, Lucy C; Cohney, Solomon J; Kausman, Joshua Y; Shortt, Jake; Hughes, Peter D; Wood, Erica M; Isbel, Nicole M; de Malmanche, Theo; Durkan, Anne; Hissaria, Pravin; Blombery, Piers; Barbour, Thomas D

2018-06-01

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. Although TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 (a disintegrin and metalloprotease thrombospondin, number 13) activity. A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. Although early confirmation of aHUS is often not possible, except in the minority of patients in whom auto-antibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA. © 2018 Royal Australasian College of Physicians.

Outcome and prognostic factors in medically treated canine prostatic carcinomas: A multi-institutional study.

PubMed

Ravicini, S; Baines, S J; Taylor, A; Amores-Fuster, I; Mason, S L; Treggiari, E

2018-05-27

Literature describing medical treatment of canine prostatic carcinoma (PC) is sparse. The aims of this study were to assess outcomes, including time to progression (TTP) and median survival time (MST), of canine PC treated with non-steroidal anti-inflammatory drugs (NSAIDs) and/or chemotherapy, and to identify prognostic factors. Records from 8 institutions were searched for dogs with cytologically or histologically confirmed PC without bladder involvement: 67 dogs were included. Presenting signs were urinary (25), gastrointestinal ([GI], 11) and systemic (3); 16 dogs had GI and urinary signs, 7 dogs had systemic signs with concurrent GI or urinary signs and in 5 dogs the tumour was an incidental finding. Out of 27 dogs, 9 (33%) had positive urine culture. Metastases were identified in 26 dogs to lymph nodes (19), lungs (10), bone (2) and liver (1). Treatment included NSAIDs and chemotherapy (32), NSAIDs alone (31) and chemotherapy alone (4). The overall MST was 82 days (range 9-752) and median TTP was 63 days (range 9-752). Dogs receiving NSAIDs combined with chemotherapy experienced a significantly longer MST (106 vs 51 days; P = .035) and TTP (76 vs 44 days; P = .02) compared to dogs receiving NSAIDs alone. Intact dogs and those with metastatic disease had significantly shorter MST (31 vs 90 days, P = .018 and 49 vs 109 days, P = .037, respectively); intact dogs also had significantly shorter TTP (25 vs 63 days, P = .0003). This study suggests that a combination of NSAIDs and chemotherapy may improve outcomes in canine PC. Metastatic disease and being entire negatively influenced prognosis. © 2018 John Wiley & Sons Ltd.

4D MRI of polycystic kidneys from rapamycin-treated Glis3-deficient mice

PubMed Central

Xie, Luke; Qi, Yi; Subashi, Ergys; Liao, Grace; Miller DeGraff, Laura; Jetten, Anton M.; Johnson, G. Allan

2015-01-01

Polycystic kidney disease (PKD) is a life-threatening disease that leads to a grotesque enlargement of the kidney and significant lose of function. Several imaging studies with MRI have demonstrated that cyst size in polycystic kidneys can determine disease severity and progression. In the present study, we found that while kidney volume and cyst volume decreased with drug treatment, renal function did not improve with treatment. Here, we applied dynamic contrast-enhanced MRI to study PKD in a Glis3-deficient mouse model. Cysts from this model have a wide range of sizes and develop at an early age. To capture this crucial stage and assess cysts in detail, we imaged during early development (3 to 17 weeks) and applied high spatiotemporal resolution MRI (125×125×125 cubic microns every 7.7 seconds). A drug treatment with rapamycin (also known as sirolimus) was applied to determine whether disease progression could be halted. The effect and synergy (interaction) of aging and treatment were evaluated using an analysis of variance (ANOVA). Structural measurements including kidney volume, cyst volume, and cyst-kidney volume ratio changed significantly with age. Drug treatment significantly decreased these metrics. Functional measurements of time-to-peak (TTP) mean and TTP variance were determined. TTP mean did not change with age, while TTP variance increased with age. The treatment of rapamycin generally did not affect these functional metrics. Synergistic effects of treatment and age were not found for any measurements. Together, the size and volume ratio of cysts decreased with drug treatment, while renal function remained the same. Quantifying renal structure and function with MRI can comprehensively assess the pathophysiology of PKD and response to treatment. PMID:25810360

Coriolus versicolor (Yunzhi) Use as Therapy in Advanced Hepatocellular Carcinoma Patients with Poor Liver Function or Who Are Unfit for Standard Therapy.

PubMed

Chay, Wen Yee; Tham, Chee Kian; Toh, Han Chong; Lim, Hwee Yong; Tan, Chee Kiat; Lim, Cindy; Wang, Who-Whong; Choo, Su-Pin

2017-08-01

The majority of patients with hepatocellular carcinoma (HCC) are inoperable and results with conventional chemotherapy are dismal. Many end up with no treatment options and resort to alternative medicine. The authors report the use of Coriolus versicolor (CV) in advanced HCC patients with poor liver function or who were unfit to receive standard therapy. Fifteen eligible cases were randomized 2:1 to either CV or placebo. The primary endpoint was the median time to progression (TTP) between both arms. Secondary endpoints include evaluating response rates, toxicity, quality of life (QOL), progression-free survival (PFS), and overall survival (OS). Further correlative studies were performed looking at the effect of CV on the immune system. The median treatment duration was 1.5 cycles and 3 cycles on the placebo and CV arm, respectively. Median TTP was 2.5 (1.4-5.3) months compared to 4.2 (0.4-4.2) months in the CV and placebo arm, respectively, hazard ratio (HR) 0.70 (0.16-3.05 p = 0.634). Median PFS was 2.5 (1.4-5.3) months in the CV and 1.1 (0.4-4.2) months in the placebo arm, HR 0.42 (0.13-1.34, p = 0.144). Median OS was 6.5 (3.3-24.1) and 2.2 (0.8-23.3) months, respectively, HR 0.35 (0.10-1.25, p = 0.105). Social and emotional functioning scores were higher in the CV group compared to placebo group on treatment. CV subjects had less appetite loss and pain symptoms compared to placebo subjects during treatment. There was no difference in TTP with use of CV compared to placebo. CV subjects generally had better QOL on treatment compared to placebo subjects. The utility of this supplement in patients whose primary treatment goal is palliation should be further explored.

Enhancement of electron correlation due to the molecular dimerization in organic superconductors β -(BDA-TTP )2X (X =I3, SbF6)

NASA Astrophysics Data System (ADS)

Aizawa, Hirohito; Kuroki, Kazuhiko; Yamada, Jun-ichi

2015-10-01

We perform a first-principles band calculation for quasi-two-dimensional organic superconductors β -(BDA -TTP) 2I3 and β -(BDA -TTP) 2SbF6. The first-principles band structures between the I3 and SbF6 salts are apparently different. We construct a tight-binding model for each material which accurately reproduces the first-principles band structure. The obtained transfer energies give the differences as follows: (i) larger dimerization in the I3 salt than the SbF6 salt, and (ii) different signs and directions of the interstacking transfer energies. To decompose the origin of the difference into the dimerization and the interstacking transfer energies, we adopt a simplified model by eliminating the dimerization effect and focus only on the difference caused by the interstacking transfer energies. From the analysis using the simplified model, we find that the difference of the band structure comes mainly from the strength of the dimerization. To compare the strength of the electron correlation having roots in the band structure, we calculate the physical properties originating from the effect of the electron correlation such as the spin susceptibility applying the two-particle self-consistent method. We find that the maximum value of the spin susceptibility for the I3 salt is larger than that of the SbF6 salt. Hypothetically decreasing the dimerization within the model of the I3 salt, the spin susceptibility takes almost the same value as that of the SbF6 salt for the same magnitude of the dimerization. We expect that the different ground state between the I3 and SbF6 salt mainly comes from the strength of the dimerization which is apparently masked in the band calculation along a particular k path.

Quantitative Assessment of Neovascularization after Indirect Bypass Surgery: Color-Coded Digital Subtraction Angiography in Pediatric Moyamoya Disease.

PubMed

Cho, H-H; Cheon, J-E; Kim, S-K; Choi, Y H; Kim, I-O; Kim, W S; Lee, S-M; You, S K; Shin, S-M

2016-05-01

For the postoperative follow-up in pediatric patients with Moyamoya disease, it is essential to evaluate the degree of neovascularization status. Our aim was to quantitatively assess the neovascularization status after bypass surgery in pediatric Moyamoya disease by using color-coded digital subtraction angiography. Time-attenuation intensity curves were generated at ROIs corresponding to surgical flap sites from color-coded DSA images of the common carotid artery, internal carotid artery, and external carotid artery angiograms obtained pre- and postoperatively in 32 children with Moyamoya disease. Time-to-peak and area under the curve values were obtained. Postoperative changes in adjusted time-to-peak (ΔTTP) and ratios of adjusted area under the curve changes (ΔAUC ratio) of common carotid artery, ICA, and external carotid artery angiograms were compared across clinical and angiographic outcome groups. To analyze diagnostic performance, we categorized clinical outcomes into favorable and unfavorable groups. The ΔTTP at the common carotid artery increased among clinical and angiographic outcomes, in that order, with significant differences (P = .003 and .005, respectively). The ΔAUC ratio at the common carotid artery and external carotid artery also increased, in that order, among clinical and angiographic outcomes with a significant difference (all, P = .000). The ΔAUC ratio of ICA showed no significant difference among clinical and angiographic outcomes (P = .418 and .424, respectively). The ΔTTP for the common carotid artery of >1.27 seconds and the ΔAUC ratio of >33.5% for the common carotid artery and 504% for the external carotid artery are revealed as optimal cutoff values between favorable and unfavorable groups. Postoperative changes in quantitative values obtained with color-coded DSA software showed a significant correlation with outcome scores and can be used as objective parameters for predicting the outcome in pediatric Moyamoya disease, with an additional cutoff value calculated through the receiver operating characteristic curve. © 2016 by American Journal of Neuroradiology.

The (oxo)[(2,3,7,8,12,13,17,18-octachloro-5,10,15,20-tetrakis(4-tolylporphyrinato)]vanadium(IV): Synthesis, UV-visible, Cyclic voltammetry and X-ray crystal structure

NASA Astrophysics Data System (ADS)

Mchiri, Chadlia; Amiri, Nesrine; Jabli, Souhir; Roisnel, Thierry; Nasri, Habib

2018-02-01

The present work is concerned with the oxo vanadium(IV) complex of 2,3,7,8,12,13,17,18-octachloro-5,10,15,20-tetrakis(4-tolylporphyrin) with formula [V(Cl8TTP)O] (I), which was prepared by reacting the (oxo)[5,10,15,20-tetrakis(4-tolylporphyrinato)]vanadium(IV) complex ([V(TTP)O]), under aerobic atmosphere, with a large excess of thionyl chloride (SOCl2). The title compound was characterized by UV-visible spectroscopy, cyclic voltammetry and X-ray crystal structure. The electron-withdrawing chlorine substituents at the pyrrole carbons in the vanadyl-Cl8TTP derivative produce remarkable redshifts of the Soret and Q absorption bands and an important anodic shift of the porphyrin ring oxidation and reduction potentials. This is an indication that the porphyrin core of complex (I) is severely nonplanar in solution. The molecular structure of our vanadyl derivative shows a very high saddle distortion and an important ruffled deformation of the porphyrin macrocycle. The crystal structure of (I) is made by one-dimensional chains parallel to the c axis where channels are located between these chains.

Mechanism of error-free DNA synthesis across N1-methyl-deoxyadenosine by human DNA polymerase-ι

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

Jain, Rinku; Choudhury, Jayati Roy; Buku, Angeliki

N1-methyl-deoxyadenosine (1-MeA) is formed by methylation of deoxyadenosine at the N1 atom. 1-MeA presents a block to replicative DNA polymerases due to its inability to participate in Watson-Crick (W-C) base pairing. Here we determine how human DNA polymerase-ι (Polι) promotes error-free replication across 1-MeA. Steady state kinetic analyses indicate that Polι is ~100 fold more efficient in incorporating the correct nucleotide T versus the incorrect nucleotide C opposite 1-MeA. To understand the basis of this selectivity, we determined ternary structures of Polι bound to template 1-MeA and incoming dTTP or dCTP. In both structures, template 1-MeA rotates to the synmore » conformation but pairs differently with dTTP versus dCTP. Thus, whereas dTTP partakes in stable Hoogsteen base pairing with 1-MeA, dCTP fails to gain a “foothold” and is largely disordered. Together, our kinetic and structural studies show how Polι maintains discrimination between correct and incorrect incoming nucleotide opposite 1-MeA in preserving genome integrity.« less

Phase diagram of pressure-induced superconductor β-(BDA-TTP)2MX4 (M=Fe, Ga and X=Cl, Br) with localized magnetic moments

NASA Astrophysics Data System (ADS)

Choi, E. S.; Graf, D.; Tokumoto, T.; Brooks, J. S.; Yamada, Jun-Ichi

2007-03-01

We have investigated transport and magnetization properties of β-(BDA-TTP)2MX4 (M=Fe, Ga and X=Cl, Br) as a function of pressure, temperature and magnetic field. The title material undergoes metal-insulator transitions above 100 K at ambient pressure. The insulating phase is suppressed with pressure and superconductivity eventually appears above Pc= 4.5 kbar (X=Cl) and 13 kbar (X=Br). The general temperature-pressure (TP) phase diagram is similar each other, while higher pressure is required for X=Br compounds to suppress the insulating state and induce the superconductivity. Pressure dependent DC magnetization studies on β-(BDA-TTP)2FeCl4 compound revealed that the AFM ordering persist well above Pc. In spite of similarity of phase diagram between M=Fe and M=Ga compounds, magnetoresistance results show distinct behaviors, which indicates the magnetic interaction with the conduction electrons are still effective. The comparison between X=Cl and X=Br compounds suggests the anion-size effect rather than the existence of localized magnetic moments plays more important role in determining the ground state.

High field ESR study of the pi-d interaction effect in beta-(BDA-TTP)2MCl4 (M=Fe, Ga)

NASA Astrophysics Data System (ADS)

Tokumoto, Takahisa; Vantol, J.; Brunel, L.-C.; Choi, E. S.; Brooks, J. S.; Kaihatsu, T.; Akutsu, H.; Yamada, J.

2007-03-01

Novel magnetic organic conductors with pi-d interaction have commanded attention since the discovery of field induced superconductivity. One of them, beta-(BDA-TTP)2FeCl4, has alternating donor molecules and quasi 2D electrical properties. Previous studies of electrical and magnetic properties show an M-I transition at 120K and an AF transition at TN=8.5K, suggesting an exchange interaction between the conduction electrons and the Fe^3+ d-electrons. The properties of beta-(BDA-TTP)2GaCl4 are similar with exception of the absence of the AF transition, which is apparently due to the absence of pi-d exchange interaction. We report angular/temperature dependent 240GHz quasi optical ESR measurements on both compounds to probe the magnetic properties. The Ga compound signals follow the donor molecule structure, and show no magnetic order at any temperature. The Fe compound signals are quite different from the Ga compound, and exhibit AF behavior below TN. The difference of Fe and Ga compounds will be discussed in terms of the interaction between localized and itinerant magnetic moments.

Involvement of tristetraprolin in transcriptional activation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase by insulin

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

Ness, Gene C., E-mail: gness@hsc.usf.edu; Edelman, Jeffrey L.; Brooks, Patricia A.

2012-03-30

Highlights: Black-Right-Pointing-Pointer siRNAs to tristetraprolin blocks transcription of HMGR in vivo in rat liver. Black-Right-Pointing-Pointer siRNAs to tristetraprolin inhibits insulin activation of HMGR transcription. Black-Right-Pointing-Pointer Insulin acts to rapidly increase tristetraprolin in liver nuclear extracts. -- Abstract: Several AU-rich RNA binding element (ARE) proteins were investigated for their possible effects on transcription of hepatic 3-hydroxy-3-methyglutaryl coenzyme A reductase (HMGR) in normal rats. Using in vivo electroporation, four different siRNAs to each ARE protein were introduced together with HMGR promoter (-325 to +20) luciferase construct and compared to saline controls. All four siRNAs to tristetraprolin (TTP) completely eliminated transcription from themore » HMGR promoter construct. Since insulin acts to rapidly increase hepatic HMGR transcription, the effect of TTP siRNA on induction by insulin was tested. The 3-fold stimulation by insulin was eliminated by this treatment. In comparison, siRNA to AU RNA binding protein/enoyl coenzyme A hydratase (AUH) had no effect. These findings indicate a role for TTP in the insulin-mediated activation of hepatic HMGR transcription.« less

Enabling real-time ultrasound imaging of soft tissue mechanical properties by simplification of the shear wave motion equation.

PubMed

Engel, Aaron J; Bashford, Gregory R

2015-08-01

Ultrasound based shear wave elastography (SWE) is a technique used for non-invasive characterization and imaging of soft tissue mechanical properties. Robust estimation of shear wave propagation speed is essential for imaging of soft tissue mechanical properties. In this study we propose to estimate shear wave speed by inversion of the first-order wave equation following directional filtering. This approach relies on estimation of first-order derivatives which allows for accurate estimations using smaller smoothing filters than when estimating second-order derivatives. The performance was compared to three current methods used to estimate shear wave propagation speed: direct inversion of the wave equation (DIWE), time-to-peak (TTP) and cross-correlation (CC). The shear wave speed of three homogeneous phantoms of different elastic moduli (gelatin by weight of 5%, 7%, and 9%) were measured with each method. The proposed method was shown to produce shear speed estimates comparable to the conventional methods (standard deviation of measurements being 0.13 m/s, 0.05 m/s, and 0.12 m/s), but with simpler processing and usually less time (by a factor of 1, 13, and 20 for DIWE, CC, and TTP respectively). The proposed method was able to produce a 2-D speed estimate from a single direction of wave propagation in about four seconds using an off-the-shelf PC, showing the feasibility of performing real-time or near real-time elasticity imaging with dedicated hardware.

In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

PubMed Central

2009-01-01

Background New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether in situ carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression. Methods Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression. Results Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP. Conclusion TMAs are not suitable for IHC analysis of in situ aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. In situ aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer cells is not predictive of response to endocrine therapy, indicating that in situ estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP. Trial registration Sub-study of trial P025 for advanced breast cancer. PMID:19531212

Antiferromagnetic d-Electron Exchange via a Spin-Singlet π-Electron Ground State in an Organic Conductor

NASA Astrophysics Data System (ADS)

Tokumoto, T.; Brooks, J. S.; Oshima, Y.; Choi, E. S.; Brunel, L. C.; Akutsu, H.; Kaihatsu, T.; Yamada, J.; van Tol, J.

2008-04-01

Electron spin resonance reveals the spin behavior of conduction (π) and localized (d) electrons in β-(BDA-TTP)2MCl4 (M=Fe, Ga). Both the Ga3+(S=0) and Fe3+(S=5/2) compounds exhibit a metal-insulator transition at 113 K with the simultaneous formation of a spin-singlet ground state in the π electron system of the donor molecules. The behavior is consistent with charge ordering in β-(BDA-TTP)2MCl4 at the metal-insulator transition. At 5 K, the Fe3+ compound orders antiferromagnetically, even though the π electrons, which normally would facilitate magnetic exchange, are localized nonmagnetic singlets.

The pressure-temperature phase diagram of pressure induced organic superconductors β-(BDA-TTP){2}MCl{4} (M = Ga, Fe)

NASA Astrophysics Data System (ADS)

Choi, E. S.; Graf, D.; Brooks, J. S.; Yamada, J.; Tokumoto, M.

2004-04-01

We investigate the pressure-temperature phase diagram of β -(BDA-TTP){2}MCl{4} (M=Ga, Fe), which shows a metal-insulator (MI) transition around 120 K at ambient pressure. By applying pressure, the insulating phase is suppressed. When the pressure is higher than 5.5 kbar, the superconducting phase appears in both salts with Tc ˜ 3 K for M=Ga and 2.2 K for M=Fe. We also observed Shubnikov-de Haas (SdH) oscillations at high magnetic field in both salts, where the SdH frequencies are found to be very similar each other. Key words. organic superconductor, pressure, phase diagram.

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

Graf, Peter; Dykes, Katherine; Scott, George

The layout of turbines in a wind farm is already a challenging nonlinear, nonconvex, nonlinearly constrained continuous global optimization problem. Here we begin to address the next generation of wind farm optimization problems by adding the complexity that there is more than one turbine type to choose from. The optimization becomes a nonlinear constrained mixed integer problem, which is a very difficult class of problems to solve. Furthermore, this document briefly summarizes the algorithm and code we have developed, the code validation steps we have performed, and the initial results for multi-turbine type and placement optimization (TTP_OPT) we have run.

Extra-analytical quality indicators and laboratory performances.

PubMed

Sciacovelli, Laura; Aita, Ada; Plebani, Mario

2017-07-01

In the last few years much progress has been made in raising the awareness of laboratory medicine professionals about the effectiveness of quality indicators (QIs) in monitoring, and improving upon, performances in the extra-analytical phases of the Total Testing Process (TTP). An effective system for management of QIs includes the implementation of an internal assessment system and participation in inter-laboratory comparison. A well-designed internal assessment system allows the identification of critical activities and their systematic monitoring. Active participation in inter-laboratory comparison provides information on the performance level of one laboratory with respect to that of other participating laboratories. In order to guarantee the use of appropriate QIs and facilitate their implementation, many laboratories have adopted the Model of Quality Indicators (MQI) proposed by Working Group "Laboratory Errors and Patient Safety" (WG-LEPS) of IFCC, since 2008, which is the result of international consensus and continuous experimentation, and updating to meet new, constantly emerging needs. Data from participating laboratories are collected monthly and reports describing the statistical results and evaluating laboratory data, utilizing the Six Sigma metric, issued regularly. Although the results demonstrate that the processes need to be improved upon, overall the comparison with data collected in 2014 shows a general stability of quality levels and that an improvement has been achieved over time for some activities. The continuous monitoring of QI data allows identification all possible improvements, thus highlighting the value of participation in the inter-laboratory program proposed by WG-LEPS. The active participation of numerous laboratories will guarantee an ever more significant State-of-the-Art, promote the reduction of errors and improve quality of the TTP, thus guaranteeing patient safety. Copyright © 2017. Published by Elsevier Inc.

Neuroimaging patterns of cerebral hyperperfusion

NASA Astrophysics Data System (ADS)

Semenov, S.; Portnov, Yu; Semenov, A.; Korotkevich, A.; Kokov, A.

2017-08-01

Cerebral hyperperfusion syndrome (CHS) after revascularization is a rare phenomenon associated with post-ischemic (reactive) hyperemia and acute pathological hyperperfusion. First described on perfusion CT as a very often moderate CBF increase, MTT/TTP decrease within 30% like a temporary effect, according to a short-time deterioration of neurological symptoms (vestibular ataxia - 58%, vegetative dysfunction - 100%, asthenic syndrome - 100%) in early postoperative period in patients with cardiac ischemia who had undergone coronary artery bypass surgery. The acute pathological hyperperfusion carotid revascularization is a casuistic phenomenon with two- or three-fold CBV and MTT/TTP increase and high hemorrhage risk. Besides, we detected similar exchanges via perfusion CT called benign hyperemia, which marks extension of MTT/TTP and an increase of CBV from 27% to 48% (average 30%), but with normal CBF-parameters, indicating that venous stasis in acute venous ischemic stroke due cerebral venous sinus-trombosis (68%), only 6% in cardioembolic stroke and appears never in arterial stroke. Territorial coincidence registered for perifocal of necrosis zones of benign hyperemia and vasogenic edema accompanied on MRI (DWI, ADC). Secondary hemorrhagic transformation registered for primary non-hemorrhagic venous stroke in 27%, only in 9% for arterial stroke and in 60% for cardioembolic stroke. Probably, congestion is an increasingly predisposing factor secondary hemorrhaging than necrosis.

Feasibility of surveillance of changes in human fertility and semen quality.

PubMed

Stewart, T M; Brown, E H; Venn, A; Mbizvo, M T; Farley, T M; Garrett, C; Baker, H W

2001-01-01

There is concern that male fertility is declining, but this is difficult to study because few men volunteer for studies of semen quality, and recruitment bias may over-represent the subfertile. The Human Reproduction Programme of the World Health Organization developed a protocol for multicentre studies of fertility involving a questionnaire for pregnant women to obtain time to pregnancy (TTP): the number of menstrual cycles taken to conceive. Male characteristics and semen quality will be determined in a subset of the partners. Our aim was to validate the TTP questionnaire, and to examine potential recruitment bias and feasibility of conducting large-scale surveillance of fertility. The questionnaire was administered to 120 pregnant women (16-32 weeks). Validation included internal reliability by consistency of responses, test-re-test reliability by repeat administration (20 women) and accuracy by comparison of gestational age from first antenatal ultrasound and menstrual dates. Internal reliability was high. Agreement between categorical responses on re-testing was very good (k > 0.8). In both the re-test and gestational age analysis, differences in TTP of 1 cycle were found (standard deviation <0.25 cycles). In this small pilot study there was no evidence of recruitment bias. Response rates indicate the feasibility of surveillance of fertility in large maternity centres.

Intracellular transport of fat-soluble vitamins A and E.

PubMed

Kono, Nozomu; Arai, Hiroyuki

2015-01-01

Vitamins are compounds that are essential for the normal growth, reproduction and functioning of the human body. Of the 13 known vitamins, vitamins A, D, E and K are lipophilic compounds and are therefore called fat-soluble vitamins. Because of their lipophilicity, fat-soluble vitamins are solubilized and transported by intracellular carrier proteins to exert their actions and to be metabolized properly. Vitamin A and its derivatives, collectively called retinoids, are solubilized by intracellular retinoid-binding proteins such as cellular retinol-binding protein (CRBP), cellular retinoic acid-binding protein (CRABP) and cellular retinal-binding protein (CRALBP). These proteins act as chaperones that regulate the metabolism, signaling and transport of retinoids. CRALBP-mediated intracellular retinoid transport is essential for vision in human. α-Tocopherol, the main form of vitamin E found in the body, is transported by α-tocopherol transfer protein (α-TTP) in hepatic cells. Defects of α-TTP cause vitamin E deficiency and neurological disorders in humans. Recently, it has been shown that the interaction of α-TTP with phosphoinositides plays a critical role in the intracellular transport of α-tocopherol and is associated with familial vitamin E deficiency. In this review, we summarize the mechanisms and biological significance of the intracellular transport of vitamins A and E. © 2014 The Authors. Traffic published by John Wiley & Sons Ltd.

Effects of pyrimidines on the guinea-pig coronary vasculature.

PubMed Central

Vials, A. J.; Burnstock, G.

1993-01-01

1. The effects of the pyrimidines, uridine 5'-triphosphate (UTP), thymidine 5'-triphosphate (TTP) and cytidine 5'-triphosphate (CTP), were examined in the guinea-pig coronary bed, by use of a Langendorff technique. Comparisons were made with the actions of the purines adenosine 5'-triphosphate (ATP), inosine 5'-triphosphate (ITP) and guanosine 5'-triphosphate (GTP). The effect of, the nitric oxide synthase inhibitor, L-NG-nitroarginine methyl ester (L-NAME) and, the prostaglandin synthesis inhibitor, indomethacin on the vasodilator response to these purines and pyrimidines was examined. The effects of these inhibitors were assessed on their ability to inhibit both the amplitude and the area of the vasodilator response. 2. The relative order of potency of the purines and pyrimidines studied was ATP > UTP > ITP >> GTP, TTP, CTP. 3. The maximum amplitude and area of the vasodilator response to the pyrimidines, UTP (5 x 10(-10)-5 x 10(-7) mol), TTP (5 x 10(-8)-5 x 10(-7) mol) and CTP (5 x 10(-7) mol), and purines, ITP (5 x 10(-9)-5 x 10(-7) mol) and GTP (5 x 10(-8)-5 x 10(-7) mol), were significantly reduced by L-NAME (3 x 10(-5) and 10(-4) M).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8298797

The influence of maternal and paternal factors on time to pregnancy--a Dutch population-based birth-cohort study: the GECKO Drenthe study.

PubMed

Mutsaerts, M A Q; Groen, H; Huiting, H G; Kuchenbecker, W K H; Sauer, P J J; Land, J A; Stolk, R P; Hoek, A

2012-02-01

Both maternal and paternal factors have been suggested to influence a couple's fecundity. To investigate this, we examined the role of several maternal and paternal lifestyle and socio-demographic factors as determinants of time to pregnancy (TTP) in a Dutch birth-cohort. Groningen Expert Center for Kids with Obesity (GECKO) Drenthe is a population-based birth-cohort study of children born between April 2006 and April 2007 in Drenthe, a province of The Netherlands. Both partners received extensive questionnaires during pregnancy. Univariable and multivariable Cox regression analyses were used to determine the impact of the investigated factors on TTP. A total of 4778 children were born, and the parents of 2997 children (63%) gave their consent to participate. After excluding unintended pregnancies and pregnancies as a result of fertility treatment, the data of 1924 couples were available for analysis. Hazards ratios and 95% confidence intervals of factors influencing TTP in multivariable Cox regression analysis were: maternal age 1.23 (0.98-1.54) for age <25 years, 1.17 (1.03-1.32) for age 25-30 years and 0.72 (0.61-0.85) for age >35 years (reference category: 30-35 years); paternal age: 1.31 (0.94-1.82) for age <25 years, 1.11 (0.97-1.28) for age 25-30 years and 0.91 (0.80-1.04 for age >35 years (reference category: 30-35 years); nulliparity: 0.76 (0.68-0.85) versus multiparity; menstrual cycle length: 1.12 (0.95-1.30) for 3 weeks, 0.72 (0.62-0.83) for 4-6 weeks, 0.68 (0.40-1.16) for >6 weeks and 0.66 (0.54-0.81) for irregular cycle (reference category: 4 weeks); prior contraceptive use: 0.78 (0.67-0.91) for no contraception, 1.68 (1.45-1.95) for condom use, 1.08 (0.89-1.33) for condom use combined with oral contraception, 1.40 (1.16-1.70) for intrauterine device and 0.50 (0.25-1.01) for contraceptive injection (reference category: oral contraception); and maternal educational level 0.75 (0.62-0.92) for low education level and 0.81 (0.73-0.90) for medium educational level (reference category: high educational level). This population-based birth-cohort study performed in fertile couples who had conceived revealed neither maternal nor paternal modifiable lifestyle factors were significantly associated with TTP after adjustment for confounding by socio-demographic factors. In contrast, several non-modifiable maternal socio-demographic factors are significant predictors of a couple's fecundity.

Urinary Concentrations of Parabens and Other Antimicrobial Chemicals and Their Association with Couples’ Fecundity

PubMed Central

Smarr, Melissa M.; Sundaram, Rajeshwari; Honda, Masato; Kannan, Kurunthachalam; Louis, Germaine M. Buck

2016-01-01

Background: Human exposure to parabens and other antimicrobial chemicals is continual and pervasive. The hormone-disrupting properties of these environmental chemicals may adversely affect human reproduction. Objective: We aimed to prospectively assess couples’ urinary concentrations of antimicrobial chemicals in the context of fecundity, measured as time to pregnancy (TTP). Methods: In a prospective cohort of 501 couples, we examined preconception urinary chemical concentrations of parabens, triclosan and triclorcarban in relation to TTP; chemical concentrations were modeled both continuously and in quartiles. Cox’s proportional odds models for discrete survival time were used to estimate fecundability odds ratios (FORs) and 95% confidence intervals (CIs) adjusting for a priori–defined confounders. In light of TTP being a couple-dependent outcome, both partner and couple-based exposure models were analyzed. In all models, FOR estimates < 1.0 denote diminished fecundity (longer TTP). Results: Overall, 347 (69%) couples became pregnant. The highest quartile of female urinary methyl paraben (MP) concentrations relative to the lowest reflected a 34% reduction in fecundity (aFOR = 0.66; 95% CI: 0.45, 0.97) and remained so when accounting for couples’ concentrations (aFOR = 0.63; 95% CI: 0.41, 0.96). Similar associations were observed between ethyl paraben (EP) and couple fecundity for both partner and couple-based models (p-trend = 0.02 and p-trend = 0.05, respectively). No associations were observed with couple fecundity when chemicals were modeled continuously. Conclusions: Higher quartiles of preconception urinary concentrations of MP and EP among female partners were associated with reduced couple fecundity in partner-specific and couple-based exposure models. Citation: Smarr MM, Sundaram R, Honda M, Kannan K, Buck Louis GM. 2016. Urinary concentrations of parabens and other antimicrobial chemicals and their association with couples’ fecundity. Environ Health Perspect 124:730–736; http://dx.doi.org/10.1289/EHP189 PMID:27286252

Time-to-pregnancy and pregnancy outcomes in a South African population

PubMed Central

2010-01-01

Background Time-to-pregnancy (TTP) has never been studied in an African setting and there are no data on the rates of adverse pregnancy outcomes in South Africa. The study objectives were to measure TTP and the rates of adverse pregnancy outcomes in South Africa, and to determine the reliability of the questionnaire tool. Methods The study was cross-sectional and applied systematic stratified sampling to obtain a representative sample of reproductive age women for a South African population. Data on socio-demographic, work, health and reproductive variables were collected on 1121 women using a standardized questionnaire. A small number (n = 73) of randomly selected questionnaires was repeated to determine reliability of the questionnaire. Data was described using simple summary statistics while Kappa and intra-class correlation statistics were calculated for reliability. Results Of the 1121 women, 47 (4.2%) had never been pregnant. Mean gravidity was 2.3 while mean parity was 2.0 There were a total of 2467 pregnancies; most (87%) resulted in live births, 9.5% in spontaneous abortion and 2.2% in still births. The proportion of planned pregnancies was 39% and the median TTP was 6 months. The reliability of the questionnaire for TTP data was good; 63% for all participants and 97% when censored at 14 months. Overall reliability of reporting adverse pregnancy outcomes was very high, ranging from 90 - 98% for most outcomes. Conclusion This is the first comprehensive population-based reproductive health study in South Africa, to describe the biologic fertility of the population, and provides rates for planned pregnancies and adverse pregnancy outcomes. The reliability of the study questionnaire was substantial, with most outcomes within 70 - 100% reliability index. The study provides important public information for health practitioners and researchers in reproductive health. It also highlights the need for public health intervention programmes and epidemiological research on biologic fertility and adverse pregnancy outcomes in the population. PMID:20858279

Effect of rituximab on B cell phenotype and serum B cell-activating factor levels in patients with thrombotic thrombocytopenic purpura

PubMed Central

Becerra, E; Scully, M A; Leandro, M J; Heelas, E O; Westwood, J-P; De La Torre, I; Cambridge, G

2015-01-01

Autoantibodies inhibiting the activity of the metalloproteinase, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), underlie the pathogenesis of thrombotic thrombocytopenic purpura (TTP). Rituximab (RTX) combined with plasma-exchange (PEX) is an effective treatment in TTP. Patients can remain in remission for extended periods following PEX/RTX, and this is associated with continuing reduction in antibodies to ADAMTS13. Factors controlling B cell differentiation to autoantibody production, including stimulation through the B cell receptor and interactions with the B cell-activating factor (BAFF), may thus impact length of remission. In this cross-sectional study, we measured naive and memory B cell phenotypes [using CD19/immunoglobulin (Ig)D/CD27] following PEX/RTX treatment in TTP patients at B cell return (n = 6) and in 12 patients in remission 10–68 months post-RTX. We also investigated relationships among serum BAFF, soluble CD23 (sCD23– a surrogate measure of acquiring B memory (CD27+) phenotype) and BAFF receptor (BAFF-R) expression. At B cell return after PEX/RTX, naive B cells predominated and BAFF-R expression was reduced compared to healthy controls (P < 0·001). In the remission group, despite numbers of CD19+ B cells within normal limits in most patients, the percentage and absolute numbers of pre-switch and memory B cells remained low, with sCD23 levels at the lower end of the normal range. BAFF levels were correlated inversely with BAFF-R expression and time after therapy. In conclusion, the long-term effects of RTX therapy in patients with TTP included slow regeneration of memory B cell subsets and persistently reduced BAFF-R expression across all B cell subpopulations. This may reflect the delay in selection and differentiation of potentially autoreactive (ADAMTS13-specific) B cells, resulting in relatively long periods of low disease activity after therapy. PMID:25339550

Effects of time-temperature profiles on glow curves of germanium-doped optical fibre

NASA Astrophysics Data System (ADS)

Lam, S. E.; Alawiah, A.; Bradley, D. A.; Mohd Noor, N.

2017-08-01

The Germanium (Ge) doped silica optical fibres have demonstrated the great potential to be developed as a thermoluminescent (TL) dosimeter that can be used in various applications in radiotherapy, diagnostic radiology, UV dosimetry system and food irradiation industry. Different time-temperature profile (TTP) parameters of the TL reader have been employed by many researchers in various of TL studies. Nevertheless, none of those studies adequately addressed the effects of the reader's preheat temperature and heating rate on the kinetic parameters of the TL glow curve specifically, the Ge-doped silica optical fibres. This research addresses the issue of TTP parameters with special attention to the determination of the kinetic parameters of the glow curve. The glow curve responses were explored and the kinetic parameters were analyzed by the WinGCF software, to show the effect of the preheat temperature and heating rate of the reader on Ge-doped fibre irradiated with 18 Gy of 6 MV photons radiation. The effect of TTP parameters was discussed and compared against the commercial fibre and tailored made fibre of 6 mol% Ge-doped of flat and cylindrical shape. The deconvolution of glow peaks and the kinetic parameters were obtained by the WinGCF software. This enables to fit accurately (1.5%

Quantifying the Cerebral Hemodynamics of Dural Arteriovenous Fistula in Transverse Sigmoid Sinus Complicated by Sinus Stenosis: A Retrospective Cohort Study.

PubMed

Guo, W-Y; Lee, C-C J; Lin, C-J; Yang, H-C; Wu, H-M; Wu, C-C; Chung, W-Y; Liu, K-D

2017-01-01

Sinus stenosis occasionally occurs in dural arteriovenous fistulas. Sinus stenosis impedes venous outflow and aggravates intracranial hypertension by reversing cortical venous drainage. This study aimed to analyze the likelihood of sinus stenosis and its impact on cerebral hemodynamics of various types of dural arteriovenous fistulas. Forty-three cases of dural arteriovenous fistula in the transverse-sigmoid sinus were reviewed and divided into 3 groups: Cognard type I, type IIa, and types with cortical venous drainage. Sinus stenosis and the double peak sign (occurrence of 2 peaks in the time-density curve of the ipsilateral drainage of the internal jugular vein) in dural arteriovenous fistula were evaluated. "TTP" was defined as the time at which a selected angiographic point reached maximum concentration. TTP of the vein of Labbé, TTP of the ipsilateral normal transverse sinus, trans-fistula time, and trans-stenotic time were compared across the 3 groups. Thirty-six percent of type I, 100% of type IIa, and 84% of types with cortical venous drainage had sinus stenosis. All sinus stenosis cases demonstrated loss of the double peak sign that occurs in dural arteriovenous fistula. Trans-fistula time (2.09 seconds) and trans-stenotic time (0.67 seconds) in types with cortical venous drainage were the most prolonged, followed by those in type IIa and type I. TTP of the vein of Labbé was significantly shorter in types with cortical venous drainage. Six patients with types with cortical venous drainage underwent venoplasty and stent placement, and 4 were downgraded to type IIa. Sinus stenosis indicated dysfunction of venous drainage and is more often encountered in dural arteriovenous fistula with more aggressive types. Venoplasty ameliorates cortical venous drainage in dural arteriovenous fistulas and serves as a bridge treatment to stereotactic radiosurgery in most cases. © 2017 by American Journal of Neuroradiology.

Time Temperature-Precipitation Behavior in An Al-Cu-Li Alloy 2195

NASA Technical Reports Server (NTRS)

Chen, P. S.; Bhat, B. N.

1999-01-01

Al-Cu-Li alloy 2195, with its combination of good cryogenic properties, low density, and high modulus, has been selected by NASA to be the main structural alloy of the Super Light Weight Tank (SLWT) for the Space Shuttle. Alloy 2195 is strengthened by an aging treatment that precipitates a particular precipitate, labeled as T1(Al2CuLi). Other phases, such as GP zone, (theta)', (theta)", theta, (delta)', S' are also present in this alloy when artificially aged. Cryogenic strength and fracture toughness are critical to the -SLWT application, since the SLWT will house liquid oxygen and hydrogen. Motivation for the Time-Temperature-Precipitation (TTP) study at lower temperature (lower than 350 F) comes in part from a recent study by Chen, The study found that the cryogenic fracture toughness of alloy 2195 is greatly influenced by the phases present in the matrix and subgrain boundaries. Therefore, the understanding of TTP behavior can help develop a guideline to select appropriate heat treatment conditions for the desirable applications. The study of TTP behavior at higher temperature (400 to 1000 F) was prompted by the fact that the SLWT requires a welded construction. Heat conduction from the weld pool affects the microstructure in the heat-affected zone (HAZ), which leads to changes in the mechanical properties. Furthermore, the SLWT may need repair welding for more than one time and any additional thermal cycles will increase precipitate instability and promote phase transformation. As a result considerable changes in HAZ microstructure and mechanical properties are expected during the construction of the SLWT. Therefore, the TTP diagrams can serve to understand the thermal history of the alloy by analyzing the welded microstructure. In the case welding, the effects of thermal cycles on the microstructure and mechanical properties can be predicted with the aid of the TTP diagrams. The 2195 alloy (nominally Al + 4 pct Cu + 1 pct Li + 0.3 pct Ag + 0.3 pct Mg + 0.1 pct Zr) used in this study was received in the form of 1.7 inch thick rolled plates. In brief goal of this study is to develop TTR diagram for the solutiontreated and stretched alloy 2195 from which the precipitation sequence at any service or aging conditions can be preducted.A subgrain boundary TTR diagram is also presented since precipitations at subgrain boundary can control and/or modify a wide veriety of material properties, such as cryogenic fracture toughness.

Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial.

PubMed

Finn, Richard S; Merle, Philippe; Granito, Alessandro; Huang, Yi-Hsiang; Bodoky, György; Pracht, Marc; Yokosuka, Osamu; Rosmorduc, Olivier; Gerolami, René; Caparello, Chiara; Cabrera, Roniel; Chang, Charissa; Sun, Weijing; LeBerre, Marie-Aude; Baumhauer, Annette; Meinhardt, Gerold; Bruix, Jordi

2018-04-26

The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50-0.78; p <0.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib. In RESORCE, 573 patients were randomized 2:1 to regorafenib 160 mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment. HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day vs. <800 mg/day) were 52%, 11%, and 15% vs. 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6-28.1) for regorafenib and 19.2 months (16.3-22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45-0.96; Q1); 0.26 (0.17-0.40; Q2); 0.40 (0.27-0.60; Q3); and 0.54 (0.36-0.81; Q4). These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose. This analysis examined characteristics and outcomes of patients with hepatocellular carcinoma who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib treatment and regardless of their last sorafenib dose. The sequence of sorafenib followed by regorafenib for hepatocellular carcinoma may extend survival beyond what has been previously reported. ClinicalTrials.gov NCT01774344. Copyright © 2018. Published by Elsevier B.V.

Compartmentalized self-replication (CSR) selection of Thermococcus litoralis Sh1B DNA polymerase for diminished uracil binding.

PubMed

Tubeleviciute, Agne; Skirgaila, Remigijus

2010-08-01

The thermostable archaeal DNA polymerase Sh1B from Thermococcus litoralis has a typical uracil-binding pocket, which in nature plays an essential role in preventing the accumulation of mutations caused by cytosine deamination to uracil and subsequent G-C base pair transition to A-T during the genomic DNA replication. The uracil-binding pocket recognizes and binds uracil base in a template strand trapping the polymerase. Since DNA replication stops, the repair systems have a chance to correct the promutagenic event. Archaeal family B DNA polymerases are employed in various PCR applications. Contrary to nature, in PCR the uracil-binding property of archaeal polymerases is disadvantageous and results in decreased DNA amplification yields and lowered sensitivity. Furthermore, in diagnostics qPCR, RT-qPCR and end-point PCR are performed using dNTP mixtures, where dTTP is partially or fully replaced by dUTP. Uracil-DNA glycosylase treatment and subsequent heating of the samples is used to degrade the DNA containing uracil and prevent carryover contamination, which is the main concern in diagnostic laboratories. A thermostable archaeal DNA polymerase with the abolished uracil binding would be a highly desirable and commercially interesting product. An attempt to disable uracil binding in DNA polymerase Sh1B from T. litoralis by generating site-specific mutants did not yield satisfactory results. However, a combination of random mutagenesis of the whole polymerase gene and compartmentalized self-replication was successfully used to select variants of thermostable Sh1B polymerase capable of performing PCR with dUTP instead of dTTP.

New Deoxyribonucleic Acid Polymerase Induced by Bacillus subtilis Bacteriophage PBS2

PubMed Central

Price, Alan R.; Cook, Sandra J.

1972-01-01

The deoxyribonucleic acid (DNA) of Bacillus subtilis phage PBS2 has been confirmed to contain uracil instead of thymine. PBS2 phage infection of wild-type cells or DNA polymerase-deficient cells results in an increase in the specific activity of DNA polymerase. This induction of DNA polymerase activity is prevented by actinomycin D and chloramphenicol. In contrast to the major B. subtilis DNA polymerase, which prefers deoxythymidine triphosphate (dTTP) to deoxyuridine triphosphate (dUTP), the DNA polymerase in crude extracts of PBS2-infected cells is equally active whether dTTP or dUTP is employed. This phage-induced polymerase may be responsible for the synthesis of uracil-containing DNA during PBS2 phage infection. PMID:4623224

[Study of dynamic contrast-enhanced characteristics of stage-I endometrial carcinomas versus polyps with 3.0 T MRI].

PubMed

Wang, Xue; Lu, Yi; Zhang, Xiaoxia; Ji, Taotao; Liu, Kun; Ye, Xinjian; Bai, Guanghui; Yan, Zhihan

2015-01-20

To comparatively analyze the dynamic contrast-enhanced (DCE) characteristics and its clinical value between stage-I endometrial carcinomas versus polyps with 3.0T magnetic resonance imaging (MRI). A retrospective analysis was performed for DCE-MRI manifestation in 27 patients with histopathologically proved endometrial masses. There were stage-I endometrial carcinomas (n = 14) and polyps (n = 13). The signal intensity of solid component was measured and time-intensity curves (TIC) was obtained. TIC of lesions were divided into 4 subtypes. The time-to-peak (TTP) and signal intensity (SI) were determined from TICs. The arterial phase relative signal increase ratio (ARSIR), maximal relative signal increase ratio (MRSIR), signal enhancement ratio (SER) and signal intensity difference values (D) of each phase were calculated based on TIC curves respectively. The TIC of 14 stage-I endometrial carcinomas included type I (n = 4), type II (n = 6) and type IV (n = 4). The TIC of 13 polyps included type III (n = 3) and type IV (n = 10). The D values in each phase of 14 stage-I endometrial carcinomas were lower than normal muscle layers. There were statistic differences (P < 0.05) of each phase including 32, 48, 64, 109, 154, 199 s. For stage-I endometrial carcinomas, MRSIR and TTP were lower (P < 0.01) than normal muscle layers while SER was higher (P < 0.01) than normal muscle layers . The each phase of D of stage-I endometrial carcinomas were lower than polyps, and there were statistic differences (P < 0.05) of each phase including 32, 48, 64, 109, 154, 199 s. The MRSIR and TTP of stage-I endometrial carcinomas were lower (P < 0.01) than those of polyps while SER was higher (P < 0.01) than polyps. DCE-MRI can reflect enhanced features of stage-I endometrial carcinomas and polyps during different phases quantitatively. Parameters of DCE-MR and TIC are helpful in the diagnosis and differential diagnosis of stage-I endometrial carcinomas versus polyps.

Wind Farm Turbine Type and Placement Optimization

NASA Astrophysics Data System (ADS)

Graf, Peter; Dykes, Katherine; Scott, George; Fields, Jason; Lunacek, Monte; Quick, Julian; Rethore, Pierre-Elouan

2016-09-01

The layout of turbines in a wind farm is already a challenging nonlinear, nonconvex, nonlinearly constrained continuous global optimization problem. Here we begin to address the next generation of wind farm optimization problems by adding the complexity that there is more than one turbine type to choose from. The optimization becomes a nonlinear constrained mixed integer problem, which is a very difficult class of problems to solve. This document briefly summarizes the algorithm and code we have developed, the code validation steps we have performed, and the initial results for multi-turbine type and placement optimization (TTP_OPT) we have run.

Wind farm turbine type and placement optimization

DOE PAGES

Graf, Peter; Dykes, Katherine; Scott, George; ...

2016-10-03

The layout of turbines in a wind farm is already a challenging nonlinear, nonconvex, nonlinearly constrained continuous global optimization problem. Here we begin to address the next generation of wind farm optimization problems by adding the complexity that there is more than one turbine type to choose from. The optimization becomes a nonlinear constrained mixed integer problem, which is a very difficult class of problems to solve. Furthermore, this document briefly summarizes the algorithm and code we have developed, the code validation steps we have performed, and the initial results for multi-turbine type and placement optimization (TTP_OPT) we have run.

Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma

PubMed Central

Lahuerta, Juan J.; Pepin, François; González, Marcos; Barrio, Santiago; Ayala, Rosa; Puig, Noemí; Montalban, María A.; Paiva, Bruno; Weng, Li; Jiménez, Cristina; Sopena, María; Moorhead, Martin; Cedena, Teresa; Rapado, Immaculada; Mateos, María Victoria; Rosiñol, Laura; Oriol, Albert; Blanchard, María J.; Martínez, Rafael; Bladé, Joan; San Miguel, Jesús; Faham, Malek; García-Sanz, Ramón

2014-01-01

We assessed the prognostic value of minimal residual disease (MRD) detection in multiple myeloma (MM) patients using a sequencing-based platform in bone marrow samples from 133 MM patients in at least very good partial response (VGPR) after front-line therapy. Deep sequencing was carried out in patients in whom a high-frequency myeloma clone was identified and MRD was assessed using the IGH-VDJH, IGH-DJH, and IGK assays. The results were contrasted with those of multiparametric flow cytometry (MFC) and allele-specific oligonucleotide polymerase chain reaction (ASO-PCR). The applicability of deep sequencing was 91%. Concordance between sequencing and MFC and ASO-PCR was 83% and 85%, respectively. Patients who were MRD– by sequencing had a significantly longer time to tumor progression (TTP) (median 80 vs 31 months; P < .0001) and overall survival (median not reached vs 81 months; P = .02), compared with patients who were MRD+. When stratifying patients by different levels of MRD, the respective TTP medians were: MRD ≥10−3 27 months, MRD 10−3 to 10−5 48 months, and MRD <10−5 80 months (P = .003 to .0001). Ninety-two percent of VGPR patients were MRD+. In complete response patients, the TTP remained significantly longer for MRD– compared with MRD+ patients (131 vs 35 months; P = .0009). PMID:24646471

Influenza A viruses suppress cyclooxygenase-2 expression by affecting its mRNA stability.

PubMed

Dudek, Sabine Eva; Nitzsche, Katja; Ludwig, Stephan; Ehrhardt, Christina

2016-06-06

Infection with influenza A viruses (IAV) provokes activation of cellular defence mechanisms contributing to the innate immune and inflammatory response. In this process the cyclooxygenase-2 (COX-2) plays an important role in the induction of prostaglandin-dependent inflammation. While it has been reported that COX-2 is induced upon IAV infection, in the present study we observed a down-regulation at later stages of infection suggesting a tight regulation of COX-2 by IAV. Our data indicate the pattern-recognition receptor RIG-I as mediator of the initial IAV-induced COX-2 synthesis. Nonetheless, during on-going IAV replication substantial suppression of COX-2 mRNA and protein synthesis could be detected, accompanied by a decrease in mRNA half-life. Interestingly, COX-2 mRNA stability was not only imbalanced by IAV replication but also by stimulation of cells with viral RNA. Our results reveal tristetraprolin (TTP), which is known to bind COX-2 mRNA and promote its rapid degradation, as regulator of COX-2 expression in IAV infection. During IAV replication and viral RNA accumulation TTP mRNA synthesis was induced, resulting in reduced COX-2 levels. Accordingly, the down-regulation of TTP resulted in increased COX-2 protein expression after IAV infection. These findings indicate a novel IAV-regulated cellular mechanism, contributing to the repression of host defence and therefore facilitating viral replication.

Adjuvant antifungal therapy using tissue tolerable plasma on oral mucosa and removable dentures in oral candidiasis patients: a randomised double-blinded split-mouth pilot study.

PubMed

Preissner, Saskia; Kastner, Isabell; Schütte, Eyke; Hartwig, Stefan; Schmidt-Westhausen, Andrea Maria; Paris, Sebastian; Preissner, Robert; Hertel, Moritz

2016-07-01

Extended use of antimycotics in oral candidiasis therapy gives rise to problems related to fungal drug resistance. The aim of this pilot study was to investigate the efficacy of tissue tolerable plasma (TTP) in denture stomatitis patients. It was hypothesised that (I): erythema and (IIa): complaint remission would be accelerated and (IIb): colony forming unit (CFU) reduction would be improved. The halves of the upper jaws of eight patients were randomly assigned to control (nystatin, chlorhexidine and placebo treatment) and test sides (nystatin, chlorhexidine and TTP administered six times each 7 days). The patients and the investigators, who were different from the therapists, were both blinded. Compared to the control sides, the erythema surface was reduced significantly more extensively on the test sides between 2 and 6 weeks of antifungal therapy (P ≤ 0.05). Visual analogue scale values and the frequency of moderate or heavy growth of Candida post-treatment did not differ significantly between both sides (P > 0.05). The primary hypothesis was confirmed, which may be interpreted as an accelerated remission. As drug therapy is usually limited to the time in which signs of infection are present, TTP might help reducing antifungal use. Even though the secondary hypotheses were not confirmed, persistence of Candida might be only colonisation. © 2016 Blackwell Verlag GmbH.

Rituximab maintenance for relapsed refractory thrombotic thrombocytopenic purpura.

PubMed

Bhagirath, Vinai C; Kelton, John G; Moore, Jane; Arnold, Donald M

2012-12-01

Rituximab, an anti-CD20 chimeric monoclonal antibody, has been used successfully to treat patients with relapsed or refractory thrombotic thrombocytopenic purpura (TTP); however, the optimal dose and frequency and the role of rituximab maintenance remain uncertain. We describe a 45-year-old woman with chronic relapsing immune thrombocytopenia who responded to rituximab retreatment administered in four doses over the course of 12 months. Previously, she had received four doses of rituximab and sustained a remission for 19 months. During her latest TTP relapse, multiple treatments were administered including rituximab retreatment. After the first dose (375 mg/m2), she developed serum sickness requiring further doses to be deferred. Three subsequent doses were administered at 4-month intervals over the course of 12 months. ADAMTS13 activity was measured by von Willebrand factor (VWF) digestion. ADAMTS13 inhibition was measured by a modification of the VWF digestion assay and anti-ADAMTS13 antibodies were measured by enzyme-linked immunoassay (enzyme-linked immunosorbent assay, American Diagnostica). Clinical and laboratory remission were achieved after one dose of rituximab, with normalization of ADAMTS13 activity and disappearance of ADAMTS13 inhibitor. Three subsequent doses of rituximab were given without incident and the patient remained in remission after 3.5 years of follow-up (2.5 years since her last dose of rituximab). Maintenance dosing of rituximab should be considered in some patients with relapsing TTP. © 2012 American Association of Blood Banks.

Preparation of fluorescent tocopherols for use in protein binding and localization with the alpha-tocopherol transfer protein.

PubMed

Nava, Phillip; Cecchini, Matt; Chirico, Sara; Gordon, Heather; Morley, Samantha; Manor, Danny; Atkinson, Jeffrey

2006-06-01

Sixteen fluorescent analogues of the lipid-soluble antioxidant vitamin alpha-tocopherol were prepared incorporating fluorophores at the terminus of omega-functionalized 2-n-alkyl-substituted chromanols (1a-d and 4a-d) that match the methylation pattern of alpha-tocopherol, the most biologically active form of vitamin E. The fluorophores used include 9-anthroyloxy (AO), 7-nitrobenz-2-oxa-1,3-diazole (NBD), N-methyl anthranilamide (NMA), and dansyl (DAN). The compounds were designed to function as fluorescent reporter ligands for protein-binding and lipid transfer assays. The fluorophores were chosen to maximize the fluorescence changes observed upon moving from an aqueous environment (low fluorescence intensity) to an hydrophobic environment such as a protein's binding site (high fluorescence intensity). Compounds 9d (anthroyloxy) and 10d (nitrobenzoxadiazole), having a C9-carbon chain between the chromanol and the fluorophore, were shown to bind specifically and reversibly to recombinant human tocopherol transfer protein (alpha-TTP) with dissociation constants of approximately 280 and 60 nM, respectively, as compared to 25 nM for the natural ligand 2R,4'R,8'R-alpha-tocopherol. Thus, compounds have been prepared that allow the investigation of the rate of alpha-TTP-mediated inter-membrane transfer of alpha-tocopherol and to investigate the mechanism of alpha-TTP function at membranes of different composition.

Thrombotic thrombocytopenic purpura

MedlinePlus

... medlineplus.gov/ency/article/000552.htm Thrombotic thrombocytopenic purpura To use the sharing features on this page, please enable JavaScript. Thrombotic thrombocytopenic purpura (TTP) is a blood disorder that causes blood ...

Performance of two blood culture systems to detect anaerobic bacteria. Is there any difference?

PubMed

Mueller-Premru, Manica; Jeverica, Samo; Papst, Lea; Nagy, Elisabeth

2017-06-01

We studied the performance characteristics of two blood culture (BC) bottles/systems, (i) BacT/ALERT-FN Plus/3D (bioMérieux, Marcy l'Étoile, France) and (ii) BACTEC-Lytic/9000 (Becton Dickinson, Sparks, USA) for detection of growth and time-to-positivity (TTP) against a balanced and diverse collection of anaerobic bacterial strains (n = 48) that included reference strains (n = 19) and clinical isolates (n = 29) of 32 species (15 Gram-negative and 17 Gram-positive). Standard suspension of bacteria was inoculated to each bottle in duplicates and incubated in the corresponding system. Overall, 62.5% (n = 30) of strains were detected by both BC bottle types. Comparing the two, 70.8% (n = 34) and 79.2% (n = 38) of strains were detected by BacT/ALERT-FN Plus and BACTEC-Lytic bottles, respectively (p = 0.38). Among Gram-negative anaerobes (n = 25) the detection rate was 76.0% (n = 19) vs. 92.0% (n = 23) (p = 0.22), respectively. Among Gram-positive anaerobes (n = 23) the detection rate was 65.2% (n = 15) in both bottles (p = 1). The average TTP per bottle was calculated only for the strains detected by both systems (n = 30) and was 40.85 h and 28.08 h for BacT/ALERT-FN Plus and BACTEC-Lytic, respectively (p < 0.001). The mean difference was 12.76 h (95% CI: 6.21-19-31 h). Six anaerobic strains were not detected by any system, including Gram-negative Porphyromonas gingivalis, and five Gram-positive strains: Finegoldia magna, Peptostreptococcus anaerobius, Propionibacterium acnes, Clostridium novyi and Clostridium clostridioforme. Furthermore, Eggerthella lenta and Prevotella bivia were detected only by BacT/ALERT-FN Plus, while Prevotella disiens and Prevotella intermedia were detected only by BACTEC-Lytic bottles. There were no major differences in detection rate among clinical and reference strains. Anaerobic bacteria represent a minority of BC isolates, however, far from ideal detection rate was observed in this study for both tested bottle/system combinations. Nevertheless, in those cases where both gave positive signal, BACTEC-Lytic was superior to BacT/ALERT FN Plus with 12.76 h shorter mean TTP. Improvements of media in blood culture bottles available for detection of anaerobes are warranted. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Anisotropic Josephson-vortex dynamics in layered organic superconductors

NASA Astrophysics Data System (ADS)

Yasuzuka, S.; Uji, S.; Satsukawa, H.; Kimata, M.; Terashima, T.; Koga, H.; Yamamura, Y.; Saito, K.; Akutsu, H.; Yamada, J.

2010-06-01

To study the anisotropic Josephson-vortex dynamics in the d-wave superconductors, the interplane resistance has been measured on layered organic superconductors κ-(ET)2Cu(NCS)2 and β-(BDA-TTP)2SbF6 under magnetic fields precisely parallel to the conducting planes. For κ-(ET)2Cu(NCS)2, in-plane angular dependence of the Josephson-vortex flow resistance is mainly described by the fourfold symmetry and dip structures appear when the magnetic field is applied parallel to the b- and c-axes. The obtained results have a relation to the d-wave superconducting gap symmetry. However, the absence of in-plane fourfold anisotropy was found for β-(BDA-TTP)2SbF6. The different anisotropic behavior is discussed in terms of the interlayer coupling strength.

Bypass of Aflatoxin B[subscript 1] Adducts by the Sulfolobus solfataricus DNA Polymerase IV

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

Banerjee, Surajit; Brown, Kyle L.; Egli, Martin

Aflatoxin B{sub 1} (AFB{sub 1}) is oxidized to an epoxide in vivo, which forms an N7-dG DNA adduct (AFB{sub 1}-N7-dG). The AFB{sub 1}-N7-dG can rearrange to a formamidopyrimidine (AFB{sub 1}-FAPY) derivative. Both AFB{sub 1}-N7-dG and the {beta}-anomer of the AFB{sub 1}-FAPY adduct yield G {yields} T transversions in Escherichia coli, but the latter is more mutagenic. We show that the Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4) bypasses AFB{sub 1}-N7-dG in an error-free manner but conducts error-prone replication past the AFB{sub 1}-FAPY adduct, including misinsertion of dATP, consistent with the G {yields} T mutations observed in E. coli. Three ternarymore » (Dpo4-DNA-dNTP) structures with AFB{sub 1}-N7-dG adducted template:primers have been solved. These demonstrate insertion of dCTP opposite the AFB{sub 1}-N7-dG adduct, and correct vs incorrect insertion of dATP vs dTTP opposite the 5'-template neighbor dT from a primed AFB{sub 1}-N7-dG:dC pair. The insertion of dTTP reveals hydrogen bonding between the template N3 imino proton and the O{sup 2} oxygen of dTTP, and between the template T O{sup 4} oxygen and the N3 imino proton of dTTP, perhaps explaining why this polymerase does not efficiently catalyze phosphodiester bond formation from this mispair. The AFB{sub 1}-N7-dG maintains the 5'-intercalation of the AFB{sub 1} moiety observed in DNA. The bond between N7-dG and C8 of the AFB{sub 1} moiety remains in plane with the alkylated guanine, creating a 16{sup o} inclination of the AFB{sub 1} moiety with respect to the guanine. A binary (Dpo4-DNA) structure with an AFB{sub 1}-FAPY adducted template:primer also maintains 5'-intercalation of the AFB{sub 1} moiety. The {beta}-deoxyribose anomer is observed. Rotation about the FAPY C5-N{sup 5} bond orients the bond between N{sup 5} and C8 of the AFB{sub 1} moiety out of plane in the 5'-direction, with respect to the FAPY base. The formamide group extends in the 3'-direction. This improves stacking of the AFB{sub 1} moiety above the 5'-face of the FAPY base, as compared to the AFB{sub 1}-N7-dG adduct. Ternary structures with AFB{sub 1}-{beta}-FAPY adducted template:primers show correct vs incorrect insertion of dATP vs dTTP opposite the 5'-template neighbor dT from a primed AFB{sub 1}-{beta}-FAPY:dC pair. For dATP, the oxygen atom of the FAPY formamide group participates in a water-mediated hydrogen bond with Arg332. The insertion of dTTP yields a structure similar to that observed for the AFB{sub 1}-N7-dG adduct. The differential accommodation of these AFB{sub 1} adducts within the active site may, in part, modulate lesion bypass.« less

Information about TTP-HUS

MedlinePlus

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Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments

PubMed Central

2013-01-01

Background This open-label study compared docetaxel/gemcitabine vs. paclitaxel/gemcitabine and a weekly (W) vs. 3-weekly (3 W) schedule in metastatic breast cancer (MBC). Methods Patients relapsed after adjuvant/neoadjuvant anthracycline-containing chemotherapy were randomized to: A) gemcitabine 1000 mg/m2 Day 1,8 + docetaxel 75 mg/m2 Day 1 q3W; B) gemcitabine 1250 mg/m2 Day 1,8 + paclitaxel 175 mg/m2 Day 1 q3W; C) gemcitabine 800 mg/m2 Day 1,8,15 + docetaxel 30 mg/m2 Day 1,8,15 q4W; D) gemcitabine 800 mg/m2 Day 1,15 + paclitaxel 80 mg/m2 Day 1,8,15 q4W. Primary endpoint was time-to-progression (TTP). Secondary endpoints were overall survival (OS) and overall response rate (ORR). Results Interim analysis led to accrual interruption (241 patients enrolled of 360 planned). Median TTP (months) was 8.33 (95% CI: 6.19-10.16) with W and 7.51 (95% CI: 5.93-8.33) with 3 W (p=0.319). No differences were observed in median TTP between docetaxel and paclitaxel, with 85.6% and 87.0% of patients progressing, respectively. OS did not differ between regimens/schedules. ORR was comparable between regimens (HR: 0.882; 95% CI: 0.523-1.488; p=0.639), while it was significantly higher in W than in the 3 W (HR: 0.504; 95% CI: 0.299-0.850; p=0.010) schedule. Grade 3/4 toxicities occurred in 69.2% and 71.9% of patients on docetaxel and paclitaxel, and in 65.8% and 75.2% in W and 3 W. Conclusions Both treatment regimens showed similar TTP. W might be associated with a better tumour response compared with 3 W. Trial registration Clinicaltrial.gov ID NCT00236899 PMID:23537313

Tuberculous Pericarditis is Multibacillary and Bacterial Burden Drives High Mortality

PubMed Central

Pasipanodya, Jotam G.; Mubanga, Mwenya; Ntsekhe, Mpiko; Pandie, Shaheen; Magazi, Beki T.; Gumedze, Freedom; Myer, Landon; Gumbo, Tawanda; Mayosi, Bongani M.

2015-01-01

Background Tuberculous pericarditis is considered to be a paucibacillary process; the large pericardial fluid accumulation is attributed to an inflammatory response to tuberculoproteins. Mortality rates are high. We investigated the role of clinical and microbial factors predictive of tuberculous pericarditis mortality using the artificial intelligence algorithm termed classification and regression tree (CART) analysis. Methods Patients were prospectively enrolled and followed in the Investigation of the Management of Pericarditis (IMPI) registry. Clinical and laboratory data of 70 patients with confirmed tuberculous pericarditis, including time-to-positive (TTP) cultures from pericardial fluid, were extracted and analyzed for mortality outcomes using CART. TTP was translated to log10 colony forming units (CFUs) per mL, and compared to that obtained from sputum in some of our patients. Findings Seventy patients with proven tuberculous pericarditis were enrolled. The median patient age was 35 (range: 20–71) years. The median, follow up was for 11.97 (range: 0·03–74.73) months. The median TTP for pericardial fluid cultures was 22 (range: 4–58) days or 3.91(range: 0·5–8·96) log10CFU/mL, which overlapped with the range of 3.24–7.42 log10CFU/mL encountered in sputum, a multi-bacillary disease. The overall mortality rate was 1.43 per 100 person-months. CART identified follow-up duration of 5·23 months on directly observed therapy, a CD4 + count of ≤ 199.5/mL, and TTP ≤ 14 days (bacillary load ≥ 5.53 log10 CFU/mL) as predictive of mortality. TTP interacted with follow-up duration in a non-linear fashion. Interpretation Patients with culture confirmed tuberculous pericarditis have a high bacillary burden, and this bacterial burden drives mortality. Thus proven tuberculosis pericarditis is not a paucibacillary disease. Moreover, the severe immunosuppression suggests limited inflammation. There is a need for the design of a highly bactericidal regimen for this condition. PMID:26870789

Traditional Chinese Medicine treatment as maintenance therapy in advanced non-small-cell lung cancer: A randomized controlled trial.

PubMed

Jiang, Yi; Liu, Ling-Shuang; Shen, Li-Ping; Han, Zhi-Fen; Jian, Hong; Liu, Jia-Xiang; Xu, Ling; Li, He-Gen; Tian, Jian-Hui; Mao, Zhu-Jun

2016-02-01

Maintenance therapy for patients with advanced non-small-cell lung cancer (NSCLC) is an increasingly hot topic in the field of clinical NSCLC research. This study aimed to evaluate the effects of Traditional Chinese Medicine (TCM) treatment as maintenance therapy on time to progression (TTP), quality of life (QOL), overall survival (OS) and 1-year survival rate in patients with advanced NSCLC. This study was conducted as a randomized, controlled, open-label trial. 64 non-progressive patients who responded to initial therapy were randomized 1:1 to the TCM arm (treated with herbal injection (Cinobufacini, 20ml/d, d1-d10), herbal decoction (d1-d21) and Chinese acupoint application (d1-d21), n=32) or to the chemotherapy arm (treated with pemetrexed (non-squamous NSCLC, 500mg/m(2), d1), docetaxel (75mg/m(2), d1) or gemcitabine (1250mg/m(2), d1 and d8), n=32). Each therapy cycle was 21 days. They were repeated until disease progression, unacceptable toxicity, or until the patients requested therapy discontinuation. The primary end point was TTP; the secondary end points were QOL, OS and 1-year survival rate. "Intention-to-treat" analysis included all randomized participants. TCM treatment prolonged median TTP for 0.7 months compared with chemotherapy, but it was not statistically significant (3.0 months vs. 2.3 months, P=0.114). Median OS time for TCM treatment did not offer a significant advantage over for chemotherapy (21.5 months vs. 18.8 months, P=0.601). 1-year survival rate of TCM treatment significantly improved than that of chemotherapy (78.1% vs. 53.1%, P=0.035). TCM treatment can significantly improve QOL when compared to chemotherapy as assessed by EORTC QLQ-C30 and EORTC QLQ-LC13 QOL instruments. TCM maintenance treatment had similar effects on TTP and OS compared with maintenance chemotherapy, but it improved patients' QOL and had higher 1-year survival rate. TCM Maintenance treatment is a promising option for advanced NSCLC patients without progression following first-line chemotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

[The revolution of monoclonal antibodies in the treatment of thrombotic microangiopathy].

PubMed

Sauvètre, G; Grange, S; Froissart, A; Veyradier, A; Coppo, P; Benhamou, Y

2015-05-01

Thrombotic microangiopathies (TMA) define a syndrome characterized by the association of microangiopathic haemolytic anaemia with schistocytes, peripheral thrombocytopenia, and organ injury of variable severity. Thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uremic syndrome (HUS) are the main forms of TMA. Recent advances in the pathophysiology of those two diseases, which include in HUS the identification of a deregulation of the alternative complement pathway, and in TTP a severe deficiency in ADAMTS-13, allowed to develop specific, pathophysiology-based therapies. Therefore, rituximab and eculizumab tends to be increasingly used, and there is an urgent need to define consensual modes of administration at the international level, as well as common definitions of response evaluation and follow-up explorations. Copyright © 2014 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Enhanced therapeutic effect of APAVAC immunotherapy in combination with dose-intense chemotherapy in dogs with advanced indolent B-cell lymphoma.

PubMed

Marconato, L; Stefanello, D; Sabattini, S; Comazzi, S; Riondato, F; Laganga, P; Frayssinet, P; Pizzoni, S; Rouquet, N; Aresu, L

2015-09-22

The aim of this non-randomized controlled trial was to compare time to progression (TTP), lymphoma-specific survival (LSS), and safety of an autologous vaccine (consisting of hydroxyapatite ceramic powder and Heat Shock Proteins purified from the dogs' tumors, HSPPCs-HA) plus chemotherapy versus chemotherapy alone in dogs with newly diagnosed, clinically advanced, histologically confirmed, multicentric indolent B-cell lymphoma. The vaccine was prepared from dogs' resected lymph nodes and administered as an intradermal injection. Forty-five client-owned dogs were enrolled: 20 dogs were treated with dose-intense chemotherapy, and 25 received concurrent immunotherapy. Both treatment arms were well tolerated, with no exacerbated toxicity in dogs also receiving the vaccine. TTP was significantly longer for dogs treated with chemo-immunotherapy versus those receiving chemotherapy only (median, 209 versus 85 days, respectively, P=0.015). LSS was not significantly different between groups: dogs treated with chemo-immunotherapy had a median survival of 349 days, and those treated with chemotherapy only had a median survival of 200 days (P=0.173). Among vaccinated dogs, those mounting an immune response had a significantly longer TTP and LSS than those with no detectable response (P=0.012 and P=0.003, respectively). Collectively these results demonstrate that vaccination with HSPPCs-HA may produce clinical benefits with no increased toxicity, thereby providing a strategy for enhancing chemotherapy in dogs with advanced indolent lymphoma. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cyclosporin A Impairs the Secretion and Activity of ADAMTS13 (A Disintegrin and Metalloprotease with Thrombospondin Type 1 Repeat)*

PubMed Central

Hershko, Klilah; Simhadri, Vijaya L.; Blaisdell, Adam; Hunt, Ryan C.; Newell, Jordan; Tseng, Sandra C.; Hershko, Alon Y.; Choi, Jae Won; Sauna, Zuben E.; Wu, Andrew; Bram, Richard J.; Komar, Anton A.; Kimchi-Sarfaty, Chava

2012-01-01

The protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat) cleaves multimers of von Willebrand factor, thus regulating platelet aggregation. ADAMTS13 deficiency leads to the fatal disorder thrombotic thrombocytopenic purpura (TTP). It has been observed that cyclosporin A (CsA) treatment, particularly in transplant patients, may sometimes be linked to the development of TTP. Until now, the reason for such a link was unclear. Here we provide evidence demonstrating that cyclophilin B (CypB) activity plays an important role in the secretion of active ADAMTS13. We found that CsA, an inhibitor of CypB, reduces the secretion of ADAMTS13 and leads to conformational changes in the protein resulting in diminished ADAMTS13 proteolytic activity. A direct, functional interaction between CypB (which possesses peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone functions) and ADAMTS13 is demonstrated using immunoprecipitation and siRNA knockdown of CypB. Finally, CypB knock-out mice were found to have reduced ADAMTS13 levels. Taken together, our findings indicate that cyclophilin-mediated activity is an important factor affecting secretion and activity of ADAMTS13. The large number of proline residues in ADAMTS13 is consistent with the important role of cis-trans isomerization in the proper folding of this protein. These results altogether provide a novel mechanistic explanation for CsA-induced TTP in transplant patients. PMID:23144461

Cyclosporin A impairs the secretion and activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat).

PubMed

Hershko, Klilah; Simhadri, Vijaya L; Blaisdell, Adam; Hunt, Ryan C; Newell, Jordan; Tseng, Sandra C; Hershko, Alon Y; Choi, Jae Won; Sauna, Zuben E; Wu, Andrew; Bram, Richard J; Komar, Anton A; Kimchi-Sarfaty, Chava

2012-12-28

The protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeat) cleaves multimers of von Willebrand factor, thus regulating platelet aggregation. ADAMTS13 deficiency leads to the fatal disorder thrombotic thrombocytopenic purpura (TTP). It has been observed that cyclosporin A (CsA) treatment, particularly in transplant patients, may sometimes be linked to the development of TTP. Until now, the reason for such a link was unclear. Here we provide evidence demonstrating that cyclophilin B (CypB) activity plays an important role in the secretion of active ADAMTS13. We found that CsA, an inhibitor of CypB, reduces the secretion of ADAMTS13 and leads to conformational changes in the protein resulting in diminished ADAMTS13 proteolytic activity. A direct, functional interaction between CypB (which possesses peptidyl-prolyl cis-trans isomerase (PPIase) and chaperone functions) and ADAMTS13 is demonstrated using immunoprecipitation and siRNA knockdown of CypB. Finally, CypB knock-out mice were found to have reduced ADAMTS13 levels. Taken together, our findings indicate that cyclophilin-mediated activity is an important factor affecting secretion and activity of ADAMTS13. The large number of proline residues in ADAMTS13 is consistent with the important role of cis-trans isomerization in the proper folding of this protein. These results altogether provide a novel mechanistic explanation for CsA-induced TTP in transplant patients.

Basal protein phosphatase 2A activity restrains cytokine expression: role for MAPKs and tristetraprolin.

PubMed

Rahman, Md Mostafizur; Rumzhum, Nowshin N; Morris, Jonathan C; Clark, Andrew R; Verrills, Nicole M; Ammit, Alaina J

2015-05-18

PP2A is a master controller of multiple inflammatory signaling pathways. It is a target in asthma; however the molecular mechanisms by which PP2A controls inflammation warrant further investigation. In A549 lung epithelial cells in vitro we show that inhibition of basal PP2A activity by okadaic acid (OA) releases restraint on MAPKs and thereby increases MAPK-mediated pro-asthmatic cytokines, including IL-6 and IL-8. Notably, PP2A inhibition also impacts on the anti-inflammatory protein - tristetraprolin (TTP), a destabilizing RNA binding protein regulated at multiple levels by p38 MAPK. Although PP2A inhibition increases TTP mRNA expression, resultant TTP protein builds up in the hyperphosphorylated inactive form. Thus, when PP2A activity is repressed, pro-inflammatory cytokines increase and anti-inflammatory proteins are rendered inactive. Importantly, these effects can be reversed by the PP2A activators FTY720 and AAL(s), or more specifically by overexpression of the PP2A catalytic subunit (PP2A-C). Moreover, PP2A plays an important role in cytokine expression in cells stimulated with TNFα; as inhibition of PP2A with OA or PP2A-C siRNA results in significant increases in cytokine production. Collectively, these data reveal the molecular mechanisms of PP2A regulation and highlight the potential of boosting the power of endogenous phosphatases as novel anti-inflammatory strategies to combat asthmatic inflammation.

Uniaxial-Strain-Orientation Dependence of the Competition between Mott and Charge Ordered Phases and their Corresponding Superconductivity of β-(BDA-TTP)2I3

NASA Astrophysics Data System (ADS)

Nuruzzaman, Md.; Yokogawa, Keiichi; Yoshino, Harukazu; Yoshimoto, Haruo; Kikuchi, Koichi; Kaihatsu, Takayuki; Yamada, Jun-ichi; Murata, Keizo

2012-12-01

We studied the electronic transport properties of the charge transfer salt β-(BDA-TTP)2I3 [BDA-TTP: 2,5-bis(1,3-dithian-2-ylidene)-1,3,4,6-tetrathiapentalene] by applying uniaxial strains along the three crystallographic axes, and obtained three corresponding temperature-pressure phase diagrams. Three phase diagrams were quite dependent on the direction of compression. Following the preceding paper by Kikuchi et al., we speculate that the insulating states are of 1/2-filled Mott insulators for the a- and b-axes compressions, and of 1/4-filled charge ordered states for the c-axis compression as well as hydrostatic pressure. The superconducting phase under uniaxial strain was realized with Tc = 5 K at 1.9 GPa along the a-axis and with Tc = 5.6 K at 1.75 GPa along the b-axis. Superconductivity was also reproduced with a Tc of 9.5 K at 1.0 GPa for the c-axis compressions in the range of 0.85 to 1.53 GPa as previously reported. We studied tentative measurement on upper critical fields, Bc2's of these superconductivities and found that the extrapolated values, Bc2(0)'s, exceeded Pauli-limit by about 2--3 times. However, at least in terms of Bc2, the difference in superconductivity associated with two different insulating states was not clear.

The Changes of Lipid Metabolism in Advanced Renal Cell Carcinoma Patients Treated with Everolimus: A New Pharmacodynamic Marker?

PubMed Central

Pantano, Francesco; Santoni, Matteo; Procopio, Giuseppe; Rizzo, Mimma; Iacovelli, Roberto; Porta, Camillo; Conti, Alessandro; Lugini, Antonio; Milella, Michele; Galli, Luca; Ortega, Cinzia; Guida, Francesco Maria; Silletta, Marianna; Schinzari, Giovanni; Verzoni, Elena; Modica, Daniela; Crucitti, Pierfilippo; Rauco, Annamaria; Felici, Alessandra; Ballatore, Valentina; Cascinu, Stefano; Tonini, Giuseppe; Carteni, Giacomo; Russo, Antonio; Santini, Daniele

2015-01-01

Background Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for the treatment of metastatic renal cell carcinoma (mRCC). We aimed to assess the association between the baseline values and treatmentrelated modifications of total serum cholesterol (C), triglycerides (T), body mass index (BMI), fasting blood glucose level (FBG) and blood pressure (BP) levels and the outcome of patients treated with everolimus for mRCC. Methods 177 patients were included in this retrospective analysis. Time to progression (TTP), clinical benefit (CB) and overall survival (OS) were evaluated. Results Basal BMI was significantly higher in patients who experienced a CB (p=0,0145). C,T and C+T raises were significantly associated with baseline BMI (p=0.0412, 0.0283 and 0.0001). Median TTP was significantly longer in patients with T raise compared to patients without T (10 vs 6, p=0.030), C (8 vs 5, p=0.042) and C+T raise (10.9 vs 5.0, p=0.003). At the multivariate analysis, only C+T increase was associated with improved TTP (p=0.005). T raise (21.0 vs 14.0, p=0.002) and C+T increase (21.0 vs 14.0, p=0.006) were correlated with improved OS but were not significant at multivariate analysis. Conclusion C+T raise is an early predictor for everolimus efficacy for patients with mRCC. PMID:25885920

The role of biological fertility in predicting family size.

PubMed

Joffe, M; Key, J; Best, N; Jensen, T K; Keiding, N

2009-08-01

It is plausible that a couple's ability to achieve the desired number of children is limited by biological fertility, especially if childbearing is postponed. Family size has declined and semen quality may have deteriorated in much of Europe, although studies have found an increase rather than a decrease in couple fertility. Using four high-quality European datasets, we took the reported time to pregnancy (TTP) as the predictor variable; births reported as following contraceptive failure were an additional category. The outcome variable was final or near-final family size. Potential confounders were maternal age when unprotected sex began prior to the first birth, and maternal smoking. Desired family size was available in only one of the datasets. Couples with a TTP of at least 12 months tended to have smaller families, with odds ratios for the risk of not having a second child approximately 1.8, and for the risk of not having a third child approximately 1.6. Below 12 months no association was observed. Findings were generally consistent across datasets. There was also a more than 2-fold risk of not achieving the desired family size if TTP was 12 months or more for the first child. Within the limits of the available data quality, family size appears to be predicted by biological fertility, even after adjustment for maternal age, if the woman was at least 20 years old when the couple's first attempt at conception started. The contribution of behavioural factors to this result also needs to be investigated.

Human equilibrative nucleoside transporter 1 (hENT1) levels predict response to gemcitabine in patients with biliary tract cancer (BTC).

PubMed

Santini, Daniele; Schiavon, Gaia; Vincenzi, Bruno; Cass, Carol E; Vasile, Enrico; Manazza, Andrea D; Catalano, Vincenzo; Baldi, Giacomo Giulio; Lai, Raymond; Rizzo, Sergio; Giacobino, Alice; Chiusa, Luigi; Caraglia, Michele; Russo, Antonio; Mackey, John; Falcone, Alfredo; Tonini, Giuseppe

2011-01-01

Translational data suggest that nucleoside transporters, in particular human equilibrative nucleoside transporter 1 (hENT1), play an important role in predicting clinical outcome after gemcitabine chemotherapy for several types of cancer. The aim of this study was to retrospectively determine patients' outcome according to the expression of hENT1 in tumoral cells of patients receiving gemcitabine-based therapy. The immunohistochemistry analysis was performed on samples from thirty-one patients with unresectable biliary tract cancer (BTC) consecutively treated with first line gemcitabine-based regimens. Positive hENT1 staining patients were 21 (67.7%); negative hENT1 staining patients were 10 (32.3%). Statistical analysis revealed no association between baseline characteristics, toxicities and tumor response to gemcitabine and hENT1 levels. In the univariate analysis, HENT1 expression was significantly correlated with time to progression (TTP) (p=0.0394; HR 2.902, 95%CI 1.053-7.996). The median TTP was 6.33 versus 2.83 months, respectively in patients with positive versus negative hENT1 staining. Moreover, patients with positive hENT1 expression showed a longer median overall survival when compared with patients with low hENT1 expression (14 versus 7 months, respectively), but this difference did not reach the statistical significance (p=0.128). Therefore, hENT1 may be a relevant predictive marker of benefit from gemcitabine-based therapies in patients with advanced BTC.

Comparing CT perfusion with oxygen partial pressure in a rabbit VX2 soft-tissue tumor model.

PubMed

Sun, Chang-Jin; Li, Chao; Lv, Hai-Bo; Zhao, Cong; Yu, Jin-Ming; Wang, Guang-Hui; Luo, Yun-Xiu; Li, Yan; Xiao, Mingyong; Yin, Jun; Lang, Jin-Yi

2014-01-01

The aim of this study was to evaluate the oxygen partial pressure of the rabbit model of the VX2 tumor using a 64-slice perfusion CT and to compare the results with that obtained using the oxygen microelectrode method. Perfusion CT was performed for 45 successfully constructed rabbit models of a VX2 brain tumor. The perfusion values of the brain tumor region of interest, the blood volume (BV), the time to peak (TTP) and the peak enhancement intensity (PEI) were measured. The results were compared with the partial pressure of oxygen (PO2) of that region of interest obtained using the oxygen microelectrode method. The perfusion values of the brain tumor region of interest in 45 successfully constructed rabbit models of a VX2 brain tumor ranged from 1.3-127.0 (average, 21.1 ± 26.7 ml/min/ml); BV ranged from 1.2-53.5 ml/100g (average, 22.2 ± 13.7 ml/100g); PEI ranged from 8.7-124.6 HU (average, 43.5 ± 28.7 HU); and TTP ranged from 8.2-62.3 s (average, 38.8 ± 14.8 s). The PO2 in the corresponding region ranged from 0.14-47 mmHg (average, 16 ± 14.8 mmHg). The perfusion CT positively correlated with the tumor PO2, which can be used for evaluating the tumor hypoxia in clinical practice.

The Reproducibility of Blood Acid Base Responses in Male Collegiate Athletes Following Individualised Doses of Sodium Bicarbonate: A Randomised Controlled Crossover Study.

PubMed

Gough, Lewis A; Deb, Sanjoy K; Sparks, Andy S; McNaughton, Lars R

2017-10-01

Current evidence suggests sodium bicarbonate (NaHCO 3 ) should be ingested based upon the individualised alkalotic peak of either blood pH or bicarbonate (HCO 3 - ) because of large inter-individual variations (10-180 min). If such a strategy is to be practical, the blood analyte response needs to be reproducible. This study aimed to evaluate the degree of reproducibility of both time to peak (TTP) and absolute change in blood pH, HCO 3 - and sodium (Na + ) following acute NaHCO 3 ingestion. Male participants (n = 15) with backgrounds in rugby, football or sprinting completed six randomised treatments entailing ingestion of two doses of 0.2 g·kg -1 body mass (BM) NaHCO 3 (SBC2a and b), two doses of 0.3 g·kg -1 BM NaHCO 3 (SBC3a and b) or two control treatments (CON1a and b) on separate days. Blood analysis included pH, HCO 3 - and Na + prior to and at regular time points following NaHCO 3 ingestion over a 3-h period. HCO 3 - displayed greater reproducibility than pH in intraclass correlation coefficient (ICC) analysis for both TTP (HCO 3 - SBC2 r = 0.77, P = 0.003; SBC3 r = 0.94, P < 0.001; pH SBC2 r = 0.62, P = 0.044; SBC3 r = 0.71, P = 0.016) and absolute change (HCO 3 - SBC2 r = 0.89, P < 0.001; SBC3 r = 0.76, P = 0.008; pH SBC2 r = 0.84, P = 0.001; SBC3 r = 0.62, P = 0.041). Our results indicate that both TTP and absolute change in HCO 3 - is more reliable than pH. As such, these data provide support for an individualised NaHCO 3 ingestion strategy to consistently elicit peak alkalosis before exercise. Future work should utilise an individualised NaHCO 3 ingestion strategy based on HCO 3 - responses and evaluate effects on exercise performance.

Radiation Segmentectomy versus TACE Combined with Microwave Ablation for Unresectable Solitary Hepatocellular Carcinoma Up to 3 cm: A Propensity Score Matching Study.

PubMed

Biederman, Derek M; Titano, Joseph J; Bishay, Vivian L; Durrani, Raisa J; Dayan, Etan; Tabori, Nora; Patel, Rahul S; Nowakowski, Francis S; Fischman, Aaron M; Kim, Edward

2017-06-01

Purpose To compare the outcomes of radiation segmentectomy (RS) and transarterial chemoembolization (TACE) combined with microwave ablation (MWA) in the treatment of unresectable solitary hepatocellular carcinoma (HCC) up to 3 cm. Materials and Methods This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived. From January 2010 to June 2015, a total of 417 and 235 consecutive patients with HCC underwent RS and TACE MWA, respectively. A cohort of 121 patients who had not previously undergone local-regional therapy (RS, 41; TACE MWA, 80; mean age, 65.4 years; 84 men [69.4%]) and who had solitary HCC up to 3 cm without vascular invasion or metastasis was retrospectively identified. Outcomes analyzed included procedure-related complications, laboratory toxicity levels, imaging response, time to progression (TTP), 90-day mortality, and survival. Propensity score matching was conducted by using a nearest-neighbor algorithm (1:1) to account for pretreatment clinical, laboratory, and imaging covariates. Postmatching statistical analysis was performed with conditional logistic regression for binary outcomes and the stratified log-rank test for time-dependent outcomes. Results Before matching, the complication rate was 8.9% and 4.9% in the TACE MWA and RS groups, respectively (P = .46). The overall complete response (CR) rate was 82.9% for RS and 82.5% for TACE MWA (odds ratio, 1.0; 95% confidence interval [CI]: 0.4, 2.8; P = .95). There were 41 (RS, 11; TACE MWA, 30) instances of progression occurring after an initial CR, of which 10 (24%) were classified as target progression (RS, one; TACE MWA, nine). Median overall TTP was 11.1 months (95% CI: 8.8 months, 25.6 months) in the RS group and 12.1 months (95% CI: 7.7 months, 19.1 months) in the TACE MWA group (P > .99). After matching, the overall CR rate (P = .94), TTP (P = .83), and overall survival (P > .99) were not significantly different between the two groups. The 90-day postoperative mortality rate was 0% in both groups. Conclusion Imaging response and progression outcomes of patients with solitary HCC up to 3 cm treated with RS were not significantly different when compared with those of patients treated with TACE MWA. © RSNA, 2016 Online supplemental material is available for this article.

Evaluation of a cross contamination model describing transfer of Salmonella spp. and Listeria monocytogenes during grinding of pork and beef.

PubMed

Møller, C O A; Sant'Ana, A S; Hansen, S K H; Nauta, M J; Silva, L P; Alvarenga, V O; Maffei, D; Silva, F F P; Lopes, J T; Franco, B D G M; Aabo, S; Hansen, T B

2016-06-02

In a previous study, a model was developed to describe the transfer and survival of Salmonella during grinding of pork (Møller, C.O.A., Nauta, M.J., Christensen, B.B., Dalgaard, P., Hansen, T.B., 2012. Modelling transfer of Salmonella typhimurium DT104 during simulation of grinding of pork. Journal of Applied Microbiology 112 (1), 90-98). The robustness of this model is now evaluated by studying its performance for predicting the transfer and survival of Salmonella spp. and Listeria monocytogenes during grinding of different types of meat (pork and beef), using two different grinders, different sizes and different numbers of pieces of meats to be ground. A total of 19 grinding trials were collected. Acceptable Simulation Zone (ASZ), visual inspection of the data, Quantitative Microbiological Risk Assessment (QMRA), as well as the Total Transfer Potential (TTP) were used as approaches to evaluate model performance and to access the quality of the cross contamination model predictions. Using the ASZ approach and considering that 70% of the observed counts have to be inside a defined acceptable zone of ±0.5 log10CFU per portion, it was found that the cross contamination parameters suggested by Møller et al. (2012) were not able to describe all 19 trials. However, for each of the collected grinding trials, the transfer event was well described when fitted to the model structure proposed by Møller et al. (2012). Parameter estimates obtained by fitting observed trials performed at different conditions, such as size and number of pieces of meat to be ground, may not be applied to describe cross contamination of unlike processing. Nevertheless, the risk estimates, as well as the TTP, revealed that the risk of disease may be reduced when the grinding of meat is performed in a grinder made of stainless steel (for all surfaces in contact with the meat), using a well-sharpened knife and holding at room temperatures lower than 4°C. Copyright © 2016 Elsevier B.V. All rights reserved.

The Kinetic Effects on Thymidine Kinase 2 by Enzyme-Bound dTTP May Explain the Mitochondrial Side Effects of Antiviral Thymidine Analogs▿†

PubMed Central

Wang, Liya; Sun, Ren; Eriksson, Staffan

2011-01-01

Mitochondrial thymidine kinase 2 (TK2) is a key enzyme in the salvage of pyrimidine deoxynucleosides needed for mitochondrial DNA synthesis. TK2 phosphorylates thymidine (dThd), deoxycytidine (dCyd), and many other antiviral pyrimidine nucleoside analogs. Zidovudine (AZT) is the first nucleoside analog approved for anti-HIV therapy, and it is still used in combination with other drugs. One of the side effects of long-term treatment with nucleoside analogs is mitochondrial DNA depletion, which has been ascribed to competition by AZT for the endogenous dThd phosphorylation carried out by TK2. Here we studied the kinetics of AZT and 3′-fluorothymidine phosphorylation by recombinant human TK2 and the effects of these and other pyrimidine nucleoside analogs on the phosphorylation of dThd and dCyd. Thymidine analogs strongly inhibited dThd phosphorylation but not dCyd phosphorylation, which instead was stimulated ∼30%. We found that recombinant human TK2 contained the feedback inhibitor dTTP in a 1:1 molar ratio and that incubation with dThd and AZT could completely remove the enzyme-bound dTTP, but dCyd was less efficient in this regard. The release of feedback inhibitor by dThd and dThd analogs most likely accounts for the observed kinetics. Similar effects were also observed with native rat liver mitochondrial TK2, strongly indicating a physiologic role for this process, which most likely is an important factor in the mitochondrial toxicity observed with antiviral nucleoside analogs. PMID:21444706

Efficacy of a rituximab regimen based on B cell depletion in thrombotic thrombocytopenic purpura with suboptimal response to standard treatment: Results of a phase II, multicenter noncomparative study.

PubMed

Benhamou, Ygal; Paintaud, Gilles; Azoulay, Elie; Poullin, Pascale; Galicier, Lionel; Desvignes, Céline; Baudel, Jean-Luc; Peltier, Julie; Mira, Jean-Paul; Pène, Frédéric; Presne, Claire; Saheb, Samir; Deligny, Christophe; Rousseau, Alexandra; Féger, Frédéric; Veyradier, Agnès; Coppo, Paul

2016-12-01

The standard four-rituximab infusions treatment in acquired thrombotic thrombocytopenic purpura (TTP) remains empirical. Peripheral B cell depletion is correlated with the decrease in serum concentrations of anti-ADAMTS13 and associated with clinical response. To assess the efficacy of a rituximab regimen based on B cell depletion, 24 TTP patients were enrolled in this prospective multicentre single arm phase II study and then compared to patients from a previous study. Patients with a suboptimal response to a plasma exchange-based regimen received two infusions of rituximab 375 mg m -2 within 4 days, and a third dose at day +15 of the first infusion if peripheral B cells were still detectable. Primary endpoint was the assessment of the time required to platelet count recovery from the first plasma exchange. Three patients died after the first rituximab administration. In the remaining patients, the B cell-driven treatment hastened remission and ADAMTS13 activity recovery as a result of rapid anti-ADAMTS13 depletion in a similar manner to the standard four-rituximab infusions schedule. The 1-year relapse-free survival was also comparable between both groups. A rituximab regimen based on B cell depletion is feasible and provides comparable results than with the four-rituximab infusions schedule. This regimen could represent a new standard in TTP. This trial was registered at www.clinicaltrials.gov (NCT00907751). Am. J. Hematol. 91:1246-1251, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Limited role of culture conversion for decision-making in individual patient care and for advancing novel regimens to confirmatory clinical trials.

PubMed

Phillips, Patrick P J; Mendel, Carl M; Burger, Divan A; Crook, Angela M; Crook, Angela; Nunn, Andrew J; Dawson, Rodney; Diacon, Andreas H; Gillespie, Stephen H

2016-02-04

Despite recent increased clinical trials activity, no regimen has proved able to replace the standard 6-month regimen for drug-sensitive tuberculosis. Understanding the relationship between microbiological markers measured during treatment and long-term clinical outcomes is critical to evaluate their usefulness for decision-making for both individual patient care and for advancing novel regimens into time-consuming and expensive pivotal phase III trials. Using data from the randomized controlled phase III trial REMoxTB, we evaluated sputum-based markers of speed of clearance of bacilli: time to smear negative status; time to culture negative status on LJ or in MGIT; daily rate of change of log10(TTP) to day 56; and smear or culture results at weeks 6, 8 or 12; as individual- and trial-level surrogate endpoints for long-term clinical outcome. Time to culture negative status on LJ or in MGIT, time to smear negative status and daily rate of change in log10(TTP) were each independent predictors of clinical outcome, adjusted for treatment (p <0.001). However, discrimination between low and high risk patients, as measured by the c-statistic, was modest and not much higher than the reference model adjusted for BMI, history of smoking, HIV status, cavitation, gender and MGIT TTP. Culture conversion during treatment for tuberculosis, however measured, has only a limited role in decision-making for advancing regimens into phase III trials or in predicting the outcome of treatment for individual patients. REMoxTB ClinicalTrials.gov number: NCT00864383.

[Rituximab as effective therapy in very severe thrombotic thrombocytopenic purpura (TTP)].

PubMed

Illner, N; Wolf, G

2010-05-01

A 26-year-old woman was admitted from another hospital because of an increased serum creatinine (170 micromol/l). She was found to have a thrombocytopenia (14Gpt/l, WHO grade IV) with anaemia and a raised lactate dehydrogenase (25.45 micromol/l). The patient was in a reduced general state when admitted to this hospital. Her mucosal membranes were pale and she had moderate scleral icterus. During the first few hours she became clearly less alert but without motor or sensory deficits. Laboratory tests showed an increased total bilirubin (73 micromol, decreased haptoglobin (< 0.08 g/l), free hemoglobin was raised (20.7 micromol/l) and the blood smear showed 5.5% fragmentocytes. Direct and indirect Coombs tests were negative. Thrombotic thrombocytic purpura (TTP) was diagnosed. Daily plasmapheresis with fresh plasma replacement and administration of corticosteroids was initiated. ADAMTS13 activity (reported later) was < 2 % and antibodies against this protease were demonstrated. After initial improvement a motor and sensory aphasia occurred. Because of progressive thrombocytopenia, immunosuppression with a total of four doses of 375 mg/m(2)/bsa rituximab was undertaken (640 mg each), every seven days. Over the next two to three weeks the platelet count very slowly rose. The plasmapheresis was ended after a total of 65 sessions. Nine months after the last plasmapheresis the platelet count and renal functions were normal. Severe autoantibody TTP can be successfully treated by administering rituximanb, an anti-CD20 antibody, in addition to the standard treatment with plasmapheresis. Georg Thieme Verlag KG Stuttgart.New York.

Temozolomide alone or in combination with doxorubicin as a rescue agent in 37 cases of canine multicentric lymphoma.

PubMed

Treggiari, E; Elliott, J W; Baines, S J; Blackwood, L

2018-06-01

Temozolomide (TMZ) is an alkylating agent previously used in conjunction with doxorubicin (DOX) to treat dogs with relapsed lymphoma. However, there are very limited data for this drug when used as single agent. The aim of this retrospective study was to evaluate the efficacy and toxicity of TMZ in dogs with relapsed multicentric lymphoma that failed multi-agent chemotherapy protocols, and compare the outcome to a group of dogs receiving the same drug in combination with DOX. Twenty-six patients were included in the TMZ group and 11 in the TMZ/DOX group. Responses were evaluated via retrospective review of the medical records. The overall median survival time (MST) for both groups was 40 days (range 1-527 days). For the TMZ group, median time to progression (TTP) was 15 days (range 1-202 days) and MST 40 days (range 1-527 days), with an overall response rate (ORR) of 32% and 46% recorded toxicities. For the TMZ/DOX group, median TTP was 19 days (range 2-87 days) and MST 24 days (range 3-91 days), with an ORR of 60% and 63% recorded toxicities. However, a proportion of haematological toxicoses may have gone undetected due to the absence of associated clinical signs. The difference in MST and TTP between the 2 groups was not statistically significant. Similarly, no negative prognostic factors were identified. Although responses were generally short lived, this study suggests that TMZ may achieve similar efficacy to TMZ/DOX whilst being associated with a lower frequency of recorded toxicities. © 2017 John Wiley & Sons Ltd.

Influence of allelic Variations of hypoxia-related and DNA repair genes on patient outcome and toxicity in head and neck cancer treated with radiotherapy plus cetuximab.

PubMed

Muñoz, Carmen; Caballero, Miguel; Hakim, Sofia; Verger, Eugenia; Grau, Juan Jose

2016-08-01

Although cetuximab plus radiotherapy is a standard treatment for patients with inoperable head and neck squamous cell carcinoma (HNSCC), its efficacy varies greatly among individuals. To identify predictive markers of efficacy, we examined the effects of single nucleotide polymorphisms (SNPs) in hypoxia-related and DNA repair genes on the clinical outcome and occurrence of skin toxicity. We analyzed 61 consecutive patients with HNSCC for the presence of specific SNPs (HIF-1α, HIF-2α, HIF-1β, VHL, FIH-1, XRCC1, and XRCC5). The results were then correlated with time to progression (TTP), overall survival (OS), and toxicity (epithelitis, mucositis, and folliculitis). The median TTP and OS were better in patients with severe vs mild mucositis (17 vs 7 months, p = 0.03; and 26 vs 12 months, p = 0.016, respectively) and folliculitis (10 vs 7 months, p = 0.01, and 26 vs 10 months, p < 0.001, respectively). Patients with the HIF-1α CT/TT genotype had better OS than those with the wild-type HIF-1α CC genotype (28 vs 13 months, p = 0.035). Patients with the XRCC5 GG/AA genotype had longer TTP than patients with the XRCC5 AG genotype (11 vs 7 months, p = 0.035). Severe skin toxicity and SNPs of HIF-1α and XRCC5 were associated with different outcomes among patients treated with radiotherapy plus cetuximab.

Free factor XIII activation peptide (fAP-FXIII) is a regulator of factor XIII activity via factor XIII-B.

PubMed

Dodt, Johannes; Pasternack, Ralf; Seitz, Rainer; Volkers, Peter

2016-02-01

In a factor XIIIa (FXIIIa) generation assay with recombinant FXIII-A2 (rFXIII-A2 ) free FXIII activation peptide (fAP-FXII) prolonged the time to peak (TTP) but did not affect the area under the curve (AUC) or concentration at peak (CP). Addition of recombinant factorXIII-B2 (rFXIII-B2 ) restored the characteristics of the FXIIIa generation parameters (AUC, TTP and CP) to those observed for plasma FXIII (FXIII-A2 B2 ). FXIII-A2 B2 reconstituted from rFXIII-A2 and rFXIII-B2 showed a similar effect on AUC, TTP and CP in the presence of fAP-FXII as observed for plasma FXIII-A2 B2 , indicating a role for FXIII-B in this observation. An effect of fAP-FXIII on thrombin, the proteolytic activator of FXIII, was excluded by thrombin generation assays and clotting experiments. In a purified system, fAP-FXIII did not interfere with the FXIIIa activity development of thrombin-cleaved rFXIII-A2 (rFXIII-A2 ') also excluding direct inhibition of FXIIIa. However, FXIIIa activity development of FXIII-A2 'B2 was inhibited in a concentration-dependent manner by fAP-FXIII, indicating that an interaction between AP-FXIII and FXIII-B2 contributes to the overall stability of FXIII-A2 'B2 . In addition to its well-known role, FXIII-B also contributes to FXIII-A2 B2 stability or dissociation depending on fAP-FXIII and calcium concentrations. © 2015 John Wiley & Sons Ltd.

Risk stratification of smoldering multiple myeloma incorporating revised IMWG diagnostic criteria.

PubMed

Lakshman, Arjun; Rajkumar, S Vincent; Buadi, Francis K; Binder, Moritz; Gertz, Morie A; Lacy, Martha Q; Dispenzieri, Angela; Dingli, David; Fonder, Amie L; Hayman, Suzanne R; Hobbs, Miriam A; Gonsalves, Wilson I; Hwa, Yi Lisa; Kapoor, Prashant; Leung, Nelson; Go, Ronald S; Lin, Yi; Kourelis, Taxiarchis V; Warsame, Rahma; Lust, John A; Russell, Stephen J; Zeldenrust, Steven R; Kyle, Robert A; Kumar, Shaji K

2018-06-12

In 2014, the International Myeloma Working Group reclassified patients with smoldering multiple myeloma (SMM) and bone marrow-plasma cell percentage (BMPC%) ≥ 60%, or serum free light chain ratio (FLCr) ≥ 100 or >1 focal lesion on magnetic resonance imaging as multiple myeloma (MM). Predictors of progression in patients currently classified as SMM are not known. We identified 421 patients with SMM, diagnosed between 2003 and 2015. The median time to progression (TTP) was 57 months (CI, 45-72). BMPC% > 20% [hazard ratio (HR): 2.28 (CI, 1.63-3.20); p < 0.0001]; M-protein > 2g/dL [HR: 1.56 (CI, 1.11-2.20); p = 0.01], and FLCr > 20 [HR: 2.13 (CI, 1.55-2.93); p < 0.0001] independently predicted shorter TTP in multivariate analysis. Age and immunoparesis were not significant. We stratified patients into three groups: low risk (none of the three risk factors; n = 143); intermediate risk (one of the three risk factors; n = 121); and high risk (≥2 of the three risk factors; n = 153). The median TTP for low-, intermediate-, and high-risk groups were 110, 68, and 29 months, respectively (p < 0.0001). BMPC% > 20%, M-protein > 2 g/dL, and FLCr > 20 at diagnosis can be used to risk stratify patients with SMM. Patients with high-risk SMM need close follow-up and are candidates for clinical trials aiming to prevent progression.

[Clinical values of hemodynamics assessment by parametric color coding of digital subtraction angiography before and after endovascular therapy for critical limb ischaemia].

PubMed

Su, Haobo; Lou, Wensheng; Gu, Jianping

2015-10-06

To investigate the feasibility of parametric color coding of digital subtraction angiography (Syngo iFlow) for hemodynamics assessment in patients with critical limb ischemia in pre- and post-endovascular therapy. To explore the correlation between Syngo iFlow and the conventional techniques. from January 2013 to December 2014, Clinical data of 21 patients with TASC II type B and type C femoropopliteal arteriosclerotic occlusive disease who were treated by percutaneous transluminal angioplasty and/or primary stent implantation in Nanjing first hospital were analyzed retrospectively. Of these patients there were 10 males and 11 females with an average age of (72±6) years (range from 58-85 years). The treatment efficacy was assessed by the variation of a series of clinical symptoms indexes (such as pain score, cold sensation score and intermittent claudication score), ankle braehial index (ABI) and transcutaneous oxygen pressure (TcPO2). Angiography was performed with the same protocol before and after treatment and parametric color coding of digital subtraction angiography was created by Syngo iFlow software on a dedicated workstation. The time to peak (TTP) of artery and tissue perfusion selected at the same regions of foot and ankle were measured and analyzed to evaluate the improvement of microcirculation and hemodynamics of the ischemic limb. The correlations between Syngo iFlow and the traditional clinical evaluation methods were explored using the Spearman rank correlation test. All patients (21 limbs) underwent successful endovaseular therapy. The mean pain score, cold sensation score, intermittent claudication score, ABI and TcPO2 before treatment were (0.48±0.68), (2.71±0.72), (2.86±0.85), ABI (0.33±0.07), TcPO2 (26.83±3.41) mmHg. While 1 week after treatment all above indicators were (2.57±0.93), (0.33±0.48), (0.90±0.54), (0.69±0.11), TcPO2 (53.75±3.60) mmHg respectively. There were significant statistical differences between pre- and post-treatment (P<0.05). The pre- and post-operative TTP of artery and tissue perfusion were (14.07±1.77) vs (10.43±2.05) s, (18.75±2.72) vs (15.38±2.78) s. For assessment of hemodynamic changes during and after treatment, parametric color coding of digital subtraction angiography (Syngo iFlow) was assumed to show the limb blood flow and perfusion were improved and the differences were statistically significant. The Spearman rank correlation test showed the TTP of artery was positively correlated with ABI, TcPO2 (r=0.65, 0.73, P<0.05), the TTP of tissue perfusion was also positively correlated with ABI, TcPO2 (r=0.60, 0.60, P<0.05). Parametric color coding of digital subtraction angiography (Syngo iFlow) is a real-time, sensitive and quantitative tool that might provide additional support in the hemodynamics evaluation of endovascular treatment for patients with lower extremity peripheral arterial occlusion disease.

Mechanism-related circulating proteins as biomarkers for clinical outcome in patients with unresectable hepatocellular carcinoma receiving sunitinib

PubMed Central

2011-01-01

Background Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-α and -β, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome. Methods Patients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT). Results At the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS. Conclusions Baseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib. Trial registration ClinicalTrials.gov: NCT00247676 PMID:21787417

Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not.

PubMed

Schendelaar, P; Van den Heuvel, E R; Heineman, M J; La Bastide-Van Gemert, S; Middelburg, K J; Seggers, J; Hadders-Algra, M

2014-12-01

Does ovarian hyperstimulation, the in vitro procedures required for in vitro fertilization (IVF)/ intracytoplasmic sperm injection or the combination of both, affect the neurological outcome of 4-year-old singletons? Ovarian hyperstimulation, the in vitro procedure and the combination of both, were not associated with the worse neurological outcome in 4-year-old singletons. Assisted reproduction techniques (ARTs) are not associated with neurological dysfunction during the first post-natal years; however, effects on the long-term neurological outcome are still inconclusive. An increased time to pregnancy (TTP, a proxy for the severity of subfertility) has been associated with a less optimal neurological condition at age 2. The present study focuses on the neurodevelopmental outcome of 4-year-old ART-offspring. Longitudinal, prospective follow-up study. Four-year-old singletons born to subfertile parents (subfertile group, n = 195), including singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 63), modified natural cycle IVF (MNC-IVF, n = 53) and natural conception (Sub-NC, n = 79). Data on underlying cause of subfertility and TTP were present. In addition, we assessed newly recruited 4-year-old singletons born to fertile parents after natural conception (reference group, n = 98). Neurological development was evaluated with the neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the occurrence of the clinically relevant form of minor neurological dysfunction (complex MND). The primary outcome was the fluency score, as fluency of movements is easily reduced by subtle brain dysfunction. Data were analysed with univariable and multivariable regression analyses, in which special attention was paid to sex differences in the neurological outcome. The fluency score, NOS and the prevalence of complex MND were similar in COH-IVF, MNC-IVF and Sub-NC children. The neurological condition of children born to subfertile parents was similar to that of children of fertile parents and was independent of the underlying cause of subfertility. No statistically significant associations were found between TTP and the fluency score and NOS. However, a positive correlation was found between TTP and the prevalence of complex MND (TTP in years, adjusted odds ratio [OR] [95% confidence interval, CI]: 1.207 [1.038 to 1.404], P = 0.014); a correlation which could be attributed to girls, in whom an evident positive correlation was present (adjusted OR [95% CI]: 1.542 [1.161 to 2.047], P = 0.003). A similar association was absent in boys. The prospective design of our study and small post-natal attrition rate (9.3%) reduced potential selection bias based on the child's development or health. The assessors were blind to the mode of conception, except for the group of children born to fertile parents, which was newly recruited. The study lacks sufficient power to conclude firmly that increased TTP is associated with a higher prevalence of complex MND. Our study suggests that the severity of subfertility, rather than its simple presence or components of IVF treatment, affects the neurological outcome. Moreover, girls may be neurologically more vulnerable for the effect of severity of subfertility. The finding that the severity of subfertility may be the decisive factor rather than the presence of a history of subfertility per se corroborates previous reports. Our results cannot be generalized to multiples, as we studied singletons only. The study was financially supported by the University Medical Center Groningen, grant number: 754510, the Junior Scientific Masterclass, the Postgraduate School Behavioural and Cognitive Neurosciences and the Cornelia Foundation, Groningen, The Netherlands. The authors have no conflicts of interest to declare. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

77 FR 14465 - Public Transportation on Indian Reservations Program; Tribal Transit Program

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-09

... DEPARTMENT OF TRANSPORTATION Federal Transit Administration Public Transportation on Indian... in funding provided by the Public Transportation on Indian Reservations Program (Tribal Transit... establishing the Public Transportation on Indian Reservations Program (Tribal Transit Program or TTP). This...

Possible green tea-induced thrombotic thrombocytopenic purpura.

PubMed

Liatsos, George D; Moulakakis, Antonios; Ketikoglou, Ioannis; Klonari, Stella

2010-04-01

A case of a patient who developed thrombotic thrombocytopenic purpura (TTP) after consuming a weight-loss product containing green tea is reported. A 38-year-old, 68-kg Caucasian woman arrived at the emergency department with a one-week history of malaise, fatigue, and petechiae of the skin. She had no symptoms of infection and denied illegal drug use. Her medical history included hypothyroidism, for which she was treated with levothyroxine 150 microg daily for the past four years. She reported that she had been using a green tea preparation for the two months before admission to lose body weight. The daily preparation contained 200 mg of green tea extract 5:1, equivalent to 1 g of natural green tea. On clinical examination, the patient appeared acutely ill and was afebrile, with pallor, petechiae, and purpura of the extremities. Laboratory test results at the time of admission revealed that the patient had anemia and marked thrombocytopenia. A peripheral blood smear demonstrated a feature of microangiopathic hemolytic anemia. Immunoglobulin G autoantibodies against ADAM metallopeptidase with thrombospondin type 1 motif, 13 were detected. On hospital day 3, the patient appeared confused and exhibited aphasia that was initially transient but then recurrent. Brain computerized tomography did not exhibit focal pathology. Over the next few days, her neurologic symptoms subsided and her platelet count and hematocrit value gradually increased. Plasmapheresis was performed (12 procedures). Corticosteroid treatment was also initiated. After 20 days of hospitalization, the patient was discharged. A 38-year-old woman developed TTP after consuming a weight-loss product containing green tea extract for two months.

Model construction and superconductivity analysis of organic conductors β-(BDA-TTP)2MF6 (M = P, As, Sb and Ta) based on first-principles band calculation

NASA Astrophysics Data System (ADS)

Aizawa, H.; Kuroki, K.; Yasuzuka, S.; Yamada, J.

2012-11-01

We perform a first-principles band calculation for a group of quasi-two-dimensional organic conductors β-(BDA-TTP)2MF6 (M = P, As, Sb and Ta). The ab-initio calculation shows that the density of states is correlated with the bandwidth of the singly occupied (highest) molecular orbital, while it is not necessarily correlated with the unit-cell volume. The direction of the major axis of the cross section of the Fermi surface lies in the Γ-B-direction, which differs from that obtained by the extended Hückel calculation. Then, we construct a tight-binding model which accurately reproduces the ab-initio band structure. The obtained transfer energies give a smaller dimerization than in the extended Hückel band. As to the difference in the anisotropy of the Fermi surface, the transfer energies along the inter-stacking direction are smaller than those obtained in the extended Hückel calculation. Assuming spin-fluctuation-mediated superconductivity, we apply random phase approximation to a two-band Hubbard model. This two-band Hubbard model is composed of the tight-binding model derived from the first-principles band structure and an on-site (intra-molecule) repulsive interaction taken as a variable parameter. The obtained superconducting gap changes sign four times along the Fermi surface like in a d-wave gap, and the nodal direction is different from that obtained in the extended Hückel model. Anion dependence of Tc is qualitatively consistent with the experimental observation.

Comparative phosphoproteomics reveals components of host cell invasion and post-transcriptional regulation during Francisella infection

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

Nakayasu, Ernesto S.; Tempel, Rebecca; Cambronne, Xiaolu A.

2013-09-22

Francisella tularensis is a facultative intracellular bacterium that causes the deadly disease tularemia. Most evidence suggests that Francisella is not well recognized by the innate immune system that normally leads to cytokine expression and cell death. In previous work, we identified new bacterial factors that were hyper-cytotoxic to macrophages. Four of the identified hyper-cytotoxic strains (lpcC, manB, manC and kdtA) had an impaired lipopolysaccharide (LPS) synthesis and produced an exposed lipid A lacking the O-antigen. These mutants were not only hyper-cytotoxic but also were phagocytosed at much higher rates compared to the wild type parent strain. To elucidate the cellularmore » signaling underlying this enhanced phagocytosis and cell death, we performed a large-scale comparative phosphoproteomic analysis of cells infected with wild-type and delta-lpcC F. novicida. Our data suggest that not only actin but also intermediate filaments and microtubules are important for F. novicida entry into the host cells. In addition, we observed differential phosphorylation of tristetraprolin (TTP), a key component of the mRNA-degrading machinery that controls the expression of a variety of genes including many cytokines. Infection with the delta-lpcC mutant induced the hyper-phosphorylation and inhibition of TTP, leading to the production of cytokines such as IL-1beta and TNF-alpha which may kill the host cells by triggering apoptosis. Together, our data provide new insights for Francisella invasion and a post-transcriptional mechanism that prevents the expression of host immune response factors that controls infection by this pathogen.« less

Impact of Tumor Factors on Survival in Patients with Hepatocellular Carcinoma Classified Based on Kinki Criteria Stage B2.

PubMed

Arizumi, Tadaaki; Minami, Tomohiro; Chishina, Hirokazu; Kono, Masashi; Takita, Masahiro; Yada, Norihisa; Hagiwara, Satoru; Minami, Yasunori; Ida, Hiroshi; Ueshima, Kazuomi; Kamata, Ken; Minaga, Kosuke; Komeda, Yoriaki; Takenaka, Mamoru; Sakurai, Toshiharu; Watanabe, Tomohiro; Nishida, Naoshi; Kudo, Masatoshi

2017-01-01

Tumors classified based on the Barcelona Clinic Liver Cancer (BCLC) stage B hepatocellular carcinoma (HCC) are heterogeneous in nature. Previously, the Kinki criterion was proposed for a more precise subclassification of tumors in BCLC-stage B. However, tumors in sub-stage B2 include various size and number of HCCs even with the Kinki criteria, which could lead to heterogeneity for overall survival (OS). In this study, we assessed how the size and number of tumors affect the OS and time to progression (TTP) in patients with Kinki criteria stage B2 tumors and treated with transarterial chemoembolization (TACE). Of 906 HCC patients treated with TACE at Kindai University Hospital, 236 patients with HCC considered as Kinki criteria stage B2 were examined. They were classified into the following 4 groups according to the maximum tumor diameter and number of tumors: B2a group, tumor size ≤6 cm and total number of tumors ≤6; B2b group, size ≤6 cm and number >6; B2c group, size >6 cm and number ≤6; and B2d group, size >6 cm and number >6. The OS and TTP of patients in each group were compared. There were 131 patients (55.5%) in the B2a group, 58 (24.6%) in the B2b group, 41 (17.4%) in the B2c group, and 6 (0.03%) in the B2d group. Comparison of the survivals revealed that the median OS was 2.8 years (95% CI 2.0-3.5) in the B2a group, 2.8 years (95% CI 2.0-3.3) in the B2b group, 1.9 years (95% CI 0.8-4.0) in the B2c group, and 2.3 years (95% CI 1.2-ND [no data]) in the B2d group, respectively (p = 0.896). The median TTP in B2a, B2b, B2c, and B2d sub-substage HCC were13.2, 12.1, 13.8, and 11.5 months, respectively (p = 0.047). The median TTP in B2a + B2c sub-substage patients was longer than that in B2b + B2d sub-substage HCC patients (14.0 months and 10.4 months; p = 0.002). No significant differences were observed in the OS among HCC patients subclassified based on the maximum tumor diameter and tumor number in Kinki criteria stage B2. Consequently, Kinki criteria stage B2 HCC is a homogeneous subgroup in terms of OS prediction. However, shorter TTP in B2b+B2c sub-substage HCC patients than that in B2a + B2c sub-substage HCC patients suggests that different treatment strategy, such as systemic therapy with targeted agents instead of TACE, may be suitable to preserve the liver function. © 2017 S. Karger AG, Basel.

ADAMTS13 Autoantibodies Cloned from Patients with Acquired Thrombotic Thrombocytopenic Purpura: 1. Structural and functional characterization in vitro

PubMed Central

Ostertag, Eric M.; Kacir, Stephen; Thiboutot, Michelle; Gulendran, Gayathri; Zheng, X. Long; Cines, Douglas B.; Siegel, Don L.

2016-01-01

BACKGROUND Acquired thrombotic thrombocytopenia purpura (TTP) is a life-threatening illness caused by autoantibodies that decrease the activity of ADAMTS13, the von Willebrand Factor cleaving protease. Despite efficacy of plasma exchange, mortality remains high and relapse is common. Improved therapies may come from understanding the diversity of pathogenic autoantibodies on a molecular/genetic level. Cloning comprehensive repertoires of patient autoantibodies can provide the necessary tools for studying immunobiology of disease and developing animal models. STUDY DESIGN AND METHODS Anti-ADAMTS13 antibodies were cloned from four patients with acquired TTP using phage display and characterized with respect to genetic origin, inhibition of ADAMTS13 proteolytic activity, and epitope specificity. Anti-idiotypic antisera raised to a subset of autoantibodies enabled comparison of their relatedness to each other and to polyclonal IgG in patient plasma. RESULTS Fifty-one unique antibodies were isolated comprising epitope specificities resembling the diversity found in circulating patient IgG. Antibodies directed to both the amino terminal domains and those requiring the ADAMTS13 cysteine-rich/spacer region for binding inhibited proteolytic activity, while those solely targeting carboxy-terminal domains were non-inhibitory. Anti-idiotypic antisera raised to a subset of antibody clones crossreacted with and reduced the inhibitory activity of polyclonal IgG from a set of unrelated patients. CONCLUSIONS Anti-ADAMTS13 autoantibodies isolated by repertoire cloning display the diversity of epitope specificities found in patient plasma and provide tools for developing animal models of acquired TTP. Shared idiotypes of inhibitory clones with circulating IgG from multiple patients suggest common features of pathogenic autoantibodies that could be exploited for developing more targeted therapies. PMID:27040144

Comparison of dynamic contrast-enhanced MRI parameters of breast lesions at 1.5 and 3.0 T: a pilot study

PubMed Central

Pineda, F D; Medved, M; Fan, X; Ivancevic, M K; Abe, H; Shimauchi, A; Newstead, G M

2015-01-01

Objective: To compare dynamic contrast-enhanced (DCE) MRI parameters from scans of breast lesions at 1.5 and 3.0 T. Methods: 11 patients underwent paired MRI examinations in both Philips 1.5 and 3.0 T systems (Best, Netherlands) using a standard clinical fat-suppressed, T1 weighted DCE-MRI protocol, with 70–76 s temporal resolution. Signal intensity vs time curves were fit with an empirical mathematical model to obtain semi-quantitative measures of uptake and washout rates as well as time-to-peak enhancement (TTP). Maximum percent enhancement and signal enhancement ratio (SER) were also measured for each lesion. Percent differences between parameters measured at the two field strengths were compared. Results: TTP and SER parameters measured at 1.5 and 3.0 T were similar; with mean absolute differences of 19% and 22%, respectively. Maximum percent signal enhancement was significantly higher at 3 T than at 1.5 T (p = 0.006). Qualitative assessment showed that image quality was significantly higher at 3 T (p = 0.005). Conclusion: Our results suggest that TTP and SER are more robust to field strength change than other measured kinetic parameters, and therefore measurements of these parameters can be more easily standardized than measurements of other parameters derived from DCE-MRI. Semi-quantitative measures of overall kinetic curve shape showed higher reproducibility than do discrete classification of kinetic curve early and delayed phases in a majority of the cases studied. Advances in knowledge: Qualitative measures of curve shape are not consistent across field strength even when acquisition parameters are standardized. Quantitative measures of overall kinetic curve shape, by contrast, have higher reproducibility. PMID:25785918

Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts.

PubMed

Baquero, Maria T; Lostritto, Karen; Gustavson, Mark D; Bassi, Kimberly A; Appia, Franck; Camp, Robert L; Molinaro, Annette M; Harris, Lyndsay N; Rimm, David L

2011-11-02

Microtubule associated proteins (MAPs) endogenously regulate microtubule stabilization and have been reported as prognostic and predictive markers for taxane response. The microtubule stabilizer, MAP-tau, has shown conflicting results. We quantitatively assessed MAP-tau expression in two independent breast cancer cohorts to determine prognostic and predictive value of this biomarker. MAP-tau expression was evaluated in the retrospective Yale University breast cancer cohort (n = 651) using tissue microarrays and also in the TAX 307 cohort, a clinical trial randomized for TAC versus FAC chemotherapy (n = 140), using conventional whole tissue sections. Expression was measured using the AQUA method for quantitative immunofluorescence. Scores were correlated with clinicopathologic variables, survival, and response to therapy. Assessment of the Yale cohort using Cox univariate analysis indicated an improved overall survival (OS) in tumors with a positive correlation between high MAP-tau expression and overall survival (OS) (HR = 0.691, 95% CI = 0.489-0.974; P = 0.004). Kaplan Meier analysis showed 10-year survival for 65% of patients with high MAP-tau expression compared to 52% with low expression (P = .006). In TAX 307, high expression was associated with significantly longer median time to tumor progression (TTP) regardless of treatment arm (33.0 versus 23.4 months, P = 0.010) with mean TTP of 31.2 months. Response rates did not differ by MAP-tau expression (P = 0.518) or by treatment arm (P = 0.584). Quantitative measurement of MAP-tau expression has prognostic value in both cohorts, with high expression associated with longer TTP and OS. Differences by treatment arm or response rate in low versus high MAP-tau groups were not observed, indicating that MAP-tau is not associated with response to taxanes and is not a useful predictive marker for taxane-based chemotherapy.

MGMT expression levels predict disease stabilisation, progression-free and overall survival in patients with advanced melanomas treated with DTIC.

PubMed

Busch, Christian; Geisler, Jürgen; Lillehaug, Johan R; Lønning, Per Eystein

2010-07-01

Metastatic melanoma responds poorly to systemic treatment. We report the results of a prospective single institution study evaluating O(6)-methylguanine-DNA methyltransferase (MGMT) status as a potential predictive and/or prognostic marker among patients treated with dacarbazine (DTIC) 800-1000 mg/m(2) monotherapy administered as a 3-weekly schedule for advanced malignant melanomas. The study was approved by the Regional Ethical Committee. Surgical biopsies from metastatic or loco-regional deposits obtained prior to DTIC treatment were snap-frozen immediately upon removal and stored in liquid nitrogen up to processing. Median time from enrolment to end of follow-up was 67 months. MGMT expression levels evaluated by qRT-PCR correlated significantly to DTIC benefit (CR/PR/SD; p=0.005), time to progression (TTP) (p=0.005) and overall survival (OS) (p=0.003). MGMT expression also correlated to Breslow thickness in the primary tumour (p=0.014). While MGMT promoter hypermethylation correlated to MGMT expression, MGMT promoter hypermethylation did not correlate to treatment benefit, TTP or OS, suggesting that other factors may be critical in determining MGMT expression levels in melanomas. In a Cox proportional regression analysis, serum lactate dehydrogenase (LDH, p<0.001), MGMT expression (p=0.022) and p16(INK4a) expression (p=0.037) independently predicted OS, while TTP correlated to DTIC benefit after 6 weeks only (p=0.001). Our data reveal MGMT expression levels to be associated with disease stabilisation and prognosis in patients receiving DTIC monotherapy for advanced melanoma. The role of MGMT expression as a predictor to DTIC sensitivity versus a general prognostic factor in advanced melanomas warrants further evaluation. Copyright 2010 Elsevier Ltd. All rights reserved.

Parametric imaging using subharmonic signals from ultrasound contrast agents in patients with breast lesions.

PubMed

Eisenbrey, John R; Dave, Jaydev K; Merton, Daniel A; Palazzo, Juan P; Hall, Anne L; Forsberg, Flemming

2011-01-01

Parametric maps showing perfusion of contrast media can be useful tools for characterizing lesions in breast tissue. In this study we show the feasibility of parametric subharmonic imaging (SHI), which allows imaging of a vascular marker (the ultrasound contrast agent) while providing near complete tissue suppression. Digital SHI clips of 16 breast lesions from 14 women were acquired. Patients were scanned using a modified LOGIQ 9 scanner (GE Healthcare, Waukesha, WI) transmitting/receiving at 4.4/2.2 MHz. Using motion-compensated cumulative maximum intensity (CMI) sequences, parametric maps were generated for each lesion showing the time to peak (TTP), estimated perfusion (EP), and area under the time-intensity curve (AUC). Findings were grouped and compared according to biopsy results as benign lesions (n = 12, including 5 fibroadenomas and 3 cysts) and carcinomas (n = 4). For each lesion CMI, TTP, EP, and AUC parametric images were generated. No significant variations were detected with CMI (P = .80), TTP (P = .35), or AUC (P = .65). A statistically significant variation was detected for the average pixel EP (P = .002). Especially, differences were seen between carcinoma and benign lesions (mean ± SD, 0.10 ± 0.03 versus 0.05 ± 0.02 intensity units [IU]/s; P = .0014) and between carcinoma and fibroadenoma (0.10 ± 0.03 versus 0.04 ± 0.01 IU/s; P = .0044), whereas differences between carcinomas and cysts were found to be nonsignificant. In conclusion, a parametric imaging method for characterization of breast lesions using the high contrast to tissue signal provided by SHI has been developed. While the preliminary sample size was limited, results show potential for breast lesion characterization based on perfusion flow parameters.

HATT: a phase IV, single-arm, open-label study of sorafenib in Taiwanese patients with advanced hepatocellular carcinoma.

PubMed

Lin, Shi-Ming; Lu, Sheng-Nan; Chen, Ping-Tsung; Jeng, Long-Bin; Chen, Shinn-Cherng; Hu, Chi-Tan; Yang, Sien-Sing; Le Berre, Marie-Aude; Liu, Xuan; Mitchell, David Y; Prins, Klaas; Grevel, Joachim; Peña, Carol A E; Meinhardt, Gerold

2017-03-01

Sorafenib significantly improves survival in patients with advanced hepatocellular carcinoma (HCC). This phase IV study assessed sorafenib efficacy/safety in Taiwanese patients with advanced HCC and Child-Pugh A status. All patients received 400 mg sorafenib BID. Safety, efficacy, sorafenib pharmacokinetics, and Child-Pugh progression were evaluated. A hand-foot skin reaction (HFSR) prevention substudy assessed HFSR incidence and grade/severity and time to HFSR in 29 and 34 patients randomized to corticosteroid and noncorticosteroid ointments, respectively, and in 88 nonrandomized patients. The 151 patients included 120 (80%) male patients and 81 (54%) with stage IV disease. Mean sorafenib dose was 626 mg/day, and median treatment duration was 4.2 months. Median overall survival (OS), progression-free survival, and time to progression (TTP) were 8.6, 2.7, and 3.8 months, respectively. Disease control and response rates (partial responses only) were 48 and 6.6%, respectively. Median TTP from Child-Pugh A to B/C was 88 days. Drug-related adverse events (AEs) occurred in 89.4% of patients; none were new or unexpected. The most frequent grade ≥3 drug-related, treatment-emergent AEs were HFSR (13.2%), diarrhea (11.9%), and hypertension (6.6%). Corticosteroid ointment tended to reduce the severity and incidence of all HFSR-associated parameters. Pharmacokinetic exposure was unaltered by Child-Pugh progression. The final pharmacokinetic model predicted 13.1 and 33.8% reductions in sorafenib exposure over 6 and 12 months, respectively. There was a trend of longer OS and TTP in Taiwanese patients with advanced HCC compared with patients with advanced HCC in the Asia-Pacific trial. Sorafenib exposure did not correlate with liver function. Reduced pharmacokinetic exposure over time was unrelated to reduced or interrupted dosing.

Cigarette smoking habit does not reduce the benefit from first line trastuzumab-based treatment in advanced breast cancer patients.

PubMed

Santini, Daniele; Vincenzi, Bruno; Adamo, Vincenzo; Addeo, Raffaele; Fusco, Vittorio; Russo, Antonio; Montemurro, Filippo; Roato, Ilaria; Redana, Stefania; Lanzetta, Gaetano; Satolli, Maria Antonietta; Berruti, Alfredo; Leoni, Valentina; Galluzzo, Sara; Antimi, Mauro; Ferraro, Giuseppa; Rossi, Maura; Del Prete, Salvatore; Valerio, Maria Rosaria; Marra, Monica; Caraglia, Michele; Tonini, Giuseppe

2011-06-01

Many ErbB2-positive cancers may show intrinsic resistance, and the frequent development of acquired resistance to ErbB-targeted agents represents a substantial clinical problem. The constitutive NF-κB activation in some HER-2/neu positive breast cancer may represent a potential cause of resistance to trastuzumab therapy. Preclinical data revealed that 4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine is able to enhance NF-κB DNA binding activity and theoretically to increase the resistance to trastuzumab. Two hundred and forty-eight women with pathologically confirmed, uni- or bidimensionally measurable, HER-2-positive metastatic breast cancer (MBC) treated with trastuzumab-based therapy as first line combination for metastatic disease were considered eligible. For all included patients data on smoking habit were detectable from medical records. We retrospectively analysed the smoking habits of 248 MBC patients and correlated these habits with activity and efficacy of trastuzumab-based therapy. No statistically significant difference in terms of response rate (RR), time to progression (TTP) and overall survival (OS) was identified between smokers (former plus active smokers) and never smokers. Moreover, no statistically significant difference in terms of RR, TTP and OS was identified either comparing active smokers and former smokers. Moreover, we did not observed any significant statistical difference in terms of TTP and OS between smokers ≥10 cigarettes/day and <10 cigarettes/day. This study clearly showed lack of any correlation between cigarette smoking habit and both activity and efficacy of trastuzumab-based first line therapy in metastatic HER2/neu positive breast cancer patients.

Phase II trial of pirfenidone in children and young adults with neurofibromatosis type 1 and progressive plexiform neurofibromas.

PubMed

Widemann, Brigitte C; Babovic-Vuksanovic, Dusica; Dombi, Eva; Wolters, Pamela L; Goldman, Stewart; Martin, Staci; Goodwin, Anne; Goodspeed, Wendy; Kieran, Mark W; Cohen, Bruce; Blaney, Susan M; King, Allison; Solomon, Jeffrey; Patronas, Nicholas; Balis, Frank M; Fox, Elizabeth; Steinberg, Seth M; Packer, Roger J

2014-09-01

Pirfenidone, an oral anti-inflammatory, antifibrotic agent with activity in idiopathic pulmonary fibrosis, may mediate anti-tumor activity in neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PN) by inhibition of fibroblast proliferation and collagen synthesis. The primary objective of this open label, single arm phase II trial was to evaluate the activity of pirfenidone in children and young adults with inoperable PN. Patients (3-21 years) with NF1-related progressive PN received pirfenidone at the previously determined optimal dose (500 mg/m(2) orally, q8h) on a continuous dosing schedule (one cycle = 28 days). Volumetric MRI analysis was used to assess response. Progression was defined as ≥ 20% PN volume increase compared to baseline. Pirfenidone would be considered active if it doubled the median time to progression (TTP) compared to the TTP on the placebo arm of a phase II trial with the farnesyltransferase inhibitor tipifarnib, which used near identical eligibility criteria. Toxicities, objective response rate, and quality of life (QOL) also were evaluated. Thirty-six patients were enrolled and tolerated pirfenidone well with intermittent nausea and vomiting as the most frequent toxicities. A dose reduction was required in only three patients. The median TTP for pirfenidone was 13.2 months compared to 10.6 months for the placebo control group from the tipifarnib trial (two-tailed P = 0.92; one-tailed P = 0.46). No objective responses were observed. Pirfenidone was well tolerated, but did not demonstrate activity as defined in this trial and does not warrant further evaluation in children with NF1 and progressive PN. © 2014 Wiley Periodicals, Inc.

LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases.

PubMed

Van Swearingen, Amanda E D; Siegel, Marni B; Deal, Allison M; Sambade, Maria J; Hoyle, Alan; Hayes, D Neil; Jo, Heejoon; Little, Paul; Dees, Elizabeth Claire; Muss, Hyman; Jolly, Trevor; Zagar, Timothy M; Patel, Nirali; Miller, C Ryan; Parker, Joel S; Smith, J Keith; Fisher, Julie; Shah, Nikita; Nabell, Lisle; Nanda, Rita; Dillon, Patrick; Abramson, Vandana; Carey, Lisa A; Anders, Carey K

2018-06-25

HER2 + breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2 + BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2 + BCBM. Eligible patients had progressive HER2 + BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. While intracranial RR to ETV was low in HER2 + BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. (NCT01305941).

Thrombin generation by activated factor VII on platelet activated by different agonists. Extending the cell-based model of hemostasis

PubMed Central

Altman, Raul; Scazziota, Alejandra Silvia; Herrera, Maria de Lourdes; Gonzalez, Claudio

2006-01-01

Background Platelet activation is crucial in normal hemostasis. Using a clotting system free of external tissue factor, we investigated whether activated Factor VII in combination with platelet agonists increased thrombin generation (TG) in vitro. Methods and results TG was quantified by time parameters: lag time (LT) and time to peak (TTP), and by amount of TG: peak of TG (PTG) and area under thrombin formation curve after 35 minutes (AUC→35min) in plasma from 29 healthy volunteers using the calibrated automated thrombography (CAT) technique. TG parameters were measured at basal conditions and after platelet stimulation by sodium arachidonate (AA), ADP, and collagen (Col). In addition, the effects of recombinant activated FVII (rFVIIa) alone or combined with the other platelet agonists on TG parameters were investigated. We found that LT and TTP were significantly decreased (p < 0.05) and PTG and AUC→35min were significantly increased (p < 0.05) in platelet rich plasma activated with AA, ADP, Col, and rFVIIa compared to non-activated platelet rich plasma from normal subjects (p = 0.01). Furthermore platelet rich plasma activated by the combined effects of rFVIIa plus AA, ADP or Col had significantly reduced LT and TTP and increased AUC→35min (but not PTG) when compared to platelet rich plasma activated with agonists in the absence of rFVIIa. Conclusion Platelets activated by AA, ADP, Col or rFVIIa triggered TG. This effect was increased by combining rFVIIa with other agonists. Our intrinsic coagulation system produced a burst in TG independent of external tissue factor activity an apparent hemostatic effect with little thrombotic capacity. Thus we suggest a modification in the cell-based model of hemostasis. PMID:16630353

Proteomic Changes of Tissue-Tolerable Plasma Treated Airway Epithelial Cells and Their Relation to Wound Healing.

PubMed

Lendeckel, Derik; Eymann, Christine; Emicke, Philipp; Daeschlein, Georg; Darm, Katrin; O'Neil, Serena; Beule, Achim G; von Woedtke, Thomas; Völker, Uwe; Weltmann, Klaus-Dieter; Jünger, Michael; Hosemann, Werner; Scharf, Christian

2015-01-01

The worldwide increasing number of patients suffering from nonhealing wounds requires the development of new safe strategies for wound repair. Recent studies suggest the possibility of nonthermal (cold) plasma application for the acceleration of wound closure. An in vitro wound healing model with upper airway S9 epithelial cells was established to determine the macroscopically optimal dosage of tissue-tolerable plasma (TTP) for wound regeneration, while a 2D-difference gel electrophoresis (2D-DIGE) approach was used to quantify the proteomic changes in a hypothesis-free manner and to evaluate the balance of beneficial and adverse effects due to TTP application. Plasma doses from 30 s up to 360 s were tested in relation to wound closure after 24 h, 48 h, 72 h, 96 h, and 120 h, in which lower doses (30, 60, and 120 s) resulted in dose-dependent improved wound healing rate compared to untreated cells. Thereby, the 120 s dose caused significantly the best wound healing properties after 96 and 120 h. The proteome analysis combined with IPA revealed that a lot of affected stress adaptation responses are linked to oxidative stress response emphasizing oxidative stress as a possible key event in the regeneration process of epithelial cells as well as in the adaptation to plasma exposure. Further cellular and molecular functions like proliferation and apoptosis were significantly up- or downregulated by all TTP treatments but mostly by the 120 s dose. For the first time, we were able to show plasma effects on cellular adaptation of upper airway epithelial S9 cells improving wound healing. This is of particular interest for plasma application, for example, in the surgery field of otorhinolaryngology or internal medicine.

ERCC1 protein as a guide for individualized therapy of late-stage advanced non-small cell lung cancer.

PubMed

Gao, Zhiqiang; Han, Baohui; Shen, Jie; Gu, Aiqin; Qi, Dajiang; Huang, Jinsu; Shi, Chunlei; Xiong, Liwen; Zhao, Yizhuo; Jiang, Liyan; Wang, Huimin; Chen, Yurong

2011-09-01

Excision repair cross-complementation group 1 (ERCC1) protein has been associated with cisplatin resistance. The objective of this study was to investigate the correlation between ERCC1 protein levels and the therapeutic effect of individualized therapy in advanced non-small cell lung cancer (NSCLC). A total of 190 advanced NSCLC patients were included in this study. Patients were randomized into either the individualized therapy group or the standard therapy group at a ratio of 2:1. Patients in the standard therapy group were treated with either gemcitabine plus cisplatin or vinorelbine plus cisplatin. The expression of ERCC1 protein in lung cancer tissues of patients from the individualized therapy group was detected with immunohistochemistry. Patients with low ERCC1 levels received either gemcitabine plus cisplatin or vinorelbine plus cisplatin, and patients with high levels received gemcitabine plus vinorelbine. The main outcome assessments were response rate (RR), overall survival (OS) and time to progression (TTP). Follow-up data were recorded until September 30, 2010. RR, 1-year survival rate and TTP were not statistically significant. The median survival time was 10.10 months in the standard therapy group (95% CI 8.48-11.92) and 13.59 months in the individualized therapy group (95% CI 11.86-14.74). The difference in median survival time was significantly different between these groups (P=0.036). The median survival time was longer in the individualized group compared to the standard therapy group. ERCC1 protein expression in advanced NSCLC patients, however, was not significantly correlated with RR, OS and TTP in the individualized therapy group. Therefore, this study suggests that ERCC1 protein levels should be assessed in combination with additional biomarkers to determine an optimal index for individualized therapy in advanced NSCLC patients.

Pharmacogenetic study of the impact of ABCB1 single-nucleotide polymorphisms on lenalidomide treatment outcomes in patients with multiple myeloma: results from a phase IV observational study and subsequent phase II clinical trial.

PubMed

Jakobsen Falk, Ingrid; Lund, Johan; Gréen, Henrik; Gruber, Astrid; Alici, Evren; Lauri, Birgitta; Blimark, Cecilie; Mellqvist, Ulf-Henrik; Swedin, Agneta; Forsberg, Karin; Carlsson, Conny; Hardling, Mats; Ahlberg, Lucia; Lotfi, Kourosh; Nahi, Hareth

2018-01-01

Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs). Ninety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G>A (Ser400Asn, rs2229109), 1236C>T (silent, rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, outcomes, and AEs were investigated. No significant associations were found between genotype and either best response rates or hematological AEs, and 1236C>T, 2677G>T or 3435C>T genotypes had no impact on survival. There was a trend towards increased time to progression (TTP) in patients carrying the 1199A variant, and a significant difference in TTP between genotypes in patients with standard-risk cytogenetics. Our findings show a limited influence of ABCB1 genotype on lenalidomide treatment efficacy and safety. The results suggest that 1199G>A may be a marker of TTP following Len treatment in standard-risk patients; however, larger studies are needed to validate and clarify the relationship.

Texture analysis of intermediate-advanced hepatocellular carcinoma: prognosis and patients' selection of transcatheter arterial chemoembolization and sorafenib

PubMed Central

Fu, Sirui; Chen, Shuting; Liang, Changhong; Liu, Zaiyi; Zhu, Yanjie; Li, Yong; Lu, Ligong

2017-01-01

Transcatheter arterial chemoembolization (TACE) and sorafenib combination treatment for unselected hepatocellular carcinoma (HCC) is controversial. We explored the potential of texture analysis for appropriate patient selection. There were 261 HCCs included (TACE group: n = 197; TACE plus sorafenib (TACE+Sorafenib) group n = 64). We applied a Gabor filter and wavelet transform with 3 band-width responses (filter 0, 1.0, and 1.5) to portal-phase computed tomography (CT) images of the TACE group. Twenty-one textural parameters per filter were extracted from the region of interests delineated around tumor outline. After testing survival correlations, the TACE group was subdivided according to parameter thresholds in receiver operating characteristic curves and compared to TACE+Sorafenib group survival. The Gabor-1-90 (filter 0) was most significantly correlated with TTP. The TACE group was accordingly divided into the TACE-1 (Gabor-1-90 ≤ 3.6190) and TACE-2 (Gabor-1-90 > 3.6190) subgroups; TTP was similar in the TACE-1 subgroup and TACE+Sorafenib group, but shorter in the TACE-2 subgroup. Only wavelet-3-D (filter 1.0) correlated with overall survival (OS), and was used for subgrouping. The TACE-5 (wavelet-3-D ≤ 12.2620) subgroup and the TACE+Sorafenib group showed similar OS, while the TACE-6 (wavelet-3-D > 12.2620) subgroup had shorter OS. Gabor-1-90 and wavelet-3-D were consistent. In dependent of tumor number or size, CT textural parameters are correlated with TTP and OS. Patients with lower Gabor-1-90 (filter 0) and wavelet-3-D (filter 1.0) should be treated with TACE and sorafenib. Texture analysis holds promise for appropriate selection of HCCs for this combination therapy. PMID:27911268

Durable Clinical Benefit in Metastatic Renal Cell Carcinoma Patients Who Discontinue PD-1/PD-L1 Therapy for Immune-Related Adverse Events.

PubMed

Martini, Dylan J; Hamieh, Lana; McKay, Rana R; Harshman, Lauren C; Brandao, Raphael; Norton, Craig K; Steinharter, John A; Krajewski, Katherine M; Gao, Xin; Schutz, Fabio A; McGregor, Bradley; Bossé, Dominick; Lalani, Aly-Khan A; De Velasco, Guillermo; Michaelson, M Dror; McDermott, David F; Choueiri, Toni K

2018-04-01

The current standard of care for treatment of metastatic renal cell carcinoma (mRCC) patients is PD-1/PD-L1 inhibitors until progression or toxicity. Here, we characterize the clinical outcomes for 19 mRCC patients who experienced an initial clinical response (any degree of tumor shrinkage), but after immune-related adverse events (irAE) discontinued all systemic therapy. Clinical baseline characteristics, outcomes, and survival data were collected. The primary endpoint was time to progression from the date of treatment cessation (TTP). Most patients had clear cell histology and received anti-PD-1/PD-L1 therapy as second-line or later treatment. Median time on PD-1/PD-L1 therapy was 5.5 months (range, 0.7-46.5) and median TTP was 18.4 months (95% CI, 4.7-54.3) per Kaplan-Meier estimation. The irAEs included arthropathies, ophthalmopathies, myositis, pneumonitis, and diarrhea. We demonstrate that 68.4% of patients ( n = 13) experienced durable clinical benefit off treatment (TTP of at least 6 months), with 36% ( n = 7) of patients remaining off subsequent treatment for over a year after their last dose of anti-PD-1/PD-L1. Three patients with tumor growth found in a follow-up visit, underwent subsequent surgical intervention, and remain off systemic treatment. Nine patients (47.4%) have ongoing irAEs. Our results show that patients who benefitted clinically from anti-PD-1/PD-L1 therapy can experience sustained beneficial responses, not needing further therapies after the initial discontinuation of treatment due to irAEs. Investigation of biomarkers indicating sustained benefit to checkpoint blockers are needed. Cancer Immunol Res; 6(4); 402-8. ©2018 AACR . ©2018 American Association for Cancer Research.

Fourier-Domain Shift Matching: A Robust Time-of-Flight Approach for Shear Wave Speed Estimation.

PubMed

Rosen, David; Jiang, Jingfeng

2018-05-01

Our primary objective of this work was to design and test a new time-of-flight (TOF) method that allows measurements of shear wave speed (SWS) following impulsive excitation in soft tissues. Particularly, under the assumption of the local plane shear wave, this work named the Fourier-domain shift matching (FDSM) method, estimates SWS by aligning a series of shear waveforms either temporally or spatially using a solution space deduced by characteristic curves of the well-known 1-D wave equation. The proposed SWS estimation method was tested using computer-simulated data, and tissue-mimicking phantom and ex vivo tissue experiments. Its performance was then compared with three other known TOF methods: lateral time-to-peak (TTP) method with robust random sampling consensus (RANSAC) fitting method, Radon sum transformation method, and a modified cross correlation method. Hereafter, these three TOF methods are referred to as the TTP-RANSAC, Radon sum, and X-corr methods, respectively. In addition to an adapted form of the 2-D Fourier transform (2-D FT)-based method in which the (group) SWS was approximated by averaging phase SWS values was considered for comparison. Based on data evaluated, we found that the overall performance of the above-mentioned temporal implementation of the proposed FDSM method was most similar to the established Radon sum method (correlation = 0.99, scale factor = 1.03, and mean difference = 0.07 m/s), and the 2-D FT (correlation = 0.98, scale factor = 1.00, and mean difference = 0.10 m/s) at high signal quality. However, results obtained from the 2-D FT method diverged (correlation = 0.201) from these of the proposed temporal implementation in the presence of diminished signal quality, whereas the agreement between the Radon sum approach and the proposed temporal implementation largely remained the same (correlation = 0.98).

Cinnamon polyphenol extract regulates tristetraprolin and related gene expression in mouse adipocytes

USDA-ARS?s Scientific Manuscript database

Cinnamon (Cinnamomum verum) has been widely used in spices, flavoring agents, and preservatives. Cinnamon polyphenol extract (CPE) may be important in the alleviation of chronic diseases, but the molecular evidence is not substantial. Tristetraprolin (TTP) family proteins have anti-inflammatory ef...

46 CFR 160.035-1 - Applicable specifications.

Code of Federal Regulations, 2010 CFR

2010-10-01

... Laminates, Fibrous Glass Reinforced, Marine Structural. MIL-P-19644—Plastic Foam, Molded Polystyrene..., Polyester, Low Pressure Laminating, Fire Retardant. MIL-P-21929—Plastic Material, Cellular Polyurethane, Rigid, Foam-In-Place, Low Density. (3) Federal specifications: TT-P-59—Paint, Ready-Mixed, International...

46 CFR 160.035-1 - Applicable specifications.

Code of Federal Regulations, 2011 CFR

2011-10-01

... Laminates, Fibrous Glass Reinforced, Marine Structural. MIL-P-19644—Plastic Foam, Molded Polystyrene..., Polyester, Low Pressure Laminating, Fire Retardant. MIL-P-21929—Plastic Material, Cellular Polyurethane, Rigid, Foam-In-Place, Low Density. (3) Federal specifications: TT-P-59—Paint, Ready-Mixed, International...

Molecular basis for allosteric specificity regulation in class Ia ribonucleotide reductase from Escherichia coli

PubMed Central

Zimanyi, Christina M; Chen, Percival Yang-Ting; Kang, Gyunghoon; Funk, Michael A; Drennan, Catherine L

2016-01-01

Ribonucleotide reductase (RNR) converts ribonucleotides to deoxyribonucleotides, a reaction that is essential for DNA biosynthesis and repair. This enzyme is responsible for reducing all four ribonucleotide substrates, with specificity regulated by the binding of an effector to a distal allosteric site. In all characterized RNRs, the binding of effector dATP alters the active site to select for pyrimidines over purines, whereas effectors dGTP and TTP select for substrates ADP and GDP, respectively. Here, we have determined structures of Escherichia coli class Ia RNR with all four substrate/specificity effector-pairs bound (CDP/dATP, UDP/dATP, ADP/dGTP, GDP/TTP) that reveal the conformational rearrangements responsible for this remarkable allostery. These structures delineate how RNR ‘reads’ the base of each effector and communicates substrate preference to the active site by forming differential hydrogen bonds, thereby maintaining the proper balance of deoxynucleotides in the cell. DOI: http://dx.doi.org/10.7554/eLife.07141.001 PMID:26754917

Outcome and toxicity associated with a dose-intensified, maintenance-free CHOP-based chemotherapy protocol in canine lymphoma: 130 cases.

PubMed

Sorenmo, Karin; Overley, B; Krick, E; Ferrara, T; LaBlanc, A; Shofer, F

2010-09-01

A dose-intensified/dose-dense chemotherapy protocol for canine lymphoma was designed and implemented at the Veterinary Hospital of the University of Pennsylvania. In this study, we describe the clinical characteristics, prognostic factors, efficacy and toxicity in 130 dogs treated with this protocol. The majority of the dogs had advanced stage disease (63.1% stage V) and sub-stage b (58.5%). The median time to progression (TTP) and lymphoma-specific survival were 219 and 323 days, respectively. These results are similar to previous less dose-intense protocols. Sub-stage was a significant negative prognostic factor for survival. The incidence of toxicity was high; 53.9 and 45% of the dogs needed dose reductions and treatment delays, respectively. Dogs that required dose reductions and treatment delays had significantly longer TTP and lymphoma-specific survival times. These results suggest that dose density is important, but likely relative, and needs to be adjusted according to the individual patient's toxicity for optimal outcome.

Chemotherapy and targeted therapy in advanced biliary tract carcinoma: a pooled analysis of clinical trials.

PubMed

Eckel, Florian; Schmid, Roland M

2014-01-01

In biliary tract cancer, gemcitabine platinum (GP) doublet palliative chemotherapy is the current standard treatment. The aim of this study was to analyze recent trials, even those small and nonrandomized, and identify superior new regimens. Trials published in English between January 2000 and January 2014 were analyzed, as well as ASCO abstracts from 2010 to 2013. In total, 161 trials comprising 6,337 patients were analyzed. The pooled results of standard therapy GP (no fluoropyrimidine, F, or other drug) were as follows: the median response rate (RR), tumor control rate (TCR), time to tumor progression (TTP) and overall survival (OS) were 25.9 and 63.5%, and 5.3 and 9.5 months, respectively. GFP triplets as well as G-based chemotherapy plus targeted therapy were significantly superior to GP concerning tumor control (TCR, TTP) and OS, with no difference in RR. Triplet combinations of GFP as well as G-based chemotherapy with (predominantly EGFR) targeted therapy are most effective concerning tumor control and survival.

Thermal conductivity of layered organic superconductor β-(BDA-TTP)2SbF6 in a parallel magnetic field: Anomalous effect of coreless vortices

NASA Astrophysics Data System (ADS)

Tanatar, M. A.; Ishiguro, T.; Toita, T.; Yamada, J.

2005-01-01

Thermal conductivity κ of the organic superconductor β-(BDA-TTP)2SbF6 was studied down to 0.3 K in magnetic fields H of varying orientation with respect to the superconducting plane. Anomalous plateau shape of the field dependence, κ vs H , is found for orientation of magnetic fields precisely parallel to the plane, in contrast to usual behavior observed in the perpendicular fields. We show that the lack of magnetic-field effect on the heat conduction results from coreless structure of vortices, causing both negligible scattering of phonons and constant in field electronic conduction up to the fields close to the upper critical field Hc2 . Usual behavior is recovered on approaching Hc2 and on slight field inclination from parallel direction, when normal cores are restored. This behavior points to the lack of bulk quasiparticle excitations induced by magnetic field, consistent with the conventional superconducting state.

Solution processed nanogap organic diodes based on liquid crystalline materials

NASA Astrophysics Data System (ADS)

Wang, Yi-Fei; Iino, Hiroaki; Hanna, Jun-ichi

2017-09-01

Co-planar nanogap organic diodes were fabricated with smectic liquid crystalline materials of the benzothienobenzothiophene (BTBT) derivative by a spin-coating technique. A high rectification ratio of the order of 106 at ±3 V was achieved when a liquid crystalline material of 2,7-didecyl benzothieno[3,2-b][1]benzothiophene (10-BTBT-10) was used in a device configuration of Al/10-BTBT-10/pentafluorobenzenethiol-treated Au on a glass substrate, which was 4 orders higher than that of the device based on non-liquid crystalline materials of 2,7-dibutyl benzothieno[3,2-b][1]benzothiophene (4-BTBT-4) and BTBT. Similar results were also observed when another liquid crystalline material of ω, ω'-dioctylterthiophene (8-TTP-8) and a non-liquid crystalline material of terthiophene (TTP) were used. These improved rectifications can be ascribed to the self-assembly properties and controllable molecular orientation of liquid crystalline materials, which made uniform perpendicular oriented polycrystalline films favorable for superior charge transport in nano-channels.

Sulfide tails management within the framework of sustainable development in mineral sand mines--the case study of Sierra Rutile Ltd.

PubMed

Kallon, Senesie B; Jabati, Ansu M; Samura, Alusine

2011-01-01

The study discussed here assessed Sierra Rutile Ltd.'s (SRLs) water-cover sulfide tails management method. Monthly and quarterly water samples from SRLs Sulfide Tails Pond (STP), Total Tails Pond (TTP), and the Titan Domestic Pond (TDP) were analyzed for 15 months. Results indicated acceptable quality for the STP. From Student's t-test analysis, it was found that the mean pH of the TTP was significantly lower than that of the TDP (p < .05). Results did not indicate pollution of the TDP by SRLs tailings management. The water-cover method significantly suppressed sulfide oxidation in the STP. Concerns to be addressed, however, include potential overtopping of the pond, water level fluctuations, and the need for periodic reinforcement of the tailings embankments. A dedicated environmental monitoring campaign that includes other proximate water bodies is suggested; this should inform timely mitigation of any environmental contamination and promote sound environmental and public health outcomes.

[Antiphospholipid syndrome with autoimmune hemolytic anemia which mimics thrombotic thrombocytopenic purpura].

PubMed

Karasawa, Naoki; Taniguchi, Yasuhiro; Hidaka, Tomonori; Katayose, Keiko; Kameda, Takuro; Side, Kotaro; Shimoda, Haruko; Nagata, Kenji; Kubuki, Yoko; Matsunaga, Takuya; Shimoda, Kazuya

2010-04-01

A 67-year-old woman was admitted to the hospital for lethargy, fever, hemolytic anemia, thrombocytopenia, and consciousness disturbance. Direct Coombs test was positive, and anti-cardiolipin beta2-glycoprotein I antibody was detected. She was diagnosed with antiphospholipid syndrome complicated with autoimmune hemolytic anemia (AIHA). She demonstrated variable consciousness disturbance, inability to distinguish right from left, dysgraphia and dyscalculia. Multiple cerebral infarctions, especially dominant cerebral hemisphere infarctions, were observed on magnetic resonance imaging. A ventilation-perfusion scan demonstrated the presence of a ventilation-perfusion mismatch in both lung fields, and multiple veinous embolisms in the right femoral, bilateral the great saphenous and popliteal veins. Therefore, pulmonary embolism and thrombophlebitis were diagnosed. Based on these findings, it was necessary to distinguish this diagnosis from thrombotic thrombocytopenic purpura (TTP). As ADAMTS-13 activity was within the normal range, TTP was denied. Thereafter, the patient was treated with 1 mg/kg of prednisolone for AIHA, 3 mg of warfarin, and 3500 units of low-molecular-weight heparin for thrombosis, and her condition improved.

Stability of gametocyte-specific Pfs25-mRNA in dried blood spots on filter paper subjected to different storage conditions

PubMed Central

2012-01-01

Background Real-time quantitative nucleic acid sequence-based amplification (QT-NASBA) is a sensitive method for detection of sub-microscopic gametocytaemia by measuring gametocyte-specific mRNA. Performing analysis on fresh whole blood samples is often not feasible in remote and resource-poor areas. Convenient methods for sample storage and transport are urgently needed. Methods Real-time QT-NASBA was performed on whole blood spiked with a dilution series of purified in-vitro cultivated gametocytes. The blood was either freshly processed or spotted on filter papers. Gametocyte detection sensitivity for QT-NASBA was determined and controlled by microscopy. Dried blood spot (DBS) samples were subjected to five different storage conditions and the loss of sensitivity over time was investigated. A formula to approximate the loss of Pfs25-mRNA due to different storage conditions and time was developed. Results Pfs25-mRNA was measured in time to positivity (TTP) and correlated well with the microscopic counts and the theoretical concentrations of the dilution series. TTP results constantly indicated higher amounts of RNA in filter paper samples extracted after 24 hours than in immediately extracted fresh blood. Among investigated storage conditions freezing at −20°C performed best with 98.7% of the Pfs25-mRNA still detectable at day 28 compared to fresh blood samples. After 92 days, the RNA detection rate was only slightly decreased to 92.9%. Samples stored at 37°C showed most decay with only 64.5% of Pfs25-mRNA detectable after one month. The calculated theoretical detection limit for 24 h-old DBS filter paper samples was 0.0095 (95% CI: 0.0025 to 0.0380) per μl. Conclusions The results suggest that the application of DBS filter papers for quantification of Plasmodium falciparum gametocytes with real-time QT-NASBA is practical and recommendable. This method proved sensitive enough for detection of sub-microscopic densities even after prolonged storage. Decay rates can be predicted for different storage conditions as well as durations. PMID:22545954

77 FR 70141 - Application(s) for Duty-Free Entry of Scientific Instruments

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-23

... Institute, 4000 Jones Bridge Rd., Chevy Chase, MD 20815. Instrument: Micro-litre and nanolitre dispensing...-litre and nanolitre dispensing system. Manufacturer: TTP Labtech Ltd, United Kingdom. Intended Use: The...: The instrument will be used to study biomaterials such as starches, lignin, and proteins, and compare...

Estimating infertility prevalence in low-to-middle-income countries: an application of a current duration approach to Demographic and Health Survey data.

PubMed

Polis, Chelsea B; Cox, Carie M; Tunçalp, Özge; McLain, Alexander C; Thoma, Marie E

2017-05-01

Can infertility prevalence be estimated using a current duration (CD) approach when applied to nationally representative Demographic and Health Survey (DHS) data collected routinely in low- or middle-income countries? Our analysis suggests that a CD approach applied to DHS data from Nigeria provides infertility prevalence estimates comparable to other smaller studies in the same region. Despite associations with serious negative health, social and economic outcomes, infertility in developing countries is a marginalized issue in sexual and reproductive health. Obtaining reliable, nationally representative prevalence estimates is critical to address the issue, but methodological and resource challenges have impeded this goal. This cross-sectional study was based on standard information available in the DHS core questionnaire and data sets, which are collected routinely among participating low-to-middle-income countries. Our research question was examined among women participating in the 2013 Nigeria DHS (n = 38 948). Among women eligible for the study, 98% were interviewed. We applied a CD approach (i.e. current length of time-at-risk of pregnancy) to estimate time-to-pregnancy (TTP) and 12-month infertility prevalence among women 'at risk' of pregnancy at the time of interview (n = 7063). Women who were 18-44 years old, married or cohabitating, sexually active within the past 4 weeks and not currently using contraception (and had not been sterilized) were included in the analysis. Estimates were based on parametric survival methods using bootstrap methods (500 bootstrap replicates) to obtain 95% CIs. The estimated median TTP among couples at risk of pregnancy was 5.1 months (95% CI: 4.2-6.3). The estimated percentage of infertile couples was 31.1% (95% CI: 27.9-34.7%)-consistent with other smaller studies from Nigeria. Primary infertility (17.4%, 95% CI: 12.9-23.8%) was substantially lower than secondary infertility (34.1%, 95% CI: 30.3-39.3%) in this population. Overall estimates for TTP >24 or >36 months dropped to 17.7% (95% CI: 15.7-20%) and 11.5% (95% CI: 10.2-13%), respectively. Subgroup analyses showed that estimates varied by age, coital frequency and fertility intentions, while being in a polygynous relationship showed minimal impact. The CD approach may be limited by assumptions on when exposure to risk of pregnancy began and methodologic assumptions required for estimation, which may be less accurate for particular subgroups or populations. Unrecognized pregnancies may have also biased our findings; however, we attempted to address this in our exclusion criteria. Limiting to married/cohabiting couples may have excluded women who are no longer in a relationship after being blamed for infertility. Although probably rare in this setting, we lack information on couples undergoing infertility treatment. Like other TTP measurement approaches, pregnancies resulting from contraceptive failure are not included, which may bias estimates. Nationally representative estimates of TTP and infertility based on a clinical definition of 12 months have been limited within developing countries. This approach represents a pragmatic advance in our ability to measure and monitor infertility in the developing world, with potentially far-reaching implications for policies and programs intended to address reproductive health. There are no competing interests and no financial support was provided for this study. Financial support for Open Access publication was provided by the World Health Organization. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Advanced and amplified BOLD fluctuations in high-grade gliomas.

PubMed

Gupta, Lalit; Gupta, Rakesh K; Postma, Alida A; Sahoo, Prativa; Gupta, Pradeep K; Patir, Rana; Ahlawat, Sunita; Saha, Indrajit; Backes, Walter H

2018-06-01

Glioma grade along with patient's age and general health are used for treatment planning and prognosis. To characterize and quantify the spontaneous blood oxygen level-dependent (BOLD) fluctuations in gliomas using measures based on T2*-weighted signal time-series and to distinguish between high- and low-grade gliomas. Retrospective. Twenty-one patients with high-grade and 13 patients with low-grade gliomas confirmed on histology were investigated. Dynamic T2*-weighted (multislice single-shot echo-planar-imaging) magnetic resonance imaging (MRI) was performed on a 3T system with an 8-element receive-only head coil to measure the BOLD fluctuations. In addition, a dynamic T 1 -weighted (3D fast field echo) dynamic contrast-enhanced (DCE) perfusion scan was performed. Three BOLD measures were determined: the temporal shift (TS), amplitude of low frequency fluctuations (ALFF), and regional homogeneity (ReHo). DCE perfusion-based cerebral blood volume (CBV) and time-to-peak (TTP) maps were concurrently evaluated for comparison. An analysis-of-variance test was first used. When the test appeared significant, post-hoc analysis was performed using analysis-of-covariance with age as covariate. Logistic regression and receiver-operator characteristic curve analysis were also performed. TS was significantly advanced in high-grade gliomas compared to the contralateral cortex (P = 0.01) and low-grade gliomas (P = 0.009). In high-grade gliomas, ALFF and CBV were significantly higher than the contralateral cortex (P = 0.041 and P = 0.008, respectively) and low-grade gliomas (P = 0.036 and P = 0.01, respectively). ReHo and TTP did not show significant differences between high- and low-grade gliomas (P = 0.46 and P = 0.42, respectively). The area-under-curve was above 0.7 only for the TS, ALFF, and CBV measures. Advanced and amplified hemodynamic fluctuations manifest in high-grade gliomas, but not in low-grade gliomas, and can be assessed using BOLD measures. Preliminary results showed that quantification of spontaneous fluctuations has potential for hemodynamic characterization of gliomas and distinguishing between high- and low-grade gliomas. 4 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:1616-1625. © 2017 International Society for Magnetic Resonance in Medicine.

ADAMTS13 test and/or PLASMIC clinical score in management of acquired thrombotic thrombocytopenic purpura: a cost-effective analysis.

PubMed

Kim, Chong H; Simmons, Sierra C; Williams, Lance A; Staley, Elizabeth M; Zheng, X Long; Pham, Huy P

2017-11-01

The ADAMTS13 test distinguishes thrombotic thrombocytopenic purpura (TTP) from other thrombotic microangiopathies (TMAs). The PLASMIC score helps determine the pretest probability of ADAMTS13 deficiency. Due to inherent limitations of both tests, and potential adverse effects and cost of unnecessary treatments, we performed a cost-effectiveness analysis (CEA) investigating the benefits of incorporating an in-hospital ADAMTS13 test and/or PLASMIC score into our clinical practice. A CEA model was created to compare four scenarios for patients with TMAs, utilizing either an in-house or a send-out ADAMTS13 assay with or without prior risk stratification using PLASMIC scoring. Model variables, including probabilities and costs, were gathered from the medical literature, except for the ADAMTS13 send-out and in-house tests, which were obtained from our institutional data. If only the cost is considered, in-house ADAMTS13 test for patients with intermediate- to high-risk PLASMIC score is the least expensive option ($4,732/patient). If effectiveness is assessed as measured by the number of averted deaths, send-out ADAMTS13 test is the most effective. Considering the cost/effectiveness ratio, the in-house ADAMTS13 test in patients with intermediate- to high-risk PLASMIC score is the best option, followed by the in-house ADAMTS13 test without the PLASMIC score. In patients with clinical presentations of TMAs, having an in-hospital ADAMTS13 test to promptly establish the diagnosis of TTP appears to be cost-effective. Utilizing the PLASMIC score further increases the cost-effectiveness of the in-house ADAMTS13 test. Our findings indicate the benefit of having a rapid and reliable in-house ADAMTS13 test, especially in the tertiary medical center. © 2017 AABB.

In vivo evaluation of glucose permeability of an immunoisolation device intended for islet transplantation: a novel application of the microdialysis technique.

PubMed

Rafael, E; Wernerson, A; Arner, P; Wu, G S; Tibell, A

1999-01-01

Immunoisolation devices consist of semipermeable membranes chosen to protect the islets from the immune system but still allow sufficient passage of nutrients, oxygen, and the therapeutic products, insulin. The exchange between the device and the microcirculation will influence the survival of the graft as well as the metabolic efficacy of the islet implant. Glucose is the important trigger factor for insulin secretion. In this study, we evaluate the in vivo glucose permeability of the Theracyte immunoisolation device at various times after implantation. Empty devices were implanted s.c. in rats. The glucose kinetics in the device was compared to that in the SC tissue during i.v. glucose tolerance tests (IVGTTs), using the microdialysis technique. In rats studied on day 1, or 1, 2, and 4 weeks after implantation, the peak glucose levels (Cmax) were significantly lower, the times-to-peak (TTP) were significantly longer, and the areas under the curve during the first 40 min (AUC(0-40)) were significantly smaller in the device than in the SC fat. However, at 3 months all parameters improved and Cmax, TTP, and AUC(0-40) in the device did not differ significantly from those measured in the SC fat. Thus, during the first 4 weeks the device constitutes a significant diffusion barrier, but at 3 months the exchange between the lumen of devices and the blood stream improves. Our data indicate that implantation of the device several months before transplantation of the cellular graft would improve the exchange across the membrane during the early posttransplant period. This should have positive effects on graft survival and function. We also suggest that microdialysis is a useful tool for evaluating the in vivo performance of macroencapsulation devices.

Color-coded perfusion analysis of CEUS for pre-interventional diagnosis of microvascularisation in cases of vascular malformations.

PubMed

Teusch, V I; Wohlgemuth, W A; Piehler, A P; Jung, E M

2014-01-01

Aim of our pilot study was the application of a contrast-enhanced color-coded ultrasound perfusion analysis in patients with vascular malformations to quantify microcirculatory alterations. 28 patients (16 female, 12 male, mean age 24.9 years) with high flow (n = 6) or slow-flow (n = 22) malformations were analyzed before intervention. An experienced examiner performed a color-coded Doppler sonography (CCDS) and a Power Doppler as well as a contrast-enhanced ultrasound after intravenous bolus injection of 1 - 2.4 ml of a second-generation ultrasound contrast medium (SonoVue®, Bracco, Milan). The contrast-enhanced examination was documented as a cine sequence over 60 s. The quantitative analysis based on color-coded contrast-enhanced ultrasound (CEUS) images included percentage peak enhancement (%peak), time to peak (TTP), area under the curve (AUC), and mean transit time (MTT). No side effects occurred after intravenous contrast injection. The mean %peak in arteriovenous malformations was almost twice as high as in slow-flow-malformations. The area under the curve was 4 times higher in arteriovenous malformations compared to the mean value of other malformations. The mean transit time was 1.4 times higher in high-flow-malformations compared to slow-flow-malformations. There was no difference regarding the time to peak between the different malformation types. The comparison between all vascular malformation and surrounding tissue showed statistically significant differences for all analyzed data (%peak, TTP, AUC, MTT; p < 0.01). High-flow and slow-flow vascular malformations had statistically significant differences in %peak (p < 0.01), AUC analysis (p < 0.01), and MTT (p < 0.05). Color-coded perfusion analysis of CEUS seems to be a promising technique for the dynamic assessment of microvasculature in vascular malformations.

Predicting axillary lymph node metastasis from kinetic statistics of DCE-MRI breast images

NASA Astrophysics Data System (ADS)

Ashraf, Ahmed B.; Lin, Lilie; Gavenonis, Sara C.; Mies, Carolyn; Xanthopoulos, Eric; Kontos, Despina

2012-03-01

The presence of axillary lymph node metastases is the most important prognostic factor in breast cancer and can influence the selection of adjuvant therapy, both chemotherapy and radiotherapy. In this work we present a set of kinetic statistics derived from DCE-MRI for predicting axillary node status. Breast DCE-MRI images from 69 women with known nodal status were analyzed retrospectively under HIPAA and IRB approval. Axillary lymph nodes were positive in 12 patients while 57 patients had no axillary lymph node involvement. Kinetic curves for each pixel were computed and a pixel-wise map of time-to-peak (TTP) was obtained. Pixels were first partitioned according to the similarity of their kinetic behavior, based on TTP values. For every kinetic curve, the following pixel-wise features were computed: peak enhancement (PE), wash-in-slope (WIS), wash-out-slope (WOS). Partition-wise statistics for every feature map were calculated, resulting in a total of 21 kinetic statistic features. ANOVA analysis was done to select features that differ significantly between node positive and node negative women. Using the computed kinetic statistic features a leave-one-out SVM classifier was learned that performs with AUC=0.77 under the ROC curve, outperforming the conventional kinetic measures, including maximum peak enhancement (MPE) and signal enhancement ratio (SER), (AUCs of 0.61 and 0.57 respectively). These findings suggest that our DCE-MRI kinetic statistic features can be used to improve the prediction of axillary node status in breast cancer patients. Such features could ultimately be used as imaging biomarkers to guide personalized treatment choices for women diagnosed with breast cancer.

Impact of Therapy Sequence with Alkylating Agents and MGMT Status in Patients with Advanced Neuroendocrine Tumors.

PubMed

Krug, Sebastian; Boch, Michael; Rexin, Peter; Gress, Thomas M; Michl, Patrick; Rinke, Anja

2017-05-01

Alkylating chemotherapeutics with either a streptozotocin-(STZ) or temozolomide-(TEM) backbone are routinely used in patients with progressive and unresectable pancreatic neuroendocrine tumors (PNET). In addition, dacarbazine (DTIC) was described as an alternative alkylating therapy option for PNETs. The optimal treatment sequence with alkylating compounds and a potential use of O6-methylguanine-DNA methyltransferase (MGMT) level as predictive biomarker have not yet been sufficiently elucidated. The aim of our study was the evaluation of therapy sequence with either STZ-based treatment followed by DTIC (group A) or the inverse schedule with upfront DTIC (group B) and to correlate MGMT status with clinicopathological characteristics and response to therapy. We retrospectively analyzed 28 patients with neuroendocrine tumors (NET) who were treated with STZ-based therapy and DTIC. Additionally, in a second group MGMT immunohistochemistry was performed from primary and metastatic tumor sites. For statistical evaluation Kaplan-Meier analysis, Cox regression methods and Fisher's exact test were used. There was no difference of objective response and disease control between either STZ-based therapy followed by DTIC treatment (group A) after progression or the reverse sequence (group B). Median time to progression (TTP) was estimated to be 21 months in both arms. First-line STZ-based chemotherapy was not superior to first-line DTIC treatment (16 vs. 13 months; p=0.8). MGMT status did not correlate with clinicopathological characteristics or response to therapy with these alkylating agents. Upfront chemotherapy with either STZ-based treatment or DTIC monotherapy showed similar efficacy and median TTP rates. In this study, MGMT protein expression assessed by immunohistochemistry did not play an important role as a predictive marker for alkylating agents. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

Module Cluster: TTP-003.00 (GSC) Modifying Academic Behavior.

ERIC Educational Resources Information Center

Brent, George

The purpose of this module cluster is to enable students to demonstrate that they can plan for changes in the academic behavior of their elementary school pupils and then change the behavior. The cluster is intended for use after the completion of normal college entrance competencies, liberal arts requirements, practicum experience, methods…

CTC Sentinel. Volume 6, Issue 5, May 2013

DTIC Science & Technology

2013-05-01

25, 2013. 9 Farrukh Saleem , “Why Karachi is Bleeding,” The News International, October 21, 2010. can find sanctuaries in Pashtun neighborhoods.10 A...suggest that of the 20 million people living in Karachi, roughly one million live in neighborhoods where the TTP has chi,” Dawn, April 26, 2013; Imran

78 FR 27284 - Public Transportation on Indian Reservations Program; Tribal Transit Program

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-09

... CFR Parts 27, 37, and 384; 4. Drug and Alcohol Testing requirements (49 CFR Part 655); 5. National...; 9. Buy America requirements (49 CFR Part 661); 10. MAP-21, Section 5329 Agency Safety Management... application of Drug and Alcohol Testing to the TTP. One commenter disagreed and stated that existing tribal...

Blind quantum computation with identity authentication

NASA Astrophysics Data System (ADS)

Li, Qin; Li, Zhulin; Chan, Wai Hong; Zhang, Shengyu; Liu, Chengdong

2018-04-01

Blind quantum computation (BQC) allows a client with relatively few quantum resources or poor quantum technologies to delegate his computational problem to a quantum server such that the client's input, output, and algorithm are kept private. However, all existing BQC protocols focus on correctness verification of quantum computation but neglect authentication of participants' identity which probably leads to man-in-the-middle attacks or denial-of-service attacks. In this work, we use quantum identification to overcome such two kinds of attack for BQC, which will be called QI-BQC. We propose two QI-BQC protocols based on a typical single-server BQC protocol and a double-server BQC protocol. The two protocols can ensure both data integrity and mutual identification between participants with the help of a third trusted party (TTP). In addition, an unjammable public channel between a client and a server which is indispensable in previous BQC protocols is unnecessary, although it is required between TTP and each participant at some instant. Furthermore, the method to achieve identity verification in the presented protocols is general and it can be applied to other similar BQC protocols.

Binding of ATP by pertussis toxin and isolated toxin subunits

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

Hausman, S.Z.; Manclark, C.R.; Burns, D.L.

1990-07-03

The binding of ATP to pertussis toxin and its components, the A subunit and B oligomer, was investigated. Whereas, radiolabeled ATP bound to the B oligomer and pertussis toxin, no binding to the A subunit was observed. The binding of ({sup 3}H)ATP to pertussis toxin and the B oligomer was inhibited by nucleotides. The relative effectiveness of the nucleotides was shown to be ATP > GTP > CTP > TTP for pertussis toxin and ATP > GTP > TTP > CTP for the B oligomer. Phosphate ions inhibited the binding of ({sup 3}H)ATP to pertussis toxin in a competitive manner;more » however, the presence of phosphate ions was essential for binding of ATP to the B oligomer. The toxin substrate, NAD, did not affect the binding of ({sup 3}H)ATP to pertussis toxin, although the glycoprotein fetuin significantly decreased binding. These results suggest that the binding site for ATP is located on the B oligomer and is distinct from the enzymatically active site but may be located near the eukaryotic receptor binding site.« less

Peripheral blood lymphocyte/monocyte ratio as a useful prognostic factor in dogs with diffuse large B-cell lymphoma receiving chemoimmunotherapy.

PubMed

Marconato, Laura; Martini, Valeria; Stefanello, Damiano; Moretti, Pierangelo; Ferrari, Roberta; Comazzi, Stefano; Laganga, Paola; Riondato, Fulvio; Aresu, Luca

2015-11-01

Diffuse large B-cell lymphoma (DLBCL) is the most frequent canine lymphoid neoplasm. Despite treatment, the majority of dogs with DLBCL experience tumour relapse and consequently die, so practical models to characterise dogs with a poor prognosis are needed. This study examined whether the lymphocyte/monocyte ratio (LMR) can predict outcome in dogs with newly diagnosed DLBCL with regard to time-to-progression (TTP) and lymphoma specific survival (LSS). A retrospective study analysed the prognostic significance of LMR obtained at diagnosis by flow cytometry (based on morphological properties and CD45 expression) in 51 dogs that underwent complete staging and received the same treatment, comprising multi-agent chemotherapy and administration of an autologous vaccine. Dogs with an LMR ≤ 1.2 (30% of all cases) were found to have significantly shorter TTP and LSS, and it was concluded that LMR was a useful independent prognostic indicator with biological relevance in dogs with DLBCL treated with chemoimmunotherapy. Copyright © 2015 Elsevier Ltd. All rights reserved.

The contribution of mitochondrial thymidylate synthesis in preventing the nuclear genome stress.

PubMed

Lee, Ming-Hsiang; Wang, Liya; Chang, Zee-Fen

2014-04-01

In quiescent fibroblasts, the expression levels of cytosolic enzymes for thymidine triphosphate (dTTP) synthesis are down-regulated, causing a marked reduction in the dTTP pool. In this study, we provide evidence that mitochondrial thymidylate synthesis via thymidine kinase 2 (TK2) is a limiting factor for the repair of ultraviolet (UV) damage in the nuclear compartment in quiescent fibroblasts. We found that TK2 deficiency causes secondary DNA double-strand breaks formation in the nuclear genome of quiescent cells at the late stage of recovery from UV damage. Despite slower repair of quiescent fibroblast deficient in TK2, DNA damage signals eventually disappeared, and these cells were capable of re-entering the S phase after serum stimulation. However, these cells displayed severe genome stress as revealed by the dramatic increase in 53BP1 nuclear body in the G1 phase of the successive cell cycle. Here, we conclude that mitochondrial thymidylate synthesis via TK2 plays a role in facilitating the quality repair of UV damage for the maintenance of genome integrity in the cells that are temporarily arrested in the quiescent state.

Efficient Workflows for Curation of Heterogeneous Data Supporting Modeling of U-Nb Alloy Aging

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

Ward, Logan Timothy; Hackenberg, Robert Errol

These are slides from a presentation summarizing a graduate research associate's summer project. The following topics are covered in these slides: data challenges in materials, aging in U-Nb Alloys, Building an Aging Model, Different Phase Trans. in U-Nb, the Challenge, Storing Materials Data, Example Data Source, Organizing Data: What is a Schema?, What does a "XML Schema" look like?, Our Data Schema: Nice and Simple, Storing Data: Materials Data Curation System (MDCS), Problem with MDCS: Slow Data Entry, Getting Literature into MDCS, Staging Data in Excel Document, Final Result: MDCS Records, Analyzing Image Data, Process for Making TTT Diagram, Bottleneckmore » Number 1: Image Analysis, Fitting a TTP Boundary, Fitting a TTP Curve: Comparable Results, How Does it Compare to Our Data?, Image Analysis Workflow, Curating Hardness Records, Hardness Data: Two Key Decisions, Before Peak Age? - Automation, Interactive Viz, Which Transformation?, Microstructure-Informed Model, Tracking the Entire Process, General Problem with Property Models, Pinyon: Toolkit for Managing Model Creation, Tracking Individual Decisions, Jupyter: Docs and Code in One File, Hardness Analysis Workflow, Workflow for Aging Models, and conclusions.« less

Evaluation of adjuvant carboplatin chemotherapy in the management of surgically excised anal sac apocrine gland adenocarcinoma in dogs.

PubMed

Wouda, R M; Borrego, J; Keuler, N S; Stein, T

2016-03-01

There is no widely accepted standard of care for canine anal sac apocrine gland adenocarcinoma (ASAGAC). Surgery alone is inadequate in many cases, but the benefit of adjuvant chemotherapy is not well established. The primary objective of this retrospective study was to evaluate the role of carboplatin chemotherapy in the post-operative management of ASAGAC. Seventy-four dogs with naturally occurring ASAGAC underwent surgery. Forty-four dogs received adjuvant carboplatin and 30 did not. Median overall survival (OS) was 703 days. Median time to progression (TTP) was 384 days. Only primary tumour size and lymph node metastasis at diagnosis significantly impacted the outcome. Differences in OS and TTP, between the dogs that received adjuvant carboplatin and those that did not, failed to reach statistical significance. Treatment of progressive disease, whilst not limited to chemotherapy, significantly prolonged the survival. This study shows that adjuvant carboplatin chemotherapy is well tolerated and may have a role in the management of dogs with ASAGAC. © 2013 John Wiley & Sons Ltd.

Biochemistry of terminal deoxynucleotidyltransferase. Identification and unity of ribo- and deoxyribonucleoside triphosphate binding site in terminal deoxynucleotidyltransferase

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

Pandey, V.N.; Modak, M.J.

Terminal deoxynucleotidyltransferase is the only DNA polymerase that is strongly inhibited in the presence of ATP. We have labeled calf terminal deoxynucleotidyltransferase with (/sup 32/P)ATP in order to identify its binding site in terminal deoxynucleotidyltransferase. The specificity of ATP cross-linking to terminal deoxynucleotidyltransferase is shown by the competitive inhibition of the overall cross-linking reaction by deoxynucleoside triphosphates, as well as the ATP analogs Ap4A and Ap5A. Tryptic peptide mapping of (/sup 32/P)ATP-labeled enzyme revealed a peptide fraction that contained the majority of cross-linked ATP. The properties, chromatographic characteristics, amino acid composition, and sequence analysis of this peptide fraction were identicalmore » with those found associated with dTTP cross-linked terminal deoxynucleotidyl-transferase peptide. The involvement of the same 2 cysteine residues in the crosslinking of both nucleotides further confirmed the unity of the ATP and dTTP binding domain that contains residues 224-237 in the primary amino acid sequence of calf terminal deoxynucleotidyltransferase.« less

Theory of the β-Type Organic Superconductivity under Uniaxial Compression

NASA Astrophysics Data System (ADS)

Suzuki, Takeo; Onari, Seiichiro; Ito, Hiroshi; Tanaka, Yukio

2011-09-01

We study theoretically the shift of the superconducting transition temperature (Tc) under uniaxial compression in β-type organic superconductors, β-(BEDT-TTF)2I3 and β-(BDA-TTP)2X (X=SbF6, AsF6), in order to clarify the electron correlation, the spin frustration, and the effect of dimerization. The transfer integrals are calculated by the extended Hückel method assuming the uniaxial strain, and the superconducting state mediated by the spin fluctuation is solved using Eliashberg's equation with the fluctuation--exchange approximation. The calculation is carried out on both the dimerized (one-band) and nondimerized (two-band) Hubbard models. We have found that (i) the behavior of Tc in β-(BEDT-TTF)2I3 with a stronger dimerization is well reproduced by the dimer model, while that in weakly dimerized β-BDA-TTP salts is rather well reproduced by the two-band model, and (ii) the competition between the spin frustration and the effect induced by the fluctuation is important in these materials, which causes the nonmonotonic shift of Tc against uniaxial compression.

Temozolomide in patients with glioblastoma at second relapse after first line nitrosourea-procarbazine failure: a phase II study.

PubMed

Brandes, Alba A; Ermani, Mario; Basso, Umberto; Paris, Myriam K; Lumachi, Franco; Berti, Franco; Amistà, Pietro; Gardiman, Marina; Iuzzolino, Paolo; Turazzi, Sergio; Monfardini, Silvio

2002-01-01

To investigate the efficacy of temozolomide (TMZ) in relationship to progression free survival at 6 months (PFS-6), median time to progression (TTP), response rate and toxicity, a phase II study was conducted in patients with recurrent glioblastoma multiforme (GBM) following surgery plus radiotherapy and a first-line regimen based on nitrosourea, procarbazine and vincristine. Forty-two patients with GBM were administered TMZ at the dose of 150 mg/m(2)/daily for 5 days every 4 weeks. The PFS-6 and at 12 months (PFS-12) was 24% (95% Confidence Interval [CI] = 14-42%) and 8% (CI = 2-27%), respectively, with a median TTP of 11.7 weeks (CI = 9-22 weeks). The response was assessed in all 42 patients; we observed 2 complete responses (CR) (4.7%), 6 partial responses (PR) (14.3%), and 9 stable disease (SD) (21.4%), with CR+PR = 19% (CI = 7-31%). TMZ as a second line regimen is a valid option in patients with heavily pretreated GBM. Copyright 2002 S. Karger AG, Basel

[Effect of TUBB3, TS and ERCC1 mRNA expression on chemoresponse and clinical outcome of advanced gastric cancer by multiplex branched-DNA liquid chip technology].

PubMed

Huang, Jin; Hu, Huabin; Xie, Yangchun; Tang, Youhong; Liu, Wei; Zhong, Meizuo

2013-06-01

To analyze the impact of β-tubulin-III (TUBB3), thymidylate synthase (TS) and excision repair cross complementation group 1 (ERCC1) mRNA expression on chemoresponse and clinical outcome of patients with advanced gastric cancer treated with TXT/CDDP/FU (DCF) regimen chemotherapy. The study population consisted of 48 patients with advanced gastric cancer. All patients were treated with DCF regimen palliative chemotherapy. The mRNA expressions of TUBB3, TS and ERCC1 of primary tumors were examined by multiplex branched-DNA liquid chip technology. The patients with low TUBB3 mRNA expression had higher response rate to chemotherapy than patients with high TUBB3 expression (P=0.011). There were no significant differences between response rate and TS or ERCC1 expression pattern. Median overall survival (OS) and median time to progression (TTP) were significantly longer in patients with low TUBB3 mRNA expression (P=0.002, P<0.001). TS or ERCC1 expression was not correlated with TTP and OS. In the combined analysis including TUBB3, TS and ERCC1, the patients with 0 or 1 high expression gene had better response rate, TTP and OS than the remaining patients (all P<0.001). Multivariate analysis revealed that ECOG (Eastern Cooperative Oncology Group)≥2 (HR=2.42, P=0.009) and TUBB3 (HR=2.34, P=0.036) mRNA expression significantly impacted on OS. High TUBB3 mRNA expression is correlated with resistance to DCF regimen chemotherapy. TUBB3 might be a predictive and prognostic factor in patients with advanced gastric cancer treated with TXT-based chemotherapy. The combined evaluation of TUBB3, TS and ERCC1 expression can promote the individual treatment in advanced gastric cancer.

Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances.

PubMed

Ashley, Neil; Adams, Susan; Slama, Abdelhamid; Zeviani, Massimo; Suomalainen, Anu; Andreu, Antonio L; Naviaux, Robert K; Poulton, Joanna

2007-06-15

Defects in mtDNA maintenance range from fatal multisystem childhood diseases, such as Alpers syndrome, to milder diseases in adults, including mtDNA depletion syndromes (MDS) and familial progressive external ophthalmoplegia (AdPEO). Most are associated with defects in genes involved in mitochondrial deoxynucleotide metabolism or utilization, such as mutations in thymidine kinase 2 (TK2) as well as the mtDNA replicative helicase, Twinkle and gamma polymerase (POLG). We have developed an in vitro system to measure incorporation of radiolabelled dNTPs into mitochondria of saponin permeabilized cells. We used this to compare the rates of mtDNA synthesis in cells from 12 patients with diseases of mtDNA maintenance. We observed reduced incorporation of exogenous alpha (32)P-dTTP in fibroblasts from a patient with Alpers syndrome associated with the A467T substitution in POLG, a patient with dGK mutations, and a patient with mtDNA depletion of unknown origin compared to controls. However, incorporation of alpha (32)P-dTTP relative to either cell doubling time or alpha (32)P-dCTP incorporation was increased in patients with thymidine kinase deficiency or PEO as the result of TWINKLE mutations compared with controls. The specific activity of newly synthesized mtDNA depends on the size of the endogenous pool diluting the exogenous labelled nucleotide. Our result is consistent with a deficiency in the intramitochondrial pool of dTTP relative to dCTP in cells from patients with TK2 deficiency and TWINKLE mutations. Such DNA precursor asymmetry could cause pausing of the replication complex and hence exacerbate the propensity for age-related mtDNA mutations. Because deviations from the normal concentrations of dNTPs are known to be mutagenic, we suggest that intramitochondrial nucleotide imbalance could underlie the multiple mtDNA mutations observed in these patients.

The serum miR-21 level serves as a predictor for the chemosensitivity of advanced pancreatic cancer, and miR-21 expression confers chemoresistance by targeting FasL.

PubMed

Wang, Peng; Zhuang, Liping; Zhang, Juan; Fan, Jie; Luo, Jianmin; Chen, Hao; Wang, Kun; Liu, Luming; Chen, Zhen; Meng, Zhiqiang

2013-06-01

miR-21 expression in cancer tissue has been reported to be associated with the clinical outcome and activity of gemcitabine in pancreatic cancer. However, resection is possible in only a minority of patients due to the advanced stages often present at the time of diagnosis, and safely obtaining sufficient quantities of pancreatic tumor tissue for molecular analysis is difficult at the unresectable stages. In this study, we investigated whether the serum level of miR-21 could be used as a predictor of chemosensitivity. We tested the levels of serum miR-21 in a cohort of 177 cases of advanced pancreatic cancer who received gemcitabine-based palliative chemotherapy. We found that a high level of miR-21 in the serum was significantly correlated with a shortened time-to-progression (TTP) and a lower overall survival (OS). The serum miR-21 level was an independent prognostic factor for both the TTP and the OS (HR 1.920; 95% CI, 1.274-2.903, p = 0.002 for TTP and HR 1.705; 95% CI, 1.147-2.535, p = 0.008 for OS). The results from a functional study showed that gemcitabine exposure down-regulated miR-21 expression and up-regulated FasL expression. The increased FasL expression following gemcitabine treatment induced cancer cell apoptosis, whereas the ectopic expression of miR-21 partially protected the cancer cells from gemcitabine-induced apoptosis. Additionally, we confirmed that FasL was a direct target of miR-21. Therefore, the serum level of miR-21 may serve as a predictor of chemosensitivity in advanced pancreatic cancer. Additionally, we identified a new mechanism of chemoresistance mediated by the effects of miR-21 on the FasL/Fas pathway. Copyright © 2012 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Outcomes with two different schedules of bortezomib, melphalan, and prednisone (VMP) for previously untreated multiple myeloma: matched pair analysis using long-term follow-up data from the phase 3 VISTA and PETHEMA/GEM05 trials.

PubMed

Mateos, Maria-Victoria; Oriol, Albert; Martínez-López, Joaquín; Teruel, Ana-Isabel; Bengoechea, Enrique; Palomera, Luis; de Arriba, Felipe; Esseltine, Dixie-Lee; Cakana, Andrew; Pei, Lixia; van de Velde, Helgi; Miguel, Jesus San

2016-12-01

Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Here, we compared outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance). A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in this retrospective analysis. Median cumulative bortezomib dose was higher in PETHEMA/GEM05 than VISTA (49.6 vs 37.0 mg/m 2 ); median dose intensity was lower (2.0 vs 5.1 mg/m 2 /month). Median progression-free survival (PFS) and time-to-progression (TTP) were significantly longer in PETHEMA/GEM05 than VISTA (PFS, 30.5 vs 20.0 months, p = 0.0265; TTP, 33.8 vs 24.2 months, p = 0.0049) after a median follow-up of 77.2 and 26.0 months, respectively. Median overall survival (OS) was similar (61.3 vs 61.0 months, p = 0.6528; median follow-up, 77.6 vs 60.1 months). Post-induction complete response rate was lower in PETHEMA/GEM05 than VISTA (19 vs 31 %; p = 0.03318); on-study (including maintenance) rate was similar (30 vs 31 %; p = 0.89437). This analysis suggests that the less-intensive PETHEMA/GEM05 VMP regimen plus maintenance may improve PFS and TTP, but not OS, compared with the VISTA VMP regimen. NCT00111319, NCT00443235.

Proteomic Changes of Tissue-Tolerable Plasma Treated Airway Epithelial Cells and Their Relation to Wound Healing

PubMed Central

Lendeckel, Derik; Eymann, Christine; Emicke, Philipp; Daeschlein, Georg; Darm, Katrin; O'Neil, Serena; Beule, Achim G.; von Woedtke, Thomas; Völker, Uwe; Weltmann, Klaus-Dieter; Jünger, Michael; Hosemann, Werner; Scharf, Christian

2015-01-01

Background. The worldwide increasing number of patients suffering from nonhealing wounds requires the development of new safe strategies for wound repair. Recent studies suggest the possibility of nonthermal (cold) plasma application for the acceleration of wound closure. Methods. An in vitro wound healing model with upper airway S9 epithelial cells was established to determine the macroscopically optimal dosage of tissue-tolerable plasma (TTP) for wound regeneration, while a 2D-difference gel electrophoresis (2D-DIGE) approach was used to quantify the proteomic changes in a hypothesis-free manner and to evaluate the balance of beneficial and adverse effects due to TTP application. Results. Plasma doses from 30 s up to 360 s were tested in relation to wound closure after 24 h, 48 h, 72 h, 96 h, and 120 h, in which lower doses (30, 60, and 120 s) resulted in dose-dependent improved wound healing rate compared to untreated cells. Thereby, the 120 s dose caused significantly the best wound healing properties after 96 and 120 h. The proteome analysis combined with IPA revealed that a lot of affected stress adaptation responses are linked to oxidative stress response emphasizing oxidative stress as a possible key event in the regeneration process of epithelial cells as well as in the adaptation to plasma exposure. Further cellular and molecular functions like proliferation and apoptosis were significantly up- or downregulated by all TTP treatments but mostly by the 120 s dose. Conclusions. For the first time, we were able to show plasma effects on cellular adaptation of upper airway epithelial S9 cells improving wound healing. This is of particular interest for plasma application, for example, in the surgery field of otorhinolaryngology or internal medicine. PMID:26539504

Phase III noninferiority trial comparing irinotecan with oxaliplatin, fluorouracil, and leucovorin in patients with advanced colorectal carcinoma previously treated with fluorouracil: N9841.

PubMed

Kim, George P; Sargent, Daniel J; Mahoney, Michelle R; Rowland, Kendrith M; Philip, Philip A; Mitchell, Edith; Mathews, Abraham P; Fitch, Tom R; Goldberg, Richard M; Alberts, Steven R; Pitot, Henry C

2009-06-10

The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m(2) every 3 weeks) or arm B (FOLFOX4). A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias. In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.

[Influence of molecular-genetic factors on prognosis in patients with oligodendroglial tumors].

PubMed

Absaliamova, O V; Korshunov, A G; Loshakov, V A; Kobiakov, G L; Golanov, A V; Urakov, S V; Amanov, R D; Lichinitser, M R

2009-01-01

Previous studies demonstrated that patients with oligodendroglial tumors (OT) have longer overall and recurrence free survival than patients with other glial tumors of the same grade. Recent investigations showed high influence of genetic alterations on patients' outcome: overall and recurrence free survival increased in the case of presence 1p19q deletion and decreased in the presence of 9p or 10q deletion and/or EGFR amplification. In the series of 241 cases (107 male, 134 female patients, median age -- 38 years, (16-73)) we analyzed the impact of histology, tumor grade and genetic alterations on time to tumor progression (TTP). All patients underwent surgical resection of tumor or biopsy from 2000 to 2005. 70 patterns (oligodendroglioma (O) -- 13 cases, oligoastrocytoma (OA) -- 13, anaplastic oligodendroglioma (AO) -- 30, anaplastic oligoastrocytoma (AOA) -- 14) were assessed by fluorescent in situ hybridization. Median follow up was 24 months. The type of tumor (pure or mixed) didn't influence survival. TTP of patients with grade II and grade III tumors was 37.7 and 48.2 months, respectively (p = 0.035). Deletion 1p19q was noted in 34 (49%) cases. In pure O codeletion 1p19q was detected more frequently (in O -- 75%, in AO -- 56%) than in mixed tumors (in OA -- 31%, in AOA -- 35%). Deletions 9p, 10q and EGFR amplification were noted in 5, 6 and 4 cases, respectively. None of the tumors with 1pl9q deletion had other genetic alterations. Thus, we generated three prognostic groups: A -- deletion 1p19q; B -- balanced chromosomal profile; C -- deletion 9p. Median TTP in groups A, B and C was 46.6, 25.3 and 6.4 months, respectively (p < 0.001). The percentage of OT with 1p19q codeletion was lower than in previous studies. Pure O more frequently had 1p19q deletion than mixed tumors. Genetic alterations predict outcome stronger than histological criteria.

Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts

PubMed Central

2011-01-01

Introduction Microtubule associated proteins (MAPs) endogenously regulate microtubule stabilization and have been reported as prognostic and predictive markers for taxane response. The microtubule stabilizer, MAP-tau, has shown conflicting results. We quantitatively assessed MAP-tau expression in two independent breast cancer cohorts to determine prognostic and predictive value of this biomarker. Methods MAP-tau expression was evaluated in the retrospective Yale University breast cancer cohort (n = 651) using tissue microarrays and also in the TAX 307 cohort, a clinical trial randomized for TAC versus FAC chemotherapy (n = 140), using conventional whole tissue sections. Expression was measured using the AQUA method for quantitative immunofluorescence. Scores were correlated with clinicopathologic variables, survival, and response to therapy. Results Assessment of the Yale cohort using Cox univariate analysis indicated an improved overall survival (OS) in tumors with a positive correlation between high MAP-tau expression and overall survival (OS) (HR = 0.691, 95% CI = 0.489-0.974; P = 0.004). Kaplan Meier analysis showed 10-year survival for 65% of patients with high MAP-tau expression compared to 52% with low expression (P = .006). In TAX 307, high expression was associated with significantly longer median time to tumor progression (TTP) regardless of treatment arm (33.0 versus 23.4 months, P = 0.010) with mean TTP of 31.2 months. Response rates did not differ by MAP-tau expression (P = 0.518) or by treatment arm (P = 0.584). Conclusions Quantitative measurement of MAP-tau expression has prognostic value in both cohorts, with high expression associated with longer TTP and OS. Differences by treatment arm or response rate in low versus high MAP-tau groups were not observed, indicating that MAP-tau is not associated with response to taxanes and is not a useful predictive marker for taxane-based chemotherapy. PMID:21888627

Effects of combined Chinese drugs and chemotherapy in treating advanced non-small cell lung cancer.

PubMed

Chen, Yan-zhi; Li, Zhan-dong; Gao, Fei; Zhang, Ying; Sun, Hong; Li, Ping-ping

2009-12-01

To evaluate the efficacy and side effects of combined Chinese drugs and chemotherapy in treating advanced non-small cell lung cancer (NSCLC). Sixty-three patients with stage III B and IV NSCLC hospitalized from October 2001 to October 2008 were enrolled and assigned to two groups using a randomizing digital table, with 33 patients in the treatment group and 30 in the control group. They were all treated with the Navelbine and Cisplatin (NP) chemotherapy, but to the treatment group the Chinese drugs Shengmai Injection () by intravenous dripping and Gujin Granule () by oral intake were given additionally. The main observation indexes were response rate (RR), median survival time, 1-year survival rate and median time to progression (TTP); secondary observation indexes were side effects and cycles of chemotherapy. Altogether, 61 patients (33 from the treatment group and 28 from the control group) completed the observation and were assessable. RR was 48.5% (16/33) in the treatment group and 32.2% (9/28) in the control group, and the median survival time were 13 months and 9 months, respectively; the difference between the two groups was significant (P=0.0373 and P=0.014 respectively). However, the differences between groups were insignificant in terms of 1-year survival rate [51.5% (17/33) vs 46.4% (13/28), P=0.4042], median TTP (5.95 months vs 4.64 months, P=0.3242), grade III or IV bone marrow inhibition occurrence rate [33.3% (11/33) vs 39.3% (11/28), P=0.3500], and mean cycles of chemotherapy applied (2.94+/-0.94 cycles vs 2.75+/-0.75 cycles, P=0.4100). Combined Chinese drugs and chemotherapy can enhance the short-term therapeutic efficacy in the treatment of NSCLC and prolong patients' median survival time, but show no evident impact on TTP.

How Y-Family DNA polymerase IV is more accurate than Dpo4 at dCTP insertion opposite an N2-dG adduct of benzo[a]pyrene.

PubMed

Sholder, Gabriel; Creech, Amanda; Loechler, Edward L

2015-11-01

To bypass DNA damage, cells have Y-Family DNA polymerases (DNAPs). One Y-Family-class includes DNAP κ and DNAP IV, which accurately insert dCTP opposite N(2)-dG adducts, including from the carcinogen benzo[a]pyrene (BP). Another class includes DNAP η and DNAP V, which insert accurately opposite UV-damage, but inaccurately opposite BP-N(2)-dG. To investigate structural differences between Y-Family-classes, regions are swapped between DNAP IV (a κ/IV-class-member) and Dpo4 (a η/V-class-member); the kinetic consequences are evaluated via primer-extension studies with a BP-N(2)-dG-containing template. Four key structural elements are revealed. (1) Y-Family DNAPs have discreet non-covalent contacts between their little finger-domain (LF-Domain) and their catalytic core-domain (CC-Domain), which we call "non-covalent bridges" (NCBs). Arg37 and Arg38 in DNAP IV's CC-Domain near the active site form a non-covalent bridge (AS-NCB) by interacting with Glu251 and Asp252, respectively, in DNAP IV's LF-Domain. Without these interactions dATP/dGTP/dTTP misinsertions increase. DNAP IV's AS-NCB suppresses misinsertions better than Dpo4's equivalent AS-NCB. (2) DNAP IV also suppresses dATP/dGTP/dTTP misinsertions via a second non-covalent bridge, which is ∼8Å from the active site (Distal-NCB). Dpo4 has no Distal-NCB, rendering it inferior at dATP/dGTP/dTTP suppression. (3) dCTP insertion is facilitated by the larger minor groove opening near the active site in DNAP IV versus Dpo4, which is sensible given that Watson/Crick-like [dCTP:BP-N(2)-dG] pairing requires the BP-moiety to be in the minor groove. (4) Compared to Dpo4, DNAP IV has a smaller major groove opening, which suppresses dGTP misinsertion, implying BP-N(2)-dG bulk in the major groove during Hoogsteen syn-adduct-dG:dGTP pairing. In summary, DNAP IV has a large minor groove opening to enhance dCTP insertion, a plugged major groove opening to suppress dGTP misinsertion, and two non-covalent bridges (near and distal to the active site) to suppress dATP/dGTP/dTTP misinsertions; collectively these four structural features enhance DNAP IV's dNTP insertion fidelity opposite a BP-N(2)-dG adduct compared to Dpo4. Copyright © 2015 Elsevier B.V. All rights reserved.

First-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer : analysis of the Italian patients enrolled in the SAiL study.

PubMed

Bearz, Alessandra; Passalacqua, Rodolfo; Alabiso, Oscar; Cinieri, Saverio; Gridelli, Cesare; Cravesana, Claudia; Crinò, Lucio

2012-11-01

First-line bevacizumab-based therapy has been shown to improve outcomes in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The recent international phase IV SAiL study (a Study of Avastin [bevacizumab] in combination with platinum-containing chemotherapy in patients with advanced or recurrent non-squamous cell Lung cancer) evaluated the safety and efficacy of bevacizumab combined with standard chemotherapy regimens in routine clinical practice. Here we report the results of a subanalysis of baseline characteristics and efficacy data for Italian patients enrolled in SAiL. In the SAiL study, patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC received bevacizumab (7.5 or 15 mg/kg) every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Efficacy was assessed in terms of time to disease progression (TTP) and overall survival (OS). The Italian intent-to-treat population comprised 215 patients from a SAiL population of 2212 patients. At baseline, Italian patients tended to have less advanced disease than the overall population. Thus, the proportion of patients at enrollment with tumour stage IIIb and IV was 23.7 and 76.3 %, respectively, for the Italian population versus 19.7 and 80.3 % for the whole SAiL population. In addition, a higher proportion of Italian patients had an Eastern Cooperative Oncology Group performance status of 0 (72.6 vs. 37.2 %) and the prevalence of co-morbid conditions was lower in Italian patients (59.5 % of Italian patients reported a co-morbid condition and 60.0 % were receiving non-oncological treatment compared with 73.3 and 73.4 %, respectively, of SAiL patients overall). The mean exposures to bevacizumab and to chemotherapy were comparable between the Italian patient group and overall patient population, although cisplatin doublets were more commonly employed in Italian patients whereas carboplatin doublets were more commonly employed in the overall SAiL population. The median TTP and OS times for Italian and SAiL populations were comparable (TTP, 7.8 months vs. 7.8 months; OS, 14.8 months vs. 14.6 months). The results of this subanalysis of the SAiL study of bevacizumab treatment in routine clinical practice suggest that Italian oncologists tend to prescribe bevacizumab to a selected population of patients with less advanced disease than is the case in the overall population. Nevertheless, the first-line use of bevacizumab in combination with chemotherapy offers clinical benefits to Italian patients with advanced or recurrent non-squamous NSCLC.

Quality Indicators in Laboratory Medicine: the status of the progress of IFCC Working Group "Laboratory Errors and Patient Safety" project.

PubMed

Sciacovelli, Laura; Lippi, Giuseppe; Sumarac, Zorica; West, Jamie; Garcia Del Pino Castro, Isabel; Furtado Vieira, Keila; Ivanov, Agnes; Plebani, Mario

2017-03-01

The knowledge of error rates is essential in all clinical laboratories as it enables them to accurately identify their risk level, and compare it with those of other laboratories in order to evaluate their performance in relation to the State-of-the-Art (i.e. benchmarking) and define priorities for improvement actions. Although no activity is risk free, it is widely accepted that the risk of error is minimized by the use of Quality Indicators (QIs) managed as a part of laboratory improvement strategy and proven to be suitable monitoring and improvement tools. The purpose of QIs is to keep the error risk at a level that minimizes the likelihood of patients. However, identifying a suitable State-of-the-Art is challenging, because it calls for the knowledge of error rates measured in a variety of laboratories throughout world that differ in their organization and management, context, and the population they serve. Moreover, it also depends on the choice of the events to keep under control and the individual procedure for measurement. Although many laboratory professionals believe that the systemic use of QIs in Laboratory Medicine may be effective in decreasing errors occurring throughout the total testing process (TTP), to improve patient safety as well as to satisfy the requirements of International Standard ISO 15189, they find it difficult to maintain standardized and systematic data collection, and to promote continued high level of interest, commitment and dedication in the entire staff. Although many laboratories worldwide express a willingness to participate to the Model of QIs (MQI) project of IFCC Working Group "Laboratory Errors and Patient Safety", few systematically enter/record their own results and/or use a number of QIs designed to cover all phases of the TTP. Many laboratories justify their inadequate participation in data collection of QIs by claiming that the number of QIs included in the MQI is excessive. However, an analysis of results suggests that QIs need to be split into further measurements. As the International Standard on Laboratory Accreditation and approved guidelines do not specify the appropriate number of QIs to be used in the laboratory, and the MQI project does not compel laboratories to use all the QIs proposed, it appears appropriate to include in the MQI all the indicators of apparent utility in monitoring critical activities. The individual laboratory should also be able to decide how many and which QIs can be adopted. In conclusion, the MQI project is proving to be an important tool that, besides providing the TTP error rate and spreading the importance of the use of QIs in enhancing patient safety, highlights critical aspects compromising the widespread and appropriate use of QIs.

Module Cluster: TTP-001.00 (GSC) Reinforcement Principles for Classroom Use.

ERIC Educational Resources Information Center

Brent, George

The purpose of this module cluster is to enable students to define the basic operant terms, to state the basic operant principles, to read operant measurement charts, and to use operant principles in elementary classrooms with both social and academic behaviors. It is intended for use by teacher education students with the cooperation of an…

JPRS Report, Telecommunications.

DTIC Science & Technology

1989-03-24

3 LATIN AMERICA MEXICO Ericsson Plans $20 Million Investment in 1989 [ Mexico City UNOMASUNO, 1 Feb 89] ............... 4 NEAR EAST...Telephone System for Azores [Lisbon DIARIO DE NOTICIAS ECONOMIA , 30 Jan 89] ........................................................... 25 UNITED...aid in Bloc. JPRS-TTP-89-004 24 March 1989 LATIN AMERICA 4 MEXICO This contract will provide Mexico with over 2 milion AXE-equivalent lines, thus

Integrated analysis of dynamic FET PET/CT parameters, histology, and methylation profiling of 44 gliomas.

PubMed

Röhrich, Manuel; Huang, Kristin; Schrimpf, Daniel; Albert, Nathalie L; Hielscher, Thomas; von Deimling, Andreas; Schüller, Ulrich; Dimitrakopoulou-Strauss, Antonia; Haberkorn, Uwe

2018-05-07

Dynamic 18 F-FET PET/CT is a powerful tool for the diagnosis of gliomas. 18 F-FET PET time-activity curves (TAC) allow differentiation between histological low-grade gliomas (LGG) and high-grade gliomas (HGG). Molecular methods such as epigenetic profiling are of rising importance for glioma grading and subclassification. Here, we analysed dynamic 18 F-FET PET data, and the histological and epigenetic features of 44 gliomas. Dynamic 18 F-FET PET was performed in 44 patients with newly diagnosed, untreated glioma: 10 WHO grade II glioma, 13 WHO grade III glioma and 21 glioblastoma (GBM). All patients underwent stereotactic biopsy or tumour resection after 18 F-FET PET imaging. As well as histological analysis of tissue samples, DNA was subjected to epigenetic analysis using the Illumina 850 K methylation array. TACs, standardized uptake values corrected for background uptake in healthy tissue (SUVmax/BG), time to peak (TTP) and kinetic modelling parameters were correlated with histological diagnoses and with epigenetic signatures. Multivariate analyses were performed to evaluate the diagnostic accuracy of 18 F-FET PET in relation to the tumour groups identified by histological and methylation-based analysis. Epigenetic profiling led to substantial tumour reclassification, with six grade II/III gliomas reclassified as GBM. Overlap of HGG-typical TACs and LGG-typical TACs was dramatically reduced when tumours were clustered on the basis of their methylation profile. SUVmax/BG values of GBM were higher than those of LGGs following both histological diagnosis and methylation-based diagnosis. The differences in TTP between GBMs and grade II/III gliomas were greater following methylation-based diagnosis than following histological diagnosis. Kinetic modeling showed that relative K1 and fractal dimension (FD) values significantly differed in histology- and methylation-based GBM and grade II/III glioma between those diagnosed histologically and those diagnosed by methylation analysis. Multivariate analysis revealed slightly greater diagnostic accuracy with methylation-based diagnosis. IDH-mutant gliomas and GBM subgroups tended to differ in their 18 F-FET PET kinetics. The status of dynamic 18 F-FET PET as a biologically and clinically relevant imaging modality is confirmed in the context of molecular glioma diagnosis.

47 CFR 17.53 - Lighting equipment and paint.

Code of Federal Regulations, 2011 CFR

2011-10-01

... AC No. 150/5345-43B 4). 116-Watt lamp No. 116 A21/TS (6,000 h). 125-Watt lamp No. 125 A21/TS (6,000 h... Administration, 800 Independence Avenue SW., Washington, D.C. 20591. 4 Copies of Federal Aviation Administration... specifications, bulletins, and drawings (lamps are referred to by standard numbers): Outside white TT-P-102 1...

The Texas Ten Percent Plan's Impact on College Enrollment

ERIC Educational Resources Information Center

Daugherty, Lindsay; Martorell, Paco; McFarlin, Isaac, Jr.

2014-01-01

The Texas Ten Percent Plan (TTP) provides students in the top 10 percent of their high-school class with automatic admission to any public university in the state, including the two flagship schools, the University of Texas at Austin and Texas A&M. Texas created the policy in 1997 after a federal appellate court ruled that the state's previous…

The contribution of mitochondrial thymidylate synthesis in preventing the nuclear genome stress

PubMed Central

Lee, Ming-Hsiang; Wang, Liya; Chang, Zee-Fen

2014-01-01

In quiescent fibroblasts, the expression levels of cytosolic enzymes for thymidine triphosphate (dTTP) synthesis are down-regulated, causing a marked reduction in the dTTP pool. In this study, we provide evidence that mitochondrial thymidylate synthesis via thymidine kinase 2 (TK2) is a limiting factor for the repair of ultraviolet (UV) damage in the nuclear compartment in quiescent fibroblasts. We found that TK2 deficiency causes secondary DNA double-strand breaks formation in the nuclear genome of quiescent cells at the late stage of recovery from UV damage. Despite slower repair of quiescent fibroblast deficient in TK2, DNA damage signals eventually disappeared, and these cells were capable of re-entering the S phase after serum stimulation. However, these cells displayed severe genome stress as revealed by the dramatic increase in 53BP1 nuclear body in the G1 phase of the successive cell cycle. Here, we conclude that mitochondrial thymidylate synthesis via TK2 plays a role in facilitating the quality repair of UV damage for the maintenance of genome integrity in the cells that are temporarily arrested in the quiescent state. PMID:24561807

Transgene expression of Drosophila melanogaster nucleoside kinase reverses mitochondrial thymidine kinase 2 deficiency.

PubMed

Krishnan, Shuba; Zhou, Xiaoshan; Paredes, João A; Kuiper, Raoul V; Curbo, Sophie; Karlsson, Anna

2013-02-15

A strategy to reverse the symptoms of thymidine kinase 2 (TK2) deficiency in a mouse model was investigated. The nucleoside kinase from Drosophila melanogaster (Dm-dNK) was expressed in TK2-deficient mice that have been shown to present with a severe phenotype caused by mitochondrial DNA depletion. The Dm-dNK(+/-) transgenic mice were shown to be able to rescue the TK2-deficient mice. The Dm-dNK(+/-)TK2(-/-) mice were normal as judged by growth and behavior during the observation time of 6 months. The Dm-dNK-expressing mice showed a substantial increase in thymidine-phosphorylating activity in investigated tissues. The Dm-dNK expression also resulted in highly elevated dTTP pools. The dTTP pool alterations did not cause specific mitochondrial DNA mutations or deletions when 6-month-old mice were analyzed. The mitochondrial DNA was also detected at normal levels. In conclusion, the Dm-dNK(+/-)TK2(-/-) mouse model illustrates how dTMP synthesized in the cell nucleus can compensate for loss of intramitochondrial dTMP synthesis in differentiated tissue. The data presented open new possibilities to treat the severe symptoms of TK2 deficiency.

A Phase II Study of the Central European Society of Anticancer-Drug Research (CESAR) Group: Results of an Open-Label Study of Gemcitabine plus Cisplatin with or without Concomitant or Sequential Gefitinib in Patients with Advanced or Metastatic Transitional Cell Carcinoma of the Urothelium.

PubMed

Miller, Kurt; Morant, Rudolf; Stenzl, Arnulf; Zuna, Ivan; Wirth, Manfred

2016-01-01

This phase II trial evaluated the efficacy and safety of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, gefitinib, in combination with first-line chemotherapy in advanced urothelial cancer. Chemotherapy-naïve patients with advanced or metastatic urothelial carcinoma were randomized 1:1:1 to receive six cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8, and cisplatin 70 mg/m2 on day 1 of every cycle) concomitantly with gefitinib 250 mg/day (arm A); or with sequential gefitinib (arm B); or alone (arm C). The primary endpoint was the time to progression (TTP). A total of 105 patients received study treatment. Median TTP for arms A, B, and C were 6.1, 6.3, and 7.8 months, respectively. There were no significant differences between treatment arms for any outcomes measured. The most common adverse events were nausea and vomiting. Gefitinib in combination with chemotherapy did not improve efficacy in advanced urothelial cancer. © 2015 S. Karger AG, Basel.

Electronic signatures for long-lasting storage purposes in electronic archives.

PubMed

Pharow, Peter; Blobel, Bernd

2005-03-01

Communication and co-operation in healthcare and welfare require a certain set of trusted third party (TTP) services describing both status and relation of communicating principals as well as their corresponding keys and attributes. Additional TTP services are needed to provide trustworthy information about dynamic issues of communication and co-operation such as time and location of processes, workflow relations, and system behaviour. Legal and ethical requirements demand securely stored patient information and well-defined access rights. Among others, electronic signatures based on asymmetric cryptography are important means for securing the integrity of a message or file as well as for accountability purposes including non-repudiation of both origin and receipt. Electronic signatures along with certified time stamps or time signatures are especially important for electronic archives in general, electronic health records (EHR) in particular, and especially for typical purposes of long-lasting storage. Apart from technical storage problems (e.g. lifetime of the storage devices, interoperability of retrieval and presentation software), this paper identifies mechanisms of e.g. re-signing and re-stamping of data items, files, messages, sets of archived items or documents, archive structures, and even whole archives.

The current duration design for estimating the time to pregnancy distribution: a nonparametric Bayesian perspective.

PubMed

Gasbarra, Dario; Arjas, Elja; Vehtari, Aki; Slama, Rémy; Keiding, Niels

2015-10-01

This paper was inspired by the studies of Niels Keiding and co-authors on estimating the waiting time-to-pregnancy (TTP) distribution, and in particular on using the current duration design in that context. In this design, a cross-sectional sample of women is collected from those who are currently attempting to become pregnant, and then by recording from each the time she has been attempting. Our aim here is to study the identifiability and the estimation of the waiting time distribution on the basis of current duration data. The main difficulty in this stems from the fact that very short waiting times are only rarely selected into the sample of current durations, and this renders their estimation unstable. We introduce here a Bayesian method for this estimation problem, prove its asymptotic consistency, and compare the method to some variants of the non-parametric maximum likelihood estimators, which have been used previously in this context. The properties of the Bayesian estimation method are studied also empirically, using both simulated data and TTP data on current durations collected by Slama et al. (Hum Reprod 27(5):1489-1498, 2012).

Oxidative damage in DNA bases revealed by UV resonant Raman spectroscopy.

PubMed

D'Amico, Francesco; Cammisuli, Francesca; Addobbati, Riccardo; Rizzardi, Clara; Gessini, Alessandro; Masciovecchio, Claudio; Rossi, Barbara; Pascolo, Lorella

2015-03-07

We report on the use of the UV Raman technique to monitor the oxidative damage of deoxynucleotide triphosphates (dATP, dGTP, dCTP and dTTP) and DNA (plasmid vector) solutions. Nucleotide and DNA aqueous solutions were exposed to hydrogen peroxide (H2O2) and iron containing carbon nanotubes (CNTs) to produce Fenton's reaction and induce oxidative damage. UV Raman spectroscopy is shown to be maximally efficient to reveal changes in the nitrogenous bases during the oxidative mechanisms occurring on these molecules. The analysis of Raman spectra, supported by numerical computations, revealed that the Fenton's reaction causes an oxidation of the nitrogenous bases in dATP, dGTP and dCTP solutions leading to the production of 2-hydroxyadenine, 8-hydroxyguanine and 5-hydroxycytosine. No thymine change was revealed in the dTTP solution under the same conditions. Compared to single nucleotide solutions, plasmid DNA oxidation has resulted in more radical damage that causes the breaking of the adenine and guanine aromatic rings. Our study demonstrates the advantage of using UV Raman spectroscopy for rapidly monitoring the oxidation changes in DNA aqueous solutions that can be assigned to specific nitrogenous bases.

Apatinib is effective for treatment of advanced hepatocellular carcinoma.

PubMed

Kong, Yinlong; Sun, Lin; Hou, Zhenyu; Zhang, Yongqiang; Chen, Ping; Cui, Yunlong; Zhu, Xiaolin; Song, Tianqiang; Li, Qiang; Li, Huikai; Zhang, Ti; Qin, Lunxiu

2017-12-01

As treatment options for hepatocellular carcinoma (HCC) are currently limited, we evaluated the efficacy and safety of oral apatinib, a VEGFR-2 inhibitor, on patients with advanced HCC. Twenty-two patients from Tianjin Medical University Cancer Institute and Hospital were enrolled for evaluation. Apatinib was administered at 500 mg/day or 250 mg/day continuously. Clinical endpoints were time to disease progression (TTP), overall survival (OS), and safety. The median TTP of treated patients was 10.4 months (95% CI 3.4 -17.5). At the last follow-up, 50% patients had survived longer than 11.4 months from the first dose. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) rates were 0%, 40.9%, 40.9%, and 18.2%, respectively. The most common apatinib-related adverse events were hand-foot skin reaction (HFSR) (81.8%) and diarrhea (77.3%). Hypertension (27.3%) and HFSR (13.6%) were the most frequent grade 3/4 adverse events. In summary, results of this small study indicate that apatinib is well tolerated and extremely effective for the treatment of advanced HCC. It is therefore imperative to design and carry out well-controlled clinical trials to confirm its efficacy.

Anisotropic superconductivity in β-(BDA-TTP)2SbF6: STM spectroscopy

NASA Astrophysics Data System (ADS)

Nomura, K.; Muraoka, R.; Matsunaga, N.; Ichimura, K.; Yamada, J.

2009-03-01

We have investigated the gap symmetry in the superconducting phase of β-(BDA-TTP)2SbF6 with use of the scanning tunneling microscope (STM). The tunneling spectra obtained on the conducting surface show a clear superconducting gap structure. Its functional form is of V-shaped similarly to κ-(BEDT-TTF)2X and suggests the anisotropic superconducting gap with line nodes. For lateral surfaces the shape of tunneling spectra varies from the U-shape with relatively large gap to the V-shape with small gap depending on the tunneling direction alternately twice between directional angle 0 and π. From the analysis of conductance curve taking the k dependence of the tunneling probability into account, it is found that the gap has maximum near the a* and c* axes and the nodes appear along near a*+c* and the a-c* directions. These indicate that the d like superconducting pair is formed in this system as the case of κ-(BEDT-TTF)2X. This node direction is consistent with the theoretical prediction based on the spin fluctuation mechanism. However, the zero-bias conductance peak has not been observed yet.

Update on hemolytic uremic syndrome: Diagnostic and therapeutic recommendations

PubMed Central

Salvadori, Maurizio; Bertoni, Elisabetta

2013-01-01

Hemolytic uremic syndrome (HUS) is a rare disease. In this work the authors review the recent findings on HUS, considering the different etiologic and pathogenetic classifications. New findings in genetics and, in particular, mutations of genes that encode the complement-regulatory proteins have improved our understanding of atypical HUS. Similarly, the complement proteins are clearly involved in all types of thrombotic microangiopathy: typical HUS, atypical HUS and thrombotic thrombocytopenic purpura (TTP). Furthermore, several secondary HUS appear to be related to abnormalities in complement genes in predisposed patients. The authors highlight the therapeutic aspects of this rare disease, examining both “traditional therapy” (including plasma therapy, kidney and kidney-liver transplantation) and “new therapies”. The latter include anti-Shiga-toxin antibodies and anti-C5 monoclonal antibody “eculizumab”. Eculizumab has been recently launched for the treatment of the atypical HUS, but it appears to be effective in the treatment of typical HUS and in TTP. Future therapies are in phases I and II. They include anti-C5 antibodies, which are more purified, less immunogenic and absorbed orally and, anti-C3 antibodies, which are more powerful, but potentially less safe. Additionally, infusions of recombinant complement-regulatory proteins are a potential future therapy. PMID:24255888

Estimating infertility prevalence in low-to-middle-income countries: an application of a current duration approach to Demographic and Health Survey data

PubMed Central

Cox, Carie M.; Tunçalp, Özge; McLain, Alexander C.; Thoma, Marie E.

2017-01-01

Abstract STUDY QUESTION Can infertility prevalence be estimated using a current duration (CD) approach when applied to nationally representative Demographic and Health Survey (DHS) data collected routinely in low- or middle-income countries? SUMMARY ANSWER Our analysis suggests that a CD approach applied to DHS data from Nigeria provides infertility prevalence estimates comparable to other smaller studies in the same region. WHAT IS KNOWN ALREADY Despite associations with serious negative health, social and economic outcomes, infertility in developing countries is a marginalized issue in sexual and reproductive health. Obtaining reliable, nationally representative prevalence estimates is critical to address the issue, but methodological and resource challenges have impeded this goal. STUDY DESIGN, SIZE, DURATION This cross-sectional study was based on standard information available in the DHS core questionnaire and data sets, which are collected routinely among participating low-to-middle-income countries. Our research question was examined among women participating in the 2013 Nigeria DHS (n = 38 948). Among women eligible for the study, 98% were interviewed. PARTICIPANTS/MATERIALS, SETTING, METHODS We applied a CD approach (i.e. current length of time-at-risk of pregnancy) to estimate time-to-pregnancy (TTP) and 12-month infertility prevalence among women ‘at risk’ of pregnancy at the time of interview (n = 7063). Women who were 18–44 years old, married or cohabitating, sexually active within the past 4 weeks and not currently using contraception (and had not been sterilized) were included in the analysis. Estimates were based on parametric survival methods using bootstrap methods (500 bootstrap replicates) to obtain 95% CIs. MAIN RESULTS AND THE ROLE OF CHANCE The estimated median TTP among couples at risk of pregnancy was 5.1 months (95% CI: 4.2–6.3). The estimated percentage of infertile couples was 31.1% (95% CI: 27.9–34.7%)—consistent with other smaller studies from Nigeria. Primary infertility (17.4%, 95% CI: 12.9–23.8%) was substantially lower than secondary infertility (34.1%, 95% CI: 30.3–39.3%) in this population. Overall estimates for TTP >24 or >36 months dropped to 17.7% (95% CI: 15.7–20%) and 11.5% (95% CI: 10.2–13%), respectively. Subgroup analyses showed that estimates varied by age, coital frequency and fertility intentions, while being in a polygynous relationship showed minimal impact. LIMITATIONS, REASONS FOR CAUTION The CD approach may be limited by assumptions on when exposure to risk of pregnancy began and methodologic assumptions required for estimation, which may be less accurate for particular subgroups or populations. Unrecognized pregnancies may have also biased our findings; however, we attempted to address this in our exclusion criteria. Limiting to married/cohabiting couples may have excluded women who are no longer in a relationship after being blamed for infertility. Although probably rare in this setting, we lack information on couples undergoing infertility treatment. Like other TTP measurement approaches, pregnancies resulting from contraceptive failure are not included, which may bias estimates. WIDER IMPLICATIONS OF THE FINDINGS Nationally representative estimates of TTP and infertility based on a clinical definition of 12 months have been limited within developing countries. This approach represents a pragmatic advance in our ability to measure and monitor infertility in the developing world, with potentially far-reaching implications for policies and programs intended to address reproductive health. STUDY FUNDING/COMPETING INTERESTS There are no competing interests and no financial support was provided for this study. Financial support for Open Access publication was provided by the World Health Organization. PMID:28204493

Multicenter phase II study of irinotecan, cisplatin, and bevacizumab in patients with metastatic gastric or gastroesophageal junction adenocarcinoma.

PubMed

Shah, Manish A; Ramanathan, Ramesh K; Ilson, David H; Levnor, Alissa; D'Adamo, David; O'Reilly, Eileen; Tse, Archie; Trocola, Robin; Schwartz, Lawrence; Capanu, Marinela; Schwartz, Gary K; Kelsen, David P

2006-11-20

Bevacizumab improves survival in several solid tumor malignancies when combined with chemotherapy. We evaluated the efficacy and safety of the addition of bevacizumab to chemotherapy in the treatment of gastric and gastroesophageal junction (GEJ) adenocarcinoma. Forty-seven patients with metastatic or unresectable gastric/GEJ adenocarcinoma were treated with bevacizumab 15 mg/kg on day 1, irinotecan 65 mg/m2, and cisplatin 30 mg/m2 on days 1 and 8, every 21 days. The primary end point was to demonstrate a 50% improvement in time to progression over historical values. Secondary end points included safety, response, and survival. Patient characteristics were as follows: median age 59 years (range, 25 to 75); Karnofsky performance status 90% (70% to 100%); male:female, 34:13; and gastric/GEJ, 24:23. With a median follow-up of 12.2 months, median time to progression was 8.3 months (95% CI, 5.5 to 9.9 months). In 34 patients with measurable disease, the overall response rate was 65% (95% CI, 46% to 80%). Median survival was 12.3 months (95% CI, 11.3 to 17.2 months). We observed no increase in chemotherapy related toxicity. Possible bevacizumab-related toxicity included a 28% incidence of grade 3 hypertension, two patients with a gastric perforation and one patient with a near perforation (6%), and one patient with a myocardial infarction (2%). Grade 3 to 4 thromboembolic events occurred in 25% of patients. Although the primary tumor was unresected in 40 patients, we observed only one patient with a significant upper gastrointestinal bleed. Bevacizumab can be safely given with chemotherapy even with primary gastric and GEJ tumors in place. The response rate, time to disease progression (TTP), and overall survival are encouraging, with TTP improved over historical controls by 75%. Further development of bevacizumab in gastric and GEJ cancers is warranted.

High pressure dielectric studies on the structural and orientational glass.

PubMed

Kaminska, E; Tarnacka, M; Jurkiewicz, K; Kaminski, K; Paluch, M

2016-02-07

High pressure dielectric studies on the H-bonded liquid D-glucose and Orientationally Disordered Crystal (ODIC) 1,6-anhydro-D-glucose (levoglucosan) were carried out. It was shown that in both compounds, the structural relaxation is weakly sensitive to compression. It is well reflected in the low pressure coefficient of the glass transition and orientational glass transition temperatures which is equal to 60 K/GPa for both D-glucose and 1,6-anhydro-D-glucose. Although it should be noted that ∂Tg(0)/∂p evaluated for the latter compound seems to be enormously high with respect to other systems forming ODIC phase. We also found that the shape of the α-loss peak stays constant for the given relaxation time independently on the thermodynamic condition. Consequently, the Time Temperature Pressure (TTP) rule is satisfied. This experimental finding seems to be quite intriguing since the TTP rule was shown to work well in the van der Waals liquids, while in the strongly associating compounds, it is very often violated. We have also demonstrated that the sensitivity of the structural relaxation process to the temperature change measured by the steepness index (mp) drops with pressure. Interestingly, this change is much more significant in the case of D-glucose with respect to levoglucosan, where the fragility changes only slightly with compression. Finally, kinetics of ODIC-crystal phase transition was studied at high compression. It is worth mentioning that in the recent paper, Tombari and Johari [J. Chem. Phys. 142, 104501 (2015)] have shown that ODIC phase in 1,6-anhydro-D-glucose is stable in the wide range of temperatures and there is no tendency to form more ordered phase at ambient pressure. On the other hand, our isochronal measurements performed at varying thermodynamic conditions indicated unquestionably that the application of pressure favors solid (ODIC)-solid (crystal) transition in 1,6-anhydro-D-glucose. This result mimics the impact of pressure on the crystallization of fully disordered supercooled van der Waals liquids.

Systems Architectures for a Tactical Naval Command and Control System

DTIC Science & Technology

2009-03-01

Supplement TST Time-sensitive Targeting TTP Tactics, Techniques, and Procedures WTP Weapons-target pairing xix GLOSSARY Analysis...target pairings ( WTPs ) and are presented to OTC [a]. 24. OTC conducts risk assessment of engagement options [a]. 25. OTC orders confirmed surface...engagement options are generated through weapon- target pairings ( WTPs ) and are presented to OTC [a]. 24. OTC conducts risk assessment of engagement

Lessons Learned from the Afghan Mission Network: Developing a Coalition Contingency Network

DTIC Science & Technology

2014-01-01

SIPRNet Secret Internet Protocol Router Network SOP Standard Operating Procedure SVTC Secure Video Teleconference (or –Conferencing) TTP Tactics...Voice over internet protocol (VOIP) telephone connectivity • Email • Web browsing • Secure video teleconferencing (SVTC...10, 2012. As of January 15, 2013: http://www.guardian.co.uk/world/2012/oct/10/us-troops-jordan-syria-crisis Baldor, Lolita C., and Pauline Jelinek

Navigation with Atom Interferometers

DTIC Science & Technology

2017-03-20

cos(1[ 2 1)( ttP g g e    (1) where  2  is the zero detuning Rabi frequency,  is the atomic dipole moment, 22  g is the...generalized Rabi frequency and oL   is the detuning of the laser from the atomic transition. Distribution A: Approved for public release; distribution

SU-E-J-07: A Functional MR Protocol for the Pancreatic Tumor Delineation

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

Andreychenko, A; Heerkens, H; Meijer, G

2014-06-01

Purpose: Pancreatic cancer is one of the cancers with the poorest survival prognosis. At the time of diagnosis most of pancreatic cancers are unresectable and those patients can be treated by radiotherapy. Radiotherapy for pancreatic cancer is limited due to uncertainties in CT-based delineations. MRI provides an excellent soft tissue contrast. Here, an MR protocol is developed to improve delineations for radiotherapy treatment of pancreatic cancer. In a later stage this protocol can also be used for on-line visualization of the pancreas during MRI guided treatments. Methods: Nine pancreatic cancer patients were included. The MR protocol included T2 weighted(T2w), T1more » weighted(T1w), diffusion weighted(DWI) and dynamic contrast enhanced(DCE) techniques. The tumor was delineated on T2w and T1w MRI by an experienced radiation oncologist. Healthy pancreas or pancreatitis (assigned by the oncologist based on T2w) areas were also delineated. Apparent diffusion coefficient(ADC), and area under the curve(AUC)/time to peak(TTP) maps were obtained from DWI and DCE scans, respectively. Results: A clear demarcation of tumor area was visible on b800 DWI images in 5 patients. ADC maps of those patients characterized tumor as an area with restricted water diffusion. Tumor delineations based on solely DCE were possible in 7 patients. In 6 of those patients AUC maps demonstrated tumor heterogeneity: a hypointense area with a hyperintense ring. TTP values clearly discriminated the tumor and the healthy pancreas but could not distinguish tumor and the pancreatitis accurately. Conclusion: MR imaging results in a more pronounced tumor contrast than contrast enhanced CT. The addition of quantitative, functional MRI provides valuable, additional information to the radiation oncologist on the spatial tumor extent by discriminating tumor from the healthy pancreas(TTP, DWI) and characterizing the tumor(ADC). Our findings indicate that tumor delineation in pancreatic cancer can greatly benefit from the addition of MRI and especially functional MR techniques.« less

Association between coffee or caffeine consumption and fecundity and fertility: a systematic review and dose-response meta-analysis.

PubMed

Lyngsø, Julie; Ramlau-Hansen, Cecilia Høst; Bay, Bjørn; Ingerslev, Hans Jakob; Hulman, Adam; Kesmodel, Ulrik Schiøler

2017-01-01

The aim was to investigate whether coffee or caffeine consumption is associated with reproductive endpoints among women with natural fertility (ie, time to pregnancy [TTP] and spontaneous abortion [SAB]) and among women in fertility treatment (ie, clinical pregnancy rate or live birth rate). This study was a systematic review and dose-response meta-analysis including data from case-control and cohort studies. An extensive literature search was conducted in MEDLINE and Embase, with no time and language restrictions. Also, reference lists were searched manually. Two independent reviewers assessed the manuscript quality using the Newcastle-Ottawa Scale (NOS). A two-stage dose-response meta-analysis was applied to assess a potential association between coffee/caffeine consumption and the outcomes: TTP, SAB, clinical pregnancy, and live birth. Heterogeneity between studies was assessed using Cochrane Q -test and I 2 statistics. Publication bias was assessed using Egger's regression test. The pooled results showed that coffee/caffeine consumption is associated with a significantly increased risk of SAB for 300 mg caffeine/day (relative risk [RR]: 1.37, 95% confidence interval [95% CI]: 1.19; 1.57) and for 600 mg caffeine/day (RR: 2.32, 95% CI: 1.62; 3.31). No association was found between coffee/caffeine consumption and outcomes of fertility treatment (based on two studies). No clear association was found between exposure to coffee/caffeine and natural fertility as measured by fecundability odds ratio (based on three studies) or waiting TTP (based on two studies). Results from this meta-analysis support the growing evidence of an association between coffee/caffeine intake and the risk of SAB. However, viewing the reproductive capacity in a broader perspective, there seems to be little, if any, association between coffee/caffeine consumption and fecundity. In general, results from this study are supportive of a precautionary principle advised by health organizations such as European Food Safety Authority (EFSA) and World Health Organization (WHO), although the advised limit of a maximum of two to three cups of coffee/200-300 mg caffeine per day may be too high.

Balancing Antiviral Potency and Host Toxicity: Identifying a Nucleotide Inhibitor with an Optimal Kinetic Phenotype for HIV-1 Reverse Transcriptase

PubMed Central

Sohl, Christal D.; Kasiviswanathan, Rajesh; Kim, Jiae; Pradere, Ugo; Schinazi, Raymond F.; Copeland, William C.; Mitsuya, Hiroaki; Baba, Masanori

2012-01-01

Two novel thymidine analogs, 3′-fluoro-3′-deoxythymidine (FLT) and 2′,3′-didehydro-3′-deoxy-4′-ethynylthymidine (Ed4T), have been investigated as nucleoside reverse transcriptase inhibitors (NRTIs) for treatment of HIV infection. Ed4T seems very promising in phase II clinical trials, whereas toxicity halted FLT development during this phase. To understand these different molecular mechanisms of toxicity, pre–steady-state kinetic studies were used to examine the interactions of FLT and Ed4T with wild-type (WT) human mitochondrial DNA polymerase γ (pol γ), which is often associated with NRTI toxicity, as well as the viral target protein, WT HIV-1 reverse transcriptase (RT). We report that Ed4T-triphosphate (TP) is the first analog to be preferred over native nucleotides by RT but to experience negligible incorporation by WT pol γ, with an ideal balance between high antiretroviral efficacy and minimal host toxicity. WT pol γ could discriminate Ed4T-TP from dTTP 12,000-fold better than RT, with only an 8.3-fold difference in discrimination being seen for FLT-TP. A structurally related NRTI, 2′,3′-didehydro-2′,3′-dideoxythymidine, is the only other analog favored by RT over native nucleotides, but it exhibits only a 13-fold difference (compared with 12,000-fold for Ed4T) in discrimination between the two enzymes. We propose that the 4′-ethynyl group of Ed4T serves as an enzyme selectivity moiety, critical for discernment between RT and WT pol γ. We also show that the pol γ mutation R964C, which predisposes patients to mitochondrial toxicity when receiving 2′,3′-didehydro-2′,3′-dideoxythymidine to treat HIV, produced some loss of discrimination for FLT-TP and Ed4T-TP. These molecular mechanisms of analog incorporation, which are critical for understanding pol γ-related toxicity, shed light on the unique toxicity profiles observed during clinical trials. PMID:22513406

Right ventricular mechanics in hypertrophic cardiomyopathy using feature tracking

PubMed Central

Badran, Hala Mahfouz; Soliman, Mahmood; Hassan, Hesham; Abdelfatah, Raed; Saadan, Haythem; Yacoub, Magdi

2013-01-01

Objectives: Right ventricular (RV) mechanics in hypertrophic cardiomyopathy (HCM) are poorly understood. We investigate global and regional deformation of the RV in HCM and its relationship to LV phenotype, using 2D strain vector velocity imaging (VVI). Methods: 100 HCM patients (42% females, 41 ± 19 years) and 30 control patients were studied using VVI. Longitudinal peak systolic strain (ϵsys), strain rate (SR), time to peak (ϵ) (TTP), displacement of RV free wall (RVFW) and septal wall were analyzed. Similar parameters were quantified in LV septal, lateral, anterior and inferior segments. Intra-V-delay was defined as SD of TTP. Inter-V-delay was estimated from TTP difference between the most delayed LV segment & RVFW. Results: ϵsys and SR of both RV & LV, showed loss of base to apex gradient and significant decline in HCM (p < 0.001). Deformation variables estimated from RVFW were strongly correlated with each other (r = 0.93, p < 0.0001). Both were directly related to LV ϵsys, SRsys, SRe, ejection fraction (EF)%, RVFW displacement (P < 0.001) and inversely related to age, positive family history (p < 0.004, 0.005), RV wall thickness, maximum wall thickness (MWT), intra-V-delay, LA volume (P < 0.0001), LVOT gradient (p < 0.02, 0.005) respectively. ROC curves were constructed to explore the cut-off point that discriminates RV dysfunction. Global and RVFW ϵsys: − 19.5% shows 77, 70% sensitivity & 97% specificity, SRsys: − 1.3s− 1 shows 82, 70% sensitivity & 30% specificity. Multivariate analyses revealed that RVFW displacement (β = − 0.9, p < 0.0001) and global LV SRsys (β = 5.9, p < 0.0001) are independent predictors of global RV deformation. Conclusions: Impairment of RV deformation is evident in HCM using feature tracking. It is independently influenced by LV mechanics and correlated to the severity of LV phenotype. RVFW deformation analysis and global RV assessment are comparable. PMID:24689019

Bevacizumab continuation versus no continuation after first-line chemotherapy plus bevacizumab in patients with metastatic colorectal cancer: a randomized phase III non-inferiority trial (SAKK 41/06).

PubMed

Koeberle, D; Betticher, D C; von Moos, R; Dietrich, D; Brauchli, P; Baertschi, D; Matter, K; Winterhalder, R; Borner, M; Anchisi, S; Moosmann, P; Kollar, A; Saletti, P; Roth, A; Frueh, M; Kueng, M; Popescu, R A; Schacher, S; Hess, V; Herrmann, R

2015-04-01

Chemotherapy plus bevacizumab is a standard option for first-line treatment in metastatic colorectal cancer (mCRC) patients. We assessed whether no continuation is non-inferior to continuation of bevacizumab after completing first-line chemotherapy. In an open-label, phase III multicentre trial, patients with mCRC without disease progression after 4-6 months of standard first-line chemotherapy plus bevacizumab were randomly assigned to continuing bevacizumab at a standard dose or no treatment. CT scans were done every 6 weeks until disease progression. The primary end point was time to progression (TTP). A non-inferiority limit for hazard ratio (HR) of 0.727 was chosen to detect a difference in TTP of 6 weeks or less, with a one-sided significance level of 10% and a statistical power of 85%. The intention-to-treat population comprised 262 patients: median follow-up was 36.7 months. The median TTP was 4.1 [95% confidence interval (CI) 3.1-5.4] months for bevacizumab continuation versus 2.9 (95% CI 2.8-3.8) months for no continuation; HR 0.74 (95% CI 0.58-0.96). Non-inferiority could not be demonstrated. The median overall survival was 25.4 months for bevacizumab continuation versus 23.8 months (HR 0.83; 95% CI 0.63-1.1; P = 0.2) for no continuation. Severe adverse events were uncommon in the bevacizumab continuation arm. Costs for bevacizumab continuation were estimated to be ∼30,000 USD per patient. Non-inferiority could not be demonstrated for treatment holidays versus continuing bevacizumab monotheray, after 4-6 months of standard first-line chemotherapy plus bevacizumab. Based on no impact on overall survival and increased treatment costs, bevacizumab as a single agent is of no meaningful therapeutic value. More efficient treatment approaches are needed to maintain control of stabilized disease following induction therapy. ClinicalTrials.gov, number NCT00544700. © The Author 2015. 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.

Phase III Noninferiority Trial Comparing Irinotecan With Oxaliplatin, Fluorouracil, and Leucovorin in Patients With Advanced Colorectal Carcinoma Previously Treated With Fluorouracil: N9841

PubMed Central

Kim, George P.; Sargent, Daniel J.; Mahoney, Michelle R.; Rowland, Kendrith M.; Philip, Philip A.; Mitchell, Edith; Mathews, Abraham P.; Fitch, Tom R.; Goldberg, Richard M.; Alberts, Steven R.; Pitot, Henry C.

2009-01-01

Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m2 every 3 weeks) or arm B (FOLFOX4). Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias. Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy. PMID:19380443

Phase III randomized study of radiation and temozolomide versus radiation and nitrosourea therapy for anaplastic astrocytoma: results of NRG Oncology RTOG 9813.

PubMed

Chang, Susan; Zhang, Peixin; Cairncross, J Gregory; Gilbert, Mark R; Bahary, Jean-Paul; Dolinskas, Carol A; Chakravarti, Arnab; Aldape, Kenneth D; Bell, Erica H; Schiff, David; Jaeckle, Kurt; Brown, Paul D; Barger, Geoffrey R; Werner-Wasik, Maria; Shih, Helen; Brachman, David; Penas-Prado, Marta; Robins, H Ian; Belanger, Karl; Schultz, Christopher; Hunter, Grant; Mehta, Minesh

2017-02-01

The primary objective of this study was to compare the overall survival (OS) of patients with anaplastic astrocytoma (AA) treated with radiotherapy (RT) and either temozolomide (TMZ) or a nitrosourea (NU). Secondary endpoints were time to tumor progression (TTP), toxicity, and the effect of IDH1 mutation status on clinical outcome. Eligible patients with centrally reviewed, histologically confirmed, newly diagnosed AA were randomized to receive either RT+TMZ (n = 97) or RT+NU (n = 99). The study closed early because the target accrual rate was not met. Median follow-up time for patients still alive was 10.1 years (1.9-12.6 y); 66% of the patients died. Median survival time was 3.9 years in the RT/TMZ arm (95% CI, 3.0-7.0) and 3.8 years in the RT/NU arm (95% CI, 2.2-7.0), corresponding to a hazard ratio (HR) of 0.94 (P = .36; 95% CI, 0.67-1.32). The differences in progression-free survival (PFS) and TTP between the 2 arms were not statistically significant. Patients in the RT+NU arm experienced more grade ≥3 toxicity (75.8% vs 47.9%, P < .001), mainly related to myelosuppression. Of the 196 patients, 111 were tested for IDH1-R132H status (60 RT+TMZ and 51 RT+NU). Fifty-four patients were IDH negative and 49 were IDH positive with a better OS in IDH-positive patients (median survival time 7.9 vs 2.8 y; P = .004, HR = 0.50; 95% CI, 0.31-0.81). RT+TMZ did not appear to significantly improve OS or TTP for AA compared with RT+ NU. RT+TMZ was better tolerated. IDH1-R132H mutation was associated with longer survival. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Association between coffee or caffeine consumption and fecundity and fertility: a systematic review and dose–response meta-analysis

PubMed Central

Lyngsø, Julie; Ramlau-Hansen, Cecilia Høst; Bay, Bjørn; Ingerslev, Hans Jakob; Hulman, Adam; Kesmodel, Ulrik Schiøler

2017-01-01

Objective The aim was to investigate whether coffee or caffeine consumption is associated with reproductive endpoints among women with natural fertility (ie, time to pregnancy [TTP] and spontaneous abortion [SAB]) and among women in fertility treatment (ie, clinical pregnancy rate or live birth rate). Design This study was a systematic review and dose–response meta-analysis including data from case–control and cohort studies. Methods An extensive literature search was conducted in MEDLINE and Embase, with no time and language restrictions. Also, reference lists were searched manually. Two independent reviewers assessed the manuscript quality using the Newcastle–Ottawa Scale (NOS). A two-stage dose–response meta-analysis was applied to assess a potential association between coffee/caffeine consumption and the outcomes: TTP, SAB, clinical pregnancy, and live birth. Heterogeneity between studies was assessed using Cochrane Q-test and I2 statistics. Publication bias was assessed using Egger’s regression test. Results The pooled results showed that coffee/caffeine consumption is associated with a significantly increased risk of SAB for 300 mg caffeine/day (relative risk [RR]: 1.37, 95% confidence interval [95% CI]: 1.19; 1.57) and for 600 mg caffeine/day (RR: 2.32, 95% CI: 1.62; 3.31). No association was found between coffee/caffeine consumption and outcomes of fertility treatment (based on two studies). No clear association was found between exposure to coffee/caffeine and natural fertility as measured by fecundability odds ratio (based on three studies) or waiting TTP (based on two studies). Conclusion Results from this meta-analysis support the growing evidence of an association between coffee/caffeine intake and the risk of SAB. However, viewing the reproductive capacity in a broader perspective, there seems to be little, if any, association between coffee/caffeine consumption and fecundity. In general, results from this study are supportive of a precautionary principle advised by health organizations such as European Food Safety Authority (EFSA) and World Health Organization (WHO), although the advised limit of a maximum of two to three cups of coffee/200–300 mg caffeine per day may be too high. PMID:29276412

Stimulation of the penetration of particles into the skin by plasma tissue interaction

NASA Astrophysics Data System (ADS)

Lademann, O.; Richter, H.; Kramer, A.; Patzelt, A.; Meinke, M. C.; Graf, C.; Gao, Q.; Korotianskiy, E.; Rühl, E.; Weltmann, K.-D.; Lademann, J.; Koch, S.

2011-10-01

A high number of treatments in dermatology are based on the penetration of topically applied drugs through the skin barrier. This process is predominantly inefficient, on account of the strong protection properties of the upper skin layer - the stratum corneum. If the skin barrier is damaged, the penetration efficiency of topically applied drugs increases. Therefore, different methods have been developed to influence the barrier properties of the skin. Recently, it could be demonstrated that a cold tissue tolerable plasma (TTP) produced by a plasma-jet can strongly enhance drug delivery through the skin. These investigations were performed by using a solution of fluorescent dye as a model drug. In the present study, these investigations were carried out using fluorescent silica particles at different sizes. The aim of the study was to investigate whether or not there is a limitation in size for topically applied substances to pass through the skin barrier after plasma treatment.

Influence of harvest residues and vegetation on microsite soil and air temperatures in a young conifer plantation.

Treesearch

W.D. Devine; C.A. Harrington

2007-01-01

This study examines the effects of bole-only harvesting with and without vegetation control (BO+VC; BO-VC) and total-tree harvesting plus removal of legacy woody debris with vegetation control (TTP+VC) on microsite soil and air temperatures in a young Douglas-fir plantation. Mean soil temperature and the diurnal range in soil temperature during the growing season...

Development of a Portable Test Kit for Field-Screening Paints

DTIC Science & Technology

1986-01-01

Use) rods. TT-P-002119 Paint, Latex Base, High Traffic Areas, Flat and Eggshell Finish Discussion (Low Lustre, For Interior Use) The applications...testing uniformity in different clean. Eggshell or flat surfaces have more pigment than laboratories. Although the methods are designed to vehicle on...samples (Table 12) were selected from the useful for determining the gloss of eggshell , semigloss, series to represent the range of gloss (glossy

Thrombotic thrombocytopenic purpura presenting with pathologic fracture: a case report.

PubMed

Berber, Ilhami; Erkurt, Mehmet Ali; Kuku, Irfan; Kaya, Emin; Unlu, Serkan; Ertem, Kadir; Nizam, Ilknur

2014-08-01

Thrombotic thrombocytopenic purpura is an acute syndrome with abnormalities in multiple organ systems, which becomes manifest with microangiopathic hemolytic anemia and thrombocytopenia. The hereditary or acquired deficiency of ADAMTS-13 activity leads to an excess of high molecular weight von Willebrand factor multimers in plasma, leading to platelet aggregation and diffuse intravascular thrombus formation, resulting in thrombotic thrombocytopenic purpura. Thrombotic lesions occurring in TTP leads to ischemia and convulsion. Depending on the properties of the bony tissue, fractures are divided into three groups as traumatic, pathological, and stress fractures. A pathologic fracture is a broken bone caused by disease leading to weakness of the bone. This process is most commonly due to osteoporosis, but may also be due to other pathologies such as cancer, infections, inherited bone disorders, or a bone cyst. We herein report a case with a pathologic fracture due to convulsion secondary to thrombotic thrombocytopenic pupura. Thrombotic lesions occurring in TTP may lead to ischemia and convulsion, as in our patient and pathological fractures presented in our case report may occur as a result of severe muscle contractions associated with convulsive activity. Thrombotic thrombocytopenic pupura is a disease that involves many organ systems and thus may have a very wide spectrum of clinical presentations. Copyright © 2014. Published by Elsevier Ltd.

Predicting phenolic acid absorption in Caco-2 cells: a theoretical permeability model and mechanistic study.

PubMed

Farrell, Tracy L; Poquet, Laure; Dew, Tristan P; Barber, Stuart; Williamson, Gary

2012-02-01

There is a considerable need to rationalize the membrane permeability and mechanism of transport for potential nutraceuticals. The aim of this investigation was to develop a theoretical permeability equation, based on a reported descriptive absorption model, enabling calculation of the transcellular component of absorption across Caco-2 monolayers. Published data for Caco-2 permeability of 30 drugs transported by the transcellular route were correlated with the descriptors 1-octanol/water distribution coefficient (log D, pH 7.4) and size, based on molecular mass. Nonlinear regression analysis was used to derive a set of model parameters a', β', and b' with an integrated molecular mass function. The new theoretical transcellular permeability (TTP) model obtained a good fit of the published data (R² = 0.93) and predicted reasonably well (R² = 0.86) the experimental apparent permeability coefficient (P(app)) for nine non-training set compounds reportedly transported by the transcellular route. For the first time, the TTP model was used to predict the absorption characteristics of six phenolic acids, and this original investigation was supported by in vitro Caco-2 cell mechanistic studies, which suggested that deviation of the P(app) value from the predicted transcellular permeability (P(app)(trans)) may be attributed to involvement of active uptake, efflux transporters, or paracellular flux.

Contrasting Pathology of the Stress Granule Proteins TIA-1 and G3BP in Tauopathies

PubMed Central

Vanderweyde, Tara; Yu, Haung; Varnum, Megan; Liu-Yesucevitz, Liqun; Citro, Allison; Ikezu, Tsuneya; Duff, Karen; Wolozin, Benjamin

2012-01-01

Stress induces aggregation of RNA-binding proteins to form inclusions, termed stress granules (SGs). Recent evidence suggests that SG proteins also colocalize with neuropathological structures, but whether this occurs in Alzheimer’s disease is unknown. We examined the relationship between SG proteins and neuropathology in brain tissue from P301L Tau transgenic mice, as well as in cases of Alzheimer’s disease and FTDP-17. The pattern of SG pathology differs dramatically based on the RNA-binding protein examined. SGs positive for T-cell intracellular antigen-1 (TIA-1) or tristetraprolin (TTP) initially do not colocalize with tau pathology, but then merge with tau inclusions as disease severity increases. In contrast, G3BP (ras GAP-binding protein) identifies a novel type of molecular pathology that shows increasing accumulation in neurons with increasing disease severity, but often is not associated with classic markers of tau pathology. TIA-1 and TTP both bind phospho-tau, and TIA-1 overexpression induces formation of inclusions containing phospho-tau. These data suggest that SG formation might stimulate tau pathophysiology. Thus, study of RNA-binding proteins and SG biology highlights novel pathways interacting with the pathophysiology of AD, providing potentially new avenues for identifying diseased neurons and potentially novel mechanisms regulating tau biology. PMID:22699908

Transgene Expression of Drosophila melanogaster Nucleoside Kinase Reverses Mitochondrial Thymidine Kinase 2 Deficiency*♦

PubMed Central

Krishnan, Shuba; Zhou, Xiaoshan; Paredes, João A.; Kuiper, Raoul V.; Curbo, Sophie; Karlsson, Anna

2013-01-01

A strategy to reverse the symptoms of thymidine kinase 2 (TK2) deficiency in a mouse model was investigated. The nucleoside kinase from Drosophila melanogaster (Dm-dNK) was expressed in TK2-deficient mice that have been shown to present with a severe phenotype caused by mitochondrial DNA depletion. The Dm-dNK+/− transgenic mice were shown to be able to rescue the TK2-deficient mice. The Dm-dNK+/−TK2−/− mice were normal as judged by growth and behavior during the observation time of 6 months. The Dm-dNK-expressing mice showed a substantial increase in thymidine-phosphorylating activity in investigated tissues. The Dm-dNK expression also resulted in highly elevated dTTP pools. The dTTP pool alterations did not cause specific mitochondrial DNA mutations or deletions when 6-month-old mice were analyzed. The mitochondrial DNA was also detected at normal levels. In conclusion, the Dm-dNK+/−TK2−/− mouse model illustrates how dTMP synthesized in the cell nucleus can compensate for loss of intramitochondrial dTMP synthesis in differentiated tissue. The data presented open new possibilities to treat the severe symptoms of TK2 deficiency. PMID:23288848

Photodynamics of intramolecular proton transfer in polar and nonpolar biflavonoid solutions

NASA Astrophysics Data System (ADS)

Bondarev, S. L.; Knyukshto, V. N.; Tikhomirov, S. A.; Buganov, O. V.; Pyrko, A. N.

2012-10-01

Using methods of steady state luminescence and femtosecond spectroscopy, we have studied the mechanism of intramolecular proton transfer in synthesized 3,7-dihydroxy-2,8-di(4-methoxyphenyl)-4H,6H-pyrano[3,2- g]chromen-4,6-dion in polar and nonpolar solutions, films, and polycrystals at 293 and 77 K. In an excited singlet state, intramolecular proton transfer occurs in two stages. At the first stage, a tautomer with one transferred proton (OTP tautomer) is formed from the Franck-Condon state within τ1 = 0.6 ps. At the second stage, the second proton is transferred within τ2 = 3.1 ps and a tautomer with two transferred protons (TTP tautomer) is formed, which fluoresces in toluene at 293 K with a high quantum yield, Φ f = 0.66, and the fluorescence spectrum of which is characterized by a large Stokes shift, 9900 cm-1. At 293 K, polar solvents (dimethylformamide, dimethyl sulfoxide, ethanol, etc.) solvate the BFV molecule in the ground state, while, in the excited state, an OTP tautomer is mainly formed. In polar ethanol at 77 K, a dual fluorescence spectrum is observed, which is caused by the fluorescence emission of polysolvates with λ{max/ f } = 460 nm and TTP phototautomers at λ{max/ f }= 610 nm.

Towards an evaluation framework for Laboratory Information Systems.

PubMed

Yusof, Maryati M; Arifin, Azila

Laboratory testing and reporting are error-prone and redundant due to repeated, unnecessary requests and delayed or missed reactions to laboratory reports. Occurring errors may negatively affect the patient treatment process and clinical decision making. Evaluation on laboratory testing and Laboratory Information System (LIS) may explain the root cause to improve the testing process and enhance LIS in supporting the process. This paper discusses a new evaluation framework for LIS that encompasses the laboratory testing cycle and the socio-technical part of LIS. Literature review on discourses, dimensions and evaluation methods of laboratory testing and LIS. A critical appraisal of the Total Testing Process (TTP) and the human, organization, technology-fit factors (HOT-fit) evaluation frameworks was undertaken in order to identify error incident, its contributing factors and preventive action pertinent to laboratory testing process and LIS. A new evaluation framework for LIS using a comprehensive and socio-technical approach is outlined. Positive relationship between laboratory and clinical staff resulted in a smooth laboratory testing process, reduced errors and increased process efficiency whilst effective use of LIS streamlined the testing processes. The TTP-LIS framework could serve as an assessment as well as a problem-solving tool for the laboratory testing process and system. Copyright © 2016 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Lutetium(iii) aqua ion: On the dynamical structure of the heaviest lanthanoid hydration complex

NASA Astrophysics Data System (ADS)

Sessa, Francesco; Spezia, Riccardo; D'Angelo, Paola

2016-05-01

The structure and dynamics of the lutetium(iii) ion in aqueous solution have been investigated by means of a polarizable force field molecular dynamics (MD). An 8-fold square antiprism (SAP) geometry has been found to be the dominant configuration of the lutetium(iii) aqua ion. Nevertheless, a low percentage of 9-fold complexes arranged in a tricapped trigonal prism (TTP) geometry has been also detected. Dynamic properties have been explored by carrying out six independent MD simulations for each of four different temperatures: 277 K, 298 K, 423 K, 632 K. The mean residence time of water molecules in the first hydration shell at room temperature has been found to increase as compared to the central elements of the lanthanoid series in agreement with previous experimental findings. Water exchange kinetic rate constants at each temperature and activation parameters of the process have been determined from the MD simulations. The obtained structural and dynamical results suggest that the water exchange process for the lutetium(iii) aqua ion proceeds with an associative mechanism, in which the SAP hydration complex undergoes temporary structural changes passing through a 9-fold TTP intermediate. Such results are consistent with the water exchange mechanism proposed for heavy lanthanoid atoms.

The ESA TTP and Recent Spin-off Successes

NASA Astrophysics Data System (ADS)

Raitt, D.; Brisson, P.

2002-01-01

In the framework of its research and development activities, the European Space Agency (ESA) spends some 250m each year and, recognizing the enormous potential of the know-how developed within its R&D activities, set up a Technology Transfer Programme (TTP) some twelve years ago. Over the years, the Programme has achieved some remarkable results with 120 successful transfers of space technologies to the non-space sector; over 120m received by companies making the technologies available; some 15 new companies established as a direct result of exploiting technologies; nearly 2500 jobs created or saved in Europe; and a portfolio of some 300 (out of over 600) active space technologies available for transfer and licencing. Some of the more recent technologies which have been successfully transferred to the non-space sector include the Mamagoose baby safety pyjamas; a spectrographic system being used to compare colours in fabrics and textiles; Earth observation technology employed to assess remotely how much agrochemicals are being used by farmers; and the Dutch solar car, Nuna, which, using European space technologies, finished first in the 2001 World Solar Challenge breaking all records. The paper will give a brief overview of the ESA Technology Transfer Programme and describe some of its recent successful technology transfers.

Lutetium(III) aqua ion: On the dynamical structure of the heaviest lanthanoid hydration complex

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

Sessa, Francesco; D’Angelo, Paola, E-mail: p.dangelo@uniroma1.it; Spezia, Riccardo

2016-05-28

The structure and dynamics of the lutetium(III) ion in aqueous solution have been investigated by means of a polarizable force field molecular dynamics (MD). An 8-fold square antiprism (SAP) geometry has been found to be the dominant configuration of the lutetium(III) aqua ion. Nevertheless, a low percentage of 9-fold complexes arranged in a tricapped trigonal prism (TTP) geometry has been also detected. Dynamic properties have been explored by carrying out six independent MD simulations for each of four different temperatures: 277 K, 298 K, 423 K, 632 K. The mean residence time of water molecules in the first hydration shellmore » at room temperature has been found to increase as compared to the central elements of the lanthanoid series in agreement with previous experimental findings. Water exchange kinetic rate constants at each temperature and activation parameters of the process have been determined from the MD simulations. The obtained structural and dynamical results suggest that the water exchange process for the lutetium(III) aqua ion proceeds with an associative mechanism, in which the SAP hydration complex undergoes temporary structural changes passing through a 9-fold TTP intermediate. Such results are consistent with the water exchange mechanism proposed for heavy lanthanoid atoms.« less

Lutetium(iii) aqua ion: On the dynamical structure of the heaviest lanthanoid hydration complex.

PubMed

Sessa, Francesco; Spezia, Riccardo; D'Angelo, Paola

2016-05-28

The structure and dynamics of the lutetium(iii) ion in aqueous solution have been investigated by means of a polarizable force field molecular dynamics (MD). An 8-fold square antiprism (SAP) geometry has been found to be the dominant configuration of the lutetium(iii) aqua ion. Nevertheless, a low percentage of 9-fold complexes arranged in a tricapped trigonal prism (TTP) geometry has been also detected. Dynamic properties have been explored by carrying out six independent MD simulations for each of four different temperatures: 277 K, 298 K, 423 K, 632 K. The mean residence time of water molecules in the first hydration shell at room temperature has been found to increase as compared to the central elements of the lanthanoid series in agreement with previous experimental findings. Water exchange kinetic rate constants at each temperature and activation parameters of the process have been determined from the MD simulations. The obtained structural and dynamical results suggest that the water exchange process for the lutetium(iii) aqua ion proceeds with an associative mechanism, in which the SAP hydration complex undergoes temporary structural changes passing through a 9-fold TTP intermediate. Such results are consistent with the water exchange mechanism proposed for heavy lanthanoid atoms.

Quantification of Circulating Clonal Plasma Cells via Multiparametric Flow Cytometry Identifies Patients with Smoldering Multiple Myeloma at High Risk of Progression

PubMed Central

Gonsalves, Wilson I.; Rajkumar, S. Vincent; Dispenzieri, Angela; Dingli, David; Timm, Michael M.; Morice, William G.; Lacy, Martha Q.; Buadi, Francis K.; Go, Ronald S.; Leung, Nelson; Kapoor, Prashant; Hayman, Suzanne R.; Lust, John A.; Russell, Stephen J.; Zeldenrust, Steven R.; Hwa, Lisa; Kourelis, Taxiarchis V.; Kyle, Robert A.; Gertz, Morie A.; Kumar, Shaji K.

2017-01-01

The presence of high numbers of circulating clonal plasma cells (cPCs) in patients with smoldering multiple myeloma (SMM), detected by a slide-based immunofluorescence assay, has been associated with a shorter time to progression (TTP) to multiple myeloma (MM). The significance of quantifying cPCs via multiparameter flow cytometry, a much more readily available diagnostic modality, in patients with SMM has not been evaluated. This study evaluated 100 patients with a known or new diagnosis of SMM who were seen at the Mayo Clinic, Rochester from January 2008 until December 2013. Patients with ≥ 150 cPCs (N = 9) were considered to have high number of cPCs based on the 97% specificity and 78% PPV of progression to MM within 2 years of cPC assessment. The median TTP of patients with ≥ 150 cPCs was 9 months compared to not reached for patients with < 150 cPCs (P < 0.001). Thus, quantification of cPCs via multiparametric flow cytometry identifies patients with SMM at very high risk of progression to MM within 2 years and warrants confirmation in larger studies. In the future, this may allow reclassification of such patients as having MM requiring therapy prior to them enduring end-organ damage. PMID:27457702

Effective and Efficient Training and Advising in Pakistan

DTIC Science & Technology

2010-06-01

the TTP’s violent tactics nevertheless see the TTP as a beneficial alternative to a government whose reach is too limited. 25 NEFA , “Interview...with Haji Muslim Khan: Chief Spokesman for the Tehrik e Taliban, Swat Valley,” NEFA Foundation, http://www1.nefafoundation.org/multimedia-intvu.html...2009. NEFA . “Interview with Haji Muslim Khan: Chief Spokesman for the Tehrik e Taliban, Swat Valley.” NEFA Foundation, http://www1.nefafoundation.org

Assembling Components with Aspect-Oriented Modeling/Specification

DTIC Science & Technology

2003-10-01

2 COM: Component Object Mod 3 EJB: Enterprise Java Beans, h 4 CCM: CORBA® Component M 5 http...nt (GM of the co mbly of ct weav el, http: ttp:// java odel, htFigure 2: Connector as a Containertructure in the form of framework, which...assembles components in EJB3 , CCM4; or a package, using such way as manifest file to JavaBeans5. Also such connector in some cases plays the role as

EFFECTS OF EXTREME AND UNUSUAL CONDITIONS ON LANA ALLOYS: INTERIM REPORT, FY14 (U)

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

Shanahan, Kirk L.

2014-04-25

The TTP proposed research aimed at determining: a) the rate at which these changes occurred and the effect of initial conditions, especially in the early phases of Hydrogen Heat Treatment (HHT), b) whether or not different LANA alloys would show similar effects, and c) whether common contaminants/poisons impacted LANA alloy hydride chemistry similarly to what had been found for Pd and Pd-alloy hydride chemistry.

Characterization of Vertical Impact Device Acceleration Pulses Using Parametric Assessment: Phase IV Dual Impact Pulses

DTIC Science & Technology

2017-01-04

response, including the time for reviewing instructions, searching existing data sources, searching existing data sources, gathering and maintaining...configurations with a restrained manikin, was evaluated in four different test series . Test Series 1 was conducted to determine the materials and...5 ms TTP. Test Series 2 was conducted to determine the materials and drop heights required for energy attenuation of the seat pan to generate a 4 m

Maternal exposure to perfluorinated chemicals and reduced fecundity: the MIREC study.

PubMed

Vélez, M P; Arbuckle, T E; Fraser, W D

2015-03-01

What is the effect of maternal exposure to perfluorooctane sulfonate (PFOS), perflurooctanoic acid (PFOA) and perfluorohexane sulfonate (PFHxS) on female fecundity? Increasing concentrations of PFOA or PFHxS in maternal plasma were associated with reduced fecundability and infertility. Perfluorinated chemicals (PFCs) are a group of synthetic compounds used in industrial production. There is a concern about the effect of PFCs on fecundity, as measured by time-to-pregnancy (TTP). Although some recent studies suggest that increasing concentrations of PFCs may decrease fecundity, divergence in the methodological approaches used to evaluate this association have prevented firm conclusions being reached. The Maternal-Infant Research on Environmental Chemicals (MIREC) Study is a cohort study of 2,001 women recruited before 14 weeks of gestation in 10 cities across Canada between 2008 and 2011. A questionnaire was administered and medical chart data and biospecimens were collected from participants. After excluding women who withdrew, those for whom data were incomplete, those whose pregnancies followed birth control failure, and accounting for male fertility, 1743 participants remained. TTP was defined as the number of months of unprotected intercourse needed to become pregnant in the current pregnancy, as self-reported in the first trimester of pregnancy. Plasma concentrations of PFOA, PFOS and PFHxS measured in the first trimester were considered as a surrogate of preconception exposure. Fecundability odds ratios (FORs) were estimated using Cox proportional hazard models for discrete time. FOR < 1 denote a longer TTP and FORs >1 denote a shorter TTP. The odds of infertility (TTP > 12 months or infertility treatment in the index pregnancy) were estimated using logistic regression. Each chemical concentration (ng/ml) was log-transformed and divided by its SD. The cumulative probabilities of pregnancy at 1, 6 and 12 months were 0.42 (95% confidence interval (CI) 0.40-0.45), 0.81 (95% CI 0.79-0.83) and 0.90 (95% CI 0.89-0.92), respectively. The mean maternal age was 32.8 (SD 5.0) years. The geometric means (ng/ml) of PFOA, PFOS and PFHxS were 1.66 (95% CI 1.61-1.71), 4.59 (95% CI 4.46-4.72) and 1.01 (95% CI 0.97-1.05), respectively. After adjustment for potential confounders, PFOA and PFHxS were associated with a 11 and 9% reduction in fecundability per one SD increase (FOR = 0.89; 95% CI 0.83-0.94; P < 0.001 for PFOA and FOR = 0.91; 95% CI 0.86-0.97; P = 0.002 for PFHxS), while no significant association was observed for PFOS (FOR = 0.96; 95% CI 0.91-1.02; P = 0.17). In addition, the odds of infertility increased by 31% per one SD increase of PFOA (odds ratio (OR) = 1.31; 95% CI 1.11-1.53; P = 0.001) and by 27% per one SD increase of PFHxS (OR = 1.27; 95% CI 1.09-1.48; P = 0.003), while no significant association was observed for PFOS (OR = 1.14; 95% CI 0.98-1.34; P = 0.09). Women with the highest concentrations of PFCs might have been excluded from the study if there is a causal association with infertility. The MIREC study did not assess concentrations of PFCs in males, semen quality, menstrual cycle characteristics or intercourse frequency. Our results add to the evidence that exposure to PFOA and PFHxS, even at lower levels than previously reported, may reduce fecundability. The MIREC study is supported by the Chemicals Management Plan of Health Canada, the Canadian Institutes for Health Research (CIHR, grant no. MOP - 81285) and the Ontario Ministry of the Environment. M.P.V. was supported by a CIHR Fellowship Award, and a CIHR-Quebec Training Network in Perinatal Research (QTNPR) Ph.D. scholarship. W.D.F. is supported by a CIHR Canada Research Chair. There are no conflicts of interest to declare. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.

Characterizing Task-Based OpenMP Programs

PubMed Central

Muddukrishna, Ananya; Jonsson, Peter A.; Brorsson, Mats

2015-01-01

Programmers struggle to understand performance of task-based OpenMP programs since profiling tools only report thread-based performance. Performance tuning also requires task-based performance in order to balance per-task memory hierarchy utilization against exposed task parallelism. We provide a cost-effective method to extract detailed task-based performance information from OpenMP programs. We demonstrate the utility of our method by quickly diagnosing performance problems and characterizing exposed task parallelism and per-task instruction profiles of benchmarks in the widely-used Barcelona OpenMP Tasks Suite. Programmers can tune performance faster and understand performance tradeoffs more effectively than existing tools by using our method to characterize task-based performance. PMID:25860023

Event-related potentials and secondary task performance during simulated driving.

PubMed

Wester, A E; Böcker, K B E; Volkerts, E R; Verster, J C; Kenemans, J L

2008-01-01

Inattention and distraction account for a substantial number of traffic accidents. Therefore, we examined the impact of secondary task performance (an auditory oddball task) on a primary driving task (lane keeping). Twenty healthy participants performed two 20-min tests in the Divided Attention Steering Simulator (DASS). The visual secondary task of the DASS was replaced by an auditory oddball task to allow recording of brain activity. The driving task and the secondary (distracting) oddball task were presented in isolation and simultaneously, to assess their mutual interference. In addition to performance measures (lane keeping in the primary driving task and reaction speed in the secondary oddball task), brain activity, i.e. event-related potentials (ERPs), was recorded. Performance parameters on the driving test and the secondary oddball task did not differ between performance in isolation and simultaneous performance. However, when both tasks were performed simultaneously, reaction time variability increased in the secondary oddball task. Analysis of brain activity indicated that ERP amplitude (P3a amplitude) related to the secondary task, was significantly reduced when the task was performed simultaneously with the driving test. This study shows that when performing a simple secondary task during driving, performance of the driving task and this secondary task are both unaffected. However, analysis of brain activity shows reduced cortical processing of irrelevant, potentially distracting stimuli from the secondary task during driving.

Effect of Multiple Simultaneous Vaccines on Polio Seroresponse and Associated Health Outcomes

DTIC Science & Technology

2015-01-01

Broderick M. Steven Oberste Deborah Moore Sandra Romero-Steiner Christian J. Hansen Dennis J. Faix Report No. 13-53 The views expressed in...michael.broderick@med.navy.mil (M.P. Broderick ). 1 Current address: Office of Public Health Preparedness and Response, CDC, tlanta, GA 30333, USA. ttp...titers examined were those of polio, not of other vaccines givenM.P. Broderick et al. / V utcomes were associated with receipt of the same vaccinations

A Rapid and Simple Integrated Extraction Amplification and Detection Device for Y. pestis

DTIC Science & Technology

2000-10-01

Yersinia pestis is transmitted by fleas. Three virulence plasmids are characteristic in Y pestis. These vary in different strains by size and...WIP# 330440), dTTP(BD WIP# 330572) and dCsTP(BD WIP# 330546). Additional SDA reagents Additional components: Bovine serum albumin (BSA) (BD WIP# 360653...in a thermocycler, with addition of enzyme following the denaturation step. Efforts to block the effect by prior exposure of the plastic to bovine

Demonstration of Smart Fluorescent and Self-Healing Coatings for Severely Corrosive Environments at Vehicle Wash Facilities

DTIC Science & Technology

2009-08-01

as well as pipe and tank exteriors providing early detection of coating erosion, cracks , and intercoat blistering. A fluorescing coating used ERDC...poor with widespread areas of peeling and cracking on the exterior siding. Areas of exposed galvanizing were rusting. Structural steel elements...and application of TT-P-86 Type 2 red lead paint and red and white colored alkyd enamel topcoats. The average dry film thickness on the exterior

Advanced Cyber Industrial Control System Tactics, Techniques, and Procedures (ACI TTP) for Department of Defense (DOD) Industrial Control Systems (ICS)

DTIC Science & Technology

2016-08-10

enable JCS managers to detect advanced cyber attacks, mitigate the effects of those attacks, and recover their networks following an attack. It also... managers of ICS networks to Detect, Mitigate, and Recover from nation-state-level cyber attacks (strategic, deliberate, well-trained, and funded...Successful Detection of cyber anomalies is best achieved when IT and ICS managers remain in close coordination. The Integrity Checks Table

E. coli derived Von Willebrand Factor-A2 domain FRET proteins that quantify ADAMTS13 activity

PubMed Central

Dayananda, Kannayakanahalli M.; Gogia, Shobhit; Neelamegham, Sriram

2010-01-01

The cleavage of the A2-domain of Von Willebrand Factor (VWF) by the metalloprotease ADAMTS13 regulates VWF size and platelet thrombosis rates. Reduction or inhibition of this enzyme activity leads to thrombotic thrombocytopenic purpura (TTP). We generated a set of novel molecules called VWF-A2 FRET proteins’, where variants of YFP (Venus) and CFP (Cerulean) flank either the entire VWF-A2 domain (175 amino acids) or truncated fragments (141, 113, 77 amino acids) of this domain. These proteins were expressed in E. coli in soluble form, and they exhibited Fluorescence/Förster Resonance Energy Transfer (FRET) properties. Results show that introduction of Venus/Cerulean itself did not alter the ability of VWF-A2 to undergo ADAMTS13 mediated cleavage. The smallest FRET protein, XS-VWF, detected plasma ADAMTS13 activity down to 10% of normal levels. Tests of acquired and inherited TTP could be completed within 30 min. VWF-A2 conformation changed progressively, and not abruptly, upon increasing urea concentration. While proteins with 77 and 113 VWF-A2 residues were cleaved in the absence of denaturant, 4M urea was required for the efficient cleavage of larger constructs. Overall, VWF-A2 FRET proteins can be applied both for the rapid diagnosis of plasma ADAMTS13 activity, and as a tool to study VWF-A2 conformation dynamics. PMID:21146487

Letrozole in advanced breast cancer: the PO25 trial

PubMed Central

2007-01-01

Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer, but more than half of patients fail to respond and time to progression is less than 12 months in responders. The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen. In the Femara Study PO25, post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg (n = 453) or tamoxifen 20 mg (n = 454) given orally daily until progressive disease occurred. Patients were permitted to cross over to the other treatment at progression. In the primary efficacy analysis, median time to progression (TTP) was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P < 0.0001). The objective response rate (ORR) was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P = 0.0002). Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival (OS) compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR, TTP, and early OS. PMID:17333340

Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy

PubMed Central

Di Fiore, F; Blanchard, F; Charbonnier, F; Le Pessot, F; Lamy, A; Galais, M P; Bastit, L; Killian, A; Sesboüé, R; Tuech, J J; Queuniet, A M; Paillot, B; Sabourin, J C; Michot, F; Michel, P; Frebourg, T

2007-01-01

The predictive value of KRAS mutation in metastatic colorectal cancer (MCRC) patients treated with cetuximab plus chemotherapy has recently been suggested. In our study, 59 patients with a chemotherapy-refractory MCRC treated with cetuximab plus chemotherapy were included and clinical response was evaluated according to response evaluation criteria in solid tumours (RECIST). Tumours were screened for KRAS mutations using first direct sequencing, then two sensitive methods based on SNaPshot and PCR-ligase chain reaction (LCR) assays. Clinical response was evaluated according to gene mutations using the Fisher exact test. Times to progression (TTP) were calculated using the Kaplan–Meier method and compared with log-rank test. A KRAS mutation was detected in 22 out of 59 tumours and, in six cases, was missed by sequencing analysis but detected using the SNaPshot and PCR-LCR assays. Remarkably, no KRAS mutation was found in the 12 patients with clinical response. KRAS mutation was associated with disease progression (P=0.0005) and TTP was significantly decreased in mutated KRAS patients (3 vs 5.5 months, P=0.015). Our study confirms that KRAS mutation is highly predictive of a non-response to cetuximab plus chemotherapy in MCRC and highlights the need to use sensitive molecular methods, such as SNaPshot or PCR-LCR assays, to ensure an efficient mutation detection. PMID:17375050

Methylenetetrahydrofolate reductase C677T polymorphism predicts response and time to progression to gemcitabine-based chemotherapy for advanced non-small cell lung cancer in a Chinese Han population*

PubMed Central

Hong, Wei; Wang, Kai; Zhang, Yi-ping; Kou, Jun-yan; Hong, Dan; Su, Dan; Mao, Wei-min; Yu, Xin-min; Xie, Fa-jun; Wang, Xiao-jian

2013-01-01

Objective: The aim of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C677T excision repair cross-complementation group 1 (ERCC1) genetic polymorphisms and the clinical efficacy of gemcitabine-based chemotherapy in advanced non-small cell lung cancer (NSCLC). Methods: A total of 135 chemonaive patients with unresectable advanced NSCLC were treated with gemcitabine/platinum regimens. The polymorphisms of MTHFR C677T, ERCC1 C8092A, and ERCC1 C118T were genotyped using the TaqMan methods. Results: The overall response rate was 28.9%. Patients with MTHFR CC genotype had a higher rate of objective response than patients with variant genotype (TT or CT) (41.2% versus 19.1%, P=0.01). Median time to progression (TTP) of patients with MTHFR CC genotype was longer than that of patients with variant genotype (7.6 months versus 5.0 months, P=0.003). No significant associations were obtained between ERCC1 C118T and C8092A polymorphisms and both response and survival. Conclusions: Our data suggest the value of MTHFR C677T polymorphism as a possible predictive marker of response and TTP in advanced NSCLC patients treated with gemcitabine/platinum. PMID:23463763

A module located at a chromosomal integration hot spot is responsible for the multidrug resistance of a reference strain from Escherichia coli clonal group A.

PubMed

Lescat, Mathilde; Calteau, Alexandra; Hoede, Claire; Barbe, Valérie; Touchon, Marie; Rocha, Eduardo; Tenaillon, Olivier; Médigue, Claudine; Johnson, James R; Denamur, Erick

2009-06-01

Escherichia coli clonal group A (CGA) commonly exhibits a distinctive multidrug antimicrobial resistance phenotype-i.e., resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, tetracycline, and trimethoprim (ACSSuTTp)-and has accounted for up to 50% of trimethoprim-sulfamethoxazole-resistant E. coli urinary tract infections in some locales. Annotation of the whole-genome sequencing of UMN026, a reference CGA strain, clarified the genetic basis for this strain's ACSSuTTp antimicrobial resistance phenotype. Most of the responsible genes were clustered in a unique 23-kbp chromosomal region, designated the genomic resistance module (GRM), which occurred within a 105-kbp genomic island situated at the leuX tRNA. The GRM is characterized by numerous remnants of mobilization and rearrangement events suggesting multiple horizontal transfers. Additionally, comparative genomic analysis of the leuX tRNA genomic island in 14 sequenced E. coli genomes showed that this region is a hot spot of integration, with the presence/absence of specific subregions being uncorrelated with either the phylogenetic group or the pathotype. Our data illustrate the importance of whole-genome sequencing in the detection of genetic elements involved in antimicrobial resistance. Additionally, this is the first documentation of the bla(TEM) and dhfrVII genes in a chromosomal location in E. coli strains.

Pernicious Anemia Associated Cobalamin Deficiency and Thrombotic Microangiopathy: Case Report and Review of the Literature

PubMed Central

Spinowitz, Bruce; Charytan, Chaim; Galler, Marilyn

2017-01-01

A 43-year-old Hispanic male without significant previous medical history was brought to emergency department for syncope following a blood draw to investigate a 40 lbs weight loss during the past 6 months associated with decreased appetite and progressive fatigue. The patient also reported a 1-month history of jaundice. On examination, he was hemodynamically stable and afebrile with pallor and diffuse jaundice but without skin rash or palpable purpura. Normal sensations and power in all extremities were evident on neurological exam. Presence of hemolytic anemia, schistocytosis, thrombocytopenia, and elevated lactate dehydrogenase (LDH) was suggestive of thrombotic thrombocytopenic purpura (TTP). However, presence of leukopenia, macrocytes, and an inadequate reticulocyte response to the degree of anemia served as initial clues to an alternative diagnosis. Two and one units of packed red blood cells were transfused on day 1 and day 3, respectively. In addition, one unit of platelets was transfused on day 2. Daily therapeutic plasma exchange (TPE) was initiated and continued until ADAMTS-13 result ruled out TTP. A low cobalamin (vitamin B12) level was evident at initial laboratory work-up and subsequent testing revealed positive intrinsic factor-blocking antibodies supporting a diagnosis of pernicious anemia with severe cobalamin deficiency. Hematological improvement was observed following vitamin B12 supplementation. The patient was discharged and markedly improved on day 9 with outpatient follow-up for cobalamin supplementation. PMID:28265287

Pernicious Anemia Associated Cobalamin Deficiency and Thrombotic Microangiopathy: Case Report and Review of the Literature.

PubMed

Yousaf, Farhanah; Spinowitz, Bruce; Charytan, Chaim; Galler, Marilyn

2017-01-01

A 43-year-old Hispanic male without significant previous medical history was brought to emergency department for syncope following a blood draw to investigate a 40 lbs weight loss during the past 6 months associated with decreased appetite and progressive fatigue. The patient also reported a 1-month history of jaundice. On examination, he was hemodynamically stable and afebrile with pallor and diffuse jaundice but without skin rash or palpable purpura. Normal sensations and power in all extremities were evident on neurological exam. Presence of hemolytic anemia, schistocytosis, thrombocytopenia, and elevated lactate dehydrogenase (LDH) was suggestive of thrombotic thrombocytopenic purpura (TTP). However, presence of leukopenia, macrocytes, and an inadequate reticulocyte response to the degree of anemia served as initial clues to an alternative diagnosis. Two and one units of packed red blood cells were transfused on day 1 and day 3, respectively. In addition, one unit of platelets was transfused on day 2. Daily therapeutic plasma exchange (TPE) was initiated and continued until ADAMTS-13 result ruled out TTP. A low cobalamin (vitamin B12) level was evident at initial laboratory work-up and subsequent testing revealed positive intrinsic factor-blocking antibodies supporting a diagnosis of pernicious anemia with severe cobalamin deficiency. Hematological improvement was observed following vitamin B12 supplementation. The patient was discharged and markedly improved on day 9 with outpatient follow-up for cobalamin supplementation.

Docetaxel/S-1 Versus Docetaxel/Capecitabine as First-Line Treatment for Advanced Breast Cancer

PubMed Central

Li, Jinyu; You, Junhao; Si, Wen; Zhu, Yanyun; Chen, Yi; Yang, Bo; Han, Chun; Linghu, Ruixia; Zhang, Xingyang; Jiao, Shunchang; Yang, Junlan

2015-01-01

Abstract The treatment efficacy of advanced breast cancer is still not promising. This study aimed to compare the efficacy and safety of docetaxel/S-1 (DS1) versus docetaxel/capecitabine (DX) as the first-line treatment for advanced breast cancer. From June 2008 to June 2013, 22 patients with advanced breast cancer were treated with the DS1 regimen. Another 26 age- and disease status-matched patients treated with the DX regimen served as controls. The 2 groups were compared in terms of time to progression (TTP), objective response rate, disease control rate, clinical benefit rate, and safety profiles. Median TTP did not differ significantly between the DS1 group and the DX group (9.04 vs 10.94 months, P = 0.473). There were no significant differences in objective response rate, disease control rate, and clinical benefit rate between the 2 groups. Both the DS1 and the DX regimens showed good tolerability. The 2 regimens showed no significant difference in adverse events except degree III hand-foot syndrome (DS1 0 vs DX 23.1%, P = 0.025). For the first-line treatment of advanced breast cancer, the DS1 and the DX regimens showed similar efficacy and safety. The DS1 regimen had less severe hand-foot syndrome than the DX regimen. PMID:26469889

Docetaxel/S-1 Versus Docetaxel/Capecitabine as First-Line Treatment for Advanced Breast Cancer: A Retrospective Study.

PubMed

Li, Jinyu; You, Junhao; Si, Wen; Zhu, Yanyun; Chen, Yi; Yang, Bo; Han, Chun; Linghu, Ruixia; Zhang, Xingyang; Jiao, Shunchang; Yang, Junlan

2015-10-01

The treatment efficacy of advanced breast cancer is still not promising. This study aimed to compare the efficacy and safety of docetaxel/S-1 (DS1) versus docetaxel/capecitabine (DX) as the first-line treatment for advanced breast cancer.From June 2008 to June 2013, 22 patients with advanced breast cancer were treated with the DS1 regimen. Another 26 age- and disease status-matched patients treated with the DX regimen served as controls. The 2 groups were compared in terms of time to progression (TTP), objective response rate, disease control rate, clinical benefit rate, and safety profiles.Median TTP did not differ significantly between the DS1 group and the DX group (9.04 vs 10.94 months, P = 0.473). There were no significant differences in objective response rate, disease control rate, and clinical benefit rate between the 2 groups. Both the DS1 and the DX regimens showed good tolerability. The 2 regimens showed no significant difference in adverse events except degree III hand-foot syndrome (DS1 0 vs DX 23.1%, P = 0.025).For the first-line treatment of advanced breast cancer, the DS1 and the DX regimens showed similar efficacy and safety. The DS1 regimen had less severe hand-foot syndrome than the DX regimen.

SU-E-I-36: A KWIC and Dirty Look at Dose Savings and Perfusion Metrics in Simulated CT Neuro Perfusion Exams

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

Hoffman, J; Martin, T; Young, S

Purpose: CT neuro perfusion scans are one of the highest dose exams. Methods to reduce dose include decreasing the number of projections acquired per gantry rotation, however conventional reconstruction of such scans leads to sampling artifacts. In this study we investigated a projection view-sharing reconstruction algorithm used in dynamic MRI – “K-space Weighted Image Contrast” (KWIC) – applied to simulated perfusion exams and evaluated dose savings and impacts on perfusion metrics. Methods: A FORBILD head phantom containing simulated time-varying objects was developed and a set of parallel-beam CT projection data was created. The simulated scans were 60 seconds long, 1152more » projections per turn, with a rotation time of one second. No noise was simulated. 5mm, 10mm, and 50mm objects were modeled in the brain. A baseline, “full dose” simulation used all projections and reduced dose cases were simulated by downsampling the number of projections per turn from 1152 to 576 (50% dose), 288 (25% dose), and 144 (12.5% dose). KWIC was further evaluated at 72 projections per rotation (6.25%). One image per second was reconstructed using filtered backprojection (FBP) and KWIC. KWIC reconstructions utilized view cores of 36, 72, 144, and 288 views and 16, 8, 4, and 2 subapertures respectively. From the reconstructed images, time-to-peak (TTP), cerebral blood flow (CBF) and the FWHM of the perfusion curve were calculated and compared against reference values from the full-dose FBP data. Results: TTP, CBF, and the FWHM were unaffected by dose reduction (to 12.5%) and reconstruction method, however image quality was improved when using KWIC. Conclusion: This pilot study suggests that KWIC preserves image quality and perfusion metrics when under-sampling projections and that the unique contrast weighting of KWIC could provided substantial dose-savings for perfusion CT scans. Evaluation of KWIC in clinical CT data will be performed in the near future. R01 EB014922, NCI Grant U01 CA181156 (Quantitative Imaging Network), and Tobacco Related Disease Research Project grant 22RT-0131.« less

Outcomes of Radioembolization in the Treatment of Hepatocellular Carcinoma with Portal Vein Invasion: Resin versus Glass Microspheres.

PubMed

Biederman, Derek M; Titano, Joseph J; Tabori, Nora E; Pierobon, Elisa S; Alshebeeb, Kutaiba; Schwartz, Myron; Facciuto, Marcelo E; Gunasekaran, Ganesh; Florman, Sander; Fischman, Aaron M; Patel, Rahul S; Nowakowski, Francis S; Kim, Edward

2016-06-01

To compare outcomes of yttrium-90 radioembolization performed with resin-based ((90)Y-resin) and glass-based ((90)Y-glass) microspheres in the treatment of hepatocellular carcinoma (HCC) with associated portal vein invasion. A single-center retrospective review (January 2005-September 2014) identified 90 patients ((90)Y-resin, 21; (90)Y-glass, 69) with HCC and ipsilateral portal vein thrombosis (PVT). Patients were stratified according to age, sex, ethnicity, Child-Pugh class, Eastern Cooperative Oncology Group status, α-fetoprotein > 400 ng/mL, extent of PVT, tumor burden, and sorafenib therapy. Outcome variables included clinical and laboratory toxicities (Common Terminology Criteria Adverse Events, Version 4.03), imaging response (modified Response Evaluation Criteria in Solid Tumors), time to progression (TTP), and overall survival (OS). Grade 3/4 bilirubin and aspartate aminotransferase toxicities developed at a 2.8-fold (95% confidence interval [CI], 1.3-6.1) and 2.6-fold (95% CI, 1.1-6.1) greater rate in the (90)Y-resin group. The disease control rate was 37.5% in the (90)Y-resin group and 54.5% in the (90)Y-glass group (P = .39). The median (95% CI) TTP was 2.8 (1.9-4.3) months in the (90)Y-resin group and 5.9 (4.2-9.1) months in the (90)Y-glass group (P = .48). Median (95% CI) survival was 3.7 (2.3-6.0) months in the (90)Y-resin group and 9.4 (7.6-15.0) months in the (90)Y-glass group (hazard ratio, 2.6; 95% CI, 1.5-4.3, P < .001). Additional multivariate predictors of improved OS included age < 65 years, Eastern Cooperative Oncology Group status < 1, α-fetoprotein ≤ 400 ng/mL, and unilobar tumor distribution. Imaging response of (90)Y treatment in patients with HCC and PVT was not significantly different between (90)Y-glass and (90)Y-resin groups. Lower toxicity and improved OS were observed in the (90)Y-glass group. Copyright © 2016 SIR. Published by Elsevier Inc. All rights reserved.

Monitoring supports performance in a dual-task paradigm involving a risky decision-making task and a working memory task

PubMed Central

Gathmann, Bettina; Schiebener, Johannes; Wolf, Oliver T.; Brand, Matthias

2015-01-01

Performing two cognitively demanding tasks at the same time is known to decrease performance. The current study investigates the underlying executive functions of a dual-tasking situation involving the simultaneous performance of decision making under explicit risk and a working memory task. It is suggested that making a decision and performing a working memory task at the same time should particularly require monitoring—an executive control process supervising behavior and the state of processing on two tasks. To test the role of a supervisory/monitoring function in such a dual-tasking situation we investigated 122 participants with the Game of Dice Task plus 2-back task (GDT plus 2-back task). This dual task requires participants to make decisions under risk and to perform a 2-back working memory task at the same time. Furthermore, a task measuring a set of several executive functions gathered in the term concept formation (Modified Card Sorting Test, MCST) and the newly developed Balanced Switching Task (BST), measuring monitoring in particular, were used. The results demonstrate that concept formation and monitoring are involved in the simultaneous performance of decision making under risk and a working memory task. In particular, the mediation analysis revealed that BST performance partially mediates the influence of MCST performance on the GDT plus 2-back task. These findings suggest that monitoring is one important subfunction for superior performance in a dual-tasking situation including decision making under risk and a working memory task. PMID:25741308

Musical expertise has minimal impact on dual task performance.

PubMed

Cocchini, Gianna; Filardi, Maria Serena; Crhonkova, Marcela; Halpern, Andrea R

2017-05-01

Studies investigating effect of practice on dual task performance have yielded conflicting findings, thus supporting different theoretical accounts about the organisation of attentional resources when tasks are performed simultaneously. Because practice has been proven to reduce the demand of attention for the trained task, the impact of long-lasting training on one task is an ideal way to better understand the mechanisms underlying dual task decline in performance. Our study compared performance during dual task execution in expert musicians compared to controls with little if any musical experience. Participants performed a music recognition task and a visuo-spatial task separately (single task) or simultaneously (dual task). Both groups showed a significant but similar performance decline during dual tasks. In addition, the two groups showed a similar decline of dual task performance during encoding and retrieval of the musical information, mainly attributed to a decline in sensitivity. Our results suggest that attention during dual tasks is similarly distributed by expert and non-experts. These findings are in line with previous studies showing a lack of sensitivity to difficulty and lack of practice effect during dual tasks, supporting the idea that different tasks may rely on different and not-sharable attentional resources.

Acute physical exercise affected processing efficiency in an auditory attention task more than processing effectiveness.

PubMed

Dutke, Stephan; Jaitner, Thomas; Berse, Timo; Barenberg, Jonathan

2014-02-01

Research on effects of acute physical exercise on performance in a concurrent cognitive task has generated equivocal evidence. Processing efficiency theory predicts that concurrent physical exercise can increase resource requirements for sustaining cognitive performance even when the level of performance is unaffected. This hypothesis was tested in a dual-task experiment. Sixty young adults worked on a primary auditory attention task and a secondary interval production task while cycling on a bicycle ergometer. Physical load (cycling) and cognitive load of the primary task were manipulated. Neither physical nor cognitive load affected primary task performance, but both factors interacted on secondary task performance. Sustaining primary task performance under increased physical and/or cognitive load increased resource consumption as indicated by decreased secondary task performance. Results demonstrated that physical exercise effects on cognition might be underestimated when only single task performance is the focus.

Dosimetric properties of dysprosium doped calcium magnesium borate glass subjected to Co-60 gamma ray

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

Omar, R. S., E-mail: ratnasuffhiyanni@gmail.com; Wagiran, H., E-mail: husin@utm.my; Saeed, M. A.

Thermoluminescence (TL) dosimetric properties of dysprosium doped calcium magnesium borate (CMB:Dy) glass are presented. This study is deemed to understand the application of calcium as the modifier in magnesium borate glass with the presence of dysprosium as the activator to be performed as TL dosimeter (TLD). The study provides fundamental knowledge of a glass system that may lead to perform new TL glass dosimetry application in future research. Calcium magnesium borate glass systems of (70-y) B{sub 2}O{sub 3} − 20 CaO – 10 MgO-(y) Dy{sub 2}O{sub 3} with 0.05  mol % ≤ y ≤ 0.7  mol % of dyprosium weremore » prepared by melt-quenching technique. The amorphous structure and TL properties of the prepared samples were determined using powder X-ray diffraction (XRD) and TL reader; model Harshaw 4500 respectively. The samples were irradiated to Co-60 gamma source at a dose of 50 Gy. Dosimetric properties such as annealing procedure, time temperature profile (TTP) setting, optimization of Dy{sub 2}O{sub 3} concentration of 0.5 mol % were determined for thermoluminescence dosimeter (TLD) reader used.« less

Effects of total sleep deprivation on divided attention performance

PubMed Central

2017-01-01

Dividing attention across two tasks performed simultaneously usually results in impaired performance on one or both tasks. Most studies have found no difference in the dual-task cost of dividing attention in rested and sleep-deprived states. We hypothesized that, for a divided attention task that is highly cognitively-demanding, performance would show greater impairment during exposure to sleep deprivation. A group of 30 healthy males aged 21–30 years was exposed to 40 h of continuous wakefulness in a laboratory setting. Every 2 h, subjects completed a divided attention task comprising 3 blocks in which an auditory Go/No-Go task was 1) performed alone (single task); 2) performed simultaneously with a visual Go/No-Go task (dual task); and 3) performed simultaneously with both a visual Go/No-Go task and a visually-guided motor tracking task (triple task). Performance on all tasks showed substantial deterioration during exposure to sleep deprivation. A significant interaction was observed between task load and time since wake on auditory Go/No-Go task performance, with greater impairment in response times and accuracy during extended wakefulness. Our results suggest that the ability to divide attention between multiple tasks is impaired during exposure to sleep deprivation. These findings have potential implications for occupations that require multi-tasking combined with long work hours and exposure to sleep loss. PMID:29166387

Effects of total sleep deprivation on divided attention performance.

PubMed

Chua, Eric Chern-Pin; Fang, Eric; Gooley, Joshua J

2017-01-01

Dividing attention across two tasks performed simultaneously usually results in impaired performance on one or both tasks. Most studies have found no difference in the dual-task cost of dividing attention in rested and sleep-deprived states. We hypothesized that, for a divided attention task that is highly cognitively-demanding, performance would show greater impairment during exposure to sleep deprivation. A group of 30 healthy males aged 21-30 years was exposed to 40 h of continuous wakefulness in a laboratory setting. Every 2 h, subjects completed a divided attention task comprising 3 blocks in which an auditory Go/No-Go task was 1) performed alone (single task); 2) performed simultaneously with a visual Go/No-Go task (dual task); and 3) performed simultaneously with both a visual Go/No-Go task and a visually-guided motor tracking task (triple task). Performance on all tasks showed substantial deterioration during exposure to sleep deprivation. A significant interaction was observed between task load and time since wake on auditory Go/No-Go task performance, with greater impairment in response times and accuracy during extended wakefulness. Our results suggest that the ability to divide attention between multiple tasks is impaired during exposure to sleep deprivation. These findings have potential implications for occupations that require multi-tasking combined with long work hours and exposure to sleep loss.

Direct Simulation Monte Carlo Application of the Three Dimensional Forced Harmonic Oscillator Model

DTIC Science & Technology

2017-12-07

quasi -classical scattering theory [3,4] or trajectory [5] calculations, semiclassical, as well as close-coupled [6,7] or full [8] quantum mechanical...the quasi -classical trajectory (QCT) calculations approach for ab initio modeling of collision processes. The DMS method builds on an earlier work...nu ar y 30 , 2 01 8 | h ttp :// ar c. ai aa .o rg | D O I: 1 0. 25 14 /1 .T 52 28 to directly use quasi -classical or quantum mechanic

Corrosion Mitigation and Materials Selection Guide for Military Construction in a Severely Corrosive Environment

DTIC Science & Technology

1988-07-01

Skylights 33 OGS Section No. 07840: Ventilators, Roof: Gravity Type 33 SOGS Section No. 07951: Calking and Sealants 34 4 CONTENTS (Cont’d) Page 7 DOORS...shall be fully bonded to the primed surface. The finished surface shall be smooth, lustrous, and impervious to moisture. Dull or porous spots shall be...Type 1 21, Type I Gloss, TT-P-645 TT-E-1593 TT-E-1593 Sunlight Resistant SOGS Section No. 07810: Skylights Environment - Exposure Materials Selection

Journal of Special Operations Medicine, Volume 7, Edition 4. Training Supplement: Tactics, Techniques, and Procedures

DTIC Science & Technology

2007-01-01

fatigued. The majority of the OIL and TTP listed here are oriented to the Level I management of combat CAX or management at the point of injury (POI) or...carried into the field by medical personnel. Time to evacuation from the POI or other casualty evacuation point (CEP) to an MTF may vary considerably...must be avoided during this time. Care must be rendered once the mission has reached an anticipated evacuation point , without pursuit, awaiting CASEVAC

Toward a Methodology for Evaluating the Impact of Situation Awareness on Unit Effectiveness of Dismounted Infantrymen

DTIC Science & Technology

2000-04-01

impact on current TTPs or SOPs as a result of having these capabilities. This review did not generally change Free - play Exercises the nature of the TTP or...these occurred within 6 environment is in a free - play exercise. minutes of critical SA elements. Free - play exercises have been used for many years to...event. This free - play exercises at the squad level. They conduct knowledge was acquired by holding an SME conference. squad exercises to practice

Analysis of Skeletal Muscle Metrics as Predictors of Functional Task Performance

NASA Technical Reports Server (NTRS)

Ryder, Jeffrey W.; Buxton, Roxanne E.; Redd, Elizabeth; Scott-Pandorf, Melissa; Hackney, Kyle J.; Fiedler, James; Ploutz-Snyder, Robert J.; Bloomberg, Jacob J.; Ploutz-Snyder, Lori L.

2010-01-01

PURPOSE: The ability to predict task performance using physiological performance metrics is vital to ensure that astronauts can execute their jobs safely and effectively. This investigation used a weighted suit to evaluate task performance at various ratios of strength, power, and endurance to body weight. METHODS: Twenty subjects completed muscle performance tests and functional tasks representative of those that would be required of astronauts during planetary exploration (see table for specific tests/tasks). Subjects performed functional tasks while wearing a weighted suit with additional loads ranging from 0-120% of initial body weight. Performance metrics were time to completion for all tasks except hatch opening, which consisted of total work. Task performance metrics were plotted against muscle metrics normalized to "body weight" (subject weight + external load; BW) for each trial. Fractional polynomial regression was used to model the relationship between muscle and task performance. CONCLUSION: LPMIF/BW is the best predictor of performance for predominantly lower-body tasks that are ambulatory and of short duration. LPMIF/BW is a very practical predictor of occupational task performance as it is quick and relatively safe to perform. Accordingly, bench press work best predicts hatch-opening work performance.

Sex differences on a computerized mental rotation task disappear with computer familiarization.

PubMed

Roberts, J E; Bell, M A

2000-12-01

The area of cognitive research that has produced the most consistent sex differences is spatial ability. Particularly, men consistently perform better on mental rotation tasks than do women. This study examined the effects of familiarization with a computer on performance of a computerized two-dimensional mental rotation task. Two groups of college students (N=44) performed the rotation task, with one group performing a color-matching task that allowed them to be familiarized with the computer prior to the rotation task. Among the participants who only performed the rotation task, the 11 men performed better than the 11 women. Among the participants who performed the computer familiarization task before the rotation task, how ever, there were no sex differences on the mental rotation task between the 10 men and 12 women. These data indicate that sex differences on this two-dimensional task may reflect familiarization with the computer, not the mental rotation component of the task. Further research with larger samples and increased range of task difficulty is encouraged.

The performance of stroke survivors in turning-while-walking while carrying out a concurrent cognitive task compared with controls.

PubMed

Chan, Wing-Nga; Tsang, William Wai-Nam

2017-01-01

Turning-while-walking is one of the commonest causes of falls in stroke survivors. It involves cognitive processing and may be challenging when performed concurrently with a cognitive task. Previous studies of dual-tasking involving turning-while-walking in stroke survivors show that the performance of physical tasks is compromised. However, the design of those studies did not address the response of stroke survivors under dual-tasking condition without specifying the task-preference and its effect on the performance of the cognitive task. First, to compare the performance of single-tasking and dual-tasking in stroke survivors. Second, to compare the performance of stroke survivors with non-stroke controls. Fifty-nine stroke survivors and 45 controls were assessed with an auditory Stroop test, a turning-while-walking test, and a combination of the two single tasks. The outcome of the cognitive task was measured by the reaction time and accuracy of the task. The physical task was evaluated by measuring the turning duration, number of steps to turn, and time to complete the turning-while-walking test. Stroke survivors showed a significantly reduced accuracy in the auditory Stroop test when dual-tasking, but there was no change in the reaction time. Their performance in the turning-while-walking task was similar under both single-tasking and dual-tasking condition. Additionally, stroke survivors demonstrated a significantly longer reaction time and lower accuracy than the controls both when single-tasking and dual-tasking. They took longer to turn, with more steps, and needed more time to complete the turning-while-walking task in both tasking conditions. The results show that stroke survivors with high mobility function performed the auditory Stroop test less accurately while preserving simultaneous turning-while-walking performance. They also demonstrated poorer performance in both single-tasking and dual-tasking as compared with controls.

Cognitive and motor dual task gait training improve dual task gait performance after stroke - A randomized controlled pilot trial.

PubMed

Liu, Yan-Ci; Yang, Yea-Ru; Tsai, Yun-An; Wang, Ray-Yau

2017-06-22

This study investigated effects of cognitive and motor dual task gait training on dual task gait performance in stroke. Participants (n = 28) were randomly assigned to cognitive dual task gait training (CDTT), motor dual task gait training (MDTT), or conventional physical therapy (CPT) group. Participants in CDTT or MDTT group practiced the cognitive or motor tasks respectively during walking. Participants in CPT group received strengthening, balance, and gait training. The intervention was 30 min/session, 3 sessions/week for 4 weeks. Three test conditions to evaluate the training effects were single walking, walking while performing cognitive task (serial subtraction), and walking while performing motor task (tray-carrying). Parameters included gait speed, dual task cost of gait speed (DTC-speed), cadence, stride time, and stride length. After CDTT, cognitive-motor dual task gait performance (stride length and DTC-speed) was improved (p = 0.021; p = 0.015). After MDTT, motor dual task gait performance (gait speed, stride length, and DTC-speed) was improved (p = 0.008; p = 0.008; p = 0.008 respectively). It seems that CDTT improved cognitive dual task gait performance and MDTT improved motor dual task gait performance although such improvements did not reach significant group difference. Therefore, different types of dual task gait training can be adopted to enhance different dual task gait performance in stroke.

An efficient approach to understanding and predicting the effects of multiple task characteristics on performance.

PubMed

Richardson, Miles

2017-04-01

In ergonomics there is often a need to identify and predict the separate effects of multiple factors on performance. A cost-effective fractional factorial approach to understanding the relationship between task characteristics and task performance is presented. The method has been shown to provide sufficient independent variability to reveal and predict the effects of task characteristics on performance in two domains. The five steps outlined are: selection of performance measure, task characteristic identification, task design for user trials, data collection, regression model development and task characteristic analysis. The approach can be used for furthering knowledge of task performance, theoretical understanding, experimental control and prediction of task performance. Practitioner Summary: A cost-effective method to identify and predict the separate effects of multiple factors on performance is presented. The five steps allow a better understanding of task factors during the design process.

Attention in a multi-task environment

NASA Technical Reports Server (NTRS)

Andre, Anthony D.; Heers, Susan T.

1993-01-01

Two experiments used a low fidelity multi-task simulation to investigate the effects of cue specificity on task preparation and performance. Subjects performed a continuous compensatory tracking task and were periodically prompted to perform one of several concurrent secondary tasks. The results provide strong evidence that subjects enacted a strategy to actively divert resources towards secondary task preparation only when they had specific information about an upcoming task to be performed. However, this strategy was not as much affected by the type of task cued (Experiment 1) or its difficulty level (Experiment 2). Overall, subjects seemed aware of both the costs (degraded primary task tracking) and benefits (improved secondary task performance) of cue information. Implications of the present results for computational human performance/workload models are discussed.

Is a Responsive Default Mode Network Required for Successful Working Memory Task Performance?

PubMed Central

Čeko, Marta; Gracely, John L.; Fitzcharles, Mary-Ann; Seminowicz, David A.; Schweinhardt, Petra

2015-01-01

In studies of cognitive processing using tasks with externally directed attention, regions showing increased (external-task-positive) and decreased or “negative” [default-mode network (DMN)] fMRI responses during task performance are dynamically responsive to increasing task difficulty. Responsiveness (modulation of fMRI signal by increasing load) has been linked directly to successful cognitive task performance in external-task-positive regions but not in DMN regions. To investigate whether a responsive DMN is required for successful cognitive performance, we compared healthy human subjects (n = 23) with individuals shown to have decreased DMN engagement (chronic pain patients, n = 28). Subjects performed a multilevel working-memory task (N-back) during fMRI. If a responsive DMN is required for successful performance, patients having reduced DMN responsiveness should show worsened performance; if performance is not reduced, their brains should show compensatory activation in external-task-positive regions or elsewhere. All subjects showed decreased accuracy and increased reaction times with increasing task level, with no significant group differences on either measure at any level. Patients had significantly reduced negative fMRI response (deactivation) of DMN regions (posterior cingulate/precuneus, medial prefrontal cortex). Controls showed expected modulation of DMN deactivation with increasing task difficulty. Patients showed significantly reduced modulation of DMN deactivation by task difficulty, despite their successful task performance. We found no evidence of compensatory neural recruitment in external-task-positive regions or elsewhere. Individual responsiveness of the external-task-positive ventrolateral prefrontal cortex, but not of DMN regions, correlated with task accuracy. These findings suggest that a responsive DMN may not be required for successful cognitive performance; a responsive external-task-positive network may be sufficient. SIGNIFICANCE STATEMENT We studied the relationship between responsiveness of the brain to increasing task demand and successful cognitive performance, using chronic pain patients as a probe. fMRI working memory studies show that two main cognitive networks [“external-task positive” and “default-mode network” (DMN)] are responsive to increasing task difficulty. The responsiveness of both of these brain networks is suggested to be required for successful task performance. The responsiveness of external-task-positive regions has been linked directly to successful cognitive task performance, as we also show here. However, pain patients show decreased engagement and responsiveness of the DMN but can perform a working memory task as well as healthy subjects, without demonstrable compensatory neural recruitment. Therefore, a responsive DMN might not be needed for successful cognitive performance. PMID:26290236

Is a Responsive Default Mode Network Required for Successful Working Memory Task Performance?

PubMed

Čeko, Marta; Gracely, John L; Fitzcharles, Mary-Ann; Seminowicz, David A; Schweinhardt, Petra; Bushnell, M Catherine

2015-08-19

In studies of cognitive processing using tasks with externally directed attention, regions showing increased (external-task-positive) and decreased or "negative" [default-mode network (DMN)] fMRI responses during task performance are dynamically responsive to increasing task difficulty. Responsiveness (modulation of fMRI signal by increasing load) has been linked directly to successful cognitive task performance in external-task-positive regions but not in DMN regions. To investigate whether a responsive DMN is required for successful cognitive performance, we compared healthy human subjects (n = 23) with individuals shown to have decreased DMN engagement (chronic pain patients, n = 28). Subjects performed a multilevel working-memory task (N-back) during fMRI. If a responsive DMN is required for successful performance, patients having reduced DMN responsiveness should show worsened performance; if performance is not reduced, their brains should show compensatory activation in external-task-positive regions or elsewhere. All subjects showed decreased accuracy and increased reaction times with increasing task level, with no significant group differences on either measure at any level. Patients had significantly reduced negative fMRI response (deactivation) of DMN regions (posterior cingulate/precuneus, medial prefrontal cortex). Controls showed expected modulation of DMN deactivation with increasing task difficulty. Patients showed significantly reduced modulation of DMN deactivation by task difficulty, despite their successful task performance. We found no evidence of compensatory neural recruitment in external-task-positive regions or elsewhere. Individual responsiveness of the external-task-positive ventrolateral prefrontal cortex, but not of DMN regions, correlated with task accuracy. These findings suggest that a responsive DMN may not be required for successful cognitive performance; a responsive external-task-positive network may be sufficient. We studied the relationship between responsiveness of the brain to increasing task demand and successful cognitive performance, using chronic pain patients as a probe. fMRI working memory studies show that two main cognitive networks ["external-task positive" and "default-mode network" (DMN)] are responsive to increasing task difficulty. The responsiveness of both of these brain networks is suggested to be required for successful task performance. The responsiveness of external-task-positive regions has been linked directly to successful cognitive task performance, as we also show here. However, pain patients show decreased engagement and responsiveness of the DMN but can perform a working memory task as well as healthy subjects, without demonstrable compensatory neural recruitment. Therefore, a responsive DMN might not be needed for successful cognitive performance. Copyright © 2015 the authors 0270-6474/15/3511596-11$15.00/0.

Unexpected Dual Task Benefits on Cycling in Parkinson Disease and Healthy Adults: A Neuro-Behavioral Model

PubMed Central

Altmann, Lori J. P.; Stegemöller, Elizabeth; Hazamy, Audrey A.; Wilson, Jonathan P.; Okun, Michael S.; McFarland, Nikolaus R.; Shukla, Aparna Wagle; Hass, Chris J.

2015-01-01

Background When performing two tasks at once, a dual task, performance on one or both tasks typically suffers. People with Parkinson’s disease (PD) usually experience larger dual task decrements on motor tasks than healthy older adults (HOA). Our objective was to investigate the decrements in cycling caused by performing cognitive tasks with a range of difficulty in people with PD and HOAs. Methods Twenty-eight participants with Parkinson’s disease and 20 healthy older adults completed a baseline cycling task with no secondary tasks and then completed dual task cycling while performing 12 tasks from six cognitive domains representing a wide range of difficulty. Results Cycling was faster during dual task conditions than at baseline, and was significantly faster for six tasks (all p<.02) across both groups. Cycling speed improved the most during the easiest cognitive tasks, and cognitive performance was largely unaffected. Cycling improvement was predicted by task difficulty (p<.001). People with Parkinson’s disease cycled slower (p<.03) and showed reduced dual task benefits (p<.01) than healthy older adults. Conclusions Unexpectedly, participants’ motor performance improved during cognitive dual tasks, which cannot be explained in current models of dual task performance. To account for these findings, we propose a model integrating dual task and acute exercise approaches which posits that cognitive arousal during dual tasks increases resources to facilitate motor and cognitive performance, which is subsequently modulated by motor and cognitive task difficulty. This model can explain both the improvement observed on dual tasks in the current study and more typical dual task findings in other studies. PMID:25970607

An empirically derived figure of merit for the quality of overall task performance

NASA Technical Reports Server (NTRS)

Lemay, Moira

1989-01-01

The need to develop an operationally relevant figure of merit for the quality of performance of a complex system such as an aircraft cockpit stems from a hypothesized dissociation between measures of performance and those of workload. Performance can be measured in terms of time, errors, or a combination of these. In most tasks performed by expert operators, errors are relatively rare and often corrected in time to avoid consequences. Moreover, perfect performance is seldom necessary to accomplish a particular task. Moreover, how well an expert performs a complex task consisting of a series of discrete cognitive tasks superimposed on a continuous task, such as flying an aircraft, does not depend on how well each discrete task is performed, but on their smooth sequencing. This makes the amount of time spent on each subtask of paramount importance in measuring overall performance, since smooth sequencing requires a minimum amount of time spent on each task. Quality consists in getting tasks done within a crucial time interval while maintaining acceptable continuous task performance. Thus, a figure of merit for overall quality of performance should be primarily a measure of time to perform discrete subtasks combined with a measure of basic vehicle control. Thus, the proposed figure of merit requires doing a task analysis on a series of performance, or runs, of a particular task, listing each discrete task and its associated time, and calculating the mean and standard deviation of these times, along with the mean and standard deviation of tracking error for the whole task. A set of simulator data on 30 runs of a landing task was obtained and a figure of merit will be calculated for each run. The figure of merit will be compared for voice and data link, so that the impact of this technology on total crew performance (not just communication performance) can be assessed. The effect of data link communication on other cockpit tasks will also be considered.

The influence of spatial congruency and movement preparation time on saccade curvature in simultaneous and sequential dual-tasks.

PubMed

Moehler, Tobias; Fiehler, Katja

2015-11-01

Saccade curvature represents a sensitive measure of oculomotor inhibition with saccades curving away from covertly attended locations. Here we investigated whether and how saccade curvature depends on movement preparation time when a perceptual task is performed during or before saccade preparation. Participants performed a dual-task including a visual discrimination task at a cued location and a saccade task to the same location (congruent) or to a different location (incongruent). Additionally, we varied saccade preparation time (time between saccade cue and Go-signal) and the occurrence of the discrimination task (during saccade preparation=simultaneous vs. before saccade preparation=sequential). We found deteriorated perceptual performance in incongruent trials during simultaneous task performance while perceptual performance was unaffected during sequential task performance. Saccade accuracy and precision were deteriorated in incongruent trials during simultaneous and, to a lesser extent, also during sequential task performance. Saccades consistently curved away from covertly attended non-saccade locations. Saccade curvature was unaffected by movement preparation time during simultaneous task performance but decreased and finally vanished with increasing movement preparation time during sequential task performance. Our results indicate that the competing saccade plan to the covertly attended non-saccade location is maintained during simultaneous task performance until the perceptual task is solved while in the sequential condition, in which the discrimination task is solved prior to the saccade task, oculomotor inhibition decays gradually with movement preparation time. Copyright © 2015 Elsevier Ltd. All rights reserved.

Task-specific motor performance and musculoskeletal response in self-classified right handers.

PubMed

Kumar, Sameer; Mandal, Manas K

2003-11-01

We examined the difference between the left and right hand motor performance (in terms of erg produced) of self-classified right handers (15 men, 15 women) for power (task involving muscle force) and skilled (task involving precision and eye hand coordination) tasks. Musculoskeletal response during task performance was measured by electromyogram to test the hypothesis that performance with the nondominant hand would trigger more generalized muscle tension. The difference between the left and right hand performance of men was nonsignificant for power task; for women, right hand performance was significantly superior than left for such task. Men excelled in power and women excelled in skilled tasks relative to their counterparts. Generalized muscle tension was significantly more during the left than the right hand performance for power but not for skilled tasks.

Effects of Non-Driving Related Task Modalities on Takeover Performance in Highly Automated Driving.

PubMed

Wandtner, Bernhard; Schömig, Nadja; Schmidt, Gerald

2018-04-01

Aim of the study was to evaluate the impact of different non-driving related tasks (NDR tasks) on takeover performance in highly automated driving. During highly automated driving, it is allowed to engage in NDR tasks temporarily. However, drivers must be able to take over control when reaching a system limit. There is evidence that the type of NDR task has an impact on takeover performance, but little is known about the specific task characteristics that account for performance decrements. Thirty participants drove in a simulator using a highly automated driving system. Each participant faced five critical takeover situations. Based on assumptions of Wickens's multiple resource theory, stimulus and response modalities of a prototypical NDR task were systematically manipulated. Additionally, in one experimental group, the task was locked out simultaneously with the takeover request. Task modalities had significant effects on several measures of takeover performance. A visual-manual texting task degraded performance the most, particularly when performed handheld. In contrast, takeover performance with an auditory-vocal task was comparable to a baseline without any task. Task lockout was associated with faster hands-on-wheel times but not altered brake response times. Results showed that NDR task modalities are relevant factors for takeover performance. An NDR task lockout was highly accepted by the drivers and showed moderate benefits for the first takeover reaction. Knowledge about the impact of NDR task characteristics is an enabler for adaptive takeover concepts. In addition, it might help regulators to make decisions on allowed NDR tasks during automated driving.

Metacognition of Multi-Tasking: How Well Do We Predict the Costs of Divided Attention?

PubMed Central

Finley, Jason R.; Benjamin, Aaron S.; McCarley, Jason S.

2014-01-01

Risky multi-tasking, such as texting while driving, may occur because people misestimate the costs of divided attention. In two experiments, participants performed a computerized visual-manual tracking task in which they attempted to keep a mouse cursor within a small target that moved erratically around a circular track. They then separately performed an auditory n-back task. After practicing both tasks separately, participants received feedback on their single-task tracking performance and predicted their dual-task tracking performance before finally performing the two tasks simultaneously. Most participants correctly predicted reductions in tracking performance under dual-task conditions, with a majority overestimating the costs of dual-tasking. However, the between-subjects correlation between predicted and actual performance decrements was near zero. This combination of results suggests that people do anticipate costs of multi-tasking, but have little metacognitive insight on the extent to which they are personally vulnerable to the risks of divided attention, relative to other people. PMID:24490818

Evaluation of WIAMan Technology Demonstrator Biofidelity Relative to Sub-Injurious PMHS Response in Simulated Under-body Blast Events.

PubMed

Pietsch, Hollie A; Bosch, Kelly E; Weyland, David R; Spratley, E Meade; Henderson, Kyvory A; Salzar, Robert S; Smith, Terrance A; Sagara, Brandon M; Demetropoulos, Constantine K; Dooley, Christopher J; Merkle, Andrew C

2016-11-01

Three laboratory simulated sub-injurious under-body blast (UBB) test conditions were conducted with whole-body Post Mortem Human Surrogates (PMHS) and the Warrior Assessment Injury Manikin (WIAMan) Technology Demonstrator (TD) to establish and assess UBB biofidelity of the WIAMan TD. Test conditions included a rigid floor and rigid seat with independently varied pulses. On the floor, peak velocities of 4 m/s and 6 m/s were applied with a 5 ms time to peak (TTP). The seat peak velocity was 4 m/s with varied TTP of 5 and 10 ms. Tests were conducted with and without personal protective equipment (PPE). PMHS response data was compiled into preliminary biofidelity response corridors (BRCs), which served as evaluation metrics for the WIAMan TD. Each WIAMan TD response was evaluated against the PMHS preliminary BRC for the loading and unloading phase of the signal time history using Correlation Analysis (CORA) software to assign a numerical score between 0 and 1. A weighted average of all responses was calculated to determine body region and whole body biofidelity scores for each test condition. The WIAMan TD received UBB biofidelity scores of 0.62 in Condition A, 0.59 in Condition B, and 0.63 in Condition C, putting it in the fair category (0.44-0.65). Body region responses with scores below a rating of good (0.65-0.84) indicate potential focus areas for the next generation of the WIAMan design.

A novel antilithiatic protein from Tribulus terrestris having cytoprotective potency.

PubMed

Aggarwal, Anshu; Tandon, Simran; Singla, Surinder Kumar; Tandon, Chanderdeep

2012-08-01

Adhesion of calcium oxalate (CaOx) crystals to kidney cells is a key event in kidney stones associated with marked hyperoxaluria. As the propensity of stone recurrence and persistent side effects are not altered by surgical techniques available, phytotherapeutic agents could be useful as an adjuvant therapy. The present study is aimed at examining the antilithiatic potency of the protein biomolecules of Tribulus terrestris, a plant which is a common constituent of herbal marketed preparations to treat urolithiasis. Various biochemical methods with mass spectrometry were used to purify and characterize the purified protein. The protective potency of the protein was tested on the oxalate induced injury on renal epithelial cell lines (NRK 52E). An antilithiatic protein having molecular weight of ~ 60kDa was purified. This purified protein showed similarities with Carotenoid cleavage dioxygenase 7 (CCD7) of Arabidopsis thaliana after matching peptide mass fingerprints in MASCOT search engine. An EF hand domain was identified in CCD7 by SCAN PROSITE. Presence of an EF hand domain, a characteristic feature of calcium binding proteins and a role in the synthesis of retinol which is transported by retinol binding protein, a protein found in kidney stone matrix; of CCD7 support the role of TTP as an antilithiatic protein. The protective potency of TTP on NRK 52E was quite comparable to the aqueous extract of cystone. Our findings suggest that this purified protein biomolecule from Tribulus terrestris could open new vista in medical management of urolithiasis.

Mini-dystrophin restores L-type calcium currents in skeletal muscle of transgenic mdx mice

PubMed Central

Friedrich, O; Both, M; Gillis, J M; Chamberlain, J S; Fink, RHA

2004-01-01

L-type calcium currents (iCa) were recorded using the two-microelectrode voltage-clamp technique in single short toe muscle fibres of three different mouse strains: (i) C57/SV129 wild-type mice (wt); (ii) mdx mice (an animal model for Duchenne muscular dystrophy; and (iii) transgenically engineered mini-dystrophin (MinD)-expressing mdx mice. The activation and inactivation properties of iCa were examined in 2- to 18-month-old animals. Ca2+ current densities at 0 mV in mdx fibres increased with age, but were always significantly smaller compared to age-matched wild-type fibres. Time-to-peak (TTP) of iCa was prolonged in mdx fibres compared to wt fibres. MinD fibres always showed similar TTP and current amplitudes compared to age-matched wt fibres. In all three genotypes, the voltage-dependent inactivation and deactivation of iCa were similar. Intracellular resting calcium concentration ([Ca2+]i) and the distribution of dihydropyridine binding sites were also not different in young animals of all three genotypes, whereas iCa was markedly reduced in mdx fibres. We conclude, that dystrophin influences L-type Ca2+ channels via a direct or indirect linkage which may be disrupted in mdx mice and may be crucial for proper excitation–contraction coupling initiating Ca2+ release from the sarcoplasmic reticulum. This linkage seems to be fully restored in the presence of mini-dystrophin. PMID:14594987

Associations between andrological measures, hormones and semen quality in fertile Australian men: inverse relationship between obesity and sperm output.

PubMed

Stewart, T M; Liu, D Y; Garrett, C; Jørgensen, N; Brown, E H; Baker, H W G

2009-07-01

The World Health Organization developed a time to pregnancy (TTP) study (number of menstrual cycles taken to conceive) to determine whether the average TTP is increasing and semen quality decreasing with time. The present study describes clinical, semen and hormone characteristics obtained from male partners of pregnant women in Melbourne, Australia, and examines the associations between these characteristics. Male partners (n = 225) of pregnant women (16-32 weeks) who conceived naturally had physical examination, health and lifestyle questionnaires, semen and hormone (FSH, LH, sex hormone-binding globulin, testosterone and Inhibin B) analyses. Previously known associations between semen, hormone and clinical variables were confirmed as significant: sperm numbers (concentration and total sperm count) correlated positively with Inhibin B and inversely with FSH and left varicocele, while total testicular volume correlated positively with sperm numbers and Inhibin B and inversely with FSH. However, only abstinence, total testicular volume, varicocele grade and obesity (BMI > 30 kg/m2) were independently significantly related to total sperm count. Compared with those with BMI < 30 (n = 188), obese subjects (n = 35) had significantly lower total sperm count (mean 324 versus 231 million, P = 0.013) and Inhibin B (187 versus 140 pg/ml, P < 0.001) but not FSH (3.4 versus 4.0 IU/l, P = 0.6). Obese fertile men appear to have reduced testicular function. Whether this is cause or effect, i.e. adiposity impairing spermatogenesis or reduced testicular function promoting fat deposition, remains to be determined.

Phase II Study of Bortezomib and Pegylated Liposomal Doxorubicin in the Treatment of Metastatic Breast Cancer

PubMed Central

Irvin, William J.; Orlowski, Robert Z.; Chiu, Wing-Keung; Carey, Lisa A.; Collichio, Frances A.; Bernard, Philip S.; Stijleman, Inge J.; Perou, Charles; Ivanova, Anastasia; Dees, E. Claire

2018-01-01

Background Based on preclinical studies and a phase I trial of the combination of bortezomib and pegylated liposomal doxorubicin (PLD), which both showed activity in breast cancer, we conducted a phase II study of this regimen in patients with metastatic breast cancer. Patients and Methods Patients received bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of an every-21-day cycle, along with PLD 30 mg/m2 on day 4. The primary objective was to evaluate the response rate of this combination, while secondary objectives were to obtain further safety data about this combination, to evaluate the time to disease progression (TTP), and to evaluate response by the breast cancer subtype. Results One of 12 evaluable patients had a partial response (8%), while 3 (25%) had stable disease. At 26 months follow-up, the median overall survival was 4.3 months (95% CI, 1.2–26.2) and the median TTP was 1.3 months (95% CI, 0.8–14.0 months). The combination was well tolerated, with the most common events including low-grade nausea and vomiting, neutropenia, and neuropathy, and no cardiac toxicity was seen. Of the 7 tumors subtyped, no association was seen between intrinsic subtype or receptor status and response. Conclusion The combination of PLD and bortezomib was well tolerated but has minimal activity in heavily pretreated unselected metastatic breast cancer. PMID:21147690

Canine nodal marginal zone lymphoma: Descriptive insight into the biological behaviour.

PubMed

Cozzi, M; Marconato, L; Martini, V; Aresu, L; Riondato, F; Rossi, F; Stefanello, D; Comazzi, S

2018-06-01

Canine nodal marginal zone lymphoma (nMZL) is classified as an indolent lymphoma. Such lymphomas are typified by low mitotic rate and slow clinical progression. While the clinical behaviour of canine splenic MZL has been described, characterized by an indolent course and a good prognosis following splenectomy, there are no studies specifically describing nMZL. The aim of this study was to describe the clinical features of and outcome for canine nMZL. Dogs with histologically confirmed nMZL undergoing a complete staging work-up (including blood analysis, flow cytometry [FC] on lymph node [LN], peripheral blood and bone marrow, imaging, histology and immunohistochemistry on a surgically removed peripheral LN) were retrospectively enrolled. Treatment consisted of chemotherapy or chemo-immunotherapy. Endpoints were response rate (RR), time to progression (TTP) and lymphoma-specific survival (LSS). A total of 35 cases were enrolled. At diagnosis, all dogs showed generalized lymphadenopathy. One-third was systemically unwell. All dogs had stage V disease; one-third also had extranodal involvement. The LN population was mainly composed of medium-sized CD21+ cells with scant resident normal lymphocytes. Histology revealed diffuse LN involvement, referring to "late-stage" MZL. Median TTP and LSS were 149 and 259 days, respectively. Increased LDH activity and substage b were significantly associated with a shorter LSS. Dogs with nMZL may show generalized lymphadenopathy and an advanced disease stage. Overall, the outcome is poor, despite the "indolent" designation. The best treatment option still needs to be defined. © 2017 John Wiley & Sons Ltd.

Impact of severe ADAMTS13 deficiency on clinical presentation and outcomes in patients with thrombotic microangiopathies: the experience of the Harvard TMA Research Collaborative.

PubMed

Bendapudi, Pavan K; Li, Ang; Hamdan, Ayad; Uhl, Lynne; Kaufman, Richard; Stowell, Christopher; Dzik, Walter; Makar, Robert S

2015-12-01

The Harvard TMA Research Collaborative is a multi-institutional registry-based effort to study thrombotic microangiopathies (TMA). Laboratory and clinical parameters were recorded for 254 cases of suspected autoimmune thrombotic thrombocytopenic purpura (TTP). Patients with severe ADAMTS13 deficiency (activity ≤10%, N = 68) were more likely to be young, female and without a history of cancer treatment or transplantation. While all patients with severe deficiency were diagnosed with autoimmune TTP, those without severe deficiency frequently had disseminated intravascular coagulation, drug-associated TMA and transplant-related TMA. Patients with severe ADAMTS13 deficiency had superior overall survival at 360 d compared to those without severe deficiency (93·0% vs. 47·5%, P < 0·0001). Almost all patients with severe deficiency received therapeutic plasma exchange (TPE), but the use of TPE in patients with ADAMTS13 activity >10% varied significantly across the institutions in our consortium (13·2-63·8%, P < 0·0001). Nevertheless, 90-d mortality was not different in patients with ADAMTS13 activity >10% between the three hospitals (P = 0·98). Our data show that patients with severe ADAMTS13 deficiency represent a clinically distinct cohort that responds well to TPE. In contrast, TMA without severe ADAMTS13 deficiency is associated with increased mortality that may not be influenced by TPE. © 2015 John Wiley & Sons Ltd.

The carry-over effect of competition in task-sharing: evidence from the joint Simon task.

PubMed

Iani, Cristina; Anelli, Filomena; Nicoletti, Roberto; Rubichi, Sandro

2014-01-01

The Simon effect, that is the advantage of the spatial correspondence between stimulus and response locations when stimulus location is a task-irrelevant dimension, occurs even when the task is performed together by two participants, each performing a go/no-go task. Previous studies showed that this joint Simon effect, considered by some authors as a measure of self-other integration, does not emerge when during task performance co-actors are required to compete. The present study investigated whether and for how long competition experienced during joint performance of one task can affect performance in a following joint Simon task. In two experiments, we required pairs of participants to perform together a joint Simon task, before and after jointly performing together an unrelated non-spatial task (the Eriksen flanker task). In Experiment 1, participants always performed the joint Simon task under neutral instructions, before and after performing the joint flanker task in which they were explicitly required either to cooperate with (i.e., cooperative condition) or to compete against a co-actor (i.e., competitive condition). In Experiment 2, they were required to compete during the joint flanker task and to cooperate during the subsequent joint Simon task. Competition experienced in one task affected the way the subsequent joint task was performed, as revealed by the lack of the joint Simon effect, even though, during the Simon task participants were not required to compete (Experiment 1). However, prior competition no longer affected subsequent performance if a new goal that created positive interdependence between the two agents was introduced (Experiment 2). These results suggest that the emergence of the joint Simon effect is significantly influenced by how the goals of the co-acting individuals are related, with the effect of competition extending beyond the specific competitive setting and affecting subsequent interactions.

Preferential processing of task-irrelevant beloved-related information and task performance: Two event-related potential studies.

PubMed

Langeslag, Sandra J E; van Strien, Jan W

2017-09-18

People who are in love have better attention for beloved-related information, but report having trouble focusing on other tasks, such as (home)work. So, romantic love can both improve and hurt cognition. Emotional information is preferentially processed, which improves task performance when the information is task-relevant, but hurts task performance when it is task-irrelevant. Because beloved-related information is highly emotional, the effects of romantic love on cognition may resemble these effects of emotion on cognition. We examined whether beloved-related information is preferentially processed even when it is task-irrelevant and whether this hurts task performance. In two event-related potential studies, participants who had recently fallen in love performed a visuospatial short-term memory task. Task-irrelevant beloved, friend, and stranger faces were presented during maintenance (Study 1), or encoding (Study 2). The Early Posterior Negativity (EPN) reflecting early automatic attentional capturing and the Late Positive Potential (LPP) reflecting sustained motivated attention were largest for beloved pictures. Thus, beloved pictures are preferentially processed even when they are task-irrelevant. Task performance and reaction times did not differ between beloved, friend, and stranger conditions. Nevertheless, self-reported obsessive thinking about the beloved tended to correlate negatively with task performance, and positively with reaction times, across conditions. So, although task-irrelevant beloved-related information does not impact task performance, more obsessive thinking about the beloved might relate to poorer and slower overall task performance. More research is needed to clarify why people experience trouble focusing on beloved-unrelated tasks and how this negative effect of love on cognition could be reduced. Copyright © 2017 Elsevier Ltd. All rights reserved.

Group benefits in joint perceptual tasks-a review.

PubMed

Wahn, Basil; Kingstone, Alan; König, Peter

2018-05-12

In daily life, humans often perform perceptual tasks together to reach a shared goal. In these situations, individuals may collaborate (e.g., by distributing task demands) to perform the task better than when the task is performed alone (i.e., attain a group benefit). In this review, we identify the factors influencing if, and to what extent, a group benefit is attained and provide a framework of measures to assess group benefits in perceptual tasks. In particular, we integrate findings from two frequently investigated joint perceptual tasks: visuospatial tasks and decision-making tasks. For both task types, we find that an exchange of information between coactors is critical to improve joint performance. Yet, the type of exchanged information and how coactors collaborate differs between tasks. In visuospatial tasks, coactors exchange information about the performed actions to distribute task demands. In perceptual decision-making tasks, coactors exchange their confidence on their individual perceptual judgments to negotiate a joint decision. We argue that these differences can be explained by the task structure: coactors distribute task demands if a joint task allows for a spatial division and stimuli can be accurately processed by one individual. Otherwise, they perform the task individually and then integrate their individual judgments. © 2018 New York Academy of Sciences.