Optimization of personalized therapies for anticancer treatment.

PubMed

Vazquez, Alexei

2013-04-12

As today, there are hundreds of targeted therapies for the treatment of cancer, many of which have companion biomarkers that are in use to inform treatment decisions. If we would consider this whole arsenal of targeted therapies as a treatment option for every patient, very soon we will reach a scenario where each patient is positive for several markers suggesting their treatment with several targeted therapies. Given the documented side effects of anticancer drugs, it is clear that such a strategy is unfeasible. Here, we propose a strategy that optimizes the design of combinatorial therapies to achieve the best response rates with the minimal toxicity. In this methodology markers are assigned to drugs such that we achieve a high overall response rate while using personalized combinations of minimal size. We tested this methodology in an in silico cancer patient cohort, constructed from in vitro data for 714 cell lines and 138 drugs reported by the Sanger Institute. Our analysis indicates that, even in the context of personalized medicine, combinations of three or more drugs are required to achieve high response rates. Furthermore, patient-to-patient variations in pharmacokinetics have a significant impact in the overall response rate. A 10 fold increase in the pharmacokinetics variations resulted in a significant drop the overall response rate. The design of optimal combinatorial therapy for anticancer treatment requires a transition from the one-drug/one-biomarker approach to global strategies that simultaneously assign makers to a catalog of drugs. The methodology reported here provides a framework to achieve this transition.

Use of Neoadjuvant Chemotherapy Plus Molecular Targeted Therapy in Colorectal Liver Metastases: A Systematic Review and Meta-analysis.

PubMed

Sabanathan, Dhanusha; Eslick, Guy D; Shannon, Jenny

2016-12-01

Surgery remains the standard of care for patients with colorectal liver metastases (CLMs), with a 5-year survival rate approaching 35%. Perioperative chemotherapy confers a survival benefit in selected patients with CLMs. The use of molecular targeted therapy combined with neoadjuvant chemotherapy for CLMs, however, remains controversial. We reviewed the published data on combination neoadjuvant chemotherapy and molecular targeted therapy for resectable and initially unresectable CLMs. A literature search of the Medline and PubMed databases was conducted to identify studies of neoadjuvant chemotherapy plus molecular targeted therapy in the management of resectable or initially unresectable CLMs. We calculated the pooled proportion and 95% confidence intervals using a random effects model for the relationship of the combination neoadjuvant treatment on the overall response rate and performed a systematic review of all identified studies. The analysis was stratified according to the study design. The data from 11 studies of 908 patients who had undergone systemic chemotherapy plus targeted therapy for CLM were analyzed. The use of combination neoadjuvant therapy was associated with an overall response rate of 68% (95% confidence interval, 63%-73%), with significant heterogeneity observed in the studies (I 2  = 89.35; P < .001). Of the 11 studies, 4 used a combination that included oxaliplatin, 2 included irinotecan, and 5 included a combination of both. Also, 7 studies used cetuximab and 4 bevacizumab. The overall progression-free survival was estimated at 14.4 months. Current evidence suggests that neoadjuvant chemotherapy plus molecular targeted agents for CLM confers high overall response rates. Combination treatment might also increase the resectability rates in initially unresectable CLM. Further studies are needed to examine the survival outcomes, with a focus on the differential role of molecular targeted therapy in the neoadjuvant versus adjuvant setting. Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Are preference and resistance to change convergent expressions of stimulus value?

PubMed

Podlesnik, Christopher A; Jimenez-Gomez, Corina; Shahan, Timothy A

2013-07-01

Behavioral momentum theory asserts that preference and relative resistance to disruption depend on reinforcement rates and provide converging expressions of the conditioned value of discriminative stimuli. However, preference and resistance to disruption diverge when assessing preference during brief extinction probes. We expanded upon this opposing relation by arranging target stimuli signaling equal variable-interval schedules across components of a multiple schedule. We paired one target stimulus with a richer reinforced alternative and the other with a leaner alternative. Furthermore, we varied reinforcement rates for the paired alternatives to assess the effects of manipulating relative conditioned value on preference and resistance to disruption by presession feeding, intercomponent food, and extinction. We replicated the opposing relation between preference and resistance to disruption but varying reinforcement rates for the paired alternatives did not systematically affect preference or resistance to disruption beyond levels observed in our initial condition. Importantly, we found that only preference between the target stimuli was related to relative baseline response rates in the presence of those stimuli. These findings suggest that preference during extinction probes might reveal more about baseline response rates between concurrently available alternatives than relative conditioned value. Resistance to disruption, conversely, appears to better reflect conditioned value because it is less confounded with baseline response rates and is a function of all sources of reinforcement obtained in the presence of a stimulus context. © Society for the Experimental Analysis of Behavior.

Transcription factor target site search and gene regulation in a background of unspecific binding sites.

PubMed

Hettich, J; Gebhardt, J C M

2018-06-02

Response time and transcription level are vital parameters of gene regulation. They depend on how fast transcription factors (TFs) find and how efficient they occupy their specific target sites. It is well known that target site search is accelerated by TF binding to and sliding along unspecific DNA and that unspecific associations alter the occupation frequency of a gene. However, whether target site search time and occupation frequency can be optimized simultaneously is mostly unclear. We developed a transparent and intuitively accessible state-based formalism to calculate search times to target sites on and occupation frequencies of promoters of arbitrary state structure. Our formalism is based on dissociation rate constants experimentally accessible in live cell experiments. To demonstrate our approach, we consider promoters activated by a single TF, by two coactivators or in the presence of a competitive inhibitor. We find that target site search time and promoter occupancy differentially vary with the unspecific dissociation rate constant. Both parameters can be harmonized by adjusting the specific dissociation rate constant of the TF. However, while measured DNA residence times of various eukaryotic TFs correspond to a fast search time, the occupation frequencies of target sites are generally low. Cells might tolerate low target site occupancies as they enable timely gene regulation in response to a changing environment. Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Probability effects on stimulus evaluation and response processes

NASA Technical Reports Server (NTRS)

Gehring, W. J.; Gratton, G.; Coles, M. G.; Donchin, E.

1992-01-01

This study investigated the effects of probability information on response preparation and stimulus evaluation. Eight subjects responded with one hand to the target letter H and with the other to the target letter S. The target letter was surrounded by noise letters that were either the same as or different from the target letter. In 2 conditions, the targets were preceded by a warning stimulus unrelated to the target letter. In 2 other conditions, a warning letter predicted that the same letter or the opposite letter would appear as the imperative stimulus with .80 probability. Correct reaction times were faster and error rates were lower when imperative stimuli confirmed the predictions of the warning stimulus. Probability information affected (a) the preparation of motor responses during the foreperiod, (b) the development of expectancies for a particular target letter, and (c) a process sensitive to the identities of letter stimuli but not to their locations.

Bayesian enhancement two-stage design for single-arm phase II clinical trials with binary and time-to-event endpoints.

PubMed

Shi, Haolun; Yin, Guosheng

2018-02-21

Simon's two-stage design is one of the most commonly used methods in phase II clinical trials with binary endpoints. The design tests the null hypothesis that the response rate is less than an uninteresting level, versus the alternative hypothesis that the response rate is greater than a desirable target level. From a Bayesian perspective, we compute the posterior probabilities of the null and alternative hypotheses given that a promising result is declared in Simon's design. Our study reveals that because the frequentist hypothesis testing framework places its focus on the null hypothesis, a potentially efficacious treatment identified by rejecting the null under Simon's design could have only less than 10% posterior probability of attaining the desirable target level. Due to the indifference region between the null and alternative, rejecting the null does not necessarily mean that the drug achieves the desirable response level. To clarify such ambiguity, we propose a Bayesian enhancement two-stage (BET) design, which guarantees a high posterior probability of the response rate reaching the target level, while allowing for early termination and sample size saving in case that the drug's response rate is smaller than the clinically uninteresting level. Moreover, the BET design can be naturally adapted to accommodate survival endpoints. We conduct extensive simulation studies to examine the empirical performance of our design and present two trial examples as applications. © 2018, The International Biometric Society.

Heterosexual men's ratings of sexual attractiveness of pubescent girls: Effects of labeling the target as under or over the age of sexual consent.

PubMed

O'Donnell, Muireann; Lowe, Rob; Brotherton, Hannah; Davies, Hannah; Panou, Anna; Bennett, Paul

2014-02-01

The study aimed to identify implicit and explicit processes involved in reporting the sexual attractiveness of photographs of the same pubescent girls labeled as either under or within the age of sexual consent in the UK, women, and men. In two studies, 53 and 70 heterosexual men (M age 25.2 and 31.0 years) rated the sexual attractiveness of photographs in each category presented via computer [seeing target photographs of girls labeled as either under- (14-15 years) or within the age of consent (16-17 years)], using a 7-point response box. Ratings in Study 1 were in response to a question asking participants to rate how sexually attractive the person in each photograph was. In Study 2, participants rated how sexually attractive they personally found the target. Response times were also recorded. Several findings were replicated in both studies (although the strength of findings differed). Mean ratings of the sexual attractiveness of the underage girls were lower than those of overage girls and women. In addition, correlations revealed significantly longer responding times when "underage" girls (and men) were rated as more highly sexually attractive. No such relationship emerged with the same girls labeled within the age of consent or women. Overall, these data suggest that men find pubescent girls identified as being under the age of consent sexually attractive, but inhibit their willingness to report this; the greater the attraction, the greater the inhibition.

Effects of Extended Camera Baseline and Image Magnification on Target Detection Time and Target Recognition with a Stereoscopic TV System.

DTIC Science & Technology

1986-02-01

rates. Target detection times were calculated by averaging response times for all trials within a treatment condition, excluding trials in which...responses in a treatment condition by the total number of valid trials within that condition. Each of these dependent measures was subjected to its own...or 1905 mm). Comparisons among the various treatment means for this effect revealed 13 4~ ~ q-. ~ ~ .-..... 2.309 A EXPERIMENT ONE. 2.29- 0 0 z 2.19

Unsteady penetration of a target by a liquid jet

PubMed Central

Uth, Tobias; Deshpande, Vikram S.

2013-01-01

It is widely acknowledged that ceramic armor experiences an unsteady penetration response: an impacting projectile may erode on the surface of a ceramic target without substantial penetration for a significant amount of time and then suddenly start to penetrate the target. Although known for more than four decades, this phenomenon, commonly referred to as dwell, remains largely unexplained. Here, we use scaled analog experiments with a low-speed water jet and a soft, translucent target material to investigate dwell. The transient target response, in terms of depth of penetration and impact force, is captured using a high-speed camera in combination with a piezoelectric force sensor. We observe the phenomenon of dwell using a soft (noncracking) target material. The results show that the penetration rate increases when the flow of the impacting water jet is reversed due to the deformation of the jet–target interface––this reversal is also associated with an increase in the force exerted by the jet on the target. Creep penetration experiments with a constant indentation force did not show an increase in the penetration rate, confirming that flow reversal is the cause of the unsteady penetration rate. Our results suggest that dwell can occur in a ductile noncracking target due to flow reversal. This phenomenon of flow reversal is rather widespread and present in a wide range of impact situations, including water-jet cutting, needleless injection, and deposit removal via a fluid jet. PMID:24277818

What Makes a Successful Survey? A Systematic Review of Surveys Used in Anterior Cruciate Ligament Reconstruction.

PubMed

Ekhtiari, Seper; Kay, Jeffrey; de Sa, Darren; Simunovic, Nicole; Musahl, Volker; Peterson, Devin C; Ayeni, Olufemi R

2017-05-01

To characterize and assess the methodological quality of patient and physician surveys related to anterior cruciate ligament reconstruction, and to analyze the factors influencing response rate. The databases MEDLINE, Embase, and PubMed were searched from database inception to search date and screened in duplicate for relevant studies. Data regarding survey characteristics, response rates, and distribution methods were extracted. A previously published list of recommendations for high-quality surveys in orthopaedics was used as a scale to assess survey quality (12 items scored 0, 1, or 2; maximum score = 24). Of the initial 1,276 studies, 53 studies published between 1986 and 2016 met the inclusion criteria. Sixty-four percent of studies were distributed to physicians, compared with 32% distributed to patients and less than 4% to coaches. The median number of items in each survey was 10.5, and the average response rate was 73% (range: 18% to 100%). In-person distribution was the most common method (40%), followed by web-based methods (28%) and mail (25%). Response rates were highest for surveys targeted at patients (77%, P < .0001) and those delivered in-person (94%, P < .0001). The median quality score was 12/24 (range = 8.5/24 to 21/24). There was high inter-rater agreement using the quality scale (intraclass correlation coefficient = 0.92), but there was no correlation with the response rate (Rho = -0.01, P = .97). Response rates vary based on target audience and distribution methods, with patients responding at a significantly higher rate than physicians and in-person distribution yielding significantly higher response rates than web or mail surveys. Level IV, systematic review of Level IV studies. Copyright © 2017 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Differing rates of antibody acquisition to merozoite antigens in malaria: implications for immunity and surveillance.

PubMed

McCallum, Fiona J; Persson, Kristina E M; Fowkes, Freya J I; Reiling, Linda; Mugyenyi, Cleopatra K; Richards, Jack S; Simpson, Julie A; Williams, Thomas N; Gilson, Paul R; Hodder, Anthony N; Sanders, Paul R; Anders, Robin F; Narum, David L; Chitnis, Chetan; Crabb, Brendan S; Marsh, Kevin; Beeson, James G

2017-04-01

Antibodies play a key role in acquired human immunity to Plasmodium falciparum (Pf) malaria and target merozoites to reduce or prevent blood-stage replication and the development of disease. Merozoites present a complex array of antigens to the immune system, and currently, there is only a partial understanding of the targets of protective antibodies and how responses to different antigens are acquired and boosted. We hypothesized that there would be differences in the rate of acquisition of antibodies to different antigens and how well they are boosted by infection, which impacts the acquisition of immunity. We examined responses to a range of merozoite antigens in 2 different cohorts of children and adults with different age structures and levels of malaria exposure. Overall, antibodies were associated with age, exposure, and active infection, and the repertoire of responses increased with age and active infection. However, rates of antibody acquisition varied between antigens and different regions within an antigen following exposure to malaria, supporting our hypothesis. Antigen-specific responses could be broadly classified into early response types in which antibodies were acquired early in childhood exposure and late response types that appear to require substantially more exposure for the development of substantial levels. We identified antigen-specific responses that were effectively boosted after recent infection, whereas other responses were not. These findings advance our understanding of the acquisition of human immunity to malaria and are relevant to the development of malaria vaccines targeting merozoite antigens and the selection of antigens for use in malaria surveillance. © Society for Leukocyte Biology.

A neural mechanism for detecting the distance of a selected target by modulating the FM sweep rate of biosonar in echolocation of bat.

PubMed

Kamata, Eigo; Inoue, Satoru; Zheng, MeiHong; Kashimori, Yoshiki; Kambara, Takeshi

2004-01-01

Most species of bats making echolocation use frequency modulated (FM) ultrasonic pulses to measure the distance to targets. These bats detect with a high accuracy the arrival time differences between emitted pulses and their echoes generated by targets. In order to clarify the neural mechanism for echolocation, we present neural model of inferior colliculus (IC), medial geniculate body (MGB) and auditory cortex (AC) along which information of echo delay times is processed. The bats increase the downward frequency sweep rate of emitted FM pulse as they approach the target. The functional role of this modulation of sweep rate is not yet clear. In order to investigate the role, we calculated the response properties of our models of IC, MGB, and AC changing the target distance and the sweep rate. We found based on the simulations that the distance of a target in various ranges may be encoded the most clearly into the activity pattern of delay time map network in AC, when the sweep rate of FM pulse used is coincided with the observed value which the bats adopt for each range of target distance.

INFLUENCES OF RESPONSE RATE AND DISTRIBUTION ON THE CALCULATION OF INTEROBSERVER RELIABILITY SCORES

PubMed Central

Rolider, Natalie U.; Iwata, Brian A.; Bullock, Christopher E.

2012-01-01

We examined the effects of several variations in response rate on the calculation of total, interval, exact-agreement, and proportional reliability indices. Trained observers recorded computer-generated data that appeared on a computer screen. In Study 1, target responses occurred at low, moderate, and high rates during separate sessions so that reliability results based on the four calculations could be compared across a range of values. Total reliability was uniformly high, interval reliability was spuriously high for high-rate responding, proportional reliability was somewhat lower for high-rate responding, and exact-agreement reliability was the lowest of the measures, especially for high-rate responding. In Study 2, we examined the separate effects of response rate per se, bursting, and end-of-interval responding. Response rate and bursting had little effect on reliability scores; however, the distribution of some responses at the end of intervals decreased interval reliability somewhat, proportional reliability noticeably, and exact-agreement reliability markedly. PMID:23322930

Using response evaluation criteria in solid tumors in real-world evidence cancer research.

PubMed

Feinberg, Bruce A; Bharmal, Murtuza; Klink, Andrew J; Nabhan, Chadi; Phatak, Hemant

2018-05-31

Real-world evidence of charted treatment responses to cancer drug therapy was compared with medical record derived radiographic measurements of target lesions per Response Evaluation Criteria in Solid Tumors (RECIST). 15 physicians treating 59 metastatic Merkel cell cancer (mMCC) patients contributed patient-level data. A comparison of medical record reported best response with radiographic measurements per RECIST of pre- and post-treatment target lesions. RECIST response rates were significantly lower compared with medical record reported with a concordance of 43.2% (95% CI: 28.0-58.4%). Subjective assessment of tumor response collected via traditional chart abstraction may overestimate benefit and limit the potential role of real-world evidence in value-based care research. The use of target lesion measurements presents an attractive alternative that better aligns with trial results.

Stimulus-driven and knowledge-driven processes in attention to warbles

NASA Astrophysics Data System (ADS)

Dowling, W. Jay; Tillmann, Barbara

2003-10-01

Listeners identified warbles differing in amplitude-modulation rate (3-10 Hz). And measured RT while listeners maintained above 90% correct responses. After a practice session listeners identified target warbles following stimulus-driven or knowledge-driven cues. The stimulus-driven cue was a 250-ms ``beep'' at the target pitch (valid) or another pitch (invalid); the knowledge-driven cue was a midrange ``melody'' pointing to the target pitch (always valid). A 500-ms target warble followed the cue after delays of 0-500 ms (250-750 ms SOA). The listener pressed a key to indicate ``slow'' or ``fast.'' RTs were shortest at the briefest delay. In contrast to results from a memory task, RTs here were much shorter, and we found no evidence for IOR or attentional blink. Listeners began generating responses while the target was still sounding. Invalid ``beeps'' slowed responses at the briefest (but not the longer) delays; adding a valid ``beep'' to the valid ``melody'' did not speed responses.

Maximising nurses' and midwives' response rates to surveys.

PubMed

Cooper, Alannah Louise; Brown, Janie

2017-12-18

Low response rates to surveys have been a long-standing issue in research. This includes research involving nurses and midwives. To gain representative samples, appropriate measures to maximise response rates need to be used. To explore ways to maximise response rates from nurses and midwives, using a hospital-wide survey as an example. All nurses and midwives at the study hospital were invited to participate in a survey. To encourage participation and elicit an adequate response rate, several strategies were used. A total of 1,000 surveys were distributed and 319 (32%) were returned. All the required age groups, levels of experience and types of nursing registration were represented in the responses and data saturation was achieved. It is important to pay attention to obtaining a representative sample. Further investigation of response rates to surveys by nurses and midwives is warranted. Strategies to maximise response rates from a target population should be used when conducting surveys. ©2017 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

Bradycardia During Targeted Temperature Management: An Early Marker of Lower Mortality and Favorable Neurologic Outcome in Comatose Out-of-Hospital Cardiac Arrest Patients.

PubMed

Thomsen, Jakob Hartvig; Nielsen, Niklas; Hassager, Christian; Wanscher, Michael; Pehrson, Steen; Køber, Lars; Bro-Jeppesen, John; Søholm, Helle; Winther-Jensen, Matilde; Pellis, Tommaso; Kuiper, Michael; Erlinge, David; Friberg, Hans; Kjaergaard, Jesper

2016-02-01

Bradycardia is common during targeted temperature management, likely being a physiologic response to lower body temperature, and has recently been associated with favorable outcome following out-of-hospital cardiac arrest in smaller observational studies. The present study sought to confirm this finding in a large multicenter cohort of patients treated with targeted temperature management at 33°C and explore the response to targeted temperature management targeting 36°C. Post hoc analysis of a prospective randomized study. Thirty-six ICUs in 10 countries. We studied 447 (targeted temperature management = 33°C) and 430 (targeted temperature management = 36°C) comatose out-of-hospital cardiac arrest patients with available heart rate data, randomly assigned in the targeted temperature management trial from 2010 to 2013. Targeted temperature management at 33°C and 36°C. Endpoints were 180-day mortality and unfavorable neurologic function (cerebral performance category 3-5). Patients were stratified by target temperature and minimum heart rate during targeted temperature management (< 50, 50-59, and ≥ 60 beats/min [reference]) at 12, 20, and 28 hours after randomization. Heart rates less than 50 beats/min and 50-59 beats/min were recorded in 132 (30%) and 131 (29%) of the 33°C group, respectively. Crude 180-day mortality increased with increasing minimum heart rate (< 50 beats/min = 32%, 50-59 beats/min = 43%, and ≥ 60 beats/min = 60%; p(log-rank) < 0.0001). Bradycardia less than 50 beats/min was independently associated with lower 180-day mortality (hazard ratio(adjusted) = 0.50 [0.34-0.74; p < 0.001]) and lower odds of unfavorable neurologic outcome (odds ratio(adjusted) = 0.38 [ 0.21-0.68; p < 0.01]) in models adjusting for potential confounders including age, initial rhythm, time to return of spontaneous circulation, and lactate at admission. Similar, albeit less strong, independent associations of lower heart rates and favorable outcome were found in patients treated with targeted temperature management at 36°C. This study confirms an independent association of bradycardia and lower mortality and favorable neurologic outcome in a large cohort of comatose out-of-hospital cardiac arrest patients treated by targeted temperature management at 33°C. Bradycardia during targeted temperature management at 33°C may thus be a novel, early marker of favorable outcome.

Effects of differential rates of alternative reinforcement on resurgence of human behavior.

PubMed

Smith, Brooke M; Smith, Gregory S; Shahan, Timothy A; Madden, Gregory J; Twohig, Michael P

2017-01-01

Despite the success of exposure-based psychotherapies in anxiety treatment, relapse remains problematic. Resurgence, the return of previously eliminated behavior following the elimination of an alternative source of reinforcement, is a promising model of operant relapse. Nonhuman resurgence research has shown that higher rates of alternative reinforcement result in faster, more comprehensive suppression of target behavior, but also in greater resurgence when alternative reinforcement is eliminated. This study investigated rich and lean rates of alternative reinforcement on response suppression and resurgence in typically developing humans. In Phase 1, three groups (Rich, n = 18; Lean, n = 18; Control, n = 10) acquired the target response. In Phase 2, target responding was extinguished and alternative reinforcement delivered on RI 1 s, RI 3 s, and extinction schedules, respectively. Resurgence was assessed during Phase 3 under extinction conditions for all groups. Target responding was suppressed most thoroughly in Rich and partially in Lean. Target responding resurged in the Rich and Lean groups, but not in the Control group. Between groups, resurgence was more pronounced in the Rich group than the Lean and Control groups. Clinical implications of these findings, including care on the part of clinicians when identifying alternative sources of reinforcement, are discussed. © 2017 Society for the Experimental Analysis of Behavior.

Log-polar mapping-based scale space tracking with adaptive target response

NASA Astrophysics Data System (ADS)

Li, Dongdong; Wen, Gongjian; Kuai, Yangliu; Zhang, Ximing

2017-05-01

Correlation filter-based tracking has exhibited impressive robustness and accuracy in recent years. Standard correlation filter-based trackers are restricted to translation estimation and equipped with fixed target response. These trackers produce an inferior performance when encountered with a significant scale variation or appearance change. We propose a log-polar mapping-based scale space tracker with an adaptive target response. This tracker transforms the scale variation of the target in the Cartesian space into a shift along the logarithmic axis in the log-polar space. A one-dimensional scale correlation filter is learned online to estimate the shift along the logarithmic axis. With the log-polar representation, scale estimation is achieved accurately without a multiresolution pyramid. To achieve an adaptive target response, a variance of the Gaussian function is computed from the response map and updated online with a learning rate parameter. Our log-polar mapping-based scale correlation filter and adaptive target response can be combined with any correlation filter-based trackers. In addition, the scale correlation filter can be extended to a two-dimensional correlation filter to achieve joint estimation of the scale variation and in-plane rotation. Experiments performed on an OTB50 benchmark demonstrate that our tracker achieves superior performance against state-of-the-art trackers.

Conspicuity of target lights: The influence of color

NASA Technical Reports Server (NTRS)

Connors, M. M.

1975-01-01

The conspicuity (or attention-getting qualities) were investigated of foveally-equated, colored lights, when seen against a star background. Subjects who were periodically engaged in a distracting cockpit task were required to search a large visual field and report the appearance of a target light as quickly as possible. Targets were red, yellow, white, green, and blue, and appeared either as steady or as flashing lights. Results indicate that red targets were missed more frequently and responded to more slowly than lights of other hues. Yellow targets were acquired more slowly than white, green, or blue targets; responses to white targets were significantly slower than responses to green or blue targets. In general, flashing lights were superior to steady lights, but this was not found for all hues. For red, the 2 Hz flash was superior to all other flash rates and to the steady light, none of which differed significantly from each other. Over all hues, conspicuity was found to peak at 2-3 Hz. Response time was found to be fastest, generally, for targets appearing at between 3 and 8 from the center of the visual field. However, this pattern was not repeated for every hue. Conspicuity response times suggest a complex relationship between hue and position in the visual field that is explained only partially by retinal sensitivity.

[Difficulties with the prescription and administration of antibiotics in routine hospital emergency department care: a survey study].

PubMed

Monclús Cols, Ester; Nicolás Ocejo, David; Sánchez Sánchez, Miquel; Ortega Romero, Mar

2015-02-01

To detect the problems hospital emergency room staff have when prescribing and administering antibiotics. A 14-item questionnaire was designed to assess staff members' knowledge of the importance of starting antibiotic treatment promptly, assigning appropriate dosing intervals, adjusting for renal function, and switching to oral therapy. Agreement with each item was expressed on a 5-point Likert scale. Items with a rate of appropriate response of less than 75% were targeted for specific attention. Two hundred questionnaires were distributed to the staff and 150 were returned completed (response rate, 75%). The following items were targeted for attention based on rates of appropriate response of less than 75%: clear medical orders (65%), understanding the implication of early empirical antibiotic therapy on prognosis in serious infections (67%), estimation of the prevalence of renal insufficiency (42%), assumption that a creatinine serum level under < 1.6 mg/dL is safe (33%), use of glomerular filtration rate to adjust dose according to renal function (47%), and an understanding of switching from intravenous to oral treatment (60%). This study revealed the difficulties medical and nursing staff have in prescribing and administering antibiotics in a hospital emergency department. The results can facilitate improvements in antibiotic therapy by pinpointing areas to target for specific training interventions or the design of electronic prescribing aids.

Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation

NASA Technical Reports Server (NTRS)

Limoli, C. L.; Corcoran, J. J.; Milligan, J. R.; Ward, J. F.; Morgan, W. F.

1999-01-01

To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

On a problematic procedure to manipulate response biases in recognition experiments: the case of "implied" base rates.

PubMed

Bröder, Arndt; Malejka, Simone

2017-07-01

The experimental manipulation of response biases in recognition-memory tests is an important means for testing recognition models and for estimating their parameters. The textbook manipulations for binary-response formats either vary the payoff scheme or the base rate of targets in the recognition test, with the latter being the more frequently applied procedure. However, some published studies reverted to implying different base rates by instruction rather than actually changing them. Aside from unnecessarily deceiving participants, this procedure may lead to cognitive conflicts that prompt response strategies unknown to the experimenter. To test our objection, implied base rates were compared to actual base rates in a recognition experiment followed by a post-experimental interview to assess participants' response strategies. The behavioural data show that recognition-memory performance was estimated to be lower in the implied base-rate condition. The interview data demonstrate that participants used various second-order response strategies that jeopardise the interpretability of the recognition data. We thus advice researchers against substituting actual base rates with implied base rates.

Circadian rhythms of visual accommodation responses and physiological correlations.

NASA Technical Reports Server (NTRS)

Murphy, M. R.; Randle, R. J.; Williams, B. A.

1972-01-01

Use of a recently developed servocontrolled infrared optometer to continuously record the state of monocular focus while subjects viewed a visual target for which the stimulus to focus was systematically varied. Calculated parameters form recorded data - e.g., speeds of accommodation to approaching and receding targets, magnitude of accommodation to step changes in target distance, and amplitude and phase lag of response to sinusoidally varying stimuli were submitted to periodicity analyses. Ear canal temperature (ECT) and heart rate (HR) rhythms were also recorded for physiological correlation with accommodation rhythms. HR demonstrated a 24-hr rhythm, but ECT data did not.

Targeted left ventricular lead placement to guide cardiac resynchronization therapy: the TARGET study: a randomized, controlled trial.

PubMed

Khan, Fakhar Z; Virdee, Mumohan S; Palmer, Christopher R; Pugh, Peter J; O'Halloran, Denis; Elsik, Maros; Read, Philip A; Begley, David; Fynn, Simon P; Dutka, David P

2012-04-24

This study sought to assess the impact of targeted left ventricular (LV) lead placement on outcomes of cardiac resynchronization therapy (CRT). Placement of the LV lead to the latest sites of contraction and away from the scar confers the best response to CRT. We conducted a randomized, controlled trial to compare a targeted approach to LV lead placement with usual care. A total of 220 patients scheduled for CRT underwent baseline echocardiographic speckle-tracking 2-dimensional radial strain imaging and were then randomized 1:1 into 2 groups. In group 1 (TARGET [Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy]), the LV lead was positioned at the latest site of peak contraction with an amplitude of >10% to signify freedom from scar. In group 2 (control) patients underwent standard unguided CRT. Patients were classified by the relationship of the LV lead to the optimal site as concordant (at optimal site), adjacent (within 1 segment), or remote (≥2 segments away). The primary endpoint was a ≥15% reduction in LV end-systolic volume at 6 months. Secondary endpoints were clinical response (≥1 improvement in New York Heart Association functional class), all-cause mortality, and combined all-cause mortality and heart failure-related hospitalization. The groups were balanced at randomization. In the TARGET group, there was a greater proportion of responders at 6 months (70% vs. 55%, p = 0.031), giving an absolute difference in the primary endpoint of 15% (95% confidence interval: 2% to 28%). Compared with controls, TARGET patients had a higher clinical response (83% vs. 65%, p = 0.003) and lower rates of the combined endpoint (log-rank test, p = 0.031). Compared with standard CRT treatment, the use of speckle-tracking echocardiography to the target LV lead placement yields significantly improved response and clinical status and lower rates of combined death and heart failure-related hospitalization. (Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronization Therapy [TARGET] study); ISRCTN19717943). Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Inhibitory control differentiates rare target search performance in children.

PubMed

Li, Hongting; Chan, John S Y; Cheung, Sui-Yin; Yan, Jin H

2012-02-01

Age-related differences in rare-target search are primarily explained by the speed-accuracy trade-off, primed responses, or decision making. The goal was to examine how motor inhibition influences visual search. Children pressed a key when a rare target was detected. On no-target trials, children withheld reactions. Response time (RT), hits, misses, correct rejection, and false alarms were measured. Tapping tests assessed motor control. Older children tapped faster, were more sensitive to rare targets (higher d'), and reacted more slowly than younger ones. Girls outperformed boys in search sensitivity but not in RT. Motor speed was closely associated with hit rate and RT. Results suggest that development of inhibitory control plays a key role in visual detection. The potential implications for cognitive-motor development and individual differences are discussed.

Enhancing the response rate of strand displacement-based electrochemical aptamer sensors using bivalent binding aptamer-cDNA probes.

PubMed

Zhang, Ziping; Tao, Cancan; Yin, Jungang; Wang, Yunhui; Li, Yanshen

2018-04-30

Electrochemical aptamer (EA) sensors based on aptamer-cDNA duplex probes (cDNA: complementary DNA) and target induced strand displacement (TISD) recognition are sensitive, selective and capable of detecting a wide variety of target analytes. While substantial research efforts have focused on engineering of new signaling mechanisms for the improvement of sensor sensitivity, little attention was paid to the enhancement of sensor response rate. Typically, the previous TISD based EA sensors exhibited relatively long response times larger than 30min, which mainly resulted from the suboptimal aptamer-cDNA probe structure in which most of aptamer bases were paired to the cDNA bases. In an effort to improve the response rate of this type of sensors, we report here the rational engineering of a quickly responsive and sensitive aptamer-cDNA probe by employing the conception of bivalent interaction in supramolecular chemistry. We design a bivalent cDNA strand through linking two short monovalent cDNA sequences, and it is simultaneously hybridized to two electrode-immobilized aptamer probes to form a bivalent binding (BB) aptamer-cDNA probe. This class of BB probe possesses the advantages of less aptamer bases paired to the cDNA bases for quick response rate and good structural stability for high sensor sensitivity. By use of the rationally designed BB aptamer-cDNA probe, a TISD based EA sensor against ATP with significantly enhanced response rate (with a displacement equilibrium time of 4min) and high sensitivity was successfully constructed. We believe that our BB probe conception will help guide future designs and applications of TISD based EA sensors. Copyright © 2017 Elsevier B.V. All rights reserved.

Generalized IRT Models for Extreme Response Style

ERIC Educational Resources Information Center

Jin, Kuan-Yu; Wang, Wen-Chung

2014-01-01

Extreme response style (ERS) is a systematic tendency for a person to endorse extreme options (e.g., strongly disagree, strongly agree) on Likert-type or rating-scale items. In this study, we develop a new class of item response theory (IRT) models to account for ERS so that the target latent trait is free from the response style and the tendency…

Masking reduces orientation selectivity in rat visual cortex

PubMed Central

Alwis, Dasuni S.; Richards, Katrina L.

2016-01-01

In visual masking the perception of a target stimulus is impaired by a preceding (forward) or succeeding (backward) mask stimulus. The illusion is of interest because it allows uncoupling of the physical stimulus, its neuronal representation, and its perception. To understand the neuronal correlates of masking, we examined how masks affected the neuronal responses to oriented target stimuli in the primary visual cortex (V1) of anesthetized rats (n = 37). Target stimuli were circular gratings with 12 orientations; mask stimuli were plaids created as a binarized sum of all possible target orientations. Spatially, masks were presented either overlapping or surrounding the target. Temporally, targets and masks were presented for 33 ms, but the stimulus onset asynchrony (SOA) of their relative appearance was varied. For the first time, we examine how spatially overlapping and center-surround masking affect orientation discriminability (rather than visibility) in V1. Regardless of the spatial or temporal arrangement of stimuli, the greatest reductions in firing rate and orientation selectivity occurred for the shortest SOAs. Interestingly, analyses conducted separately for transient and sustained target response components showed that changes in orientation selectivity do not always coincide with changes in firing rate. Given the near-instantaneous reductions observed in orientation selectivity even when target and mask do not spatially overlap, we suggest that monotonic visual masking is explained by a combination of neural integration and lateral inhibition. PMID:27535373

Rape blame as a function of alcohol presence and resistance type.

PubMed

Sims, Calvin M; Noel, Nora E; Maisto, Stephen A

2007-12-01

Attributions of rape blame may be related to variables such as alcohol presence and resistance type used during a sexual assault. The current study sought to assess participants' attributions of responsibility for a sexual assault based on these two variables through the use of several written scenarios. Two hundred and thirteen male and female college students participated in the study. Results indicated that responsibility ratings given to the victim varied by the presence of alcohol but not by resistance type. If the female target had been drinking, she was judged as being more responsible for the assault than if she had not been drinking. However, how she resisted the assault did not affect ratings of her responsibility. Additionally, participant gender was found to not be an important factor for attributing blame to the woman target. Future research should focus on two important factors: 1) how participants' judgments of blame may change during actual alcohol administration and 2) how the use of video, rather than written vignettes, may produce stronger effects.

Ligand-based targeted therapy: a novel strategy for hepatocellular carcinoma

PubMed Central

Li, Min; Zhang, Weiyue; Wang, Birong; Gao, Yang; Song, Zifang; Zheng, Qi Chang

2016-01-01

Hepatocellular carcinoma (HCC) is the most common primary liver cancer with high morbidity and mortality worldwide. Chemotherapy is recommended to patients with intermediate or advanced stage cancer. However, the conventional chemotherapy yields low desired response rates due to multidrug resistance, fast clearance rate, nonspecific delivery, severe side effects, low drug concentration in cancer cells, and so on. Nanoparticle-mediated targeted drug delivery system can surmount the aforementioned obstacles through enhanced permeability and retention effect and active targeting as a novel approach of therapeutics for HCC in recent years. The active targeting is triggered by ligands on the delivery system, which recognize with and internalize into hepatoma cells with high specificity and efficiency. This review focuses on the latest targeted delivery systems for HCC and summarizes the ligands that can enhance the capacity of active targeting, to provide some insight into future research in nanomedicine for HCC. PMID:27920520

Event related potentials during covert orientation of visual attention: effects of cue validity and directionality.

PubMed

Wright, M J; Geffen, G M; Geffen, L B

1995-10-01

Covert orientation of attention was studied in 30 adults who fixated warning cues and pressed a button at target onset. Directional cues (arrows) indicated the most probable (p = 0.8) side of target occurrence. Subjects responded fastest when validly cued, slowest to invalidly cued targets, and at an intermediate rate when the cue (a cross) was not directional. Directional cues took longer to evaluate (increased N1 and P2 latencies) and produced more focussed attention and greater response preparation (enhanced CNV and P3 amplitude) than non-directional cues. These findings indicate that the expectancy of a target can be manipulated by a spatial cue at three levels, sensory, attention, and response preparation, and lead to changes in the sensory perceptual processing of the target. Validly cued targets produced an increase in P1 amplitude reflecting attention enhanced sensory processing whereas invalidly cued targets increased N1 and P3 amplitudes reflecting the re-orientation of attention, and further processing and updating of information required of low probability stimuli respectively. P3 latency to invalidly cued targets was also delayed reflecting the additional processes required to shift attention to a new location. The P3 latency validity effect was smaller than that found for response time suggesting response execution may also be affected by spatial attention.

Real-Time Gas Identification by Analyzing the Transient Response of Capillary-Attached Conductive Gas Sensor

PubMed Central

Bahraminejad, Behzad; Basri, Shahnor; Isa, Maryam; Hambli, Zarida

2010-01-01

In this study, the ability of the Capillary-attached conductive gas sensor (CGS) in real-time gas identification was investigated. The structure of the prototype fabricated CGS is presented. Portions were selected from the beginning of the CGS transient response including the first 11 samples to the first 100 samples. Different feature extraction and classification methods were applied on the selected portions. Validation of methods was evaluated to study the ability of an early portion of the CGS transient response in target gas (TG) identification. Experimental results proved that applying extracted features from an early part of the CGS transient response along with a classifier can distinguish short-chain alcohols from each other perfectly. Decreasing time of exposition in the interaction between target gas and sensing element improved the reliability of the sensor. Classification rate was also improved and time of identification was decreased. Moreover, the results indicated the optimum interval of the early transient response of the CGS for selecting portions to achieve the best classification rates. PMID:22219666

Different Neuroplasticity for Task Targets and Distractors

PubMed Central

Spingath, Elsie Y.; Kang, Hyun Sug; Plummer, Thane; Blake, David T.

2011-01-01

Adult learning-induced sensory cortex plasticity results in enhanced action potential rates in neurons that have the most relevant information for the task, or those that respond strongly to one sensory stimulus but weakly to its comparison stimulus. Current theories suggest this plasticity is caused when target stimulus evoked activity is enhanced by reward signals from neuromodulatory nuclei. Prior work has found evidence suggestive of nonselective enhancement of neural responses, and suppression of responses to task distractors, but the differences in these effects between detection and discrimination have not been directly tested. Using cortical implants, we defined physiological responses in macaque somatosensory cortex during serial, matched, detection and discrimination tasks. Nonselective increases in neural responsiveness were observed during detection learning. Suppression of responses to task distractors was observed during discrimination learning, and this suppression was specific to cortical locations that sampled responses to the task distractor before learning. Changes in receptive field size were measured as the area of skin that had a significant response to a constant magnitude stimulus, and these areal changes paralleled changes in responsiveness. From before detection learning until after discrimination learning, the enduring changes were selective suppression of cortical locations responsive to task distractors, and nonselective enhancement of responsiveness at cortical locations selective for target and control skin sites. A comparison of observations in prior studies with the observed plasticity effects suggests that the non-selective response enhancement and selective suppression suffice to explain known plasticity phenomena in simple spatial tasks. This work suggests that differential responsiveness to task targets and distractors in primary sensory cortex for a simple spatial detection and discrimination task arise from nonselective increases in response over a broad cortical locus that includes the representation of the task target, and selective suppression of responses to the task distractor within this locus. PMID:21297962

Target representation of naturalistic echolocation sequences in single unit responses from the inferior colliculus of big brown bats

NASA Astrophysics Data System (ADS)

Sanderson, Mark I.; Simmons, James A.

2005-11-01

Echolocating big brown bats (Eptesicus fuscus) emit trains of frequency-modulated (FM) biosonar signals whose duration, repetition rate, and sweep structure change systematically during interception of prey. When stimulated with a 2.5-s sequence of 54 FM pulse-echo pairs that mimic sounds received during search, approach, and terminal stages of pursuit, single neurons (N=116) in the bat's inferior colliculus (IC) register the occurrence of a pulse or echo with an average of <1 spike/sound. Individual IC neurons typically respond to only a segment of the search or approach stage of pursuit, with fewer neurons persisting to respond in the terminal stage. Composite peristimulus-time-histogram plots of responses assembled across the whole recorded population of IC neurons depict the delay of echoes and, hence, the existence and distance of the simulated biosonar target, entirely as on-response latencies distributed across time. Correlated changes in pulse duration, repetition rate, and pulse or echo amplitude do modulate the strength of responses (probability of the single spike actually occurring for each sound), but registration of the target itself remains confined exclusively to the latencies of single spikes across cells. Modeling of echo processing in FM biosonar should emphasize spike-time algorithms to explain the content of biosonar images.

The Decision To Recruit Online: A Descriptive Study.

ERIC Educational Resources Information Center

Galanaki, Eleanna

2002-01-01

Responses from 34 of 99 United Kingdom information technology companies explored effects of cost effectiveness, response rate and quality, company image, targeting, time and effort, and overload. The effectiveness of online recruiting depends largely on its implementation and the quality of the recruitment process as a whole. (Contains 38…

Specificity of the Human Frequency Following Response for Carrier and Modulation Frequency Assessed Using Adaptation.

PubMed

Gockel, Hedwig E; Krugliak, Alexandra; Plack, Christopher J; Carlyon, Robert P

2015-12-01

The frequency following response (FFR) is a scalp-recorded measure of phase-locked brainstem activity to stimulus-related periodicities. Three experiments investigated the specificity of the FFR for carrier and modulation frequency using adaptation. FFR waveforms evoked by alternating-polarity stimuli were averaged for each polarity and added, to enhance envelope, or subtracted, to enhance temporal fine structure information. The first experiment investigated peristimulus adaptation of the FFR for pure and complex tones as a function of stimulus frequency and fundamental frequency (F0). It showed more adaptation of the FFR in response to sounds with higher frequencies or F0s than to sounds with lower frequency or F0s. The second experiment investigated tuning to modulation rate in the FFR. The FFR to a complex tone with a modulation rate of 213 Hz was not reduced more by an adaptor that had the same modulation rate than by an adaptor with a different modulation rate (90 or 504 Hz), thus providing no evidence that the FFR originates mainly from neurons that respond selectively to the modulation rate of the stimulus. The third experiment investigated tuning to audio frequency in the FFR using pure tones. An adaptor that had the same frequency as the target (213 or 504 Hz) did not generally reduce the FFR to the target more than an adaptor that differed in frequency (by 1.24 octaves). Thus, there was no evidence that the FFR originated mainly from neurons tuned to the frequency of the target. Instead, the results are consistent with the suggestion that the FFR for low-frequency pure tones at medium to high levels mainly originates from neurons tuned to higher frequencies. Implications for the use and interpretation of the FFR are discussed.

Response-to-Intervention in California Public Schools: Has It Helped Address Disproportional Placement Rates for Students with Learning Disabilities?

ERIC Educational Resources Information Center

Bouman, Sam H.

2010-01-01

Response-to-intervention (RTI) as applied in several California school districts was investigated by analyzing responses to questionnaires completed by 190 school psychologists representing 142 school districts. This analysis targeted the depth and breadth of RTI in these public K-12 school districts. A majority (80.7%) of the respondents…

I Don't Know It but I Like You: The Influence of Nonconscious Affect on Person Perception.

ERIC Educational Resources Information Center

Monahan, Jennifer L.

1998-01-01

Proposes a model of unconscious affect. Tests predictions about the influence of nonconscious affect on evaluations made of undergraduate student conversational interactants. Uses a subliminal priming task to induce a positive nonconscious affective response toward the target persons. Rates primed target as more likable and attractive yet not more…

The Enhancement of Phototropin-Induced Phototropic Curvature in Arabidopsis Occurs via a Photoreversible Phytochrome A-Dependent Modulation of Auxin Responsiveness1

PubMed Central

Stowe-Evans, Emily L.; Luesse, Darron R.; Liscum, Emmanuel

2001-01-01

The induction of phototropism in etiolated (dark-grown) seedlings exposed to an unidirectional pulse or extended irradiation with low fluence rate blue light (BL) requires the action of the phototropin (nph1) BL receptor. Although cryptochromes and phytochromes are not required for phototropic induction, these photoreceptors do modulate the magnitude of curvature resulting from phototropin activation. Modulatory increases in the magnitude of phototropic curvature have been termed “enhancement.” Here, we show that phototropic enhancement is primarily a phytochrome A (phyA)-dependent red/far-red-reversible low fluence response. This phyA-dependent response is genetically separable from the basal phototropin-dependent response, as demonstrated by its retention under extended irradiation conditions in the nph4 mutant background, which normally lacks the basal BL-induced response. It is interesting that the nph4 mutants fail to exhibit the basal phototropin-dependent and phyA-dependent enhancement responses under limiting light conditions. Given that NPH4 encodes a transcriptional activator, auxin response factor 7 (ARF7), we hypothesize that the ultimate target(s) of phyA action during the phototropic enhancement response is a rate-limiting ARF-containing transcriptional complex in which the constituent ARFs can vary in identity or activity depending upon the irradiation condition. PMID:11402210

Cognitive biases toward Internet game-related pictures and executive deficits in individuals with an Internet game addiction.

PubMed

Zhou, Zhenhe; Yuan, Guozhen; Yao, Jianjun

2012-01-01

The cue-related go/no-go switching task provides an experimental approach to study individual's flexibility in changing situations. Because Internet addiction disorder (IAD) belongs to the compulsive-impulsive spectrum of disorders, it should present cognitive bias and executive functioning deficit characteristics of some of these types of disorders. Until now, no studies have been reported on cognitive bias and executive function involving mental flexibility and response inhibition in IAD. A total of 46 subjects who met the criteria of the modified Young's Diagnostic Questionnaire for Internet addiction (YDQ) were recruited as an Internet game addiction (IGA) group, along with 46 healthy control individuals. All participants performed the Internet game-shifting task. Using hit rate, RT, d' and C as the dependent measures, a three-way ANOVA (group × target × condition) was performed. For hit rate, a significant effect of group, type of target and condition were found. The group-target interaction effect was significant. For RT, significant effects were revealed for group and type of target. The group-target interaction effect was significant. Comparisons of the means revealed that the slowing down of IGA relative to NIA was more pronounced when the target stimuli were neutral as opposed to Internet game-related pictures. In addition, the group-condition interaction effect was significant. For d', significant effects of group, type of target and condition were found. The group-target interaction effect was significant. For C, the type of target produced a significant effect. There was a positive correlation between the length of the addiction (number of years) and the severity of the cognitive bias. IGA present cognitive biases towards information related to Internet gaming. These biases, as well as poor executive functioning skills (lower mental flexibility and response inhibition), might be responsible for Internet game addiction. The assessment of cognitive biases in IGA might provide a methodology for evaluation of therapeutic effects.

A mathematical analysis of rebound in a target-mediated drug disposition model: II. With feedback.

PubMed

Aston, Philip J; Derks, Gianne; Agoram, Balaji M; van der Graaf, Piet H

2017-07-01

We consider the possibility of free receptor (antigen/cytokine) levels rebounding to higher than the baseline level after the application of an antibody drug using a target-mediated drug disposition model. It is assumed that the receptor synthesis rate experiences homeostatic feedback from the receptor levels. It is shown for a very fast feedback response, that the occurrence of rebound is determined by the ratio of the elimination rates, in a very similar way as for no feedback. However, for a slow feedback response, there will always be rebound. This result is illustrated with an example involving the drug efalizumab for patients with psoriasis. It is shown that slow feedback can be a plausible explanation for the observed rebound in this example.

The Stranger effect: the rejection of affective deviants.

PubMed

Szczurek, Lauren; Monin, Benoît; Gross, James J

2012-10-01

What happens when affective displays deviate from normative expectations? In this study, participants evaluated target individuals displaying flat, incongruent, or congruent expressions seemingly in response to pictures eliciting positive, neutral, or negative affect. Relative to targets who displayed normative reactions, those who violated affective norms (affective deviants) were rated more negatively on various dimensions of social judgment. Participants also preferred greater social distance from affective deviants, reported more moral outrage in response to them, and inferred that these targets did not share their moral values. Incongruent affect resulted in more negative social judgment than did flat affect, and this relationship was moderated by stimulus valence. Finally, the relationship between targets' affective expressions and participants' avoidant intentions was mediated by the extent to which participants thought the targets shared their moral values. These findings demonstrate the interpersonal costs of affective deviance, revealing the pervasiveness and force of affective norms.

Evaluation of biofidelity of THUMS pedestrian model under a whole-body impact conditions with a generic sedan buck.

PubMed

Wu, Taotao; Kim, Taewung; Bollapragada, Varun; Poulard, David; Chen, Huipeng; Panzer, Matthew B; Forman, Jason L; Crandall, Jeff R; Pipkorn, Bengt

2017-05-29

The goal of this study was to evaluate the biofidelity of the Total Human Model for Safety (THUMS; Ver. 4.01) pedestrian finite element models (PFEM) in a whole-body pedestrian impact condition using a well-characterized generic pedestrian buck model. The biofidelity of THUMS PFEM was evaluated with respect to data from 3 full-scale postmortem human subject (PMHS) pedestrian impact tests, in which a pedestrian buck laterally struck the subjects using a pedestrian buck at 40 km/h. The pedestrian model was scaled to match the anthropometry of the target subjects and then positioned to match the pre-impact postures of the target subjects based on the 3-dimensional motion tracking data obtained during the experiments. An objective rating method was employed to quantitatively evaluate the correlation between the responses of the models and the PMHS. Injuries in the models were predicted both probabilistically and deterministically using empirical injury risk functions and strain measures, respectively, and compared with those of the target PMHS. In general, the model exhibited biofidelic kinematic responses (in the Y-Z plane) regarding trajectories (International Organization for Standardization [ISO] ratings: Y = 0.90 ± 0.11, Z = 0.89 ± 0.09), linear resultant velocities (ISO ratings: 0.83 ± 0.07), accelerations (ISO ratings: Y = 0.58 ± 0.11, Z = 0.52 ± 0.12), and angular velocities (ISO ratings: X = 0.48 ± 0.13) but exhibited stiffer leg responses and delayed head responses compared to those of the PMHS. This indicates potential biofidelity issues with the PFEM for regions below the knee and in the neck. The model also demonstrated comparable reaction forces at the buck front-end regions to those from the PMHS tests. The PFEM generally predicted the injuries that the PMHS sustained but overestimated injuries in the ankle and leg regions. Based on the data considered, the THUMS PFEM was considered to be biofidelic for this pedestrian impact condition and vehicle. Given the capability of the model to reproduce biomechanical responses, it shows potential as a valuable tool for developing novel pedestrian safety systems.

Structure of the Francisella response regulator QseB receiver domain, and characterization of QseB inhibition by antibiofilm 2-aminoimidazole-based compounds: Inhibition of response regulator QseB by antibiofilm compounds

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

Milton, Morgan E.; Allen, C. Leigh; Feldmann, Erik A.

With antibiotic resistance increasing at alarming rates, targets for new antimicrobial therapies must be identified. A particularly promising target is the bacterial two-component system. Two-component systems allow bacteria to detect, evaluate and protect themselves against changes in the environment, such as exposure to antibiotics and also to trigger production of virulence factors. Drugs that target the response regulator portion of two-component systems represent a potent new approach so far unexploited. Here, we focus efforts on the highly virulent bacterium Francisella tularensis tularensis. Francisella contains only three response regulators, making it an ideal system to study. In this study, we initiallymore » present the structure of the N-terminal domain of QseB, the response regulator responsible for biofilm formation. Subsequently, using binding assays, computational docking and cellular studies, we show that QseB interacts with2-aminoimidazole based compounds that impede its function. This information will assist in tailoring compounds to act as adjuvants that will enhance the effect of antibiotics.« less

Low Voltage Activated Calcium Channels - Their Role in HER2 Driven Breast Cancer and Potential as a New Therapeutic Target

DTIC Science & Technology

2016-10-01

combined with chemotherapy , but chemotherapy causes undesirable side effects due to off-target effects on normal tissue, which diminishes quality of life...highest response rates when combined with chemotherapy , but chemotherapy causes undesirable side effects due to off-target effects on normal...patients. Therefore, the overall goal of this proposal is to develop a tumor-specific, safe and effective therapy for breast cancer. We concentrate on

How effective are the ESC/EAS and 2013 ACC/AHA guidelines in treating dyslipidemia? Lessons from a lipid clinic.

PubMed

Barkas, Fotios; Milionis, Haralampos; Kostapanos, Michael S; Mikhailidis, Dimitri P; Elisaf, Moses; Liberopoulos, Evangelos

2015-02-01

There is a paucity of data regarding the attainment of lipid-lowering treatment goals according to the recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The aim of the present study was to assess how applicable these 2013 recommendations are in the setting of an Outpatient University Hospital Lipid Clinic. This was a retrospective (from 1999 to 2013) observational study including 1000 consecutive adults treated for hyperlipidemia and followed up for ≥3 years. Comparisons for the applicability of current European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) and recent ACC/AHA guidelines were performed. Achievement rates of low density lipoprotein cholesterol (LDL-C) targets set by ESC/EAS were 21%, 44% and 62% among patients at very high, high and moderate cardiovascular risk, respectively, receiving statin monotherapy. Among individuals on high-intensity statins only 47% achieved the anticipated ≥50% LDL-C reduction, i.e. the ACC/AHA target. The corresponding rate was significantly greater among those on statin + ezetimibe (76%, p < 0.05). Likewise, higher rates of LDL-C target attainment according to ESC/EAS guidelines were observed in patients on statin + ezetimibe compared with statin monotherapy (37, 50 and 71% for the three risk groups, p < 0.05 for the very high risk group). The application of the ACC/AHA guidelines may be associated with undertreatment of high risk patients due to suboptimal LDL-C response to high-intensity statins in clinical practice. Adding ezetimibe substantially increases the rate of the ESC/EAS LDL-C target achievement together with the rate of LDL-C lowering response suggested by the ACC/AHA.

Attributions of Responsibility and Blame for Procrastination Behavior.

PubMed

Rahimi, Sonia; Hall, Nathan C; Pychyl, Timothy A

2016-01-01

The present study examined the relationship between procrastination, delay, blameworthiness, and moral responsibility. Undergraduate students (N = 240) were provided two scenarios in which the reason for inaction (procrastination, delay), the target (self, other), and the outcome (positive, negative) were manipulated, and students were asked to rate the moral responsibility and blameworthiness of the agent. Results indicated that individuals who procrastinated were seen as more morally responsible and blameworthy than those who experienced delay. More specifically, after a negative outcome, procrastination was associated with more moral responsibility, whereas delay was associated with less moral responsibility. After a positive outcome, individuals perceived procrastination as deserving of less moral responsibility, and delays as associated with more moral responsibility. Finally, a three-way interaction showed that participants rated procrastination that resulted in failure as deserving of responsibility when engaged in by others as opposed to oneself.

Unconscious response priming during continuous flash suppression

PubMed Central

Grassini, Simone

2018-01-01

Continuous flash suppression (CFS) has become a popular tool for studying unconscious processing, but the level at which unconscious processing of visual stimuli occurs under CFS is not clear. Response priming is a robust and well-understood phenomenon, in which the prime stimulus facilitates overt responses to targets if the prime and target are associated with the same response. We used CFS to study unconscious response priming of shape: arrows with left or right orientation served as primes and targets. The prime was presented near the limen of consciousness and each trial was followed by subjective rating of visibility and a forced-choice response concerning the orientation of the prime in counterbalanced order. In trials without any reported awareness of the presence of the prime, discrimination of the prime’s orientation was at chance level. However, priming was elicited in such unconscious trials. Unconscious priming was not influenced by the prime-target onset-asynchrony (SOA)/prime duration, whereas conscious processing, as indicated by the enhanced discriminability of the prime’s orientation and conscious priming, increased at the longest SOAs/prime durations. These results show that conscious and unconscious processes can be dissociated with CFS and that CFS-masking does not completely suppress unconscious visual processing of shape. PMID:29401503

Intolerance of Uncertainty Predicts Anxiety Outcomes Following CBT in Youth with ASD

ERIC Educational Resources Information Center

Keefer, Amy; Kreiser, Nicole L.; Singh, Vini; Blakeley-Smith, Audrey; Duncan, Amie; Johnson, Catherine; Klinger, Laura; Meyer, Allison; Reaven, Judy; Vasa, Roma A.

2017-01-01

Modified cognitive-behavioral therapy (MCBT) has been demonstrated to reduce anxiety in youth with autism spectrum disorder (ASD). However, non-response rates are fairly high. Few studies have investigated factors associated with response. Intolerance of uncertainty (IU) is a treatment target for anxiety and worry in neurotypical populations and…

Emerging drugs for head and neck cancer

PubMed Central

Wen, Yihui; Grandis, Jennifer R

2017-01-01

Introduction Despite improvements in treatment, survival rates of head and neck squamous cell carcinoma (HNSCC) are stagnant. The existing chemotherapeutic agents are non-selective and associated with toxicities. Combinations of the only the US FDA-approved epidermal growth factor receptor (EGFR)-targeted agent, cetuximab, with chemotherapy or radiation improves overall survival. However, the response rates to cetuximab are modest. Thus, there is an urgent need for new agents that can be safely integrated into current treatment regimens to improve outcome. Areas covered Current EGFR-targeted drugs under clinical development include mAbs and tyrosine kinase inhibitors. The modest efficacy of these drugs implicates intrinsic or acquired resistance. Novel molecular agents inhibiting alternative targets to overcome anti-EGFR resistance in HNSCC are under investigation. Gene therapy and immunotherapy are also promising strategies to improve efficacy and reduce toxicity. Expert opinion To date, only six drugs have been FDA-approved for the treatment of head and neck cancer. Cetuximab is the only approved molecular targeting agent for HNSCC and despite ubiquitous expression of EGFR in HNSCC tumors, clinical responses are limited. Genetic and epigenetic characterization of HNSCC tumors, coupled with improved preclinical models, should facilitate the development of more effective drugs. PMID:25826749

State-Targeted Funding and Technical Assistance to Increase Access to Medication Treatment for Opioid Use Disorder.

PubMed

Abraham, Amanda J; Andrews, Christina M; Grogan, Colleen M; Pollack, Harold A; D'Aunno, Thomas; Humphreys, Keith; Friedmann, Peter D

2018-04-01

As the United States grapples with an opioid epidemic, expanding access to effective treatment for opioid use disorder is a major public health priority. Identifying effective policy tools that can be used to expand access to care is critically important. This article examines the relationship between state-targeted funding and technical assistance and adoption of three medications for treating opioid use disorder: oral naltrexone, injectable naltrexone, and buprenorphine. This study draws from the 2013-2014 wave of the National Drug Abuse Treatment System Survey, a nationally representative, longitudinal study of substance use disorder treatment programs. The sample includes data from 695 treatment programs (85.5% response rate) and representatives from single-state agencies in 49 states and Washington, D.C. (98% response rate). Logistic regression was used to examine the relationships of single-state agency targeted funding and technical assistance to availability of opioid use disorder medications among treatment programs. State-targeted funding was associated with increased program-level adoption of oral naltrexone (adjusted odds ratio [AOR]=3.14, 95% confidence interval [CI]=1.49-6.60, p=.004) and buprenorphine (AOR=2.47, 95% CI=1.31-4.67, p=.006). Buprenorphine adoption was also correlated with state technical assistance to support medication provision (AOR=1.18, 95% CI=1.00-1.39, p=.049). State-targeted funding for medications may be a viable policy lever for increasing access to opioid use disorder medications. Given the historically low rates of opioid use disorder medication adoption in treatment programs, single-state agency targeted funding is a potentially important tool to reduce mortality and morbidity associated with opioid disorders and misuse.

How does aging affect the types of error made in a visual short-term memory ‘object-recall’ task?

PubMed Central

Sapkota, Raju P.; van der Linde, Ian; Pardhan, Shahina

2015-01-01

This study examines how normal aging affects the occurrence of different types of incorrect responses in a visual short-term memory (VSTM) object-recall task. Seventeen young (Mean = 23.3 years, SD = 3.76), and 17 normally aging older (Mean = 66.5 years, SD = 6.30) adults participated. Memory stimuli comprised two or four real world objects (the memory load) presented sequentially, each for 650 ms, at random locations on a computer screen. After a 1000 ms retention interval, a test display was presented, comprising an empty box at one of the previously presented two or four memory stimulus locations. Participants were asked to report the name of the object presented at the cued location. Errors rates wherein participants reported the names of objects that had been presented in the memory display but not at the cued location (non-target errors) vs. objects that had not been presented at all in the memory display (non-memory errors) were compared. Significant effects of aging, memory load and target recency on error type and absolute error rates were found. Non-target error rate was higher than non-memory error rate in both age groups, indicating that VSTM may have been more often than not populated with partial traces of previously presented items. At high memory load, non-memory error rate was higher in young participants (compared to older participants) when the memory target had been presented at the earliest temporal position. However, non-target error rates exhibited a reversed trend, i.e., greater error rates were found in older participants when the memory target had been presented at the two most recent temporal positions. Data are interpreted in terms of proactive interference (earlier examined non-target items interfering with more recent items), false memories (non-memory items which have a categorical relationship to presented items, interfering with memory targets), slot and flexible resource models, and spatial coding deficits. PMID:25653615

How does aging affect the types of error made in a visual short-term memory 'object-recall' task?

PubMed

Sapkota, Raju P; van der Linde, Ian; Pardhan, Shahina

2014-01-01

This study examines how normal aging affects the occurrence of different types of incorrect responses in a visual short-term memory (VSTM) object-recall task. Seventeen young (Mean = 23.3 years, SD = 3.76), and 17 normally aging older (Mean = 66.5 years, SD = 6.30) adults participated. Memory stimuli comprised two or four real world objects (the memory load) presented sequentially, each for 650 ms, at random locations on a computer screen. After a 1000 ms retention interval, a test display was presented, comprising an empty box at one of the previously presented two or four memory stimulus locations. Participants were asked to report the name of the object presented at the cued location. Errors rates wherein participants reported the names of objects that had been presented in the memory display but not at the cued location (non-target errors) vs. objects that had not been presented at all in the memory display (non-memory errors) were compared. Significant effects of aging, memory load and target recency on error type and absolute error rates were found. Non-target error rate was higher than non-memory error rate in both age groups, indicating that VSTM may have been more often than not populated with partial traces of previously presented items. At high memory load, non-memory error rate was higher in young participants (compared to older participants) when the memory target had been presented at the earliest temporal position. However, non-target error rates exhibited a reversed trend, i.e., greater error rates were found in older participants when the memory target had been presented at the two most recent temporal positions. Data are interpreted in terms of proactive interference (earlier examined non-target items interfering with more recent items), false memories (non-memory items which have a categorical relationship to presented items, interfering with memory targets), slot and flexible resource models, and spatial coding deficits.

Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics.

PubMed

Mo, Charlie Y; Manning, Sara A; Roggiani, Manuela; Culyba, Matthew J; Samuels, Amanda N; Sniegowski, Paul D; Goulian, Mark; Kohli, Rahul M

2016-01-01

The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in promoting survival and the evolution of resistance under antibiotic stress. As a result, targeting the SOS response has been proposed as an adjuvant strategy to revitalize our current antibiotic arsenal. However, the optimal molecular targets and partner antibiotics for such an approach remain unclear. In this study, focusing on the two key regulators of the SOS response, LexA and RecA, we provide the first comprehensive assessment of how to target the SOS response in order to increase bacterial susceptibility and reduce mutagenesis under antibiotic treatment.

Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics

PubMed Central

Mo, Charlie Y.; Manning, Sara A.; Roggiani, Manuela; Culyba, Matthew J.; Samuels, Amanda N.; Sniegowski, Paul D.; Goulian, Mark

2016-01-01

ABSTRACT The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in promoting survival and the evolution of resistance under antibiotic stress. As a result, targeting the SOS response has been proposed as an adjuvant strategy to revitalize our current antibiotic arsenal. However, the optimal molecular targets and partner antibiotics for such an approach remain unclear. In this study, focusing on the two key regulators of the SOS response, LexA and RecA, we provide the first comprehensive assessment of how to target the SOS response in order to increase bacterial susceptibility and reduce mutagenesis under antibiotic treatment. PMID:27536734

Web-Based Recruitment and Survey Methodology to Maximize Response Rates from Followers of Popular Diets: the Adhering to Dietary Approaches for Personal Taste (ADAPT) Feasibility Survey

PubMed Central

Karlsen, Micaela C; Lichtenstein, Alice H; Economos, Christina D; Folta, Sara C; Rogers, Gail; Jacques, Paul F; Livingston, Kara A; Rancaño, Katherine M; McKeown, Nicola M

2018-01-01

Abstract Background Although there is interest in popular diets such as vegan and vegetarian, Paleo, and other “whole food” diets, existing cohort studies lack data for these subgroups. The use of electronic data capture and Web-based surveys in nutrition research may be valuable for future studies by allowing targeting of specific dietary subgroups. Objective The aim was to perform a Feasibility Survey (FS) to assess the practicality of Web-based research methods to gather data and to maximize response rates among followers of popular diets. Methods The FS was an open, voluntary, 15-min survey conducted over 8 wk in the summer of 2015. Recruitment targeted self-identified followers of popular diets from a convenience sample, offering no incentives, via social media and e-newsletters shared by recruitment partners. Feasibility was assessed by number of responses, survey completion rate, distribution of diets, geographic location, and willingness to participate in future research. Results A total of 14,003 surveys were initiated; 13,787 individuals consented, and 9726 completed the survey (71% of consented). The numbers of unique visitors to the questionnaire site, view rate, and participation rate were not captured. Among respondents with complete demographic data, 83% were female and 93% were white. Diet designations were collapsed into the following groups: whole-food, plant-based (25%); vegan and raw vegan (19%); Paleo (14%); try to eat healthy (11%); vegetarian and pescatarian (9%); whole food (8%); Weston A Price (5%); and low-carbohydrate (low-carb) (4%). Forced-response, multiple-choice questions produced the highest response rates (0–2% selected “prefer not to answer”). The percentage who were willing to complete future online questionnaires was 86%, diet recall was 93%, and food diary was 75%; the percentages willing to provide a finger-stick blood sample, venipuncture blood sample, urine sample, and stool sample were 60%, 44%, 58%, and 42%, respectively. Conclusions This survey suggests that recruiting followers of popular diets is feasible with the use of Web-based methods. The unbalanced sample with respect to sex and race/ethnicity could be corrected with specific recruitment strategies using targeted online marketing techniques. PMID:29955724

Response time scores on a reflexive attention task predict a child's inattention score from a parent report.

PubMed

Lundwall, Rebecca A; Sgro, Jordan F; Fanger, Julia

2018-01-01

Compared to sustained attention, only a small proportion of studies examine reflexive attention as a component of everyday attention. Understanding the significance of reflexive attention to everyday attention may inform better treatments for attentional disorders. Children from a general population (recruited when they were from 9-16 years old) completed an exogenously-cued task measuring the extent to which attention is captured by peripheral cue-target conditions. Parents completed a questionnaire reporting their child's day-to-day attention. A general linear model indicated that parent-rated inattention predicted the increase in response time over baseline when a bright cue preceded the target (whether it was valid or invalid) but not when a dim cue preceded the target. More attentive children had more pronounced response time increases from baseline. Our findings suggest a link between a basic measure of cognition (response time difference scores) and parent observations. The findings have implications for increased understanding of the role of reflexive attention in the everyday attention of children.

Directing driver attention with augmented reality cues

PubMed Central

Rusch, Michelle L.; Schall, Mark C.; Gavin, Patrick; Lee, John D.; Dawson, Jeffrey D.; Vecera, Shaun; Rizzo, Matthew

2013-01-01

This simulator study evaluated the effects of augmented reality (AR) cues designed to direct the attention of experienced drivers to roadside hazards. Twenty-seven healthy middle-aged licensed drivers with a range of attention capacity participated in a 54 mile (1.5 hour) drive in an interactive fixed-base driving simulator. Each participant received AR cues to potential roadside hazards in six simulated straight (9 mile long) rural roadway segments. Drivers were evaluated on response time for detecting a potentially hazardous event, detection accuracy for target (hazard) and non-target objects, and headway with respect to the hazards. Results showed no negative outcomes associated with interference. AR cues did not impair perception of non-target objects, including for drivers with lower attentional capacity. Results showed near significant response time benefits for AR cued hazards. AR cueing increased response rate for detecting pedestrians and warning signs but not vehicles. AR system false alarms and misses did not impair driver responses to potential hazards. PMID:24436635

Detecting target changes in multiple object tracking with peripheral vision: More pronounced eccentricity effects for changes in form than in motion.

PubMed

Vater, Christian; Kredel, Ralf; Hossner, Ernst-Joachim

2017-05-01

In the current study, dual-task performance is examined with multiple-object tracking as a primary task and target-change detection as a secondary task. The to-be-detected target changes in conditions of either change type (form vs. motion; Experiment 1) or change salience (stop vs. slowdown; Experiment 2), with changes occurring at either near (5°-10°) or far (15°-20°) eccentricities (Experiments 1 and 2). The aim of the study was to test whether changes can be detected solely with peripheral vision. By controlling for saccades and computing gaze distances, we could show that participants used peripheral vision to monitor the targets and, additionally, to perceive changes at both near and far eccentricities. Noticeably, gaze behavior was not affected by the actual target change. Detection rates as well as response times generally varied as a function of change condition and eccentricity, with faster detections for motion changes and near changes. However, in contrast to the effects found for motion changes, sharp declines in detection rates and increased response times were observed for form changes as a function of the eccentricities. This result can be ascribed to properties of the visual system, namely to the limited spatial acuity in the periphery and the comparably receptive motion sensitivity of peripheral vision. These findings show that peripheral vision is functional for simultaneous target monitoring and target-change detection as saccadic information suppression can be avoided and covert attention can be optimally distributed to all targets. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

CCK response in bulimia nervosa and following remission

PubMed Central

Hannon-Engel, Sandra L.; Filin, Evgeniy E.; Wolfe, Barbara E.

2013-01-01

The core defining features of bulimia nervosa (BN) are repeated binge eating episodes and inappropriate compensatory (e.g. purging) behavior. Previous studies suggest an abnormal postprandial response in the satiety-signaling peptide cholecystokinin (CCK) in persons with BN. It is unknown whether this altered response persists following remission or if it may be a potential target for the development of clinical treatment strategies. To examine the nature of this altered response, this study assessed whether CCK normalizes following remission from BN (RBN). This study prospectively evaluated the plasma CCK response and corresponding eating behavior-related ratings (e.g. satiety, fullness, hunger, urge to binge and vomit) in individuals with BN-purging subtype (n=10), RBN-purging subtype (n =14), and healthy controls (CON, n=13) at baseline, +15, +30, and +60 minutes following the ingestion of a standardized liquid test meal. Subject groups did not significantly differ in CCK response to the test meal. A significant relationship between CCK response and satiety ratings was observed in the RBN group (r=.59, p<.05 two-tailed). A new and unanticipated finding in the BN group was a significant relationship between CCK response and ratings of “urge to vomit” (r=.86, p < .01, two-tailed). Unlike previous investigations CCK response did not differ in BN and CON groups. Thus the role of symptom severity remains an area of further investigation. Additionally, findings suggest that in this sample, CCK functioning following remission from BN-purging subtype is not different from controls. It remains unknown whether or not CCK functioning may be a protective or liability factor in the stabilization and recovery process. Replication studies utilizing a larger sample size are needed to further elucidate the role of CCK in recovery from BN and its potential target of related novel treatment strategies. PMID:23988345

Psychophysiological responses to auditory change.

PubMed

Chuen, Lorraine; Sears, David; McAdams, Stephen

2016-06-01

A comprehensive characterization of autonomic and somatic responding within the auditory domain is currently lacking. We studied whether simple types of auditory change that occur frequently during music listening could elicit measurable changes in heart rate, skin conductance, respiration rate, and facial motor activity. Participants heard a rhythmically isochronous sequence consisting of a repeated standard tone, followed by a repeated target tone that changed in pitch, timbre, duration, intensity, or tempo, or that deviated momentarily from rhythmic isochrony. Changes in all parameters produced increases in heart rate. Skin conductance response magnitude was affected by changes in timbre, intensity, and tempo. Respiratory rate was sensitive to deviations from isochrony. Our findings suggest that music researchers interpreting physiological responses as emotional indices should consider acoustic factors that may influence physiology in the absence of induced emotions. © 2016 Society for Psychophysiological Research.

Gift card incentives and non-response bias in a survey of vaccine providers: the role of geographic and demographic factors.

PubMed

Van Otterloo, Joshua; Richards, Jennifer L; Seib, Katherine; Weiss, Paul; Omer, Saad B

2011-01-01

This study investigates the effects of non-response bias in a 2010 postal survey assessing experiences with H1N1 influenza vaccine administration among a diverse sample of providers (N = 765) in Washington state. Though we garnered a high response rate (80.9%) by using evidence-based survey design elements, including intensive follow-up and a gift card incentive from Target, non-response bias could exist if there were differences between respondents and non-respondents. We investigated differences between the two groups for seven variables: road distance to the nearest Target store, practice type, previous administration of vaccines, region, urbanicity, size of practice, and Vaccines for Children (VFC) program enrollment. We also examined the effect of non-response bias on survey estimates. Statistically significant differences between respondents and non-respondents were found for four variables: miles to the nearest Target store, type of medical practice, whether the practice routinely administered additional vaccines besides H1N1, and urbanicity. Practices were more likely to respond if they were from a small town or rural area (OR = 7.68, 95% CI = 1.44-40.88), were a non-traditional vaccine provider type (OR = 2.08, 95% CI = 1.06-4.08) or a pediatric provider type (OR = 4.03, 95% CI = 1.36-11.96), or administered additional vaccines besides H1N1 (OR = 1.80, 95% CI = 1.03-3.15). Of particular interest, for each ten mile increase in road distance from the nearest Target store, the likelihood of provider response decreased (OR = 0.73, 95% CI = 0.60-0.89). Of those variables associated with response, only small town or rural practice location was associated with a survey estimate of interest, suggesting that non-response bias had a minimal effect on survey estimates. These findings show that gift card incentives alongside survey design elements and follow-up can achieve high response rates. However, there is evidence that practices farther from the nearest place to redeem gift cards may be less likely to respond to the survey.

Age differences in visual search for compound patterns: long- versus short-range grouping.

PubMed

Burack, J A; Enns, J T; Iarocci, G; Randolph, B

2000-11-01

Visual search for compound patterns was examined in observers aged 6, 8, 10, and 22 years. The main question was whether age-related improvement in search rate (response time slope over number of items) was different for patterns defined by short- versus long-range spatial relations. Perceptual access to each type of relation was varied by using elements of same contrast (easy to access) or mixed contrast (hard to access). The results showed large improvements with age in search rate for long-range targets; search rate for short-range targets was fairly constant across age. This pattern held regardless of whether perceptual access to a target was easy or hard, supporting the hypothesis that different processes are involved in perceptual grouping at these two levels. The results also point to important links between ontogenic and microgenic change in perception (H. Werner, 1948, 1957).

Cis-regulatory element based targeted gene finding: genome-wide identification of abscisic acid- and abiotic stress-responsive genes in Arabidopsis thaliana.

PubMed

Zhang, Weixiong; Ruan, Jianhua; Ho, Tuan-Hua David; You, Youngsook; Yu, Taotao; Quatrano, Ralph S

2005-07-15

A fundamental problem of computational genomics is identifying the genes that respond to certain endogenous cues and environmental stimuli. This problem can be referred to as targeted gene finding. Since gene regulation is mainly determined by the binding of transcription factors and cis-regulatory DNA sequences, most existing gene annotation methods, which exploit the conservation of open reading frames, are not effective in finding target genes. A viable approach to targeted gene finding is to exploit the cis-regulatory elements that are known to be responsible for the transcription of target genes. Given such cis-elements, putative target genes whose promoters contain the elements can be identified. As a case study, we apply the above approach to predict the genes in model plant Arabidopsis thaliana which are inducible by a phytohormone, abscisic acid (ABA), and abiotic stress, such as drought, cold and salinity. We first construct and analyze two ABA specific cis-elements, ABA-responsive element (ABRE) and its coupling element (CE), in A.thaliana, based on their conservation in rice and other cereal plants. We then use the ABRE-CE module to identify putative ABA-responsive genes in A.thaliana. Based on RT-PCR verification and the results from literature, this method has an accuracy rate of 67.5% for the top 40 predictions. The cis-element based targeted gene finding approach is expected to be widely applicable since a large number of cis-elements in many species are available.

Attributions of Responsibility and Blame for Procrastination Behavior

PubMed Central

Rahimi, Sonia; Hall, Nathan C.; Pychyl, Timothy A.

2016-01-01

The present study examined the relationship between procrastination, delay, blameworthiness, and moral responsibility. Undergraduate students (N = 240) were provided two scenarios in which the reason for inaction (procrastination, delay), the target (self, other), and the outcome (positive, negative) were manipulated, and students were asked to rate the moral responsibility and blameworthiness of the agent. Results indicated that individuals who procrastinated were seen as more morally responsible and blameworthy than those who experienced delay. More specifically, after a negative outcome, procrastination was associated with more moral responsibility, whereas delay was associated with less moral responsibility. After a positive outcome, individuals perceived procrastination as deserving of less moral responsibility, and delays as associated with more moral responsibility. Finally, a three-way interaction showed that participants rated procrastination that resulted in failure as deserving of responsibility when engaged in by others as opposed to oneself. PMID:27547197

Commissioning a Rotating Target Wheel Assembly for Heavy Element Studies

NASA Astrophysics Data System (ADS)

Fields, L. D.; Bennett, M. E.; Mayorov, D. A.; Folden, C. M.

2013-10-01

The heaviest elements are produced artificially by fusing nuclei of light elements within an accelerator to form heavier nuclei. The most direct method to increase the production rate of nuclei is to increase the beam intensity, necessitating the use of a rotating target to minimize damage to the target by deposited heat. Such a target wheel was constructed for heavy element research at Texas A&M University, Cyclotron Institute, consisting of a wheel with three banana-shaped target cutouts. The target is designed to rotate at 1700 rpm, and a fiber optic cable provides a signal to trigger beam pulsing in order to avoid irradiating the spokes between target segments. Following minor mechanical modifications and construction of a dedicated electrical panel, the rotating target assembly was commissioned for a beam experiment. A 15 MeV/u beam of 20Ne was delivered from the K500 cyclotron and detected by a ruggedized silicon detector. The beam pulsing response time was characterized as a function of the rational frequency of the target wheel. Preliminary analysis suggests that the K500 is capable of pulsing at rates of up to 250 Hz, which is sufficient for planned future experiments. Funded by DOE and NSF-REU Program.

Heat Shock Response in Yeast Involves Changes in Both Transcription Rates and mRNA Stabilities

PubMed Central

Castells-Roca, Laia; García-Martínez, José; Moreno, Joaquín; Herrero, Enrique; Bellí, Gemma; Pérez-Ortín, José E.

2011-01-01

We have analyzed the heat stress response in the yeast Saccharomyces cerevisiae by determining mRNA levels and transcription rates for the whole transcriptome after a shift from 25°C to 37°C. Using an established mathematical algorithm, theoretical mRNA decay rates have also been calculated from the experimental data. We have verified the mathematical predictions for selected genes by determining their mRNA decay rates at different times during heat stress response using the regulatable tetO promoter. This study indicates that the yeast response to heat shock is not only due to changes in transcription rates, but also to changes in the mRNA stabilities. mRNA stability is affected in 62% of the yeast genes and it is particularly important in shaping the mRNA profile of the genes belonging to the environmental stress response. In most cases, changes in transcription rates and mRNA stabilities are homodirectional for both parameters, although some interesting cases of antagonist behavior are found. The statistical analysis of gene targets and sequence motifs within the clusters of genes with similar behaviors shows that both transcriptional and post-transcriptional regulons apparently contribute to the general heat stress response by means of transcriptional factors and RNA binding proteins. PMID:21364882

Load-induced modulation of signal transduction networks.

PubMed

Jiang, Peng; Ventura, Alejandra C; Sontag, Eduardo D; Merajver, Sofia D; Ninfa, Alexander J; Del Vecchio, Domitilla

2011-10-11

Biological signal transduction networks are commonly viewed as circuits that pass along information--in the process amplifying signals, enhancing sensitivity, or performing other signal-processing tasks--to transcriptional and other components. Here, we report on a "reverse-causality" phenomenon, which we call load-induced modulation. Through a combination of analytical and experimental tools, we discovered that signaling was modulated, in a surprising way, by downstream targets that receive the signal and, in doing so, apply what in physics is called a load. Specifically, we found that non-intuitive changes in response dynamics occurred for a covalent modification cycle when load was present. Loading altered the response time of a system, depending on whether the activity of one of the enzymes was maximal and the other was operating at its minimal rate or whether both enzymes were operating at submaximal rates. These two conditions, which we call "limit regime" and "intermediate regime," were associated with increased or decreased response times, respectively. The bandwidth, the range of frequency in which the system can process information, decreased in the presence of load, suggesting that downstream targets participate in establishing a balance between noise-filtering capabilities and a circuit's ability to process high-frequency stimulation. Nodes in a signaling network are not independent relay devices, but rather are modulated by their downstream targets.

Measuring target detection performance in paradigms with high event rates.

PubMed

Bendixen, Alexandra; Andersen, Søren K

2013-05-01

Combining behavioral and neurophysiological measurements inevitably implies mutual constraints, such as when the neurophysiological measurement requires fast-paced stimulus presentation and hence the attribution of a behavioral response to a particular preceding stimulus becomes ambiguous. We develop and test a method for validly assessing behavioral detection performance in spite of this ambiguity. We examine four approaches taken in the literature to treat such situations. We analytically derive a new variant of computing the classical parameters of signal detection theory, hit and false alarm rates, adapted to fast-paced paradigms. Each of the previous approaches shows specific shortcomings (susceptibility towards response window choice, biased estimates of behavioral detection performance). Superior performance of our new approach is demonstrated for both simulated and empirical behavioral data. Further evidence is provided by reliable correspondence between behavioral performance and the N2b component as an electrophysiological indicator of target detection. The appropriateness of our approach is substantiated by both theoretical and empirical arguments. We demonstrate an easy-to-implement solution for measuring target detection performance independent of the rate of event presentation. Thus overcoming the measurement bias of previous approaches, our method will help to clarify the behavioral relevance of different measures of cortical activation. Copyright © 2012 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Inotuzumab ozogamicin in the management of acute lymphoblastic leukaemia.

PubMed

Morley, N J; Marks, D I

2016-01-01

Whilst most adult patients with acute lymphoblastic leukaemia will go into remission with standard induction chemotherapy, many will relapse. Response rates to standard salvage chemotherapy regimens are low and the outlook on relapse is very poor and associated with significant morbidity and mortality hence the need for newer targeted approaches. Inotuzumab ozogamicin (previously known as CMC-544) is an antibody-drug conjugate and consists of a monoclonal anti-CD22 antibody bound to calicheamicin. The target, CD22, is widely expressed on acute lymphoblastic leukaemia cells making it a potential therapeutic target. The calicheamicin is delivered intracellularly and causes leukaemia cell apoptosis. Overall response rates of 57% were observed in a Phase II study and the final results of a Phase III randomised controlled trial comparing this drug to the investigator choice 'standard of care' chemotherapy are eagerly awaited. Whilst initial results are promising, there have been concerns regarding liver toxicity and the incidence of veno-occlusive disease of the liver especially in patients who have previously received or go on to allogeneic stem cell transplant.

Advances in targeted therapy for acute myeloid leukaemia.

PubMed

Kayser, Sabine; Levis, Mark J

2018-02-01

In the past few years, research in the underlying pathogenic mechanisms of acute myeloid leukaemia (AML) has led to remarkable advances in our understanding of the disease. Cytogenetic and molecular aberrations are the most important factors in determining response to chemotherapy as well as long-term outcome, but beyond prognostication are potential therapeutic targets. Our increased understanding of the pathogenesis of AML, facilitated by next-generation sequencing, has spurred the development of new compounds in the treatment of AML, particularly the creation of small molecules that target the disease on a molecular level. Various new agents, such as tyrosine kinase inhibitors, immune checkpoint inhibitors, monoclonal or bispecific T-cell engager antibodies, metabolic and pro-apoptotic agents are currently investigated within clinical trials. The highest response rates are often achieved when new molecularly targeted therapies are combined with standard chemotherapy. Presented here is an overview of novel therapies currently being evaluated in AML. © 2017 John Wiley & Sons Ltd.

Stereotype threat prevents perceptual learning

PubMed Central

Shiffrin, Richard M.; Boucher, Kathryn L.; Van Loo, Katie; Rydell, Michael T.

2010-01-01

Stereotype threat (ST) refers to a situation in which a member of a group fears that her or his performance will validate an existing negative performance stereotype, causing a decrease in performance. For example, reminding women of the stereotype “women are bad at math” causes them to perform more poorly on math questions from the SAT and GRE. Performance deficits can be of several types and be produced by several mechanisms. We show that ST prevents perceptual learning, defined in our task as an increasing rate of search for a target Chinese character in a display of such characters. Displays contained two or four characters and half of these contained a target. Search rate increased across a session of training for a control group of women, but not women under ST. Speeding of search is typically explained in terms of learned “popout” (automatic attraction of attention to a target). Did women under ST learn popout but fail to express it? Following training, the women were shown two colored squares and asked to choose the one with the greater color saturation. Superimposed on the squares were task-irrelevant Chinese characters. For women not trained under ST, the presence of a trained target on one square slowed responding, indicating that training had caused the learning of an attention response to targets. Women trained under ST showed no slowing, indicating that they had not learned such an attention response. PMID:20660737

Targeted ablation of cardiac sympathetic neurons reduces resting, reflex and exercise-induced sympathetic activation in conscious rats.

PubMed

Lujan, Heidi L; Palani, Gurunanthan; Chen, Ying; Peduzzi, Jean D; Dicarlo, Stephen E

2009-05-01

Cholera toxin B subunit conjugated to saporin (SAP, a ribosomal inactivating protein that binds to and inactivates ribosomes) was injected in both stellate ganglia to evaluate the physiological response to targeted ablation of cardiac sympathetic neurons. Resting cardiac sympathetic activity (cardiac sympathetic tonus), exercise-induced sympathetic activity (heart rate responses to graded exercise), and reflex sympathetic activity (heart rate responses to graded doses of sodium nitroprusside, SNP) were determined in 18 adult conscious Sprague-Dawley male rats. Rats were randomly divided into the following three groups (n = 6/group): 1) control (no injection), 2) bilateral stellate ganglia injection of unconjugated cholera toxin B (CTB), and 3) bilateral stellate ganglia injection of cholera toxin B conjugated to SAP (CTB-SAP). CTB-SAP rats, compared with control and CTB rats, had reduced cardiac sympathetic tonus and reduced heart rate responses to graded exercise and graded doses of SNP. Furthermore, the number of stained neurons in the stellate ganglia and spinal cord (segments T(1)-T(4)) was reduced in CTB-SAP rats. Thus CTB-SAP retrogradely transported from the stellate ganglia is effective at ablating cardiac sympathetic neurons and reducing resting, exercise, and reflex sympathetic activity. Additional studies are required to further characterize the physiological responses to this procedure as well as determine if this new approach is safe and efficacious for the treatment of conditions associated with excess sympathetic activity (e.g., autonomic dysreflexia, hypertension, heart failure, and ventricular arrhythmias).

Addressing the selective role of distinct prefrontal areas in response suppression: A study with brain tumor patients.

PubMed

Arbula, Sandra; Pacella, Valentina; De Pellegrin, Serena; Rossetto, Marta; Denaro, Luca; D'Avella, Domenico; Della Puppa, Alessandro; Vallesi, Antonino

2017-06-01

The diverging evidence for functional localization of response inhibition within the prefrontal cortex might be justified by the still unclear involvement of other intrinsically related cognitive processes like response selection and sustained attention. In this study, the main aim was to understand whether inhibitory impairments, previously found in patients with both left and right frontal lesions, could be better accounted for by assessing these potentially related cognitive processes. We tested 37 brain tumor patients with left prefrontal, right prefrontal and non-prefrontal lesions and a healthy control group on Go/No-Go and Foreperiod tasks. In both types of tasks inhibitory impairments are likely to cause false alarms, although additionally the former task requires response selection and the latter target detection abilities. Irrespective of the task context, patients with right prefrontal damage showed frequent Go and target omissions, probably due to sustained attention lapses. Left prefrontal patients, on the other hand, showed both Go and target omissions and high false alarm rates to No-Go and warning stimuli, suggesting a decisional rather than an inhibitory impairment. An exploratory whole-brain voxel-based lesion-symptom mapping analysis confirmed the association of left ventrolateral and dorsolateral prefrontal lesions with target discrimination failure, and right ventrolateral and medial prefrontal lesions with target detection failure. Results from this study show how left and right prefrontal areas, which previous research has linked to response inhibition, underlie broader cognitive control processes, particularly involved in response selection and target detection. Based on these findings, we suggest that successful inhibitory control relies on more than one functionally distinct process which, if assessed appropriately, might help us to better understand inhibitory impairments across different pathologies. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Participation rates, response bias and response behaviours in the community survey of the Swiss Spinal Cord Injury Cohort Study (SwiSCI).

PubMed

Fekete, Christine; Segerer, Wolfgang; Gemperli, Armin; Brinkhof, Martin W G

2015-10-08

Surveying persons with disabilities is challenging, as targeted subjects may experience specific barriers to survey participation. Here we report on participation rates and response behaviour in a community survey of people with spinal cord injury (SCI) in Switzerland. The cross-sectional survey was implemented as part of the Swiss Spinal Cord Injury Cohort Study (SwiSCI) and represents the largest population-based SCI survey in Europe including nearly 2000 persons. Design features to enhance participation rates included the division of the questionnaire volume over three successive modules; recurrent and mixed-mode reminding of non-responders; and mixed-mode options for response. We describe participation rates of the SwiSCI community survey (absolute and cumulative cooperation, contact, response, and attrition rates) and report on response rates in relation to recruitment efforts. Potential non-response bias and the association between responders' characteristics and response behaviour (response speed: reminding until participation; response mode: paper-pencil vs. online completion) were assessed using regression modelling. Over the successive modules, absolute response rates were 61.1, 80.6 and 87.3% which resulted in cumulative response rates of 49.3 and 42.6% for the second and third modules. Written reminders effectively increased response rates, with the first reminder showing the largest impact. Telephone reminders, partly with direct telephone interviewing, enhanced response rate to the first module, but were essentially redundant in subsequent modules. Non-response to the main module was related to current age, membership of Swiss Paraplegic Association (SPA) and time since injury, but not to gender, lesion level and preferred language of response. Response speed increased with household income, but was not associated to other sociodemographic factors, lesion characteristics or health indicators. We found significant associations between online completion and male gender, younger age, higher education, higher income, SPA membership, tetraplegia, longer time since injury, higher quality of life, and more participation restrictions. In this sample with little non-response bias, recurrent and mixed-mode reminding and mixed-mode options for response were key features of optimizing survey design.

Present and future molecular testing of lung carcinoma.

PubMed

Dacic, Sanja; Nikiforova, Marina N

2014-03-01

The rapid development of targeted therapies has tremendously changed clinical management of lung carcinoma patients and set the stage for similar developments in other tumor types. Many studies have been published in the past decade in search for the most acceptable method of assessment for predictors of response to targeted therapies in lung cancer. As a result, several guidelines for molecular testing have been published in a past couple of years. Because of accumulated evidence that targetable drugs show the best efficacy and improved progression survival rates in lung cancer patients whose tumors have a specific genotype, molecular testing for predictors of therapy response has became standard of care. Presently, testing for EGFR mutations and ALK rearrangements in lung adenocarcinoma has been standardized. The landscape of targetable genomic alterations in lung carcinoma is expanding, but none of other potentially targetable biomarkers have been standardized outside of clinical trials. This review will summarize current practice of molecular testing. Future methods in molecular testing of lung carcinoma will be briefly reviewed.

A network meta-analysis on the efficacy of sixteen targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer

PubMed Central

Ba-Sang, Dan-Zeng; Long, Zi-Wen; Teng, Hao; Zhao, Xu-Peng; Qiu, Jian; Li, Ming-Shan

2016-01-01

Objective A network meta-analysis was conducted comparing the short-term efficacies of 16 targeted drugs in combination with chemotherapy for treatment of advanced/metastatic colorectal cancer (CRC). Results Twenty-seven RCTs were ultimately incorporated into this network meta-analysis. Compared with chemotherapy alone, bevacizumab + chemotherapy, panitumumab + chemotherapy and conatumumab + chemotherapy had higher PR rate. Bevacizumab + chemotherapy, cetuximab + chemotherapy, panitumumab + chemotherapy, trebananib + chemotherapy and conatumumab + chemotherapy had higher ORR rate in comparison to chemotherapy alone. Furthermore, bevacizumab + chemotherapy had higher DCR rate than chemotherapy alone. The results of our cluster analysis showed that chemotherapy combined with bevacizumab, cetuximab, panitumumab, conatumumab, ganitumab, or brivanib + cetuximab had better efficacies for the treatment of advanced/metastatic CRC in comparison to chemotherapy alone. Materials and Methods Electronic databases were comprehensively searched for potential and related randomized controlled trials (RCTs). Direct and indirect evidence were incorporated for evaluation of stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR) and overall response ratio (ORR) by calculating odds ratio (OR) and 95% confidence intervals (CI), and using the surface under the cumulative ranking curve (SUCRA). Conclusions These results indicated that bevacizumab + chemotherapy, panitumumab + chemotherapy, conatumumab + chemotherapy and brivanib + cetuximab + chemotherapy may have better efficacies for the treatment of advanced/metastatic CRC. PMID:27806321

Laser-based irradiation apparatus and methods for monitoring the dose-rate response of semiconductor devices

DOEpatents

Horn, Kevin M [Albuquerque, NM

2006-03-28

A scanned, pulsed, focused laser irradiation apparatus can measure and image the photocurrent collection resulting from a dose-rate equivalent exposure to infrared laser light across an entire silicon die. Comparisons of dose-rate response images or time-delay images from before, during, and after accelerated aging of a device, or from periodic sampling of devices from fielded operational systems allows precise identification of those specific age-affected circuit structures within a device that merit further quantitative analysis with targeted materials or electrical testing techniques. Another embodiment of the invention comprises a broad-beam, dose rate-equivalent exposure apparatus. The broad-beam laser irradiation apparatus can determine if aging has affected the device's overall functionality. This embodiment can be combined with the synchronized introduction of external electrical transients into a device under test to simulate the electrical effects of the surrounding circuitry's response to a radiation exposure.

A model for the pilot's use of motion cues in roll-axis tracking tasks

NASA Technical Reports Server (NTRS)

Levison, W. H.; Junker, A. M.

1977-01-01

Simulated target-following and disturbance-regulation tasks were explored with subjects using visual-only and combined visual and motion cues. The effects of motion cues on task performance and pilot response behavior were appreciably different for the two task configurations and were consistent with data reported in earlier studies for similar task configurations. The optimal-control model for pilot/vehicle systems provided a task-independent framework for accounting for the pilot's use of motion cues. Specifically, the availability of motion cues was modeled by augmenting the set of perceptual variables to include position, rate, acceleration, and accleration-rate of the motion simulator, and results were consistent with the hypothesis of attention-sharing between visual and motion variables. This straightforward informational model allowed accurate model predictions of the effects of motion cues on a variety of response measures for both the target-following and disturbance-regulation tasks.

Are there differential symptom profiles that improve in response to different pharmacological treatments of premenstrual syndrome/premenstrual dysphoric disorder?

PubMed

Halbreich, Uriel; O'Brien, P M Shaughn; Eriksson, Elias; Bäckström, Torbjörn; Yonkers, Kimberly A; Freeman, Ellen W

2006-01-01

Current evidence suggests that the accepted treatments for premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) have similar overall efficacy. While these treatments are more effective than placebo, response rates associated with them are far from satisfactory (<60%), such that, irrespective of treatment modality, there remain a significant number of women who are unresponsive to current conventional pharmacological therapy. The available data on response rates of specific types of premenstrual symptoms to, or symptom profiles that are most amenable to, each treatment modality are limited and not well defined because most studies were not designed to assess specific symptom profiles. Those studies that have attempted to evaluate which symptom profiles respond to specific therapies have revealed variations within the individual modalities, as well as between the different modalities. It appears that suppression of ovulation ameliorates a broad range of behavioural as well as physical premenstrual symptoms. SSRIs are most effective for irritability and anxiety symptoms, with lesser efficacy for 'atypical' premenstrual symptoms. GABAergic compounds are most efficacious for anxiety and anxious/depressive symptoms, while dopamine agonists, particularly bromocriptine, are perhaps most efficacious for mastalgia. Overall treatment response rates may improve if treatments are targeted at well-defined subgroups of patients. Re-analysis of available datasets from randomised clinical trials may shed more light on the notion that targeting women with specific premenstrual symptom profiles for specific treatment modalities would improve response rates beyond the current ceiling of approximately 60%. Such information would also improve understanding of the putative pathophysiological mechanisms underlying PMS and PMDD, and may point to a more specific diagnosis of these conditions.

Biodistribution mechanisms of therapeutic monoclonal antibodies in health and disease.

PubMed

Tabrizi, Mohammad; Bornstein, Gadi Gazit; Suria, Hamza

2010-03-01

The monoclonal antibody market continues to witness an impressive rate of growth and has become the leading source of expansion in the biologic segment within the pharmaceutical industry. Currently marketed monoclonal antibodies target a diverse array of antigens. These antigens are distributed in a variety of tissues such as tumors, lungs, synovial fluid, psoriatic plaques, and lymph nodes. As the concentration of drug at the proximity of the biological receptor determines the magnitude of the observed pharmacological responses, a significant consideration in effective therapeutic application of monoclonal antibodies is a thorough understanding of the processes that regulate antibody biodistribution. Monoclonal antibody distribution is affected by factors such as molecular weight, blood flow, tissue and tumor heterogeneity, structure and porosity, target antigen density, turnover rate, and the target antigen expression profile.

Elementary Teachers' Perspectives of the Implementation of Response to Intervention and Special Education Rates

ERIC Educational Resources Information Center

Dupuis, Susan D.

2010-01-01

Response to Intervention (RTI) employs a multi-tiered approach to providing targeted interventions for students who are at risk for school failure. With the reauthorization of the Individual with Disabilities Act (IDEA) 2004 and No Child Left Behind (NCLB) 2001 districts are given the option to implement RTI prior to student referral for special…

Feasibility of Using a Multilingual Web Survey in Studying the Health of Ethnic Minority Youth

PubMed Central

Malin, Maili; Raisamo, Susanna Ulrika; Lindfors, Pirjo Liisa; Pere, Lasse Antero; Rimpelä, Arja Hannele

2015-01-01

Background Monolingual Web survey is a common tool for studying adolescent health. However, national languages may cause difficulties for some immigrant-origin youths, which lower their participation rate. In national surveys, the number of ethnic minority groups is often too small to assess their well-being. Objective We studied the feasibility of a multilingual Web survey targeted at immigrant-origin youths by selection of response language, and compared participation in different language groups with a monolingual survey. Methods The Adolescent Health and Lifestyle Survey (AHLS), Finland, with national languages (Finnish/Swedish) was modified into a multilingual Web survey targeted at a representative sample of 14- and 16-year olds (N=639) whose registry-based mother tongue was other than the national languages. The survey was conducted in 2010 (16-year olds) and 2011 (14-year olds). The response rate of the multilingual survey in 2011 is compared with the AHLS of 2011. We also describe the translation process and the e-form modification. Results Of the respondents, 57.6% answered in Finnish, whereas the remaining 42.4% used their mother tongue (P=.002). A majority of youth speaking Somali, Middle Eastern, Albanian, and Southeast Asian languages chose Finnish. The overall response rate was 48.7% with some nonsignificant variation between the language groups. The response rate in the multilingual Web survey was higher (51.6%, 163/316) than the survey with national languages (46.5%, 40/86) in the same age group; however, the difference was not significant (P=.47). The adolescents who had lived in Finland for 5 years or less (58.0%, 102/176) had a higher response rate than those having lived in Finland for more than 5 years (45.1%, 209/463; P=.005). Respondents and nonrespondents did not differ according to place of birth (Finland/other) or residential area (capital city area/other). The difference in the response rates of girls and boys was nearly significant (P=.06). Girls of the Somali and Middle Eastern language groups were underrepresented among the respondents. Conclusions A multilingual Web survey is a feasible method for gathering data from ethnic youth, although it does not necessarily yield a higher response rate than a monolingual survey. The respondents answered more often in the official language of the host country than their mother tongue. The varying response rates by time of residence, ethnicity, and gender pose challenges for developing tempting surveys for youth. PMID:25953412

Heart Rate and the Role of the Active Receiver during Contingent Electric Shock for Severe Self-Injurious Behavior

ERIC Educational Resources Information Center

Duker, Pieter C.; Van den Munckhof, Marcia

2007-01-01

Five individuals, who were treated for severe self-injurious behaviors (SIB) with contingent electric shock, participated. Hereby, each occurrence of the target response was followed by a remotely administered aversive consequence. Participants' heart rates were compared at times when the active device of the equipment for the above procedure was…

Differentiation and Response Bias in Episodic Memory: Evidence from Reaction Time Distributions

ERIC Educational Resources Information Center

Criss, Amy H.

2010-01-01

In differentiation models, the processes of encoding and retrieval produce an increase in the distribution of memory strength for targets and a decrease in the distribution of memory strength for foils as the amount of encoding increases. This produces an increase in the hit rate and decrease in the false-alarm rate for a strongly encoded compared…

Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer

PubMed Central

Siena, S; Sartore-Bianchi, A; Marsoni, S; Hurwitz, H I; McCall, S J; Penault-Llorca, F; Srock, S; Bardelli, A; Trusolino, L

2018-01-01

Abstract Human epidermal growth factor receptor 2 (HER2) is an oncogenic driver, and a well-established therapeutic target in breast and gastric cancers. Using functional and genomic analyses of patient-derived xenografts, we previously showed that a subset (approximately 5%) of metastatic colorectal cancer (CRC) tumors is driven by amplification or mutation of HER2. This paper reviews the role of HER2 amplification as an oncogenic driver, a prognostic and predictive biomarker, and a clinically actionable target in CRC, considering the specifics of HER2 testing in this tumor type. While the role of HER2 as a biomarker for prognosis in CRC remains uncertain, its relevance as a therapeutic target has been established. Indeed, independent studies documented substantial clinical benefit in patients treated with biomarker-driven HER2-targeted therapies, with an impact on response rates and duration of response that compared favorably with immunotherapy and other examples of precision oncology. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of metastatic CRC patients. PMID:29659677

The use of incentives in vulnerable populations for a telephone survey: a randomized controlled trial.

PubMed

Knoll, Megan; Soller, Lianne; Ben-Shoshan, Moshe; Harrington, Daniel; Fragapane, Joey; Joseph, Lawrence; La Vieille, Sebastien; St-Pierre, Yvan; Wilson, Kathi; Elliott, Susan; Clarke, Ann

2012-10-19

Poor response rates in prevalence surveys can lead to nonresponse bias thereby compromising the validity of prevalence estimates. We conducted a telephone survey of randomly selected households to estimate the prevalence of food allergy in the 10 Canadian provinces between May 2008 and March 2009 (the SCAAALAR study: Surveying Canadians to Assess the Prevalence of Common Food Allergies and Attitudes towards Food LAbeling and Risk). A household response rate of only 34.6% was attained, and those of lower socioeconomic status, lower education and new Canadians were underrepresented. We are now attempting to target these vulnerable populations in the SPAACE study (Surveying the Prevalence of Food Allergy in All Canadian Environments) and are evaluating strategies to increase the response rate. Although the success of incentives to increase response rates has been demonstrated previously, no studies have specifically examined the use of unconditional incentives in these vulnerable populations in a telephone survey. The pilot study will compare response rates between vulnerable Canadian populations receiving and not receiving an incentive. Randomly selected households were randomly assigned to receive either a $5 incentive or no incentive. The between group differences in response rates and 95% confidence intervals (CIs) were calculated. The response rates for the incentive and non-incentive groups were 36.1% and 28.7% respectively, yielding a between group difference of 7.4% (-0.7%, 15.6%). Although the wide CI precludes definitive conclusions, our results suggest that unconditional incentives are effective in vulnerable populations for telephone surveys.

Impaired Context Processing is Attributable to Global Neuropsychological Impairment in Schizophrenia and Psychotic Bipolar Disorder

PubMed Central

Hill, S. Kristian; Gold, James M.; Keefe, Richard S. E.; Clementz, Brett A.; Gershon, Elliot; Keshavan, Matcheri S.; Pearlson, Godfrey; Tamminga, Carol A.; Sweeney, John A.

2017-01-01

Abstract Background: Context processing may reflect a specific cognitive impairment in schizophrenia. Whether impaired context processing is observed across psychotic disorders or among relatives of affected individuals, and whether it is a deficit that is independent from the generalized neuropsychological deficits seen in psychotic disorders, are less established. Methods: Schizophrenia, schizoaffective, and psychotic bipolar probands (n = 660), their first-degree relatives (n = 741), and healthy individuals (n = 308) studied by the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium performed an expectancy task requiring use of contextual information to overcome a pre-potent response. Sensitivity for target detection and false alarm rates on trials requiring inhibition or goal maintenance were measured. Results: Proband groups and relatives with psychosis spectrum personality traits demonstrated reduced target sensitivity and elevated false alarm rates. False alarm rate was higher under inhibition vs goal maintenance conditions although this difference was attenuated in schizophrenia and schizoaffective proband groups. After accounting for global neuropsychological impairment, as reflected by the composite score from the Brief Assessment of Cognition in Schizophrenia neuropsychological battery, deficits in schizophrenia and bipolar proband groups were no longer significant. Performance measures were moderately familial. Conclusion: Reduced target detection, but not a specific deficit in context processing, is observed across psychotic disorders. Impairments in both goal maintenance and response inhibition appear to contribute comparably to deficits in schizophrenia and schizoaffective disorder, whereas greater difficulty with response inhibition underlies deficits in bipolar disorder. Yet, these deficits are not independent from the generalized neurocognitive impairment observed in schizophrenia and psychotic bipolar disorder. PMID:27306316

Proof of concept and dose estimation with binary responses under model uncertainty.

PubMed

Klingenberg, B

2009-01-30

This article suggests a unified framework for testing Proof of Concept (PoC) and estimating a target dose for the benefit of a more comprehensive, robust and powerful analysis in phase II or similar clinical trials. From a pre-specified set of candidate models, we choose the ones that best describe the observed dose-response. To decide which models, if any, significantly pick up a dose effect, we construct the permutation distribution of the minimum P-value over the candidate set. This allows us to find critical values and multiplicity adjusted P-values that control the familywise error rate of declaring any spurious effect in the candidate set as significant. Model averaging is then used to estimate a target dose. Popular single or multiple contrast tests for PoC, such as the Cochran-Armitage, Dunnett or Williams tests, are only optimal for specific dose-response shapes and do not provide target dose estimates with confidence limits. A thorough evaluation and comparison of our approach to these tests reveal that its power is as good or better in detecting a dose-response under various shapes with many more additional benefits: It incorporates model uncertainty in PoC decisions and target dose estimation, yields confidence intervals for target dose estimates and extends to more complicated data structures. We illustrate our method with the analysis of a Phase II clinical trial. Copyright (c) 2008 John Wiley & Sons, Ltd.

Killing of targets by effector CD8 T cells in the mouse spleen follows the law of mass action

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

Ganusov, Vitaly V

2009-01-01

In contrast with antibody-based vaccines, it has been difficult to measure the efficacy of T cell-based vaccines and to correlate the efficacy of CD8 T cell responses with protection again viral infections. In part, this difficulty is due to poor understanding of the in vivo efficacy of CD8 T cells produced by vaccination. Using a: recently developed experimental method of in vivo cytotoxicity we have investigated quantitative aspects of killing of peptide-pulsed targets by effector and memory CD8 T cells, specific to three epitopes of lymphocytic choriomeningitis virus (LCMV), in the mouse spleen. By analyzing data on killing of targetsmore » with varying number of epitope-specific effector and memory CD8 T cells, we find that killing of targets by effectors follows the law of mass-action, that is the death rate of peptide-pulsed targets is proportional to the frequency of CTLs in the spleen. In contrast, killing of targets by memory CD8 T cells does not follow the mass action law because the death rate of targets saturates at high frequencies of memory CD8 T cells. For both effector and memory cells, we also find little support for the killing term that includes the decrease of the death rate of targets with target cell density. Interestingly, our analysis suggests that at low CD8 T cell frequencies, memory CD8 T cells on the per capita basis are more efficient at killing peptide-pulsed targets than effectors, but at high frequencies, effectors are more efficient killers than memory T cells. Comparison of the estimated killing efficacy of effector T cells with the value that is predicted from theoretical physics and based on motility of T cells in lymphoid tissues, suggests that limiting step in the killing of peptide-pulsed targets is delivering the lethal hit and not finding the target. Our results thus form a basis for quantitative understanding of the process of killing of virus-infected cells by T cell responses in tissues and can be used to correlate the phenotype of vaccine-induced memory CD8 T cells with their killing efficacy in vivo.« less

A basic mathematical model of the immune response

NASA Astrophysics Data System (ADS)

Mayer, H.; Zaenker, K. S.; an der Heiden, U.

1995-03-01

Interaction of the immune system with a target population of, e.g., bacteria, viruses, antigens, or tumor cells must be considered as a dynamic process. We describe this process by a system of two ordinary differential equations. Although the model is strongly idealized it demonstrates how the combination of a few proposed nonlinear interaction rules between the immune system and its targets are able to generate a considerable variety of different kinds of immune responses, many of which are observed both experimentally and clinically. In particular, solutions of the model equations correspond to states described by immunologists as ``virgin state,'' ``immune state'' and ``state of tolerance.'' The model successfully replicates the so-called primary and secondary response. Moreover, it predicts the existence of a threshold level for the amount of pathogen germs or of transplanted tumor cells below which the host is able to eliminate the infectious organism or to reject the tumor graft. We also find a long time coexistence of targets and immune competent cells including damped and undamped oscillations of both. Plausibly the model explains that if the number of transformed cells or pathogens exeeds definable values (poor antigenicity, high reproduction rate) the immune system fails to keep the disease under control. On the other hand, the model predicts apparently paradoxical situations including an increased chance of target survival despite enhanced immune activity or therapeutically achieved target reduction. A further obviously paradoxical behavior consists of a positive effect for the patient up to a complete cure by adding an additional target challenge where the benefit of the additional targets depends strongly on the time point and on their amount. Under periodically pulsed stimulation the model may show a chaotic time behavior of both target growth and immune response.

Risk Factors and Therapeutic Targets in Pancreatic Cancer

PubMed Central

Wörmann, Sonja Maria; Algül, Hana

2013-01-01

Pancreatic cancer (PC) is one of the most challenging tumor entities worldwide, characterized as a highly aggressive disease with dismal overall prognosis and an incidence rate equalling mortality rate. Over the last decade, substantial progress has been made to define the morphological changes and key genetic events in pancreatic carcinogenesis. And yet, it is still unclear what factors trigger PC. Some risk factors appear to be associated with sex, age, race/ethnicity, or other rare genetic conditions. Additionally, modifying factors such as smoking, obesity, diabetes, occupational risk factors, etc., increase the potential for acquiring genetic mutations that may result in PC. Another hallmark of PC is its poor response to radio- and chemo-therapy. Current chemotherapeutic regimens could not provide substantial survival benefit with a clear increase in overall survival. Recently, several new approaches to significantly improve the clinical outcome of PC have been described involving downstream signaling cascades desmoplasia and stromal response as well as tumor microenvironment, immune response, vasculature, and angiogenesis. This review summarizes major risk factors for PC and tries to illuminate relevant targets considerable for new therapeutic approaches. PMID:24303367

Chemoresistance and targeted therapies in ovarian and endometrial cancers

PubMed Central

Brasseur, Kevin; Gévry, Nicolas; Asselin, Eric

2017-01-01

Gynecological cancers are known for being very aggressive at their advanced stages. Indeed, the survival rate of both ovarian and endometrial cancers is very low when diagnosed lately and the success rate of current chemotherapy regimens is not very efficient. One of the main reasons for this low success rate is the acquired chemoresistance of these cancers during their progression. The mechanisms responsible for this acquired chemoresistance are numerous, including efflux pumps, repair mechanisms, survival pathways (PI3K/AKT, MAPK, EGFR, mTOR, estrogen signaling) and tumor suppressors (P53 and Par-4). To overcome these resistances, a new type of therapy has emerged named targeted therapy. The principle of targeted therapy is simple, taking advantage of changes acquired in malignant cancer cells (receptors, proteins, mechanisms) by using compounds specifically targeting these, thus limiting their action on healthy cells. Targeted therapies are emerging and many clinical trials targeting these pathways, frequently involved in chemoresistance, have been tested on gynecological cancers. Despite some targets being less efficient than expected as mono-therapies, the combination of compounds seems to be the promising avenue. For instance, we demonstrate using ChIP-seq analysis that estrogen downregulate tumor suppressor Par-4 in hormone-dependent cells by directly binding to its DNA regulatory elements and inhibiting estrogen signaling could reinstate Par-4 apoptosis-inducing abilities. This review will focus on the chemoresistance mechanisms and the clinical trials of targeted therapies associated with these, specifically for endometrial and ovarian cancers. PMID:28008141

Medicare program; Medicare hospital reimbursement reforms: limitations on reimbursable costs and the rate of hospital cost increases--HCFA. Interim final rule with comment period.

PubMed

1982-09-30

These rules implement section 1886 of the Social Security Act (established by section 101 of the Tax Equity and Fiscal Responsibility Act of 1982). These rules amend current regulations on hospital cost limits, providing for new exemptions and exceptions. These amendments make exceptions available to hospitals consistent with the new cost limits published elsewhere in this issue of the Federal Register, and specifically exempt from those cost limits rural hospitals with less than 50 beds in existence as of the enactment of the law. These rules also set forth new regulations establishing a three-year ceiling on the allowable annual rate of increase in operating costs per case for inpatient hospital services. This ceiling takes the form of a target amount of cost per case against which a hospital's incurred cost per case will be compared. Hospitals are provided incentives to keep their cost increases below the target rate. A hospital that has costs per case less than the target amount will be paid a portion of the difference between actual cost and the target amount. A hospital that has costs per case that are greater than the target amount will be paid the target amount plus 25 percent of its costs in excess of the target for the first two years of the ceiling, and none of the excess in the third year. However, payment to a hospital under these new target rate regulations will not be greater than the amount determined under the new schedule of limits on hospital inpatient operating costs published elsewhere in this issue of the Federal Register.

Probing mass-transport and binding inhomogeneity in macromolecular interactions by molecular interferometric imaging

NASA Astrophysics Data System (ADS)

Zhao, Ming; Wang, Xuefeng; Nolte, David

2009-02-01

In solid-support immunoassays, the transport of target analyte in sample solution to capture molecules on the sensor surface controls the detected binding signal. Depletion of the target analyte in the sample solution adjacent to the sensor surface leads to deviations from ideal association, and causes inhomogeneity of surface binding as analyte concentration varies spatially across the sensor surface. In the field of label-free optical biosensing, studies of mass-transport-limited reaction kinetics have focused on the average response on the sensor surface, but have not addressed binding inhomogeneities caused by mass-transport limitations. In this paper, we employ Molecular Interferometric Imaging (MI2) to study mass-transport-induced inhomogeneity of analyte binding within a single protein spot. Rabbit IgG binding to immobilized protein A/G was imaged at various concentrations and under different flow rates. In the mass-transport-limited regime, enhanced binding at the edges of the protein spots was caused by depletion of analyte towards the center of the protein spots. The magnitude of the inhomogeneous response was a function of analyte reaction rate and sample flow rate.

Mechanisms and biological importance of photon-induced bystander responses: do they have an impact on low-dose radiation responses

PubMed Central

Tomita, Masanori; Maeda, Munetoshi

2015-01-01

Abstract Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced bystander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. PMID:25361549

Brand name confusion: Subjective and objective measures of orthographic similarity.

PubMed

Burt, Jennifer S; McFarlane, Kimberley A; Kelly, Sarah J; Humphreys, Michael S; Weatherall, Kimberlee; Burrell, Robert G

2017-09-01

Determining brand name similarity is vital in areas of trademark registration and brand confusion. Students rated the orthographic (spelling) similarity of word pairs (Experiments 1, 2, and 4) and brand name pairs (Experiment 5). Similarity ratings were consistently higher when words shared beginnings rather than endings, whereas shared pronunciation of the stressed vowel had small and less consistent effects on ratings. In Experiment 3 a behavioral task confirmed the similarity of shared beginnings in lexical processing. Specifically, in a task requiring participants to decide whether 2 words presented in the clear (a probe and a later target) were the same or different, a masked prime word preceding the target shortened response latencies if it shared its initial 3 letters with the target. The ratings of students for word and brand name pairs were strongly predicted by metrics of orthographic similarity from the visual word identification literature based on the number of shared letters and their relative positions. The results indicate a potential use for orthographic metrics in brand name registration and trademark law. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

National survey of physicians to determine the effect of unconditional incentives on response rates of physician postal surveys

PubMed Central

Abdulaziz, Kasim; Brehaut, Jamie; Taljaard, Monica; Émond, Marcel; Sirois, Marie-Josée; Lee, Jacques S; Wilding, Laura; Perry, Jeffrey J

2015-01-01

Objectives Physicians are a commonly targeted group in health research surveys, but their response rates are often relatively low. The goal of this paper was to evaluate the effect of unconditional incentives in the form of a coffee card on physician postal survey response rates. Design Following 13 key informant interviews and eight cognitive interviews a survey questionnaire was developed. Participants A random sample of 534 physicians, stratified by physician group (geriatricians, family physicians, emergency physicians) was selected from a national medical directory. Setting Using computer generated random numbers; half of the physicians in each stratum were allocated to receive a coffee card to a popular national coffee chain together with the first survey mailout. Interventions The intervention was a $10 Tim Hortons gift card given to half of the physicians who were randomly allocated to receive the incentive. Results 265 (57.0%) physicians completed the survey. The response rate was significantly higher in the group allocated to receive the incentive (62.7% vs 51.3% in the control group; p=0.01). Conclusions Our results indicate that an unconditional incentive in the form of a coffee gift card can substantially improve physician response rates. Future research can look at the effect of varying amounts of cash on the gift cards on response rates. PMID:25694460

Dorsal premotor cortex: neural correlates of reach target decisions based on a color-location matching rule and conflicting sensory evidence

PubMed Central

Coallier, Émilie; Michelet, Thomas

2015-01-01

We recorded single-neuron activity in dorsal premotor (PMd) and primary motor cortex (M1) of two monkeys in a reach-target selection task. The monkeys chose between two color-coded potential targets by determining which target's color matched the predominant color of a multicolored checkerboard-like Decision Cue (DC). Different DCs contained differing numbers of colored squares matching each target. The DCs provided evidence about the correct target ranging from unambiguous (one color only) to very ambiguous and conflicting (nearly equal number of squares of each color). Differences in choice behavior (reach response times and success rates as a function of DC ambiguity) of the monkeys suggested that each applied a different strategy for using the target-choice evidence in the DCs. Nevertheless, the appearance of the DCs evoked a transient coactivation of PMd neurons preferring both potential targets in both monkeys. Reach response time depended both on how long it took activity to increase in neurons that preferred the chosen target and on how long it took to suppress the activity of neurons that preferred the rejected target, in both correct-choice and error-choice trials. These results indicate that PMd neurons in this task are not activated exclusively by a signal proportional to the net color bias of the DCs. They are instead initially modulated by the conflicting evidence supporting both response choices; final target selection may result from a competition between representations of the alternative choices. The results also indicate a temporal overlap between action selection and action initiation processes in PMd and M1. PMID:25787952

Mathematical models of immune effector responses to viral infections: Virus control versus the development of pathology

NASA Astrophysics Data System (ADS)

Wodarz, Dominik

2005-12-01

This article reviews mathematical models which have investigated the importance of lytic and non-lytic immune responses for the control of viral infections. Lytic immune responses fight the virus by killing infected cells, while non-lytic immune responses fight the virus by inhibiting viral replication while leaving the infected cell alive. The models suggest which types or combinations of immune responses are required to resolve infections which vary in their characteristics, such as the rate of viral replication and the rate of virus-induced target cell death. This framework is then applied to persistent infections and viral evolution. It is investigated how viral evolution and antigenic escape can influence the relative balance of lytic and non-lytic responses over time, and how this might correlate with the transition from an asymptomatic infection to pathology. This is discussed in the specific context of hepatitis C virus infection.

Effects of lure composition and release rate on catch of EDRR target species and other forest coleoptera.

Treesearch

Brian L. Strom; Sheri L. Smith; James R. Meeker; Robert J. Rabaglia

2009-01-01

The USDA Forest Service's Early Detection and Rapid Response Program (EDRR) is a nationally coordinated program that employs traps for detecting, delimiting, and monitoring newly introduced exotic bark and ambrosia beetles. The...

Warming caused by cumulative carbon emissions towards the trillionth tonne.

PubMed

Allen, Myles R; Frame, David J; Huntingford, Chris; Jones, Chris D; Lowe, Jason A; Meinshausen, Malte; Meinshausen, Nicolai

2009-04-30

Global efforts to mitigate climate change are guided by projections of future temperatures. But the eventual equilibrium global mean temperature associated with a given stabilization level of atmospheric greenhouse gas concentrations remains uncertain, complicating the setting of stabilization targets to avoid potentially dangerous levels of global warming. Similar problems apply to the carbon cycle: observations currently provide only a weak constraint on the response to future emissions. Here we use ensemble simulations of simple climate-carbon-cycle models constrained by observations and projections from more comprehensive models to simulate the temperature response to a broad range of carbon dioxide emission pathways. We find that the peak warming caused by a given cumulative carbon dioxide emission is better constrained than the warming response to a stabilization scenario. Furthermore, the relationship between cumulative emissions and peak warming is remarkably insensitive to the emission pathway (timing of emissions or peak emission rate). Hence policy targets based on limiting cumulative emissions of carbon dioxide are likely to be more robust to scientific uncertainty than emission-rate or concentration targets. Total anthropogenic emissions of one trillion tonnes of carbon (3.67 trillion tonnes of CO(2)), about half of which has already been emitted since industrialization began, results in a most likely peak carbon-dioxide-induced warming of 2 degrees C above pre-industrial temperatures, with a 5-95% confidence interval of 1.3-3.9 degrees C.

Metabolic profiling of triple-negative breast cancer cells reveals metabolic vulnerabilities.

PubMed

Lanning, Nathan J; Castle, Joshua P; Singh, Simar J; Leon, Andre N; Tovar, Elizabeth A; Sanghera, Amandeep; MacKeigan, Jeffrey P; Filipp, Fabian V; Graveel, Carrie R

2017-01-01

Among breast cancers, the triple-negative breast cancer (TNBC) subtype has the worst prognosis with no approved targeted therapies and only standard chemotherapy as the backbone of systemic therapy. Unique metabolic changes in cancer progression provide innovative therapeutic opportunities. The receptor tyrosine kinases (RTKs) epidermal growth factor receptor (EGFR), and MET receptor are highly expressed in TNBC, making both promising therapeutic targets. RTK signaling profoundly alters cellular metabolism by increasing glucose consumption and subsequently diverting glucose carbon sources into metabolic pathways necessary to support the tumorigenesis. Therefore, detailed metabolic profiles of TNBC subtypes and their response to tyrosine kinase inhibitors may identify therapeutic sensitivities. We quantified the metabolic profiles of TNBC cell lines representing multiple TNBC subtypes using gas chromatography mass spectrometry. In addition, we subjected MDA-MB-231, MDA-MB-468, Hs578T, and HCC70 cell lines to metabolic flux analysis of basal and maximal glycolytic and mitochondrial oxidative rates. Metabolic pool size and flux measurements were performed in the presence and absence of the MET inhibitor, INC280/capmatinib, and the EGFR inhibitor, erlotinib. Further, the sensitivities of these cells to modulators of core metabolic pathways were determined. In addition, we annotated a rate-limiting metabolic enzymes library and performed a siRNA screen in combination with MET or EGFR inhibitors to validate synergistic effects. TNBC cell line models displayed significant metabolic heterogeneity with respect to basal and maximal metabolic rates and responses to RTK and metabolic pathway inhibitors. Comprehensive systems biology analysis of metabolic perturbations, combined siRNA and tyrosine kinase inhibitor screens identified a core set of TCA cycle and fatty acid pathways whose perturbation sensitizes TNBC cells to small molecule targeting of receptor tyrosine kinases. Similar to the genomic heterogeneity observed in TNBC, our results reveal metabolic heterogeneity among TNBC subtypes and demonstrate that understanding metabolic profiles and drug responses may prove valuable in targeting TNBC subtypes and identifying therapeutic susceptibilities in TNBC patients. Perturbation of metabolic pathways sensitizes TNBC to inhibition of receptor tyrosine kinases. Such metabolic vulnerabilities offer promise for effective therapeutic targeting for TNBC patients.

Experimental and computational investigation of lateral gauge response in polycarbonate

NASA Astrophysics Data System (ADS)

Eliot, Jim; Harris, Ernst; Hazell, Paul; Appleby-Thomas, Gareth; Winter, Ronald; Wood, David; Owen, Gareth

2011-06-01

Polycarbonate's use in personal armour systems means its high strain-rate response has been extensively studied. Interestingly, embedded lateral manganin stress gauges in polycarbonate have shown gradients behind incident shocks, suggestive of increasing shear strength. However, such gauges need to be embedded in a central (typically) epoxy interlayer - an inherently invasive approach. Recently, research has suggested that in such metal systems interlayer/target impedance may contribute to observed gradients in lateral stress. Here, experimental T-gauge (Vishay Micro-Measurements® type J2M-SS-580SF-025) traces from polycarbonate targets are compared to computational simulations. This work extends previous efforts such that similar impedance exists between the interlayer and matrix (target) interface. Further, experiments and simulations are presented investigating the effects of a ``dry joint'' in polycarbonate, in which no encapsulating medium is employed.

CCK response in bulimia nervosa and following remission.

PubMed

Hannon-Engel, Sandra L; Filin, Evgeniy E; Wolfe, Barbara E

2013-10-02

The core defining features of bulimia nervosa (BN) are repeated binge eating episodes and inappropriate compensatory (e.g., purging) behavior. Previous studies suggest an abnormal post-prandial response in the satiety-signaling peptide cholecystokinin (CCK) in persons with BN. It is unknown whether this altered response persists following remission or if it may be a potential target for the development of clinical treatment strategies. To examine the nature of this altered response, this study assessed whether CCK normalizes following remission from BN (RBN). This study prospectively evaluated the plasma CCK response and corresponding eating behavior-related ratings (e.g., satiety, fullness, hunger, urge to binge and vomit) in individuals with BN-purging subtype (n=10), RBN-purging subtype (n=14), and healthy controls (CON, n=13) at baseline, +15, +30, and +60 min following the ingestion of a standardized liquid test meal. Subject groups did not significantly differ in CCK response to the test meal. A significant relationship between CCK response and satiety ratings was observed in the RBN group (r=.59, p<.05 two-tailed). A new and unanticipated finding in the BN group was a significant relationship between CCK response and ratings of "urge to vomit" (r=.86, p<.01, two-tailed). Unlike previous investigations, CCK response did not differ in BN and CON groups. Thus the role of symptom severity remains an area of further investigation. Additionally, findings suggest that in this sample, CCK functioning following remission from BN-purging subtype is not different from controls. It remains unknown whether or not CCK functioning may be a protective or liability factor in the stabilization and recovery process. Replication studies utilizing a larger sample size are needed to further elucidate the role of CCK in recovery from BN and its potential target of related novel treatment strategies. © 2013 Elsevier Inc. All rights reserved.

Atomoxetine Increased Effect over Time in Adults with Attention-Deficit/Hyperactivity Disorder Treated for up to 6 Months: Pooled Analysis of Two Double-Blind, Placebo-Controlled, Randomized Trials.

PubMed

Wietecha, Linda A; Clemow, David B; Buchanan, Andrew S; Young, Joel L; Sarkis, Elias H; Findling, Robert L

2016-07-01

Changes in the magnitude of efficacy throughout 26 weeks of atomoxetine treatment, along with impact of dosing, were evaluated in adults with ADHD from two randomized, double-blind, placebo-controlled studies. Pooled placebo (n = 485) and atomoxetine (n = 518) patients, dosed 25, 40, 60, 80 (target dose), or 100 mg daily, were assessed. Change from baseline in Conners' Adult ADHD Rating Scale-Investigator Rated Scale: Screening Version (CAARS) total ADHD symptoms score and Adult ADHD Investigator Symptom Rating Scale (AISRS) total score were analyzed using mixed-model repeated measures, with least squares mean change, effect size, and response rate calculated at 1, 2, 4, 8, 12, 16, 22, and 26 weeks. Decreases on CAARS for atomoxetine- versus placebo-treated patients were consistently statistically significantly greater at every time point beginning at one week (P ≤ 0.006, 0.28 effect size). By 4 weeks, comparison was -13.19 compared with -8.84 (P < 0.0001, 0.45 effect size). By 26 weeks, mean change was -15.42 versus -9.71 (0.52 effect size); increase in effect size over time was most pronounced in the 80 mg group (0.82 effect size). AISRS demonstrated similar results. Atomoxetine response rate (CAARS 50% decrease) continued to increase throughout 26 weeks. Atomoxetine treatment in adults with ADHD was associated with small effect sizes after 4 weeks and moderate effect sizes by 6 months of treatment. The data support increased effect size and response rate over time during longer-term treatment at target dose. © 2016 Eli Lilly and Company. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Higher rate alternative non-drug reinforcement produces faster suppression of cocaine seeking but more resurgence when removed.

PubMed

Craig, Andrew R; Nall, Rusty W; Madden, Gregory J; Shahan, Timothy A

2016-06-01

Relapse following removal of an alternative source of reinforcement introduced during extinction of a target behavior is called resurgence. This form of relapse may be related to relapse of drug taking following loss of alternative non-drug reinforcement in human populations. Laboratory investigations of factors mediating resurgence with food-maintained behavior suggest higher rates of alternative reinforcement produce faster suppression of target behavior but paradoxically generate more relapse when alternative reinforcement is discontinued. At present, it is unknown if a similar effect occurs when target behavior is maintained by drug reinforcement and the alternative is a non-drug reinforcer. In the present experiment three groups of rats were trained to lever press for infusions of cocaine during baseline. Next, during treatment, cocaine reinforcement was suspended and an alternative response was reinforced with either high-rate, low-rate, or no alternative food reinforcement. Finally, all reinforcement was suspended to test for relapse of cocaine seeking. Higher rate alternative reinforcement produced faster elimination of cocaine seeking than lower rates or extinction alone, but when treatment was suspended resurgence of cocaine seeking occurred following only high-rate alternative reinforcement. Thus, although higher rate alternative reinforcement appears to more effectively suppress drug seeking, should it become unavailable, it can have the unfortunate effect of increasing relapse. Copyright © 2016 Elsevier B.V. All rights reserved.

Characterization and response of newly developed high-grade glioma cultures to the tyrosine kinase inhibitors, erlotinib, gefitinib and imatinib

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

Kinsella, Paula, E-mail: paula.kinsella@dcu.ie; Howley, Rachel, E-mail: rhowley@rcsi.ie; Doolan, Padraig, E-mail: padraig.doolan@dcu.ie

2012-03-10

High-grade gliomas (HGG), are the most common aggressive brain tumours in adults. Inhibitors targeting growth factor signalling pathways in glioma have shown a low clinical response rate. To accurately evaluate response to targeted therapies further in vitro studies are necessary. Growth factor pathway expression using epidermal growth factor receptor (EGFR), mutant EGFR (EGFRvIII), platelet derived growth factor receptor (PDGFR), C-Kit and C-Abl together with phosphatase and tensin homolog (PTEN) expression and downstream activation of AKT and phosphorylated ribosomal protein S6 (P70S6K) was analysed in 26 primary glioma cultures treated with the tyrosine kinase inhibitors (TKIs) erlotinib, gefitinib and imatinib. Responsemore » to TKIs was assessed using 50% inhibitory concentrations (IC{sub 50}). Response for each culture was compared with the EGFR/PDGFR immunocytochemical pathway profile using hierarchical cluster analysis (HCA) and principal component analysis (PCA). Erlotinib response was not strongly associated with high expression of the growth factor pathway components. PTEN expression did not correlate with response to any of the three TKIs. Increased EGFR expression was associated with gefitinib response; increased PDGFR-{alpha} expression was associated with imatinib response. The results of this in vitro study suggest gefitinib and imatinib may have therapeutic potential in HGG tumours with a corresponding growth factor receptor expression profile. -- Highlights: Black-Right-Pointing-Pointer Non-responders had low EGFR expression, high PDGFR-{beta}, and a low proliferation rate. Black-Right-Pointing-Pointer PTEN is not indicative of response to a TKI. Black-Right-Pointing-Pointer Erlotinib response was not associated with expression of the proteins examined. Black-Right-Pointing-Pointer Imatinib-response correlated with expression of PDGFR-{alpha}. Black-Right-Pointing-Pointer Gefitinib response correlated with increased expression of EGFR.« less

Crizotinib-Induced Abnormal Signal Processing in the Retina

PubMed Central

Ishii, Toshiyuki; Iwasawa, Shunichiro; Kurimoto, Ryota; Maeda, Akemi; Takiguchi, Yuichi; Kaneda, Makoto

2015-01-01

Molecular target therapy for cancer is characterized by unique adverse effects that are not usually observed with cytotoxic chemotherapy. For example, the anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor crizotinib causes characteristic visual disturbances, whereas such effects are rare when another ALK-tyrosine kinase inhibitor, alectinib, is used. To elucidate the mechanism responsible for these visual disturbances, the responses to light exhibited by retinal ganglion cells treated with these agents were evaluated using a C57BL6 mouse ex vivo model. Both crizotinib and alectinib changed the firing rate of ON and OFF type retinal ganglion cells. However, the ratio of alectinib-affected cells (15.7%) was significantly lower than that of crizotinib-affected cells (38.6%). Furthermore, these drugs changed the response properties to light stimuli of retinal ganglion cells in some of the affected cells, i.e., OFF cells responded to both ON and OFF stimuli, etc. Finally, the expressions of ALK (a target receptor of both crizotinib and alectinib) and of MET and ROS1 (additional target receptors of crizotinib) were observed at the mRNA level in the retina. Our findings suggest that these drugs might target retinal ganglion cells and that the potency of the drug actions on the light responses of retinal ganglion cells might be responsible for the difference in the frequencies of visual disturbances observed between patients treated with crizotinib and those treated with alectinib. The present experimental system might be useful for screening new molecular target agents prior to their use in clinical trials. PMID:26271036

Discriminative correlation filter tracking with occlusion detection

NASA Astrophysics Data System (ADS)

Zhang, Shuo; Chen, Zhong; Yu, XiPeng; Zhang, Ting; He, Jing

2018-03-01

Aiming at the problem that the correlation filter-based tracking algorithm can not track the target of severe occlusion, a target re-detection mechanism is proposed. First of all, based on the ECO, we propose the multi-peak detection model and the response value to distinguish the occlusion and deformation in the target tracking, which improve the success rate of tracking. And then we add the confidence model to update the mechanism to effectively prevent the model offset problem which due to similar targets or background during the tracking process. Finally, the redetection mechanism of the target is added, and the relocation is performed after the target is lost, which increases the accuracy of the target positioning. The experimental results demonstrate that the proposed tracker performs favorably against state-of-the-art methods in terms of robustness and accuracy.

Colour and spatial cueing in low-prevalence visual search.

PubMed

Russell, Nicholas C C; Kunar, Melina A

2012-01-01

In visual search, 30-40% of targets with a prevalence rate of 2% are missed, compared to 7% of targets with a prevalence rate of 50% (Wolfe, Horowitz, & Kenner, 2005). This "low-prevalence" (LP) effect is thought to occur as participants are making motor errors, changing their response criteria, and/or quitting their search too soon. We investigate whether colour and spatial cues, known to improve visual search when the target has a high prevalence (HP), benefit search when the target is rare. Experiments 1 and 2 showed that although knowledge of the target's colour reduces miss errors overall, it does not eliminate the LP effect as more targets were missed at LP than at HP. Furthermore, detection of a rare target is significantly impaired if it appears in an unexpected colour-more so than if the prevalence of the target is high (Experiment 2). Experiment 3 showed that, if a rare target is exogenously cued, target detection is improved but still impaired relative to high-prevalence conditions. Furthermore, if the cue is absent or invalid, the percentage of missed targets increases. Participants were given the option to correct motor errors in all three experiments, which reduced but did not eliminate the LP effect. The results suggest that although valid colour and spatial cues improve target detection, participants still miss more targets at LP than at HP. Furthermore, invalid cues at LP are very costly in terms of miss errors. We discuss our findings in relation to current theories and applications of LP search.

Accounting for rate-dependent category boundary shifts in speech perception.

PubMed

Bosker, Hans Rutger

2017-01-01

The perception of temporal contrasts in speech is known to be influenced by the speech rate in the surrounding context. This rate-dependent perception is suggested to involve general auditory processes because it is also elicited by nonspeech contexts, such as pure tone sequences. Two general auditory mechanisms have been proposed to underlie rate-dependent perception: durational contrast and neural entrainment. This study compares the predictions of these two accounts of rate-dependent speech perception by means of four experiments, in which participants heard tone sequences followed by Dutch target words ambiguous between /ɑs/ "ash" and /a:s/ "bait". Tone sequences varied in the duration of tones (short vs. long) and in the presentation rate of the tones (fast vs. slow). Results show that the duration of preceding tones did not influence target perception in any of the experiments, thus challenging durational contrast as explanatory mechanism behind rate-dependent perception. Instead, the presentation rate consistently elicited a category boundary shift, with faster presentation rates inducing more /a:s/ responses, but only if the tone sequence was isochronous. Therefore, this study proposes an alternative, neurobiologically plausible account of rate-dependent perception involving neural entrainment of endogenous oscillations to the rate of a rhythmic stimulus.

Old-fashioned responses in an updating memory task.

PubMed

Ruiz, M; Elosúa, M R; Lechuga, M T

2005-07-01

Errors in a running memory task are analysed. Participants were presented with a variable-length list of items and were asked to report the last four items. It has been proposed (Morris & Jones, 1990) that this task requires two mechanisms: the temporal storage of the target set by the articulatory loop and its updating by the central executive. Two implicit assumptions in this proposal are (a) the preservation of serial order, and (b) participants' capacity to discard earlier items from the target subset as list presentation is running, and new items are appended. Order preservation within the updated target list and the inhibition of the outdated list items should imply a relatively higher rate of location errors for items from the medial positions of the target list and a lower rate of intrusion errors from the outdated and inhibited items from the pretarget positions. Contrary to these expectations, for both consonants (Experiment 1) and words (Experiment 2) we found recency effects and a relatively high rate of intrusions from the final pretarget positions, most of them from the very last. Similar effects were apparent with the embedded four-item lists for catch trials. These results are clearly at odds with the presumed updating by the central executive.

Targeting fibroblast growth factor receptors and immune checkpoint inhibitors for the treatment of advanced bladder cancer: New direction and New Hope.

PubMed

Morales-Barrera, Rafael; Suárez, Cristina; de Castro, Ana Martínez; Racca, Fabricio; Valverde, Claudia; Maldonado, Xavier; Bastaros, Juan Maria; Morote, Juan; Carles, Joan

2016-11-01

Bladder cancer is one of the leading causes of death in Europe and the United States. About 25% of patients with bladder cancer have advanced disease (muscle-invasive or metastatic disease) at presentation and are candidates for systemic chemotherapy. In the setting of metastatic disease, use of cisplatin-based regimens improves survival. However, despite initial high response rates, the responses are typically not durable leading to recurrence and death in the vast majority of these patients with median overall survival of 15months and a 5-year survival rate of ⩽10%. Furthermore, unfit patients for cisplatin have no standard of care for first line therapy in advance disease Most second-line chemotherapeutic agents tested have been disappointing. Newer targeted drugs and immunotherapies are being studied in the metastatic setting, their usefulness in the neoadjuvant and adjuvant settings is also an intriguing area of ongoing research. Thus, new treatment strategies are clearly needed. The comprehensive evaluation of multiple molecular pathways characterized by The Cancer Genome Atlas project has shed light on potential therapeutic targets for bladder urothelial carcinomas. We have focused especially on emerging therapies in locally advanced and metastatic urothelial carcinoma with an emphasis on immune checkpoints inhibitors and FGFR targeted therapies, which have shown great promise in early clinical studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Scalable and responsive event processing in the cloud

PubMed Central

Suresh, Visalakshmi; Ezhilchelvan, Paul; Watson, Paul

2013-01-01

Event processing involves continuous evaluation of queries over streams of events. Response-time optimization is traditionally done over a fixed set of nodes and/or by using metrics measured at query-operator levels. Cloud computing makes it easy to acquire and release computing nodes as required. Leveraging this flexibility, we propose a novel, queueing-theory-based approach for meeting specified response-time targets against fluctuating event arrival rates by drawing only the necessary amount of computing resources from a cloud platform. In the proposed approach, the entire processing engine of a distinct query is modelled as an atomic unit for predicting response times. Several such units hosted on a single node are modelled as a multiple class M/G/1 system. These aspects eliminate intrusive, low-level performance measurements at run-time, and also offer portability and scalability. Using model-based predictions, cloud resources are efficiently used to meet response-time targets. The efficacy of the approach is demonstrated through cloud-based experiments. PMID:23230164

Design of protein-responsive micro-sized hydrogels for self-regulating microfluidic systems

NASA Astrophysics Data System (ADS)

Hirayama, Mayu; Tsuruta, Kazuhiro; Kawamura, Akifumi; Ohara, Masayuki; Shoji, Kan; Kawano, Ryuji; Miyata, Takashi

2018-03-01

Diagnosis sensors using micro-total analysis systems (µ-TAS) have been developed for detecting target biomolecules such as proteins and saccharides because they are signal biomolecules for monitoring body conditions and diseases. In this study, biomolecularly stimuli-responsive micro-sized hydrogels that exhibited quick shrinkage in response to lectin concanavalinA (ConA) were prepared in a microchannel by photopolymerization using a fluorescence microscope. In preparing the micro-size hydrogels, glycosyloxyethyl methacrylate (GEMA) as a ligand monomer was copolymerized with a crosslinker in the presence of template ConA in molecular imprinting. The ConA-imprinted micro-hydrogel showed greater shrinkage in response to target ConA than nonimprinted micro-hydrogel. When a buffer solution was switched to an aqueous ConA solution in the Y-shaped microchannel, the flow rates changed quickly because of the responsive shrinkage of the micro-hydrogel prepared in the microchannel. These results suggest that the ConA-imprinted micro-hydrogel acted as a self-regulated microvalve in microfluidic systems.

Global biodiversity: indicators of recent declines

USGS Publications Warehouse

Butchart, Stuart H.M.; Walpole, Matt; Collen, Ben; Van Strien, Arco; Scharlemann, Jorn P.W.; Almond, Rosamunde E.A.; Baillie, Jonathan E.M.; Bomhard, Bastian; Brown, Claire; Bruno, John; Carpenter, Kent E.; Carr, Genevieve M.; Chanson, Janice; Chenery, Anna M.; Csirke, Jorge; Davidson, Nick C.; Dentener, Frank; Foster, Matt; Galli, Alessandro; Galloway, James N.; Genovesi, Piero; Gregory, Richard D.; Hockings, Marc; Kapos, Valerie; Lamarque, Jean-Francois; Leverington, Fiona; Loh, Jonathan; McGeoch, Melodie A.; McRae, Louise; Minasyan, Anahit; Morcillo, Monica Hernandez; Oldfield, Thomasina E.E.; Pauly, Daniel; Quader, Suhel; Revenga, Carmen; Sauer, John R.; Skolnik, Benjamin; Spear, Dian; Stanwell-Smith, Damon; Stuart, Simon N.; Symes, Andy; Tierney, Megan; Tyrrell, Tristan D.; Vie, Jean-Christophe; Watson, Reg

2011-01-01

In 2002, world leaders committed, through the Convention on Biological Diversity, to achieve a significant reduction in the rate of biodiversity loss by 2010. We compiled 31 indicators to report on progress toward this target. Most indicators of the state of biodiversity (covering species' population trends, extinction risk, habitat extent and condition, and community composition) showed declines, with no significant recent reductions in rate, whereas indicators of pressures on biodiversity (including resource consumption, invasive alien species, nitrogen pollution, overexploitation, and climate change impacts) showed increases. Despite some local successes and increasing responses (including extent and biodiversity coverage of protected areas, sustainable forest management, policy responses to invasive alien species, and biodiversity-related aid), the rate of biodiversity loss does not appear to be slowing.

Excluded Facility Financial Status and Options for Payment System Modification

PubMed Central

Schneider, John E.; Cromwell, Jerry; McGuire, Thomas P.

1993-01-01

Psychiatric, rehabilitation, long-term care, and children's facilities have remained under the reimbursement system established under the Tax Equity and Fiscal Responsibility Act (TEFRA) of 1982 (Public Law 97-248). The number of TEFRA facilities and discharges has been increasing while their average profit rates have been steadily declining. Modifying TEFRA would require either rebasing the target amount or adjusting cost sharing for facilities exceeding their cost target. Based on our simulations of alternative payment systems, we recommend rebasing facilities' target amounts using a 50/50 blend of own costs and national average costs. Cost sharing above the target amount could be increased to include more government sharing of losses. PMID:10135345

Parabolic quantitative structure-activity relationships and photodynamic therapy: application of a three-compartment model with clearance to the in vivo quantitative structure-activity relationships of a congeneric series of pyropheophorbide derivatives used as photosensitizers for photodynamic therapy.

PubMed

Potter, W R; Henderson, B W; Bellnier, D A; Pandey, R K; Vaughan, L A; Weishaupt, K R; Dougherty, T J

1999-11-01

An open three-compartment pharmacokinetic model was applied to the in vivo quantitative structure-activity relationship (QSAR) data of a homologous series of pyropheophorbide photosensitizers for photodynamic therapy (PDT). The physical model was a lipid compartment sandwiched between two identical aqueous compartments. The first compartment was assumed to clear irreversibly at a rate K0. The measured octanol-water partition coefficients, P(i) (where i is the number of carbons in the alkyl chain) and the clearance rate K0 determined the clearance kinetics of the drugs. Solving the coupled differential equations of the three-compartment model produced clearance kinetics for each of the sensitizers in each of the compartments. The third compartment was found to contain the target of PDT. This series of compounds is quite lipophilic. Therefore these drugs are found mainly in the second compartment. The drug level in the third compartment represents a small fraction of the tissue level and is thus not accessible to direct measurement by extraction. The second compartment of the model accurately predicted the clearance from the serum of mice of the hexyl ether of pyropheophorbide a, one member of this series of compounds. The diffusion and clearance rate constants were those found by fitting the pharmacokinetics of the third compartment to the QSAR data. This result validated the magnitude and mechanistic significance of the rate constants used to model the QSAR data. The PDT response to dose theory was applied to the kinetic behavior of the target compartment drug concentration. This produced a pharmacokinetic-based function connecting PDT response to dose as a function of time postinjection. This mechanistic dose-response function was fitted to published, single time point QSAR data for the pheophorbides. As a result, the PDT target threshold dose together with the predicted QSAR as a function of time postinjection was found.

A remorin gene SiREM6, the target gene of SiARDP, from foxtail millet (Setaria italica) promotes high salt tolerance in transgenic Arabidopsis.

PubMed

Yue, Jing; Li, Cong; Liu, Yuwei; Yu, Jingjuan

2014-01-01

Remorin proteins (REMs) form a plant-specific protein family, with some REMs being responsive to abiotic stress. However, the precise functions of REMs in abiotic stress tolerance are not clear. In this study, we identified 11 remorin genes from foxtail millet (Setaria italica) and cloned a remorin gene, SiREM6, for further investigation. The transcript level of SiREM6 was increased by high salt stress, low temperature stress and abscisic acid (ABA) treatment, but not by drought stress. The potential oligomerization of SiREM6 was examined by negative staining electron microscopy. The overexpression of SiREM6 improved high salt stress tolerance in transgenic Arabidopsis at the germination and seedling stages as revealed by germination rate, survival rate, relative electrolyte leakage and proline content. The SiREM6 promoter contains two dehydration responsive elements (DRE) and one ABA responsive element (ABRE). An ABA responsive DRE-binding transcription factor, SiARDP, and an ABRE-binding transcription factor, SiAREB1, were cloned from foxtail millet. SiARDP could physically bind to the DREs, but SiAREB1 could not. These results revealed that SiREM6 is a target gene of SiARDP and plays a critical role in high salt stress tolerance.

Hypermutation in derepressed operons of Escherichia coli K12

PubMed Central

Wright, Barbara E.; Longacre, Angelika; Reimers, Jacqueline M.

1999-01-01

This article presents evidence that starvation for leucine in an Escherichia coli auxotroph triggers metabolic activities that specifically target the leu operon for derepression, increased rates of transcription, and mutation. Derepression of the leu operon was a prerequisite for its activation by the signal nucleotide, guanosine tetraphosphate, which accumulates in response to nutritional stress (the stringent response). A quantitative correlation was established between leuB mRNA abundance and leuB− reversion rates. To further demonstrate that derepression increased mutation rates, the chromosomal leu operon was placed under the control of the inducible tac promoter. When the leu operon was induced by isopropyl-d-thiogalactoside, both leuB mRNA abundance and leuB− reversion rates increased. These investigations suggest that guanosine tetraphosphate may contribute as much as attenuation in regulating leu operon expression and that higher rates of mutation are specifically associated with the derepressed leu operon. PMID:10220423

Natural healing-inspired collagen-targeting surgical protein glue for accelerated scarless skin regeneration.

PubMed

Jeon, Eun Young; Choi, Bong-Hyuk; Jung, Dooyup; Hwang, Byeong Hee; Cha, Hyung Joon

2017-07-01

Skin scarring after deep dermal injuries is a major clinical problem due to the current therapies limited to established scars with poor understanding of healing mechanisms. From investigation of aberrations within the extracellular matrix involved in pathophysiologic scarring, it was revealed that one of the main factors responsible for impaired healing is abnormal collagen reorganization. Here, inspired by the fundamental roles of decorin, a collagen-targeting proteoglycan, in collagen remodeling, we created a scar-preventive collagen-targeting glue consisting of a newly designed collagen-binding mussel adhesive protein and a specific glycosaminoglycan. The collagen-targeting glue specifically bound to type I collagen in a dose-dependent manner and regulated the rate and the degree of fibrillogenesis. In a rat skin excisional model, the collagen-targeting glue successfully accelerated initial wound regeneration as defined by effective reepithelialization, neovascularization, and rapid collagen synthesis. Moreover, the improved dermal collagen architecture was demonstrated by uniform size of collagen fibrils, their regular packing, and a restoration of healthy tissue component. Collectively, our natural healing-inspired collagen-targeting glue may be a promising therapeutic option for improving the healing rate with high-quality and effective scar inhibition. Copyright © 2017 Elsevier Ltd. All rights reserved.

Reducing nonuse of restraints by children ages 5 to 7 : traffic tech.

DOT National Transportation Integrated Search

2010-02-01

NHTSAs Misuse of Child Restraints study (DOT HS 809 : 671) identified high rates of unrestrained children of booster : seat age and weight. This project was undertaken in response : to those findings, selecting 5- to 7-year-olds to target be...

National survey of physicians to determine the effect of unconditional incentives on response rates of physician postal surveys.

PubMed

Abdulaziz, Kasim; Brehaut, Jamie; Taljaard, Monica; Émond, Marcel; Sirois, Marie-Josée; Lee, Jacques S; Wilding, Laura; Perry, Jeffrey J

2015-02-18

Physicians are a commonly targeted group in health research surveys, but their response rates are often relatively low. The goal of this paper was to evaluate the effect of unconditional incentives in the form of a coffee card on physician postal survey response rates. Following 13 key informant interviews and eight cognitive interviews a survey questionnaire was developed. A random sample of 534 physicians, stratified by physician group (geriatricians, family physicians, emergency physicians) was selected from a national medical directory. Using computer generated random numbers; half of the physicians in each stratum were allocated to receive a coffee card to a popular national coffee chain together with the first survey mailout. The intervention was a $10 Tim Hortons gift card given to half of the physicians who were randomly allocated to receive the incentive. 265 (57.0%) physicians completed the survey. The response rate was significantly higher in the group allocated to receive the incentive (62.7% vs 51.3% in the control group; p=0.01). Our results indicate that an unconditional incentive in the form of a coffee gift card can substantially improve physician response rates. Future research can look at the effect of varying amounts of cash on the gift cards on response rates. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Quantification and classification of neuronal responses in kernel-smoothed peristimulus time histograms

PubMed Central

Fried, Itzhak; Koch, Christof

2014-01-01

Peristimulus time histograms are a widespread form of visualizing neuronal responses. Kernel convolution methods transform these histograms into a smooth, continuous probability density function. This provides an improved estimate of a neuron's actual response envelope. We here develop a classifier, called the h-coefficient, to determine whether time-locked fluctuations in the firing rate of a neuron should be classified as a response or as random noise. Unlike previous approaches, the h-coefficient takes advantage of the more precise response envelope estimation provided by the kernel convolution method. The h-coefficient quantizes the smoothed response envelope and calculates the probability of a response of a given shape to occur by chance. We tested the efficacy of the h-coefficient in a large data set of Monte Carlo simulated smoothed peristimulus time histograms with varying response amplitudes, response durations, trial numbers, and baseline firing rates. Across all these conditions, the h-coefficient significantly outperformed more classical classifiers, with a mean false alarm rate of 0.004 and a mean hit rate of 0.494. We also tested the h-coefficient's performance in a set of neuronal responses recorded in humans. The algorithm behind the h-coefficient provides various opportunities for further adaptation and the flexibility to target specific parameters in a given data set. Our findings confirm that the h-coefficient can provide a conservative and powerful tool for the analysis of peristimulus time histograms with great potential for future development. PMID:25475352

Grouping principles in direct competition.

PubMed

Schmidt, Filipp; Schmidt, Thomas

2013-08-09

We (1) introduce a primed flanker task as an objective method to measure perceptual grouping, and (2) use it to directly compare the efficiency of different grouping cues in rapid visuomotor processing. In two experiments, centrally presented primes were succeeded by flanking targets with varying stimulus-onset asynchronies (SOAs). Primes and targets were grouped by the same or by different grouping cues (Exp. 1: brightness/shape, Exp. 2: brightness/size) and were consistent or inconsistent with respect to the required response. Subjective grouping strength was varied to identify its influence on overall response times, error rates, and priming effects, that served as a measure of visual feedforward processing. Our results show that stronger grouping in the targets enhanced overall response times while stronger grouping in the primes enhanced priming effects in motor responses. Also, we obtained differences between rapid visuomotor processing and the subjective impression with cues of brightness and shape but not with cues of brightness and size. Our findings establish the primed flanker task as an objective method to study the speeded visuomotor processing of grouping cues, making it a useful method for the comparative study of feedforward-transmitted base groupings (Roelfsema & Houtkamp, 2011). Copyright © 2013 Elsevier Ltd. All rights reserved.

Spall response of annealed copper to direct explosive loading

NASA Astrophysics Data System (ADS)

Finnegan, S. G.; Burns, M. J.; Markland, L.; Goff, M.; Ferguson, J. W.

2017-01-01

Taylor wave spall experiments were conducted on annealed copper targets using direct explosive loading. The targets were mounted on the back of an explosive disc which was being used for a shock to detonation transition (SDT) test in a gas gun. This technique allows two experiments to be conducted with one piece of explosive. Explosive loading creates a high stress state within the target with a lower strain rate than an equivalent plate impact experiment, although the shock front will also have some curvature. Three shots were performed on two differently annealed batches of copper to investigate the viability of the technique and the effect of annealing on the spall response. One pair of targets was annealed at 850°C for four hours and the other target was annealed at 600°C for one hour. The free surface velocity (FSV) profiles were recorded using a Photonic Doppler Velocimetry (PDV) probe focused on the center of the target. The profiles were compared to predictions from the CREST reactive burn model. One profile recorded a significantly lower peak velocity which was attributed to the probe being located off center. Despite this, all three calculated spall strengths closely agreed and it was concluded that the technique is a viable one for loading an inert target.

Comparing success levels of different neural network structures in extracting discriminative information from the response patterns of a temperature-modulated resistive gas sensor

NASA Astrophysics Data System (ADS)

Hosseini-Golgoo, S. M.; Bozorgi, H.; Saberkari, A.

2015-06-01

Performances of three neural networks, consisting of a multi-layer perceptron, a radial basis function, and a neuro-fuzzy network with local linear model tree training algorithm, in modeling and extracting discriminative features from the response patterns of a temperature-modulated resistive gas sensor are quantitatively compared. For response pattern recording, a voltage staircase containing five steps each with a 20 s plateau is applied to the micro-heater of the sensor, when 12 different target gases, each at 11 concentration levels, are present. In each test, the hidden layer neuron weights are taken as the discriminatory feature vector of the target gas. These vectors are then mapped to a 3D feature space using linear discriminant analysis. The discriminative information content of the feature vectors are determined by the calculation of the Fisher’s discriminant ratio, affording quantitative comparison among the success rates achieved by the different neural network structures. The results demonstrate a superior discrimination ratio for features extracted from local linear neuro-fuzzy and radial-basis-function networks with recognition rates of 96.27% and 90.74%, respectively.

Defective bone formation and anabolic response to exogenous estrogen in mice with targeted disruption of endothelial nitric oxide synthase.

PubMed

Armour, K E; Armour, K J; Gallagher, M E; Gödecke, A; Helfrich, M H; Reid, D M; Ralston, S H

2001-02-01

Nitric oxide (NO) is a pleiotropic signaling molecule that is produced by bone cells constitutively and in response to diverse stimuli such as proinflammatory cytokines, mechanical strain, and sex hormones. Endothelial nitric oxide synthase (eNOS) is the predominant NOS isoform expressed in bone, but its physiological role in regulating bone metabolism remains unclear. Here we studied various aspects of bone metabolism in female mice with targeted disruption of the eNOS gene. Mice with eNOS deficiency (eNOS KO) had reduced bone mineral density, and cortical thinning when compared with WT controls and histomorphometric analysis of bone revealed profound abnormalities of bone formation, with reduced osteoblast numbers, surfaces and mineral apposition rate. Studies in vitro showed that osteoblasts derived from eNOS KO mice had reduced rates of growth when compared with WT and were less well differentiated as reflected by lower levels of alkaline phosphatase activity. Mice with eNOS deficiency lost bone normally following ovariectomy but exhibited a significantly blunted anabolic response to high dose exogenous estrogen. We conclude that the eNOS pathway plays an essential role in regulating bone mass and bone turnover by modulating osteoblast function.

Implementation of false discovery rate for exploring novel paradigms and trait dimensions with ERPs.

PubMed

Crowley, Michael J; Wu, Jia; McCreary, Scott; Miller, Kelly; Mayes, Linda C

2012-01-01

False discovery rate (FDR) is a multiple comparison procedure that targets the expected proportion of false discoveries among the discoveries. Employing FDR methods in event-related potential (ERP) research provides an approach to explore new ERP paradigms and ERP-psychological trait/behavior relations. In Study 1, we examined neural responses to escape behavior from an aversive noise. In Study 2, we correlated a relatively unexplored trait dimension, ostracism, with neural response. In both situations we focused on the frontal cortical region, applying a channel by time plots to display statistically significant uncorrected data and FDR corrected data, controlling for multiple comparisons.

Competitive integration of visual and goal-related signals on neuronal accumulation rate: a correlate of oculomotor capture in the superior colliculus.

PubMed

White, Brian J; Marino, Robert A; Boehnke, Susan E; Itti, Laurent; Theeuwes, Jan; Munoz, Douglas P

2013-10-01

The mechanisms that underlie the integration of visual and goal-related signals for the production of saccades remain poorly understood. Here, we examined how spatial proximity of competing stimuli shapes goal-directed responses in the superior colliculus (SC), a midbrain structure closely associated with the control of visual attention and eye movements. Monkeys were trained to perform an oculomotor-capture task [Theeuwes, J., Kramer, A. F., Hahn, S., Irwin, D. E., & Zelinsky, G. J. Influence of attentional capture on oculomotor control. Journal of Experimental Psychology. Human Perception and Performance, 25, 1595-1608, 1999], in which a target singleton was revealed via an isoluminant color change in all but one item. On a portion of the trials, an additional salient item abruptly appeared near or far from the target. We quantified how spatial proximity between the abrupt-onset and the target shaped the goal-directed response. We found that the appearance of an abrupt-onset near the target induced a transient decrease in goal-directed discharge of SC visuomotor neurons. Although this was indicative of spatial competition, it was immediately followed by a rebound in presaccadic activation, which facilitated the saccadic response (i.e., it induced shorter saccadic RT). A similar suppression also occurred at most nontarget locations even in the absence of the abrupt-onset. This is indicative of a mechanism that enabled monkeys to quickly discount stimuli that shared the common nontarget feature. These results reveal a pattern of excitation/inhibition across the SC visuomotor map that acted to facilitate optimal behavior-the short duration suppression minimized the probability of capture by salient distractors, whereas a subsequent boost in accumulation rate ensured a fast goal-directed response. Such nonlinear dynamics should be incorporated into future biologically plausible models of saccade behavior.

The asymmetry of U.S. monetary policy: Evidence from a threshold Taylor rule with time-varying threshold values

NASA Astrophysics Data System (ADS)

Zhu, Yanli; Chen, Haiqiang

2017-05-01

In this paper, we revisit the issue whether U.S. monetary policy is asymmetric by estimating a forward-looking threshold Taylor rule with quarterly data from 1955 to 2015. In order to capture the potential heterogeneity for regime shift mechanism under different economic conditions, we modify the threshold model by assuming the threshold value as a latent variable following an autoregressive (AR) dynamic process. We use the unemployment rate as the threshold variable and separate the sample into two periods: expansion periods and recession periods. Our findings support that the U.S. monetary policy operations are asymmetric in these two regimes. More precisely, the monetary authority tends to implement an active Taylor rule with a weaker response to the inflation gap (the deviation of inflation from its target) and a stronger response to the output gap (the deviation of output from its potential level) in recession periods. The threshold value, interpreted as the targeted unemployment rate of monetary authorities, exhibits significant time-varying properties, confirming the conjecture that policy makers may adjust their reference point for the unemployment rate accordingly to reflect their attitude on the health of general economy.

Predicting Romantic Interest at Zero Acquaintance: Evidence of Sex Differences in Trait Perception but Not in Predictors of Interest

PubMed Central

Olderbak, Sally G.; Malter, Frederic; Wolf, Pedro Sofio Abril; Jones, Daniel N.; Figueredo, Aurelio José

2016-01-01

We evaluated five competing hypotheses about what predicts romantic interest. Through a half-block quasi-experimental design, a large sample of young adults (i.e., responders; n = 335) viewed videos of opposite-sex persons (i.e., targets) talking about themselves and responders rated the targets’ traits and their romantic interest in the target. We tested whether similarity, dissimilarity, or overall trait levels on mate value, physical attractiveness, life history strategy, and the Big-Five personality factors predicted romantic interest at zero acquaintance, and whether sex acted as a moderator. We tested the responders’ individual perception of the targets’ traits, in addition to the targets’ own self-reported trait levels and a consensus rating of the targets made by the responders. We used polynomial regression with response surface analysis within multilevel modeling to test support for each of the hypotheses. Results suggest a large sex difference in trait perception; when women rated men, they agreed in their perception more often than when men rated women. However, as a predictor of romantic interest, there were no sex differences. Only the responders’ perception of the targets’ physical attractiveness predicted romantic interest; specifically, responders’ who rated the targets’ physical attractiveness as higher than themselves reported more romantic interest. PMID:28736483

Delay times of a LiDAR-guided precision sprayer control system

USDA-ARS?s Scientific Manuscript database

Accurate flow control systems in triggering sprays against detected targets are needed for precision variable-rate sprayer development. System delay times due to the laser-sensor data buffer, software operation, and hydraulic-mechanical component response were determined for a control system used fo...

Relationship between Corporate Governance and Information Security Governance Effectiveness in United States Corporations

ERIC Educational Resources Information Center

Davis, Robert E.

2017-01-01

Cyber attackers targeting large corporations achieved a high perimeter penetration success rate during 2013, resulting in many corporations incurring financial losses. Corporate information technology leaders have a fiduciary responsibility to implement information security domain processes that effectually address the challenges for preventing…

Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition.

PubMed

Kasner, Margaret T; Mick, Rosemarie; Jeschke, Grace R; Carabasi, Matthew; Filicko-O'Hara, Joanne; Flomenberg, Neal; Frey, Noelle V; Hexner, Elizabeth O; Luger, Selina M; Loren, Alison W; Mangan, James K; Wagner, John L; Weiss, Mark; Carroll, Martin; Perl, Alexander E

2018-04-02

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.

Abstract conceptual feature ratings predict gaze within written word arrays: evidence from a Visual Wor(l)d paradigm

PubMed Central

Primativo, Silvia; Reilly, Jamie; Crutch, Sebastian J

2016-01-01

The Abstract Conceptual Feature (ACF) framework predicts that word meaning is represented within a high-dimensional semantic space bounded by weighted contributions of perceptual, affective, and encyclopedic information. The ACF, like latent semantic analysis, is amenable to distance metrics between any two words. We applied predictions of the ACF framework to abstract words using eye tracking via an adaptation of the classical ‘visual word paradigm’. Healthy adults (N=20) selected the lexical item most related to a probe word in a 4-item written word array comprising the target and three distractors. The relation between the probe and each of the four words was determined using the semantic distance metrics derived from ACF ratings. Eye-movement data indicated that the word that was most semantically related to the probe received more and longer fixations relative to distractors. Importantly, in sets where participants did not provide an overt behavioral response, the fixation rates were none the less significantly higher for targets than distractors, closely resembling trials where an expected response was given. Furthermore, ACF ratings which are based on individual words predicted eye fixation metrics of probe-target similarity at least as well as latent semantic analysis ratings which are based on word co-occurrence. The results provide further validation of Euclidean distance metrics derived from ACF ratings as a measure of one facet of the semantic relatedness of abstract words and suggest that they represent a reasonable approximation of the organization of abstract conceptual space. The data are also compatible with the broad notion that multiple sources of information (not restricted to sensorimotor and emotion information) shape the organization of abstract concepts. Whilst the adapted ‘visual word paradigm’ is potentially a more metacognitive task than the classical visual world paradigm, we argue that it offers potential utility for studying abstract word comprehension. PMID:26901571

Genomic identification of potential targets unique to Candida albicans for the discovery of antifungal agents.

PubMed

Tripathi, Himanshu; Luqman, Suaib; Meena, Abha; Khan, Feroz

2014-01-01

Despite of modern antifungal therapy, the mortality rates of invasive infection with human fungal pathogen Candida albicans are up to 40%. Studies suggest that drug resistance in the three most common species of human fungal pathogens viz., C. albicans, Aspergillus fumigatus (causing mortality rate up to 90%) and Cryptococcus neoformans (causing mortality rate up to 70%) is due to mutations in the target enzymes or high expression of drug transporter genes. Drug resistance in human fungal pathogens has led to an imperative need for the identification of new targets unique to fungal pathogens. In the present study, we have used a comparative genomics approach to find out potential target proteins unique to C. albicans, an opportunistic fungus responsible for severe infection in immune-compromised human. Interestingly, many target proteins of existing antifungal agents showed orthologs in human cells. To identify unique proteins, we have compared proteome of C. albicans [SC5314] i.e., 14,633 total proteins retrieved from the RefSeq database of NCBI, USA with proteome of human and non-pathogenic yeast Saccharomyces cerevisiae. Results showed that 4,568 proteins were identified unique to C. albicans as compared to those of human and later when these unique proteins were compared with S. cerevisiae proteome, finally 2,161 proteins were identified as unique proteins and after removing repeats total 1,618 unique proteins (42 functionally known, 1,566 hypothetical and 10 unknown) were selected as potential antifungal drug targets unique to C. albicans.

Induction Speed Is Not a Determinant of Propofol Pharmacodynamics

PubMed Central

Doufas, Anthony G.; Bakhshandeh, Maryam; Bjorksten, Andrew R.; Shafer, Steven L.; Sessler, Daniel I.

2005-01-01

Summary We used individual pharmacodynamic modeling to demonstrate that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate of propofol. Background Evidence suggests that the rate at which they are infused may influence plasma-effect site equilibration of intravenous anesthetics. We used 5 different rates of propofol administration to test the hypothesis that different sedation endpoints occur at the same effect site propofol concentration, independent of the infusion rate. We concurrently evaluated the automated responsiveness monitor (ARM) against other sedation measures and the propofol effect site concentration. Methods With Human Studies Committee approval, 18 healthy volunteers received 5 consecutive target-controlled propofol infusions. During each infusion the effect site concentration was increased by a rate of 0.1, 0.3, 0.5, 0.7, or 0.9 μg·ml−1·min−1. Bispectral index and ARM were recorded at frequent intervals. The times of syringe drop and loss and recovery of responsiveness were noted. Pharmacokinetic and pharmacodynamic modeling was performed using NONMEM. Results Once the correct rate of plasma-effect site equilibration (ke0) was determined for each individual (ke0 = 0.17 min−1, time-to-peak effect = 2.7 min), the effect site concentrations associated with each clinical measure were not affected by the rate of rise of effect site propofol concentration. ARM correlated with all clinical measures of drug effect. Subjects invariably stopped responding to ARM at lower effect site propofol concentrations than those associated with loss of responsiveness. Conclusions Population-based pharmacokinetics, combined with real-time electroencephalographic measures of drug effect, may provide a means to individualize pharmacodynamic modeling during target-controlled drug delivery. ARM appears useful as an automated measure of sedation and may provide the basis for automated monitoring and titration of sedation for a propofol delivery system. PMID:15505446

Targeting radioimmunotherapy of hepatocellular carcinoma with iodine ({sup 131}I) metuximab injection: Clinical Phase I/II trials

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

Chen Zhinan; Mi Li; Xu Jing

2006-06-01

Purpose: HAb18G/CD147 is a hepatocellular carcinoma (HCC)-associated antigen. We developed iodine ({sup 131}I) metuximab injection (Licartin), a novel {sup 131}I-labeled HAb18G/CD147-specific monoclonal antibody F(ab'){sub 2} fragment, and evaluated its safety, pharmacokinetics, and clinical efficacy on HCC in Phase I/II trials. Methods and Materials: In a Phase I trial, 28 patients were randomly assigned to receive the injection in 9.25-, 18.5-, 27.75-, or 37-MBq/kg doses by hepatic artery infusion. In a multicenter Phase II trial, 106 patients received the injection (27.75 MBq/kg) on Day 1 of a 28-day cycle. Response rate and survival rate were the endpoints. Results: No life-threatening toxicmore » effects were found. The safe dosage was 27.75 MBq/kg. The blood clearance fitted a biphasic model, and its half-life was 90.56-63.93 h. In the Phase II trial, the injection was found to be targeted and concentrated to tumor tissues. Of the 73 patients completing two cycles, 6 (8.22%) had a partial response, 14 (19.18%) minor response, and 43 (58.90%) stable disease. The 21-month survival rate was 44.54%. The survival rate of progression-free patients was significantly higher than that of patients with progressive disease after either one or two cycles (p < 0.0001 or p 0.0019). Conclusion: Iodine ({sup 131}I) metuximab injection is safe and active for HCC patients.« less

Targeting to carcinoma cells with chitosan- and starch-coated magnetic nanoparticles for magnetic hyperthermia.

PubMed

Kim, Dong-Hyun; Kim, Kyoung-Nam; Kim, Kwang-Mahn; Lee, Yong-Keun

2009-01-01

The delivery of hyperthermic thermoseeds to a specific target site with minimal side effects is an important challenge in targeted hyperthermia, which employs magnetic method and functional polymers. An external magnetic field is used to control the site-specific targeting of the magnetic nanoparticles. Polymer-coated magnetic nanoparticles can confer a higher affinity to the biological cell membranes. In this study, uncoated, chitosan-coated, and starch-coated magnetic nanoparticles were synthesized for use as a hyperthermic thermoseed. Each sample was examined with respect to their applications to hyperthermia using XRD, VSM, and FTIR. In addition, the temperature changes under an alternating magnetic field were observed. As in vitro tests, the magnetic responsiveness of chitosan- and starch-coated magnetite was determined by a simple blood vessel model under various intensities of magnetic field. L929 normal cells and KB carcinoma cells were used to examine the cytotoxicity and affinity of each sample using the MTT method. The chitosan-coated magnetic nanoparticles generated a higher DeltaT of 23 degrees C under an AC magnetic field than the starch-coated magnetite, and the capturing rate of the particles was 96% under an external magnetic field of 0.4 T. The highest viability of L929 cells was 93.7%. Comparing the rate of KB cells capture with the rate of L929 cells capture, the rate of KB cells capture relatively increased with 10.8% in chitosan-coated magnetic nanoparticles. Hence, chitosan-coated magnetic nanoparticles are biocompatible and have a selective affinity to KB cells. The targeting of magnetic nanoparticles in hyperthermia was improved using a controlled magnetic field and a chitosan-coating. Therefore, chitosan-coated magnetic nanoparticles are expected to be promising materials for use in magnetic targeted hyperthermia. 2008 Wiley Periodicals, Inc.

Acute myeloid leukemia: advancing clinical trials and promising therapeutics

PubMed Central

Daver, Naval; Cortes, Jorge; Kantarjian, Hagop; Ravandi, Farhad

2016-01-01

Recent progress in understanding the biology of acute myeloid leukemia (AML) and the identification of targetable driver mutations, leukemia specific antigens and signal transduction pathways has ushered in a new era of therapy. In many circumstances the response rates with such targeted or antibody-based therapies are superior to those achieved with standard therapy and with decreased toxicity. In this review we discuss novel therapies in AML with a focus on two major areas of unmet need: (1) single agent and combination strategies to improve frontline therapy in elderly patients with AML and (2) molecularly targeted therapies in the frontline and salvage setting in all patients with AML. PMID:26910051

The pharmacogenomics of drug resistance to protein kinase inhibitors

PubMed Central

Gillis, Nancy K.; McLeod, Howard L.

2016-01-01

Dysregulation of growth factor cell signaling is a major driver of most human cancers. This has led to development of numerous drugs targeting protein kinases, with demonstrated efficacy in the treatment of a wide spectrum of cancers. Despite their high initial response rates and survival benefits, the majority of patients eventually develop resistance to these targeted therapies. This review article discusses examples of established mechanisms of drug resistance to anticancer therapies, including drug target mutations or gene amplifications, emergence of alternate signaling pathways, and pharmacokinetic variation. This reveals a role for pharmacogenomic analysis to identify and monitor for resistance, with possible therapeutic strategies to combat chemoresistance. PMID:27620953

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs.

PubMed

Fulkerson, Christopher M; Dhawan, Deepika; Ratliff, Timothy L; Hahn, Noah M; Knapp, Deborah W

2017-01-01

Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed.

Naturally Occurring Canine Invasive Urinary Bladder Cancer: A Complementary Animal Model to Improve the Success Rate in Human Clinical Trials of New Cancer Drugs

PubMed Central

Fulkerson, Christopher M.; Ratliff, Timothy L.; Hahn, Noah M.

2017-01-01

Genomic analyses are defining numerous new targets for cancer therapy. Therapies aimed at specific genetic and epigenetic targets in cancer cells as well as expanded development of immunotherapies are placing increased demands on animal models. Traditional experimental models do not possess the collective features (cancer heterogeneity, molecular complexity, invasion, metastasis, and immune cell response) critical to predict success or failure of emerging therapies in humans. There is growing evidence, however, that dogs with specific forms of naturally occurring cancer can serve as highly relevant animal models to complement traditional models. Invasive urinary bladder cancer (invasive urothelial carcinoma (InvUC)) in dogs, for example, closely mimics the cancer in humans in pathology, molecular features, biological behavior including sites and frequency of distant metastasis, and response to chemotherapy. Genomic analyses are defining further intriguing similarities between InvUC in dogs and that in humans. Multiple canine clinical trials have been completed, and others are in progress with the aim of translating important findings into humans to increase the success rate of human trials, as well as helping pet dogs. Examples of successful targeted therapy studies and the challenges to be met to fully utilize naturally occurring dog models of cancer will be reviewed. PMID:28487862

[Effects of a voice metronome on compression rate and depth in telephone assisted, bystander cardiopulmonary resuscitation: an investigator-blinded, 3-armed, randomized, simulation trial].

PubMed

van Tulder, Raphael; Roth, Dominik; Krammel, Mario; Laggner, Roberta; Schriefl, Christoph; Kienbacher, Calvin; Lorenzo Hartmann, Alexander; Novosad, Heinz; Constantin Chwojka, Christof; Havel, Christoph; Schreiber, Wolfgang; Herkner, Harald

2015-01-01

We investigated the effect on compression rate and depth of a conventional metronome and a voice metronome in simulated telephone-assisted, protocol-driven bystander Cardiopulmonary resucitation (CPR) compared to standard instruction. Thirty-six lay volunteers performed 10 minutes of compression-only CPR in a prospective, investigator-blinded, 3-arm study on a manikin. Participants were randomized either to standard instruction ("push down firmly, 5 cm"), a regular metronome pacing 110 beats per minute (bpm), or a voice metronome continuously prompting "deep-deepdeep- deeper" at 110 bpm. The primary outcome was deviation from the ideal chest compression target range (50 mm compression depth x 100 compressions per minute x 10 minutes = 50 m). Secondary outcomes were CPR quality measures (compression and leaning depth, rate, no-flow times) and participants' related physiological response (heart rate, blood pressure and nine hole peg test and borg scales score). We used a linear regression model to calculate effects. The mean (SD) deviation from the ideal target range (50 m) was -11 (9) m in the standard group, -20 (11) m in the conventional metronome group (adjusted difference [95%, CI], 9.0 [1.2-17.5 m], P=.03), and -18 (9) m in the voice metronome group (adjusted difference, 7.2 [-0.9-15.3] m, P=.08). Secondary outcomes (CPR quality measures and physiological response of participants to CPR performance) showed no significant differences. Compared to standard instruction, the conventional metronome showed a significant negative effect on the chest compression target range. The voice metronome showed a non-significant negative effect and therefore cannot be recommended for regular use in telephone-assisted CPR.

Impact of stimulus uncanniness on speeded response

PubMed Central

Takahashi, Kohske; Fukuda, Haruaki; Samejima, Kazuyuki; Watanabe, Katsumi; Ueda, Kazuhiro

2015-01-01

In the uncanny valley phenomenon, the causes of the feeling of uncanniness as well as the impact of the uncanniness on behavioral performances still remain open. The present study investigated the behavioral effects of stimulus uncanniness, particularly with respect to speeded response. Pictures of fish were used as visual stimuli. Participants engaged in direction discrimination, spatial cueing, and dot-probe tasks. The results showed that pictures rated as strongly uncanny delayed speeded response in the discrimination of the direction of the fish. In the cueing experiment, where a fish served as a task-irrelevant and unpredictable cue for a peripheral target, we again observed that the detection of a target was slowed when the cue was an uncanny fish. Conversely, the dot-probe task suggested that uncanny fish, unlike threatening stimulus, did not capture visual spatial attention. These results suggested that stimulus uncanniness resulted in the delayed response, and importantly this modulation was not mediated by the feelings of threat. PMID:26052297

Process optimization for the preparation of oligomycin-loaded folate-conjugated chitosan nanoparticles as a tumor-targeted drug delivery system using a two-level factorial design method.

PubMed

Zu, Yuangang; Zhao, Qi; Zhao, Xiuhua; Zu, Shuchong; Meng, Li

2011-01-01

Oligomycin-A (Oli-A), an anticancer drug, was loaded to the folate (FA)-conjugated chitosan as a tumor-targeted drug delivery system for the purpose of overcoming the nonspecific targeting characteristics and the hydrophobicity of the compound. The two-level factorial design (2-LFD) was applied to modeling the preparation process, which was composed of five independent variables, namely FA-conjugated chitosan (FA-CS) concentration, Oli-A concentration, sodium tripolyphosphate (TPP) concentration, the mass ratio of FA-CS to TPP, and crosslinking time. The mean particle size (MPS) and the drug loading rate (DLR) of the resulting Oli-loaded FA-CS nanoparticles (FA-Oli-CSNPs) were used as response variables. The interactive effects of the five independent variables on the response variables were studied. The characteristics of the nanoparticles, such as amount of FA conjugation, drug entrapment rate (DER), DLR, surface morphology, and release kinetics properties in vitro were investigated. The FA-Oli-CSNPs with MPS of 182.6 nm, DER of 17.3%, DLR of 58.5%, and zeta potential (ZP) of 24.6 mV were obtained under optimum conditions. The amount of FA conjugation was 45.9 mg/g chitosan. The FA-Oli-CSNPs showed sustained-release characteristics for 576 hours in vitro. The results indicated that FA-Oli-CSNPs obtained as a targeted drug delivery system could be effective in the therapy of leukemia in the future.

Delivering an Optimised Behavioural Intervention (OBI) to people with low back pain with high psychological risk; results and lessons learnt from a feasibility randomised controlled trial of Contextual Cognitive Behavioural Therapy (CCBT) vs. Physiotherapy.

PubMed

Pincus, Tamar; Anwar, Shamaila; McCracken, Lance M; McGregor, Alison; Graham, Liz; Collinson, Michelle; McBeth, John; Watson, Paul; Morley, Stephen; Henderson, Juliet; Farrin, Amanda J

2015-06-16

Low Back Pain (LBP) remains a common and costly problem. Psychological obstacles to recovery have been identified, but psychological and behavioural interventions have produced only moderate improvements. Reviews of trials have suggested that the interventions lack clear theoretical basis, are often compromised by low dose, lack of fidelity, and delivery by non-experts. In addition, interventions do not directly target known risk mechanisms. We identified a theory driven intervention (Contexual Cognitive Behavioural Therapy, CCBT) that directly targets an evidence-based risk mechanism (avoidance and ensured dose and delivery were optimised. This feasibility study was designed to test the credibility and acceptability of optimised CCBT against physiotherapy for avoidant LBP patients, and to test recruitment, delivery of the intervention and response rates prior to moving to a full definitive trial. A randomised controlled feasibility trial with patients randomised to receive CCBT or physiotherapy. CCBT was delivered by trained supervised psychologists on a one to one basis and comprised up to 8 one-hour sessions. Physiotherapy comprised back to fitness group exercises with at least 60 % of content exercise-based. Patients were eligible to take part if they had back pain for more than 3 months, and scored above a threshold indicating fear avoidance, catastrophic beliefs and distress. 89 patients were recruited. Uptake rates were above those predicted. Scores for credibility and acceptability of the interventions met the set criteria. Response rates at three and six months fell short of the 75 % target. Problems associated with poor response rates were identified and successfully resolved, rates increased to 77 % at 3 months, and 68 % at 6 months. Independent ratings of treatment sessions indicated that CCBT was delivered to fidelity. Numbers were too small for formal analysis. Although average scores for acceptance were higher in the CCBT group than in the group attending physiotherapy (increase of 7.9 versus 5.1) and change in disability and pain from baseline to 6 months were greater in the CCBT group than in the physiotherapy group, these findings should be interpreted with caution. CCBT is a credible and acceptable intervention for LBP patients who exhibit psychological obstacles to recovery. ISRCTN43733490 , registered 15/12/2010.

[Performance based regulation: a strategy to increase breastfeeding rates].

PubMed

Cobo-Armijo, Fernanda; Charvel, Sofía; Hernández-Ávila, Mauricio

2017-01-01

The decreasing breastfeeding rate in México is of public health concern. In this paper we discus an innovative regulatory approach -Performance Based Regulation- and its application to improve breastfeeding rates. This approach, forces industry to take responsibility for the lack of breastfeeding and its consequences. Failure to comply with this targets results in financial penalties. Applying performance based regulation as a strategy to improve breastfeeding is feasible because: the breastmilk substitutes market is an oligopoly, hence it is easy to identify the contribution of each market participant; the regulation's target population is clearly defined; it has a clear regulatory standard which can be easily evaluated, and sanctions to infringement can be defined under objective parameters. modify public policy, celebrate concertation agreements with the industry, create persuasive sanctions, strengthen enforcement activities and coordinate every action with the International Code of Marketing of Breast-milk Substitutes.

Electric stimulus duration alters network-mediated responses depending on retinal ganglion cell type

NASA Astrophysics Data System (ADS)

Im, Maesoon; Werginz, Paul; Fried, Shelley I.

2018-06-01

Objective. To improve the quality of artificial vision that arises from retinal prostheses, it is important to bring electrically-elicited neural activity more in line with the physiological signaling patterns that arise normally in the healthy retina. Our previous study reported that indirect activation produces a closer match to physiological responses in ON retinal ganglion cells (RGCs) than in OFF cells (Im and Fried 2015 J. Physiol. 593 3677-96). This suggests that a preferential activation of ON RGCs would shape the overall retinal response closer to natural signaling. Recently, we found that changes to the rate at which stimulation was delivered could bias responses towards a stronger ON component (Im and Fried 2016a J. Neural Eng. 13 025002), raising the possibility that changes to other stimulus parameters can similarly bias towards stronger ON responses. Here, we explore the effects of changing stimulus duration on the responses in ON and OFF types of brisk transient (BT) and brisk sustained (BS) RGCs. Approach. We used cell-attached patch clamp to record RGC spiking in the isolated rabbit retina. Targeted RGCs were first classified as ON or OFF type by their light responses, and further sub-classified as BT or BS types by their responses to both light and electric stimuli. Spiking in targeted RGCs was recorded in response to electric pulses with durations varying from 5 to100 ms. Stimulus amplitude was adjusted at each duration to hold total charge constant for all experiments. Main results. We found that varying stimulus durations modulated responses differentially for ON versus OFF cells: in ON cells, spike counts decreased significantly with increasing stimulus duration while in OFF cells the changes were more modest. The maximum ratio of ON versus OFF responses occurred at a duration of ~10 ms. The difference in response strength for BT versus BS cells was much larger in ON cells than in OFF cells. Significance. The stimulation rates preferred by subjects during clinical trials are similar to the rates that maximize the ON/OFF response ratio in in vitro testing (Im and Fried 2016a J. Neural Eng. 13 025002). Here, we determine the stimulus duration that produces the strongest bias towards ON responses and speculate that it will further enhance clinical effectiveness.

Perpetrators and targets of bullying at work: role stress and individual differences.

PubMed

Matthiesen, Stig Berge; Einarsen, Ståle

2007-01-01

A workplace survey study (N = 2215, response rate 47%) revealed that about 16% of the sample may be categorized as either perpetrators (5.4%), provocative victims (2.1%), or as targets of bullying (8.3%). Targets of bullying, provocative victims, and bullies were compared with those 84% who do not report any involvement with respect to bullying at work, self-esteem, aggressive tendencies, prior experiences of bullying, or experiences of role stress. Perpetrators were found to have a higher level of aggression than did the comparison group and the targets. Provocative victims manifested a low level of self-esteem and social competency combined with a high level of aggressiveness. Targets of bullying revealed low levels of self-esteem and social competency. Targets, provocative victims, and perpetrators reported elevated levels of role stress in the form of unclear or conflicting demands and expectations around work tasks and daily work.

Mate-choice copying in single and coupled women: the influence of mate acceptance and mate rejection decisions of other women.

PubMed

Deng, Yan; Zheng, Yong

2015-01-26

Studies of humans and non-human animals indicate that females tend to change the likelihood of choosing a potential mate based on the decisions of other females; this is known as mate-choice copying. In a sample of both single and coupled women, we examined the influence of other women's (model) mate-choice decisions, including mate acceptance and mate rejection, on participants' attractiveness ratings of men (target) and willingness of mate selection. We also examined whether different types of relationships between the target men and the model women affected mate-choice copying. We found that both the single and coupled women showed mate-choice copying, but their response patterns differed. The significant effects for single women were dependent on a decrease in attractiveness ratings when they perceived the models' mate rejection. However, the significant findings for coupled women relied on an increase in attractiveness ratings when they observed the models' mate acceptance. Furthermore, the relationship status between the target men and the model women affected the magnitude of mate-choice copying effects for the single women. Specifically, they showed less mate-choice copying when the targets and models were in a committed romantic relationship than when in a temporary relationship.

Factors influencing the return rate in a direct mail campaign to inform minority women about prevention of cervical cancer.

PubMed Central

Dignan, M B; Michielutte, R; Jones-Lighty, D D; Bahnson, J

1994-01-01

The Forsyth County Cervical Cancer Prevention Project was a 5-year community-based health education program funded by the National Cancer Institute. The program was developed to reduce cervical cancer mortality among black women in Forsyth County, and it was targeted to those ages 18 and older. The program tried to educate the target population through a combination of mass media and direct education. This paper reports on an experiment conducted to investigate sources of influence on the effectiveness of direct mail, a technique used to augment mass media health education. Direct mail has shown promise as a method for reaching target populations that are difficult to reach with other mass media approaches. Using commercially prepared mailing lists sorted by zip code and other characteristics of the resident, health-related materials can be targeted to persons at their homes. A randomized experiment involving 1,000 households was carried out to estimate the influence of type of postage and address (name versus "resident or occupant") on the response rate to direct mail. Results indicated that there was no significant advantage from use of first class over bulk rate postage, but the return was significantly greater when the envelope bore a name rather than "resident or occupant." PMID:8041850

Factors influencing the return rate in a direct mail campaign to inform minority women about prevention of cervical cancer.

PubMed

Dignan, M B; Michielutte, R; Jones-Lighty, D D; Bahnson, J

1994-01-01

The Forsyth County Cervical Cancer Prevention Project was a 5-year community-based health education program funded by the National Cancer Institute. The program was developed to reduce cervical cancer mortality among black women in Forsyth County, and it was targeted to those ages 18 and older. The program tried to educate the target population through a combination of mass media and direct education. This paper reports on an experiment conducted to investigate sources of influence on the effectiveness of direct mail, a technique used to augment mass media health education. Direct mail has shown promise as a method for reaching target populations that are difficult to reach with other mass media approaches. Using commercially prepared mailing lists sorted by zip code and other characteristics of the resident, health-related materials can be targeted to persons at their homes. A randomized experiment involving 1,000 households was carried out to estimate the influence of type of postage and address (name versus "resident or occupant") on the response rate to direct mail. Results indicated that there was no significant advantage from use of first class over bulk rate postage, but the return was significantly greater when the envelope bore a name rather than "resident or occupant."

50 ways to trace your veteran: increasing response rates can be cheap and effective

PubMed Central

Fear, Nicola Townsend; Van Staden, Lauren; Iversen, Amy; Hall, John; Wessely, Simon

2010-01-01

Background while low response rates need not introduce bias into research, having a lower percentage of responders does increase the potential for this to occur. This is of particular concern given the decline that has been occurring in response rates since the 1950s. However, there are various methods that can be incorporated into the study design, which can assist in increasing levels of participation. Objective To outline the methods used by the King's Centre for Military Health Research (KCMHR) when conducting a recent telephone survey of serving and ex-Service military personnel. Design Using participants who had already taken part in a questionnaire-based study on the health effects of serving in the UK Armed Forces (n=10,272), a subsample was selected for an in-depth telephone interview-based follow-up study. The subsample consisted of 1,105 participants, selected on the basis of their mental health status. An adjusted response rate of 76% was achieved (n=821). Results Various methods of contact were used in this study to ensure an adequate response rate was achieved. Conclusions Simple research strategies increase response rates and are likely to reduce bias. Use of multiple simultaneous tracing methods and customisation of the approach to the target population increases rapport between participants, ensuring that those who take part feel valued as members of the study. In the current climate of decreasing participation in studies, research teams need to engage with their study population and devise innovative strategies to keep participants involved in the research being undertaken. PMID:22893795

Homeostatic modulation on unconscious hedonic responses to food.

PubMed

Sato, Wataru; Sawada, Reiko; Kubota, Yasutaka; Toichi, Motomi; Fushiki, Tohru

2017-10-26

Hedonic/affective responses to food play a critical role in eating behavior. Previous behavioral studies have shown that hedonic responses to food are elicited consciously and unconsciously. Although the studies also showed that hunger and satiation have a modulatory effect on conscious hedonic responses to food, the effect of these homeostatic states on unconscious hedonic responses to food remains unknown. We investigated unconscious hedonic responses to food in hungry and satiated participants using the subliminal affective priming paradigm. Food images or corresponding mosaic images were presented in the left or right peripheral visual field during 33 ms. Then photographs of target faces with emotionally neutral expressions were presented, and the participants evaluated their preference for the faces. Additionally, daily eating behaviors were assessed using questionnaires. Preference for the target faces was increased by food images relative to the mosaics in the hungry, but not the satiated, state. The difference in preference ratings between the food and mosaic conditions was positively correlated with the tendency for external eating in the hungry, but not the satiated, group. Our findings suggest that homeostatic states modulate unconscious hedonic responses to food and that this phenomenon is related to daily eating behaviors.

Medical Aspects of Disaster Preparedness and Response: A System Overview of Civil and Military Resources and New Potential

DTIC Science & Technology

2007-01-01

primary care facilities, necessitating the establishment of surge capacity sub-acute treatment in nursing homes, retirement homes, school gymnasiums and...see Figure 1, below) rated by their ability to field, equip and sustain their mixed compliments of doctors, nurses , EMTs PAs, paramedics and support...200-member National Nursing Response Teams (NNRT) (which are primarily targeted to provide mass pre or post incident inoculations) share personnel and

Daylight methyl-aminolevulinate photodynamic therapy versus ingenol mebutate for the treatment of actinic keratoses: an intraindividual comparative analysis.

PubMed

Genovese, Giovanni; Fai, Dario; Fai, Carlotta; Mavilia, Luciano; Mercuri, Santo R

2016-05-01

Daylight-photodynamic therapy (D-PDT) and ingenol mebutate (IM) are novel therapies directed to actinic keratoses (AK). The purpose of our study was to compare effectiveness, tolerability, cosmetic outcome and patient preference of D-PDT versus IM in the treatment of grade I and II AK. Twenty-seven patients with AK on the face or scalp were enrolled. Each patient received, in a 25 cm(2) target area, D-PDT on right side and IM on left side. Overall 323 AK were treated. Both target areas achieved complete response in 40.47% of the cases and average AK clearance rate was similar for D-PDT and IM (p=0.74). In D-PDT areas mean grade II AK clearance rate was lower compared with that of grade I AK (p=0.015). In IM areas grade I and II AK average clearance rates were similar (p=0.28). At week 1 and month 1, mean local skin responses (LSR) score were higher in areas treated with IM. IM areas showed more severe pain and cosmetic sequelae. D-PDT had similar effectiveness to IM, even if IM demonstrated higher grade II AK clearance rate. Tolerability profile was superior for D-PDT in terms of LSR and pain. D-PDT was more cosmetically acceptable. Patients preferred D-PDT to IM in most cases. © 2016 Wiley Periodicals, Inc.

Efficacy and Safety of Antiintegrin Antibody for Inflammatory Bowel Disease

PubMed Central

Lin, Lianjie; Liu, Xiang; Wang, Dongxu; Zheng, Changqing

2015-01-01

Abstract We sought to evaluate the safety and efficacy of available biologics that inhibit T-cell migration by blocking α4β7 integrins in inflammatory bowel diseases. The aim of this study is to evaluate whether Crohn disease (CD) patients receiving either vedolizumab or natalizumab have any different effect in CD Activity Index (CDAI). Using Medline, Excerpta Medica dataBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar until October 31, 2013, we identified 10 studies examining the safety and efficacy of specific integrin inhibitors—vedolizumab, which targets an epitope comprising the α4β7 heterodimer; natalizumab, which recognizes the α4 integrin subunit; etrolizumab, which is specific for the β7 subunit—in the treatment of CD and ulcerative colitis (UC). CD patients receiving either vedolizumab or natalizumab demonstrated a modest increase in remission rate, when compared with that of the placebo group. Further, although both treatments reduced the CDAI slightly, the observed clinical response was less robust than that of the remission rate. UC patients treated with vedolizumab and natalizumab were found to show more prominent increases in both remission and clinical response, compared with placebo, than patients with CD. Etrolizumab, however, was not found to significantly affect either response or remission rates in UC patients. Biologics targeting integrins show promise as therapeutics in the treatment of inflammatory bowel disease in patients who are either nonresponsive or intolerant to traditional approaches, though further research is necessary to optimize treatment efficacies. PMID:25761174

Signaling pathways underpinning the manifestations of ionizing radiation-induced bystander effects.

PubMed

Hamada, Nobuyuki; Maeda, Munetoshi; Otsuka, Kensuke; Tomita, Masanori

2011-06-01

For nearly a century, ionizing radiation has been indispensable to medical diagnosis. Furthermore, various types of electromagnetic and particulate radiation have also been used in cancer therapy. However, the biological mechanism of radiation action remains incompletely understood. In this regard, a rapidly growing body of experimental evidence indicates that radiation exposure induces biological effects in cells whose nucleus has not been irradiated. This phenomenon termed the 'non-targeted effects' challenges the long-held tenet that radiation traversal through the cell nucleus is a prerequisite to elicit genetic damage and biological responses. The non-targeted effects include biological effects in cytoplasm-irradiated cells, bystander effects that arise in non-irradiated cells having received signals from irradiated cells, and genomic instability occurring in the progeny of irradiated cells. Such non-targeted responses are interrelated, and the bystander effect is further related with an adaptive response that manifests itself as the attenuated stressful biological effects of acute high-dose irradiation in cells that have been pre-exposed to low-dose or low-dose-rate radiation. This paper reviews the current body of knowledge about the bystander effect with emphasis on experimental approaches, in vitro and in vivo manifestations, radiation quality dependence, temporal and spatial dependence, proposed mechanisms, and clinical implications. Relations of bystander responses with the effects in cytoplasm-irradiated cells, genomic instability and adaptive response will also be briefly discussed.

[Application of laboratory information system in the management of the key indicators of quality inspection].

PubMed

Guo, Ye; Chen, Qian; Wu, Wei; Cui, Wei

2015-03-31

To establish a system of monitoring the key indicator of quality for inspection (KIQI) on a laboratory information system (LIS), and to have a better management of KIQI. Clinical sample made in PUMCH were collected during the whole of 2014. Next, interactive input program were designed to accomplish data collecting of the disqualification rate of samples, the mistake rate of samples and the occasions of losing samples, etc. Then, a series moment of sample collection, laboratory sample arrived, sample test, sample check, response to critical value, namely, trajectory information left on LIS were recorded and the qualification rate of TAT, the notification rate of endangering result were calculated. Finally, the information about quality control were collected to build an internal quality control database and the KIQI, such as the out-of-control rate of quality control and the total error of test items were monitored. The inspection of the sample management shows the disqualification rates in 2014 were all below the target, but the rates in January and February were a little high and the rates of four wards were above 2%. The mistake rates of samples was 0.47 cases/10 000 cases, attaining the target (< 2 cases/10 000 cases). Also, there was no occasion of losing samples in 2014, attaining the target too. The inspection of laboratory reports shows the qualification rates of TAT was within the acceptable range (> 95%), however the rates of blood routine in November (94.75%) was out of range. We have solved the problem by optimizing the processes. The notification rate of endangering result attained the target (≥ 98%), while the rate of timely notification is needed to improve. Quality inspection shows the CV of APTT in August (5.02%) was rising significantly, beyond the accepted CV (5.0%). We have solved the problem by changing the reagent. The CV of TT in 2014 were all below the allowable CV, thus the allowable CV of the next year lower to 10%. It is an objective and effective method to manage KIQI with the powerful management mode of database and information process capability on LIS.

Combining in silico evolution and nonlinear dimensionality reduction to redesign responses of signaling networks

NASA Astrophysics Data System (ADS)

Prescott, Aaron M.; Abel, Steven M.

2016-12-01

The rational design of network behavior is a central goal of synthetic biology. Here, we combine in silico evolution with nonlinear dimensionality reduction to redesign the responses of fixed-topology signaling networks and to characterize sets of kinetic parameters that underlie various input-output relations. We first consider the earliest part of the T cell receptor (TCR) signaling network and demonstrate that it can produce a variety of input-output relations (quantified as the level of TCR phosphorylation as a function of the characteristic TCR binding time). We utilize an evolutionary algorithm (EA) to identify sets of kinetic parameters that give rise to: (i) sigmoidal responses with the activation threshold varied over 6 orders of magnitude, (ii) a graded response, and (iii) an inverted response in which short TCR binding times lead to activation. We also consider a network with both positive and negative feedback and use the EA to evolve oscillatory responses with different periods in response to a change in input. For each targeted input-output relation, we conduct many independent runs of the EA and use nonlinear dimensionality reduction to embed the resulting data for each network in two dimensions. We then partition the results into groups and characterize constraints placed on the parameters by the different targeted response curves. Our approach provides a way (i) to guide the design of kinetic parameters of fixed-topology networks to generate novel input-output relations and (ii) to constrain ranges of biological parameters using experimental data. In the cases considered, the network topologies exhibit significant flexibility in generating alternative responses, with distinct patterns of kinetic rates emerging for different targeted responses.

Examining the Sustainability of an Evidence-Based Preschool Curriculum: The REDI Program

PubMed Central

Sanford DeRousie, Rebecca M.; Bierman, Karen L.

2011-01-01

This study examined the extent to which an evidence-based preschool curriculum (Head Start REDI) was sustained by 20 teachers during the year following a randomized controlled efficacy trial, when teachers were no longer required by the research project to implement the curriculum. Two quantitative measures of sustainability (teacher ratings, REDI coach ratings) and a qualitative measure (teacher interview) were collected and compared. Sustainability varied by the specific curriculum component, with higher rates of sustainability for the social-emotional component (Preschool PATHS) than for the language and literacy components. Estimates of sustainability were affected by the method of measurement, with REDI coach ratings and qualitative teacher interviews more closely aligned than teacher ratings. Responses from qualitative interviews identified the main factors that teachers thought affected sustainability. Teacher responses suggest that efforts to promote sustainability are best targeted at reducing barriers, such as competing demands, rather than simply highlighting the benefits of the new curriculum. PMID:22408287

Increasing the persistence of a heterogeneous behavior chain: Studies of extinction in a rat model of search behavior of working dogs

PubMed Central

Thrailkill, Eric A.; Kacelnik, Alex; Porritt, Fay; Bouton, Mark E.

2016-01-01

Dogs trained to search for contraband perform a chain of behavior in which they first search for a target and then make a separate response that indicates to the trainer that they have found one. The dogs often conduct multiple searches without encountering a target and receiving the reinforcer (i.e., no contraband is present). Understanding extinction (i.e., the decline in work rate when reinforcers are no longer encountered) may assist in training dogs to work in conditions where targets are rare. We therefore trained rats on a search-target behavior chain modeled on the search behavior of working dogs. A discriminative stimulus signaled that a search response (e.g., chain pull) led to a second stimulus that set the occasion for a target response (e.g., lever press) that was reinforced by a food pellet. In Experiment 1 training with longer search durations and intermittent (partial) reinforcement of searching (i.e. some trials had no target present) both led to more persistent search responding in extinction. The loss of search behavior in extinction was primarily dependent on the number of non-reinforced searches rather than time searching without reinforcement. In Experiments 2 and 3, delivery of non-contingent reinforcers during extinction increased search persistence provided they had also been presented during training. Thus, results with rats suggest that the persistence of working dog performance (or chained behavior generally) may be improved by training with partial reinforcement of searching and non-contingent reinforcement during both training and work (extinction). PMID:27306694

How our own speech rate influences our perception of others.

PubMed

Bosker, Hans Rutger

2017-08-01

In conversation, our own speech and that of others follow each other in rapid succession. Effects of the surrounding context on speech perception are well documented but, despite the ubiquity of the sound of our own voice, it is unknown whether our own speech also influences our perception of other talkers. This study investigated context effects induced by our own speech through 6 experiments, specifically targeting rate normalization (i.e., perceiving phonetic segments relative to surrounding speech rate). Experiment 1 revealed that hearing prerecorded fast or slow context sentences altered the perception of ambiguous vowels, replicating earlier work. Experiment 2 demonstrated that talking at a fast or slow rate prior to target presentation also altered target perception, though the effect of preceding speech rate was reduced. Experiment 3 showed that silent talking (i.e., inner speech) at fast or slow rates did not modulate the perception of others, suggesting that the effect of self-produced speech rate in Experiment 2 arose through monitoring of the external speech signal. Experiment 4 demonstrated that, when participants were played back their own (fast/slow) speech, no reduction of the effect of preceding speech rate was observed, suggesting that the additional task of speech production may be responsible for the reduced effect in Experiment 2. Finally, Experiments 5 and 6 replicate Experiments 2 and 3 with new participant samples. Taken together, these results suggest that variation in speech production may induce variation in speech perception, thus carrying implications for our understanding of spoken communication in dialogue settings. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

PSMA Theranostics: Current Status and Future Directions

PubMed Central

Afshar-Oromieh, Ali; Jadvar, Hossein; Ahmadzadehfar, Hojjat

2018-01-01

Prostate-specific membrane antigen (PSMA) is a promising target for imaging diagnostics and targeted radionuclide therapy (theranostics) of prostate cancer and its metastases. There is increasing evidence of encouraging response rates and a low toxicity profile of radioligand therapy (RLT) of metastatic castration-resistant prostate cancer using 177Lu-labeled PSMA ligands. In this article, we review the current status of diagnostics and therapy using radiolabeled PSMA ligands. We also suggest protocols for patient selection criteria and conduct of PSMA-based RLT. Challenges and opportunities of PSMA theranostics are discussed. PMID:29873291

Integrating Dimensional and Discrete Theories of Emotions: A New Set of Anger- and Fear-Eliciting Stimuli for Children.

PubMed

Scaini, Simona; Rancoita, Paola M V; Martoni, Riccardo M; Omero, Micol; Ogliari, Anna; Brombin, Chiara

2017-01-01

The selection of appropriate stimuli for inducing specific emotional states has become one of the most challenging topics in psychological research. In the literature there is a lack of affective picture database specifically suited to investigate emotional response in children. Here the authors present the methodology that led us to create a new database (called Anger- and Fear-Eliciting Stimuli for Children) of affective stimuli inducing experiences of 3 target emotions (neutral, anger, and fear) to use in experimental session involving children. A total of 84 children were asked to (a) indicate the perceived emotion and its intensity and (b) rate the three affective dimensions of the Self-Assessment Manikin (SAM). Based on concordance between labeled and expected target emotion, the authors decided to select 15 stimuli to be included in Multivariate modeling techniques were applied to evaluate the association between expected target emotion and SAM ratings. The authors found that the hit rate for the neutral pictures was good (greater than 81%), for fear-eliciting pictures it was greater than 64%, and for anger-eliciting pictures it was moderate (between 45% and 56%). The study results reveal also an age effect only in the arousal scale. However, the authors did not find significant gender-related differences in SAM ratings.

A Phase II study of Dovitinib in Patients With Recurrent or Metastatic Adenoid Cystic Carcinoma

PubMed Central

Dillon, Patrick M.; Petroni, Gina R.; Horton, Bethany J.; Moskaluk, Christopher A.; Fracasso, Paula M.; Douvas, Michael G; Varhegyi, Nikole; Zaja-Milatovic, Snjezana; Thomas, Christopher Y.

2017-01-01

Purpose Genetic and preclinical studies have implicated fibroblast growth factor receptor (FGFR) signaling in the pathogenesis of adenoid cystic carcinoma (ACC). Dovitinib, a suppressor FGFR activity, may be active in ACC. Methods In a two-stage phase II study, 35 patients with progressive ACC were treated with dovitinib 500mg orally for 5 of 7 days continuously. The primary endpoints were objective response rate (ORR) and change in tumor growth rate (TGR). Progression-free survival (PFS), overall survival (OS), metabolic response, biomarker and QOL were secondary endpoints. Results Of thirty-four evaluable patients, two (6%) had a partial response and 22 (65%) had stable disease >4 months. Median PFS was 8.2 months and OS was 20.6 months. The slope of the overall TGR fell from 1.95 to 0.63 on-treatment (p<0.001). Toxicity was moderate; 63% of patients developed grade 3–4 toxicity, 94% required dose modifications, and 21% stopped treatment early. An early metabolic response based on 18FDG-PET scans was seen in 3/15 patients but did not correlate with RECIST response. MYB gene translocation was observed and significantly correlated with over-expression of MYB but did not correlate with FGFR1 phosphorylation or clinical response to dovitinib. Conclusion Dovitinib produced few objective responses in patients with ACC but did suppress the TGR with a PFS that compares favorably to those reported with other targeted agents. Future studies of more potent and selective FGFR inhibitors in biomarker-selected patients will be required to determine if FGFR signaling is a valid therapeutic target in ACC. PMID:28377480

75 FR 29776 - Tobacco Product Advertising and Promotion to Youth and Racial and Ethnic Minority Populations...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-05-27

... designed to appeal to specific racial and ethnic minority populations in the United States. For the same... Tobacco products are responsible for more than 440,000 deaths each year. The rates of tobacco use and..., ``[t]argeting of various population groups--including * * * specific racial and ethnic populations...

Frequency of anti-collision observing responses by solo pilots as a function of traffic density, ATC traffic warnings, and competing behavior.

DOT National Transportation Integrated Search

1973-04-01

Eighteen instrument-rated pilots were flown in two-hour simulated solo missions during which the frequency of traffic, ATC warnings, and ATC clearances were varied, while the visibility of the target was held constant at 100%. : In order to observe t...

Working from the Inside Out: A Case Study of Mackay Safe Community

ERIC Educational Resources Information Center

Hanson, Dale; Gunning, Colleen; Rose, Judy; McFarlane, Kathryn; Franklin, Richard C.

2015-01-01

Mackay Whitsunday Safe Community (MWSC) was established in 2000 in response to high rates of injury observed in the region. MWSC assumed an ecological perspective, incorporating targeted safety promotion campaigns reinforced by supportive environments and policy. By involving the community in finding its own solutions, MWSC attempted to catalyze…

Which plant trait explains the variations in relative growth rate and its response to elevated carbon dioxide concentration among Arabidopsis thaliana ecotypes derived from a variety of habitats?

PubMed

Oguchi, Riichi; Ozaki, Hiroshi; Hanada, Kousuke; Hikosaka, Kouki

2016-03-01

Elevated atmospheric carbon dioxide (CO2) concentration ([CO2]) enhances plant growth, but this enhancement varies considerably. It is still uncertain which plant traits are quantitatively related to the variation in plant growth. To identify the traits responsible, we developed a growth analysis model that included primary parameters associated with morphology, nitrogen (N) use, and leaf and root activities. We analysed the vegetative growth of 44 ecotypes of Arabidopsis thaliana L. grown at ambient and elevated [CO2] (800 μmol mol(-1)). The 44 ecotypes were selected such that they were derived from various altitudes and latitudes. Relative growth rate (RGR; growth rate per unit plant mass) and its response to [CO2] varied by 1.5- and 1.7-fold among ecotypes, respectively. The variation in RGR at both [CO2]s was mainly explained by the variation in leaf N productivity (LNP; growth rate per leaf N),which was strongly related to photosynthetic N use efficiency (PNUE). The variation in the response of RGR to [CO2] was also explained by the variation in the response of LNP to [CO2]. Genomic analyses indicated that there was no phylogenetic constraint on inter-ecotype variation in the CO2 response of RGR or LNP. We conclude that the significant variation in plant growth and its response to [CO2] among ecotypes reflects the variation in N use for photosynthesis among ecotypes, and that the response of PNUE to CO2 is an important target for predicting and/or breeding plants that have high growth rates at elevated [CO2].

Iodine-131 tositumomab (Bexxar) in a radiation oncology environment

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

Macklis, Roger M.

2006-10-01

Iodine-131 (I-131) tositumomab (Bexxar; GlaxoSmithKline, Research Triangle Park, NC) is one of two recently approved radiolabeled antibodies directed against the CD20 surface antigen found on normal B cells and in more than 95% of B cell non-Hodgkin's lymphoma. The compound itself is formulated as an IgG2a immunoglobulin radiolabeled with the mixed beta/gamma emitter I-131. Multicenter clinical trials have repeatedly shown impressive clinical responses (20-40% complete response rates and 60-80% overall response rates) in the patient groups for whom this treatment is indicated. Treatment-related toxicity is generally extremely mild and typically involves only reversible hematopoietic suppression and (in some cases) amore » risk of treatment-induced hypothyroidism. Owing to Radiation safety concerns necessitated by the clinical use of this targeted radiopharmaceutical, it is important for radiation oncology departments wishing to participate in the care of these patients to establish methodologies and standard operating procedures for safe and efficient departmental use. This summary reviews the pertinent background information related to the current clinical experience with I-131 tositumomab and highlights some of the major opportunities for the participation of radiation oncology in the patient evaluation and treatment process. I-131 tositumomab provides an excellent example of the way in which the increasingly important new field of 'targeted therapy' intersects with the practice of clinical radiotherapy. The author contends that it will be worth the time and effort involved in establishing a firm basis for the development of a comprehensive program for systemic targeted radiopharmaceutical therapies (STaRT) within Radiation medicine domain.« less

Histology-specific therapy for advanced soft tissue sarcoma and benign connective tissue tumors.

PubMed

Silk, Ann W; Schuetze, Scott M

2012-09-01

Molecularly targeted agents have shown activity in soft tissue sarcoma (STS) and benign connective tissue tumors over the past ten years, but response rates differ by histologic subtype. The field of molecularly targeted agents in sarcoma is increasingly complex. Often, clinicians must rely on phase II data or even case series due to the rarity of these diseases. In subtypes with a clear role of specific factors in the pathophysiology of disease, such as giant cell tumor of the bone and diffuse-type tenosynovial giant cell tumor, it is reasonable to treat with newer targeted therapies, when available, in place of chemotherapy when systemic treatment is needed to control disease. In diseases without documented implication of a pathway in disease pathogenesis (e.g. soft tissue sarcoma and vascular endothelial growth factor), clear benefit from drug treatment should be established in randomized phase III trials before implementation into routine clinical practice. Histologic subtype will continue to emerge as a critical factor in treatment selection as we learn more about the molecular drivers of tumor growth and survival in different subtypes. Many of the drugs that have been recently developed affect tumor growth more than survival, therefore progression-free survival may be a more clinically relevant intermediate endpoint than objective response rate using Response Evaluation Criteria In Solid Tumors (RECIST) in early phase sarcoma trials. Because of the rarity of disease and increasing need for multidisciplinary management, patients with connective tissue tumors should be evaluated at a center with expertise in these diseases. Participation in clinical trials, when available, is highly encouraged.

Enhanced startle responsivity 24 hours after acute stress exposure.

PubMed

Herten, Nadja; Otto, Tobias; Adolph, Dirk; Pause, Bettina M; Kumsta, Robert; Wolf, Oliver T

2016-10-01

Cortisol release in a stressful situation can be beneficial for memory encoding and memory consolidation. Stimuli, such as odors, related to the stressful episode may successfully cue memory contents of the stress experience. The current investigation aimed at testing the potency of stress to influence startle responsivity 24 hr later and to implicitly reactivate emotional memory traces triggered by an odor involved. Participants were assigned to either a stress (Trier Social Stress Test [TSST]) or control (friendly TSST [f-TSST]) condition featuring an ambient odor. On the next day, participants underwent an auditory startle paradigm while their eyeblink reflex was recorded by an electrooculogram. Three different olfactory stimuli were delivered, one being the target odor presented the day before. Additionally, negative, positive, and pictures of the committee members were included for comparing general startle responsivity and fear-potentiated startle. Participants of the stress group demonstrated an enhanced startle response across all stimuli compared to participants of the control group. There were no specific effects with regard to the target odor. The typical fear-potentiated startle response occurred. Stressed participants tended to rate the target odor more aversive than control participants. Odor recognition memory did not differ between the groups, suggesting an implicit effect on odor valence. Our results show that acute stress exposure enhances startle responsivity 24 hr later. This effect might be caused by a shift of amygdala function causing heightened sensitivity, but lower levels of specificity. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Rapid Two-Millisecond Interrogation of Electrochemical, Aptamer-Based Sensor Response Using Intermittent Pulse Amperometry.

PubMed

Santos-Cancel, Mirelis; Lazenby, Robert A; White, Ryan J

2018-06-22

In this manuscript, we employ the technique intermittent pulse amperometry (IPA) to interrogate equilibrium and kinetic target binding to the surface of electrochemical, aptamer-based (E-AB) sensors, achieving as fast as 2 ms time resolution. E-AB sensors comprise an electrode surface modified with a flexible nucleic acid aptamer tethered at the 3'-terminus with a redox-active molecule. The introduction of a target changes the conformation and flexibility of the nucleic acid, which alters the charge transfer rate of the appended redox molecule. Typically, changes in charge transfer rate within this class of sensor are monitored via voltammetric methods. Here, we demonstrate that the use of IPA enables the detection of changes in charge transfer rates (i.e., current) at times <100 μs after the application of a potential pulse. Changes in sensor current are quantitatively related to target analyte concentration and can be used to create binding isotherms. Furthermore, the application of IPA enables rapid probing of the electrochemical surface with a time resolution equivalent to as low as twice the applied potential pulse width, not previously demonstrated with traditional voltammetric techniques employed with E-AB sensors (alternating current, square wave, cyclic). To visualize binding, we developed false-color plots analogous to those used in the field of fast-scan cyclic voltammetry. The use of IPA is universal, as demonstrated with two representative small molecule E-AB sensors directed against the aminoglycoside antibiotic tobramycin and adenosine triphosphate (ATP). Intermittent pulse amperometry exhibits an unprecedented sub-microsecond temporal response and is a general method for measuring rapid sensor performance.

Improving patient outcomes to targeted therapies in melanoma.

PubMed

Eroglu, Zeynep; Smalley, Keiran S M; Sondak, Vernon K

2016-06-01

The arrival of targeted therapies has led to significant improvements in clinical outcomes for patients with BRAFV600 mutated advanced melanoma over the past five years. In several clinical trials, BRAF and MEK inhibitors have shown improvement in progression free and overall survival, along with much higher tumor response rates in comparison to chemotherapy, with the combination of these drugs superior to monotherapy. These agents are also being tested in earlier-stage patients, in addition to alternative dosing regimens and in combinations with other therapeutics. Efforts are also ongoing to expand the success found with targeted therapies to other subtypes of melanoma, including NRAS and c-kit mutated melanomas, uveal melanomas, and BRAF/NRAS wild type melanomas. Expert Commentary: We aim to provide an overview of clinical outcomes with targeted therapies in melanoma patients.

Child Modifiability as a Predictor of Language Abilities in Deaf Children Who Use American Sign Language.

PubMed

Mann, Wolfgang; Peña, Elizabeth D; Morgan, Gary

2015-08-01

This research explored the use of dynamic assessment (DA) for language-learning abilities in signing deaf children from deaf and hearing families. Thirty-seven deaf children, aged 6 to 11 years, were identified as either stronger (n = 26) or weaker (n = 11) language learners according to teacher or speech-language pathologist report. All children received 2 scripted, mediated learning experience sessions targeting vocabulary knowledge—specifically, the use of semantic categories that were carried out in American Sign Language. Participant responses to learning were measured in terms of an index of child modifiability. This index was determined separately at the end of the 2 individual sessions. It combined ratings reflecting each child's learning abilities and responses to mediation, including social-emotional behavior, cognitive arousal, and cognitive elaboration. Group results showed that modifiability ratings were significantly better for stronger language learners than for weaker language learners. The strongest predictors of language ability were cognitive arousal and cognitive elaboration. Mediator ratings of child modifiability (i.e., combined score of social-emotional factors and cognitive factors) are highly sensitive to language-learning abilities in deaf children who use sign language as their primary mode of communication. This method can be used to design targeted interventions.

Clinically Effective Treatment of Fibromyalgia Pain With High-Definition Transcranial Direct Current Stimulation: Phase II Open-Label Dose Optimization.

PubMed

Castillo-Saavedra, Laura; Gebodh, Nigel; Bikson, Marom; Diaz-Cruz, Camilo; Brandao, Rivail; Coutinho, Livia; Truong, Dennis; Datta, Abhishek; Shani-Hershkovich, Revital; Weiss, Michal; Laufer, Ilan; Reches, Amit; Peremen, Ziv; Geva, Amir; Parra, Lucas C; Fregni, Felipe

2016-01-01

Despite promising preliminary results in treating fibromyalgia (FM) pain, no neuromodulation technique has been adopted in clinical practice because of limited efficacy, low response rate, or poor tolerability. This phase II open-label trial aims to define a methodology for a clinically effective treatment of pain in FM by establishing treatment protocols and screening procedures to maximize efficacy and response rate. High-definition transcranial direct current stimulation (HD-tDCS) provides targeted subthreshold brain stimulation, combining tolerability with specificity. We aimed to establish the number of HD-tDCS sessions required to achieve a 50% FM pain reduction, and to characterize the biometrics of the response, including brain network activation pain scores of contact heat-evoked potentials. We report a clinically significant benefit of a 50% pain reduction in half (n = 7) of the patients (N = 14), with responders and nonresponders alike benefiting from a cumulative effect of treatment, reflected in significant pain reduction (P = .035) as well as improved quality of life (P = .001) over time. We also report an aggregate 6-week response rate of 50% of patients and estimate 15 as the median number of HD-tDCS sessions to reach clinically meaningful outcomes. The methodology for a pivotal FM neuromodulation clinical trial with individualized treatment is thus supported. Registered in Clinicaltrials.gov under registry number NCT01842009. In this article, an optimized protocol for the treatment of fibromyalgia pain with targeted subthreshold brain stimulation using high-definition transcranial direct current stimulation is outlined. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Effectiveness of Albendazole for Hookworm Varies Widely by Community and Correlates with Nutritional Factors: A Cross-Sectional Study of School-Age Children in Ghana.

PubMed

Humphries, Debbie; Nguyen, Sara; Kumar, Sunny; Quagraine, Josephine E; Otchere, Joseph; Harrison, Lisa M; Wilson, Michael; Cappello, Michael

2017-02-08

Mass drug administration (MDA) targeting school-age children is recommended by the World Health Organization for the global control of soil-transmitted helminth (STH) infections. Although considered safe and cost-effective to deliver, benzimidazole anthelminthics are variably effective against the three most common STHs, and widespread use has raised concern about the potential for emerging resistance. To identify factors mediating response to albendazole, we conducted a cross-sectional study of hookworm infection in the Kintampo North Municipality of Ghana in 2011. Among 140 school-age children residing in five contiguous communities, the hookworm prevalence was 59% (82/140). The overall cure rate following administration of single-dose albendazole (400 mg) was 35% (27/76), with a community-wide fecal egg reduction rate (ERR) of 61% (95% confidence interval: 51.8-71.1). Significant disparities were observed in albendazole effectiveness by community, with a cure rate as low as 0% ( N = 24) in Jato Akuraa and ERRs ranging from 53% to 95% across the five study sites. Individual host factors associated with response to deworming treatment included time since last meal, pretreatment blood hemoglobin level, and mid-upper arm circumference. These data demonstrate significant community-level variation in the effectiveness of albendazole, even among populations living in close proximity. Identification of host factors that influence response to albendazole, most notably the timing of drug administration and nutritional factors, creates an opportunity to enhance the effectiveness of deworming through targeted interventions. These findings also demonstrate the importance of measuring anthelminthic response as part of the monitoring and evaluation of community-based deworming programs. © The American Society of Tropical Medicine and Hygiene.

Effectiveness of Albendazole for Hookworm Varies Widely by Community and Correlates with Nutritional Factors: A Cross-Sectional Study of School-Age Children in Ghana

PubMed Central

Humphries, Debbie; Nguyen, Sara; Kumar, Sunny; Quagraine, Josephine E.; Otchere, Joseph; Harrison, Lisa M.; Wilson, Michael; Cappello, Michael

2017-01-01

Mass drug administration (MDA) targeting school-age children is recommended by the World Health Organization for the global control of soil-transmitted helminth (STH) infections. Although considered safe and cost-effective to deliver, benzimidazole anthelminthics are variably effective against the three most common STHs, and widespread use has raised concern about the potential for emerging resistance. To identify factors mediating response to albendazole, we conducted a cross-sectional study of hookworm infection in the Kintampo North Municipality of Ghana in 2011. Among 140 school-age children residing in five contiguous communities, the hookworm prevalence was 59% (82/140). The overall cure rate following administration of single-dose albendazole (400 mg) was 35% (27/76), with a community-wide fecal egg reduction rate (ERR) of 61% (95% confidence interval: 51.8–71.1). Significant disparities were observed in albendazole effectiveness by community, with a cure rate as low as 0% (N = 24) in Jato Akuraa and ERRs ranging from 53% to 95% across the five study sites. Individual host factors associated with response to deworming treatment included time since last meal, pretreatment blood hemoglobin level, and mid-upper arm circumference. These data demonstrate significant community-level variation in the effectiveness of albendazole, even among populations living in close proximity. Identification of host factors that influence response to albendazole, most notably the timing of drug administration and nutritional factors, creates an opportunity to enhance the effectiveness of deworming through targeted interventions. These findings also demonstrate the importance of measuring anthelminthic response as part of the monitoring and evaluation of community-based deworming programs. PMID:27895280

CD4+ T-cell recovery with suppressive ART-induced rapid sequence evolution in hepatitis C virus envelope but not NS3.

PubMed

Liu, Lin; Nardo, David; Li, Eric; Wang, Gary P

2016-03-13

CD4 T-cell depletion from HIV infection leads to a global decline in anti-hepatitis C virus (HCV) envelope neutralizing antibody (nAb) response, which may play a role in accelerating liver fibrosis. An increase in anti-HCV nAb titers has been reported during antiretroviral therapy (ART) but its impact on HCV remains poorly understood. The objective of this study is to determine the effects of ART on long-term HCV evolution. We examined HCV quasispecies structure and long-term evolution in HIV/HCV coinfected patients with ART-induced CD4 T-cell recovery, and compared with patients with CD4 T-cell depletion from delayed ART. We applied a single-variant sequencing (SVS) method to construct authentic viral quasispecies and compared sequence evolution in HCV envelope, the primary target for humoral immune responses, and NS3, a target for cellular immunity, between the two cohorts. The SVS method corrected biases known to skew the proportions of viral variants, revealing authentic HCV quasispeices structures. We observed higher rates of HCV envelope sequence evolution in patients with ART-induced CD4 T-cell recovery, compared with patients with CD4 T-cell depletion from delayed ART (P = 0.03). Evolutionary rates for NS3 were considerably lower than the rates for envelope (P < 0.01), with no significant difference observed between the two groups. ART-induced CD4 T-cell recovery results in rapid sequence evolution in HCV envelope, but not in NS3. These results suggest that suppressive ART disproportionally enhances HCV-specific humoral responses more than cellular responses, resulting in rapid sequence evolution in HCV envelope but not NS3.

Numerical Simulation of Ballistic Impact on Particulate Composite Target using Discrete Element Method: 1-D and 2-D Models

NASA Astrophysics Data System (ADS)

Nair, Rajesh P.; Lakshmana Rao, C.

2014-01-01

Ballistic impact (BI) is a study that deals with a projectile hitting a target and observing its effects in terms of deformation and fragmentation of the target. The Discrete Element Method (DEM) is a powerful numerical technique used to model solid and particulate media. Here, an attempt is made to simulate the BI process using DEM. 1-D DEM for BI is developed and depth of penetration (DOP) is obtained. The DOP is compared with results obtained from 2-D DEM. DEM results are found to match empirical results. Effects of strain rate sensitivity of the material response on DOP are also simulated.

Conjunctive search for one and two identical targets.

PubMed

Ward, R; McClelland, J L

1989-11-01

The assumptions of feature integration theory as a blind, serial, self-terminating search (SSTS) mechanism are extended to displays containing 2 identical targets. The SSTS predicts no differences in negative-response displays, which require an exhaustive search of the display. Quantitative predictions are confirmed for the positive responses, but not for the negatives, suggesting that the SSTS model is incorrect. Two possible explanations for the results in the negative conditions, differential search rates and early quitting in the negatives, are rejected. It is suggested that using any self-terminating search mechanism will lead to difficulty in interpreting the results, including accounts for which the search is parallel over small groups of items. A resource-limited parallel model, which is based on the diffusion model of Ratcliff (1978), appears to fit the data well.

Intolerance of Uncertainty Predicts Anxiety Outcomes Following CBT in Youth with ASD.

PubMed

Keefer, Amy; Kreiser, Nicole L; Singh, Vini; Blakeley-Smith, Audrey; Duncan, Amie; Johnson, Catherine; Klinger, Laura; Meyer, Allison; Reaven, Judy; Vasa, Roma A

2017-12-01

Modified cognitive-behavioral therapy (MCBT) has been demonstrated to reduce anxiety in youth with autism spectrum disorder (ASD). However, non-response rates are fairly high. Few studies have investigated factors associated with response. Intolerance of uncertainty (IU) is a treatment target for anxiety and worry in neurotypical populations and has been linked to anxiety and ASD. We sought to examine whether IU affects outcomes following MCBT in 43 children, ages 8-14 years, with ASD without intellectual disability. Consistent with prior data, there was a significant reduction in parent reported anxiety following MCBT. Higher levels of pre-intervention IU predicted higher anxiety and worry pre- and post-intervention. These findings suggest that targeting IU may improve outcomes following MCBT in youth with ASD and anxiety.

Similar efficacy for phase I trials in comparison with DTIC for advanced malignant melanoma: an analysis of melanoma outcomes in CTEP-sponsored phase I trials 1995-2011.

PubMed

Luke, Jason J; Rubinstein, Lawrence V; Smith, Gary L; Ivy, S Percy; Harris, Pamela J

2013-04-01

After ipilimumab, vemurafenib, and interleukin-2, standard of care chemotherapy for melanoma remains dacarbazine (response rate ∼9%). Despite this, many physicians hesitate to refer patients to phase I protocols given a perceived lack of clinical benefit and potential for harm. To better understand the validity of these perceptions, the experience of all patients with melanoma treated on phase I trials sponsored by the National Cancer Institute-Cancer Therapy Evaluation Program (NCI-CTEP) from 1995 to 2011 were analyzed and compared with the pooled results of six contemporary phase III trials of dacarbazine. A total of 937 patients with melanoma were treated in 148 CTEP phase I trials. The majority were men with a median of two prior therapies (46% receiving prior dacarbazine). Response and clinical benefit rates in these trials were not clinically different from those of dacarbazine (phase I: 6.3 and 26.8% vs. dacarbazine: 8.8 and 27.9%) although grades 3 and 4 toxicity was significantly higher (54 vs. 28%). Efficacy and toxicity were generally consistent within phase I subgroups (targeted agents, immunotherapies, or chemotherapeutics) though targeted therapy was associated with a lower response rate, immunotherapy with lower clinical benefit rate, and chemotherapy with higher incidence of grade 4 toxicity. Thus, the perception of limited efficacy of phase I trials for patients with melanoma was disproven, whereas the perception of toxicity was observed. However, this difference in toxicity may have been largely because of the nature of phase I vs. phase III trials (i.e. more heavily pretreated) and because of the phase I trials often being multiagent as opposed to dacarbazine alone. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Fire flame detection based on GICA and target tracking

NASA Astrophysics Data System (ADS)

Rong, Jianzhong; Zhou, Dechuang; Yao, Wei; Gao, Wei; Chen, Juan; Wang, Jian

2013-04-01

To improve the video fire detection rate, a robust fire detection algorithm based on the color, motion and pattern characteristics of fire targets was proposed, which proved a satisfactory fire detection rate for different fire scenes. In this fire detection algorithm: (a) a rule-based generic color model was developed based on analysis on a large quantity of flame pixels; (b) from the traditional GICA (Geometrical Independent Component Analysis) model, a Cumulative Geometrical Independent Component Analysis (C-GICA) model was developed for motion detection without static background and (c) a BP neural network fire recognition model based on multi-features of the fire pattern was developed. Fire detection tests on benchmark fire video clips of different scenes have shown the robustness, accuracy and fast-response of the algorithm.

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.

Finding an emotional face in a crowd: emotional and perceptual stimulus factors influence visual search efficiency.

PubMed

Lundqvist, Daniel; Bruce, Neil; Öhman, Arne

2015-01-01

In this article, we examine how emotional and perceptual stimulus factors influence visual search efficiency. In an initial task, we run a visual search task, using a large number of target/distractor emotion combinations. In two subsequent tasks, we then assess measures of perceptual (rated and computational distances) and emotional (rated valence, arousal and potency) stimulus properties. In a series of regression analyses, we then explore the degree to which target salience (the size of target/distractor dissimilarities) on these emotional and perceptual measures predict the outcome on search efficiency measures (response times and accuracy) from the visual search task. The results show that both emotional and perceptual stimulus salience contribute to visual search efficiency. The results show that among the emotional measures, salience on arousal measures was more influential than valence salience. The importance of the arousal factor may be a contributing factor to contradictory history of results within this field.

Trends and Issues in California's Low Carbon Fuel Standard - Learning from Response to Existing Climate Policy

NASA Astrophysics Data System (ADS)

Witcover, J.

2015-12-01

Debate over lower greenhouse gas (GHG) emissions from transportation has included heated discussion about appropriate policies and their cost and feasibility. One prominent policy mechanism, a carbon intensity standard, rates transport fuels based on analysis of lifecycle GHG emissions, and targets lower fuel pool carbon intensity through a market mechanism that uses a system of tradable, bankable credits and deficits. California instituted such a policy -- the Low Carbon Fuel Standard (LCFS) - in 2010, which targets a 10% carbon intensity (CI) reduction by 2020. The program rolled out amid concerns over slow development of new fuels expected to be very low carbon (such as cellulosic) and has faced court challenges that added considerable policy uncertainty. Since the program's start, state transport energy mix has shifted modestly but noticeably. Looking ahead, emerging issues for the program include amendments and re-adoption in response to a court ruling, potential interaction with California's multi-sector cap on carbon emissions (which started covering transport fuels in 2015), and impacts from similar CI standards in other jurisdictions. This study provides an analysis of fuel mix changes since the LCFS was implemented in 2011, and a discussion of emerging issues focusing on policy interaction. Descriptive statistics on alternative fuel use, available fuel pathways, and CI ratings are presented based on data from the California Air Resources Board (which runs the program). They document a shift towards more alternative fuels in a more diverse mix, with lower average CI ratings for most alternative fuel types. Financial incentives for various fuels are compared under the LCFS and the US federal Renewable Fuel Standard; disincentives from conceptually different carbon pricing schemes under the LCFS and the Cap-and-Trade are also outlined. The results provide important information on response to an existing market-based policy mechanism for addressing GHG emissions in transportation, as other jurisdictions weigh similar climate policies and debate mechanisms and costs and California announced an ambitious target of halving petroleum use by 2030.

Ionization enhancement in atmospheric pressure chemical ionization and suppression in electrospray ionization between target drugs and stable-isotope-labeled internal standards in quantitative liquid chromatography/tandem mass spectrometry.

PubMed

Liang, H R; Foltz, R L; Meng, M; Bennett, P

2003-01-01

The phenomena of ionization suppression in electrospray ionization (ESI) and enhancement in atmospheric pressure chemical ionization (APCI) were investigated in selected-ion monitoring and selected-reaction monitoring modes for nine drugs and their corresponding stable-isotope-labeled internal standards (IS). The results showed that all investigated target drugs and their co-eluting isotope-labeled IS suppress each other's ionization responses in ESI. The factors affecting the extent of suppression in ESI were investigated, including structures and concentrations of drugs, matrix effects, and flow rate. In contrast to the ESI results, APCI caused seven of the nine investigated target drugs and their co-eluting isotope-labeled IS to enhance each other's ionization responses. The mutual ionization suppression or enhancement between drugs and their isotope-labeled IS could possibly influence assay sensitivity, reproducibility, accuracy and linearity in quantitative liquid chromatography/mass spectrometry (LC/MS) and liquid chromatography/tandem mass spectrometry (LC/MS/MS). However, calibration curves were linear if an appropriate IS concentration was selected for a desired calibration range to keep the response factors constant. Copyright 2003 John Wiley & Sons, Ltd.

Genetic modulation of plasma NPY stress response is suppressed in substance abuse: association with clinical outcomes.

PubMed

Xu, Ke; Hong, Kwangik Adam; Zhou, Zhifeng; Hauger, Richard L; Goldman, David; Sinha, Rajita

2012-04-01

Neuropeptide Y (NPY) is involved in stress regulation. Genetic variations predict plasma NPY and neural correlates of emotion and stress. We examined whether the functional NPY haplotype modulates stress-induced NPY and anxiety responses, and if plasma NPY stress responses are associated with substance dependence outcomes. Thirty-seven treatment-engaged, abstinent substance dependent (SD) patients and 28 healthy controls (HCs) characterized on NPY diplotypes (HH: high expression; HLLL: intermediate/low expression) were exposed to stress, alcohol/drug cues and neutral relaxing cues, using individualized guided imagery, in a 3-session laboratory experiment. Plasma NPY, heart rate and anxiety were assessed. Patients were prospectively followed for 90-days post-treatment to assess relapse outcomes. HH individuals showed significantly lower stress-induced NPY with greater heart rate and anxiety ratings, while the HLLL group showed the reverse pattern of NPY, anxiety and heart rate responses. This differential genetic modulation of NPY stress response was suppressed in the SD group, who showed no stress-related increases in NPY and higher heart rate and greater anxiety, regardless of diplotype. Lower NPY predicted subsequent higher number of days and greater amounts of post-treatment drug use. These preliminary findings are the first to document chronic drug abuse influences on NPY diplotype expression where NPY diplotype modulation of stress-related plasma NPY, heart rate and anxiety responses was absent in the substance abuse sample. The finding that lower stress-related NPY is predictive of greater relapse severity provides support for therapeutic development of neuropeptide Y targets in the treatment of substance use disorders. Copyright © 2011 Elsevier Ltd. All rights reserved.

Research and Development for the Mu2e Extinction Monitor

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

Mott, Casey Benjamin

Mu2e is a planned experiment to search for flavor-violating conversion from a muon to an electron. The experiment will use a pulsed 8 GeV proton beam to produce muons which will then stop in an aluminum target. Mu2e will search for themore » $$\\mu^- + Al \\rightarrow e^- + Al$$ process. For Mu2e, an extinction rate of 10$$^{-10}$$ is required to reduce the backgrounds to an acceptable level. Extinction is the ratio of the amount of protons striking the production target between beam pulses to the number striking it during the beam pulse. One of the backgrounds, off-target interactions, was simulated using G4beamline and Fermilab's Grid setup to confirm that an extinction rate of 10$$^{-10}$$ is possible. The extinction level will be measured by the extinction monitor which will include scintillation counters read out by photomultiplier tubes. In order to build a beam time profile, low fake responses (after pulses) are needed in the photomultiplier tubes. This thesis determines the best combination of resistors, voltage, and other components that provide the lowest after pulse rate.« less

Increasing response rates to lifestyle surveys: a pragmatic evidence review.

PubMed

McCluskey, S; Topping, A E

2011-03-01

Lifestyle surveys are often a key component of a local Joint Strategic Needs Assessment (JSNA), undertaken to inform public health planning. They are usually administered to a large number of people in order to provide a comprehensive profile of population health. However, declining response rates coupled with the under-representation of certain population groups in lifestyle survey data has led to doubts concerning the reliability of findings. In order to inform the design of their own lifestyle survey, NHS Calderdale commissioned an evidence-based review of the methodological literature relating to the administration of lifestyle surveys, with the specific aim of identifying practical and resource-efficient strategies shown to be effective for maximizing whole-population response rates. A pragmatic review of the published literature was undertaken, specifically to explore the most practical and resource-efficient ways to maximize lifestyle survey response rates to the most commonly used methods (postal surveys, face-to-face interviews, telephone interviews and electronic surveys). Electronic databases including MEDLINE, CINAHL, DARE, EMBASE and PsychINFO were searched. Empirical evidence published in the last 10 years was identified and citation tracking performed on all retrieved articles. An internet search for 'grey literature' was also conducted. The postal questionnaire remains an important lifestyle survey tool, but reported response rates have decreased rapidly in recent years. Interviews and telephone surveys are recommended in order to supplement data from postal questionnaires and increase response rates in some population groups, but costs may be prohibitive. Electronic surveys are a cheaper alternative, but the empirical evidence on effectiveness is inconclusive. Careful planning and tailoring of survey design to the characteristics of target populations can increase response rates and representativeness of lifestyle survey data. The results of this pragmatic review could provide a valuable resource for those involved in the design and administration of lifestyle surveys.

Vestibulo-Ocular Reflex to Transient Surge Translation: Complex Geometric Response Ablated by Normal Aging

PubMed Central

Tian, Jun-ru; Mokuno, Eriko; Demer, Joseph L.

2007-01-01

The linear vestibulo-ocular reflex (LVOR) to surge (fore-aft) translation has complex kinematics varying with target eccentricity and distance. To determine normal responses and aging changes, 9 younger [age, 28 ± 2 (SE) yr] and 11 older subjects (age, 69 ± 2 yr) underwent 0.5g whole body surge transients while wearing binocular scleral search coils. Linear chair position and head acceleration were measured with a potentiometer and accelerometer. Subjects viewed centered and 10° horizontally and vertically eccentric targets 50, 25, or 15 cm distant before unpredictable onset of randomly directed surge in darkness (LVOR) and light (V-LVOR). Response directions were kinematically appropriate to eccentricity in all subjects, but there were significantly more measurable LVOR and V-LVOR responses (63–79%) in younger than older subjects (38–44%, P < 0.01). Minimal LVOR latency averaged 48 ± 4 ms for younger and significantly longer at 70 ± 6 ms for older subjects. In the interval 200–300 ms after surge onset, horizontal LVOR gain (relative to ideal velocity) of younger subjects averaged over all target distances was 0.55 ± 0.04 and was significantly reduced in older subjects to 0.33 ± 0.04. Horizontal V-LVOR gain was 0.58 ± 0.04 in younger and significantly lower at 0.35 ± 0.06 in older subjects. Vertical gains did not differ significantly between groups. Target visibility had no effect in either group during the initial 200 ms. The LVOR and V-LVOR were augmented by saccades in younger more than older subjects. Aging thus decreases LVOR velocity gain, response rate, and saccade augmentation, but prolongs latency. PMID:16551841

Spot cooling. Part 1: Human responses to cooling with air jets

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

Melikov, A.K.; Halkjaer, L.; Arakelian, R.S.

Eight standing male subjects and a thermal manikin were studied for thermal, physiological, and subjective responses to cooling with an air jet at room temperatures of 28 C, 33 C, and 38 C and a constant relative humidity of 50%. The subjects wore a standard uniform and performed light work. A vertical jet and a horizontal jet were employed The target area of the jet, i.e., the cross section of the jet where it first met the subject, had a diameter of 0.4 m and was located 0.5 m from the outlet. Experiments were performed at average temperatures at themore » jet target area of 20 C, 24 C, and 28 C. Each experiment lasted 190 minutes and was performed with three average velocities at the target area: 1 and 2 m/s and the preferred velocity selected by the subjects. The impact of the relative humidity of the room air, the jet`s turbulence intensity, and the use of a helmet on the physiological and subjective responses of the eight subjects was also studied The responses of the eight subjects were compared with the responses of a group of 29 subjects. The spot cooling improved the thermal conditions of the occupants. The average general thermal sensation for the eight subjects was linearly correlated to the average mean skin temperature and the average sweat rate. An average mean skin temperature of 33 C and an average sweat rate of 33 g{center_dot}h{sup {minus}1} m{sup {minus}2} were found to correspond to a neutral thermal sensation. The local thermal sensation at the neck and at the arm exposed to the cooling jet was found to be a function of the room air temperature and the local air velocity and temperature of the jet. The turbulence intensity of the cooling jet and the humidity of the room air had no impact on the subjects` physiological and subjective responses. Large individual differences were observed in the evaluation of the environment and in the air velocity preferred by the subjects.« less

Multicenter Phase II Trial of Temsirolimus and Bevacizumab in Pancreatic Neuroendocrine Tumors

PubMed Central

Hobday, Timothy J.; Qin, Rui; Reidy-Lagunes, Diane; Moore, Malcolm J.; Strosberg, Jonathan; Kaubisch, Andreas; Shah, Manisha; Kindler, Hedy Lee; Lenz, Heinz-Josef; Chen, Helen; Erlichman, Charles

2015-01-01

Purpose There are few effective therapies for pancreatic neuroendocrine tumors (PNETs). Recent placebo-controlled phase III trials of the mammalian target of rapamycin (mTOR) inhibitor everolimus and the vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor inhibitor sunitinib have noted improved progression-free survival (PFS). Preclinical studies have suggested enhanced antitumor effects with combined mTOR and VEGF pathway–targeted therapy. We conducted a clinical trial to evaluate combination therapy against these targets in PNETs. Patients and Methods We conducted a two-stage single-arm phase II trial of the mTOR inhibitor temsirolimus 25 mg intravenously (IV) once per week and the VEGF-A monoclonal antibody bevacizumab 10 mg/kg IV once every 2 weeks in patients with well or moderately differentiated PNETs and progressive disease by RECIST within 7 months of study entry. Coprimary end points were tumor response rate and 6-month PFS. Results A total of 58 patients were enrolled, and 56 patients were eligible for response assessment. Confirmed response rate (RR) was 41% (23 of 56 patients). PFS at 6 months was 79% (44 of 56). Median PFS was 13.2 months (95% CI, 11.2 to 16.6). Median overall survival was 34 months (95% CI, 27.1 to not reached). For evaluable patients, the most common grade 3 to 4 adverse events attributed to therapy were hypertension (21%), fatigue (16%), lymphopenia (14%), and hyperglycemia (14%). Conclusion The combination of temsirolimus and bevacizumab had substantial activity and reasonable tolerability in a multicenter phase II trial, with RR of 41%, well in excess of single targeted agents in patients with progressive PNETs. Six-month PFS was a notable 79% in a population of patients with disease progression by RECIST criteria within 7 months of study entry. On the basis of this trial, continued evaluation of combination mTOR and VEGF pathway inhibitors is warranted. PMID:25488966

Prostate-specific membrane antigen for prostate cancer theranostics: from imaging to targeted therapy.

PubMed

Arsenault, Frédéric; Beauregard, Jean-Mathieu; Pouliot, Frédéric

2018-06-22

In recent years, major advances in molecular imaging of prostate cancers (PCa) were made with the development and clinical validation of highly accurate PET tracers to stage and restage the disease. Prostate-specific membrane antigen (PSMA) is a transmembrane protein highly expressed in PCa, and its expression has led to the development of PSMA-binding radiopharmaceuticals for molecular imaging or radioligand therapy (RLT). We herein review the recent literature published on diagnostic and therapeutic (i.e. theranostic) PSMA tracers. Development in small PSMA-targeted molecules labeled with gallium-68 and fluorine-18 show promising results for primary staging and detection of disease at biochemical recurrence using PET/computed tomography (PET/CT). Studies show a higher sensitivity and specificity, along with an improved detection rate over conventional imaging (CT scan and bone scan) or choline PET tracers, especially for restaging after prostate-specific antigen failure following loco-regional therapy. In addition, some PSMA tracers can be labeled with beta-minus and alpha particle emitters, yielding encouraging response rates and low toxicity, and potentially offering a new line of targeted therapy for metastatic castration-resistant PCa. PSMA-targeted tracers have shown unprecedented accuracy to stage and restage PCa using PET/CT. Given their specific biodistribution toward PCa tissue, PSMA RLT now offers new therapeutic possibilities to target metastatic PCa. Prospective multicenter randomized studies investigating the clinical impact management impacts of PSMA-targeted molecules are urgently needed.

One Size Does Not Fit All: Effective Community-Engaged Outreach Practices with Immigrant Communities

ERIC Educational Resources Information Center

Smalkoski, Kari; Axtell, Sara; Zimmer, Jeanne; Noor, Ibrahim

2016-01-01

Generic outreach approaches are commonly used to target as many individuals as possible in a cultural community to achieve a greater response rate. However, this one-size-fits-all tactic is rarely effective. Community-engaged outreach practices have been successful with immigrant communities in Minnesota's Twin Cities. When practitioners,…

Mothers' Judgments of Students with Emotional Disturbance and Social Maladjustment/Conduct Disorder: Comparisons of Target Students and Siblings

ERIC Educational Resources Information Center

Easler, Ray C., Jr.; Medway, Frederic J.

2004-01-01

In response to United States special education law requirements, this study attempted to differentiate emotionally disturbed and socially maladjusted students using parent ratings on the FACES III and a newly developed interview measure of primarily internalizing and externalizing behaviors. Forty mothers of students in special education and 40…

Trials and tribulations of recruiting 2,000 older women onto a clinical trial investigating falls and fractures: Vital D study

PubMed Central

2009-01-01

Background Randomised, placebo-controlled trials are needed to provide evidence demonstrating safe, effective interventions that reduce falls and fractures in the elderly. The quality of a clinical trial is dependent on successful recruitment of the target participant group. This paper documents the successes and failures of recruiting over 2,000 women aged at least 70 years and at higher risk of falls or fractures onto a placebo-controlled trial of six years duration. The characteristics of study participants at baseline are also described for this study. Methods The Vital D Study recruited older women identified at high risk of fracture through the use of an eligibility algorithm, adapted from identified risk factors for hip fracture. Participants were randomised to orally receive either 500,000 IU vitamin D3 (cholecalciferol) or placebo every autumn for five consecutive years. A variety of recruitment strategies were employed to attract potential participants. Results Of the 2,317 participants randomised onto the study, 74% (n = 1716/2317) were consented onto the study in the last five months of recruiting. This was largely due to the success of a targeted mail-out. Prior to this only 541 women were consented in the 18 months of recruiting. A total of 70% of all participants were recruited as a result of targeted mail-out. The response rate from the letters increased from 2 to 7% following revision of the material by a public relations company. Participant demographic or risk factor profile did not differ between those recruited by targeted mail-outs compared with other methods. Conclusion The most successful recruitment strategy was the targeted mail-out and the response rate was no higher in the local region where the study had extensive exposure through other recruiting strategies. The strategies that were labour-intensive and did not result in successful recruitment include the activities directed towards the GP medical centres. Comprehensive recruitment programs employ overlapping strategies simultaneously with ongoing assessment of recruitment rates. In our experience, and others direct mail-outs work best although rights to privacy must be respected. Trial registration ISRCTN83409867 and ACTR12605000658617. PMID:19930724

Outcome of Molecular Targeted Agents Plus Chemotherapy for Second-Line Therapy of Metastatic Colorectal Cancer: A Meta-Analysis of Randomized Trials.

PubMed

Pei, Xueqing; Liu, Yu; Sun, Liwei; Zhang, Jun; Fang, Yuanyuan; Liao, Xin; Liu, Jian; Zhang, Cuntai; Yin, Tiejun

2016-12-01

The aim of this study was to evaluate the efficacy and toxicity of molecular targeted agents plus chemotherapy compared with chemotherapy alone as second-line therapy for patients with metastatic colorectal cancer (mCRC). We identified randomized controlled trials that compared molecular targeted agents plus chemotherapy with chemotherapy alone by searching the PubMed and Embase databases for articles published between January 2000 and September 2015. The outcome measures included progression-free survival, overall survival, objective response rate, and adverse events. Two investigators independently performed the information retrieval, screening, and data extraction. Stata 10.0 software was used to statistically analyze the extracted data. In accordance with our inclusion criteria, 11 trials, with a total of 7440 patients, were included in this meta-analysis through rounds of selection. We divided the biologic agents used into 3 subgroups based on the type of biologic agents-vascular endothelial growth factor (VEGF) inhibitor, epidermal growth factor receptor inhibitor, and other pathway inhibitors. Our results suggested that the regimen of a molecular targeted agent plus chemotherapy had a significant advantage in progression-free survival, overall survival, and objective response rate over chemotherapy alone (hazard ratio, 0.74; 95% confidence interval [CI], 0.70-0.78; hazard ratio, 0.88; 95% CI, 0.83-0.93; risk ratio, 2.24; 95% CI: 1.58-3.17, respectively). However, the rate of grade ≥ 3 adverse events was also higher in the combination therapy arm (risk ratio, 1.25; 95% CI, 1.17-1.33). Subgroup analysis showed that the combination of VEGF inhibitor with chemotherapy had a significant advantage in PFS, OS, and ORR over chemotherapy alone, but there was also a higher risk ratio in adverse events for this combination compared with the control group. In conclusion, a molecular targeted agent, especially VEGF inhibitor, plus chemotherapy is a worthwhile combination for patients with metastatic colorectal cancer as second-line therapy. However, more randomized controlled trials on a larger scale are needed for evaluating the value of epidermal growth factor receptor and other pathway inhibitors. Copyright © 2016 Elsevier Inc. All rights reserved.

Control of voice fundamental frequency in speaking versus singing

NASA Astrophysics Data System (ADS)

Natke, Ulrich; Donath, Thomas M.; Kalveram, Karl Th.

2003-03-01

In order to investigate control of voice fundamental frequency (F0) in speaking and singing, 24 adults had to utter the nonsense word ['ta:tatas] repeatedly, while in selected trials their auditory feedback was frequency-shifted by 100 cents downwards. In the speaking condition the target speech rate and prosodic pattern were indicated by a rhythmic sequence made of white noise. In the singing condition the sequence consisted of piano notes, and subjects were instructed to match the pitch of the notes. In both conditions a response in voice F0 begins with a latency of about 150 ms. As predicted, response magnitude is greater in the singing condition (66 cents) than in the speaking condition (47 cents). Furthermore the singing condition seems to prolong the after-effect which is a continuation of the response in trials after the frequency shift. In the singing condition, response magnitude and the ability to match the target F0 correlate significantly. Results support the view that in speaking voice F0 is monitored mainly supra-segmentally and controlled less tightly than in singing.

Control of voice fundamental frequency in speaking versus singing.

PubMed

Natke, Ulrich; Donath, Thomas M; Kalveram, Karl Th

2003-03-01

In order to investigate control of voice fundamental frequency (F0) in speaking and singing, 24 adults had to utter the nonsense word ['ta:tatas] repeatedly, while in selected trials their auditory feedback was frequency-shifted by 100 cents downwards. In the speaking condition the target speech rate and prosodic pattern were indicated by a rhythmic sequence made of white noise. In the singing condition the sequence consisted of piano notes, and subjects were instructed to match the pitch of the notes. In both conditions a response in voice F0 begins with a latency of about 150 ms. As predicted, response magnitude is greater in the singing condition (66 cents) than in the speaking condition (47 cents). Furthermore the singing condition seems to prolong the after-effect which is a continuation of the response in trials after the frequency shift. In the singing condition, response magnitude and the ability to match the target F0 correlate significantly. Results support the view that in speaking voice F0 is monitored mainly supra-segmentally and controlled less tightly than in singing.

Long non-coding RNA GAS5 sensitizes renal cell carcinoma to sorafenib via miR-21/SOX5 pathway.

PubMed

Liu, Lei; Pang, Xinlu; Shang, Wenjin; Xie, Hongchang; Feng, Yonghua; Feng, Guiwen

2018-06-12

Although the use of sorafenib appears to increase the survival rate of renal cell carcinoma (RCC) patients, there is also a proportion of patients who exhibit a poor primary response to sorafenib treatment. Therefore, it is critical to elucidate the mechanisms underlying sorafenib resistance and find representative biomarkers for sorafenib treatment in RCC patients. Herein, we identified that a long noncoding RNA GAS5 was downregulated in sorafenib nonresponsive RCCs. GAS5 overexpression conferred sorafenib sensitive to nonresponsive RCC cells, whereas knockdown of GAS5 promoted responsive RCC cells resistant to sorafenib treatment in vitro and in vivo. Mechanistically, GAS5 functioned as competing endogenous RNA to repress miR-21, which controlled its down-stream target SOX5. We proposed that GAS5 was responsible for sorafenib resistance in RCC cells and GAS5 exerted its function through the miR-21/ SOX5 axis. Our findings suggested that GAS5 downregulation may be a new marker of poor response to sorafenib and GAS5 could be a potential therapeutic target for sorafenib treatment in RCC.

Sedation-analgesia with propofol and remifentanil: concentrations required to avoid gag reflex in upper gastrointestinal endoscopy.

PubMed

Borrat, Xavier; Valencia, José Fernando; Magrans, Rudys; Gimenez-Mila, Marc; Mellado, Ricard; Sendino, Oriol; Perez, Maria; Nunez, Matilde; Jospin, Mathieu; Jensen, Erik Weber; Troconiz, Inaki; Gambus, Pedro L

2015-07-01

The purpose of this study was to identify optimal target propofol and remifentanil concentrations to avoid a gag reflex in response to insertion of an upper gastrointestinal endoscope. Patients presenting for endoscopy received target-controlled infusions (TCI) of both propofol and remifentanil for sedation-analgesia. Patients were randomized to 4 groups of fixed target effect-site concentrations: remifentanil 1 ng•mL (REMI 1) or 2 ng•mL (REMI 2) and propofol 2 μg•mL (PROP 2) or 3 μg•mL (PROP 3). For each group, the other drug (propofol for the REMI groups and vice versa) was increased or decreased using the "up-down" method based on the presence or absence of a gag response in the previous patient. A modified isotonic regression method was used to estimate the median effective Ce,50 from the up-down method in each group. A concentration-effect (sigmoid Emax) model was built to estimate the corresponding Ce,90 for each group. These data were used to estimate propofol bolus doses and remifentanil infusion rates that would achieve effect-site concentrations between Ce,50 and Ce,90 when a TCI system is not available for use. One hundred twenty-four patients were analyzed. To achieve between a 50% and 90% probability of no gag response, propofol TCIs were between 2.40 and 4.23 μg•mL (that could be achieved with a bolus of 1 mg•kg) when remifentanil TCI was fixed at 1 ng•mL, and target propofol TCIs were between 2.15 and 2.88 μg•mL (that could be achieved with a bolus of 0.75 mg•kg) when remifentanil TCI was fixed at 2 ng•mL. Remifentanil ranges were 1.00 to 4.79 ng•mL and 0.72 to 3.19 ng•mL when propofol was fixed at 2 and 3 μg•mL, respectively. We identified a set of propofol and remifentanil TCIs that blocked the gag response to endoscope insertion in patients undergoing endoscopy. Propofol bolus doses and remifentanil infusion rates designed to achieve similar effect-site concentrations can be used to prevent gag response when TCI is not available.

Increasing the persistence of a heterogeneous behavior chain: Studies of extinction in a rat model of search behavior of working dogs.

PubMed

Thrailkill, Eric A; Kacelnik, Alex; Porritt, Fay; Bouton, Mark E

2016-08-01

Dogs trained to search for contraband perform a chain of behavior in which they first search for a target and then make a separate response that indicates to the trainer that they have found one. The dogs often conduct multiple searches without encountering a target and receiving the reinforcer (i.e., no contraband is present). Understanding extinction (i.e., the decline in work rate when reinforcers are no longer encountered) may assist in training dogs to work in conditions where targets are rare. We therefore trained rats on a search-target behavior chain modeled on the search behavior of working dogs. A discriminative stimulus signaled that a search response (e.g., chain pull) led to a second stimulus that set the occasion for a target response (e.g., lever press) that was reinforced by a food pellet. In Experiment 1 training with longer search durations and intermittent (partial) reinforcement of searching (i.e. some trials had no target present) both led to more persistent search responding in extinction. The loss of search behavior in extinction was primarily dependent on the number of non-reinforced searches rather than time searching without reinforcement. In Experiments 2 and 3, delivery of non-contingent reinforcers during extinction increased search persistence provided they had also been presented during training. Thus, results with rats suggest that the persistence of working dog performance (or chained behavior generally) may be improved by training with partial reinforcement of searching and non-contingent reinforcement during both training and work (extinction). Copyright © 2016 Elsevier B.V. All rights reserved.

Moving Beyond Maximum Tolerated Dose for Targeted Oncology Drugs: Use of Clinical Utility Index to Optimize Venetoclax Dosage in Multiple Myeloma Patients.

PubMed

Freise, K J; Jones, A K; Verdugo, M E; Menon, R M; Maciag, P C; Salem, A H

2017-12-01

Exposure-response analyses of venetoclax in combination with bortezomib and dexamethasone in previously treated patients with multiple myeloma (MM) were performed on a phase Ib venetoclax dose-ranging study. Logistic regression models were utilized to determine relationships, identify subpopulations with different responses, and optimize the venetoclax dosage that balanced both efficacy and safety. Bortezomib refractory status and number of prior treatments were identified to impact the efficacy response to venetoclax treatment. Higher venetoclax exposures were estimated to increase the probability of achieving a very good partial response (VGPR) or better through venetoclax doses of 1,200 mg. However, the probability of neutropenia (grade ≥3) was estimated to increase at doses >800 mg. Using a clinical utility index, a venetoclax dosage of 800 mg daily was selected to optimally balance the VGPR or better rates and neutropenia rates in MM patients administered 1-3 prior lines of therapy and nonrefractory to bortezomib. © 2017 American Society for Clinical Pharmacology and Therapeutics.

Unconscious Affective Responses to Food.

PubMed

Sato, Wataru; Sawada, Reiko; Kubota, Yasutaka; Toichi, Motomi; Fushiki, Tohru

2016-01-01

Affective or hedonic responses to food are crucial for humans, both advantageously (e.g., enhancing survival) and disadvantageously (e.g., promoting overeating and lifestyle-related disease). Although previous psychological studies have reported evidence of unconscious cognitive and behavioral processing related to food, it remains unknown whether affective reactions to food can be triggered unconsciously and its relationship with daily eating behaviors. We investigated these issues by using the subliminal affective priming paradigm. Photographs of food or corresponding mosaic images were presented in the peripheral visual field for 33 ms. Target photos of faces with emotionally neutral expressions were then presented, and participants rated their preferences for the faces. Eating behaviors were also assessed using questionnaires. The food images, relative to the mosaics, increased participants' preference for subsequent target faces. Furthermore, the difference in the preference induced by food versus mosaic images was positively correlated with the tendency to engage in external eating. These results suggest that unconscious affective reactions are elicited by the sight of food and that these responses contribute to daily eating behaviors related to overeating.

How automatic is the hand's automatic pilot? Evidence from dual-task studies.

PubMed

McIntosh, Robert D; Mulroue, Amy; Brockmole, James R

2010-10-01

The ability to correct reaching movements for changes in target position has been described as the hand's 'automatic pilot'. These corrections are preconscious and occur by default in double-step reaching tasks, even if the goal is to react to the target jump in some other way, for instance by stopping the movement (STOP instruction). Nonetheless, corrections are strongly modulated by conscious intention: participants make more corrections when asked to follow the target (GO instruction) and can suppress them when explicitly asked not to follow the target (NOGO instruction). We studied the influence of a cognitively demanding (auditory 1-back) task upon correction behaviour under GO, STOP and NOGO instructions. Correction rates under the STOP instruction were unaffected by cognitive load, consistent with the assumption that they reflect the default behaviour of the automatic pilot. Correction rates under the GO instruction were also unaffected, suggesting that minimal cognitive resources are required to enhance online correction. By contrast, cognitive load impeded the ability to suppress online corrections under the NOGO instruction. These data reveal a constitutional bias in the automatic pilot system: intentional suppression of the default correction behaviour is cognitively demanding, but enhancement towards greater responsiveness is seemingly effortless.

Using the Multipole Resonance Probe to Stabilize the Electron Density During a Reactive Sputter Process

NASA Astrophysics Data System (ADS)

Oberberg, Moritz; Styrnoll, Tim; Ries, Stefan; Bienholz, Stefan; Awakowicz, Peter

2015-09-01

Reactive sputter processes are used for the deposition of hard, wear-resistant and non-corrosive ceramic layers such as aluminum oxide (Al2O3) . A well known problem is target poisoning at high reactive gas flows, which results from the reaction of the reactive gas with the metal target. Consequently, the sputter rate decreases and secondary electron emission increases. Both parameters show a non-linear hysteresis behavior as a function of the reactive gas flow and this leads to process instabilities. This work presents a new control method of Al2O3 deposition in a multiple frequency CCP (MFCCP) based on plasma parameters. Until today, process controls use parameters such as spectral line intensities of sputtered metal as an indicator for the sputter rate. A coupling between plasma and substrate is not considered. The control system in this work uses a new plasma diagnostic method: The multipole resonance probe (MRP) measures plasma parameters such as electron density by analyzing a typical resonance frequency of the system response. This concept combines target processes and plasma effects and directly controls the sputter source instead of the resulting target parameters.

Biomechanical responses of PMHS in moderate-speed rear impacts and development of response targets for evaluating the internal and external biofidelity of ATDS.

PubMed

Kang, Yun-Seok; Bolte, John H; Moorhouse, Kevin; Donnelly, Bruce; Herriott, Rodney; Mallory, Ann

2012-10-01

The objectives of this study were to obtain biomechanical responses of post mortem human subjects (PMHS) by subjecting them to two moderate-speed rear impact sled test conditions (8.5g, 17 km/h; 10.5g, 24 km/h) while positioned in an experimental seat system, and to create biomechanical targets for internal and external biofidelity evaluation of rear impact ATDs. The experimental seat was designed to measure external loads on the head restraint (4 load cells), seat back (6 load cells), and seat pan (4 load cells) such that subject dynamic interaction with the seat could be evaluated. This seat system was capable of simulating the dynamic characteristics of modern vehicle seat backs by considering the moment-rotation properties of a typical passenger vehicle, thus providing a more realistic test environment than using a rigid seat with a non-rotating seat back as done in previous studies. Instrumentation used to measure biomechanical responses of the PMHS included both accelerometers and angular rate sensors (ARS). A total of fourteen sled tests using eight PMHS (males 175.8 ± 6.2 cm of stature and 78.4 ± 7.2 kg of weight) provided data sets of seven PMHS for both test conditions. The biomechanical responses are described at both speeds, and cervical spine injuries are documented. Biomechanical targets are also created for internal and external biofidelity evaluation of rear impact anthropomorphic test devices (ATDs).

SU-F-SPS-11: The Dosimetric Comparison of Truebeam 2.0 and Cyberknife M6 Treatment Plans for Brain SRS Treatment

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

Mabhouti, H; Sanli, E; Cebe, M

Purpose: Brain stereotactic radiosurgery involves the use of precisely directed, single session radiation to create a desired radiobiologic response within the brain target with acceptable minimal effects on surrounding structures or tissues. In this study, the dosimetric comparison of Truebeam 2.0 and Cyberknife M6 treatment plans were made. Methods: For Truebeam 2.0 machine, treatment planning were done using 2 full arc VMAT technique with 6 FFF beam on the CT scan of Randophantom simulating the treatment of sterotactic treatments for one brain metastasis. The dose distribution were calculated using Eclipse treatment planning system with Acuros XB algorithm. The treatment planningmore » of the same target were also done for Cyberknife M6 machine with Multiplan treatment planning system using Monte Carlo algorithm. Using the same film batch, the net OD to dose calibration curve was obtained using both machine by delivering 0- 800 cGy. Films were scanned 48 hours after irradiation using an Epson 1000XL flatbed scanner. Dose distribution were measured using EBT3 film dosimeter. The measured and calculated doses were compared. Results: The dose distribution in the target and 2 cm beyond the target edge were calculated on TPSs and measured using EBT3 film. For cyberknife plans, the gamma analysis passing rates between measured and calculated dose distributions were 99.2% and 96.7% for target and peripheral region of target respectively. For Truebeam plans, the gamma analysis passing rates were 99.1% and 95.5% for target and peripheral region of target respectively. Conclusion: Although, target dose distribution calculated accurately by Acuros XB and Monte Carlo algorithms, Monte carlo calculation algorithm predicts dose distribution around the peripheral region of target more accurately than Acuros algorithm.« less

Customization of therapy for gastroesophageal adenocarcinoma patients.

PubMed

Mizrak Kaya, Dilsa; Harada, Kazuto; Amlashi, Fatemeh G; Vasilakopoulou, Maria; Ajani, Jaffer A

2018-03-01

Gastroesophageal adenocarcinomas (GEACs) remain a global health problem. These are most often diagnosed at advanced stage and the estimated 5-year relative survival rate is about 5%. Although cure is not possible for patients with advanced GEAC, systemic therapy (chemotherapy or biochemotherapy) can palliate symptoms, improve survival and provide a better quality of life. One of the most promising options for some patients with advanced stage GEAC is immunotherapy, which can result in durable responses. Numerous phase III trials evaluating targeted therapies in different lines are ongoing and it is hoped that better biomarkers will emerge to identify patients who can benefit from targeted agents and immunotherapy in the future. Surgery remains as the corner stone for localized GEAC and adjunctive therapies can increase the survival rates by about 10%. The high toxicity and low completion rates of adjuvant therapy led to the strategies of preoperative treatment. With the results of ongoing pre-operative therapy trials we will be able to determine the optimal adjunctive approach for resectable GEAC.

Stability of a general delayed virus dynamics model with humoral immunity and cellular infection

NASA Astrophysics Data System (ADS)

Elaiw, A. M.; Raezah, A. A.; Alofi, A. S.

2017-06-01

In this paper, we investigate the dynamical behavior of a general nonlinear model for virus dynamics with virus-target and infected-target incidences. The model incorporates humoral immune response and distributed time delays. The model is a four dimensional system of delay differential equations where the production and removal rates of the virus and cells are given by general nonlinear functions. We derive the basic reproduction parameter R˜0 G and the humoral immune response activation number R˜1 G and establish a set of conditions on the general functions which are sufficient to determine the global dynamics of the models. We use suitable Lyapunov functionals and apply LaSalle's invariance principle to prove the global asymptotic stability of the all equilibria of the model. We confirm the theoretical results by numerical simulations.

Generalization of the disruptive effects of alternative stimuli when combined with target stimuli in extinction.

PubMed

Podlesnik, Christopher A; Miranda-Dukoski, Ludmila; Jonas Chan, C K; Bland, Vikki J; Bai, John Y H

2017-09-01

Differential-reinforcement treatments reduce target problem behavior in the short term but at the expense of making it more persistent long term. Basic and translational research based on behavioral momentum theory suggests that combining features of stimuli governing an alternative response with the stimuli governing target responding could make target responding less persistent. However, changes to the alternative stimulus context when combining alternative and target stimuli could diminish the effectiveness of the alternative stimulus in reducing target responding. In an animal model with pigeons, the present study reinforced responding in the presence of target and alternative stimuli. When combining the alternative and target stimuli during extinction, we altered the alternative stimulus through changes in line orientation. We found that (1) combining alternative and target stimuli in extinction more effectively decreased target responding than presenting the target stimulus on its own; (2) combining these stimuli was more effective in decreasing target responding trained with lower reinforcement rates; and (3) changing the alternative stimulus reduced its effectiveness when it was combined with the target stimulus. Therefore, changing alternative stimuli (e.g., therapist, clinical setting) during behavioral treatments that combine alternative and target stimuli could reduce the effectiveness of those treatments in disrupting problem behavior. © 2017 Society for the Experimental Analysis of Behavior.

An analytical and experimental study of the behavior of semi-infinite metal targets under hypervelocity impact

NASA Technical Reports Server (NTRS)

Chakrapani, B.; Rand, J. L.

1971-01-01

The material strength and strain rate effects associated with the hypervelocity impact problem were considered. A yield criterion involving the second and third invariants of the stress deviator and a strain rate sensitive constitutive equation were developed. The part of total deformation which represents change in shape is attributable to the stress deviator. Constitutive equation is a means for analytically describing the mechanical response of a continuum under study. The accuracy of the yield criterion was verified utilizing the published two and three dimensional experimental data. The constants associated with the constitutive equation were determined from one dimensional quasistatic and dynamic experiments. Hypervelocity impact experiments were conducted on semi-infinite targets of 1100 aluminum, 6061 aluminum alloy, mild steel, and commercially pure lead using spherically shaped and normally incident pyrex projectiles.

TANDIR: projectile warning system using uncooled bolometric technology

NASA Astrophysics Data System (ADS)

Horovitz-Limor, Z.; Zahler, M.

2007-04-01

Following the demand for affordable, various range and light-weight protection against ATGM's, Elisra develops a cost-effective passive IR system for ground vehicles. The system is based on wide FOV uncooled bolometric sensors with full azimuth coverage and a lightweight processing & control unit. The system design is based on the harsh environmental conditions. The basic algorithm discriminates the target from its clutter and predicts the time to impact (TTI) and the target aiming direction with relation to vehicle. The current detector format is 320*240 pixels and frame rate is 60 Hz, Spectral response is on Far Infrared (8-14μ). The digital video output has 14bit resolution & wide dynamic range. Future goal is to enhance detection performance by using large format uncooled detector (640X480) with improved sensitivity and higher frame rates (up to 120HZ).

Task-irrelevant fear enhances amygdala-FFG inhibition and decreases subsequent face processing.

PubMed

Schulte Holthausen, Barbara; Habel, Ute; Kellermann, Thilo; Schelenz, Patrick D; Schneider, Frank; Christopher Edgar, J; Turetsky, Bruce I; Regenbogen, Christina

2016-09-01

Facial threat is associated with changes in limbic activity as well as modifications in the cortical face-related N170. It remains unclear if task-irrelevant threat modulates the response to a subsequent facial stimulus, and whether the amygdala's role in early threat perception is independent and direct, or modulatory. In 19 participants, crowds of emotional faces were followed by target faces and a rating task while simultaneous EEG-fMRI were recorded. In addition to conventional analyses, fMRI-informed EEG analyses and fMRI dynamic causal modeling (DCM) were performed. Fearful crowds reduced EEG N170 target face amplitudes and increased responses in a fMRI network comprising insula, amygdala and inferior frontal cortex. Multimodal analyses showed that amygdala response was present ∼60 ms before the right fusiform gyrus-derived N170. DCM indicated inhibitory connections from amygdala to fusiform gyrus, strengthened when fearful crowds preceded a target face. Results demonstrated the suppressing influence of task-irrelevant fearful crowds on subsequent face processing. The amygdala may be sensitive to task-irrelevant fearful crowds and subsequently strengthen its inhibitory influence on face-responsive fusiform N170 generators. This provides spatiotemporal evidence for a feedback mechanism of the amygdala by narrowing attention in order to focus on potential threats. © The Author (2016). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Nanotechnology Approaches to Improving Cancer Immunotherapy.

PubMed

Hagan, C Tilden; Medik, Yusra B; Wang, Andrew Z

2018-01-01

Cancer immunotherapy is a powerful, growing treatment approach to cancer that can be combined with chemotherapy, radiotherapy, and oncosurgery. Modulating the immune system to enhance anticancer response by several strategies has yielded improved cancer survival. Despite this progress, the success rate for immunotherapy has been below expectations due to unpredictable efficacy and off-target side effects from systemic dosing. Nanotechnology offers numerous different materials and targeting properties to overcome many of these challenges in immunotherapy. In this chapter, we review current immunotherapy and its challenges as well as the latest nanotechnology applications in cancer immunotherapy. © 2018 Elsevier Inc. All rights reserved.

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

PubMed

Dawood, Shaheenah; Rugo, Hope S

2016-12-01

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

Characterization of pulse amplitude and pulse rate modulation for a human vestibular implant during acute electrical stimulation

NASA Astrophysics Data System (ADS)

Nguyen, T. A. K.; DiGiovanna, J.; Cavuscens, S.; Ranieri, M.; Guinand, N.; van de Berg, R.; Carpaneto, J.; Kingma, H.; Guyot, J.-P.; Micera, S.; Perez Fornos, A.

2016-08-01

Objective. The vestibular system provides essential information about balance and spatial orientation via the brain to other sensory and motor systems. Bilateral vestibular loss significantly reduces quality of life, but vestibular implants (VIs) have demonstrated potential to restore lost function. However, optimal electrical stimulation strategies have not yet been identified in patients. In this study, we compared the two most common strategies, pulse amplitude modulation (PAM) and pulse rate modulation (PRM), in patients. Approach. Four subjects with a modified cochlear implant including electrodes targeting the peripheral vestibular nerve branches were tested. Charge-equivalent PAM and PRM were applied after adaptation to baseline stimulation. Vestibulo-ocular reflex eye movement responses were recorded to evaluate stimulation efficacy during acute clinical testing sessions. Main results. PAM evoked larger amplitude eye movement responses than PRM. Eye movement response axes for lateral canal stimulation were marginally better aligned with PRM than with PAM. A neural network model was developed for the tested stimulation strategies to provide insights on possible neural mechanisms. This model suggested that PAM would consistently cause a larger ensemble firing rate of neurons and thus larger responses than PRM. Significance. Due to the larger magnitude of eye movement responses, our findings strongly suggest PAM as the preferred strategy for initial VI modulation.

Drug Resistance Mechanisms in Non-Small Cell Lung Carcinoma

PubMed Central

Wangari-Talbot, Janet; Hopper-Borge, Elizabeth

2014-01-01

Lung cancer is the most commonly diagnosed cancer in the world. “Driver” and “passenger” mutations identified in lung cancer indicate that genetics play a major role in the development of the disease, progression, metastasis and response to therapy. Survival rates for lung cancer treatment have remained stagnant at ~15% over the past 40 years in patients with disseminated disease despite advances in surgical techniques, radiotherapy and chemotherapy. Resistance to therapy; either intrinsic or acquired has been a major hindrance to treatment leading to great interest in studies seeking to understand and overcome resistance. Genetic information gained from molecular analyses has been critical in identifying druggable targets and tumor profiles that may be predictors of therapeutic response and mediators of resistance. Mutated or overexpressed epidermal growth factor receptor (EGFR) and translocations in the echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) genes (EML4-ALK) are examples of genetic aberrations resulting in targeted therapies for both localized and metastatic disease. Positive clinical responses have been noted in patients harboring these genetic mutations when treated with targeted therapies compared to patients lacking these mutations. Resistance is nonetheless a major factor contributing to the failure of targeted agents and standard cytotoxic agents. In this review, we examine molecular mechanisms that are potential drivers of resistance in non-small cell lung carcinoma, the most frequently diagnosed form of lung cancer. The mechanisms addressed include resistance to molecular targeted therapies as well as conventional chemotherapeutics through the activity of multidrug resistance proteins. PMID:24634705

Simultaneous population pharmacokinetic modelling of plasma and intracellular PBMC miltefosine concentrations in New World cutaneous leishmaniasis and exploration of exposure-response relationships.

PubMed

Kip, Anke E; Castro, María Del Mar; Gomez, Maria Adelaida; Cossio, Alexandra; Schellens, Jan H M; Beijnen, Jos H; Saravia, Nancy Gore; Dorlo, Thomas P C

2018-05-10

Leishmania parasites reside within macrophages and the direct target of antileishmanial drugs is therefore intracellular. We aimed to characterize the intracellular PBMC miltefosine kinetics by developing a population pharmacokinetic (PK) model simultaneously describing plasma and intracellular PBMC pharmacokinetics. Furthermore, we explored exposure-response relationships and simulated alternative dosing regimens. A population PK model was developed with NONMEM, based on 339 plasma and 194 PBMC miltefosine concentrations from Colombian cutaneous leishmaniasis patients [29 children (2-12 years old) and 22 adults] receiving 1.8-2.5 mg/kg/day miltefosine for 28 days. A three-compartment model with miltefosine distribution into an intracellular PBMC effect compartment best fitted the data. Intracellular PBMC distribution was described with an intracellular-to-plasma concentration ratio of 2.17 [relative standard error (RSE) 4.9%] and intracellular distribution rate constant of 1.23 day-1 (RSE 14%). In exploring exposure-response relationships, both plasma and intracellular model-based exposure estimates significantly influenced probability of cure. A proposed PK target for the area under the plasma concentration-time curve (day 0-28) of >535 mg·day/L corresponded to >95% probability of cure. In linear dosing simulations, 18.3% of children compared with 2.8% of adults failed to reach 535 mg·day/L. In children, this decreased to 1.8% after allometric dosing simulation. The developed population PK model described the rate and extent of miltefosine distribution from plasma into PBMCs. Miltefosine exposure was significantly related to probability of cure in this cutaneous leishmaniasis patient population. We propose an exploratory PK target, which should be validated in a larger cohort study.

Assessing the potential additionality of certification by the Round table on Responsible Soybeans and the Roundtable on Sustainable Palm Oil

NASA Astrophysics Data System (ADS)

Garrett, Rachael D.; Carlson, Kimberly M.; Rueda, Ximena; Noojipady, Praveen

2016-04-01

Multi-stakeholder roundtables offering certification programs are promising voluntary governance mechanisms to address sustainability issues associated with international agricultural supply chains. Yet, little is known about whether roundtable certifications confer additionality, the benefits of certification beyond what would be expected from policies and practices currently in place. Here, we examine the potential additionality of the Round table on Responsible Soybeans (RTRS) and the Roundtable on Sustainable Palm Oil (RSPO) in mitigating conversion of native vegetation to cropland. We develop a metric of additionality based on business as usual land cover change dynamics and roundtable standard stringency relative to existing policies. We apply this metric to all countries with RTRS (n = 8) and RSPO (n = 12) certified production in 2013-2014, as well as countries that have no certified production but are among the top ten global producers in terms of soy (n = 2) and oil palm (n = 2). We find RSPO and RTRS both have substantially higher levels of stringency than existing national policies except in Brazil and Uruguay. In regions where these certification standards are adopted, the mean estimated rate of tree cover conversion to the target crop is similar for both standards. RTRS has higher mean relative stringency than the RSPO, yet RSPO countries have slightly higher enforcement levels. Therefore, mean potential additionality of RTRS and RSPO is similar across regions. Notably, countries with the highest levels of additionality have some adoption. However, with extremely low adoption rates (0.41% of 2014 global harvested area), RTRS likely has lower impact than RSPO (14%). Like most certification programs, neither roundtable is effectively targeting smallholder producers. To improve natural ecosystem protection, roundtables could target adoption to regions with low levels of environmental governance and high rates of forest-to-cropland conversion.

Do 'flexicurity' Policies Work for People With Low Education and Health Problems? A Comparison of Labour Market Policies and Employment Rates in Denmark, The Netherlands, Sweden, and the United Kingdom 1990-2010.

PubMed

McAllister, Ashley; Nylén, Lotta; Backhans, Mona; Boye, Katarina; Thielen, Karsten; Whitehead, Margaret; Burström, Bo

2015-01-01

People with limiting longstanding illness and low education may experience problems in the labor market. Reduced employment protection that maintains economic security for the individual, known as "flexicurity," has been proposed as a way to increase overall employment. We compared the development of labor market policies and employment rates from 1990 to 2010 in Denmark and the Netherlands (representing flexicurity), the United Kingdom, and Sweden. Employment rates in all countries were much lower in the target group than for other groups over the study period. However, "flexicurity" as practiced in Denmark, far from being a "magic bullet," appeared to fail low-educated people with longstanding illness in particular. The Swedish policy, on the other hand, with higher employment protection and higher economic security, particularly earlier in the study period, led to higher employment rates in this group. Findings also revealed that economic security policies in all countries were eroding and shifting toward individual responsibility. Finally, results showed that active labor market policies need to be subcategorized to better understand which types are best suited for the target group. Increasing employment among the target group could reduce adverse health consequences and contribute to decreasing inequalities in health. © The Author(s) 2015.

β1 -Adrenoceptor, but not β2 -adrenoceptor, subtype regulates heart rate in type 2 diabetic rats in vivo.

PubMed

Cook, Rosalind F; Bussey, Carol T; Mellor, Kimberley M; Cragg, Patricia A; Lamberts, Regis R

2017-08-01

What is the central question of the study? The sympathetic system regulates heart rate via β-adrenoceptors; this is impaired during diabetes. However, the specific β-adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the β 1 -adrenoceptor subtype, and not the β 2 -adrenoceptor, regulated the lower resting heart rate and increased β-adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence. β-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific contributions of β 1 - and β 2 -adrenoceptor subtypes to chronotropic responses in type 2 diabetes in vivo, which are currently unknown. Type 2 diabetic and non-diabetic rats were implanted with radiotelemeters to measure arterial blood pressure and derive heart rate in conscious conditions. Vascular access ports were implanted to inject isoprenaline (β 1 - and β 2 -adrenoceptor agonist, 0.1-300 μg kg -1 ) in the presence of atenolol (β 1 -adrenoceptor antagonist, 2000 μg kg -1 ) or nadolol (β 1 - and β 2 -adrenoceptor agonist, 4000 μg kg -1 ) to determine the chronotropic contributions of the β-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 ± 62 versus 290 ± 37 beats min -1 non-diabetic versus diabetic, P < 0.05, mean ± SD), which remained after atenolol or nadolol administration. Overall β-adrenoceptor chronotropic responsiveness was increased in diabetic rats (change in heart rate at highest dose of isoprenaline: 135 ± 66 versus 205 ± 28 beats min -1 , non-diabetic versus diabetic, P < 0.05), a difference that diminished after β 1 -adrenoceptor blockade with atenolol (change in heart rate at highest dose of isoprenaline: 205 ± 37 versus 195 ± 22 beats min -1 , non-diabetic versus diabetic, P < 0.05). In conclusion, the β 1 -adrenoceptor is the main subtype to modulate chronotropic β-adrenoceptor responses in healthy and diabetic rats. This study provides new insights into the pathological basis of dysregulation of heart rate in type 2 diabetes, which could be important for improving the current therapeutic strategies targeting diabetic chronotropic incompetence. © 2017 The Authors. Experimental Physiology © 2017 The Physiological Society.

Cetuximab plus FOLFOX for Patients with Metastatic Colorectal Cancer with Poor Performance Status and/or Severe Tumor-Related Complications

PubMed Central

Shitara, Kohei; Yokota, Tomoya; Takahari, Daisuke; Shibata, Takashi; Sato, Yozo; Tajika, Masahiro; Ura, Takashi; Muro, Kei

2010-01-01

Introduction Cetuximab-based chemotherapy showed a statistically significantly higher response rate compared with chemotherapy such as FOLFOX. Therefore, FOLFOX plus cetuximab is suspected to be the best regimen to alleviate tumor-related symptoms with a high response rate. Case Report Here we present the results of 8 consecutive patients with metastatic colorectal cancer with poor performance status and/or severe complications who were treated with first-line FOLFOX with cetuximab. Six of 8 patients achieved an apparent clinical benefit, including radiological response and symptoms improvement. Two patients with BRAF mutation could achieve neither clinical benefit nor radiological response. Conclusion Although an optimal line of therapy with cetuximab is unclear yet with bevacizumab in mind, we propose that patients who need a tumor response to alleviate their symptoms due to advanced disease might be candidates for first-line cetuximab-based therapy as shown in our cases. Additionally, patients with BRAF mutant tumors might be important candidates for novel targeted therapy in the future to improve their poor prognosis. PMID:21347194

Dedicated high dose rate 192Ir brachytherapy radiation fields for in vitro cell exposures at variable source-target cell distances: killing of mammalian cells depends on temporal dose rate fluctuation

NASA Astrophysics Data System (ADS)

Veigel, Cornelia; Hartmann, Günther H.; Fritz, Peter; Debus, Jürgen; Weber, Klaus-Josef

2017-02-01

Afterloading brachytherapy is conducted by the stepwise movement of a radioactive source through surgically implanted applicator tubes where at predefined dwell positions calculated dwell times optimize spatial dose delivery with respect to a planned dose level. The temporal exposure pattern exhibits drastic fluctuations in dose rate at a given coordinate and within a single treatment session because of the discontinuous and repeated source movement into the target volume. This could potentially affect biological response. Therefore, mammalian cells were exposed as monolayers to a high dose rate 192Ir source by utilizing a dedicated irradiation device where the distance between a planar array of radioactive source positions and the plane of the cell monolayer could be varied from 2.5 mm to 40 mm, thus varying dose rate pattern for any chosen total dose. The Gammamed IIi afterloading system equipped with a nominal 370 GBq (10 Ci) 192-Ir source was used to irradiate V79 Chinese hamster lung fibroblasts from both confluent and from exponential growth phase with dose up to 12 Gy (at room temperature, total exposure not exceeding 1 h). For comparison, V79 cells were also exposed to 6 MV x-rays from a clinical linear accelerator (dose rate of 2.5 Gy min-1). As biological endpoint, cell survival was determined by standard colony forming assay. Dose measurements were conducted with a diamond detector (sensitive area 7.3 mm2), calibrated by means of 60Co radiation. Additionally, dose delivery was simulated by Monte Carlo calculations using the EGSnrc code system. The calculated secondary electron fluence spectra at the cell location did not indicate a significant change of radiation quality (i.e. higher linear energy transfer) at the lower distances. Clonogenic cell survival curves obtained after brachytherapy exhibited an altered biological response compared to x-rays which was characterized by a significant reduction of the survival curve shoulder when dose rate fluctuations were high. Therefore, also for the time scale of the present investigation, cellular effects of radiation are not invariant to the temporal pattern in dose rate. We propose that with high dose rate variation the cells activate less efficiently their DNA damage response than after continuous irradiation.

A New Standardized Emotional Film Database for Asian Culture

PubMed Central

Deng, Yaling; Yang, Meng; Zhou, Renlai

2017-01-01

Researchers interested in emotions have endeavored to elicit emotional responses in the laboratory and have determined that films were one of the most effective ways to elicit emotions. The present study presented the development of a new standardized emotional film database for Asian culture. There were eight kinds of emotion: fear, disgust, anger, sadness, neutrality, surprise, amusement, and pleasure. Each kind included eight film clips, and a total of 64 emotional films were viewed by 110 participants. We analyzed both the subjective experience (valence, arousal, motivation, and dominance) and physiological response (heart rate and respiration rate) to the presentation of each film. The results of the subjective ratings indicated that our set of 64 films successfully elicited the target emotions. Heart rate declined while watching high-arousal films compared to neutral ones. Films that expressed amusement elicited the lowest respiration rate, whereas fear elicited the highest. The amount and category of emotional films in this database were considerable. This database may help researchers choose applicable emotional films for study according to their own purposes and help in studies of cultural differences in emotion. PMID:29163312

Reservoir response to thermal and high-pressure well stimulation efforts at Raft River, Idaho

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

Plummer, Mitchell; Bradford, Jacob; Moore, Joseph

An injection stimulation test begun at the Raft River geothermal reservoir in June, 2013 has produced a wealth of data describing well and reservoir response via high-resolution temperature logging and distributed temperature sensing, seismic monitoring, periodic borehole televiewer logging, periodic stepped flow rate tests and tracer injections before and after stimulation efforts. One of the primary measures of response to the stimulation is the relationship between fluid pressure and flow rate, short-term during forced flow rate changes and the long-term change in injectivity. In this paper we examine that hydraulic response using standard pumping test analysis methods, largely because pressuremore » response to the stimulation was not detected, or measurable, in other wells. Analysis of stepped rate flow tests supports the inference from other data that a large fracture, with a radial extent of one to several meters, intersects the well in the target reservoir, suggests that the flow regime is radial to a distance of only several meters and demonstrates that the pressure build-up cone reaches an effective constant head at that distance. The well’s longer term hydraulic response demonstrated continually increasing injectivity but at a dramatically faster rate later from ~2 years out and continuing to the present. The net change in injectivity is significantly greater than observed in other longterm injectivity monitoring studies, with an approximately 150–fold increase occurring over ~2.5 years. While gradually increasing injectivity is a likely consequence of slow migration of a cooling front, and consequent dilation of fractures, the steady, ongoing, rate of increase is contrary to what would be expected in a radial or linear flow regime, where the cooling front would slow with time. As a result, occasional step-like changes in injectivity, immediately following high-flow rate tests suggest that hydro shearing during high-pressure testing altered the near-well permeability structure.« less

Non-response to sad mood induction: implications for emotion research.

PubMed

Rottenberg, Jonathan; Kovacs, Maria; Yaroslavsky, Ilya

2018-05-01

Experimental induction of sad mood states is a mainstay of laboratory research on affect and cognition, mood regulation, and mood disorders. Typically, the success of such mood manipulations is reported as a statistically significant pre- to post-induction change in the self-rated intensity of the target affect. The present commentary was motivated by an unexpected finding in one of our studies concerning the response rate to a well-validated sad mood induction. Using the customary statistical approach, we found a significant mean increase in self-rated sadness intensity with a moderate effect size, verifying the "success" of the mood induction. However, that "success" masked that, between one-fifth and about one-third of our samples (adolescents who had histories of childhood-onset major depressive disorder and healthy controls) reported absolutely no sadness in response to the mood induction procedure. We consider implications of our experience for emotion research by (1) commenting upon the typically overlooked phenomenon of nonresponse, (2) suggesting changes in reporting practices regarding mood induction success, and (3) outlining future directions to help scientists determine why some subjects do not respond to experimental mood induction.

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

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

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

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

Transcriptional responses to glucose at different glycolytic rates in Saccharomyces cerevisiae.

PubMed

Elbing, Karin; Ståhlberg, Anders; Hohmann, Stefan; Gustafsson, Lena

2004-12-01

The addition of glucose to Saccharomyces cerevisiae cells causes reprogramming of gene expression. Glucose is sensed by membrane receptors as well as (so far elusive) intracellular sensing mechanisms. The availability of four yeast strains that display different hexose uptake capacities allowed us to study glucose-induced effects at different glycolytic rates. Rapid glucose responses were observed in all strains able to take up glucose, consistent with intracellular sensing. The degree of long-term responses, however, clearly correlated with the glycolytic rate: glucose-stimulated expression of genes encoding enzymes of the lower part of glycolysis showed an almost linear correlation with the glycolytic rate, while expression levels of genes encoding gluconeogenic enzymes and invertase (SUC2) showed an inverse correlation. Glucose control of SUC2 expression is mediated by the Snf1-Mig1 pathway. Mig1 dephosphorylation upon glucose addition is known to lead to repression of target genes. Mig1 was initially dephosphorylated upon glucose addition in all strains able to take up glucose, but remained dephosphorylated only at high glycolytic rates. Remarkably, transient Mig1-dephosphorylation was accompanied by the repression of SUC2 expression at high glycolytic rates, but stimulated SUC2 expression at low glycolytic rates. This suggests that Mig1-mediated repression can be overruled by factors mediating induction via a low glucose signal. At low and moderate glycolytic rates, Mig1 was partly dephosphorylated both in the presence of phosphorylated, active Snf1, and unphosphorylated, inactive Snf1, indicating that Mig1 was actively phosphorylated and dephosphorylated simultaneously, suggesting independent control of both processes. Taken together, it appears that glucose addition affects the expression of SUC2 as well as Mig1 activity by both Snf1-dependent and -independent mechanisms that can now be dissected and resolved as early and late/sustained responses.

Criteria for Side-Force Control in Air-to-Ground Target Acquisition and Tracking

NASA Technical Reports Server (NTRS)

Sammonds, Robert I.; McNeill, Walter E.; Bunnell, John W.

1982-01-01

A moving-base simulator experiment conducted at Ames Research Center demonstrated that a wings-level-turn control mode improved flying qualities for air-to-ground weapons delivery compared with those of a conventional aircraft. Evaluations of criteria for dynamic response for this system have shown that pilot ratings correlate well with equivalent time constant of the initial response and with system bandwidth. Ranges of this time constant, as well as digital-system transport delays and lateral-acceleration control authorities that encompassed level 1 through level 3 handling qualities, were determined.

STAT3 Mediates Nilotinib Response in KIT-Altered Melanoma: A Phase II Multicenter Trial of the French Skin Cancer Network.

PubMed

Delyon, Julie; Chevret, Sylvie; Jouary, Thomas; Dalac, Sophie; Dalle, Stephane; Guillot, Bernard; Arnault, Jean-Philippe; Avril, Marie-Françoise; Bedane, Christophe; Bens, Guido; Pham-Ledard, Anne; Mansard, Sandrine; Grange, Florent; Machet, Laurent; Meyer, Nicolas; Legoupil, Delphine; Saiag, Philippe; Idir, Zakia; Renault, Victor; Deleuze, Jean-François; Hindie, Elif; Battistella, Maxime; Dumaz, Nicolas; Mourah, Samia; Lebbe, Celeste

2018-01-01

Mutated oncogenic KIT is a therapeutic target in melanoma. We conducted a multicenter phase II trial on the KIT inhibitor nilotinib in patients with unresectable melanoma harboring KIT alteration. The primary endpoint was the response rate (complete response or partial response following Response Evaluation Criteria in Solid Tumors criteria) at 6 months. Pharmacodynamic studies using KIT sequencing, qPCR array, and immunostaining of downstream KIT effectors were performed during treatment. Twenty-five patients were included and received 400 mg oral nilotinib twice daily. At 6 months, nilotinib induced tumor response in four patients. The best overall response rate was 20% and the disease control rate was 56%, limited to patients harboring exon 11 or 13 mutations. Four patients exhibited durable response, including three persisting (3.6 and 2.8 years for two patients with stage IIIC and 2.5 years for one with IVM1b melanoma). A reduction in signal transducer and activator of transcription (STAT) 3 phosphorylation and its effectors (BCL-2, MCL-1) in tumors during follow-up was significantly associated with clinical response. In the KIT-mutated melanoma cell line M230, nilotinib reduced STAT3 signaling and STAT inhibitors were as efficient as KIT inhibitors in reducing cell proliferation. Our study evidences a significant association between STAT3 inhibition and response to nilotinib, and provides a rationale for future research assessing STAT inhibitors in KIT-mutated melanoma. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Successful customer intercept interview recruitment outside small and midsize urban food retailers.

PubMed

Pelletier, Jennifer E; Caspi, Caitlin E; Schreiber, Liana R N; Erickson, Darin J; Harnack, Lisa; Laska, Melissa N

2016-10-05

Customer intercept interviews are increasingly used to characterize food purchases at retail food outlets and restaurants; however, methodological procedures, logistical issues and response rates using intercept methods are not well described in the food environment literature. The aims of this manuscript were to 1) describe the development and implementation of a customer intercept interview protocol in a large, NIH-funded study assessing food purchases in small and midsize food retailers in Minneapolis and St. Paul, Minnesota, 2) describe intercept interview response rates by store type and environmental factors (e.g., neighborhood socioeconomic status, day/time, weather), and 3) compare demographic characteristics (e.g., gender, race/ethnicity) of participants versus non-participants. After a pilot phase involving 28 stores, a total of 616 interviews were collected from customers exiting 128 stores in fall 2014. The number of eligible customers encountered per hour (a measure of store traffic), participants successfully recruited per hour, and response rates were calculated overall and by store type, neighborhood socio-economic status, day and time of data collection, and weather. Response rates by store type, neighborhood socio-economic status, time and day of data collection, and weather, and characteristics of participants and non-participants were compared using chi-square tests. The overall response rate was 35 %, with significantly higher response rates at corner/small grocery stores (47 %) and dollar stores (46 %) compared to food-gas marts (32 %) and pharmacies (26 %), and for data collection between 4:00-6:00 pm on weekdays (40 %) compared to weekends (32 %). The distribution of race/ethnicity, but not gender, differed between participants and non-participants (p < 0.01), with greater participation rates among those identified as Black versus White. Customer intercept interviews can be successfully used to recruit diverse samples of customers at small and midsize food retailers. Future community-based studies using customer intercept interviews should collect data sufficient to report response rates and consider potential differences between the racial/ethnic composition of the recruited sample and the target population.

Strategies of biochemical adaptation for hibernation in a South American marsupial Dromiciops gliroides: 1. Mitogen-activated protein kinases and the cell stress response.

PubMed

Wijenayake, Sanoji; Luu, Bryan E; Zhang, Jing; Tessier, Shannon N; Quintero-Galvis, Julian F; Gaitán-Espitia, Juan Diego; Nespolo, Roberto F; Storey, Kenneth B

2017-12-14

Hibernation is a period of torpor and heterothermy that is typically associated with a strong reduction in metabolic rate, global suppression of transcription and translation, and upregulation of various genes/proteins that are central to the cellular stress response such as protein kinases, antioxidants, and heat shock proteins. The current study examined cell signaling cascades in hibernating monito del monte, Dromiciops gliroides, a South American marsupial of the Order Microbiotheria. Responses to hibernation by members of the mitogen-activated protein kinase (MAPK) pathways, and their roles in coordinating hibernator metabolism were examined in liver, kidney, heart and brain of control and versus hibernating (4days continuous torpor) D. gliroides. The targets evaluated included key protein kinases in their activated phosphorylated forms (p-ERK/MAPK 1/2, p-MEK1, p-MSK1, p-p38, p-JNK) and related target proteins (p-CREB 2, p-ATF2, p-c-Jun and p-p53). Liver exhibited a strong coordinated response by MAPK members to hibernation with significant increases in protein phosphorylation levels of p-MEK1, p-ERK/MAPK1/2, p-MSK1, p-JNK and target proteins c-Jun, and p-ATF2, all combining to signify a strong activation of MAPK signaling during hibernation. Kidney also showed activation of MAPK cascades with significant increases in p-MEK1, p-ERK/MAPK1/2, p-p38, and p-c-Jun levels in hibernating animals. By contrast, responses by heart and brain indicated reduced MAPK pathway function during torpor with reduced phosphorylation of targets including p-ERK/MAPK 1/2 in both tissues as well as lower p-p38 and p-JNK content in heart. Overall, the data indicate a vital role for MAPK signaling in regulating the cell stress response during marsupial hibernation. Copyright © 2017 Elsevier Inc. All rights reserved.

A Generalizable Platform for Interrogating Target- and Signal-Specific Consequences of Electrophilic Modifications in Redox-Dependent Cell Signaling

PubMed Central

Lin, Hong-Yu; Haegele, Joseph A.; Disare, Michael T.; Lin, Qishan; Aye, Yimon

2015-01-01

Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized “electrophile toolbox” with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology—T-REX (targetable reactive electrophiles & oxidants)—is established by: (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein—one of several redox-sensitive regulators of the Nrf2–ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2–ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background. PMID:25909755

A generalizable platform for interrogating target- and signal-specific consequences of electrophilic modifications in redox-dependent cell signaling.

PubMed

Lin, Hong-Yu; Haegele, Joseph A; Disare, Michael T; Lin, Qishan; Aye, Yimon

2015-05-20

Despite the known propensity of small-molecule electrophiles to react with numerous cysteine-active proteins, biological actions of individual signal inducers have emerged to be chemotype-specific. To pinpoint and quantify the impacts of modifying one target out of the whole proteome, we develop a target-protein-personalized "electrophile toolbox" with which specific intracellular targets can be selectively modified at a precise time by specific reactive signals. This general methodology, T-REX (targetable reactive electrophiles and oxidants), is established by (1) constructing a platform that can deliver a range of electronic and sterically different bioactive lipid-derived signaling electrophiles to specific proteins in cells; (2) probing the kinetics of targeted delivery concept, which revealed that targeting efficiency in cells is largely driven by initial on-rate of alkylation; and (3) evaluating the consequences of protein-target- and small-molecule-signal-specific modifications on the strength of downstream signaling. These data show that T-REX allows quantitative interrogations into the extent to which the Nrf2 transcription factor-dependent antioxidant response element (ARE) signaling is activated by selective electrophilic modifications on Keap1 protein, one of several redox-sensitive regulators of the Nrf2-ARE axis. The results document Keap1 as a promiscuous electrophile-responsive sensor able to respond with similar efficiencies to discrete electrophilic signals, promoting comparable strength of Nrf2-ARE induction. T-REX is also able to elicit cell activation in cases in which whole-cell electrophile flooding fails to stimulate ARE induction prior to causing cytotoxicity. The platform presents a previously unavailable opportunity to elucidate the functional consequences of small-molecule-signal- and protein-target-specific electrophilic modifications in an otherwise unaffected cellular background.

Decreasing Echolalia of the Instruction "Say" during Echoic Training through Use of the Cues-Pause-Point Procedure

ERIC Educational Resources Information Center

Valentino, Amber L.; Shillingsburg, M. Alice; Conine, Daniel E.; Powell, Nicole M.

2012-01-01

Echolalia is common in children with autism and may interfere with the development of functional language. Given the variety of vocal stimuli included in teaching language to children with autism, it is possible that discrimination between instructions and targeted responses may not always occur. Thus, children may engage in very high rates of…

SU-F-SPS-10: The Dosimetric Comparison of GammaKnife and Cyberknife Treatment Plans for Brain SRS Treatment

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

Sanli, E; Mabhouti, H; Cebe, M

Purpose: Brain stereotactic radiosurgery (SRS) involves the use of precisely directed, single session radiation to create a desired radiobiologic response within the brain target with acceptable minimal effects on surrounding structures or tissues. In this study, the dosimetric comparison of GammaKnife perfection and Cyberknife M6 treatment plans were made. Methods: Treatment plannings were done for GammaKnife perfection unit using Gammaplan treatment planning system (TPS) on the CT scan of head and neck randophantom simulating the treatment of sterotactic treatments for one brain metastasis. The dose distribution were calculated using TMR 10 algorithm. The treatment planning for the same target weremore » also done for Cyberknife M6 machine using Multiplan (TPS) with Monte Carlo algorithm. Using the same film batch, the net OD to dose calibration curve was obtained using both machine by delivering 0- 800 cGy. Films were scanned 48 hours after irradiation using an Epson 1000XL flatbed scanner. Dose distribution were measured using EBT3 film dosimeter. The measured and calculated doses were compared. Results: The dose distribution in the target and 2 cm beyond the target edge were calculated on TPSs and measured using EBT3 film. For cyberknife treatment plans, the gamma analysis passing rates between measured and calculated dose distributions were 99.2% and 96.7% for target and peripheral region of target respectively. For gammaknife treatment plans, the gamma analysis passing rates were 98.9% and 93.2% for target and peripheral region of target respectively. Conclusion: The study shows that dosimetrically comparable plans are achievable with Cyberknife and GammaKnife. Although TMR 10 algorithm predicts the target dose.« less

EGRINs (Environmental Gene Regulatory Influence Networks) in Rice That Function in the Response to Water Deficit, High Temperature, and Agricultural Environments[OPEN

PubMed Central

Hafemeister, Christoph; Nicotra, Adrienne B.; Jagadish, S.V. Krishna; Bonneau, Richard; Purugganan, Michael

2016-01-01

Environmental gene regulatory influence networks (EGRINs) coordinate the timing and rate of gene expression in response to environmental signals. EGRINs encompass many layers of regulation, which culminate in changes in accumulated transcript levels. Here, we inferred EGRINs for the response of five tropical Asian rice (Oryza sativa) cultivars to high temperatures, water deficit, and agricultural field conditions by systematically integrating time-series transcriptome data, patterns of nucleosome-free chromatin, and the occurrence of known cis-regulatory elements. First, we identified 5447 putative target genes for 445 transcription factors (TFs) by connecting TFs with genes harboring known cis-regulatory motifs in nucleosome-free regions proximal to their transcriptional start sites. We then used network component analysis to estimate the regulatory activity for each TF based on the expression of its putative target genes. Finally, we inferred an EGRIN using the estimated transcription factor activity (TFA) as the regulator. The EGRINs include regulatory interactions between 4052 target genes regulated by 113 TFs. We resolved distinct regulatory roles for members of the heat shock factor family, including a putative regulatory connection between abiotic stress and the circadian clock. TFA estimation using network component analysis is an effective way of incorporating multiple genome-scale measurements into network inference. PMID:27655842

Music-induced positive mood broadens the scope of auditory attention

PubMed Central

Makkonen, Tommi; Eerola, Tuomas

2017-01-01

Abstract Previous studies indicate that positive mood broadens the scope of visual attention, which can manifest as heightened distractibility. We used event-related potentials (ERP) to investigate whether music-induced positive mood has comparable effects on selective attention in the auditory domain. Subjects listened to experimenter-selected happy, neutral or sad instrumental music and afterwards participated in a dichotic listening task. Distractor sounds in the unattended channel elicited responses related to early sound encoding (N1/MMN) and bottom-up attention capture (P3a) while target sounds in the attended channel elicited a response related to top-down-controlled processing of task-relevant stimuli (P3b). For the subjects in a happy mood, the N1/MMN responses to the distractor sounds were enlarged while the P3b elicited by the target sounds was diminished. Behaviorally, these subjects tended to show heightened error rates on target trials following the distractor sounds. Thus, the ERP and behavioral results indicate that the subjects in a happy mood allocated their attentional resources more diffusely across the attended and the to-be-ignored channels. Therefore, the current study extends previous research on the effects of mood on visual attention and indicates that even unfamiliar instrumental music can broaden the scope of auditory attention via its effects on mood. PMID:28460035

Molecular diagnostics of lung cancer in the clinic.

PubMed

Sholl, Lynette

2017-10-01

According to current practice guidelines, all patients with advanced non-small cell lung cancer (NSCLC) should undergo predictive biomarker testing. For squamous cell carcinoma patients, PD-L1 immunohistochemistry is indicated to select patients for immunotherapy in the first line. For lung adenocarcinoma, all patients with advanced disease should undergo testing for epidermal growth factor receptor ( EGFR ) mutations, ALK and ROS1 rearrangements, and PD-L1 expression to predict response to EGFR, ALK, or ROS1 targeted inhibitors or immunotherapy, respectively. Besides these, a number of other biomarkers are under clinical investigation as predictors of response to targeted therapies, including BRAF , ERBB2 , MET splice mutations and amplification, and RET rearrangements. Successful testing for this complex array of molecular targets demands careful coordination between proceduralists, pathologists and molecular laboratories to ensure proper tumor tissue handling following biopsy as well as judicious use of diagnostic immunohistochemistry. Even so, sample failure rates due to inadequate tumor tissue are high in practice, particularly when using sequential testing methods. Use of next generation sequencing (NGS) in clinical practice can enable detection of multiple targets and multiple alteration types (mutation, gene copy change, and rearrangement) simultaneously even with small amounts of input nucleic acids, thus increasing molecular testing success rates. In patients with an established lung cancer diagnosis but with prohibitively limited amounts of tumor tissue or who are experiencing relapse, analyses of circulating tumor DNA (ctDNA) from the plasma can serve as an alternate testing substrate, however the more limited clinical sensitivity of this approach must be taken into account. This review will explore the indications for and pitfalls of routine NGS and plasma genotyping in the clinic, including the intersection of these technologies.

Molecular diagnostics of lung cancer in the clinic

PubMed Central

2017-01-01

According to current practice guidelines, all patients with advanced non-small cell lung cancer (NSCLC) should undergo predictive biomarker testing. For squamous cell carcinoma patients, PD-L1 immunohistochemistry is indicated to select patients for immunotherapy in the first line. For lung adenocarcinoma, all patients with advanced disease should undergo testing for epidermal growth factor receptor (EGFR) mutations, ALK and ROS1 rearrangements, and PD-L1 expression to predict response to EGFR, ALK, or ROS1 targeted inhibitors or immunotherapy, respectively. Besides these, a number of other biomarkers are under clinical investigation as predictors of response to targeted therapies, including BRAF, ERBB2, MET splice mutations and amplification, and RET rearrangements. Successful testing for this complex array of molecular targets demands careful coordination between proceduralists, pathologists and molecular laboratories to ensure proper tumor tissue handling following biopsy as well as judicious use of diagnostic immunohistochemistry. Even so, sample failure rates due to inadequate tumor tissue are high in practice, particularly when using sequential testing methods. Use of next generation sequencing (NGS) in clinical practice can enable detection of multiple targets and multiple alteration types (mutation, gene copy change, and rearrangement) simultaneously even with small amounts of input nucleic acids, thus increasing molecular testing success rates. In patients with an established lung cancer diagnosis but with prohibitively limited amounts of tumor tissue or who are experiencing relapse, analyses of circulating tumor DNA (ctDNA) from the plasma can serve as an alternate testing substrate, however the more limited clinical sensitivity of this approach must be taken into account. This review will explore the indications for and pitfalls of routine NGS and plasma genotyping in the clinic, including the intersection of these technologies. PMID:29114472

Extinction in multiple contexts: Effects on the rate of extinction and the strength of response recovery.

PubMed

Bustamante, Javier; Uengoer, Metin; Thorwart, Anna; Lachnit, Harald

2016-09-01

In two human predictive-learning experiments, we investigated the effects of extinction in multiple contexts on the rate of extinction and the strength of response recovery. In each experiment, participants initially received acquisition training with a target cue in one context, followed by extinction either in a different context (extinction in a single context) or in three different contexts (extinction in multiple contexts). The results of both experiments showed that conducting extinction in multiple contexts led to higher levels of responding during extinction than did extinction in a single context. Additionally, Experiment 2 showed that extinction in multiple contexts prevented ABC renewal but had no detectable impact on ABA renewal. Our results are discussed within the framework of contemporary learning theories of contextual control and extinction.

Preparation of molecule-responsive microsized hydrogels via photopolymerization for smart microchannel microvalves.

PubMed

Shiraki, Yusuke; Tsuruta, Kazuhiro; Morimoto, Junpei; Ohba, Chihiro; Kawamura, Akifumi; Yoshida, Ryo; Kawano, Ryuji; Uragami, Tadashi; Miyata, Takashi

2015-03-01

Microdevices designed for practical environmental pollution monitoring need to detect specific pollutants such as dioxins. Bisphenol A (BPA) has been widely used as a monomer for the synthesis of polycarbonate and epoxy resins. However, the recent discovery of its high potential ability to disrupt human endocrine systems has made the development of smart systems and microdevices for its detection and removal necessary. Molecule-responsive microsized hydrogels with β-cycrodextrin (β-CD) as ligands are prepared by photopolymerization using a fluorescence microscope. The molecule-responsive micro-hydrogels show ultra-quick shrinkage in response to target BPA. Furthermore, the flow rate of a microchannel is autonomously regulated by the molecule-responsive shrinking of their hydrogels as smart microvalves. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Reduced ERPs and theta oscillations underlie working memory deficits in Toxoplasma gondii infected seniors.

PubMed

Gajewski, Patrick D; Falkenstein, Michael; Hengstler, Jan G; Golka, Klaus

2016-10-01

Toxoplasma gondii is one of the most widespread infections in humans. Recent studies give evidence for memory deficits in infected older adults. To investigate working memory dysfunction in infected elderly, a double-blinded electrophysiological study was conducted. 84 persons derived from a sample of 131 healthy participants with the mean age of 70 years were assigned to two groups of 42 non-infected and 42 infected individuals. The outcome measures were behavioral performance, target and response-related ERPs, and time-frequency wavelets during performance in a n-back working-memory task. The infected individuals showed a reduced rate of detected targets and diminished P3b amplitude both in target-locked as well as response-locked data compared to the non-infected group. Time-frequency decomposition of the EEG-signals revealed lower evoked power in the theta frequency range in the target-locked as well as in the response-locked data in infected individuals. The reported effects were comparable with differences between healthy young and old adults described previously. Taking together, the reduced working-memory performance accompanied by an attenuated P3b and frontal theta activity may suggest neurotransmitter imbalance like dopamine and norepinephrine in T. gondii infected individuals. In face of a high prevalence of T. gondii infection and the increasing ratio of older population their accelerated memory decline may have substantial socioeconomic consequences. Copyright © 2016 Elsevier B.V. All rights reserved.

Conformational stability as a design target to control protein aggregation.

PubMed

Costanzo, Joseph A; O'Brien, Christopher J; Tiller, Kathryn; Tamargo, Erin; Robinson, Anne Skaja; Roberts, Christopher J; Fernandez, Erik J

2014-05-01

Non-native protein aggregation is a prevalent problem occurring in many biotechnological manufacturing processes and can compromise the biological activity of the target molecule or induce an undesired immune response. Additionally, some non-native aggregation mechanisms lead to amyloid fibril formation, which can be associated with debilitating diseases. For natively folded proteins, partial or complete unfolding is often required to populate aggregation-prone conformational states, and therefore one proposed strategy to mitigate aggregation is to increase the free energy for unfolding (ΔGunf) prior to aggregation. A computational design approach was tested using human γD crystallin (γD-crys) as a model multi-domain protein. Two mutational strategies were tested for their ability to reduce/increase aggregation rates by increasing/decreasing ΔGunf: stabilizing the less stable domain and stabilizing the domain-domain interface. The computational protein design algorithm, RosettaDesign, was implemented to identify point variants. The results showed that although the predicted free energies were only weakly correlated with the experimental ΔGunf values, increased/decreased aggregation rates for γD-crys correlated reasonably well with decreases/increases in experimental ΔGunf, illustrating improved conformational stability as a possible design target to mitigate aggregation. However, the results also illustrate that conformational stability is not the sole design factor controlling aggregation rates of natively folded proteins.

Optimizing clinical benefit with targeted treatment in mRCC: "Tumor growth rate" as an alternative clinical endpoint.

PubMed

Milella, Michele

2016-06-01

Tumor growth rate (TGR), usually defined as the ratio between the slope of tumor growth before the initiation of treatment and the slope of tumor growth during treatment, between the nadir and disease progression, is a measure of the rate at which tumor volume increases over time. In patients with metastatic renal cell carcinoma (mRCC), TGR has emerged as a reliable alternative parameter to allow a quantitative and dynamic evaluation of tumor response. This review presents evidence on the correlation between TGR and treatment outcomes and discusses the potential role of this tool within the treatment scenario of mRCC. Current evidence, albeit of retrospective nature, suggests that TGR might represent a useful tool to assess whether treatment is altering the course of the disease, and has shown to be significantly associated with progression-free survival and overall survival. Therefore, TGR may represent a valuable endpoint for clinical trials evaluating new molecularly targeted therapies. Most importantly, incorporation of TGR in the assessment of individual patients undergoing targeted therapies may help clinicians decide if a given agent is no longer able to control disease growth and whether continuing therapy beyond RECIST progression may still produce clinical benefit. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Design, Synthesis and Bio-evaluation of an EphA2-based Targeted Delivery System

PubMed Central

Barile, Elisa; Wang, Si; Das, Swadesh K.; Noberini, Roberta; Dahl, Russell; Stebbins, John L.; Pasquale, Elena B.; Fisher, Paul B.; Pellecchia, Maurizio

2014-01-01

We recently described a new targeted delivery system based on specific EphA2 receptor targeting peptides conjugated with the chemotherapeutic agent paclitaxel. In this manuscript we investigate the chemical determinants responsible for the stability and degradation of these agents in plasma. Introducing modifications in both the peptide and the linker between the peptide and paclitaxel, resulted in drug conjugates that are both long-lived in rat plasma and that markedly reduced tumor size in a prostate cancer xenograft model compared to paclitaxel alone treatment. These studies identify critical rate-limiting degradation sites on the peptide-drug conjugates, enabling the design of agents with increased stability and efficacy. These results provide support for our central hypothesis that peptide-drug conjugates targeting the EphA2 receptor represent an innovative and potentially effective strategy to selectively deliver cytotoxic drugs to cancer cells. PMID:24677792

MiR-285 targets P450 (CYP6N23) to regulate pyrethroid resistance in Culex pipiens pallens.

PubMed

Tian, Mengmeng; Liu, Bingqian; Hu, Hongxia; Li, Xixi; Guo, Qin; Zou, Feifei; Liu, Xianmiao; Hu, Mengxue; Guo, Juxin; Ma, Lei; Zhou, Dan; Sun, Yan; Shen, Bo; Zhu, Changliang

2016-12-01

MicroRNAs play critical roles in post-transcriptional regulation of gene expression, which participate in the modulation of almost all of the cellular processes. Although emerging evidence indicates that microRNAs are related with antineoplastic drugs resistance, whether microRNAs are responsible for insecticide resistance in mosquitos is poorly understood. In this paper, we found that miR-285 was significantly upregulated in the deltamethrin-resistant strain of Culex pipiens pallens, and overexpression miR-285 through microinjection increased mosquito survival rate against deltamethrin treatement. Using bioinformatic software, quantitative reverse transcription PCR, luciferase reporter assay and microinjection approaches, we conformed that CYP6N23 was the target of miR-285. Lower expression of CYP6N23 was observed in the deltamethrin-resistant strain. While, mosquito mortality rate was decreased after downregulating expression of CYP6N23 by dsRNA against CYP6N23 or miR-285 mimic microinjection. These findings revealed that miR-285 could target CYP6N23 to regulate pyrethroid resistance, providing new insights into mosquito insecticide resistance surveillance and control.

Glyphosate and dicamba herbicide tank mixture effects on native plant and non-genetically engineered soybean seedlings.

PubMed

Olszyk, David; Pfleeger, Thomas; Lee, E Henry; Plocher, Milton

2015-07-01

Crops engineered to contain genes for tolerance to multiple herbicides may be treated with several herbicides to manage weeds resistant to each herbicide. Thus, nearby non-target plants may be subjected to increased exposure to several herbicides used in combination. Of particular concern are native plants, as well as adjacent crops which have not been genetically engineered for tolerance to herbicides. We evaluated responses of seven species of native plants grown in a greenhouse and treated less than field application rates of glyphosate and/or dicamba: Andropogon gerardii, Asclepias syriaca, Eutrochium purpureum, Oenothera biennis, Polyganum lapathifolium, Solidago canadensis and Tridens flavus, and non-herbicide resistant soybean (Glycine max, Oregon line M4). Herbicide concentrations were 0.03 or 0.1 × field application rates of 1122 g ha(-1) active ingredient (a.i) (831 g ha(-1) acid glyphosate) for glyphosate and 562 g ha(-1) a.i. for dicamba. In general, plant growth responses to combinations of glyphosate and dicamba were less than the sum of growth responses to the individual herbicides (i.e., antagonistic effect), primarily when one or both herbicides alone caused a large reduction in growth. E. purpureum, P. lapathifolium and S. canadensis were the most sensitive species to both herbicides, while A. gerardii was the most tolerant, with no response to either herbicide. The combinations of herbicides resulted in responses most similar to that from dicamba alone for G. max and from glyphosate alone for T. flavus. The results of this study indicated the need for more data such as effects on native plants in the field to assess risks to non-target plants from combinations of herbicides.

Immune-related tumor response dynamics in melanoma patients treated with pembrolizumab: Identifying markers for clinical outcome and treatment decisions

PubMed Central

Nishino, Mizuki; Giobbie-Hurder, Anita; Manos, Michael P.; Bailey, Nancy D.; Buchbinder, Elizabeth I.; Ott, Patrick A.; Ramaiya, Nikhil H.; Hodi, F. Stephen

2017-01-01

Purpose Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma. Experimental Design The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS. Results Among 107 patients, 96 patients had measurable tumor burden and 11 had non-target lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median:-18.5%). Overall response rate was 44% (42/96; 5 irCR, 37 irPR). Tumor burden remained <20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with <20% tumor burden increase from baseline had longer OS than pts with ≥20% increase (12-month OS rate: 82 vs. 53%). In extended Cox models, patients with <20% tumor burden increase during therapy had significantly reduced hazards of death (HR=0.19, 95%CI:0.08–0.43, p<0.0001 univariate; HR=0.18, 95%CI:0.08-0.41, p<0.0001, multivariable). Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed irPD. One patient without measurable disease progressed with new lesion that subsequently regressed. Conclusions Tumor burden increase of <20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention. PMID:28592629

The locus of taboo context effects in picture naming.

PubMed

Hansen, Samuel J; McMahon, Katie L; Burt, Jennifer S; de Zubicaray, Greig I

2016-07-20

Speakers respond more slowly when naming pictures presented with taboo (i.e., offensive/embarrassing) than with neutral distractor words in the picture-word interference paradigm. Over four experiments, we attempted to localize the processing stage at which this effect occurs during word production and determine whether it reflects the socially offensive/embarrassing nature of the stimuli. Experiment 1 demonstrated taboo interference at early stimulus onset asynchronies of -150 ms and 0 ms although not at 150 ms. In Experiment 2, taboo distractors sharing initial phonemes with target picture names eliminated the interference effect. Using additive factors logic, Experiment 3 demonstrated that taboo interference and phonological facilitation effects do not interact, indicating that the two effects originate at different processing levels within the speech production system. In Experiment 4, interference was observed for masked taboo distractors, including those sharing initial phonemes with the target picture names, indicating that the effect cannot be attributed to a processing level involving responses in an output buffer. In two of the four experiments, the magnitude of the interference effect correlated significantly with arousal ratings of the taboo words. However, no significant correlations were found for either offensiveness or valence ratings. These findings are consistent with a locus for the taboo interference effect prior to the processing stage responsible for word form encoding. We propose a pre-lexical account in which taboo distractors capture attention at the expense of target picture processing due to their high arousal levels.

Clinical trials in drug development: a minimalistic approach.

PubMed

Verweij, Jaap

2012-05-01

Drug development in oncology finds itself at the crossroad of unique opportunities and major challenges. The old paradigms should and can be replaced by a system that better matches the right patients to the right compounds and puts much more emphasis on the early stages of drug development. The clinical phases of drug development will no longer be split into phase I, II, and III studies, but rather into 'functional target pharmacology studies', followed by 'proof of concept studies'. The resulting development flow becomes Apollo-capsule shaped. Although randomized studies will still be needed for drugs using targets in the tumor environment, or for combinations of agents, drug registration might proceed without these if all of the following criteria are met in early development: availability of preclinical convincing evidence that the drug's target is the functional driver behind the disease phenotype, availability of a predictive biomarker that enables appropriate and actual patient selection in early pharmacology studies, a Response Evaluation Criteria In Solid Tumors (RECIST)-based single agent response rate of at least 50%, and/or a progression at first tumor assessment rate of 15% or less, a duration of absence of progression (stable disease) beyond doubt and considered clinically relevant, and no major safety concern. This set is not yet mature, but may be adapted over time. The concerns related to registering agents on the basis of small datasets can be adequately addressed by obligatory postmarketing hypothesis driven studies.

Front-line window therapy with cisplatin in patients with primary disseminated Ewing sarcoma: A study by the Associazione Italiana di Ematologia ed Oncologia Pediatrica and Italian Sarcoma Group.

PubMed

Luksch, Roberto; Grignani, Giovanni; D'Angelo, Paolo; Prete, Arcangelo; Puma, Nadia; Podda, Marta; Casanova, Michela; Ferrari, Andrea; Morosi, Carlo; Fagioli, Franca; Aglietta, Massimo; Ferrari, Stefano; Picci, Piero; Massimino, Maura

2017-12-01

The aim was to assess the activity of cisplatin (CDDP) in Ewing sarcoma (ES). The study consisted of front-line window therapy with CDDP 120 mg/sqm every 3 weeks for two courses in children and young adults with primary disseminated ES. Response was assessed using the Response Evaluation Criteria in Solid Tumours criteria, and Simon's two-stage design was applied. Twelve consecutive patients were enrolled in stage 1. Only one objective response was observed. Since the target response rate was not achieved, accrual was stopped and CDDP as a single agent in ES was judged unworthy of further assessment. © 2017 Wiley Periodicals, Inc.

Does conal prime CANAL more than cinal? Masked phonological priming effects in Spanish with the lexical decision task.

PubMed

Pollatsek, Alexander; Perea, Manuel; Carreiras, Manuel

2005-04-01

Evidence for an early involvement of phonology in word identification usually relies on the comparison between a target word preceded by a homophonic prime and an orthographic control (rait-RATE vs. raut-RATE). This comparison rests on the assumption that the two control primes are equally orthographically similar to the target. Here, we tested for phonological effects with a masked priming paradigm in which orthographic similarity between priming conditions was perfectly controlled at the letter level and in which identification of the prime was virtually at chance for both stimulus onset asynchronies (SOAs) (66 and 50 msec). In the key prime-target pairs, each prime differed from the target by one vowel letter, but one changed the sound of the initial c, and the other did not (cinal-CANAL vs. conal-CANAL). In the control prime-target pairs, the primes had the identical vowel manipulation, but neither changed the initial consonant sound (pinel-PANEL vs. ponel-PANEL). For both high- and low-frequency words, lexical decision responses to the target were slower when the prime changed the sound of the c than when it did not, whereas there was no difference for the controls at both SOAs. However, this phonological effect was small and was not significant when the SOA was 50 msec. The pattern of data is consistent with an early phonological coding of primes that occurs just a little later than orthographic coding.

Contrast-Enhanced Computed Tomography Evaluation of Hepatic Metastases in Breast Cancer Patients Before and After Cytotoxic Chemotherapy or Targeted Therapy.

PubMed

He, Hongying; Cai, Chunyan; Charnsangavej, Chusilp; Theriault, Richard L; Green, Marjorie; Quraishi, Mohammad A; Yang, Wei T

2015-11-01

To evaluate change in size vs computed tomography (CT) density of hepatic metastases in breast cancer patients before and after cytotoxic chemotherapy or targeted therapy. A database search in a single institution identified 48 breast cancer patients who had hepatic metastases treated with either cytotoxic chemotherapy alone or targeted therapy alone, and who had contrast-enhanced CT (CECT) scans of the abdomen at baseline and within 4 months of initiation of therapy in the past 10 years. Two radiologists retrospectively evaluated CT scans and identified up to 2 index lesions in each patient. The size (centimeters) of each lesion was measured according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, and CT density (Hounsfield units) was measured by drawing a region of interest around the margin of the entire lesion. The percent change in sum of lesion size and mean CT density on pre- and post-treatment scans was computed for each patient; results were compared within each treatment group. Thirty-nine patients with 68 lesions received cytotoxic chemotherapy only; 9 patients with 15 lesions received targeted therapy only. The mean percent changes in sum of lesion size and mean CT density were statistically significant within the cytotoxic chemotherapy group before and after treatment, but not significant in the targeted therapy group. The patients in the targeted therapy group tend to have better 2-year survival. The patients who survived at 2 years tend to have more decrease in tumour size in the cytotoxic chemotherapy group. Cytotoxic chemotherapy produced significant mean percent decrease in tumour size and mean CT density of hepatic metastases from breast cancer before and after treatment, whereas targeted therapy did not. Nonetheless, there is a trend that the patients in the targeted therapy group had better 2-year survival rate. This suggests that RECIST is potentially inadequate in evaluating tumour response in breast cancer liver metastases treated with targeted therapy alone, calling for an alternative marker for response evaluation in this subset of patients. Copyright © 2015 Canadian Association of Radiologists. Published by Elsevier Inc. All rights reserved.

How well does a single question about health predict the financial health of Medicare managed care plans?

PubMed

Bierman, A S; Bubolz, T A; Fisher, E S; Wasson, J H

1999-01-01

Responses to simple questions that predict subsequent health care utilization are of interest to both capitated health plans and the payer. To determine how responses to a single question about general health status predict subsequent health care expenditures. Participants in the 1992 Medicare Current Beneficiary Survey were asked the following question: "In general, compared to other people your age, would you say your health is: excellent, very good, good, fair or poor?" To obtain each participant's total Medicare expenditures and number of hospitalizations in the ensuing year, we linked the responses to this question with data from the 1993 Medicare Continuous History Survey. Nationally representative sample of 8775 noninstitutionalized Medicare beneficiaries 65 years of age and older. Annual age- and sex-adjusted Medicare expenditures and hospitalization rates. Eighteen percent of the beneficiaries rated their health as excellent, 56% rated it as very good or good, 17% rated it as fair, and 7% rated it as poor. Medicare expenditures had a marked inverse relation to self-assessed health ratings. In the year after assessment, age- and sex-adjusted annual expenditures varied fivefold, from $8743 for beneficiaries rating their health as poor to $1656 for beneficiaries rating their health as excellent. Hospitalization rates followed the same pattern: Respondents who rated their health as poor had 675 hospitalizations per 1000 beneficiaries per year compared with 136 per 1000 for those rating their health as excellent. The response to a single question about general health status strongly predicts subsequent health care utilization. Self-reports of fair or poor health identify a group of high-risk patients who may benefit from targeted interventions. Because the current Medicare capitation formula does not account for health status, health plans can maximize profits by disproportionately enrolling beneficiaries who judge their health to be good. However, they are at a competitive disadvantage if they enroll beneficiaries who view themselves as sick.

Radionuclides in radiation-induced bystander effect; may it share in radionuclide therapy?

PubMed

Widel, M

2017-01-01

For many years in radiobiology and radiotherapy predominated the conviction that cellular DNA is the main target for ionizing radiation, however, the view has changed in the past 20 years. Nowadays, it is assumed that not only directed (targeted) radiation effect, but also an indirect (non-targeted) effect may contribute to the result of radiation treatment. Non-targeted effect is relatively well recognized after external beam irradiation in vitro and in vivo, and comprises such phenomena like radiation-induced bystander effect (RIBE), genomic instability, adaptive response and abscopal (out of field) effect. These stress-induced and molecular signaling mediated phenomena appear in non-targeted cells as variety responses resembling that observed in directly hit cells. Bystander effects can be both detrimental and beneficial in dependence on dose, dose-rate, cell type, genetic status and experimental condition. Less is known about radionuclide-induced non-targeted effects in radionuclide therapy, although, based on characteristics of the radionuclide radiation, on experiments in vitro utilizing classical and 3-D cell cultures, and preclinical study on animals it seems obvious that exposure to radionuclide is accompanied by various bystander effects, mostly damaging, less often protective. This review summarizes existing data on radionuclide induced bystander effects comprising radionuclides emitting beta- and alpha-particles and Auger electrons used in tumor radiotherapy and diagnostics. So far, separation of the direct effect of radionuclide decay from crossfire and bystander effects in clinical targeted radionuclide therapy is impossible because of the lack of methods to assess whether, and to what extent bystander effect is involved in human organism. Considerations on this topic are also included.

Targeted therapies in gastric cancer treatment: where we are and where we are going.

PubMed

Tomasello, Gianluca; Ghidini, Michele; Liguigli, Wanda; Ratti, Margherita; Toppo, Laura; Passalacqua, Rodolfo

2016-06-01

Gastric cancer (GC) is one of the most common malignancies and a major cause of cancer-related deaths worldwide. Its incidence has significantly declined over the last few decades, probably due to the identification of specific etiologic agents such as Helicobacter pylori and other dietary and environmental risk factors. Nevertheless, most of the cases are unfortunately diagnosed at an advanced stage justifying median overall survival rates frequently not exceeding one year. Palliative combination chemotherapy usually represented by a platinum-based doublet is the mainstay of treatment in the metastatic setting. Adding a third drug such as an anthracycline or a taxane has been shown to improve response rate and provide limited survival benefits in fit selected patients. Unlike other tumors, the introduction of molecularly targeted drugs in the medical armamentarium for GC is relatively recent with trastuzumab and ultimately ramucirumab constituting the only agents approved to date. Recent advances in the understanding of GC biology have led to the development of novel targeted therapies holding the promise to further improve treatment outcomes. The aim of this paper is to review the main available data coming from clinical trials of targeted drugs and to describe some of the most interesting molecules in clinical development in GC. These include drugs targeting EGFR, angiogenesis, c-MET, FGFR2, mTOR and immune checkpoints.

Is facial skin tone sufficient to produce a cross-racial identification effect?

PubMed

Alley, T R; Schultheis, J A

2001-06-01

Research clearly supports the existence of an other race effect for human faces whereby own-race faces are more accurately perceived and recognized. Why this occurs remains unclear. A computerized program (Mac-a-Mug Pro) for face composition was used to create pairs of target and distractor faces that differed only in skin tone. The six target faces were rated on honesty and aggressiveness by 72 university students, with just one 'Black' and one 'White' face viewed by each student. One week later, they attempted to identify these faces in four lineups: two with target-present and two with target-absent. The order of presentation of targets, lineups, and faces within lineups was varied. Own-race identification was slightly better than cross-racial identification. There was no significant difference in the confidence of responses to own- versus other-race faces. These results indicate that neither morphological variation nor differential confidence is necessary for a cross-racial identification effect.

Society of Flight Test Engineers, Annual Symposium, 21st, Garden Grove, CA, Aug. 6-10, 1990, Proceedings

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

Not Available

1990-01-01

The present conference on flight testing encompasses avionics, flight-testing programs, technologies for flight-test predictions and measurements, testing tools, analysis methods, targeting techniques, and flightline testing. Specific issues addressed include flight testing of a digital terrain-following system, a digital Doppler rate-of-descent indicator, a high-technology testbed, a low-altitude air-refueling flight-test program, techniques for in-flight frequency-response testing for helicopters, limit-cycle oscillation and flight-flutter testing, and the research flight test of a scaled unmanned air vehicle. Also addressed are AV-8B V/STOL performance analysis, incorporating pilot-response time in failure-case testing, the development of pitot static flightline testing, targeting techniques for ground-based hover testing, a low-profilemore » microsensor for aerodynamic pressure measurement, and the use of a variable-capacitance accelerometer for flight-test measurements.« less

ALK mutation and inhibition in lung cancer

PubMed Central

Le, Tri; Gerber, David E.

2016-01-01

The advent of precision medicine in non-small cell lung cancer has remarkably altered the direction of research and improved clinical outcomes. The identification of molecular subsets with differential response to targeted therapies began with the identification of epidermal growth factor receptor mutated tumors in subsets of non-small cell lung cancer (NSCLC). Emboldened by unprecedented response rates to kinase inhibitors seen in that subset, the oncologic community searched for other molecular subsets featuring oncogene addiction. An early result of this search was the discovery of NSCLC driven by activating rearrangements of the anaplastic lymphoma kinase (ALK) gene. In an astoundingly brief period following the recognition of ALK-positive NSCLC, details of the biology, clinicopathologic features, development of targeted inhibitors, mechanisms of therapeutic resistance, and new generations of treatment were elucidated. This review summarizes the current understanding of the pathologic features, diagnostic approach, treatment options, resistance mechanisms, and future research areas for ALK-positive NSCLC. PMID:27637426

Efficacy of TACE in TIPS Patients: Comparison of Treatment Response to Chemoembolization for Hepatocellular Carcinoma in Patients With and Without a Transjugular Intrahepatic Portosystemic Shunt

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

Kuo, Yuo-Chen, E-mail: yuo-chen.kuo@ucsf.edu; Kohi, Maureen P., E-mail: maureen.kohi@ucsf.edu; Naeger, David M., E-mail: david.naeger@ucsf.edu

Purpose: To compare treatment response after transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) in patients with and without a transjugular intrahepatic portosystemic shunt (TIPS). Materials and Methods: A retrospective review of patients who underwent conventional TACE for HCC between January 2005 and December 2009 identified 10 patients with patent TIPS. From the same time period, 23 patients without TIPS were selected to control for comparable Model for End-Stage Liver Disease and Child-Pugh-Turcotte scores. The two groups showed similar distribution of Barcelona Clinic Liver Cancer and United Network of Organ Sharing stages. Target HCC lesions were evaluated according to the modifiedmore » response evaluation criteria in solid tumors (mRECIST) guidelines. Transplantation rate, time to tumor progression, and overall survival (OS) were documented. Results: After TACE, the rate of complete response was significantly greater in non-TIPS patients compared with TIPS patients (74 vs. 30 %, p = 0.03). Objective response rate (complete and partial response) trended greater in the non-TIPS group (83 vs. 50 %, p = 0.09). The liver transplantation rate was 80 and 74 % in the TIPS and non-TIPS groups, respectively (p = 1.0). Time to tumor progression was similar (p = 0.47) between the two groups. OS favored the non-TIPS group (p = 0.01) when censored for liver transplantation. Conclusion: TACE is less effective in achieving complete or partial response using mRECIST criteria in TIPS patients compared with those without a TIPS. Nevertheless, similar clinical outcomes may be achieved, particularly in TIPS patients who are liver-transplantation candidates.« less

Personalized Symptom Goals and Patient Global Impression on Clinical Changes in Advanced Cancer Patients.

PubMed

Mercadante, Sebastiano; Adile, Claudio; Lanzetta, Gaetano; Mystakidou, Kyriaki; Maltoni, Marco; Soares, Luiz Guilherme; De Santis, Stefano; Ferrera, Patrizia; Valenti, Marco; Rosati, Marta; Rossi, Romina; Cortegiani, Andrea; Masedu, Francesco; Marinangeli, Franco; Aielli, Federica

2018-05-16

The aim of this study was to assess the patients' global impression (PGI) after symptom management, as well as the achievement of personalized symptom goals (PSG). The secondary outcome was to assess related factors. Subjects, Materials, and Methods . Advanced cancer patients admitted to palliative care units rated symptom intensity by using the Edmonton Symptom Assessment Score (ESAS) at admission and then after 1 week. For each symptom, patient-reported PGI and PSG, as well as the rate of PSG response, were evaluated. Eight hundred seventy-six patients were taken into consideration for this study. A mean of 1.71-2.16 points was necessary to perceive a bit better improvement of symptom intensity. Most patients had a PSG of ≤3. A statistically significant number of patients achieved their PSG after starting palliative care. Patients with high intensity of ESAS items at admission achieved a more favorable PGI response. In the multivariate analysis, symptom intensity and PSG were the most frequent factors independently associated to a best PGI, whereas high levels of Karnofsky had a lower odd ratio. PSG and PGI seem to be relevant for patients' assessment and decision-making process, translating in terms of therapeutic intervention. Some factors may be implicated in determining the individual target and clinical response. Personalized symptom goals and global impression of change are relevant for patients' assessment and decision-making process, translating in terms of therapeutic intervention. Some factors may be implicated in determining the individual target and clinical response. © AlphaMed Press 2018.

CAR T-cells merge into the fast lane of cancer care.

PubMed

Frey, Noelle V; Porter, David L

2016-01-01

Chimeric antigen receptors (CARs) can be introduced into T-cells redirecting them to target specific tumor antigens. CAR-modified T cells targeting CD19 have shown remarkable activity against CD19+ malignancies including B cell acute lymphocytic leukemia (ALL), chronic lymphocytic leukemia (CLL), and non-Hodgkin lymphomas (NHL). Complete remission rates as high as 90% have been observed for patients with relapsed and refractory ALL and greater than 50% response rates have been seen in heavily pre-treated CLL and NHL. Excitingly, some remissions have been durable without any additional therapy, a finding which correlates with in-vivo T-cell persistence and B-cell aplasia. The major treatment related toxicities include B-cell aplasia, neurologic toxicities, and a potentially severe cytokine release syndrome. This review summarizes outcomes for patients treated with CD19-CAR T-cells while exploring the field's challenges and future directions. © 2015 Wiley Periodicals, Inc.

Predictive and therapeutic markers in ovarian cancer

DOEpatents

Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

2013-03-26

Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha-Targeting Antibody-Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study.

PubMed

Moore, Kathleen N; Martin, Lainie P; O'Malley, David M; Matulonis, Ursula A; Konner, Jason A; Perez, Raymond P; Bauer, Todd M; Ruiz-Soto, Rodrigo; Birrer, Michael J

2017-04-01

Purpose This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody-drug conjugate consisting of a humanized anti-folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer. Patients and Methods Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRα positivity by immunohistochemistry (≥ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. Results Forty-six patients were enrolled. Adverse events were generally mild (≤ grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. Conclusion IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease.

Safety and Activity of Mirvetuximab Soravtansine (IMGN853), a Folate Receptor Alpha–Targeting Antibody–Drug Conjugate, in Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer: A Phase I Expansion Study

PubMed Central

Martin, Lainie P.; O’Malley, David M.; Matulonis, Ursula A.; Konner, Jason A.; Perez, Raymond P.; Bauer, Todd M.; Ruiz-Soto, Rodrigo; Birrer, Michael J.

2017-01-01

Purpose This phase I expansion cohort study evaluated the safety and clinical activity of mirvetuximab soravtansine (IMGN853), an antibody–drug conjugate consisting of a humanized anti–folate receptor alpha (FRα) monoclonal antibody linked to the tubulin-disrupting maytansinoid DM4, in a population of patients with FRα-positive and platinum-resistant ovarian cancer. Patients and Methods Patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer received IMGN853 at 6.0 mg/kg (adjusted ideal body weight) once every 3 weeks. Eligibility included a minimum requirement of FRα positivity by immunohistochemistry (≥ 25% of tumor cells with at least 2+ staining intensity). Adverse events, tumor response (via Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), and progression-free survival (PFS) were determined. Results Forty-six patients were enrolled. Adverse events were generally mild (≤ grade 2), with diarrhea (44%), blurred vision (41%), nausea (37%), and fatigue (30%) being the most commonly observed treatment-related toxicities. Grade 3 fatigue and hypotension were reported in two patients each (4%). For all evaluable patients, the confirmed objective response rate was 26%, including one complete and 11 partial responses, and the median PFS was 4.8 months. The median duration of response was 19.1 weeks. Notably, in the subset of patients who had received three or fewer prior lines of therapy (n = 23), an objective response rate of 39%, PFS of 6.7 months, and duration of response of 19.6 weeks were observed. Conclusion IMGN853 exhibited a manageable safety profile and was active in platinum-resistant ovarian cancer, with the strongest signals of efficacy observed in less heavily pretreated individuals. On the basis of these findings, the dose, schedule, and target population were identified for a phase III trial of IMGN853 monotherapy in patients with platinum-resistant disease. PMID:28029313

Adoptive cell therapy with CD4+ T helper 1 cells and CD8+ cytotoxic T cells enhances complete rejection of an established tumour, leading to generation of endogenous memory responses to non-targeted tumour epitopes.

PubMed

Li, Kunyu; Donaldson, Braeden; Young, Vivienne; Ward, Vernon; Jackson, Christopher; Baird, Margaret; Young, Sarah

2017-10-01

The results of adoptive T-cell therapies (ACTs) are very encouraging and show clinical evidence that ACT can provide a cure for patients with metastatic disease. However, various response rates and long-term cancer remission have been observed in different ACT trials. The types of T cells, prior treatment with chemotherapy and co-administration of other immune-target therapies have been found to influence the efficacy of ACT. In this study, we investigate the ability of ACT using CD4 + T helper 1 (Th1) cells and CD8 + cytotoxic T lymphocytes (CTLs) to reject the growth of established B16-ovalbumin (OVA) melanoma. CD8 + CTLs were found to be the main effector T cells that mediated tumour regression. However, low tumour-free survival rates were observed in ACT with CD8 + CTLs only. Co-transferring CD4 + Th1 cells and CD8 + CTLs has been observed to induce a synergistic antitumour response, resulting in complete regression in 80% of the tumour-bearing mice. We also examined a prior Dacarbazine (DTIC) and after virus-like particle (VLP)-OVA vaccine treatment to enhance ACT, but no therapeutic benefit was observed during primary B16-OVA tumour growth. Nevertheless, the ACT-mediated antitumour response was able to generate memory responses to both B16-OVA and B16-gp33 tumours. VLP-OVA vaccination following ACT enhances the memory responses to tumours that express a heterogenic population of both B16-OVA and B16-gp33 cells; however, it abolished the memory response to tumours consisting of only gp33-expressing cells. These findings provide important information for designing therapeutic treatments for patients with metastatic disease and cancer relapse to achieve durable cancer remission.

Adoptive cell therapy with CD4+ T helper 1 cells and CD8+ cytotoxic T cells enhances complete rejection of an established tumour, leading to generation of endogenous memory responses to non-targeted tumour epitopes

PubMed Central

Li, Kunyu; Donaldson, Braeden; Young, Vivienne; Ward, Vernon; Jackson, Christopher; Baird, Margaret; Young, Sarah

2017-01-01

The results of adoptive T-cell therapies (ACTs) are very encouraging and show clinical evidence that ACT can provide a cure for patients with metastatic disease. However, various response rates and long-term cancer remission have been observed in different ACT trials. The types of T cells, prior treatment with chemotherapy and co-administration of other immune-target therapies have been found to influence the efficacy of ACT. In this study, we investigate the ability of ACT using CD4+ T helper 1 (Th1) cells and CD8+ cytotoxic T lymphocytes (CTLs) to reject the growth of established B16-ovalbumin (OVA) melanoma. CD8+ CTLs were found to be the main effector T cells that mediated tumour regression. However, low tumour-free survival rates were observed in ACT with CD8+ CTLs only. Co-transferring CD4+ Th1 cells and CD8+ CTLs has been observed to induce a synergistic antitumour response, resulting in complete regression in 80% of the tumour-bearing mice. We also examined a prior Dacarbazine (DTIC) and after virus-like particle (VLP)-OVA vaccine treatment to enhance ACT, but no therapeutic benefit was observed during primary B16-OVA tumour growth. Nevertheless, the ACT-mediated antitumour response was able to generate memory responses to both B16-OVA and B16-gp33 tumours. VLP-OVA vaccination following ACT enhances the memory responses to tumours that express a heterogenic population of both B16-OVA and B16-gp33 cells; however, it abolished the memory response to tumours consisting of only gp33-expressing cells. These findings provide important information for designing therapeutic treatments for patients with metastatic disease and cancer relapse to achieve durable cancer remission. PMID:29114389

Bounded Empathy: Neural Responses to Outgroup Targets’ (Mis)fortunes

PubMed Central

Cikara, Mina; Fiske, Susan T.

2013-01-01

The current study investigates whether mere stereotypes are sufficient to modulate empathic responses to other people’s (mis)fortunes, how these modulations manifest in the brain, and whether affective and neural responses relate to endorsing harm against different outgroup targets. Participants feel least bad when misfortunes befall envied targets, and worst when misfortunes befall pitied targets, as compared to ingroup targets. Participants are also least willing to endorse harming pitied targets, despite pitied targets being outgroup members. However, those participants who exhibit increased activation in functionally-defined insula/MFG when viewing pity targets experience positive events not only report feeling worse about those events, but also more willing to harm pity targets in a tradeoff scenario. Similarly, increased activation in anatomically-defined bilateral anterior insula, in response to positive events, predicts increased willingness to harm envy targets, but decreased willingness to harm ingroup targets, above and beyond self-reported affect in response to the events. Stereotypes’ specific content, and not just outgroup membership, modulates empathic responses and related behavioral consequences including harm. PMID:21671744

Right anterior cerebellum BOLD responses reflect age related changes in Simon task sequential effects.

PubMed

Aisenberg, D; Sapir, A; Close, A; Henik, A; d'Avossa, G

2018-01-31

Participants are slower to report a feature, such as color, when the target appears on the side opposite the instructed response, than when the target appears on the same side. This finding suggests that target location, even when task-irrelevant, interferes with response selection. This effect is magnified in older adults. Lengthening the inter-trial interval, however, suffices to normalize the congruency effect in older adults, by re-establishing young-like sequential effects (Aisenberg et al., 2014). We examined the neurological correlates of age related changes by comparing BOLD signals in young and old participants performing a visual version of the Simon task. Participants reported the color of a peripheral target, by a left or right-hand keypress. Generally, BOLD responses were greater following incongruent than congruent targets. Also, they were delayed and of smaller amplitude in old than young participants. BOLD responses in visual and motor regions were also affected by the congruency of the previous target, suggesting that sequential effects may reflect remapping of stimulus location onto the hand used to make a response. Crucially, young participants showed larger BOLD responses in right anterior cerebellum to incongruent targets, when the previous target was congruent, but smaller BOLD responses to incongruent targets when the previous target was incongruent. Old participants, however, showed larger BOLD responses to congruent than incongruent targets, irrespective of the previous target congruency. We conclude that aging may interfere with the trial by trial updating of the mapping between the task-irrelevant target location and response, which takes place during the inter-trial interval in the cerebellum and underlays sequential effects in a Simon task. Copyright © 2017 Elsevier Ltd. All rights reserved.

Parietal blood oxygenation level-dependent response evoked by covert visual search reflects set-size effect in monkeys.

PubMed

Atabaki, A; Marciniak, K; Dicke, P W; Karnath, H-O; Thier, P

2014-03-01

Distinguishing a target from distractors during visual search is crucial for goal-directed behaviour. The more distractors that are presented with the target, the larger is the subject's error rate. This observation defines the set-size effect in visual search. Neurons in areas related to attention and eye movements, like the lateral intraparietal area (LIP) and frontal eye field (FEF), diminish their firing rates when the number of distractors increases, in line with the behavioural set-size effect. Furthermore, human imaging studies that have tried to delineate cortical areas modulating their blood oxygenation level-dependent (BOLD) response with set size have yielded contradictory results. In order to test whether BOLD imaging of the rhesus monkey cortex yields results consistent with the electrophysiological findings and, moreover, to clarify if additional other cortical regions beyond the two hitherto implicated are involved in this process, we studied monkeys while performing a covert visual search task. When varying the number of distractors in the search task, we observed a monotonic increase in error rates when search time was kept constant as was expected if monkeys resorted to a serial search strategy. Visual search consistently evoked robust BOLD activity in the monkey FEF and a region in the intraparietal sulcus in its lateral and middle part, probably involving area LIP. Whereas the BOLD response in the FEF did not depend on set size, the LIP signal increased in parallel with set size. These results demonstrate the virtue of BOLD imaging in monkeys when trying to delineate cortical areas underlying a cognitive process like visual search. However, they also demonstrate the caution needed when inferring neural activity from BOLD activity. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Practical Challenges of Current Video Rate OCT Elastography: Accounting for Dynamic and Static Tissue Properties

PubMed Central

Brezinski, Mark E

2017-01-01

Optical coherence tomography (OCT) elastography (OCTE) has the potential to be an important diagnostic tool for pathologies including coronary artery disease, osteoarthritis, malignancies, and even dental caries. Many groups have performed OCTE, including our own, using a wide range of approaches. However, we will demonstrate current OCTE approaches are not scalable to real-time, in vivo imaging. As will be discussed, among the most important reasons is current designs focus on the system and not the target. Specifically, tissue dynamic responses are not accounted, with examples being the tissue strain response time, preload variability, and conditioning variability. Tissue dynamic responses, and to a lesser degree static tissue properties, prevent accurate video rate modulus assessments for current embodiments. Accounting for them is the focus of this paper. A top-down approach will be presented to overcome these challenges to real time in vivo tissue characterization. Discussed first is an example clinical scenario where OTCE would be of substantial relevance, the prevention of acute myocardial infarction or heart attacks. Then the principles behind OCTE are examined. Next, constrains on in vivo application of current OCTE are evaluated, focusing on dynamic tissue responses. An example is the tissue strain response, where it takes about 20 msec after a stress is applied to reach plateau. This response delay is not an issue at slow acquisition rates, as most current OCTE approaches are preformed, but it is for video rate OCTE. Since at video rate each frame is only 30 msec, for essentially all current approaches this means the strain for a given stress is changing constantly during the B-scan. Therefore the modulus can’t be accurately assessed. This serious issue is an even greater problem for pulsed techniques as it means the strain/modulus for a given stress (at a location) is unpredictably changing over a B-scan. The paper concludes by introducing a novel video rate approach to overcome these challenges. PMID:29286052

Practical Challenges of Current Video Rate OCT Elastography: Accounting for Dynamic and Static Tissue Properties.

PubMed

Brezinski, Mark E

2014-12-01

Optical coherence tomography (OCT) elastography (OCTE) has the potential to be an important diagnostic tool for pathologies including coronary artery disease, osteoarthritis, malignancies, and even dental caries. Many groups have performed OCTE, including our own, using a wide range of approaches. However, we will demonstrate current OCTE approaches are not scalable to real-time, in vivo imaging. As will be discussed, among the most important reasons is current designs focus on the system and not the target. Specifically, tissue dynamic responses are not accounted, with examples being the tissue strain response time, preload variability, and conditioning variability. Tissue dynamic responses, and to a lesser degree static tissue properties, prevent accurate video rate modulus assessments for current embodiments. Accounting for them is the focus of this paper. A top-down approach will be presented to overcome these challenges to real time in vivo tissue characterization. Discussed first is an example clinical scenario where OTCE would be of substantial relevance, the prevention of acute myocardial infarction or heart attacks. Then the principles behind OCTE are examined. Next, constrains on in vivo application of current OCTE are evaluated, focusing on dynamic tissue responses. An example is the tissue strain response, where it takes about 20 msec after a stress is applied to reach plateau. This response delay is not an issue at slow acquisition rates, as most current OCTE approaches are preformed, but it is for video rate OCTE. Since at video rate each frame is only 30 msec, for essentially all current approaches this means the strain for a given stress is changing constantly during the B-scan. Therefore the modulus can't be accurately assessed. This serious issue is an even greater problem for pulsed techniques as it means the strain/modulus for a given stress (at a location) is unpredictably changing over a B-scan. The paper concludes by introducing a novel video rate approach to overcome these challenges.

Anger responses to psychosocial stress predict heart rate and cortisol stress responses in men but not women.

PubMed

Lupis, Sarah B; Lerman, Michelle; Wolf, Jutta M

2014-11-01

While previous research has suggested that anger and fear responses to stress are linked to distinct sympathetic nervous system (SNS) stress responses, little is known about how these emotions predict hypothalamus-pituitary-adrenal (HPA) axis reactivity. Further, earlier research primarily relied on retrospective self-report of emotion. The current study aimed at addressing both issues in male and female individuals by assessing the role of anger and fear in predicting heart rate and cortisol stress responses using both self-report and facial coding analysis to assess emotion responses. We exposed 32 healthy students (18 female; 19.6±1.7 yr) to an acute psychosocial stress paradigm (TSST) and measured heart rate and salivary cortisol levels throughout the protocol. Anger and fear before and after stress exposure was assessed by self-report, and video recordings of the TSST were assessed by a certified facial coder to determine emotion expression (FACS). Self-reported emotions and emotion expressions did not correlate (all p>.23). Increases in self-reported fear predicted blunted cortisol responses in men (β=0.41, p=.04). Also for men, longer durations of anger expression predicted exaggerated cortisol responses (β=0.67 p=.004), and more anger incidences predicted exaggerated cortisol and heart rate responses (β=0.51, p=.033; β=0.46, p=.066, resp.). Anger and fear did not predict SNS or HPA activity for females (all p>.23). The current differential self-report and facial coding findings support the use of multiple modes of emotion assessment. Particularly, FACS but not self-report revealed a robust anger-stress association that could have important downstream health effects for men. For women, future research may clarify the role of other emotions, such as self-conscious expressions of shame, for physiological stress responses. A better understanding of the emotion-stress link may contribute to behavioral interventions targeting health-promoting ways of responding emotionally to stress. Copyright © 2014 Elsevier Ltd. All rights reserved.

Anger responses to psychosocial stress predict heart rate and cortisol stress responses in men but not women

PubMed Central

Lupis, Sarah B.; Lerman, Michelle; Wolf, Jutta M.

2014-01-01

While previous research has suggested that anger and fear responses to stress are linked to distinct sympathetic nervous system (SNS) stress responses, little is known about how these emotions predict hypothalamus-pituitary-adrenal (HPA) axis reactivity. Further, earlier research primarily relied on retrospective self-report of emotion. The current study aimed at addressing both issues in male and female individuals by assessing the role of anger and fear in predicting heart rate and cortisol stress responses using both self-report and facial coding analysis to assess emotion responses. We exposed 32 healthy students (18 female; 19.6+/−1.7 yrs.) to an acute psychosocial stress paradigm (TSST) and measured heart rate and salivary cortisol levels throughout the protocol. Anger and fear before and after stress exposure was assessed by self-report, and video recordings of the TSST were assessed by a certified facial coder to determine emotion expression (FACS). Self-reported emotions and emotion expressions did not correlate (all p > .23). Increases in self-reported fear predicted blunted cortisol responses in men (β = 0.41, p = .04). Also for men, longer durations of anger expression predicted exaggerated cortisol responses (β = 0.67 p = .004), and more anger incidences predicted exaggerated cortisol and heart rate responses (β = 0.51, p = .033; β = 0.46, p = .066, resp.). Anger and fear did not predict SNS or HPA activity for females (all p > .23). The current differential self-report and facial coding findings support the use of multiple modes of emotion assessment. Particularly, FACS but not self-report revealed a robust anger-stress association that could have important downstream health effects for men. For women, future research may clarify the role of other emotions, such as self-conscious expressions of shame, for physiological stress responses. A better understanding of the emotion-stress link may contribute to behavioral interventions targeting health-promoting ways of responding emotionally to stress. PMID:25064831

Laser immunotherapy for metastatic pancreatic cancer (Conference Presentation)

NASA Astrophysics Data System (ADS)

Zhou, Feifan

2017-02-01

Pancreatic cancer is an extremely malignant disease with high mortality rate. Currently there is no effective therapeutic strategy for highly metastatic pancreatic cancers. Laser immunotherapy (LIT) is a combination therapeutic approach of targeted phototherapy and immunotherapy, which could destroy treated primary tumors with elimination of untreated metastases. LIT affords a remarkable efficacy in suppressing tumor growth in pancreatic tumors in mice, and results in complete tumor regression in many cases. LIT could synergize targeted phototherapy and immunological effects of immunoadjuvant, which represent a promising treatment modality to induce systemic antitumor response through a local intervention, paving the way for the treatment of highly metastatic pancreatic cancers.

Bayesian performance metrics of binary sensors in homeland security applications

NASA Astrophysics Data System (ADS)

Jannson, Tomasz P.; Forrester, Thomas C.

2008-04-01

Bayesian performance metrics, based on such parameters, as: prior probability, probability of detection (or, accuracy), false alarm rate, and positive predictive value, characterizes the performance of binary sensors; i.e., sensors that have only binary response: true target/false target. Such binary sensors, very common in Homeland Security, produce an alarm that can be true, or false. They include: X-ray airport inspection, IED inspections, product quality control, cancer medical diagnosis, part of ATR, and many others. In this paper, we analyze direct and inverse conditional probabilities in the context of Bayesian inference and binary sensors, using X-ray luggage inspection statistical results as a guideline.

MicroRNA-26b Enhances the Radiosensitivity of Hepatocellular Carcinoma Cells by Targeting EphA2.

PubMed

Jin, Qiao; Li, Xiang Jun; Cao, Pei Guo

2016-02-01

Sensitizing hepatocellular carcinoma (HCC) cells to irradiation is important to achieve satisfactory therapeutic effect with low-dose radiotherapy. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) is a member of the Eph receptor family that constitutes the largest family of tyrosine kinase receptors. EphA2 overexpression is one of the poor prognostic factors in many progressive cancers. Importantly, EphA2 is a potential target of microRNA-26b (miR-26b), and miR-26b expression is down-regulated in several types of cancer. In this study, we measured the expression levels of miR-26b and EphA2 protein in seven human HCC cell lines by quantitative PCR and western blot analysis, respectively. Overall, lower miR-26b expression levels tended to be associated with higher EphA2 levels in HCC cell lines. Among the cell lines examined, 97H HCC cells expressed the lowest level of miR-26b and highest level of EphA2 protein. Thus, using 97H HCC cells, EphA2 mRNA was verified as the target of miR-26b by the luciferase reporter assay. Accordingly, a synthetic miR-26b, miR-26b mimics, was used to mimic the function of endogenous miR-26b. In 97H HCC cells transfected with miR-26b mimics or short-hairpin RNA targeting EphA2 mRNA, expression of EphA2 protein was reduced, which was associated with significantly lower proliferation rate and invasion ability and with higher apoptosis rate in response to low-dose irradiation, compared to control cells. In contrast, 97H HCC cells over-expressing EphA2 showed higher proliferation rate and invasion ability and lower apoptosis rate upon irradiation. These data suggest that miR-26b enhances the radiosensitivity of 97H HCC cells by targeting EphA2 protein.

Enhanced negative emotion and alcohol craving, and altered physiological responses following stress and cue exposure in alcohol dependent individuals.

PubMed

Sinha, Rajita; Fox, Helen C; Hong, Kwangik A; Bergquist, Keri; Bhagwagar, Zubin; Siedlarz, Kristen M

2009-04-01

Chronic alcohol abuse is associated with changes in stress and reward pathways that could alter vulnerability to emotional stress and alcohol craving. This study examines whether chronic alcohol abuse is associated with altered stress and alcohol craving responses. Treatment-engaged, 28-day abstinent alcohol-dependent individuals (ADs; 6F/22M), and social drinkers (SDs; 10F/18M) were exposed to a brief guided imagery of a personalized stressful, alcohol-related and neutral-relaxing situation, one imagery condition per session, presented in random order across 3 days. Alcohol craving, anxiety and emotion ratings, behavioral distress responses, heart rate, blood pressure, and salivary cortisol measures were assessed. Alcohol patients showed significantly elevated basal heart rate and salivary cortisol levels. Stress and alcohol cue exposure each produced a significantly enhanced and persistent craving state in alcohol patients that was marked by increased anxiety, negative emotion, systolic blood pressure responses, and, in the case of alcohol cue, behavioral distress responses, as compared to SDs. Blunted stress-induced cortisol responses were observed in the AD compared to the SD group. These data are the first to document that stress and cue exposure induce a persistent negative emotion-related alcohol craving state in abstinent alcoholics accompanied by dysregulated HPA and physiological arousal responses. As laboratory models of stress and negative mood-induced alcohol craving are predictive of relapse outcomes, one implication of the current data is that treatments targeting decreases in stress and alcohol cue-induced craving and regulation of stress responses could be of benefit in improving alcohol relapse outcomes.

Role of expected reward in frontal eye field during natural scene search

PubMed Central

Lawlor, Patrick N.; Ramkumar, Pavan; Kording, Konrad P.; Segraves, Mark A.

2016-01-01

When a saccade is expected to result in a reward, both neural activity in oculomotor areas and the saccade itself (e.g., its vigor and latency) are altered (compared with when no reward is expected). As such, it is unclear whether the correlations of neural activity with reward indicate a representation of reward beyond a movement representation; the modulated neural activity may simply represent the differences in motor output due to expected reward. Here, to distinguish between these possibilities, we trained monkeys to perform a natural scene search task while we recorded from the frontal eye field (FEF). Indeed, when reward was expected (i.e., saccades to the target), FEF neurons showed enhanced responses. Moreover, when monkeys accidentally made eye movements to the target, firing rates were lower than when they purposively moved to the target. Thus, neurons were modulated by expected reward rather than simply the presence of the target. We then fit a model that simultaneously included components related to expected reward and saccade parameters. While expected reward led to shorter latency and higher velocity saccades, these behavioral changes could not fully explain the increased FEF firing rates. Thus, FEF neurons appear to encode motivational factors such as reward expectation, above and beyond the kinematic and behavioral consequences of imminent reward. PMID:27169506

Targeted Proteomics Predicts a Sustained Complete-Response after Transarterial Chemoembolization and Clinical Outcomes in Patients with Hepatocellular Carcinoma: A Prospective Cohort Study.

PubMed

Yu, Su Jong; Kim, Hyunsoo; Min, Hophil; Sohn, Areum; Cho, Young Youn; Yoo, Jeong-Ju; Lee, Dong Hyeon; Cho, Eun Ju; Lee, Jeong-Hoon; Gim, Jungsoo; Park, Taesung; Kim, Yoon Jun; Kim, Chung Yong; Yoon, Jung-Hwan; Kim, Youngsoo

2017-03-03

This study was aimed to identify blood-based biomarkers to predict a sustained complete response (CR) after transarterial chemoembolization (TACE) using targeted proteomics. Consecutive patients with HCC who had undergone TACE were prospectively enrolled (training (n = 100) and validation set (n = 80)). Serum samples were obtained before and 6 months after TACE. Treatment responses were evaluated using the modified Response Evaluation Criteria in Solid Tumors (mRECIST). In the training set, the MRM-MS assay identified five marker candidate proteins (LRG1, APCS, BCHE, C7, and FCN3). When this five-marker panel was combined with the best-performing clinical variables (tumor number, baseline PIVKA, and baseline AFP), the resulting ensemble model had the highest area under the receiver operating curve (AUROC) value in predicting a sustained CR after TACE in the training and validation sets (0.881 and 0.813, respectively). Furthermore, the ensemble model was an independent predictor of rapid progression (hazard ratio (HR), 2.889; 95% confidence interval (CI), 1.612-5.178; P value < 0.001) and overall an unfavorable survival rate (HR, 1.985; 95% CI, 1.024-3.848; P value = 0.042) in the entire population by multivariate analysis. Targeted proteomics-based ensemble model can predict clinical outcomes after TACE. Therefore, this model can aid in determining the best candidates for TACE and the need for adjuvant therapy.

The pupillary response discriminates between subjective and objective familiarity and novelty.

PubMed

Kafkas, Alexandros; Montaldi, Daniela

2015-10-01

The pupil response discriminates between old and new stimuli, with old stimuli characterized by larger pupil dilation patterns than new stimuli. We sought to explore the cause of the pupil old/new effect and discount the effect of targetness, effort, recollection retrieval, and complexity of the recognition decision. Two experiments are reported in which the pupil response and the eye fixation patterns were measured, while participants identified novel and familiar object stimuli, in two separate tasks, emphasizing either novelty or familiarity detection. In Experiment 1, familiarity and novelty decisions were taken using a rating scale, while in Experiment 2 a simpler yes/no decision was used. In both experiments, we found that detection of target familiar stimuli resulted in greater pupil dilation than the detection of target novel stimuli, while the duration of the first fixation discriminated between familiar and novel stimuli as early as within 320 ms after stimulus onset. Importantly, the pupil response distinguished between the objective (during an earlier temporal component) and the subjective (during a later temporal component) status of the stimulus for misses and false alarms. In the light of previous findings, we suggest that the pupil and fixation old/new effects reflect the distinct neural and cognitive mechanisms involved in the familiarity and novelty decisions. The findings also have important implications for the use of pupil dilation and eye movement patterns to explore explicit and implicit memory processes. © 2015 The Authors. Psychophysiology published by Wiley Periodicals, Inc. on behalf of Society for Psychophysiological Research.

Dissecting patterns of preparatory activity in the frontal eye fields during pursuit target selection.

PubMed

Raghavan, Ramanujan T; Joshua, Mati

2017-10-01

We investigated the composition of preparatory activity of frontal eye field (FEF) neurons in monkeys performing a pursuit target selection task. In response to the orthogonal motion of a large and a small reward target, monkeys initiated pursuit biased toward the direction of large reward target motion. FEF neurons exhibited robust preparatory activity preceding movement initiation in this task. Preparatory activity consisted of two components, ramping activity that was constant across target selection conditions, and a flat offset in firing rates that signaled the target selection condition. Ramping activity accounted for 50% of the variance in the preparatory activity and was linked most strongly, on a trial-by-trial basis, to pursuit eye movement latency rather than to its direction or gain. The offset in firing rates that discriminated target selection conditions accounted for 25% of the variance in the preparatory activity and was commensurate with a winner-take-all representation, signaling the direction of large reward target motion rather than a representation that matched the parameters of the upcoming movement. These offer new insights into the role that the frontal eye fields play in target selection and pursuit control. They show that preparatory activity in the FEF signals more strongly when to move rather than where or how to move and suggest that structures outside the FEF augment its contributions to the target selection process. NEW & NOTEWORTHY We used the smooth eye movement pursuit system to link between patterns of preparatory activity in the frontal eye fields and movement during a target selection task. The dominant pattern was a ramping signal that did not discriminate between selection conditions and was linked, on trial-by-trial basis, to movement latency. A weaker pattern was composed of a constant signal that discriminated between selection conditions but was only weakly linked to the movement parameters. Copyright © 2017 the American Physiological Society.

The timing of sequences of saccades in visual search.

PubMed Central

Van Loon, E M; Hooge, I Th C; Van den Berg, A V

2002-01-01

According to the LATER model (linear approach to thresholds with ergodic rate), the latency of a single saccade in response to target appearance can be understood as a decision process, which is subject to (i) variations in the rate of (visual) information processing; and (ii) the threshold for the decision. We tested whether the LATER model can also be applied to the sequences of saccades in a multiple fixation search, during which latencies of second and subsequent saccades are typically shorter than that of the initial saccade. We found that the distributions of the reciprocal latencies for later saccades, unlike those of the first saccade, are highly asymmetrical, much like a gamma distribution. This suggests that the normal distribution of the rate r, which the LATER model assumes, is not appropriate to describe the rate distributions of subsequent saccades in a scanning sequence. By contrast, the gamma distribution is also appropriate to describe the distribution of reciprocal latencies for the first saccade. The change of the gamma distribution parameters as a function of the ordinal number of the saccade suggests a lowering of the threshold for second and later saccades, as well as a reduction in the number of target elements analysed. PMID:12184827

7 CFR 761.208 - Target participation rates for socially disadvantaged groups.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 7 Agriculture 7 2011-01-01 2011-01-01 false Target participation rates for socially disadvantaged... Farm Loan Programs Funds to State Offices § 761.208 Target participation rates for socially disadvantaged groups. (a) General. (1) The Agency establishes target participation rates for providing FO, CL...

Exposure-Response Modeling to Characterize the Relationship Between Ixekizumab Serum Drug Concentrations and Efficacy Responses at Week 12 in Patients With Moderate to Severe Plaque Psoriasis.

PubMed

Chigutsa, Emmanuel; de Mendizabal, Nieves Velez; Chua, Laiyi; Heathman, Michael; Friedrich, Stuart; Jackson, Kimberley; Reich, Kristian

2018-06-07

Ixekizumab, a high-affinity monoclonal antibody, selectively targets interleukin-17A and has been shown to be efficacious in the treatment of moderate to severe psoriasis. The objective was to describe the relationship between ixekizumab concentrations and efficacy response (static Physician Global Assessment [sPGA] and the Psoriasis Activity and Severity Index [PASI) scores] after 12 weeks of ixekizumab treatment in psoriasis patients from 3 phase 3 studies. Data from 2888 psoriasis patients randomized to receive placebo or 80 mg ixekizumab every 2 weeks or every 4 weeks were analyzed. Separate logistic regression models describing the relationship between ixekizumab concentrations and sPGA or PASI scores at week 12 were used to determine the probability of patients achieving a response and to investigate the impact of various patient factors other than drug concentrations on response rates. Both dosing regimens were efficacious, with higher rates of response achieved with the higher range of observed ixekizumab concentrations after every-2-week dosing. Although higher bodyweight, palmoplantar involvement, lower baseline disease state, or high baseline C-reactive protein were associated with slightly lower response rates, the magnitude of effect of these factors on sPGA(0,1) response was small, with all subgroups able to achieve high levels of response. Other factors tested had no effect including age, sex, and antidrug antibody status. Logistic regression modeling of ixekizumab concentration and efficacy data accurately identified the proportion of responders using sPGA or PASI end points. The higher concentration ranges achieved with 80 mg every 2 weeks versus every 4 weeks were associated with higher response levels. © 2018, The American College of Clinical Pharmacology.

Testing the disgust conditioning theory of food-avoidance in adolescents with recent onset anorexia nervosa.

PubMed

Hildebrandt, Tom; Grotzinger, Andrew; Reddan, Marianne; Greif, Rebecca; Levy, Ifat; Goodman, Wayne; Schiller, Daniela

2015-08-01

Anorexia nervosa is characterized by chronic food avoidance that is resistant to change. Disgust conditioning offers one potential unexplored mechanism for explaining this behavioral disturbance because of its specific role in facilitating food avoidance in adaptive situations. A food based reversal learning paradigm was used to study response flexibility in 14 adolescent females with restricting subtype anorexia nervosa (AN-R) and 15 healthy control (HC) participants. Expectancy ratings were coded as a behavioral measure of flexibility and electromyography recordings from the levator labii (disgust), zygomaticus major (pleasure), and corrugator (general negative affect) provided psychophysiological measures of emotion. Response inflexibility was higher for participants with AN-R, as evidenced by lower extinction and updated expectancy ratings during reversal. EMG responses to food stimuli were predictive of both extinction and new learning. Among AN-R patients, disgust specific responses to food were associated with impaired extinction, as were elevated pleasure responses to the cued absence of food. Disgust conditioning appears to influence food learning in acutely ill patients with AN-R and may be maintained by counter-regulatory acquisition of a pleasure response to food avoidance and an aversive response to food presence. Developing strategies to target disgust may improve existing interventions for patients with AN. Copyright © 2015 Elsevier Ltd. All rights reserved.

Brentuximab vedotin in refractory CD30+ lymphomas: a bridge to allogeneic transplantation in approximately one quarter of patients treated on a Named Patient Programme at a single UK center

PubMed Central

Gibb, Adam; Jones, Craig; Bloor, Adrian; Kulkarni, Samar; Illidge, Tim; Linton, Kim; Radford, John

2013-01-01

The CD30-targeted agent brentuximab vedotin has shown impressive activity in relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma in phase II studies. We have treated 24 patients with relapsed/refratory disease enrolled onto a Named Patient Programme during 2010-11 at a single UK center. Overall response rate across all histologies was 67% (Hodgkin 72%; anaplastic large cell 60%), complete response rate 25% (Hodgkin 17%; anaplastic large cell 60%), median progression-free survival 5.1 months, and toxicity mild to moderate in the majority of cases. Six patients proceeded to allogeneic transplantation and one patient awaits this procedure. These results are similar to phase II data and show that brentuximab vedotin provides a bridge to allogeneic transplantation in approximately one quarter of patients refractory to conventional salvage therapies. Best response was seen after four doses, so consideration of allogeneic transplantation should be made early and scheduled following the first assessment indicating response. PMID:23065511

Identifying factors for optimal development of health-related websites: a delphi study among experts and potential future users.

PubMed

Schneider, Francine; van Osch, Liesbeth; de Vries, Hein

2012-02-14

The Internet has become a popular medium for offering tailored and targeted health promotion programs to the general public. However, suboptimal levels of program use in the target population limit the public health impact of these programs. Optimizing program development is considered as one of the main processes to increase usage rates. To distinguish factors potentially related to optimal development of health-related websites by involving both experts and potential users. By considering and incorporating the opinions of experts and potential users in the development process, involvement in the program is expected to increase, consequently resulting in increased appreciation, lower levels of attrition, and higher levels of sustained use. We conducted a systematic three-round Delphi study through the Internet. Both national and international experts (from the fields of health promotion, health psychology, e-communication, and technical Web design) and potential users were invited via email to participate. During this study an extensive list of factors potentially related to optimal development of health-related websites was identified, by focusing on factors related to layout, general and risk information provision, questionnaire use, additional services, and ease of use. Furthermore, we assessed the extent to which experts and potential users agreed on the importance of these factors. Differences as well as similarities among experts and potentials users were deduced. In total, 20 of 62 contacted experts participated in the first round (32% response rate); 60 of 200 contacted experts (30% response rate) and 210 potential users (95% response rate) completed the second-round questionnaire, and 32 of 60 contacted experts completed the third round (53% response rate). Results revealed important factors consented upon by experts and potential users (eg, ease of use, clear structure, and detailed health information provision), as well as differences regarding important factors consented upon by experts (eg, visual aids, self-monitoring tool, and iterative health feedback) or by potential users only (eg, bread crumb navigation and prevention of receiving spam). This study is an important first step in determining the agreed-upon factors that should be taken into account when developing online health promotion programs. The public health impact of these programs will be improved by optimizing the development process in line with these factors.

Unconscious Affective Responses to Food

PubMed Central

Sato, Wataru; Sawada, Reiko; Kubota, Yasutaka; Toichi, Motomi; Fushiki, Tohru

2016-01-01

Affective or hedonic responses to food are crucial for humans, both advantageously (e.g., enhancing survival) and disadvantageously (e.g., promoting overeating and lifestyle-related disease). Although previous psychological studies have reported evidence of unconscious cognitive and behavioral processing related to food, it remains unknown whether affective reactions to food can be triggered unconsciously and its relationship with daily eating behaviors. We investigated these issues by using the subliminal affective priming paradigm. Photographs of food or corresponding mosaic images were presented in the peripheral visual field for 33 ms. Target photos of faces with emotionally neutral expressions were then presented, and participants rated their preferences for the faces. Eating behaviors were also assessed using questionnaires. The food images, relative to the mosaics, increased participants’ preference for subsequent target faces. Furthermore, the difference in the preference induced by food versus mosaic images was positively correlated with the tendency to engage in external eating. These results suggest that unconscious affective reactions are elicited by the sight of food and that these responses contribute to daily eating behaviors related to overeating. PMID:27501443

Emerging combination therapies for metastatic colorectal cancer – impact of trifluridine/tipiracil

PubMed Central

Puthiamadathil, Jeevan M; Weinberg, Benjamin A

2017-01-01

Patients with metastatic colorectal cancer (mCRC) are surviving longer now than ever before, but mortality rates are still high and more effective therapies are clearly needed. For patients with disease that is refractory to fluoropyrimidines, oxaliplatin, irinotecan, and biologic agents targeting the vascular endothelial growth factor and epidermal growth factor receptor pathways, novel treatment options trifluridine/tipiracil (TAS-102) and regorafenib can be effective disease stabilizers. However, objective clinical responses are rare and toxicities are manageable but common. In order to tackle poor clinical responses to TAS-102, there is an ongoing effort to effectively combine this drug with other agents, particularly those targeting angiogenesis. Certain subpopulations appear to benefit more than others from TAS-102; those that benefit often have underlying genetic defects in DNA repair pathways and/or develop neutropenia. In this review, we focus on the role of TAS-102 in the treatment of mCRC, including its use in combination with other agents, potential predictive biomarkers of response to TAS-102, and possible future directions. PMID:29056855

Depression and treatment response: dynamic interplay of signaling pathways and altered neural processes

PubMed Central

Duric, Vanja

2014-01-01

Since the 1960s, when the first tricyclic and monoamine oxidase inhibitor antidepressant drugs were introduced, most of the ensuing agents were designed to target similar brain pathways that elevate serotonin and/or norepinephrine signaling. Fifty years later, the main goal of the current depression research is to develop faster-acting, more effective therapeutic agents with fewer side effects, as currently available antidepressants are plagued by delayed therapeutic onset and low response rates. Clinical and basic science research studies have made significant progress towards deciphering the pathophysiological events within the brain involved in development, maintenance, and treatment of major depressive disorder. Imaging and postmortem brain studies in depressed human subjects, in combination with animal behavioral models of depression, have identified a number of different cellular events, intracellular signaling pathways, proteins, and target genes that are modulated by stress and are potentially vital mediators of antidepressant action. In this review, we focus on several neural mechanisms, primarily within the hippocampus and prefrontal cortex, which have recently been implicated in depression and treatment response. PMID:22585060

The conditioning and extinction of fear in youths: What’s sex got to do with it?

PubMed Central

Chauret, Mélissa; La Buissonnière-Ariza, Valérie; Tremblay, Vickie Lamoureux; Suffren, Sabrina; Servonnet, Alice; Pine, Daniel S.; Maheu, Françoise S.

2015-01-01

Adult work shows differences in emotional processing influenced by sexes of both the viewer and expresser of facial expressions. We investigated this in 120 healthy youths (57 boys; 10–17 years old) randomly assigned to fear conditioning and extinction tasks using either neutral male or female faces as the conditioned threat and safety cues, and a fearful face paired with a shrieking scream as the unconditioned stimulus. Fear ratings and skin conductance responses (SCRs) were assessed. Male faces triggered increased fear ratings in all participants during conditioning and extinction. Greater differential SCRs were observed in boys viewing male faces and in girls viewing female faces during conditioning. During extinction, differential SCR findings remained significant in boys viewing male faces. Our findings demonstrate how sex of participant and sex of target interact to shape fear responses in youths, and how the type of measure may lead to distinct profiles of fear responses. PMID:24929048

[New treatments for hepatitis C, which targets, what timeline?].

PubMed

Goossens, Nicolas; Negro, Francesco

2011-09-07

The hepatitis C virus (HCV) is a global major health burden, its response to current treatment is unfortunately inadequate, in particular for genotype 1. Two new direct acting antivirals, that inhibit NS3/4A viral protease, will soon be available on the Swiss market: telaprevir and boceprevir. These substances increase the rate of sustained viral response, in HCV genotype 1 infected patients, when coadministered with pegylated interferon and ribavirin. However, these new molecules may lead to serious adverse effects and drug interactions with which the specialist and the primary care physician must be familiar.

Experimental and numerical analysis of the dynamic behaviour in tension of an armour steel for applications in defence industry

NASA Astrophysics Data System (ADS)

Cadoni, Ezio; Dotta, Matteo; Forni, Daniele; Riganti, Gianmario; Kaufmann, Hanspeter

2015-09-01

The dynamic behaviour of armour steel in tension was investigated over a wide range of strain-rates on round specimens. The experiments were carried out by means of a Split Hopkinson Tensile Bar device and by a Hydro Pneumatic Machine. The target strain rate were set at the following six levels: 10-3, 5, 25, 100, 500 and 1000 s-1. Two material models were calibrated and used to replicate the experiments and to simulate blasting event on steel plate. Finally, the two responses are compared.

A Needs Assessment for a Longitudinal Emergency Medicine Intern Curriculum.

PubMed

Shappell, Eric; Ahn, James

2017-01-01

A key task of emergency medicine (EM) training programs is to develop a consistent knowledge of core content in recruits with heterogeneous training backgrounds. The traditional model for delivering core content is lecture-based weekly conference; however, a growing body of literature finds this format less effective and less appealing than alternatives. We sought to address this challenge by conducting a needs assessment for a longitudinal intern curriculum for millennial learners. We surveyed all residents from the six EM programs in the greater Chicago area regarding the concept, format, and scope of a longitudinal intern curriculum. We received 153 responses from the 300 residents surveyed (51% response rate). The majority of respondents (80%; 82% of interns) agreed or strongly agreed that a dedicated intern curriculum would add value to residency education. The most positively rated teaching method was simulation sessions (91% positive responses), followed by dedicated weekly conference time (75% positive responses) and dedicated asynchronous resources (71% positive responses). Less than half of respondents (47%; 26% of interns) supported use of textbook readings in the curriculum. There is strong learner interest in a longitudinal intern curriculum. This needs assessment can serve to inform the development of a universal intern curriculum targeting the millennial generation.

Inhibitors of Cytotoxic T Lymphocyte Antigen 4 and Programmed Death 1/Programmed Death 1 Ligand for Metastatic Melanoma, Dual Versus Monotherapy-Summary of Advances and Future Directions for Studying These Drugs.

PubMed

Loo, Kimberly; Daud, Adil I

Immense progress in the field of cancer immunotherapy has garnered several novel and successful treatments for metastatic melanoma. Beginning with therapies targeting cytotoxic T lymphocyte antigen 4 (CTLA-4), objective response rates, overall survival, and long-term survival were significantly increased when compared with glycoprotein 100 vaccine therapies. Expanding the breadth of therapies aimed to "release the breaks" on the active immune system, anti-programmed death 1 (PD-1) and anti-programmed death 1 ligand (PD-L1) therapies further improved overall survival, progression-free survival, and objective tumor response while exhibiting more favorable safety profiles compared with ipilimumab and to chemotherapy agents. Given the power of these agents as monotherapies, a combination approach sought to combine the anti-CTLA agent ipilimumab and anti-PD-1 agent, nivolumab, to form a double-pronged attack and target several mechanisms within the active immune system. Given the promise in elevated response rates and progression-free survival, the future appears promising along the immunotherapy front. Continuing the push for progress, biomarkers to uncover the profile of responders to the various therapies will become vital in the treatment of metastatic melanoma patients. Here, we highlight the advances of CTLA-4 and PD-1/PD-L1 inhibitors in the metastatic melanoma setting and discuss future directions for uncovering the full potential of these therapies.

NCI–RTOG Translational Program Strategic Guidelines for the Early-Stage Development of Radiosensitizers

PubMed Central

2013-01-01

The addition of chemotherapeutic agents to ionizing radiation has improved survival in many malignancies. Cure rates may be further improved by adding novel targeted agents to current radiotherapy or radiochemotherapy regimens. Despite promising laboratory data, progress in the clinical development of new drugs with radiation has been limited. To define and address the problems involved, a collaborative effort between individuals within the translational research program of the Radiation Oncology Therapy Group and the National Cancer Institute was established. We discerned challenges to drug development with radiation including: 1) the limited relevance of preclinical work, 2) the pharmaceutical industry’s diminished interest, and 3) the important individual skills and institutional commitments required to ensure a successful program. The differences between early-phase trial designs with and without radiation are noted as substantial. The traditional endpoints for early-phase clinical trials—acute toxicity and maximum-tolerated dose—are of limited value when combining targeted agents with radiation. Furthermore, response rate is not a useful surrogate marker of activity in radiation combination trials.Consequently, a risk-stratified model for drug-dose escalation with radiation is proposed, based upon the known and estimated adverse effects. The guidelines discuss new clinical trial designs, such as the time-to-event continual reassessment method design for phase I trials, randomized phase II “screening” trials, and the use of surrogate endpoints, such as pathological response. It is hoped that by providing a clear pathway, this article will accelerate the rate of drug development with radiation. PMID:23231975

A Feedback Model of Attention Explains the Diverse Effects of Attention on Neural Firing Rates and Receptive Field Structure.

PubMed

Miconi, Thomas; VanRullen, Rufin

2016-02-01

Visual attention has many effects on neural responses, producing complex changes in firing rates, as well as modifying the structure and size of receptive fields, both in topological and feature space. Several existing models of attention suggest that these effects arise from selective modulation of neural inputs. However, anatomical and physiological observations suggest that attentional modulation targets higher levels of the visual system (such as V4 or MT) rather than input areas (such as V1). Here we propose a simple mechanism that explains how a top-down attentional modulation, falling on higher visual areas, can produce the observed effects of attention on neural responses. Our model requires only the existence of modulatory feedback connections between areas, and short-range lateral inhibition within each area. Feedback connections redistribute the top-down modulation to lower areas, which in turn alters the inputs of other higher-area cells, including those that did not receive the initial modulation. This produces firing rate modulations and receptive field shifts. Simultaneously, short-range lateral inhibition between neighboring cells produce competitive effects that are automatically scaled to receptive field size in any given area. Our model reproduces the observed attentional effects on response rates (response gain, input gain, biased competition automatically scaled to receptive field size) and receptive field structure (shifts and resizing of receptive fields both spatially and in complex feature space), without modifying model parameters. Our model also makes the novel prediction that attentional effects on response curves should shift from response gain to contrast gain as the spatial focus of attention drifts away from the studied cell.

Single toxin dose-response models revisited

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

Demidenko, Eugene, E-mail: eugened@dartmouth.edu

The goal of this paper is to offer a rigorous analysis of the sigmoid shape single toxin dose-response relationship. The toxin efficacy function is introduced and four special points, including maximum toxin efficacy and inflection points, on the dose-response curve are defined. The special points define three phases of the toxin effect on mortality: (1) toxin concentrations smaller than the first inflection point or (2) larger then the second inflection point imply low mortality rate, and (3) concentrations between the first and the second inflection points imply high mortality rate. Probabilistic interpretation and mathematical analysis for each of the fourmore » models, Hill, logit, probit, and Weibull is provided. Two general model extensions are introduced: (1) the multi-target hit model that accounts for the existence of several vital receptors affected by the toxin, and (2) model with a nonzero mortality at zero concentration to account for natural mortality. Special attention is given to statistical estimation in the framework of the generalized linear model with the binomial dependent variable as the mortality count in each experiment, contrary to the widespread nonlinear regression treating the mortality rate as continuous variable. The models are illustrated using standard EPA Daphnia acute (48 h) toxicity tests with mortality as a function of NiCl or CuSO{sub 4} toxin. - Highlights: • The paper offers a rigorous study of a sigmoid dose-response relationship. • The concentration with highest mortality rate is rigorously defined. • A table with four special points for five morality curves is presented. • Two new sigmoid dose-response models have been introduced. • The generalized linear model is advocated for estimation of sigmoid dose-response relationship.« less

Impact of vitamin D3 on cardiovascular responses to glucocorticoid excess.

PubMed

Ahmed, Mona A

2013-06-01

Although the cardiovascular system is not a classical target for 1,25-dihydroxyvitamin D3, both cardiac myocytes and vascular smooth muscle cells respond to this hormone. The present study aimed to elucidate the effect of active vitamin D3 on cardiovascular functions in rats exposed to glucocorticoid excess. Adult male Wistar rats were allocated into three groups: control group, dexamethasone (Dex)-treated group receiving Dex (200 μg/kg) subcutaneously for 12 days, and vitamin D3-Dex-treated group receiving 1,25-(OH)2D3 (100 ng/kg) and Dex (200 μg/kg) subcutaneously for 12 days. Rats were subjected to measurement of systolic (SBP), diastolic (DBP), and mean arterial (MAP) blood pressures and heart rate. Rate pressure product (RPP) was calculated. Rats' isolated hearts were perfused in Langendorff preparation and studied for basal activities (heart rate, peaked developed tension, time to peak tension, half relaxation time, and myocardial flow rate) and their responses to isoproterenol infusion. Blood samples were collected for determination of plasma level of nitrite, nitric oxide surrogate. Dex-treated group showed significant increase in SBP, DBP, MAP, and RPP, as well as cardiac hypertrophy and enhancement of basal cardiac performance evidenced by increased heart rate, rapid and increased contractility, and accelerated lusitropy, together with impaired contractile and myocardial flow rate responsiveness to beta-adrenergic activation and depressed inotropic and coronary vascular reserves. Such alterations were accompanied by low plasma nitrite. These changes were markedly improved by vitamin D3 treatment. In conclusion, vitamin D3 is an efficacious modulator of the deleterious cardiovascular responses induced by glucocorticoid excess, probably via accentuation of nitric oxide.

Advances in identification and validation of protein targets of natural products without chemical modification.

PubMed

Chang, J; Kim, Y; Kwon, H J

2016-05-04

Covering: up to February 2016Identification of the target proteins of natural products is pivotal to understanding the mechanisms of action to develop natural products for use as molecular probes and potential therapeutic drugs. Affinity chromatography of immobilized natural products has been conventionally used to identify target proteins, and has yielded good results. However, this method has limitations, in that labeling or tagging for immobilization and affinity purification often result in reduced or altered activity of the natural product. New strategies have recently been developed and applied to identify the target proteins of natural products and synthetic small molecules without chemical modification of the natural product. These direct and indirect methods for target identification of label-free natural products include drug affinity responsive target stability (DARTS), stability of proteins from rates of oxidation (SPROX), cellular thermal shift assay (CETSA), thermal proteome profiling (TPP), and bioinformatics-based analysis of connectivity. This review focuses on and reports case studies of the latest advances in target protein identification methods for label-free natural products. The integration of newly developed technologies will provide new insights and highlight the value of natural products for use as biological probes and new drug candidates.

Using Roadside Billboard Posters to Increase Admission Rates to Problem Gambling Services: Reflections on Failure.

PubMed

Calderwood, Kimberly A; Wellington, William J

2015-07-01

Based on the stimulus-response model of advertising, this study sought to increase admission rates to a local problem gambling service (PGS) in Windsor, Ontario, Canada, by adding a series of locally based 10 foot by 20 foot roadside billboard posters to PGS's existing communications tools for a 24-week period. Using proof of performance reports, a pre-post survey of new callers to PGS, a website visit counter, and a media awareness survey, the findings showed that at least some individuals were influenced by billboard exposure, but admission rates continued to decline during the billboard campaign period. While one possible explanation for the communications failure was that the whole PGS communications campaign was below the minimal threshold for communications perception, another possible explanation is that the stimulus-response model of advertising used may not have been appropriate for such advertising that targets behavior change. Reflections on using an information-processing model instead of a stimulus-response model, and considerations of a two-step flow of communication, are provided. Recommendations are made regarding matching communications messages to stages of behavior change, use of online promotion, and strategies for future research. © 2015 Society for Public Health Education.

The Effects of Spatial Endogenous Pre-cueing across Eccentricities

PubMed Central

Feng, Jing; Spence, Ian

2017-01-01

Frequently, we use expectations about likely locations of a target to guide the allocation of our attention. Despite the importance of this attentional process in everyday tasks, examination of pre-cueing effects on attention, particularly endogenous pre-cueing effects, has been relatively little explored outside an eccentricity of 20°. Given the visual field has functional subdivisions that attentional processes can differ significantly among the foveal, perifoveal, and more peripheral areas, how endogenous pre-cues that carry spatial information of targets influence our allocation of attention across a large visual field (especially in the more peripheral areas) remains unclear. We present two experiments examining how the expectation of the location of the target shapes the distribution of attention across eccentricities in the visual field. We measured participants’ ability to pick out a target among distractors in the visual field after the presentation of a highly valid cue indicating the size of the area in which the target was likely to occur, or the likely direction of the target (left or right side of the display). Our first experiment showed that participants had a higher target detection rate with faster responses, particularly at eccentricities of 20° and 30°. There was also a marginal advantage of pre-cueing effects when trials of the same size cue were blocked compared to when trials were mixed. Experiment 2 demonstrated a higher target detection rate when the target occurred at the cued direction. This pre-cueing effect was greater at larger eccentricities and with a longer cue-target interval. Our findings on the endogenous pre-cueing effects across a large visual area were summarized using a simple model to assist in conceptualizing the modifications of the distribution of attention over the visual field. We discuss our finding in light of cognitive penetration of perception, and highlight the importance of examining attentional process across a large area of the visual field. PMID:28638353

The Effects of Spatial Endogenous Pre-cueing across Eccentricities.

PubMed

Feng, Jing; Spence, Ian

2017-01-01

Frequently, we use expectations about likely locations of a target to guide the allocation of our attention. Despite the importance of this attentional process in everyday tasks, examination of pre-cueing effects on attention, particularly endogenous pre-cueing effects, has been relatively little explored outside an eccentricity of 20°. Given the visual field has functional subdivisions that attentional processes can differ significantly among the foveal, perifoveal, and more peripheral areas, how endogenous pre-cues that carry spatial information of targets influence our allocation of attention across a large visual field (especially in the more peripheral areas) remains unclear. We present two experiments examining how the expectation of the location of the target shapes the distribution of attention across eccentricities in the visual field. We measured participants' ability to pick out a target among distractors in the visual field after the presentation of a highly valid cue indicating the size of the area in which the target was likely to occur, or the likely direction of the target (left or right side of the display). Our first experiment showed that participants had a higher target detection rate with faster responses, particularly at eccentricities of 20° and 30°. There was also a marginal advantage of pre-cueing effects when trials of the same size cue were blocked compared to when trials were mixed. Experiment 2 demonstrated a higher target detection rate when the target occurred at the cued direction. This pre-cueing effect was greater at larger eccentricities and with a longer cue-target interval. Our findings on the endogenous pre-cueing effects across a large visual area were summarized using a simple model to assist in conceptualizing the modifications of the distribution of attention over the visual field. We discuss our finding in light of cognitive penetration of perception, and highlight the importance of examining attentional process across a large area of the visual field.

The role of mental health and specific responsivity in juvenile justice rehabilitation.

PubMed

McCormick, Sarah; Peterson-Badali, Michele; Skilling, Tracey A

2017-02-01

Understanding the role that mental health issues play in justice-involved youth poses challenges for research, policy, and practice. While mental health problems are generally not risk factors for criminal behavior according to the risk-needs-responsivity (RNR) framework of correctional psychology practice, prevalence rates are very high and RNR principles suggest that mental health as a responsivity variable may moderate the success of interventions targeted to criminogenic needs. In this study we investigated the relationships among mental health status, criminogenic needs treatment, and recidivism in a sample of 232 youth referred for court-ordered assessments and followed through their community supervision sentence (probation). Youth with mental health needs were no more likely than youth without these needs to reoffend, regardless of whether those needs were treated. Youth who received mental health treatment also more frequently had their criminogenic needs matched across several domains, suggesting an association between mental health treatment and intermediate treatment targets. However, mental health did not moderate the effect of criminogenic needs treatment: youth who had a greater proportion of criminogenic needs targeted through appropriate services were less likely to reoffend, regardless of mental health status. Findings are consistent with the RNR stance that, within a correctional context in which the primary goal of intervention is preventing recidivism, treatment for mental health needs should be in addition to criminogenic needs treatment, not in replacement of it. They also point to the need for continued research to understand precisely how mental health treatment interacts with intervention targeting criminogenic needs. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Pertuzumab/Trastuzumab/CT Versus Trastuzumab/CT Therapy for HER2+ Breast Cancer: Results from the Prospective Neoadjuvant Breast Registry Symphony Trial (NBRST).

PubMed

Beitsch, Peter; Whitworth, Pat; Baron, Paul; Rotkis, Michael C; Mislowsky, Angela M; Richards, Paul D; Murray, Mary K; Pellicane, James V; Dul, Carrie L; Nash, Charles H; Stork-Sloots, Lisette; de Snoo, Femke; Untch, Sarah; Lee, Laura A

2017-09-01

Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping. Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment. In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (p = 0.00001) and the 45 tumors (15%) classified as basal (44%) (p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%). The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.

Predictive encoding of moving target trajectory by neurons in the parabigeminal nucleus

PubMed Central

Ma, Rui; Cui, He; Lee, Sang-Hun; Anastasio, Thomas J.

2013-01-01

Intercepting momentarily invisible moving objects requires internally generated estimations of target trajectory. We demonstrate here that the parabigeminal nucleus (PBN) encodes such estimations, combining sensory representations of target location, extrapolated positions of briefly obscured targets, and eye position information. Cui and Malpeli (Cui H, Malpeli JG. J Neurophysiol 89: 3128–3142, 2003) reported that PBN activity for continuously visible tracked targets is determined by retinotopic target position. Here we show that when cats tracked moving, blinking targets the relationship between activity and target position was similar for ON and OFF phases (400 ms for each phase). The dynamic range of activity evoked by virtual targets was 94% of that of real targets for the first 200 ms after target offset and 64% for the next 200 ms. Activity peaked at about the same best target position for both real and virtual targets. PBN encoding of target position takes into account changes in eye position resulting from saccades, even without visual feedback. Since PBN response fields are retinotopically organized, our results suggest that activity foci associated with real and virtual targets at a given target position lie in the same physical location in the PBN, i.e., a retinotopic as well as a rate encoding of virtual-target position. We also confirm that PBN activity is specific to the intended target of a saccade and is predictive of which target will be chosen if two are offered. A Bayesian predictor-corrector model is presented that conceptually explains the differences in the dynamic ranges of PBN neuronal activity evoked during tracking of real and virtual targets. PMID:23365185

Use of anticoagulant rodenticides by pest management professionals in Massachusetts, USA.

PubMed

Memmott, Kristin; Murray, Maureen; Rutberg, Allen

2017-01-01

Secondary exposure to chemical rodenticides, specifically second-generation anticoagulant rodenticides (SGARs), poses a threat to non-target wildlife including birds of prey. Federal regulations in the United States currently limit homeowner access to SGARs as a way of minimizing this threat. With legal access to SGARs, pest management professionals (PMPs) represent a potential linkage to non-target exposure. There is limited research focused on rodent control practices, chemical rodenticide preferences, level of concern and awareness, or opinions on rodenticide regulations as they relate to PMPs. An online survey was sent to PMP companies across Massachusetts, USA, between October and November 2015. Thirty-five responses were obtained, a 20 % response rate. The preferred rodent control method among responding PMP companies was chemical rodenticides, specifically the SGAR bromadiolone. Respondents varied in their level of concern regarding the impact of chemical rodenticides on non-target species and showed a low level of awareness regarding SGAR potency and half-life. All responding companies reported using integrated pest management (IPM) strategies, with nearly all utilizing chemical rodenticides at some point. Enhanced education focused on SGAR potency, bioaccumulation potential, exposure routes, and negative impacts on non-target wildlife may improve efforts made by PMPs to minimize risk to wildlife and decrease dependence on chemical rodenticide use. Future studies evaluating use of anticoagulant rodenticide (ARs) by PMPs and the association with AR residues found in non-target wildlife is necessary to determine if current EPA regulations need to be modified to effectively reduce the risk of SGARs to non-target wildlife.

The ethology of empathy: a taxonomy of real-world targets of need and their effect on observers

PubMed Central

Preston, Stephanie D.; Hofelich, Alicia J.; Stansfield, R. Brent

2013-01-01

Empathy is inherently interpersonal, but the majority of research has only examined observers. Targets of need have been largely held constant through hypothetical and fictionalized depictions of sympathetic distress and need. In the real world, people's response to life stressors varies widely—from stoicism to resilience to complete breakdown—variations that should profoundly influence the prosocial exchange. The current study examined naturally-varying affect in real hospital patients with serious chronic or terminal illness during videotaped interviews about quality of life. Participants viewed each video while psychophysiological data were recorded and then rated each patient's and their own emotion. Patients displayed three major emotion factors (disturbed, softhearted, and amused) that were used to classify them into five basic types (distraught, resilient, sanguine, reticent, wistful). These types elicited four major emotions in observers [personal distress (PD), empathic concern (EC), horror, pleasure], two of which were never discovered previously with fictionalized targets. Across studies and measures, distraught targets usually received the greatest aid, but approximately as many observers preferred the positive and likeable resilient patients or the quietly sad wistful targets, with multiple observers even giving their greatest aid to sanguine or reticent targets who did not display distress or need. Trait empathy motivated aid toward more emotive targets while perspective taking (PT) motivated aid for those who did not overtly display distress. A second study replicated key results without even providing the content of patients' speech. Through an ecological examination of real need we discovered variation and commonality in the emotional response to need that interacts strongly with the preferences of observers. Social interactions need to be studied in ethological contexts that retain the complex interplay between senders and receivers. PMID:23986680

The ethology of empathy: a taxonomy of real-world targets of need and their effect on observers.

PubMed

Preston, Stephanie D; Hofelich, Alicia J; Stansfield, R Brent

2013-01-01

Empathy is inherently interpersonal, but the majority of research has only examined observers. Targets of need have been largely held constant through hypothetical and fictionalized depictions of sympathetic distress and need. In the real world, people's response to life stressors varies widely-from stoicism to resilience to complete breakdown-variations that should profoundly influence the prosocial exchange. The current study examined naturally-varying affect in real hospital patients with serious chronic or terminal illness during videotaped interviews about quality of life. Participants viewed each video while psychophysiological data were recorded and then rated each patient's and their own emotion. Patients displayed three major emotion factors (disturbed, softhearted, and amused) that were used to classify them into five basic types (distraught, resilient, sanguine, reticent, wistful). These types elicited four major emotions in observers [personal distress (PD), empathic concern (EC), horror, pleasure], two of which were never discovered previously with fictionalized targets. Across studies and measures, distraught targets usually received the greatest aid, but approximately as many observers preferred the positive and likeable resilient patients or the quietly sad wistful targets, with multiple observers even giving their greatest aid to sanguine or reticent targets who did not display distress or need. Trait empathy motivated aid toward more emotive targets while perspective taking (PT) motivated aid for those who did not overtly display distress. A second study replicated key results without even providing the content of patients' speech. Through an ecological examination of real need we discovered variation and commonality in the emotional response to need that interacts strongly with the preferences of observers. Social interactions need to be studied in ethological contexts that retain the complex interplay between senders and receivers.

Resurgence as Choice.

PubMed

Shahan, Timothy A; Craig, Andrew R

2017-08-01

Resurgence is typically defined as an increase in a previously extinguished target behavior when a more recently reinforced alternative behavior is later extinguished. Some treatments of the phenomenon have suggested that it might also extend to circumstances where either the historic or more recently reinforced behavior is reduced by other non-extinction related means (e.g., punishment, decreases in reinforcement rate, satiation, etc.). Here we present a theory of resurgence suggesting that the phenomenon results from the same basic processes governing choice. In its most general form, the theory suggests that resurgence results from changes in the allocation of target behavior driven by changes in the values of the target and alternative options across time. Specifically, resurgence occurs when there is an increase in the relative value of an historically effective target option as a result of a subsequent devaluation of a more recently effective alternative option. We develop a more specific quantitative model of how extinction of the target and alternative responses in a typical resurgence paradigm might produce such changes in relative value across time using a temporal weighting rule. The example model does a good job in accounting for the effects of reinforcement rate and related manipulations on resurgence in simple schedules where Behavioral Momentum Theory has failed. We also discuss how the general theory might be extended to other parameters of reinforcement (e.g., magnitude, quality), other means to suppress target or alternative behavior (e.g., satiation, punishment, differential reinforcement of other behavior), and other factors (e.g., non- contingent versus contingent alternative reinforcement, serial alternative reinforcement, and multiple schedules). Copyright © 2016 Elsevier B.V. All rights reserved.

Targeting B7x and B7-H3 as New Immunotherapies for Prostate Cancer

DTIC Science & Technology

2017-11-01

treat rheumatoid arthritis and prevent acute kidney transplant rejection (Fiocco et al., 2008; Vincenti et al., 2011). The past decade has witnessed a...cell lines. The first Phase I trial with pidilizumab recruited patients with hematologic malignancies, including acute myeloid leukemia (AML), chronic... radiation , chemotherapy, other coinhibi- tory antibodies, or vaccines can improve the response rate in cancers. Predictive biomarkers need to be developed

U.S. Dietary and Physical Activity Guideline Knowledge and Corresponding Behaviors among 4th and 5th Grade Students: A Multi-Site Pilot Study

ERIC Educational Resources Information Center

Bea, Jennifer W.; Martinez, Stephanie; Armstrong-Florian, Traci; Farrell, Vanessa; Martinez, Cathy; Whitmer, Evelyn; Hartz, Vern; Blake, Samuel; Nicolini, Ariana; Misner, Scottie

2014-01-01

Knowledge of U.S. dietary and physical activity recommendations and corresponding behaviors were surveyed among 4th and 5th graders in five Arizona counties to determine the need for related education in SNAP-Ed eligible schools. A <70% target response rate was the criterion. Participants correctly identified recommendations for: fruit, 20%;…

DNA Vaccine Electroporation and Molecular Adjuvants

DTIC Science & Technology

2016-03-16

lethal species with a mortality range of 60-90% in human outbreaks [2]. The Marburgvirus genus currently includes a single viral species, Marburg...single viral species, Lloviu cuevavirus, and one defined virus, Lloviu virus (LLOV). Due to the high mortality rate, person to person TR-16-113...correlates of protective immunity, but progress has recently been made. The viral envelope glycoprotein, GP, is the main target of antibody responses [1

Effectiveness of bait tubes for brown treesnake control on Guam

USGS Publications Warehouse

Lardner, B.; Savidge, J.A.; Rodda, G.H.; Reed, R.N.; Yackel Adams, A.A.; Clark, C.S.

2011-01-01

A bait tube is a device with which a toxicant inserted in a dead mouse (Mus musculus) can be delivered to invasive brown treesnakes (Boiga irregularis) with low risk of non-target bait take. We tested two bait tube designs in a 5ha snake enclosure where the identity of virtually every snake is known. Instead of using toxicants, we implanted radio transmitters in small (6.6±1.4 g) and large (21.8±2.9 g) bait mice. Knowing all snakes present in the population allowed us to characterize not only covariates of snakes taking bait, but also those of snakes evading our mock control effort, and if snake covariates interacted with any design variable in determining targeting rate. Tube design had no effect on take rate. Snake snout-vent length was a strong predictor of success: none of the 29 snakes smaller than 843 mm took any bait, while the 126 snakes ≥843 mm were responsible for a total of 164 bait takes. The smallest of these snakes were able to ingest small and large mice, but tended to consume small bait at a higher rate than large bait. The main reason for our failure to target smallest snakes appears not to be gape limitation, but rather that small snakes prefer other prey (lizards). The time it takes a snake to grow from the size threshold observed to the size of maturation has implications for the interval between discrete efforts using toxic bait. Targeting all snakes before reproduction can occur is highly desirable; otherwise, a new cohort of refractory snakes may enter the population.

Music-induced positive mood broadens the scope of auditory attention.

PubMed

Putkinen, Vesa; Makkonen, Tommi; Eerola, Tuomas

2017-07-01

Previous studies indicate that positive mood broadens the scope of visual attention, which can manifest as heightened distractibility. We used event-related potentials (ERP) to investigate whether music-induced positive mood has comparable effects on selective attention in the auditory domain. Subjects listened to experimenter-selected happy, neutral or sad instrumental music and afterwards participated in a dichotic listening task. Distractor sounds in the unattended channel elicited responses related to early sound encoding (N1/MMN) and bottom-up attention capture (P3a) while target sounds in the attended channel elicited a response related to top-down-controlled processing of task-relevant stimuli (P3b). For the subjects in a happy mood, the N1/MMN responses to the distractor sounds were enlarged while the P3b elicited by the target sounds was diminished. Behaviorally, these subjects tended to show heightened error rates on target trials following the distractor sounds. Thus, the ERP and behavioral results indicate that the subjects in a happy mood allocated their attentional resources more diffusely across the attended and the to-be-ignored channels. Therefore, the current study extends previous research on the effects of mood on visual attention and indicates that even unfamiliar instrumental music can broaden the scope of auditory attention via its effects on mood. © The Author (2017). Published by Oxford University Press.

From receptor binding kinetics to signal transduction; a missing link in predicting in vivo drug-action.

PubMed

Nederpelt, Indira; Kuzikov, Maria; de Witte, Wilbert E A; Schnider, Patrick; Tuijt, Bruno; Gul, Sheraz; IJzerman, Adriaan P; de Lange, Elizabeth C M; Heitman, Laura H

2017-10-26

An important question in drug discovery is how to overcome the significant challenge of high drug attrition rates due to lack of efficacy and safety. A missing link in the understanding of determinants for drug efficacy is the relation between drug-target binding kinetics and signal transduction, particularly in the physiological context of (multiple) endogenous ligands. We hypothesized that the kinetic binding parameters of both drug and endogenous ligand play a crucial role in determining cellular responses, using the NK1 receptor as a model system. We demonstrated that the binding kinetics of both antagonists (DFA and aprepitant) and endogenous agonists (NKA and SP) have significantly different effects on signal transduction profiles, i.e. potency values, in vitro efficacy values and onset rate of signal transduction. The antagonistic effects were most efficacious with slowly dissociating aprepitant and slowly associating NKA while the combination of rapidly dissociating DFA and rapidly associating SP had less significant effects on the signal transduction profiles. These results were consistent throughout different kinetic assays and cellular backgrounds. We conclude that knowledge of the relationship between in vitro drug-target binding kinetics and cellular responses is important to ultimately improve the understanding of drug efficacy in vivo.

Power-law modeling based on least-squares minimization criteria.

PubMed

Hernández-Bermejo, B; Fairén, V; Sorribas, A

1999-10-01

The power-law formalism has been successfully used as a modeling tool in many applications. The resulting models, either as Generalized Mass Action or as S-systems models, allow one to characterize the target system and to simulate its dynamical behavior in response to external perturbations and parameter changes. The power-law formalism was first derived as a Taylor series approximation in logarithmic space for kinetic rate-laws. The especial characteristics of this approximation produce an extremely useful systemic representation that allows a complete system characterization. Furthermore, their parameters have a precise interpretation as local sensitivities of each of the individual processes and as rate-constants. This facilitates a qualitative discussion and a quantitative estimation of their possible values in relation to the kinetic properties. Following this interpretation, parameter estimation is also possible by relating the systemic behavior to the underlying processes. Without leaving the general formalism, in this paper we suggest deriving the power-law representation in an alternative way that uses least-squares minimization. The resulting power-law mimics the target rate-law in a wider range of concentration values than the classical power-law. Although the implications of this alternative approach remain to be established, our results show that the predicted steady-state using the least-squares power-law is closest to the actual steady-state of the target system.

Targeting TREM-1 Signaling in the Presence of Antibiotics is Effective Against Streptococcal Toxic-Shock-Like Syndrome (STSLS) Caused by Streptococcus suis.

PubMed

Yang, Chao; Zhao, Jianqing; Lin, Lan; Pan, Shan; Fu, Lei; Han, Li; Jin, Meilin; Zhou, Rui; Zhang, Anding

2015-01-01

Streptococcus suis (S.suis), a major swine pathogen, is also a severe threat to human health. Infection with highly virulent strains of S. suis can cause human Streptococcal toxic-shock-like syndrome (STSLS), which is associated with high serum pro-inflammatory cytokine levels and a high mortality rate. Our previous study indicated that highly virulent S. suis infection could activate the TREM-1 signaling pathway, which promotes host clearance of S. suis during early infection. However, it remained to be elicited whether TREM-1 signaling could be a target against STSLS in the presence of antibiotic. In the present study, mice were infected with a highly virulent S. suis strain and then treated with rTREM-1 (the recombinant extracellular domain of TREM-1) to block TREM-1 signaling, antibiotics, both rTREM-1 and antibiotics, or PBS. The survival rates, clinical signs, serum IL-1β and TNF-α levels, and serum bacterial loads were evaluated. Treatment with rTREM-1 could aggravate the outcome of infection as described previously. Although the conventional treatment with antibiotics contributed to effective S. suis clearance, it did not improve survival significantly. In comparison, due to the reduction of the exaggerated pro-inflammatory response, treatment combined with rTREM-1 and antibiotics not only led to efficient bacterial clearance but also alleviated inflammation. In conclusion, TREM-1 signaling contributed to severe inflammatory response and benefited S. suis clearance. Therefore, blocking TREM-1 signaling could still be a target for the treatment of STSLS in the presence of antibiotics.

Targeting TREM-1 Signaling in the Presence of Antibiotics is Effective Against Streptococcal Toxic-Shock-Like Syndrome (STSLS) Caused by Streptococcus suis

PubMed Central

Yang, Chao; Zhao, Jianqing; Lin, Lan; Pan, Shan; Fu, Lei; Han, Li; Jin, Meilin; Zhou, Rui; Zhang, Anding

2015-01-01

Streptococcus suis (S.suis), a major swine pathogen, is also a severe threat to human health. Infection with highly virulent strains of S. suis can cause human Streptococcal toxic-shock-like syndrome (STSLS), which is associated with high serum pro-inflammatory cytokine levels and a high mortality rate. Our previous study indicated that highly virulent S. suis infection could activate the TREM-1 signaling pathway, which promotes host clearance of S. suis during early infection. However, it remained to be elicited whether TREM-1 signaling could be a target against STSLS in the presence of antibiotic. In the present study, mice were infected with a highly virulent S. suis strain and then treated with rTREM-1 (the recombinant extracellular domain of TREM-1) to block TREM-1 signaling, antibiotics, both rTREM-1 and antibiotics, or PBS. The survival rates, clinical signs, serum IL-1β and TNF-α levels, and serum bacterial loads were evaluated. Treatment with rTREM-1 could aggravate the outcome of infection as described previously. Although the conventional treatment with antibiotics contributed to effective S. suis clearance, it did not improve survival significantly. In comparison, due to the reduction of the exaggerated pro-inflammatory response, treatment combined with rTREM-1 and antibiotics not only led to efficient bacterial clearance but also alleviated inflammation. In conclusion, TREM-1 signaling contributed to severe inflammatory response and benefited S. suis clearance. Therefore, blocking TREM-1 signaling could still be a target for the treatment of STSLS in the presence of antibiotics. PMID:26618144

Breast cancer vaccines delivered by dendritic cell-targeted lentivectors induce potent antitumor immune responses and protect mice from mammary tumor growth.

PubMed

Bryson, Paul D; Han, Xiaolu; Truong, Norman; Wang, Pin

2017-10-13

Breast cancer immunotherapy is a potent treatment option, with antibody therapies such as trastuzumab increasing 2-year survival rates by 50%. However, active immunotherapy through vaccination has generally been clinically ineffective. One potential means of improving vaccine therapy is by delivering breast cancer antigens to dendritic cells (DCs) for enhanced antigen presentation. To accomplish this in vivo, we pseudotyped lentiviral vector (LV) vaccines with a modified Sindbis Virus glycoprotein so that they could deliver genes encoding the breast cancer antigen alpha-lactalbumin (Lalba) or erb-b2 receptor tyrosine kinase 2 (ERBB2 or HER2) directly to resident DCs. We hypothesized that utilizing these DC-targeting lentiviral vectors asa breast cancer vaccine could lead to an improved immune response against self-antigens found in breast cancer tumors. Indeed, single injections of the vaccine vectors were able to amplify antigen-specific CD8T cells 4-6-fold over naïve mice, similar to the best published vaccine regimens. Immunization of these mice completely inhibited tumor growth in a foreign antigen environment (LV-ERBB2 in wildtype mice), and it reduced the rate of tumor growth in a self-antigen environment (LV-Lalba in wildtype or LV-ERBB2 in MMTV-huHER2 transgenic). These results show that a single injection with targeted lentiviral vectors can be an effective immunotherapy for breast cancer. Furthermore, they could be combined with other immunotherapeutic regimens to improve outcomes for patients with breast cancer. Copyright © 2017 Elsevier Ltd. All rights reserved.

He said what? Physiological and cognitive responses to imagining and witnessing outgroup racism.

PubMed

Karmali, Francine; Kawakami, Kerry; Page-Gould, Elizabeth

2017-08-01

Responses to outgroup racism can have serious implications for the perpetuation of bias, yet research examining this process is rare. The present research investigated self-reported, physiological, and cognitive responses among "experiencers" who witnessed and "forecasters" who imagined a racist comment targeting an outgroup member. Although previous research indicates that experiencers self-reported less distress and chose a racist partner more often than forecasters, the present results explored the possibility that experiencers may actually be distressed in such situation but regulate their initial affective reactions. The results from Experiment 1 demonstrated that participants in both roles showed (a) no activation of the hypothalamic pituitary adrenal stress axis (decreased cortisol) and (b) activation of the sympathetic autonomic nervous system (increased skin conductance). However, experiencers but not forecasters displayed a physiological profile indicative of an orienting response (decreased heart rate and increased skin conductance) rather than a defensive response (increased heart rate and increased skin conductance). Furthermore, the results from Experiment 2 provided additional evidence that experiencers are not distressed or regulating their emotional responses. In particular, experiencers showed less cognitive impairment on a Stroop task than forecasters. Together these findings indicate that when people actually encounter outgroup bias, they respond with apathy and do not censure the racist. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

Neoadjuvant therapy in the treatment of breast cancer

PubMed Central

Teshome, Mediget; Hunt, Kelly K.

2014-01-01

Synopsis Neoadjuvant systemic therapy in the treatment of breast cancer was initially employed for patients with inoperable disease. Over the past several decades this treatment approach has proved beneficial in many other patients including those with early-stage, operable breast cancer. Several randomized prospective studies have shown comparable survival rates when compared with adjuvant systemic therapy. Additionally, neoadjuvant chemotherapy can decrease the tumor burden facilitating breast conservation in selected patients without significant increases in local recurrence. Response to therapy has proven to be a strong predictor of outcome, with patients achieving pathologic complete response (pCR) demonstrating improved survival compared with those achieving less than a pCR. Furthermore, molecular subtype analysis has shown improved response following neoadjuvant chemotherapy in certain tumor types providing patients with the most aggressive subtypes a chance at cure with targeted therapies. In particular, targeting the HER2-positive subtype with trastuzumab and other HER2-directed therapies has markedly improved the outcome in these patients. Conversely, the early recognition of poor responders is important in limiting the toxicity of ineffective therapy and altering management. Neoadjuvant endocrine therapy in postmenopausal women with hormone receptor-positive tumors consistently decreases tumor size improving rates of breast conservation. Aromatase inhibitors have demonstrated superiority to tamoxifen with improved response and favorable toxicity profiles. Imaging modalities have shown promise in predicting patients with pCR, however they have not yet eliminated the need for surgical intervention. Less invasive surgical strategies such as breast conserving surgery and sentinel lymph node dissection have been shown to be safe following neoadjuvant chemotherapy in selected patients. A multidisciplinary approach with primary systemic therapy when indicated, improves the likelihood for breast conservation, provides a window into tumor biology and predicts patient outcomes. PMID:24882348

Conservative and compensatory evolution in oxidative phosphorylation complexes of angiosperms with highly divergent rates of mitochondrial genome evolution.

PubMed

Havird, Justin C; Whitehill, Nicholas S; Snow, Christopher D; Sloan, Daniel B

2015-12-01

Interactions between nuclear and mitochondrial gene products are critical for eukaryotic cell function. Nuclear genes encoding mitochondrial-targeted proteins (N-mt genes) experience elevated rates of evolution, which has often been interpreted as evidence of nuclear compensation in response to elevated mitochondrial mutation rates. However, N-mt genes may be under relaxed functional constraints, which could also explain observed increases in their evolutionary rate. To disentangle these hypotheses, we examined patterns of sequence and structural evolution in nuclear- and mitochondrial-encoded oxidative phosphorylation proteins from species in the angiosperm genus Silene with vastly different mitochondrial mutation rates. We found correlated increases in N-mt gene evolution in species with fast-evolving mitochondrial DNA. Structural modeling revealed an overrepresentation of N-mt substitutions at positions that directly contact mutated residues in mitochondrial-encoded proteins, despite overall patterns of conservative structural evolution. These findings support the hypothesis that selection for compensatory changes in response to mitochondrial mutations contributes to the elevated rate of evolution in N-mt genes. We discuss these results in light of theories implicating mitochondrial mutation rates and mitonuclear coevolution as drivers of speciation and suggest comparative and experimental approaches that could take advantage of heterogeneity in rates of mtDNA evolution across eukaryotes to evaluate such theories. © 2015 The Author(s). Evolution © 2015 The Society for the Study of Evolution.

Variability in Proactive and Reactive Cognitive Control Processes Across the Adult Lifespan

PubMed Central

Karayanidis, Frini; Whitson, Lisa Rebecca; Heathcote, Andrew; Michie, Patricia T.

2011-01-01

Task-switching paradigms produce a highly consistent age-related increase in mixing cost [longer response time (RT) on repeat trials in mixed-task than single-task blocks] but a less consistent age effect on switch cost (longer RT on switch than repeat trials in mixed-task blocks). We use two approaches to examine the adult lifespan trajectory of control processes contributing to mixing cost and switch cost: latent variables derived from an evidence accumulation model of choice, and event-related potentials (ERP) that temporally differentiate proactive (cue-driven) and reactive (target-driven) control processes. Under highly practiced and prepared task conditions, aging was associated with increasing RT mixing cost but reducing RT switch cost. Both effects were largely due to the same cause: an age effect for mixed-repeat trials. In terms of latent variables, increasing age was associated with slower non-decision processes, slower rate of evidence accumulation about the target, and higher response criterion. Age effects on mixing costs were evident only on response criterion, the amount of evidence required to trigger a decision, whereas age effects on switch cost were present for all three latent variables. ERPs showed age-related increases in preparation for mixed-repeat trials, anticipatory attention, and post-target interference. Cue-locked ERPs that are linked to proactive control were associated with early emergence of age differences in response criterion. These results are consistent with age effects on strategic processes controlling decision caution. Consistent with an age-related decline in cognitive flexibility, younger adults flexibly adjusted response criterion from trial-to-trial on mixed-task blocks, whereas older adults maintained a high criterion for all trials. PMID:22073037

A quick responding quartz crystal microbalance sensor array based on molecular imprinted polyacrylic acids coating for selective identification of aldehydes in body odor.

PubMed

Jha, Sunil K; Hayashi, Kenshi

2015-03-01

In present work, a novel quartz crystal microbalance (QCM) sensor array has been developed for prompt identification of primary aldehydes in human body odor. Molecularly imprinted polymers (MIP) are prepared using the polyacrylic acid (PAA) polymer matrix and three organic acids (propenoic acid, hexanoic acid and octanoic acid) as template molecules, and utilized as QCM surface coating layer. The performance of MIP films is characterized by 4-element QCM sensor array (three coated with MIP layers and one with pure PAA for reference) dynamic and static responses to target aldehydes: hexanal, heptanal, and nonanal in single, binary, and tertiary mixtures at distinct concentrations. The target aldehydes were selected subsequent to characterization of body odor samples with solid phase-micro extraction gas chromatography mass spectrometer (SPME-GC-MS). The hexanoic acid and octanoic acid imprinted PAA exhibit fast response, and better sensitivity, selectivity and reproducibility than the propenoic acid, and non-imprinted PAA in array. The response time and recovery time for hexanoic acid imprinted PAA are obtained as 5 s and 12 s respectively to typical concentrations of binary and tertiary mixtures of aldehydes using the static response. Dynamic sensor array response matrix has been processed with principal component analysis (PCA) for visual, and support vector machine (SVM) classifier for quantitative identification of target odors. Aldehyde odors were identified successfully in principal component (PC) space. SVM classifier results maximum recognition rate 79% for three classes of binary odors and 83% including single, binary, and tertiary odor classes in 3-fold cross validation. Copyright © 2014 Elsevier B.V. All rights reserved.

Cardiovascular disease management through restrained inflammatory responses.

PubMed

Jabir, Nasimudeen R; Tabrez, Shams

2016-01-01

Cardio vascular disease (CVD) is the end result of the accumulation of atheromatous plaques within the walls of the coronary arteries and remains the leading cause of death worldwide. Vascular inflammation and associated ongoing inflammatory responses have been considered as the critical culprits in the pathogenesis of CVD. Moreover, the activation of inflammatory pathways is not confined to coronary lesions only but involves the activation of neutrophils, monocytes and lymphocytes in peripheral blood. In view of high mortality rate associated with this devastated disease, it is essential that CVD and related complications should be taken care off at its earliest. To achieve that goal, some inflammatory mediators could be potentially targeted. In the current article, we will highlight targeting some inflammatory mediators viz. IL-1, IL-6, TNF-α etc for CVD management. As far as our knowledge goes, we are for the first time reporting the targeting inflammatory mediators especially IL-1, IL-6 and TNF-α together in a single article. Based on our review, we believe that scientific community will come up with certain anti-inflammatory agents against atherosclerosis in near future and hopefully that will be used for the successful management of CVD patients.

Memory for musical tones: the impact of tonality and the creation of false memories.

PubMed

Vuvan, Dominique T; Podolak, Olivia M; Schmuckler, Mark A

2014-01-01

Although the relation between tonality and musical memory has been fairly well-studied, less is known regarding the contribution of tonal-schematic expectancies to this relation. Three experiments investigated the influence of tonal expectancies on memory for single tones in a tonal melodic context. In the first experiment, listener responses indicated superior recognition of both expected and unexpected targets in a major tonal context than for moderately expected targets. Importantly, and in support of previous work on false memories, listener responses also revealed a higher false alarm rate for expected than unexpected targets. These results indicate roles for tonal schematic congruency as well as distinctiveness in memory for melodic tones. The second experiment utilized minor melodies, which weakened tonal expectancies since the minor tonality can be represented in three forms simultaneously. Finally, tonal expectancies were abolished entirely in the third experiment through the use of atonal melodies. Accordingly, the expectancy-based results observed in the first experiment were disrupted in the second experiment, and disappeared in the third experiment. These results are discussed in light of schema theory, musical expectancy, and classic memory work on the availability and distinctiveness heuristics.

Mechanistic Insights into Molecular Targeting and Combined Modality Therapy for Aggressive, Localized Prostate Cancer

PubMed Central

Dal Pra, Alan; Locke, Jennifer A.; Borst, Gerben; Supiot, Stephane; Bristow, Robert G.

2016-01-01

Radiation therapy (RT) is one of the mainstay treatments for prostate cancer (PCa). The potentially curative approaches can provide satisfactory results for many patients with non-metastatic PCa; however, a considerable number of individuals may present disease recurrence and die from the disease. Exploiting the rich molecular biology of PCa will provide insights into how the most resistant tumor cells can be eradicated to improve treatment outcomes. Important for this biology-driven individualized treatment is a robust selection procedure. The development of predictive biomarkers for RT efficacy is therefore of utmost importance for a clinically exploitable strategy to achieve tumor-specific radiosensitization. This review highlights the current status and possible opportunities in the modulation of four key processes to enhance radiation response in PCa by targeting the: (1) androgen signaling pathway; (2) hypoxic tumor cells and regions; (3) DNA damage response (DDR) pathway; and (4) abnormal extra-/intracell signaling pathways. In addition, we discuss how and which patients should be selected for biomarker-based clinical trials exploiting and validating these targeted treatment strategies with precision RT to improve cure rates in non-indolent, localized PCa. PMID:26909338

Memory for musical tones: the impact of tonality and the creation of false memories

PubMed Central

Vuvan, Dominique T.; Podolak, Olivia M.; Schmuckler, Mark A.

2014-01-01

Although the relation between tonality and musical memory has been fairly well-studied, less is known regarding the contribution of tonal-schematic expectancies to this relation. Three experiments investigated the influence of tonal expectancies on memory for single tones in a tonal melodic context. In the first experiment, listener responses indicated superior recognition of both expected and unexpected targets in a major tonal context than for moderately expected targets. Importantly, and in support of previous work on false memories, listener responses also revealed a higher false alarm rate for expected than unexpected targets. These results indicate roles for tonal schematic congruency as well as distinctiveness in memory for melodic tones. The second experiment utilized minor melodies, which weakened tonal expectancies since the minor tonality can be represented in three forms simultaneously. Finally, tonal expectancies were abolished entirely in the third experiment through the use of atonal melodies. Accordingly, the expectancy-based results observed in the first experiment were disrupted in the second experiment, and disappeared in the third experiment. These results are discussed in light of schema theory, musical expectancy, and classic memory work on the availability and distinctiveness heuristics. PMID:24971071

Molecular Biology of Lung Cancer

PubMed Central

Nana-Sinkam, Serge Patrick

2013-01-01

Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics. PMID:23649444

Liraglutide as adjunct to insulin treatment in type 1 diabetes does not interfere with glycaemic recovery or gastric emptying rate during hypoglycaemia: A randomized, placebo-controlled, double-blind, parallel-group study.

PubMed

Frandsen, Christian S; Dejgaard, Thomas F; Andersen, Henrik U; Holst, Jens J; Hartmann, Bolette; Thorsteinsson, Birger; Madsbad, Sten

2017-06-01

Glucagon-like peptide-1 receptor agonist (GLP-1RA) therapy is a potential treatment as adjunct to insulin in type 1 diabetes (T1D). However, GLP-1RAs inhibit glucagon secretion and delay the gastric emptying (GE) rate and may impair recovery from hypoglycaemia. We evaluated the effect of the GLP-1RA liraglutide on counterregulatory responses and GE rate during hypoglycaemia in persons with T1D. In a 12-week, randomized, double-blind, placebo-controlled study, 20 patients aged >18 years with T1D and HbA1c ≥8% (64 mmol/mol) were randomly assigned (1:1) to liraglutide 1.2 mg once daily or placebo as add-on to insulin treatment. Before and at end of treatment a hypoglycaemic clamp (plasma glucose target 2.5 mmol/L) was carried out, followed by a liquid meal. Primary endpoint was change in GE rate (evaluated by area under the paracetamol curve and time to peak). Secondary endpoints included changes in glycaemic recovery, counter-regulatory hormones, pancreatic polypeptide (PP), GLP-1, blood pressure and heart rate. During the period June 2013 to October 2014, 20 patients were enrolled. After 12 weeks of treatment, changes in GE rates did not differ significantly between groups ( P  = .96), with no significant changes from baseline, whether evaluated from AUCs or time to peak. The secondary endpoints, glycaemic recovery, counter-regulatory hormone responses, systolic blood pressure and GLP-1 and PP responses, were also similar. Heart rate increased with liraglutide from 69 ± 4 to 80 ± 5 beats/min ( P  = .02). Liraglutide does not compromise glycaemic recovery, GE rate or counter-regulatory hormone responses in T1D patients during hypoglycaemia. No treatment-related safety issues were identified. © 2016 John Wiley & Sons Ltd.

Patient Characteristics Associated With a Successful Response to Nurse-Led Care Programs Targeting the Oldest-Old: A Comparison of Two RCTs.

PubMed

Bleijenberg, Nienke; Imhof, Lorenz; Mahrer-Imhof, Romy; Wallhagen, Margaret I; de Wit, Niek J; Schuurmans, Marieke J

2017-06-01

To improve the effectiveness of community-based care programs, especially those targeting the oldest-old population (80+), data are needed that elucidate those factors associated with a successful response to the intervention. Two comparable nurse-led care programs have been evaluated in two large randomized controlled trials (RCTs), one in Switzerland and one in the Netherlands. To identify common patient characteristics that are related to a successful response to proactive nurse-led care, we explored if and to what extent, identical factors were present in both study populations. A secondary data analysis using trial data from the intervention group of both RCTs was conducted. The study sample consisted 461 older adults, 230 from the U-PROFIT trial (the Netherlands) and 231 from the HPC trial (Switzerland). The mean age of the total sample was 85.1 years (SD 3.7). The UPROFIT intervention, delivered by registered nurses, included a frailty assessment and a comprehensive geriatric assessment (CGA) at home followed by an individualized evidence-based care plan, care coordination, and follow-up. The HCP intervention was delivered by advanced practice nurses consisting of four home visits and three phone calls, and was guided by the principles of health promotion, empowerment, partnership, and family-centeredness. A successful response was defined as "stable" or "no decline" in daily functioning at follow-up. Daily functioning was measured with 13 items of activities of daily living and instrumental activities of daily living. Multivariate logistic regression models were applied to calculate the association between individual characteristics and a successful response. Almost half of the participants in the U-PROFIT trial (50.9%), and two-thirds (65.7%) of the participants in the HCP trial had a successful response at follow-up. Fewer comorbidities and a better self-rated health had the strongest predictive value for benefiting from the intervention (OR = 0.83 [95% CI 0.66-1.03], and OR = 1.5 [95% CI 0.92-2.45]), respectively. Two large RCTs demonstrated that a preventive nurse-led care program can preserve daily functioning in the oldest-old population. Older people with few comorbidities and higher self-rated health had a higher likelihood of a positive outcome. Unraveling the characteristics associated with a successful response provides important information for further refining and targeting an intervention to obtain maximum effectiveness. More effort is needed to modify interventions for the oldest-old with multiple morbidities and low levels of education. © 2017 Sigma Theta Tau International.

Potential approaches to the treatment of Ewing's sarcoma

PubMed Central

Huang, Lin

2017-01-01

Ewing’s sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the transcription factor FLI1 gene. ES is managed with standard treatments, including chemotherapy, surgery and radiation. Although the 5-year survival rate for primary ES has improved, the survival rate for ES patients with metastases or recurrence remains low. Several novel molecular targets in ES have recently been identified and investigated in preclinical and clinical settings, and targeting the function of receptor tyrosine kinases (RTKs), the fusion protein EWS-FLI1 and mTOR has shown promise. There has also been increasing interest in the immune responses of ES patients. Immunotherapies using T cells, NK cells, cancer vaccines and monoclonal antibodies have been considered for ES, especially for recurrent patients. Because understanding the pathogenesis of ES is extremely important for the development of novel treatments, this review focuses on the mechanisms and functions of targeted therapies and immunotherapies in ES. It is anticipated that integrating the knowledge obtained from basic research and translational and clinical studies will lead to the development of novel therapeutic strategies for the treatment of ES. PMID:27740934

Potential approaches to the treatment of Ewing's sarcoma.

PubMed

Yu, Hongjiu; Ge, Yonggui; Guo, Lianying; Huang, Lin

2017-01-17

Ewing's sarcoma (ES) is a highly aggressive and metastatic tumor in children and young adults caused by a chromosomal fusion between the Ewing sarcoma breakpoint region 1 (EWSR1) gene and the transcription factor FLI1 gene. ES is managed with standard treatments, including chemotherapy, surgery and radiation. Although the 5-year survival rate for primary ES has improved, the survival rate for ES patients with metastases or recurrence remains low. Several novel molecular targets in ES have recently been identified and investigated in preclinical and clinical settings, and targeting the function of receptor tyrosine kinases (RTKs), the fusion protein EWS-FLI1 and mTOR has shown promise. There has also been increasing interest in the immune responses of ES patients. Immunotherapies using T cells, NK cells, cancer vaccines and monoclonal antibodies have been considered for ES, especially for recurrent patients. Because understanding the pathogenesis of ES is extremely important for the development of novel treatments, this review focuses on the mechanisms and functions of targeted therapies and immunotherapies in ES. It is anticipated that integrating the knowledge obtained from basic research and translational and clinical studies will lead to the development of novel therapeutic strategies for the treatment of ES.

Catecholamine-Independent Heart Rate Increases Require CaMKII

PubMed Central

Gao, Zhan; Singh, Madhu V; Hall, Duane D; Koval, Olha M.; Luczak, Elizabeth D.; Joiner, Mei-ling A.; Chen, Biyi; Wu, Yuejin; Chaudhary, Ashok K; Martins, James B; Hund, Thomas J; Mohler, Peter J; Song, Long-Sheng; Anderson, Mark E.

2011-01-01

Background Catecholamines increase heart rate by augmenting the cAMP responsive HCN4 ‘pacemaker current’ (If) and/or by promoting inward Na+/Ca2+ exchanger current (INCX), by a ‘Ca2+ clock’ mechanism in sinoatrial nodal cells (SANCs). The importance, identity and function of signals that connect If and Ca2+ clock mechanisms are uncertain and controversial, but the multifunctional Ca2+ and calmodulin-dependent protein kinase II (CaMKII) is required for physiological heart rate responses to β-adrenergic receptor (β-AR) stimulation. The aim of this stuy is to measure the contribution of the Ca2+ clock and CaMKII to cardiac pacing independent of β-AR agonist stimulation. Methods and Results We used the L-type Ca2+ channel agonist BayK 8644 (BayK) to activate the SANC Ca2+ clock. BayK and isoproterenol were similarly effective in increasing rates in SANCs and Langendorff-perfused hearts from WT control mice. In contrast, SANCs and isolated hearts from mice with CaMKII inhibition by transgenic expression of an inhibitory peptide (AC3-I) were resistant to rate increases by BayK. BayK only activated CaMKII in control SANCs, but increased ICa equally in all SANCs, indicating that increasing ICa was insufficient and suggesting CaMKII activation was required for heart rate increases by BayK. BayK did not increase If or protein kinase A (PKA)-dependent phosphorylation of phospholamban (at Ser16), indicating that increased SANC Ca2+ by BayK did not augment cAMP/PKA signaling at these targets. Late diastolic intracellular Ca2+ release and INCX were significantly reduced in AC3-I SANCs and the response to BayK was eliminated by ryanodine in all groups. Conclusions The Ca2+ clock is capable of supporting physiological fight or flight responses, independent of β-AR stimulation or If increases. Complete Ca2+ clock and β-AR stimulation responses require CaMKII. PMID:21406683

Higher Crash and Near-Crash Rates in Teenaged Drivers With Lower Cortisol Response

PubMed Central

Ouimet, Marie Claude; Brown, Thomas G.; Guo, Feng; Klauer, Sheila G.; Simons-Morton, Bruce G.; Fang, Youjia; Lee, Suzanne E.; Gianoulakis, Christina; Dingus, Thomas A.

2014-01-01

IMPORTANCE Road traffic crashes are one of the leading causes of injury and death among teenagers worldwide. Better understanding of the individual pathways to driving risk may lead to better-targeted intervention in this vulnerable group. OBJECTIVE To examine the relationship between cortisol, a neurobiological marker of stress regulation linked to risky behavior, and driving risk. DESIGN, SETTING, AND PARTICIPANTS The Naturalistic Teenage Driving Study was designed to continuously monitor the driving behavior of teenagers by instrumenting vehicles with kinematic sensors, cameras, and a global positioning system. During 2006–2008, a community sample of 42 newly licensed 16-year-old volunteer participants in the United States was recruited and driving behavior monitored. It was hypothesized in teenagers that higher cortisol response to stress is associated with (1) lower crash and near-crash (CNC) rates during their first 18 months of licensure and (2) faster reduction in CNC rates over time. MAIN OUTCOMES AND MEASURES Participants’ cortisol response during a stress-inducing task was assessed at baseline, followed by measurement of their involvement in CNCs and driving exposure during their first 18 months of licensure. Mixed-effect Poisson longitudinal regression models were used to examine the association between baseline cortisol response and CNC rates during the follow-up period. RESULTS Participants with a higher baseline cortisol response had lower CNC rates during the follow-up period (exponential of the regression coefficient, 0.93; 95%CI, 0.88–0.98) and faster decrease in CNC rates over time (exponential of the regression coefficient, 0.98; 95%, CI, 0.96–0.99). CONCLUSIONS AND RELEVANCE Cortisol is a neurobiological marker associated with teenaged-driving risk. As in other problem-behavior fields, identification of an objective marker of teenaged-driving risk promises the development of more personalized intervention approaches. PMID:24710522

The influence of question type, reasoning level, and wait time on student participation rates when using clicker questions with large classes

NASA Astrophysics Data System (ADS)

Hartman, K.; Koh, J.; Murty, S. A.; Ramos, R. D. P.; Goodkin, N.

2017-12-01

"Wait time" is defined as the length of the pause between an instructor initiating a question and either the student answering it or the instructor interjecting (Rowe, 1974). However, the nature of the question-answer dynamic changes with student response systems that allow hundreds of students to answer the same question simultaneously before displaying the results to the class. In this study, we looked at 129 student response questions asked across 240 minutes of class lectures to determine if longer wait times were associated with higher student response rates. We also examined whether the type and reasoning level of the questions were diagnostic of their response rates. 644 undergraduate science students enrolled in an interdisciplinary environmental science course. During each of the course's lessons, the instructor presented a mix of lecture content, short student response activities (clicker questions), and small group discussion opportunities. Using the recorded videos, we coded each student response question for its question type and reasoning level. We divided the question types into three categories: yes/no questions, yes/no/maybe questions, and other questions. To code for the reasoning level necessary to answer each question, we used a collapsed version of Bloom's Revised Taxonomy (Krathwohl, 2002). Questions that had a definite answer and relied on recalling facts or paraphrasing the lecture content were coded as "knowledge" questions. Questions that required students to apply what they had learned to analyze a new scenario, or come to a judgement were coded as "higher order" questions. An analysis of variance (ANOVA) using the question type and reasoning level as fixed factors and wait time as a covariate to predict student response rate indicated a strong interaction between question type and reasoning level F(6, 94) = 4.53, p<.01. In general, knowledge questions were answered by a higher percentage (M=91%) of students than higher order questions (M=85%). In particular, yes/no/maybe questions targeting higher order reasoning were the least answered (M=71%). Interestingly, wait time was not associated with increased response rates. The implication is certain types of yes/no/maybe questions may lend themselves to lower response rates due to the introduction of ambiguity into the question.

Updated Outcome and Analysis of Tumor Response in Mobile Spine and Sacral Chordoma Treated With Definitive High-Dose Photon/Proton Radiation Therapy

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

Kabolizadeh, Peyman, E-mail: peyman.kabolizadeh@beaumont.org; Chen, Yen-Lin; Liebsch, Norbert

Purpose: Treatment of spine and sacral chordoma generally involves surgical resection, usually in conjunction with radiation therapy. In certain circumstances where resection may result in significant neurologic or organ dysfunction, patients can be treated definitively with radiation therapy alone. Herein, we report the outcome and the assessment of tumor response to definitive radiation therapy. Methods and Materials: A retrospective analysis was performed on 40 patients with unresected chordoma treated with photon/proton radiation therapy. Nineteen patients had complete sets of imaging scans. The soft tissue and bone compartments of the tumor were defined separately. Tumor response was evaluated by the modifiedmore » Response Evaluation Criteria in Solid Tumors (RECIST) and volumetric analysis. Results: With a median follow-up time of 50.3 months, the rates of 5-year local control, overall survival, disease-specific survival, and distant failure were 85.4%, 81.9%, 89.4%, and 20.2%, respectively. Eighty-four computed tomographic and magnetic resonance imaging scans were reviewed. Among the 19 patients, only 4 local failures occurred, and the median tumor dose was 77.4 GyRBE. Analysis at a median follow-up time of 18 months showed significant volumetric reduction of the total target volume (TTV) and the soft tissue target volume (STTV) within the first 24 months after treatment initiation, followed by further gradual reduction throughout the rest of the follow-up period. The median maximum percentage volumetric regressions of TTV and STTV were 43.2% and 70.4%, respectively. There was only a small reduction in bone target volume over time. In comparison with the modified RECIST, volumetric analysis was more reliable, more reproducible, and could help in measuring minimal changes in the tumor volume. Conclusion: These results continue to support the use of high-dose definitive radiation therapy for selected patients with unresected spine and sacral chordomas. Assessment of tumor response to radiation therapy by volumetric analysis is superior to modified RECIST in chordoma patients. Evaluating the soft tissue target volume is an excellent indicator of tumor response.« less

Behavioral Momentum Theory Fails to Account for the Effects of Reinforcement Rate on Resurgence

PubMed Central

Craig, Andrew R.; Shahan, Timothy A.

2017-01-01

The behavioral-momentum model of resurgence predicts reinforcer rates within a resurgence preparation should have three effects on target behavior. First, higher reinforcer rates in baseline (Phase 1) produce more persistent target behavior during extinction plus alternative reinforcement. Second, higher rate alternative reinforcement during Phase 2 generates greater disruption of target responding during extinction. Finally, higher rates of either reinforcement source should produce greater responding when alternative reinforcement is suspended in Phase 3. Recent empirical reports have produced mixed results in terms of these predictions. Thus, the present experiment further examined reinforcer-rate effects on persistence and resurgence. Rats pressed target levers for high-rate or low-rate variable-interval food during Phase 1. In Phase 2, target-lever pressing was extinguished, an alternative nose-poke became available, and nose-poking produced either high-rate variable-interval, low-rate variable-interval, or no (an extinction control) alternative reinforcement. Alternative reinforcement was suspended in Phase 3. For groups that received no alternative reinforcement, target-lever pressing was less persistent following high-rate than low-rate Phase-1 reinforcement. Target behavior was more persistent with low-rate alternative reinforcement than with high-rate alternative reinforcement or extinction alone. Finally, no differences in Phase-3 responding were observed for groups that received either high-rate or low-rate alternative reinforcement, and resurgence occurred only following high-rate alternative reinforcement. These findings are inconsistent with the momentum-based model of resurgence. We conclude this model mischaracterizes the effects of rein-forcer rates on persistence and resurgence of operant behavior. PMID:27193242

Aging and the rate of visual information processing.

PubMed

Guest, Duncan; Howard, Christina J; Brown, Louise A; Gleeson, Harriet

2015-01-01

Multiple methods exist for measuring how age influences the rate of visual information processing. The most advanced methods model the processing dynamics in a task in order to estimate processing rates independently of other factors that might be influenced by age, such as overall performance level and the time at which processing onsets. However, such modeling techniques have produced mixed evidence for age effects. Using a time-accuracy function (TAF) analysis, Kliegl, Mayr, and Krampe (1994) showed clear evidence for age effects on processing rate. In contrast, using the diffusion model to examine the dynamics of decision processes, Ratcliff and colleagues (e.g., Ratcliff, Thapar, & McKoon, 2006) found no evidence for age effects on processing rate across a range of tasks. Examination of these studies suggests that the number of display stimuli might account for the different findings. In three experiments we measured the precision of younger and older adults' representations of target stimuli after different amounts of stimulus exposure. A TAF analysis found little evidence for age differences in processing rate when a single stimulus was presented (Experiment 1). However, adding three nontargets to the display resulted in age-related slowing of processing (Experiment 2). Similar slowing was observed when simply presenting two stimuli and using a post-cue to indicate the target (Experiment 3). Although there was some interference from distracting objects and from previous responses, these age-related effects on processing rate seem to reflect an age-related difficulty in processing multiple objects, particularly when encoding them into visual working memory.

Inhalable Magnetic Nanoparticles for Targeted Hyperthermia in Lung Cancer Therapy

PubMed Central

Sadhukha, Tanmoy; Wiedmann, Timothy Scott; Panyam, Jayanth

2015-01-01

Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need for developing an effective means to treat NSCLC. Magnetic hyperthermia is a non-invasive approach for tumor ablation, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance while non-targeted delivery of these particles to the healthy tissues can result in toxicity. In our studies, we evaluated the effectiveness of tumor-targeted SPIO nanoparticles for magnetic hyperthermia of lung cancer. EGFR-targeted, inhalable SPIO nanoparticles were synthesized and characterized for targeting lung tumor cells as well as for magnetic hyperthermia-mediated antitumor efficacy in a mouse orthotopic model of NSCLC. Our results show that EGFR targeting enhances tumor retention of SPIO nanoparticles. Further, magnetic hyperthermia treatment using targeted SPIO nanoparticles resulted in significant inhibition of in vivo lung tumor growth. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC based on targeted magnetic hyperthermia. PMID:23591395

Inhalable magnetic nanoparticles for targeted hyperthermia in lung cancer therapy.

PubMed

Sadhukha, Tanmoy; Wiedmann, Timothy S; Panyam, Jayanth

2013-07-01

Lung cancer (specifically, non-small cell lung cancer; NSCLC) is the leading cause of cancer-related deaths in the United States. Poor response rates and survival with current treatments clearly indicate the urgent need for developing an effective means to treat NSCLC. Magnetic hyperthermia is a non-invasive approach for tumor ablation, and is based on heat generation by magnetic materials, such as superparamagnetic iron oxide (SPIO) nanoparticles, when subjected to an alternating magnetic field. However, inadequate delivery of magnetic nanoparticles to tumor cells can result in sub-lethal temperature change and induce resistance while non-targeted delivery of these particles to the healthy tissues can result in toxicity. In our studies, we evaluated the effectiveness of tumor-targeted SPIO nanoparticles for magnetic hyperthermia of lung cancer. EGFR-targeted, inhalable SPIO nanoparticles were synthesized and characterized for targeting lung tumor cells as well as for magnetic hyperthermia-mediated antitumor efficacy in a mouse orthotopic model of NSCLC. Our results show that EGFR targeting enhances tumor retention of SPIO nanoparticles. Further, magnetic hyperthermia treatment using targeted SPIO nanoparticles resulted in significant inhibition of in vivo lung tumor growth. Overall, this work demonstrates the potential for developing an effective anticancer treatment modality for the treatment of NSCLC based on targeted magnetic hyperthermia. Copyright © 2013 Elsevier Ltd. All rights reserved.

Targeted neonatal echocardiography services: need for standardized training and quality assurance.

PubMed

Finan, Emer; Sehgal, Arvind; Khuffash, Afif El; McNamara, Patrick J

2014-10-01

Targeted neonatal echocardiography refers to a focused assessment of myocardial performance and hemodynamics directed by a specific clinical question. It has become the standard of care in many parts of the world, but practice is variable, and there has been a lack of standardized training and evaluation to date. Targeted neonatal echocardiography was first introduced to Canada in 2006. The purpose of this study was to examine the characteristics of targeted neonatal echocardiography practice and training methods in Canadian neonatal intensive care units (NICUs). A total of 142 Canadian neonatologists were invited to participate in an online survey, which was conducted in September 2010. The survey consisted of questions related to the availability of targeted neonatal echocardiography, clinical indications, benefits and risks, and training methods. The overall survey response rate was 65%. Forty-eight respondents (34%) indicated that targeted neonatal echocardiography was available in their units, and the program was introduced within the preceding 1 to 5 years. In centers where it was unavailable, lack of on-site echocardiography expertise was cited as the major barrier to implementation. The most common indications for targeted neonatal echocardiography included evaluation of a hemodynamically significant ductus arteriosus, systemic or pulmonary blood flow, and response to cardiovascular treatments. Only 27% of respondents, working in centers where targeted neonatal echocardiography existed, actually performed the studies themselves; most individuals completed 11 to 20 studies per month. Almost half of the respondents said that training was available in their institutions, but methods of training and evaluation were inconsistent. Eighty-seven percent of respondents reported no formalized process for assessment of ongoing competency after the initial training period. Targeted neonatal echocardiography is becoming more widely available and is gaining acceptance in Canadian NICUs. Although training is provided in many institutions, the process is not well established, and formal evaluation is rarely performed. This study emphasizes the need for development of standards for formalized training, evaluation, and quality assurance. © 2014 by the American Institute of Ultrasound in Medicine.

Comparative Study of SSVEP- and P300-Based Models for the Telepresence Control of Humanoid Robots.

PubMed

Zhao, Jing; Li, Wei; Li, Mengfan

2015-01-01

In this paper, we evaluate the control performance of SSVEP (steady-state visual evoked potential)- and P300-based models using Cerebot-a mind-controlled humanoid robot platform. Seven subjects with diverse experience participated in experiments concerning the open-loop and closed-loop control of a humanoid robot via brain signals. The visual stimuli of both the SSVEP- and P300- based models were implemented on a LCD computer monitor with a refresh frequency of 60 Hz. Considering the operation safety, we set the classification accuracy of a model over 90.0% as the most important mandatory for the telepresence control of the humanoid robot. The open-loop experiments demonstrated that the SSVEP model with at most four stimulus targets achieved the average accurate rate about 90%, whereas the P300 model with the six or more stimulus targets under five repetitions per trial was able to achieve the accurate rates over 90.0%. Therefore, the four SSVEP stimuli were used to control four types of robot behavior; while the six P300 stimuli were chosen to control six types of robot behavior. Both of the 4-class SSVEP and 6-class P300 models achieved the average success rates of 90.3% and 91.3%, the average response times of 3.65 s and 6.6 s, and the average information transfer rates (ITR) of 24.7 bits/min 18.8 bits/min, respectively. The closed-loop experiments addressed the telepresence control of the robot; the objective was to cause the robot to walk along a white lane marked in an office environment using live video feedback. Comparative studies reveal that the SSVEP model yielded faster response to the subject's mental activity with less reliance on channel selection, whereas the P300 model was found to be suitable for more classifiable targets and required less training. To conclude, we discuss the existing SSVEP and P300 models for the control of humanoid robots, including the models proposed in this paper.

Comparative Study of SSVEP- and P300-Based Models for the Telepresence Control of Humanoid Robots

PubMed Central

Li, Mengfan

2015-01-01

In this paper, we evaluate the control performance of SSVEP (steady-state visual evoked potential)- and P300-based models using Cerebot—a mind-controlled humanoid robot platform. Seven subjects with diverse experience participated in experiments concerning the open-loop and closed-loop control of a humanoid robot via brain signals. The visual stimuli of both the SSVEP- and P300- based models were implemented on a LCD computer monitor with a refresh frequency of 60 Hz. Considering the operation safety, we set the classification accuracy of a model over 90.0% as the most important mandatory for the telepresence control of the humanoid robot. The open-loop experiments demonstrated that the SSVEP model with at most four stimulus targets achieved the average accurate rate about 90%, whereas the P300 model with the six or more stimulus targets under five repetitions per trial was able to achieve the accurate rates over 90.0%. Therefore, the four SSVEP stimuli were used to control four types of robot behavior; while the six P300 stimuli were chosen to control six types of robot behavior. Both of the 4-class SSVEP and 6-class P300 models achieved the average success rates of 90.3% and 91.3%, the average response times of 3.65 s and 6.6 s, and the average information transfer rates (ITR) of 24.7 bits/min 18.8 bits/min, respectively. The closed-loop experiments addressed the telepresence control of the robot; the objective was to cause the robot to walk along a white lane marked in an office environment using live video feedback. Comparative studies reveal that the SSVEP model yielded faster response to the subject’s mental activity with less reliance on channel selection, whereas the P300 model was found to be suitable for more classifiable targets and required less training. To conclude, we discuss the existing SSVEP and P300 models for the control of humanoid robots, including the models proposed in this paper. PMID:26562524

Cabozantinib versus Everolimus in Advanced Renal-Cell Carcinoma.

PubMed

Choueiri, Toni K; Escudier, Bernard; Powles, Thomas; Mainwaring, Paul N; Rini, Brian I; Donskov, Frede; Hammers, Hans; Hutson, Thomas E; Lee, Jae-Lyun; Peltola, Katriina; Roth, Bruce J; Bjarnason, Georg A; Géczi, Lajos; Keam, Bhumsuk; Maroto, Pablo; Heng, Daniel Y C; Schmidinger, Manuela; Kantoff, Philip W; Borgman-Hagey, Anne; Hessel, Colin; Scheffold, Christian; Schwab, Gisela M; Tannir, Nizar M; Motzer, Robert J

2015-11-05

Cabozantinib is an oral, small-molecule tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR) as well as MET and AXL, each of which has been implicated in the pathobiology of metastatic renal-cell carcinoma or in the development of resistance to antiangiogenic drugs. This randomized, open-label, phase 3 trial evaluated the efficacy of cabozantinib, as compared with everolimus, in patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. We randomly assigned 658 patients to receive cabozantinib at a dose of 60 mg daily or everolimus at a dose of 10 mg daily. The primary end point was progression-free survival. Secondary efficacy end points were overall survival and objective response rate. Median progression-free survival was 7.4 months with cabozantinib and 3.8 months with everolimus. The rate of progression or death was 42% lower with cabozantinib than with everolimus (hazard ratio, 0.58; 95% confidence interval [CI] 0.45 to 0.75; P<0.001). The objective response rate was 21% with cabozantinib and 5% with everolimus (P<0.001). A planned interim analysis showed that overall survival was longer with cabozantinib than with everolimus (hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P=0.005) but did not cross the significance boundary for the interim analysis. Adverse events were managed with dose reductions; doses were reduced in 60% of the patients who received cabozantinib and in 25% of those who received everolimus. Discontinuation of study treatment owing to adverse events occurred in 9% of the patients who received cabozantinib and in 10% of those who received everolimus. Progression-free survival was longer with cabozantinib than with everolimus among patients with renal-cell carcinoma that had progressed after VEGFR-targeted therapy. (Funded by Exelixis; METEOR ClinicalTrials.gov number, NCT01865747.).

Applications of polymeric micelles with tumor targeted in chemotherapy

NASA Astrophysics Data System (ADS)

Ding, Hui; Wang, Xiaojun; Zhang, Song; Liu, Xinli

2012-11-01

Polymeric micelles (PMs) have gained more progress as a carrier system with the quick development of biological and nanoparticle techniques. In particular, PMs with smart targeting can deliver anti-cancer drugs directly into tumor cells at a sustained rate. PMs with core-shell structure (with diameters of 10 100 nm) have been prepared by a variety of biodegradable and biocompatible polymers via a self-assembly process. The preparation of polymeric micelles with stimuli-responsive block copolymers or modification of target molecules on polymeric micelles' surface are able to significantly improve the efficiency of drug delivery. Polymeric micelles, which have been considered as a novel promising drug carrier for cancer therapeutics, are rapidly evolving and being introduced in an attempt to overcome several limitations of traditional chemotherapeutics, including water solubility, tumor-specific accumulation, anti-tumor efficacy, and non-specific toxicity. This review describes the preparation of polymeric micelles and the targeted modification which greatly enhance the effects of chemotherapeutic agents.

[Allocation of attentional resource and monitoring processes under rapid serial visual presentation].

PubMed

Nishiura, K

1998-08-01

With the use of rapid serial visual presentation (RSVP), the present study investigated the cause of target intrusion errors and functioning of monitoring processes. Eighteen students participated in Experiment 1, and 24 in Experiment 2. In Experiment 1, different target intrusion errors were found depending on different kinds of letters --romaji, hiragana, and kanji. In Experiment 2, stimulus set size and context information were manipulated in an attempt to explore the cause of post-target intrusion errors. Results showed that as stimulus set size increased, the post-target intrusion errors also increased, but contextual information did not affect the errors. Results concerning mean report probability indicated that increased allocation of attentional resource to response-defining dimension was the cause of the errors. In addition, results concerning confidence rating showed that monitoring of temporal and contextual information was extremely accurate, but it was not so for stimulus information. These results suggest that attentional resource is different from monitoring resource.

Dual responsive PNIPAM-chitosan targeted magnetic nanopolymers for targeted drug delivery

NASA Astrophysics Data System (ADS)

Yadavalli, Tejabhiram; Ramasamy, Shivaraman; Chandrasekaran, Gopalakrishnan; Michael, Isaac; Therese, Helen Annal; Chennakesavulu, Ramasamy

2015-04-01

A dual stimuli sensitive magnetic hyperthermia based drug delivery system has been developed for targeted cancer treatment. Thermosensitive amine terminated poly-N-isopropylacrylamide complexed with pH sensitive chitosan nanoparticles was prepared as the drug carrier. Folic acid and fluorescein were tagged to the nanopolymer complex via N-hydroxysuccinimide and ethyl-3-(3-dimethylaminopropyl)carbodiimide reaction to form a fluorescent and cancer targeting magnetic carrier system. The formation of the polymer complex was confirmed using infrared spectroscopy. Gadolinium doped nickel ferrite nanoparticles prepared by a hydrothermal method were encapsulated in the polymer complex to form a magnetic drug carrier system. The proton relaxation studies on the magnetic carrier system revealed a 200% increase in the T1 proton relaxation rate. These magnetic carriers were loaded with curcumin using solvent evaporation method with a drug loading efficiency of 86%. Drug loaded nanoparticles were tested for their targeting and anticancer properties on four cancer cell lines with the help of MTT assay. The results indicated apoptosis of cancer cell lines within 3 h of incubation.

Targeted therapy according to next generation sequencing-based panel sequencing.

PubMed

Saito, Motonobu; Momma, Tomoyuki; Kono, Koji

2018-04-17

Targeted therapy against actionable gene mutations shows a significantly higher response rate as well as longer survival compared to conventional chemotherapy, and has become a standard therapy for many cancers. Recent progress in next-generation sequencing (NGS) has enabled to identify huge number of genetic aberrations. Based on sequencing results, patients recommend to undergo targeted therapy or immunotherapy. In cases where there are no available approved drugs for the genetic mutations detected in the patients, it is recommended to be facilitate the registration for the clinical trials. For that purpose, a NGS-based sequencing panel that can simultaneously target multiple genes in a single investigation has been used in daily clinical practice. To date, various types of sequencing panels have been developed to investigate genetic aberrations with tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics. Because sequencing panels are efficient and cost-effective, they are quickly being adopted outside the lab, in hospitals and clinics, in order to identify personal targeted therapy for individual cancer patients.

Use of Targeted Therapeutics in Epithelial Ovarian Cancer: A Review of Current Literature and Future Directions.

PubMed

Vetter, Monica Hagan; Hays, John L

2018-03-01

Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer death in the United States. Most patients will ultimately fail platinum-based chemotherapy and have the disease recur. Interest is increasing in the use of targeted therapies in the treatment of EOC. This review focuses on the current use of targeted therapeutics in EOC as well as future directions. A literature search of Medline and PubMed was conducted (January 2000-October 2017) to identify recent reports of targeted drugs in EOC. A wide range of targeted therapeutics is currently being used as both monotherapy and in combination in the treatment of EOC. Clinically, the most commonly used classes of drugs currently are antiangiogenics and poly (ADP-ribose) polymerase inhibitors. However, a number of drugs in varying stages in development target a wide range of biochemical pathways. Activity and response rates of these drugs vary greatly. Questions continue about combination drug therapy and appropriate patient selection. The use of targeted therapeutics in the treatment of EOC, both as monotherapy and in combination, will continue to expand as more mechanisms of tumorigenesis are identified. Multiple clinical trials of a wide range of targeted therapeutics are currently ongoing. Evidence-based selection of drug targets and appropriate patient populations will allow strategic application of targeted therapeutics. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

Saccadic adaptation to a systematically varying disturbance.

PubMed

Cassanello, Carlos R; Ohl, Sven; Rolfs, Martin

2016-08-01

Saccadic adaptation maintains the correct mapping between eye movements and their targets, yet the dynamics of saccadic gain changes in the presence of systematically varying disturbances has not been extensively studied. Here we assessed changes in the gain of saccade amplitudes induced by continuous and periodic postsaccadic visual feedback. Observers made saccades following a sequence of target steps either along the horizontal meridian (Two-way adaptation) or with unconstrained saccade directions (Global adaptation). An intrasaccadic step-following a sinusoidal variation as a function of the trial number (with 3 different frequencies tested in separate blocks)-consistently displaced the target along its vector. The oculomotor system responded to the resulting feedback error by modifying saccade amplitudes in a periodic fashion with similar frequency of variation but lagging the disturbance by a few tens of trials. This periodic response was superimposed on a drift toward stronger hypometria with similar asymptotes and decay rates across stimulus conditions. The magnitude of the periodic response decreased with increasing frequency and was smaller and more delayed for Global than Two-way adaptation. These results suggest that-in addition to the well-characterized return-to-baseline response observed in protocols using constant visual feedback-the oculomotor system attempts to minimize the feedback error by integrating its variation across trials. This process resembles a convolution with an internal response function, whose structure would be determined by coefficients of the learning model. Our protocol reveals this fast learning process in single short experimental sessions, qualifying it for the study of sensorimotor learning in health and disease. Copyright © 2016 the American Physiological Society.

Saccadic adaptation to a systematically varying disturbance

PubMed Central

Ohl, Sven; Rolfs, Martin

2016-01-01

Saccadic adaptation maintains the correct mapping between eye movements and their targets, yet the dynamics of saccadic gain changes in the presence of systematically varying disturbances has not been extensively studied. Here we assessed changes in the gain of saccade amplitudes induced by continuous and periodic postsaccadic visual feedback. Observers made saccades following a sequence of target steps either along the horizontal meridian (Two-way adaptation) or with unconstrained saccade directions (Global adaptation). An intrasaccadic step—following a sinusoidal variation as a function of the trial number (with 3 different frequencies tested in separate blocks)—consistently displaced the target along its vector. The oculomotor system responded to the resulting feedback error by modifying saccade amplitudes in a periodic fashion with similar frequency of variation but lagging the disturbance by a few tens of trials. This periodic response was superimposed on a drift toward stronger hypometria with similar asymptotes and decay rates across stimulus conditions. The magnitude of the periodic response decreased with increasing frequency and was smaller and more delayed for Global than Two-way adaptation. These results suggest that—in addition to the well-characterized return-to-baseline response observed in protocols using constant visual feedback—the oculomotor system attempts to minimize the feedback error by integrating its variation across trials. This process resembles a convolution with an internal response function, whose structure would be determined by coefficients of the learning model. Our protocol reveals this fast learning process in single short experimental sessions, qualifying it for the study of sensorimotor learning in health and disease. PMID:27098027

A simple two-stage model predicts response time distributions.

PubMed

Carpenter, R H S; Reddi, B A J; Anderson, A J

2009-08-15

The neural mechanisms underlying reaction times have previously been modelled in two distinct ways. When stimuli are hard to detect, response time tends to follow a random-walk model that integrates noisy sensory signals. But studies investigating the influence of higher-level factors such as prior probability and response urgency typically use highly detectable targets, and response times then usually correspond to a linear rise-to-threshold mechanism. Here we show that a model incorporating both types of element in series - a detector integrating noisy afferent signals, followed by a linear rise-to-threshold performing decision - successfully predicts not only mean response times but, much more stringently, the observed distribution of these times and the rate of decision errors over a wide range of stimulus detectability. By reconciling what previously may have seemed to be conflicting theories, we are now closer to having a complete description of reaction time and the decision processes that underlie it.

Multimodal imaging guided preclinical trials of vascular targeting in prostate cancer

PubMed Central

Kalmuk, James; Folaron, Margaret; Buchinger, Julian; Pili, Roberto; Seshadri, Mukund

2015-01-01

The high mortality rate associated with castration-resistant prostate cancer (CRPC) underscores the need for improving therapeutic options for this patient population. The purpose of this study was to examine the potential of vascular targeting in prostate cancer. Experimental studies were carried out in subcutaneous and orthotopic Myc-CaP prostate tumors implanted into male FVB mice to examine the efficacy of a novel microtubule targeted vascular disrupting agent (VDA), EPC2407 (Crolibulin™). A non-invasive multimodality imaging approach based on magnetic resonance imaging (MRI), bioluminescence imaging (BLI), and ultrasound (US) was utilized to guide preclinical trial design and monitor tumor response to therapy. Imaging results were correlated with histopathologic assessment, tumor growth and survival analysis. Contrast-enhanced MRI revealed potent antivascular activity of EPC2407 against subcutaneous and orthotopic Myc-CaP tumors. Longitudinal BLI of Myc-CaP tumors expressing luciferase under the androgen response element (Myc-CaP/ARE-luc) revealed changes in AR signaling and reduction in intratumoral delivery of luciferin substrate following castration suggestive of reduced blood flow. This reduction in blood flow was validated by US and MRI. Combination treatment resulted in sustained vascular suppression, inhibition of tumor regrowth and conferred a survival benefit in both models. These results demonstrate the therapeutic potential of vascular targeting in combination with androgen deprivation against prostate cancer. PMID:26203773

Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets.

PubMed

Miller, Martin L; Molinelli, Evan J; Nair, Jayasree S; Sheikh, Tahir; Samy, Rita; Jing, Xiaohong; He, Qin; Korkut, Anil; Crago, Aimee M; Singer, Samuel; Schwartz, Gary K; Sander, Chris

2013-09-24

Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depends on the activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies.

Drug Synergy Screen and Network Modeling in Dedifferentiated Liposarcoma Identifies CDK4 and IGF1R as Synergistic Drug Targets

PubMed Central

Miller, Martin L.; Molinelli, Evan J.; Nair, Jayasree S.; Sheikh, Tahir; Samy, Rita; Jing, Xiaohong; He, Qin; Korkut, Anil; Crago, Aimee M.; Singer, Samuel; Schwartz, Gary K.; Sander, Chris

2014-01-01

Dedifferentiated liposarcoma (DDLS) is a rare but aggressive cancer with high recurrence and low response rates to targeted therapies. Increasing treatment efficacy may require combinations of targeted agents that counteract the effects of multiple abnormalities. To identify a possible multicomponent therapy, we performed a combinatorial drug screen in a DDLS-derived cell line and identified cyclin-dependent kinase 4 (CDK4) and insulin-like growth factor 1 receptor (IGF1R) as synergistic drug targets. We measured the phosphorylation of multiple proteins and cell viability in response to systematic drug combinations and derived computational models of the signaling network. These models predict that the observed synergy in reducing cell viability with CDK4 and IGF1R inhibitors depend on activity of the AKT pathway. Experiments confirmed that combined inhibition of CDK4 and IGF1R cooperatively suppresses the activation of proteins within the AKT pathway. Consistent with these findings, synergistic reductions in cell viability were also found when combining CDK4 inhibition with inhibition of either AKT or epidermal growth factor receptor (EGFR), another receptor similar to IGF1R that activates AKT. Thus, network models derived from context-specific proteomic measurements of systematically perturbed cancer cells may reveal cancer-specific signaling mechanisms and aid in the design of effective combination therapies. PMID:24065146

[Methodological design of the National Health and Nutrition Survey 2016].

PubMed

Romero-Martínez, Martín; Shamah-Levy, Teresa; Cuevas-Nasu, Lucía; Gómez-Humarán, Ignacio Méndez; Gaona-Pineda, Elsa Berenice; Gómez-Acosta, Luz María; Rivera-Dommarco, Juan Ángel; Hernández-Ávila, Mauricio

2017-01-01

Describe the design methodology of the halfway health and nutrition national survey (Ensanut-MC) 2016. The Ensanut-MC is a national probabilistic survey whose objective population are the inhabitants of private households in Mexico. The sample size was determined to make inferences on the urban and rural areas in four regions. Describes main design elements: target population, topics of study, sampling procedure, measurement procedure and logistics organization. A final sample of 9 479 completed household interviews, and a sample of 16 591 individual interviews. The response rate for households was 77.9%, and the response rate for individuals was 91.9%. The Ensanut-MC probabilistic design allows valid statistical inferences about interest parameters for Mexico´s public health and nutrition, specifically on overweight, obesity and diabetes mellitus. Updated information also supports the monitoring, updating and formulation of new policies and priority programs.

Interactive learning media based on flash for basic electronic engineering development for SMK Negeri 1 Driyorejo - Gresik

NASA Astrophysics Data System (ADS)

Mandigo Anggana Raras, Gustav

2018-04-01

This research aims to produce a product in the form of flash based interactive learning media on a basic electronic engineering subject that reliable to be used and to know students’ responses about the media. The target of this research is X-TEI 1 class at SMK Negeri 1 Driyorejo – Gresik. The method used in this study is R&D that has been limited into seven stages only (1) potential and problems, (2) data collection, (3) product design, (4) product validation, (5) product revision, (6) field test, and (7) analysis and writing. The obtained result is interactive learning media named MELDASH. Validation process used to produce a valid interactive learning media. The result of media validation state that the interactive learning media has a 90.83% rating. Students’ responses to this interactive learning media is really good with 88.89% rating.

Clinical Response to Ingenol Mebutate in Patients With Actinic Keratoses.

PubMed

Batalla, A; Flórez, Á; Feal, C; Peón, G; Abalde, M T; Salgado-Boquete, L; de la Torre, C

2015-12-01

Cryotherapy is the most common treatment for actinic keratosis, but its effect is limited to individual lesions. Several topical drugs, however, are available that, in addition to treating individual actinic keratoses, target field cancerization and thereby act on subclinical lesions. Examples are 5-fluorouracil, imiquimod, diclofenac, and ingenol mebutate. We report on 17 patients with actinic keratoses treated with ingenol mebutate and describe our findings on treatment effectiveness, adherence, and tolerance. Complete and partial response rates were 35% and 53%, respectively. Ninety-four percent of patients fully adhered to treatment and 18% developed severe local reactions. Ingenol mebutate is an effective treatment for actinic keratosis. Although it has a similar rate of local reactions to other treatments available for actinic keratosis, its short treatment regimen favors better adherence. Copyright © 2014 Elsevier España, S.L.U. y AEDV. All rights reserved.

Antibody responses after vaccination against equine influenza in the Republic of Korea in 2013.

PubMed

Kim, Eun-Ju; Kim, Bo-Hye; Yang, Sunjoo; Choi, Eun-Jin; Shin, Ye-Jin; Song, Jae-Young; Shin, Yeun-Kyung

2015-11-01

In this study, antibody responses after equine influenza vaccination were investigated among 1,098 horses in Korea using the hemagglutination inhibition (HI) assay. The equine influenza viruses, A/equine/South Africa/4/03 (H3N8) and A/equine/Wildeshausen/1/08 (H3N8), were used as antigens in the HI assay. The mean seropositive rates were 91.7% (geometric mean antibody levels (GMT), 56.8) and 93.6% (GMT, 105.2) for A/equine/South Africa/4/03 and A/equine/Wildeshausen/1/08, respectively. Yearlings and two-year-olds in training exhibited lower positive rates (68.1% (GMT, 14) and 61.7% (GMT, 11.9), respectively, with different antigens) than average. Horses two years old or younger may require more attention in vaccination against equine influenza according to the vaccination regime, because they could be a target of the equine influenza virus.

Appropriate uses and considerations for online surveying in human dimensions research

USGS Publications Warehouse

Sexton, Natalie R.; Miller, Holly M.; Dietsch, Alia M.

2011-01-01

Online surveying has gained attention in recent years for its applicability to human dimensions research as an efficient and inexpensive data-collection method; however, online surveying is not a panacea. In this article, we provide some guidelines for alleviating or avoiding the criticisms and pitfalls suggested of online survey methods and explore two case studies demonstrating different approaches to online surveying. The first was a mixed-mode study of visitors to 52 participating National Wildlife Refuges. The response rate was 72%, with over half of respondents completing the survey online, resulting in cost-savings and efficiencies that would not have otherwise been realized. The second highlighted an online-only approach targeting specialized users of satellite imagery. Through branching and skipping, the online mode allowed flexibilities in administration impractical in a mail survey. The response rate of 53% was higher than typical for online surveys. Both case studies provide examples of appropriate uses of online surveying.

Identification of reduced-order thermal therapy models using thermal MR images: theory and validation.

PubMed

Niu, Ran; Skliar, Mikhail

2012-07-01

In this paper, we develop and validate a method to identify computationally efficient site- and patient-specific models of ultrasound thermal therapies from MR thermal images. The models of the specific absorption rate of the transduced energy and the temperature response of the therapy target are identified in the reduced basis of proper orthogonal decomposition of thermal images, acquired in response to a mild thermal test excitation. The method permits dynamic reidentification of the treatment models during the therapy by recursively utilizing newly acquired images. Such adaptation is particularly important during high-temperature therapies, which are known to substantially and rapidly change tissue properties and blood perfusion. The developed theory was validated for the case of focused ultrasound heating of a tissue phantom. The experimental and computational results indicate that the developed approach produces accurate low-dimensional treatment models despite temporal and spatial noises in MR images and slow image acquisition rate.

Prestimulus EEG Power Predicts Conscious Awareness But Not Objective Visual Performance

PubMed Central

Veniero, Domenica

2017-01-01

Abstract Prestimulus oscillatory neural activity has been linked to perceptual outcomes during performance of psychophysical detection and discrimination tasks. Specifically, the power and phase of low frequency oscillations have been found to predict whether an upcoming weak visual target will be detected or not. However, the mechanisms by which baseline oscillatory activity influences perception remain unclear. Recent studies suggest that the frequently reported negative relationship between α power and stimulus detection may be explained by changes in detection criterion (i.e., increased target present responses regardless of whether the target was present/absent) driven by the state of neural excitability, rather than changes in visual sensitivity (i.e., more veridical percepts). Here, we recorded EEG while human participants performed a luminance discrimination task on perithreshold stimuli in combination with single-trial ratings of perceptual awareness. Our aim was to investigate whether the power and/or phase of prestimulus oscillatory activity predict discrimination accuracy and/or perceptual awareness on a trial-by-trial basis. Prestimulus power (3–28 Hz) was inversely related to perceptual awareness ratings (i.e., higher ratings in states of low prestimulus power/high excitability) but did not predict discrimination accuracy. In contrast, prestimulus oscillatory phase did not predict awareness ratings or accuracy in any frequency band. These results provide evidence that prestimulus α power influences the level of subjective awareness of threshold visual stimuli but does not influence visual sensitivity when a decision has to be made regarding stimulus features. Hence, we find a clear dissociation between the influence of ongoing neural activity on conscious awareness and objective performance. PMID:29255794

MicroRNA-211 Regulates Oxidative Phosphorylation and Energy Metabolism in Human Vitiligo.

PubMed

Sahoo, Anupama; Lee, Bongyong; Boniface, Katia; Seneschal, Julien; Sahoo, Sanjaya K; Seki, Tatsuya; Wang, Chunyan; Das, Soumen; Han, Xianlin; Steppie, Michael; Seal, Sudipta; Taieb, Alain; Perera, Ranjan J

2017-09-01

Vitiligo is a common chronic skin disorder characterized by loss of epidermal melanocytes and progressive depigmentation. Vitiligo has complex immune, genetic, environmental, and biochemical causes, but the exact molecular mechanisms of vitiligo development and progression, particularly those related to metabolic control, are poorly understood. In this study we characterized the human vitiligo cell line PIG3V and the normal human melanocyte line HEM-l by RNA sequencing, targeted metabolomics, and shotgun lipidomics. Melanocyte-enriched microRNA-211, a known metabolic switch in nonpigmented melanoma cells, was severely down-regulated in vitiligo cell line PIG3V and skin biopsy samples from vitiligo patients, whereas its predicted targets PPARGC1A, RRM2, and TAOK1 were reciprocally up-regulated. microRNA-211 binds to PGC1-α 3' untranslated region locus and represses it. Although mitochondrial numbers were constant, mitochondrial complexes I, II, and IV and respiratory responses were defective in vitiligo cells. Nanoparticle-coated microRNA-211 partially augmented the oxygen consumption rate in PIG3V cells. The lower oxygen consumption rate, changes in lipid and metabolite profiles, and increased reactive oxygen species production observed in vitiligo cells appear to be partly due to abnormal regulation of microRNA-211 and its target genes. These genes represent potential biomarkers and therapeutic targets in human vitiligo. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Selective pH-Responsive Core-Sheath Nanofiber Membranes for Chem/Bio/Med Applications: Targeted Delivery of Functional Molecules.

PubMed

Han, Daewoo; Steckl, Andrew J

2017-12-13

Core-sheath fibers using different Eudragit materials were successfully produced, and their controlled multi-pH responses have been demonstrated. Core-sheath fibers made of Eudragit L 100 (EL100) core and Eudragit S 100 (ES100) sheath provide protection and/or controlled release of core material at pH 6 by adjusting the sheath thickness (controlled by the flow rate of source polymer solution). The thickest sheath (∼250 nm) provides the least core release ∼1.25%/h, while the thinnest sheath (∼140 nm) provides much quicker release ∼16.75%/h. Furthermore, switching core and sheath material dramatically altered the pH response. Core-sheath fibers made of ES100 core and EL100 sheath can provide a consistent core release rate, while the sheath release rate becomes higher as the sheath layer becomes thinner. For example, the thinnest sheath (∼120 nm) provides a core and sheath release ratio of 1:2.5, while the thickest sheath (∼200 nm) shows only a ratio of 1:1.7. All core-sheath Eudragit fibers show no noticeable release at pH 5, while they are completely dissolved at pH 7. Extremely high surface area in the porous network of the fiber membranes provides much faster (>30 times) response to external pH changes as compared to that of equivalent cast films.

Dose rate mapping of VMAT treatments

NASA Astrophysics Data System (ADS)

Podesta, Mark; Antoniu Popescu, I.; Verhaegen, Frank

2016-06-01

Human tissues exhibit a varying response to radiation dose depending on the dose rate and fractionation scheme used. Dose rate effects have been reported for different radiations, and tissue types. The literature indicates that there is not a significant difference in response for low-LET radiation when using dose rates between 1 Gy min-1 and 12 Gy min-1 but lower dose rates have an observable sparing effect on tissues and a differential effect between tissues. In intensity-modulated radiotherapy such as volumetric modulated arc therapy (VMAT) the dose can be delivered with a wide range of dose rates. In this work we developed a method based on time-resolved Monte Carlo simulations to quantify the dose rate frequency distribution for clinical VMAT treatments for three cancer sites, head and neck, lung, and pelvis within both planning target volumes (PTV) and normal tissues. The results show a wide range of dose rates are used to deliver dose in VMAT and up to 75% of the PTV can have its dose delivered with dose rates  <1 Gy min-1. Pelvic plans on average have a lower mean dose rate within the PTV than lung or head and neck plans but a comparable mean dose rate within the organs at risk. Two VMAT plans that fulfil the same dose objectives and constraints may be delivered with different dose rate distributions, particularly when comparing single arcs to multiple arc plans. It is concluded that for dynamic plans, the dose rate range used varies to a larger degree than previously assumed. The effect of the dose rate range in VMAT on clinical outcome is unknown.

A peptide of heparin cofactor II inhibits endotoxin-mediated shock and invasive Pseudomonas aeruginosa infection.

PubMed

Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; van der Plas, Mariena J A; Mörgelin, Matthias; Malmsten, Martin; Schmidtchen, Artur

2014-01-01

Sepsis and septic shock remain important medical problems with high mortality rates. Today's treatment is based mainly on using antibiotics to target the bacteria, without addressing the systemic inflammatory response, which is a major contributor to mortality in sepsis. Therefore, novel treatment options are urgently needed to counteract these complex sepsis pathologies. Heparin cofactor II (HCII) has recently been shown to be protective against Gram-negative infections. The antimicrobial effects were mapped to helices A and D of the molecule. Here we show that KYE28, a 28 amino acid long peptide representing helix D of HCII, is antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida albicans. Moreover, KYE28 binds to LPS and thereby reduces LPS-induced pro-inflammatory responses by decreasing NF-κB/AP-1 activation in vitro. In mouse models of LPS-induced shock, KYE28 significantly enhanced survival by dampening the pro-inflammatory cytokine response. Finally, in an invasive Pseudomonas infection model, the peptide inhibited bacterial growth and reduced the pro-inflammatory response, which lead to a significant reduction of mortality. In summary, the peptide KYE28, by simultaneously targeting bacteria and LPS-induced pro-inflammatory responses represents a novel therapeutic candidate for invasive infections.

A Peptide of Heparin Cofactor II Inhibits Endotoxin-Mediated Shock and Invasive Pseudomonas aeruginosa Infection

PubMed Central

Kalle, Martina; Papareddy, Praveen; Kasetty, Gopinath; van der Plas, Mariena J. A.; Mörgelin, Matthias; Malmsten, Martin; Schmidtchen, Artur

2014-01-01

Sepsis and septic shock remain important medical problems with high mortality rates. Today's treatment is based mainly on using antibiotics to target the bacteria, without addressing the systemic inflammatory response, which is a major contributor to mortality in sepsis. Therefore, novel treatment options are urgently needed to counteract these complex sepsis pathologies. Heparin cofactor II (HCII) has recently been shown to be protective against Gram-negative infections. The antimicrobial effects were mapped to helices A and D of the molecule. Here we show that KYE28, a 28 amino acid long peptide representing helix D of HCII, is antimicrobial against the Gram-negative bacteria Escherichia coli and Pseudomonas aeruginosa, the Gram-positive Bacillus subtilis and Staphylococcus aureus, as well as the fungus Candida albicans. Moreover, KYE28 binds to LPS and thereby reduces LPS-induced pro-inflammatory responses by decreasing NF-κB/AP-1 activation in vitro. In mouse models of LPS-induced shock, KYE28 significantly enhanced survival by dampening the pro-inflammatory cytokine response. Finally, in an invasive Pseudomonas infection model, the peptide inhibited bacterial growth and reduced the pro-inflammatory response, which lead to a significant reduction of mortality. In summary, the peptide KYE28, by simultaneously targeting bacteria and LPS-induced pro-inflammatory responses represents a novel therapeutic candidate for invasive infections. PMID:25047075

From social talk to social action: shaping the social triad with emotion sharing.

PubMed

Peters, Kim; Kashima, Yoshihisa

2007-11-01

Seemingly trivial social talk provides fertile ground for emotion sharing (a narrator and audience's realization that they experience the same emotional response toward a target), which in turn creates a coalition between the narrator and the audience, configures the narrator and audience's relationship with the target, and coordinates their target-directed action. In this article, the authors use 4 studies to investigate this thesis. In Studies 1 and 2--where participants rated scenarios in which narrators told them anecdotes--the authors found that when there was emotion sharing (a) participants were more bonded with narrators, (b) the narrator and audience's relationship with the target (as reflected in action tendencies) was determined by the emotionality of the anecdotes, and (c) they coordinated their target-directed actions. Study 3 demonstrated that this effect was indeed due to emotion sharing. Study 4 provided behavioral evidence for the effects of emotion sharing using a 2-person trust game. Together, these studies reveal that the everyday act of social talk is a powerful act that is able to shape the social triad of the narrator, the audience, and the social target, with powerful consequences for social structure and group action. (c) 2007 APA, all rights reserved.

Deficits in cue detection underlie event-based prospective memory impairment in major depression: an eye tracking study.

PubMed

Chen, Siyi; Zhou, Renlai; Cui, Hong; Chen, Xinyin

2013-10-30

This study examined the cue detection in the non-focal event-based prospective memory (PM) of individuals with and without a major depressive disorder using behavioural and eye tracking assessments. The participants were instructed to search on each trial for a different target stimulus that could be present or absent and to make prospective responses to the cue object. PM tasks included cue only and target plus cue, whereas ongoing tasks included target only and distracter only. The results showed that a) participants with depression performed more poorly than those without depression in PM; b) participants with depression showed more fixations and longer total and average fixation durations in both ongoing and PM conditions; c) participants with depression had lower scores on accuracy in target-plus-cue trials than in cue-only trials and had a higher gaze rate of targets on hits and misses in target-plus-cue trials than did those without depression. The results indicate that the state of depression may impair top-down cognitive control function, which in turn results in particular deficits in the engagement of monitoring for PM cues. Copyright © 2013. Published by Elsevier Ireland Ltd.

Development of targeted therapy and immunotherapy for treatment of small cell lung cancer.

PubMed

Saito, Motonobu; Shiraishi, Kouya; Goto, Akiteru; Suzuki, Hiroyuki; Kohno, Takashi; Kono, Koji

2018-05-14

Targeted therapy against druggable genetic aberrations has shown a significantly positive response rate and longer survival in various cancers, including lung cancer. In lung adenocarcinoma (LADC), specific thyroxin kinase inhibitors against EGFR mutations and ALK fusions are used as a standard treatment regimen and show significant positive efficacy. On the other hand, targeted therapy against driver gene aberrations has not been adapted yet in small cell lung cancer (SCLC). This is because driver genes and druggable aberrations are rarely identified by next generation sequencing in SCLC. Recent advances in the understanding of molecular biology have revealed several candidate therapeutic targets. To date, poly [ADP-ribose] polymerase (PARP), enhancer of zeste homologue 2 (EZH2) or delta-like canonical Notch ligand 3 (DLL3) are considered to be druggable targets in SCLC. In addition, another candidate of personalized therapy for SCLC is immune blockade therapy of programmed death-1 (PD-1) and its ligand, PD-L1. PD-1/PD-L1 blockade therapy is not a standard therapy for SCLC, so many clinical trials have been performed to investigate its efficacy. Herein, we review gene aberrations exploring the utility of targeted therapy and discuss blockade of immune checkpoints therapy in SCLC.

Robust Targeting for the Smartphone Video Guidance Sensor

NASA Technical Reports Server (NTRS)

Carter, Christopher

2017-01-01

The Smartphone Video Guidance Sensor (SVGS) is a miniature, self-contained autonomous rendezvous and docking sensor developed using a commercial off the shelf Android-based smartphone. It aims to provide a miniaturized solution for rendezvous and docking, enabling small satellites to conduct proximity operations and formation flying while minimizing interference with a primary payload. Previously, the sensor was limited by a slow (2 Hz) refresh rate and its use of retro-reflectors, both of which contributed to a limited operating environment. To advance the technology readiness level, a modified approach was developed, combining a multi-colored LED target with a focused target-detection algorithm. Alone, the use of an LED system was determined to be much more reliable, though slower, than the retro-reflector system. The focused target-detection system was developed in response to this problem to mitigate the speed reduction of using color. However, it also improved the reliability. In combination these two methods have been demonstrated to dramatically increase sensor speed and allow the sensor to select the target even with significant noise interfering with the sensor, providing millimeter level accuracy at a range of two meters with a 1U target.

Robust Targeting for the Smartphone Video Guidance Sensor

NASA Technical Reports Server (NTRS)

Carter, C.

2017-01-01

The Smartphone Video Guidance Sensor (SVGS) is a miniature, self-contained autonomous rendezvous and docking sensor developed using a commercial off the shelf Android-based smartphone. It aims to provide a miniaturized solution for rendezvous and docking, enabling small satellites to conduct proximity operations and formation flying while minimizing interference with a primary payload. Previously, the sensor was limited by a slow (2 Hz) refresh rate and its use of retro-reflectors, both of which contributed to a limited operating environment. To advance the technology readiness level, a modified approach was developed, combining a multi-colored LED target with a focused target-detection algorithm. Alone, the use of an LED system was determined to be much more reliable, though slower, than the retro-reflector system. The focused target-detection system was developed in response to this problem to mitigate the speed reduction of using color. However it also improved the reliability. In combination these two methods have been demonstrated to dramatically increase sensor speed and allow the sensor to select the target even with significant noise interfering with the sensor, providing millimeter level precision at a range of two meters with a 1U target.

Edge Response and NIIRS Estimates for Commercial Remote Sensing Satellites

NASA Technical Reports Server (NTRS)

Blonski, Slawomir; Ryan, Robert E.; Pagnutti, mary; Stanley, Thomas

2006-01-01

Spatial resolution of panchromatic imagery from commercial remote sensing satellites was characterized based on edge response measurements using edge targets and the tilted-edge technique. Relative Edge Response (RER) was estimated as a geometric mean of normalized edge response differences measured in two directions of image pixels at points distanced from the edge by -0.5 and 0.5 of ground sample distance. RER is one of the engineering parameters used in the General Image Quality Equation to provide predictions of imaging system performance expressed in terms of the National Imagery Interpretability Rating Scale (NIIRS). By assuming a plausible range of signal-to-noise ratio and assessing the effects of Modulation Transfer Function compensation, the NIIRS estimates were made and then compared with vendor-provided values and evaluations conducted by the National Geospatial-Intelligence Agency.

A new display stream compression standard under development in VESA

NASA Astrophysics Data System (ADS)

Jacobson, Natan; Thirumalai, Vijayaraghavan; Joshi, Rajan; Goel, James

2017-09-01

The Advanced Display Stream Compression (ADSC) codec project is in development in response to a call for technologies from the Video Electronics Standards Association (VESA). This codec targets visually lossless compression of display streams at a high compression rate (typically 6 bits/pixel) for mobile/VR/HDR applications. Functionality of the ADSC codec is described in this paper, and subjective trials results are provided using the ISO 29170-2 testing protocol.

Targeting the T-cell co-stimulatory CD27/CD70 pathway in cancer immunotherapy: rationale and potential.

PubMed

van de Ven, Koen; Borst, Jannie

2015-01-01

In 2013, cancer immunotherapy was named 'breakthrough of the year' based on the outcome of clinical trials with blocking antibodies to the T-cell co-inhibitory receptors CTLA-4 and PD-1. This success has emphasized that cytotoxic T-cell responses to cancer can occur, but are limited by peripheral tolerance and by immunosuppression in the tumor microenvironment. Targeting of CTLA-4, PD-1 or its ligands partly overcomes these limitations and can now be applied in multiple immunogenic cancer types. Furthermore, an increased success rate is expected from combining CTLA-4 and/or PD-1 blocking with deliberate engagement of T-cell co-stimulatory receptors, particularly TNF receptor (R) family members. The TNFR family includes CD27 (Tnfrsf7), for which an agonistic antibody has recently entered clinical trials. In this review, we describe how CD27 co-stimulation impacts the T-cell response, with the purpose to illuminate how CD27 agonism can be exploited in cancer immunotherapy.

Simultaneously targeting inflammatory response and parasite sequestration in brain to treat Experimental Cerebral Malaria

PubMed Central

Dende, Chaitanya; Meena, Jairam; Nagarajan, Perumal; Panda, Amulya K.; Rangarajan, Pundi N.; Padmanaban, Govindarajan

2015-01-01

Malaria afflicts around 200 million people annually, with a mortality number close to 600,000. The mortality rate in Human Cerebral Malaria (HCM) is unacceptably high (15–20%), despite the availability of artemisinin-based therapy. An effective adjunct therapy is urgently needed. Experimental Cerebral Malaria (ECM) in mice manifests many of the neurological features of HCM. Migration of T cells and parasite-infected RBCs (pRBCs) into the brain are both necessary to precipitate the disease. We have been able to simultaneously target both these parameters of ECM. Curcumin alone was able to reverse all the parameters investigated in this study that govern inflammatory responses, CD8+ T cell and pRBC sequestration into the brain and blood brain barrier (BBB) breakdown. But the animals eventually died of anemia due to parasite build-up in blood. However, arteether-curcumin (AC) combination therapy even after the onset of symptoms provided complete cure. AC treatment is a promising therapeutic option for HCM. PMID:26227888

Non-redundant odor coding by sister mitral cells revealed by light addressable glomeruli in the mouse

PubMed Central

Dhawale, Ashesh K.; Hagiwara, Akari; Bhalla, Upinder S.; Murthy, Venkatesh N.; Albeanu, Dinu F.

2011-01-01

Sensory inputs frequently converge on the brain in a spatially organized manner, often with overlapping inputs to multiple target neurons. Whether the responses of target neurons with common inputs become decorrelated depends on the contribution of local circuit interactions. We addressed this issue in the olfactory system using newly generated transgenic mice expressing channelrhodopsin-2 in all olfactory sensory neurons. By selectively stimulating individual glomeruli with light, we identified mitral/tufted (M/T) cells that receive common input (sister cells). Sister M/T cells had highly correlated responses to odors as measured by average spike rates, but their spike timing in relation to respiration was differentially altered. In contrast, non-sister M/T cells correlated poorly on both these measures. We suggest that sister M/T cells carry two different channels of information: average activity representing shared glomerular input, and phase-specific information that refines odor representations and is substantially independent for sister M/T cells. PMID:20953197

Laughter catches attention!

PubMed

Pinheiro, Ana P; Barros, Carla; Dias, Marcelo; Kotz, Sonja A

2017-12-01

In social interactions, emotionally salient and sudden changes in vocal expressions attract attention. However, only a few studies examined how emotion and attention interact in voice processing. We investigated neutral, happy (laughs) and angry (growls) vocalizations in a modified oddball task. Participants silently counted the targets in each block and rated the valence and arousal of the vocalizations. A combined event-related potential and time-frequency analysis focused on the P3 and pre-stimulus alpha power to capture attention effects in response to unexpected events. Whereas an early differentiation between emotionally salient and neutral vocalizations was reflected in the P3a response, the P3b was selectively enhanced for happy voices. The P3b modulation was predicted by pre-stimulus frontal alpha desynchronization, and by the perceived pleasantness of the targets. These findings indicate that vocal emotions may be differently processed based on task relevance and valence. Increased anticipation and attention to positive vocal cues (laughter) may reflect their high social relevance. Copyright © 2017 Elsevier B.V. All rights reserved.

Immunoproteomics of Aspergillus for the development of biomarkers and immunotherapies.

PubMed

Kniemeyer, Olaf; Ebel, Frank; Krüger, Thomas; Bacher, Petra; Scheffold, Alexander; Luo, Ting; Strassburger, Maria; Brakhage, Axel A

2016-10-01

Filamentous fungi of the genus Aspergillus play significant roles as pathogens causing superficial and invasive infections as well as allergic reactions in humans. Particularly invasive mycoses caused by Aspergillus species are characterized by high mortality rates due to difficult diagnosis and insufficient antifungal therapy. The application of immunoproteomic approaches has a great potential to identify new targets for the diagnosis, therapy, and vaccine development of diseases caused by Aspergillus species. Serological proteome analyses (SERPA) that combine 2D electrophoresis with Western blotting are still one of the most popular techniques for the identification of antigenic proteins. However, recently a growing number of approaches have been developed to identify proteins, which either provoke an antibody response or which represent targets of T-cell immunity in patients with allergy or fungal infections. Here, we review advances in the studies of immune responses against pathogenic Aspergilli as well as the current status of diagnosis and immunotherapy of Aspergillus infections. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Enzyme-Responsive Liposomes for the Delivery of Anticancer Drugs

PubMed Central

Fouladi, Farnaz; Steffen, Kristine J.; Mallik, Sanku

2017-01-01

Liposomes are nanocarriers that deliver the payloads at the target site, leading to therapeutic drug concentrations at the diseased site and reduced toxic effects in healthy tissues. Several approaches have been used to enhance the ability of the nanocarrier to target the specific tissues, including ligand-targeted liposomes and stimuli-responsive liposomes. Ligand-targeted liposomes exhibit higher uptake by the target tissue due to the targeting ligand attached to the surface, while, the stimuli-responsive liposomes do not release their cargo unless they expose to an endogenous or exogenous stimulant at the target site. In this review, we mainly focus on the liposomes that are responsive to pathologically increased levels of enzymes at the target site. Enzyme-responsive liposomes release their cargo upon contact with the enzyme through several destabilization mechanisms: a) structural perturbation in the lipid bilayer, b) removal of a shielding polymer from the surface and increased cellular uptake, c) cleavage of a lipopeptide or lipopolymer incorporated in the bilayer, and d) activation of a prodrug in the liposomes. PMID:28201868

Enzyme-Responsive Liposomes for the Delivery of Anticancer Drugs.

PubMed

Fouladi, Farnaz; Steffen, Kristine J; Mallik, Sanku

2017-04-19

Liposomes are nanocarriers that deliver the payloads at the target site, leading to therapeutic drug concentrations at the diseased site and reduced toxic effects in healthy tissues. Several approaches have been used to enhance the ability of the nanocarrier to target the specific tissues, including ligand-targeted liposomes and stimuli-responsive liposomes. Ligand-targeted liposomes exhibit higher uptake by the target tissue due to the targeting ligand attached to the surface, while the stimuli-responsive liposomes do not release their cargo unless they expose to an endogenous or exogenous stimulant at the target site. In this review, we mainly focus on the liposomes that are responsive to pathologically increased levels of enzymes at the target site. Enzyme-responsive liposomes release their cargo upon contact with the enzyme through several destabilization mechanisms: (1) structural perturbation in the lipid bilayer, (2) removal of a shielding polymer from the surface and increased cellular uptake, (3) cleavage of a lipopeptide or lipopolymer incorporated in the bilayer, and (4) activation of a prodrug in the liposomes.

Subliminal perception of others' physical pain and pleasure.

PubMed

Chiesa, Patrizia Andrea; Liuzza, Marco Tullio; Acciarino, Adriano; Aglioti, Salvatore Maria

2015-08-01

Studies indicate that explicit and implicit processing of affectively charged stimuli may be reflected in specific behavioral markers and physiological signatures. This study investigated whether the pleasantness ratings of a neutral target were affected by subliminal perception of pleasant and painful facial expressions. Participants were presented images depicting face of non-famous models being slapped (painful condition), caressed (pleasant condition) or touched (neutral condition) by the right hand of another individual. In particular, we combined the continuous flash suppression technique with the affective misattribution procedure (AMP) to explore subliminal empathic processing. Measures of pupil reactivity along with empathy traits were also collected. Results showed that participants rated the neutral target as less or more likeable congruently with the painful or pleasant facial expression presented, respectively. Pupil dilation was associated both with the implicit attitudes (AMP score) and with empathic concern. Thus, the results provide behavioral and physiological evidence that state-related empathic reactivity can occur at an entirely subliminal level and that it is linked to autonomic responses and empathic traits.

Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors.

PubMed

Sun, D; Samuelson, L C; Yang, T; Huang, Y; Paliege, A; Saunders, T; Briggs, J; Schnermann, J

2001-08-14

Adenosine is a determinant of metabolic control of organ function increasing oxygen supply through the A2 class of adenosine receptors and reducing oxygen demand through A1 adenosine receptors (A1AR). In the kidney, activation of A1AR in afferent glomerular arterioles has been suggested to contribute to tubuloglomerular feedback (TGF), the vasoconstriction elicited by elevations in [NaCl] in the macula densa region of the nephron. To further elucidate the role of A1AR in TGF, we have generated mice in which the entire A1AR coding sequence was deleted by homologous recombination. Homozygous A1AR mutants that do not express A1AR mRNA transcripts and do not respond to A1AR agonists are viable and without gross anatomical abnormalities. Plasma and urinary electrolytes were not different between genotypes. Likewise, arterial blood pressure, heart rates, and glomerular filtration rates were indistinguishable between A1AR(+/+), A1AR(+/-), and A1AR(-/-) mice. TGF responses to an increase in loop of Henle flow rate from 0 to 30 nl/min, whether determined as change of stop flow pressure or early proximal flow rate, were completely abolished in A1AR(-/-) mice (stop flow pressure response, -6.8 +/- 0.55 mmHg and -0.4 +/- 0.2 in A1AR(+/+) and A1AR(-/-) mice; early proximal flow rate response, -3.4 +/- 0.4 nl/min and +0.02 +/- 0.3 nl/min in A1AR(+/+) and A1AR(-/-) mice). Absence of TGF responses in A1AR-deficient mice suggests that adenosine is a required constituent of the juxtaglomerular signaling pathway. A1AR null mutant mice are a promising tool to study the functional role of A1AR in different target tissues.

Staircase-scene-based nonuniformity correction in aerial point target detection systems.

PubMed

Huo, Lijun; Zhou, Dabiao; Wang, Dejiang; Liu, Rang; He, Bin

2016-09-01

Focal-plane arrays (FPAs) are often interfered by heavy fixed-pattern noise, which severely degrades the detection rate and increases the false alarms in airborne point target detection systems. Thus, high-precision nonuniformity correction is an essential preprocessing step. In this paper, a new nonuniformity correction method is proposed based on a staircase scene. This correction method can compensate for the nonlinear response of the detector and calibrate the entire optical system with computational efficiency and implementation simplicity. Then, a proof-of-concept point target detection system is established with a long-wave Sofradir FPA. Finally, the local standard deviation of the corrected image and the signal-to-clutter ratio of the Airy disk of a Boeing B738 are measured to evaluate the performance of the proposed nonuniformity correction method. Our experimental results demonstrate that the proposed correction method achieves high-quality corrections.

Biased lineup instructions and face identification from video images.

PubMed

Thompson, W Burt; Johnson, Jaime

2008-01-01

Previous eyewitness memory research has shown that biased lineup instructions reduce identification accuracy, primarily by increasing false-positive identifications in target-absent lineups. Because some attempts at identification do not rely on a witness's memory of the perpetrator but instead involve matching photos to images on surveillance video, the authors investigated the effects of biased instructions on identification accuracy in a matching task. In Experiment 1, biased instructions did not affect the overall accuracy of participants who used video images as an identification aid, but nearly all correct decisions occurred with target-present photo spreads. Both biased and unbiased instructions resulted in high false-positive rates. In Experiment 2, which focused on video-photo matching accuracy with target-absent photo spreads, unbiased instructions led to more correct responses (i.e., fewer false positives). These findings suggest that investigators should not relax precautions against biased instructions when people attempt to match photos to an unfamiliar person recorded on video.

Behavioral responses of freshwater mussels to experimental dewatering

USGS Publications Warehouse

Galbraith, Heather S.; Blakeslee, Carrie J.; Lellis, William A.

2015-01-01

Understanding the effects of flow alteration on freshwater ecosystems is critical for predicting species responses and restoring appropriate flow regimes. We experimentally evaluated the effects of 3 dewatering rates on behavior of 6 freshwater mussel species in the context of water-removal rates observed in 21 Atlantic Coast rivers. Horizontal movement differed significantly among species and dewatering rates, but a significant species × dewatering interaction suggested that these factors influence movement in complex ways. Species differences in movement were evident only in controls and under slow dewatering rates, but these differences disappeared at moderate and fast dewatering rates. Burrowing behavior did not differ with respect to species identity or dewatering rate. The proportion of individuals that became stranded did not differ among species, but most individuals became stranded under low and moderate dewatering, and all individuals became stranded under fast dewatering. Mortality after stranding differed strongly among species along a gradient from 25% inPyganodon cataracta to 92% in Alasmidonta marginata. Together, these results suggest that species behavior may differ under gradual dewatering, but all species in our study are poorly adapted for rapid dewatering. Most of the 21 rivers we assessed experienced dewatering events comparable to our moderate rate, and several experienced events comparable to our fast rate. Dewatering events that exceed the movement or survival capability of most mussel species can be expected to result in assemblage-wide impacts. Consequently, the rate of water level change may be important in refining target flow conditions for restoration.

miR-26b enhances radiosensitivity of hepatocellular carcinoma cells by targeting EphA2.

PubMed

Jin, Qiao; Li, Xiang Jun; Cao, Pei Guo

2016-08-01

Although low-dose radiotherapy (RT) that involves low collateral damage is more suitable for hepatocellular carcinoma (HCC) than traditional high-dose RT, but to achieve satisfactory therapeutic effect with low-dose RT, it is necessary to sensitize HCC cells to irradiation. This study was aimed to determine whether radiosensitivity of HCC cells can be enhanced using miR-26b by targeting erythropoietin producing human hepatocelluar A2 (EphA2). The levels of miR-26b and EphA2 expression in multiple HCC cell lines were assessed by qPCR and western blotting, respectively, and compared with those in a hepatic cell line. HCC 97H cells were transfected with miR-26b mimics, EphA2-ShRNA or EphA2 over-expression vector before exposure to low-dose irradiation. Different degrees of miR-26b down-regulation and EphA2 up-regulation were observed in all HCC cell lines, among which the HCC 97H cell line expressed the lowest level of miR-26b and highest level of EphA2. EphA2 was verified as the target of miR-26b by dual luciferase reporter assay. HCC 97H cells transfected with miR-26b mimics or EphA2-ShRNA reduced the expression of EphA2 protein, with significantly lower cell proliferation rate and cell invasion ability and higher apoptosis rate in response to low-dose irradiation than those in the non-transfected cells. These results were reversed after EphA2 was overexpressed by transfection with the EphA2 overexpression vector. Co-transfection with miR-26b mimics and EphA2 overexpression vector barely altered EphA2 expression level and cell response to low-dose irradiation. These data suggest that miR-26b enhances radiosensitivity of HCC 97H cells by targeting EphA2 protein.

Optimal Battery Utilization Over Lifetime for Parallel Hybrid Electric Vehicle to Maximize Fuel Economy

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

Patil, Chinmaya; Naghshtabrizi, Payam; Verma, Rajeev

This paper presents a control strategy to maximize fuel economy of a parallel hybrid electric vehicle over a target life of the battery. Many approaches to maximizing fuel economy of parallel hybrid electric vehicle do not consider the effect of control strategy on the life of the battery. This leads to an oversized and underutilized battery. There is a trade-off between how aggressively to use and 'consume' the battery versus to use the engine and consume fuel. The proposed approach addresses this trade-off by exploiting the differences in the fast dynamics of vehicle power management and slow dynamics of batterymore » aging. The control strategy is separated into two parts, (1) Predictive Battery Management (PBM), and (2) Predictive Power Management (PPM). PBM is the higher level control with slow update rate, e.g. once per month, responsible for generating optimal set points for PPM. The considered set points in this paper are the battery power limits and State Of Charge (SOC). The problem of finding the optimal set points over the target battery life that minimize engine fuel consumption is solved using dynamic programming. PPM is the lower level control with high update rate, e.g. a second, responsible for generating the optimal HEV energy management controls and is implemented using model predictive control approach. The PPM objective is to find the engine and battery power commands to achieve the best fuel economy given the battery power and SOC constraints imposed by PBM. Simulation results with a medium duty commercial hybrid electric vehicle and the proposed two-level hierarchical control strategy show that the HEV fuel economy is maximized while meeting a specified target battery life. On the other hand, the optimal unconstrained control strategy achieves marginally higher fuel economy, but fails to meet the target battery life.« less

Human centromedian-parafascicular complex signals sensory cues for goal-oriented behavior selection.

PubMed

Schepers, Inga M; Beck, Anne-Kathrin; Bräuer, Susann; Schwabe, Kerstin; Abdallat, Mahmoud; Sandmann, Pascale; Dengler, Reinhard; Rieger, Jochem W; Krauss, Joachim K

2017-05-15

Experimental research has shown that the centromedian-parafascicular complex (CM-Pf) of the intralaminar thalamus is activated in attentional orienting and processing of behaviorally relevant stimuli. These observations resulted in the hypothesis that the CM-Pf plays a pivotal role in goal-oriented behavior selection. We here set out to test this hypothesis with electrophysiological recordings from patients with electrodes implanted in CM-Pf for deep brain stimulation (DBS) treatment of chronic neuropathic pain. Six patients participated in (1) an auditory three-class oddball experiment, which required a button press to target tones, but not to standard and deviant tones and in (2) a multi-speaker experiment with a target word that required attention selection and a target image that required response selection. Subjects showed transient neural responses (8-15Hz) to the target tone and the target word. Two subjects additionally showed transient neural responses (15-25Hz) to the target image. All sensory target stimuli were related to an internal goal and required a behavior selection (attention selection, response selection). In group analyses, neural responses were greater to target tones than deviant and standard tones and to target words than other task-relevant words that did not require attention selection. The transient neural responses occurred after the target stimuli but prior to the overt behavioral response. Our results demonstrate that in human subjects the CM-Pf is involved in signaling sensory inputs related to goal-oriented selection of behavior. Copyright © 2017 Elsevier Inc. All rights reserved.

Work demands and health consequences of organizational and technological measures introduced to enhance the quality of home care services--A subgroup analysis.

PubMed

Andersen, Gunn Robstad; Bendal, Synne; Westgaard, Rolf H

2015-11-01

This study of home care workers in a Norwegian municipality aimed to examine the effect of two measures involving organizational (job checklists) and technological (personal digital assistants) job aids on perceived work demands and musculoskeletal health. Questionnaire data was collected in 2009 (n = 138, response rate 76.2%) and 2011 (n = 80, response rate 54%). Forty-six home care workers responded at both waves. Respondents were assigned into 'high', 'moderate' and 'low' strain groups based on their responses to open and closed survey questions regarding impact of the two measures. One-way ANOVA with post-hoc t-tests and regression analyses investigated group differences and examined development in variables. Perceived work demands and health effects over the two-year study period were unchanged overall, yet significant differences between subgroups were highlighted. Work demands and shoulder-neck pain remained high for high-strain workers, but were reduced for low and moderate strain workers. Management should be aware of diversity in worker responses to rationalizations and give priority to supplementary, targeted measures to counteract adverse effects. Copyright © 2015 Elsevier Ltd and The Ergonomics Society. All rights reserved.

Investigating the effect of tumor vascularization on magnetic targeting in vivo using retrospective design of experiment.

PubMed

Mei, Kuo-Ching; Bai, Jie; Lorrio, Silvia; Wang, Julie Tzu-Wen; Al-Jamal, Khuloud T

2016-11-01

Nanocarriers take advantages of the enhanced permeability and retention (EPR) to accumulate passively in solid tumors. Magnetic targeting has shown to further enhance tumor accumulation in response to a magnetic field gradient. It is widely known that passive accumulation of nanocarriers varies hugely in tumor tissues of different tumor vascularization. It is hypothesized that magnetic targeting is likely to be influenced by such factors. In this work, magnetic targeting is assessed in a range of subcutaneously implanted murine tumors, namely, colon (CT26), breast (4T1), lung (Lewis lung carcinoma) cancer and melanoma (B16F10). Passively- and magnetically-driven tumor accumulation of the radiolabeled polymeric magnetic nanocapsules are assessed with gamma counting. The influence of tumor vasculature, namely, the tumor microvessel density, permeability and diameter on passive and magnetic tumor targeting is assessed with the aid of the retrospective design of experiment (DoE) approach. It is clear that the three tumor vascular parameters contribute greatly to both passive and magnetically targeted tumor accumulation but play different roles when nanocarriers are targeted to the tumor with different strategies. It is concluded that tumor permeability is a rate-limiting factor in both targeting modes. Diameter and microvessel density influence passive and magnetic tumor targeting, respectively. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Recruitment of private practices for primary care research: experience in a preventive services clinical trial.

PubMed

McBride, P E; Massoth, K M; Underbakke, G; Solberg, L I; Beasley, J W; Plane, M B

1996-10-01

Recruitment of community primary care practices for studies to improve health service delivery is important to many health care organizations. Prior studies have focused on individual physician recruitment or academic settings. This descriptive study evaluated the efficiency and utility of three different recruitment methods to encourage community practice participation in a preventive services research trial. Primary care practices in four midwestern states were recruited using different sources for initial mailings (physician lists, practice lists, and a managed care organization's primary care network) and different recruiting methods. Outcome measures included response rates, participation rates, and comparative costs of each method. Of the 86 eligible practices contacted, 52 (60%) consented to participate. Mailing to individual physicians was the most cumbersome and expensive method and had the lowest response rate. Initial contacts with practice medical directors increased the participation rate substantially, and practice recruitment meetings improved both study participation and practice-project communication. Experience with these three methods suggests that the most efficient way to recruit practices for participation in a preventive services research trial involves targeted mailings and phone calls to medical directors, followed by on-site practice meetings.

Does the Brain Extrapolate the Position of a Transient Moving Target?

PubMed

Quinet, Julie; Goffart, Laurent

2015-08-26

When an object moves in the visual field, its motion evokes a streak of activity on the retina and the incoming retinal signals lead to robust oculomotor commands because corrections are observed if the trajectory of the interceptive saccade is perturbed by a microstimulation in the superior colliculus. The present study complements a previous perturbation study by investigating, in the head-restrained monkey, the generation of saccades toward a transient moving target (100-200 ms). We tested whether the saccades land on the average of antecedent target positions or beyond the location where the target disappeared. Using target motions with different speed profiles, we also examined the sensitivity of the process that converts time-varying retinal signals into saccadic oculomotor commands. The results show that, for identical overall target displacements on the visual display, saccades toward a faster target land beyond the endpoint of saccades toward a target moving slower. The rate of change in speed matters in the visuomotor transformation. Indeed, in response to identical overall target displacements and durations, the saccades have smaller amplitude when they are made in response to an accelerating target than to a decelerating one. Moreover, the motion-related signals have different weights depending upon their timing relative to the target onset: early signals are more influential in the specification of saccade amplitude than later signals. We discuss the "predictive" properties of the visuo-saccadic system and the nature of this location where the saccades land, after providing some critical comments to the "hic-et-nunc" hypothesis (Fleuriet and Goffart, 2012). Complementing the work of Fleuriet and Goffart (2012), this study is a contribution to the more general scientific research aimed at understanding how ongoing action is dynamically and adaptively adjusted to the current spatiotemporal aspects of its goal. Using the saccadic eye movement as a probe, we provide results that are critical for investigating and understanding the neural basis of motion extrapolation and prediction. Copyright © 2015 the authors 0270-6474/15/3511780-11$15.00/0.

Sex Differences in Workplace Satisfaction and Engagement of Academic Pathologists: Opportunities to Enhance Faculty Diversity.

PubMed

Howell, Lydia Pleotis; Lyons, Mary Lipscomb; Thor, Ann; Dandar, Valerie

2015-07-01

There is attrition of women across professorial ranks in academic pathology. Women are underrepresented as leaders; 15.4% of academic pathology departments are chaired by women, according to the Association of American Medical Colleges (AAMC). To identify areas for targeted interventions that can advance academic and leadership development of women faculty by examining (1) sex differences in career satisfaction in US medical school pathology departments participating in the AAMC's Faculty Forward Engagement Survey, and (2) findings from a survey of the Association of Pathology Chairs (APC). The AAMC Faculty Forward Engagement Survey data are from 14 US medical schools participating in the 2011-2012 survey. Pathologists' response rate was 66% (461 of 697). To investigate sex differences, t tests and χ(2) analyses were used. The APC survey, administered to academic department chairs, had a 55% response rate (104 of 189). According to the Faculty Forward Engagement Survey, women report more time in patient care and less time in research. Women consider formal mentorship, feedback, and career advancement more important than men do and are less satisfied with communication and governance. The APC survey shows that 20% to 40% of nonchair department leaders are women. More than half of chairs report satisfaction with the sex diversity of their departmental leaders. Opportunities exist for department chairs and professional organizations to create targeted interventions to support career satisfaction, recruitment, retention, and career and leadership development for women in academic pathology. Although chairs report satisfaction with diversity within department leadership, responses of women faculty indicate there is work to be done to grow more women leaders.

Evaluation of the Jonker-Volgenant-Castanon (JVC) assignment algorithm for track association

NASA Astrophysics Data System (ADS)

Malkoff, Donald B.

1997-07-01

The Jonker-Volgenant-Castanon (JVC) assignment algorithm was used by Lockheed Martin Advanced Technology Laboratories (ATL) for track association in the Rotorcraft Pilot's Associate (RPA) program. RPA is Army Aviation's largest science and technology program, involving an integrated hardware/software system approach for a next generation helicopter containing advanced sensor equipments and applying artificial intelligence `associate' technologies. ATL is responsible for the multisensor, multitarget, onboard/offboard track fusion. McDonnell Douglas Helicopter Systems is the prime contractor and Lockheed Martin Federal Systems is responsible for developing much of the cognitive decision aiding and controls-and-displays subsystems. RPA is scheduled for flight testing beginning in 1997. RPA is unique in requiring real-time tracking and fusion for large numbers of highly-maneuverable ground (and air) targets in a target-dense environment. It uses diverse sensors and is concerned with a large area of interest. Target class and identification data is tightly integrated with spatial and kinematic data throughout the processing. Because of platform constraints, processing hardware for track fusion was quite limited. No previous experience using JVC in this type environment had been reported. ATL performed extensive testing of the JVC, concentrating on error rates and run- times under a variety of conditions. These included wide ranging numbers and types of targets, sensor uncertainties, target attributes, differing degrees of target maneuverability, and diverse combinations of sensors. Testing utilized Monte Carlo approaches, as well as many kinds of challenging scenarios. Comparisons were made with a nearest-neighbor algorithm and a new, proprietary algorithm (the `Competition' algorithm). The JVC proved to be an excellent choice for the RPA environment, providing a good balance between speed of operation and accuracy of results.

Meta-analysis for deriving age- and gender-specific dose-response relationships between urinary cadmium concentration and {beta} {sub 2}-microglobulinuria under environmental exposure

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

Gamo, Masashi; Ono, Kyoko; Nakanishi, Junko

2006-05-15

A meta-analysis was conducted to derive age- and gender-specific dose-response relationships between urinary cadmium (Cd) concentration and {beta} {sub 2}-microglobulinuria ({beta}2MG-uria) under environmental exposure. {beta}2MG-uria was defined by a cutoff point of 1000 {mu}g {beta} {sub 2}-microglobulin/g creatinine. We proposed a model for describing the relationships among the interindividual variabilities in urinary Cd concentration, the ratio of Cd concentrations in the target organ and in urine, and the threshold Cd concentration in the target organ. The parameters in the model were determined so that good agreement might be achieved between the prevalence rates of {beta}2MG-uria reported in the literature andmore » those estimated by the model. In this analysis, only the data from the literature on populations environmentally exposed to Cd were used. Using the model and estimated parameters, the prevalence rate of {beta}2MG-uria can be estimated for an age- and gender-specific subpopulation for which the distribution of urinary Cd concentrations is known. The maximum permissible level of urinary Cd concentration was defined as the maximum geometric mean of the urinary Cd concentration in an age- and gender-specific subpopulation that would not result in a statistically significant increase in the prevalence rate of {beta}2MG-uria. This was estimated to be approximately 3 {mu}g/g creatinine for a population in a small geographical area and approximately 2 {mu}g/g creatinine for a nationwide population.« less

Intracellular Activation of Interferon Regulatory Factor-1 by Nanobodies to the Multifunctional (Mf1) Domain*

PubMed Central

Möller, Angeli; Pion, Emmanuelle; Narayan, Vikram; Ball, Kathryn L.

2010-01-01

IRF-1 is a tumor suppressor protein that activates gene expression from a range of promoters in response to stimuli spanning viral infection to DNA damage. Studies on the post-translational regulation of IRF-1 have been hampered by a lack of suitable biochemical tools capable of targeting the endogenous protein. In this study, phage display technology was used to develop a monoclonal nanobody targeting the C-terminal Mf1 domain (residues 301–325) of IRF-1. Intracellular expression of the nanobody demonstrated that the transcriptional activity of IRF-1 is constrained by the Mf1 domain as nanobody binding gave an increase in expression from IRF-1-responsive promoters of up to 8-fold. Furthermore, Mf1-directed nanobodies have revealed an unexpected function for this domain in limiting the rate at which the IRF-1 protein is degraded. Thus, the increase in IRF-1 transcriptional activity observed on nanobody binding is accompanied by a significant reduction in the half-life of the protein. In support of the data obtained using nanobodies, a single point mutation (P325A) involving the C-terminal residue of IRF-1 has been identified, which results in greater transcriptional activity and a significant increase in the rate of degradation. The results presented here support a role for the Mf1 domain in limiting both IRF-1-dependent transcription and the rate of IRF-1 turnover. In addition, the data highlight a route for activation of downstream genes in the IRF-1 tumor suppressor pathway using biologics. PMID:20817723

Spatial representation and cognitive modulation of response variability in the lateral intraparietal area priority map.

PubMed

Falkner, Annegret L; Goldberg, Michael E; Krishna, B Suresh

2013-10-09

The lateral intraparietal area (LIP) in the macaque contains a priority-based representation of the visual scene. We previously showed that the mean spike rate of LIP neurons is strongly influenced by spatially wide-ranging surround suppression in a manner that effectively sharpens the priority map. Reducing response variability can also improve the precision of LIP's priority map. We show that when a monkey plans a visually guided delayed saccade with an intervening distractor, variability (measured by the Fano factor) decreases both for neurons representing the saccade goal and for neurons representing the broad spatial surround. The reduction in Fano factor is maximal for neurons representing the saccade goal and steadily decreases for neurons representing more distant locations. LIP Fano factor changes are behaviorally significant: increasing expected reward leads to lower variability for the LIP representation of both the target and distractor locations, and trials with shorter latency saccades are associated with lower Fano factors in neurons representing the surround. Thus, the LIP Fano factor reflects both stimulus and behavioral engagement. Quantitative modeling shows that the interaction between mean spike count and target-receptive field (RF) distance in the surround during the predistractor epoch is multiplicative: the Fano factor increases more steeply with mean spike count further away from the RF. A negative-binomial model for LIP spike counts captures these findings quantitatively, suggests underlying mechanisms based on trial-by-trial variations in mean spike rate or burst-firing patterns, and potentially provides a principled framework to account simultaneously for the previously observed unsystematic relationships between spike rate and variability in different brain areas.

Targeted cardiopulmonary resuscitation training focused on the family members of high-risk patients at a regional medical center: A comparison between family members of high-risk and no-risk patients.

PubMed

Han, Kap Su; Lee, Ji Sung; Kim, Su Jin; Lee, Sung Woo

2018-05-01

We developed a hospital-based cardiopulmonary resuscitation (CPR) training model focused on the target population (family members of patients with potential risks for cardiac arrest) and compared the outcome of CPR training between target and non-target populations for validity. Family members of patients in training were divided into three groups on the basis of patients' diseases, as follows: 1) the cardio-specific (CS) risk group, including family members of patients with cardiac disease at risk of cardiac arrest; 2) the cardiovascular (CV) risk group, including family members of patients with risk factors for cardiovascular disease; and 3) the no-risk group. Pre- and posttraining surveys and skill tests as well as a post-training 3-month telephone survey were conducted. Educational outcomes were analyzed. A total of 203 family members were enrolled into 21 CPR training classes. The CS group (n=88) included elderly persons and housewives with a lower level of education compared with the CV (n=79) and no-risk groups (n=36). The CS group was motivated by healthcare professionals and participated in the training course. The CS, CV, and no-risk groups showed improvements in knowledge, willingness to perform CPR, and skills. Despite the older age and lower level of education in the CS group, the effects of education were similar to those in the other groups. A high rate of response and secondary propagation of CPR training were observed in the CS group. Family members of patients with heart disease could be an appropriate target population for CPR training, particularly in terms of recruitment and secondary propagation. Targeted intervention may be an effective training strategy to improve bystander CPR rates.

A Needs Assessment for a Longitudinal Emergency Medicine Intern Curriculum

PubMed Central

Shappell, Eric; Ahn, James

2017-01-01

Introduction A key task of emergency medicine (EM) training programs is to develop a consistent knowledge of core content in recruits with heterogeneous training backgrounds. The traditional model for delivering core content is lecture-based weekly conference; however, a growing body of literature finds this format less effective and less appealing than alternatives. We sought to address this challenge by conducting a needs assessment for a longitudinal intern curriculum for millennial learners. Methods We surveyed all residents from the six EM programs in the greater Chicago area regarding the concept, format, and scope of a longitudinal intern curriculum. Results We received 153 responses from the 300 residents surveyed (51% response rate). The majority of respondents (80%; 82% of interns) agreed or strongly agreed that a dedicated intern curriculum would add value to residency education. The most positively rated teaching method was simulation sessions (91% positive responses), followed by dedicated weekly conference time (75% positive responses) and dedicated asynchronous resources (71% positive responses). Less than half of respondents (47%; 26% of interns) supported use of textbook readings in the curriculum. Conclusion There is strong learner interest in a longitudinal intern curriculum. This needs assessment can serve to inform the development of a universal intern curriculum targeting the millennial generation. PMID:28116005

[Associations between workplace bullying, harassment, and stress reactions of professional caregivers at welfare facilities for the elderly in Japan].

PubMed

Taniguchi, Toshiyo; Takaki, Jiro; Harano, Kaori; Hirokawa, Kumi; Takahashi, Kazumi; Fukuoka, Etsuko

2012-01-01

The purpose of this study was to describe workplace bullying experienced by professional caregivers at welfare facilities for the elderly in Japan and to confirm its effects on stress reactions. A cross-sectional survey was carried out using self-administered questionnaires in 2009 of all the employees working in rural area of facilities for long-term care. Among the 1,233 respondents who filled out all questionnaires concerning stress reactions the Japanese version of the Negative Acts Questionnaire (NAQ) (response rate: 63.9%), we analyzed 897 professional caregivers. We measured stress reactions by using the stress reaction scores of the Brief Job Stress Questionnaire (29 items) and workplace bullying and harassment by using NAQ. We used the unpaired t-test and analysis of covariance (ANCOVA) to compare crude and adjusted average stress reactions with groups classified on the basis of each subscale of the NAQ or all of them. About 40% of both men and women suffered from "malicious gossip" and over 60% of both men and women experienced "someone withholding necessary information so that their work gets complicated". Among women, scores of the lack of vigor and fatigue were significantly higher in caregivers targeted by person-related bullying than those not targeted (p<0.05). Scores of depression were significantly higher in caregivers targeted by work-related bullying than those not targeted (p<0.05). Scores of anxiety were significantly higher among caregivers targeted by sexual harassment than those not targeted (p<0.05). Among men, scores of the lack of vigor were significantly lower in caregivers targeted by work-related bullying than those not targeted (p<0.05). Among women, workplace bullying or harassment could may aggravate effects on psychological stress responses. While among men, work-related bullying was positively associated with vigor.

The stigma of clean dieting and orthorexia nervosa.

PubMed

Nevin, Suzanne M; Vartanian, Lenny R

2017-01-01

Although the stigma of eating disorders such as anorexia has been well established, little is known about the social consequences of "clean dieting" and orthorexia nervosa. In two studies, we examined the social stigma of clean dieting and orthorexia. In Study 1, participants read a vignette describing a woman following a "clean" diet, a woman with anorexia, or a control target (minimal information about the individual). In Study 2, participants read a vignette describing a woman with orthorexia, a woman displaying identical orthorexic behaviors but without the orthorexia label, a woman with anorexia, or a control target. Participants then rated the target individual on a range of measures assessing stereotypes, emotions, and behavioral intentions toward the target. Study 1 found that the clean-dieting target was evaluated more negatively than the control target on some dimensions, but less negatively than the target with anorexia nervosa. Study 2 found that evaluations of the targets with orthorexia nervosa were more negative than evaluations of a control target, but did not differ from evaluations of the target with anorexia nervosa. Perceptions of the target's control over her behavior were associated with more positive evaluations (Studies 1 and 2), whereas perceptions of blame and responsibility for the condition were associated with more negative evaluations (Study 2). Overall, these findings highlight the potential negative social consequences of clean dieting and orthorexia nervosa, and point to perceptions of control and blame as potential mechanisms underlying the stigma of these conditions.

Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope

PubMed Central

Anthony, Colin; York, Talita; Bekker, Valerie; Matten, David; Selhorst, Philippe; Ferreria, Roux-Cil; Garrett, Nigel J.; Karim, Salim S. Abdool; Morris, Lynn; Wood, Natasha T.; Moore, Penny L.

2017-01-01

ABSTRACT V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch, which took just 7.5 weeks to reach >50% frequency. In contrast, escape from the bNAbs was mediated via multiple pathways and took longer, with escape first occurring through an increase in V1 loop length, which took 46 weeks to reach 50% frequency, followed by an N332-to-N334 reversion, which took 66 weeks. Importantly, bNAb escape was incomplete, with contemporaneous neutralization observed up to 3 years postinfection. Both the ssNAb response and the bNAb response were modulated by the presence/absence of the N332 glycan, indicating an overlap between the two epitopes. Thus, selective pressure by ssNAbs to maintain the N332 glycan may have constrained the bNAb escape pathway. This slower and incomplete viral escape resulted in prolonged exposure of the bNAb epitope, which may in turn have aided the maturation of the bNAb lineage. IMPORTANCE The development of an HIV-1 vaccine is of paramount importance, and broadly neutralizing antibodies are likely to be a key component of a protective vaccine. The V3-glycan-targeting bNAb responses are among the most promising vaccine targets, as they are commonly elicited during infection. Understanding the interplay between viral evolution and the development of these antibodies provides insights that may guide immunogen design. Our work contrasted the dynamics of the early strain-specific antibodies and the later broadly neutralizing responses to a common Env target (V3C3), showing slower and more complex escape from bNAbs. Constrained bNAb escape, together with evidence of contemporaneous autologous virus neutralization, supports the proposal that prolonged exposure of the bNAb epitope enabled the maturation of the bNAb lineage. PMID:28679760

Pathologic response after preoperative therapy predicts prognosis of Chinese colorectal cancer patients with liver metastases.

PubMed

Wang, Yun; Yuan, Yun-Fei; Lin, Hao-Cheng; Li, Bin-Kui; Wang, Feng-Hua; Wang, Zhi-Qiang; Ding, Pei-Rong; Chen, Gong; Wu, Xiao-Jun; Lu, Zhen-Hai; Pan, Zhi-Zhong; Wan, De-Sen; Sun, Peng; Yan, Shu-Mei; Xu, Rui-Hua; Li, Yu-Hong

2017-10-02

Pathologic response is evaluated according to the extent of tumor regression and is used to estimate the efficacy of preoperative treatment. Several studies have reported the association between the pathologic response and clinical outcomes of colorectal cancer patients with liver metastases who underwent hepatectomy. However, to date, no data from Chinese patients have been reported. In this study, we aimed to evaluate the association between the pathologic response to pre-hepatectomy chemotherapy and prognosis in a cohort of Chinese patients. In this retrospective study, we analyzed the data of 380 liver metastases in 159 patients. The pathologic response was evaluated according to the tumor regression grade (TRG). The prognostic role of pathologic response in recurrence-free survival (RFS) and overall survival (OS) was assessed using Kaplan-Meier curves with the log-rank test and multivariate Cox models. Factors that had potential influence on pathologic response were also analyzed using multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests. Patients whose tumors achieved pathologic response after preoperative chemotherapy had significant longer RFS and OS than patients whose tumor had no pathologic response to chemotherapy (median RFS: 9.9 vs. 6.5 months, P = 0.009; median OS: 40.7 vs. 28.1 months, P = 0.040). Multivariate logistic regression and Kruskal-Wallis/Mann-Whitney U tests showed that metastases with small diameter, metastases from the left-side primary tumors, and metastases from patients receiving long-duration chemotherapy had higher pathologic response rates than their control metastases (all P < 0.05). A decrease in the serum carcinoembryonic antigen (CEA) level after preoperative chemotherapy predicted an increased pathologic response rate (P < 0.05). Although the application of targeted therapy did not significantly influence TRG scores of all cases of metastases, the addition of cetuximab to chemotherapy resulted in a higher pathologic response rate when combined with irinotecan-based regimens rather than with oxaliplatin-based regimens. We found that the evaluation of pathologic response may predict the prognosis of Chinese colorectal cancer patients with liver metastases after preoperative chemotherapy. Small tumor diameter, long-duration chemotherapy, left primary tumor, and decreased serum CEA level after chemotherapy are associated with increased pathologic response rates.

Validation of social skills of adolescent males in an interview conversation with a previously unknown adult.

PubMed

Spence, S H

1981-01-01

Seventy convicted young male offenders were videotaped during a 5-min standardized interview with a previously unknown adult. In order to determine the social validity of the behavioral components of social interaction for this population, measures of 13 behaviors were obtained from the tapes. These measures were then correlated with ratings of friendliness, social anxiety, social skills performance, and employability made by four independent adult judges from the same tapes. It was found that measures of eye contact and verbal initiations were correlated significantly with all four criterion rating scales. The frequencies of smiling and speech dysfluencies were both significantly correlated with ratings of friendliness and employability. The amount spoken was found to be a significant predictor of social skills performance whereas the frequency of head movements influenced judgments of social anxiety. The latency of response was negatively correlated with social skills and employability ratings and the frequency of question-asking and interruptions correlated significantly with friendliness, social skills, and employability ratings. Finally, the levels of gestures, gross body movements, and attention feedback responses were not found to influence judgments on any of the criterion scales. The implications of the study for selection of targets for social skills training for adolescent male offenders are discussed.

Validation of social skills of adolescent males in an interview conversation with a previously unknown adult.

PubMed Central

Spence, S H

1981-01-01

Seventy convicted young male offenders were videotaped during a 5-min standardized interview with a previously unknown adult. In order to determine the social validity of the behavioral components of social interaction for this population, measures of 13 behaviors were obtained from the tapes. These measures were then correlated with ratings of friendliness, social anxiety, social skills performance, and employability made by four independent adult judges from the same tapes. It was found that measures of eye contact and verbal initiations were correlated significantly with all four criterion rating scales. The frequencies of smiling and speech dysfluencies were both significantly correlated with ratings of friendliness and employability. The amount spoken was found to be a significant predictor of social skills performance whereas the frequency of head movements influenced judgments of social anxiety. The latency of response was negatively correlated with social skills and employability ratings and the frequency of question-asking and interruptions correlated significantly with friendliness, social skills, and employability ratings. Finally, the levels of gestures, gross body movements, and attention feedback responses were not found to influence judgments on any of the criterion scales. The implications of the study for selection of targets for social skills training for adolescent male offenders are discussed. PMID:7287599

Effects of the herbicide glyphosate on non-target plant native species from Chaco forest (Argentina).

PubMed

Florencia, Ferreira María; Carolina, Torres; Enzo, Bracamonte; Leonardo, Galetto

2017-10-01

Agriculture based on transgenic crops has expanded in Argentina into areas formerly occupied by Chaco forest. Even though glyphosate is the herbicide most widely used in the world, increasing evidence indicates severe ecotoxicological effects on non-target organisms as native plants. The aim of this work is to determine glyphosate effects on 23 native species present in the remaining Chaco forests immersed in agricultural matrices. This is a laboratory/greenhouse approach studying acute effects on seedlings after 21 days. A gradient of glyphosate rates (525, 1050, 2100, 4200, and 8400g ai/Ha; recommended field application rate (RFAR) = 2100g ai/Ha) was applied on four-week seedlings cultivated in a greenhouse and response variables (phytotoxicity, growth reduction, and sensitivity to the herbicide) were measured. This gradient of herbicide rates covers realistic rates of glyphosate applications in the crop field and also those that can reach vegetation of forest relicts by off-target drift and overspray. Testing was performed following guidelines for vegetative vigour (post-germination spray). All species showed lethal or sublethal effects after the application of the 25% of RFAR (50% of species showed severe phytotoxicity or death and 70% of species showed growth reduction). The results showed a gradient of sensitivity to glyphosate by which some of the studied species are very sensitive to glyphosate and seedlings died with 25% of RFAR while other species can be classified as herbicide-tolerant. Thus, the vegetation present in the forest relicts could be strongly affected by glyphosate application on crops. Lethal and sublethal effects of glyphosate on non-target plants could promote both the loss of biodiversity in native forest relicts immersed in the agroecosystems and the selection of new crop weeds considering that some biotypes are continuously exposed to low doses of glyphosate. Copyright © 2017 Elsevier Inc. All rights reserved.

Mixed oxidizer hybrid propulsion system optimization under uncertainty using applied response surface methodology and Monte Carlo simulation

NASA Astrophysics Data System (ADS)

Whitehead, James Joshua

The analysis documented herein provides an integrated approach for the conduct of optimization under uncertainty (OUU) using Monte Carlo Simulation (MCS) techniques coupled with response surface-based methods for characterization of mixture-dependent variables. This novel methodology provides an innovative means of conducting optimization studies under uncertainty in propulsion system design. Analytic inputs are based upon empirical regression rate information obtained from design of experiments (DOE) mixture studies utilizing a mixed oxidizer hybrid rocket concept. Hybrid fuel regression rate was selected as the target response variable for optimization under uncertainty, with maximization of regression rate chosen as the driving objective. Characteristic operational conditions and propellant mixture compositions from experimental efforts conducted during previous foundational work were combined with elemental uncertainty estimates as input variables. Response surfaces for mixture-dependent variables and their associated uncertainty levels were developed using quadratic response equations incorporating single and two-factor interactions. These analysis inputs, response surface equations and associated uncertainty contributions were applied to a probabilistic MCS to develop dispersed regression rates as a function of operational and mixture input conditions within design space. Illustrative case scenarios were developed and assessed using this analytic approach including fully and partially constrained operational condition sets over all of design mixture space. In addition, optimization sets were performed across an operationally representative region in operational space and across all investigated mixture combinations. These scenarios were selected as representative examples relevant to propulsion system optimization, particularly for hybrid and solid rocket platforms. Ternary diagrams, including contour and surface plots, were developed and utilized to aid in visualization. The concept of Expanded-Durov diagrams was also adopted and adapted to this study to aid in visualization of uncertainty bounds. Regions of maximum regression rate and associated uncertainties were determined for each set of case scenarios. Application of response surface methodology coupled with probabilistic-based MCS allowed for flexible and comprehensive interrogation of mixture and operating design space during optimization cases. Analyses were also conducted to assess sensitivity of uncertainty to variations in key elemental uncertainty estimates. The methodology developed during this research provides an innovative optimization tool for future propulsion design efforts.

Multispectral imaging method and apparatus

DOEpatents

Sandison, D.R.; Platzbecker, M.R.; Vargo, T.D.; Lockhart, R.R.; Descour, M.R.; Richards-Kortum, R.

1999-07-06

A multispectral imaging method and apparatus are described which are adapted for use in determining material properties, especially properties characteristic of abnormal non-dermal cells. A target is illuminated with a narrow band light beam. The target expresses light in response to the excitation. The expressed light is collected and the target's response at specific response wavelengths to specific excitation wavelengths is measured. From the measured multispectral response the target's properties can be determined. A sealed, remote probe and robust components can be used for cervical imaging. 5 figs.

Multispectral imaging method and apparatus

DOEpatents

Sandison, David R.; Platzbecker, Mark R.; Vargo, Timothy D.; Lockhart, Randal R.; Descour, Michael R.; Richards-Kortum, Rebecca

1999-01-01

A multispectral imaging method and apparatus adapted for use in determining material properties, especially properties characteristic of abnormal non-dermal cells. A target is illuminated with a narrow band light beam. The target expresses light in response to the excitation. The expressed light is collected and the target's response at specific response wavelengths to specific excitation wavelengths is measured. From the measured multispectral response the target's properties can be determined. A sealed, remote probe and robust components can be used for cervical imaging

Frequency Modulation of Transcriptional Bursting Enables Sensitive and Rapid Gene Regulation.

PubMed

Li, Congxin; Cesbron, François; Oehler, Michael; Brunner, Michael; Höfer, Thomas

2018-04-25

Gene regulation is a complex non-equilibrium process. Here, we show that quantitating the temporal regulation of key gene states (transcriptionally inactive, active, and refractory) provides a parsimonious framework for analyzing gene regulation. Our theory makes two non-intuitive predictions. First, for transcription factors (TFs) that regulate transcription burst frequency, as opposed to amplitude or duration, weak TF binding is sufficient to elicit strong transcriptional responses. Second, refractoriness of a gene after a transcription burst enables rapid responses to stimuli. We validate both predictions experimentally by exploiting the natural, optogenetic-like responsiveness of the Neurospora GATA-type TF White Collar Complex (WCC) to blue light. Further, we demonstrate that differential regulation of WCC target genes is caused by different gene activation rates, not different TF occupancy, and that these rates are tuned by both the core promoter and the distance between TF-binding site and core promoter. In total, our work demonstrates the relevance of a kinetic, non-equilibrium framework for understanding transcriptional regulation. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Biological effectiveness of nuclear fragments produced by high-energy protons interacting in tissues near the bone- soft tissue interface

NASA Astrophysics Data System (ADS)

Shavers, Mark Randall

1999-12-01

High-energy protons in the galactic cosmic rays (GCR)-or generated by nuclear interactions of GCR heavy-ions with material-are capable of penetrating great thicknesses of shielding to irradiate humans in spacecraft or in lunar or Martian habitats. As protons interact with the nuclei of the elemental constituents of soft tissue and bone, low energy nuclei-target fragments-are emitted into the cells responsible for bone development and maintenance and for hematopoiesis. Leukemogenesis is the principal endpoint of concern because it is the most likely deleterious effect, and it has a short latency period and comparatively low survival rate, although other myelo- proliferative disorders and osteosarcoma also may be induced. A one-dimensional proton-target fragment transport model was used to calculate the energy spectra of fragments produced in bone and soft tissue, and present in marrow cavities at distances from a bone interface. In terms of dose equivalent, the target fragments are as significant as the incident protons. An average radiation quality factor was found to be between 1.8 and 2.6. Biological response to the highly non- uniform energy deposition of the target fragments is such that an alternative approach to conventional predictive risk assessment is needed. Alternative procedures are presented. In vitro cell response and relative biological effectiveness were calculated from the radial dose distribution of each fragment produced by 1-GeV protons using parameters of a modified Ion-Gamma- Kill (IGK) model of radiation action. The modelled endpoints were survival of C3H10t 1/2 and V79 cells, neoplastic transformation of C3H10t1/2 cells, and mutation of the X-linked hypoxanthine phosphoribosyltransferase (HPRT) locus in V79 cells. The dose equivalent and cell responses increased by 10% or less near the interface. Since RBE increases with decreasing dose in the IGK model, comparisons with quality factors were made at dose levels 0.01 <= D [Gy] <= 2. Applying average quality factors derived herein to GCR exposures results in a <= 5% increase of in average quality. Calculated RBEs indicate that accepted quality factors for high-energy protons may be too low due to the relatively high effectiveness of the low-charged target fragments. Derived RBEs for target fragments increase the calculated biological effectiveness of GCR by 20% to 180%.

Recruitment of young adults for weight gain prevention: randomized comparison of direct mail strategies.

PubMed

Crane, Melissa M; LaRose, Jessica Gokee; Espeland, Mark A; Wing, Rena R; Tate, Deborah F

2016-06-08

Recruiting young adults (ages 18-35 years) into weight gain prevention intervention studies is challenging and men are particularly difficult to reach. This paper describes two studies designed to improve recruitment for a randomized trial of weight gain prevention interventions. Study 1 used a quasi-experimental design to test the effect of two types of direct mailings on their overall reach. Study 2 used a randomized design to test the effect of using targeted messages to increase recruitment of men into the trial. For Study 1, 60,000 male and female young-adult households were randomly assigned to receive either a recruitment brochure or postcard. Visits to recruitment websites during each mailing period were used to assess response to each mailing. Study 2 focused on postcard recruitment only. These households received either a targeted or generic recruitment postcard, where targeted postcards included the word "Men" in the headline text. Response rates to each type of card were categorized based on participant report of mailing received. The reach of the postcards and brochures were similar (421 and 386 website visits, respectively; P = 0.22). Individuals who received the brochure were more likely to initiate the online screener than those who received a postcard (P = 0.01). In Study 2, of those who completed the telephone screening, 60.9 % of men (n = 23) had received the targeted postcard as compared to the generic postcard (39.1 %, P = 0.30). The reverse was true for women (n = 62, 38.7 vs. 61.3 %, P = 0.08). These studies suggest there was little difference in the reach of postcards versus brochures. However, recipients of brochures were more likely to continue to the next stage of study participation. As expected, men's response to the weight gain prevention messages was lower than women's response; but using targeted messages appears to have modestly increased the proportion of male respondents. These studies add to the limited experimental literature on recruitment messaging and provide further indication for using targeted messages to reach underrepresented populations while providing initial evidence on the effect of mailing type on message reach. The Study of Novel Approaches to Weight Gain Prevention was registered with ClinicalTrials.gov (identifier: NCT01183689 ) on 13 August 2010.

IDENTIFYING AND TARGETING TUMOR-INITIATING CELLS IN THE TREATMENT OF BREAST CANCER

PubMed Central

Wei, Wei; Lewis, Michael T.

2015-01-01

Breast cancer is the most common cancer in women (exclusive of skin cancer), and is the second leading cause of cancer-related deaths. Although conventional and targeted therapies have improved survival rates, there are still considerable challenges in treating breast cancer, including treatment resistance, disease recurrence, and metastasis. Treatment resistance can be either de novo - due to traits that tumor cells possess prior to treatment, or acquired, - due to traits that tumor cells gain in response to treatment. A recently proposed mechanism of de novo resistance invokes existence of a specialized subset of cancer cells defined as tumor-initiating cells (TICs), or cancer stem cells (CSC). TICs have the capacity to self-renew and regenerate new tumors that consist of all clonally-derived cell types present in the parental tumor. There are data to suggest that TICs are resistant to many conventional cancer therapies, and survive treatment in spite of dramatic shrinkage of the tumor. Residual TICs can then eventually regrow resulting in disease relapse. It is also hypothesized that TIC may be responsible for metastatic disease. If these hypotheses are correct, targeting TICs may be imperative to achieve cure. In this review, we discuss evidence for breast TICs and their apparent resistance to conventional chemotherapy and radiotherapy, as well as to various targeted therapies. We also address the potential impact of breast TIC plasticity and metastatic potential on therapeutic strategies. Finally, we describe several genes and signaling pathways that appear important for TIC function that may represent promising therapeutic targets. PMID:25876646

Design and evaluation of dual CD44 receptor and folate receptor-targeting double-smart pH-response multifunctional nanocarrier

NASA Astrophysics Data System (ADS)

Chen, Daquan; Song, Xiaoyan; Wang, Kaili; Guo, Chunjing; Yu, Yueming; Fan, Huaying; Zhao, Feng

2017-12-01

In this article, in order to enhance the bioavailiability and tumor targeting of curcumin (Cur), the oligosaccharides of hyaluronan conjugates, folic acid-oligosaccharides of hyaluronan-acetal-menthone 1,2-glycerol ketal (FA-oHA-Ace-MGK) carried oHA as a ligand to CD44 receptor, double-pH-sensitive Ace-MGK as hydrophobic moieties, and FA as the target of folate receptor. The structure characteristics of this smart response multifunctional dual-targeting nano-sized carrier was measured by fourier-transform infrared (FT-IR) and nuclear magnetic resonance (1H-NMR). Cur, an anticancer drug, was successfully loaded in FA-oHA-Ace-MGK micelles by self-assembly. The measurement results of transmission electron microscopy (TEM) presented that the Cur-loaded micelles were spherical in shape with the average size of 166.3 ± 2.12 nm and zeta potential - 30.07 mV. Much more encapsulated Cur could be released at mildly acidic environments than at pH 7.4, from the Cur-FA-oHA-Ace-MGK micelles. Cytotoxicity assay indicated that non-Cur loaded micelles mostly had no cytotoxicity to MCF-7 cells and A549 cells, and Cur-loaded micelles had significantly lower survival rate than Cur suspension in the same concentration, which proved that the drug-loaded micelles can effectively inhibit tumor cell growth. The targeting of CD44 receptors and folate receptors was proved in vitro cellular uptake assay. These results showed the promising potential of FA-oHA-Ace-MGK as an effective nano-sized carrier for anti-tumor drug delivery.

Tumor-targeted IL-2 amplifies T cell-mediated immune response induced by gene therapy with single-chain IL-12

PubMed Central

Lode, Holger N.; Xiang, Rong; Duncan, Steven R.; Theofilopoulos, Argyrios N.; Gillies, Stephen D.; Reisfeld, Ralph A.

1999-01-01

Induction, maintenance, and amplification of tumor-protective immunity after cytokine gene therapy is essential for the clinical success of immunotherapeutic approaches. We investigated whether this could be achieved by single-chain IL-12 (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein containing a tumor-specific recombinant anti-ganglioside GD2 antibody and IL-2 (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we demonstrate the absence of liver and bone marrow metastases after a lethal challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated with scIL-12-producing NXS2 cells and given a booster injection of low-dose ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3 months after initial vaccination, in contrast to control animals treated with a nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed a reactivation of CD8+ T cells and subsequent MHC class I-restricted tumor target cell lysis in vitro. The sequential increase in the usage of TCR chains Vβ11 and -13 in mouse CD8+ T cells after vaccination and amplification with ch14.18-IL-2 suggests that the initial polyclonal CD8+ T cell response is effectively boosted by targeted IL-2. In conclusion, we demonstrate that a successful boost of a partially protective memory T cell immune response that is induced by scIL-12 gene therapy could be generated by tumor-specific targeting of IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success rates of clinical cancer vaccine trials. PMID:10411920

Multifunctional nanosheets based on folic acid modified manganese oxide for tumor-targeting theranostic application

NASA Astrophysics Data System (ADS)

Hao, Yongwei; Wang, Lei; Zhang, Bingxiang; Zhao, Hongjuan; Niu, Mengya; Hu, Yujie; Zheng, Cuixia; Zhang, Hongling; Chang, Junbiao; Zhang, Zhenzhong; Zhang, Yun

2016-01-01

It is highly desirable to develop smart nanocarriers with stimuli-responsive drug-releasing and diagnostic-imaging functions for cancer theranostics. Herein, we develop a reduction and pH dual-responsive tumor theranostic platform based on degradable manganese dioxide (MnO2) nanosheets. The MnO2 nanosheets with a size of 20-60 nm were first synthesized and modified with (3-Aminopropyl) trimethoxysilane (APTMS) to get amine-functionalized MnO2, and then functionalized by NH2-PEG2000-COOH (PEG). The tumor-targeting group, folic acid (FA), was finally conjugated with the PEGylated MnO2 nanosheets. Then, doxorubicin (DOX), a chemotherapeutic agent, was loaded onto the modified nanosheets through a physical adsorption, which was designated as MnO2-PEG-FA/DOX. The prepared MnO2-PEG-FA/DOX nanosheets with good biocompatibility can not only efficiently deliver DOX to tumor cells in vitro and in vivo, leading to enhanced anti-tumor efficiency, but can also respond to a slightly acidic environment and high concentration of reduced glutathione (GSH), which caused degradation of MnO2 into manganese ions enabling magnetic resonance imaging (MRI). The longitudinal relaxation rate r 1 was 2.26 mM-1 s-1 at pH 5.0 containing 2 mM GSH. These reduction and pH dual-responsive biodegradable nanosheets combining efficient MRI and chemotherapy provide a novel and promising platform for tumor-targeting theranostic application.

Mitochondrial alkaline pH-responsive drug release mediated by Celastrol loaded glycolipid-like micelles for cancer therapy.

PubMed

Tan, Yanan; Zhu, Yun; Zhao, Yue; Wen, Lijuan; Meng, Tingting; Liu, Xuan; Yang, Xiqin; Dai, Suhuan; Yuan, Hong; Hu, Fuqiang

2018-02-01

Mitochondria, crucial regulators of inducing tumor cells apoptosis, can be treated as the prime target for tumor therapy. The selective and responsive release of proapoptotic therapeutics into mitochondria may notably improve antitumor efficiency. Herein, (4-Carboxybutyl) triphenylphosphonium bromide (CTPP), a lipophilic cation, was conjugated with glucolipid-like conjugates (CSOSA) to produce mitochondria-targeted conjugates (CTPP-CSOSA). Loading with weakly acidic drug Celastrol (Cela), CTPP-CSOSA/Cela micelles could selectively respond to mitochondrial alkaline pH (pH 8.0), controlled by the weaker interaction between hydrophobic core of micelles and Cela with higher solubility at pH 8.0. However, there was a slow drug release behavior at pH 7.4 and pH 5.0. It illustrated that CTPP-CSOSA/Cela could realize mitochondrial fast drug release, and decrease drug leakage in the cytoplasm and lysosome. CTPP-CSOSA/Cela highly enhanced ROS levels, which further induced mitochondria membrane potential decreasing and more Cytochrome C releasing into cytoplasm, then promoted tumor cells apoptosis notably. In vivo, CTPP-CSOSA had an enhanced accumulation in tumor tissue, compared with CSOSA. Moreover, the tumor-inhibition rate of CTPP-CSOSA/Cela was 80.17%, which was significantly higher than CSOSA/Cela (58.35%) and Cela (54.89%). Thus, CTPP-CSOSA/Cela micelles with mitochondrial targeting and alkaline pH-responsive release capability could provide a new strategy for tumor therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Low-dose oral microemulsion ciclosporin for severe, refractory ulcerative colitis.

PubMed

de Saussure, P; Soravia, C; Morel, P; Hadengue, A

2005-08-01

The optimal modalities of treatment with oral microemulsion ciclosporin in patients with severe, steroid-refractory ulcerative colitis are uncertain. To assess the applicability, in terms of efficacy and tolerability, of a standard oral microemulsion ciclosporin treatment protocol targeting relatively low blood ciclosporin concentrations, in patients with severe, steroid-resistant ulcerative colitis. Patients with a severe attack of ulcerative colitis and no satisfactory response to intravenous corticosteroids were started on oral microemulsion ciclosporin. Dosages were adapted according to a standard protocol, targeting a blood predose ciclosporin concentration (C0) of 100-200 ng/mL. Patients without a clinical response on day 8 were scheduled for colectomy. Sixteen patients were enrolled. A clinical response was observed in 14/16 (88%). The mean clinical activity index scores and concentrations of C-reactive protein on days 0, 4 and 8 were 11.8, 6.7 and 4.1, and 50.3, 19.3 and 9.7 mg/L respectively. The mean C0 (days 0-8) was 149 pg/mL. The mean creatinine clearance rates on days 0 and 8 were 88 and 96 mL/min. One patient had an acute elevation of transaminases that resulted in discontinuing ciclosporin. Even when dosed for a target C0 of 100-200 ng/mL, oral microemulsion ciclosporin for severe, steroid-refractory ulcerative colitis achieves an efficacy similar to that attained with higher, potentially more toxic levels. The oral route should replace intravenous treatment in this clinical setting.

No significant impact of response to prior androgen receptor-axis-targeted agents on the efficacy of subsequent docetaxel in patients with metastatic castration-resistant prostate cancer.

PubMed

Miyake, Hideaki; Matsushita, Yuto; Tamura, Keita; Motoyama, Daisuke; Ito, Toshiki; Sugiyama, Takayuki; Otsuka, Atsushi

2018-06-01

To investigate whether the response to an androgen receptor-axis-targeted (ARAT) agent is associated with the efficacy of subsequent docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients. This study included 114 consecutive mCRPC patients, comprising 54 and 60 patients who progressed with abiraterone acetate (AA) and enzalutamide (Enz), respectively, before the introduction of docetaxel. The impact of the response to either ARAT agent on the activity of docetaxel was assessed. Following ARAT therapy, a prostate-specific antigen (PSA) response was observed in 73 of the 114 patients, of whom 33 and 40 received AA and Enz, respectively. In the 114 patients, PSA response to docetaxel was achieved in 48 (42.1%) patients, and median PSA progression-free survival (PFS) and overall survival (OS) with docetaxel were 7.2 and 17.5 months, respectively. No significant difference was noted in PSA response rate, PSA PFS or OS with docetaxel between responders and non-responders to a prior ARAT agent in the overall 114 patients, 54 receiving AA and 60 receiving Enz. Despite the absence of a significant impact of the response to a prior ARAT agent on PSA PFS or OS by univariate analysis, independent prognostic predictors were identified by multivariate analysis, as performance status (PS) for PSA PFS, and PS and visceral metastasis for OS. Disease control by docetaxel may not be affected by the response to a prior ARAT agent. Therefore, a prior response to an ARAT agent should not influence the decision on the subsequent introduction of docetaxel for mCRPC patients.

Green tea proanthocyanidins cause impairment of hormone-regulated larval development and reproductive fitness via repression of juvenile hormone acid methyltransferase, insulin-like peptide and cytochrome P450 genes in Anopheles gambiae sensu stricto.

PubMed

Muema, Jackson M; Nyanjom, Steven G; Mutunga, James M; Njeru, Sospeter N; Bargul, Joel L

2017-01-01

Successful optimization of plant-derived compounds into control of nuisance insects would benefit from scientifically validated targets. However, the close association between the genotypic responses and physiological toxicity effects mediated by these compounds remains underexplored. In this study, we evaluated the sublethal dose effects of proanthocyanidins (PAs) sourced from green tea (Camellia sinensis) on life history traits of Anopheles gambiae (sensu stricto) mosquitoes with an aim to unravel the probable molecular targets. Based on the induced phenotypic effects, genes selected for study targeted juvenile hormone (JH) biosynthesis, signal transduction, oxidative stress response and xenobiotic detoxification in addition to vitellogenesis in females. Our findings suggest that chronic exposure of larval stages (L3/L4) to sublethal dose of 5 ppm dramatically extended larval developmental period for up to 12 days, slowed down pupation rates, induced abnormal larval-pupal intermediates and caused 100% inhibition of adult emergence. Further, females exhibited significant interference of fecundity and egg hatchability relative to controls (p < 0.001). Using reverse transcription quantitative polymerase chain reaction (RT-qPCR), our findings show that PA-treated larvae exhibited significant repression of AgamJHAMT (p < 0.001), AgamILP1 (p < 0.001) and AgamCYP6M2 (p < 0.001) with up-regulation of Hsp70 (p < 0.001). Females exposed as larvae demonstrated down-regulation of AgamVg (p = 0.03), AgamILP1 (p = 0.009), AgamCYP6M2 (p = 0.05) and AgamJHAMT (p = 0.02). Our findings support that C. sinensis proanthocyanidins affect important vectorial capacity components such as mosquito survival rates and reproductive fitness thus could be potentially used for controlling populations of malaria vectors.

Targeting CD22 in B-cell malignancies: current status and clinical outlook.

PubMed

Sullivan-Chang, Loretta; O'Donnell, Robert T; Tuscano, Joseph M

2013-08-01

CD22 is a B-cell-specific transmembrane glycoprotein found on the surface of most B cells; it modulates B-cell function, survival and apoptosis. CD22 has emerged as an ideal target for monoclonal antibody (mAb)-based therapy of B-cell malignancies including most lymphomas and many leukemias. Epratuzumab, an anti-CD22 mAb, has been developed in various forms, including as an unlabeled (naked) mAb, as a radioimmunotherapeutic, as an antibody drug conjugate (ADC), and as a vehicle for CD22-targeted nanoparticles. While clinical trials with unlabeled epratuzumab have demonstrated modest results, its combination with rituximab in phase II studies has been more encouraging. Based on the potential for CD22 to become internalized, CD22-targeted constructs carrying radioisotopes or toxins have generated promising results. Radioimmunotherapy, utilizing ⁹⁰Y-labeled epratuzumab, was shown to be highly effective in patients with follicular lymphoma, generating a complete response (CR) rate of 92 % and progression-free survival of more than 2 years. ADC therapy is a promising therapeutic approach to B-cell malignancies which includes the direct conjugation of mAbs with cytotoxic agents. Phase II studies of inotuzumab ozogamicin, an ADC which combines anti-CD22 mAb with calicheamicin, an enediyne antibiotic which mediates apoptosis, in patients with acute lymphoblastic leukemia have produced an overall response rate (ORR) of greater than 50 % in treatment-refractory patients. Phase I trials of moxetumomab pasudotox, an ADC which combines anti-CD22 with PE38, a fragment of Pseudomonas exotoxin A, have been completed in hairy cell leukemia with a ORR of 86 %. Finally, a review of CD22-targeted nanoparticles, that include a doxorubicin-containing lipid complex that uses synthetic high-affinity CD22 ligand mimetics as well as anti-CD22 mAb-coated pegylated liposomas doxorubin (PLD), has demonstrated promising results in pre-clinical models of human lymphoma. Moreover, novel anti-CD22 mAb that block CD22 ligand binding as well as second generation ADC that utilize biodegradable linkers and more potent toxins hold great hope for the future of CD22-targeted therapeutics that may translate into better outcomes for patients with CD22-positive malignancies.

Gaze pursuit responses in nucleus reticularis tegmenti pontis of head-unrestrained macaques.

PubMed

Suzuki, David A; Betelak, Kathleen F; Yee, Robert D

2009-01-01

Eye-head gaze pursuit-related activity was recorded in rostral portions of the nucleus reticularis tegmenti pontis (rNRTP) in alert macaques. The head was unrestrained in the horizontal plane, and macaques were trained to pursue a moving target either with their head, with the eyes stationary in the orbits, or with their eyes, with their head voluntarily held stationary in space. Head-pursuit-related modulations in rNRTP activity were observed with some cells exhibiting increases in firing rate with increases in head-pursuit frequency. For many units, this head-pursuit response appeared to saturate at higher frequencies (>0.6 Hz). The response phase re:peak head-pursuit velocity formed a continuum, containing cells that could encode head-pursuit velocity and those encoding head-pursuit acceleration. The latter cells did not exhibit head position-related activity. Sensitivities were calculated with respect to peak head-pursuit velocity and averaged 1.8 spikes/s/deg/s. Of the cells that were tested for both head- and eye-pursuit-related activity, 86% exhibited responses to both head- and eye-pursuit and therefore carried a putative gaze-pursuit signal. For these gaze-pursuit units, the ratio of head to eye response sensitivities averaged approximately 1.4. Pursuit eccentricity seemed to affect head-pursuit response amplitude even in the absence of a head position response per se. The results indicated that rNRTP is a strong candidate for the source of an active head-pursuit signal that projects to the cerebellum, specifically to the target-velocity and gaze-velocity Purkinje cells that have been observed in vermal lobules VI and VII.

A clinically parameterized mathematical model of Shigella immunity to inform vaccine design

PubMed Central

Wahid, Rezwanul; Toapanta, Franklin R.; Simon, Jakub K.; Sztein, Marcelo B.

2018-01-01

We refine and clinically parameterize a mathematical model of the humoral immune response against Shigella, a diarrheal bacteria that infects 80-165 million people and kills an estimated 600,000 people worldwide each year. Using Latin hypercube sampling and Monte Carlo simulations for parameter estimation, we fit our model to human immune data from two Shigella EcSf2a-2 vaccine trials and a rechallenge study in which antibody and B-cell responses against Shigella′s lipopolysaccharide (LPS) and O-membrane proteins (OMP) were recorded. The clinically grounded model is used to mathematically investigate which key immune mechanisms and bacterial targets confer immunity against Shigella and to predict which humoral immune components should be elicited to create a protective vaccine against Shigella. The model offers insight into why the EcSf2a-2 vaccine had low efficacy and demonstrates that at a group level a humoral immune response induced by EcSf2a-2 vaccine or wild-type challenge against Shigella′s LPS or OMP does not appear sufficient for protection. That is, the model predicts an uncontrolled infection of gut epithelial cells that is present across all best-fit model parameterizations when fit to EcSf2a-2 vaccine or wild-type challenge data. Using sensitivity analysis, we explore which model parameter values must be altered to prevent the destructive epithelial invasion by Shigella bacteria and identify four key parameter groups as potential vaccine targets or immune correlates: 1) the rate that Shigella migrates into the lamina propria or epithelium, 2) the rate that memory B cells (BM) differentiate into antibody-secreting cells (ASC), 3) the rate at which antibodies are produced by activated ASC, and 4) the Shigella-specific BM carrying capacity. This paper underscores the need for a multifaceted approach in ongoing efforts to design an effective Shigella vaccine. PMID:29304144

A clinically parameterized mathematical model of Shigella immunity to inform vaccine design.

PubMed

Davis, Courtney L; Wahid, Rezwanul; Toapanta, Franklin R; Simon, Jakub K; Sztein, Marcelo B

2018-01-01

We refine and clinically parameterize a mathematical model of the humoral immune response against Shigella, a diarrheal bacteria that infects 80-165 million people and kills an estimated 600,000 people worldwide each year. Using Latin hypercube sampling and Monte Carlo simulations for parameter estimation, we fit our model to human immune data from two Shigella EcSf2a-2 vaccine trials and a rechallenge study in which antibody and B-cell responses against Shigella's lipopolysaccharide (LPS) and O-membrane proteins (OMP) were recorded. The clinically grounded model is used to mathematically investigate which key immune mechanisms and bacterial targets confer immunity against Shigella and to predict which humoral immune components should be elicited to create a protective vaccine against Shigella. The model offers insight into why the EcSf2a-2 vaccine had low efficacy and demonstrates that at a group level a humoral immune response induced by EcSf2a-2 vaccine or wild-type challenge against Shigella's LPS or OMP does not appear sufficient for protection. That is, the model predicts an uncontrolled infection of gut epithelial cells that is present across all best-fit model parameterizations when fit to EcSf2a-2 vaccine or wild-type challenge data. Using sensitivity analysis, we explore which model parameter values must be altered to prevent the destructive epithelial invasion by Shigella bacteria and identify four key parameter groups as potential vaccine targets or immune correlates: 1) the rate that Shigella migrates into the lamina propria or epithelium, 2) the rate that memory B cells (BM) differentiate into antibody-secreting cells (ASC), 3) the rate at which antibodies are produced by activated ASC, and 4) the Shigella-specific BM carrying capacity. This paper underscores the need for a multifaceted approach in ongoing efforts to design an effective Shigella vaccine.

Levels of Information Processing in a Fitts law task (LIPFitts)

NASA Technical Reports Server (NTRS)

Mosier, K. L.; Hart, S. G.

1986-01-01

State-of-the-art flight technology has restructured the task of human operators, decreasing the need for physical and sensory resources, and increasing the quantity of cognitive effort required, changing it qualitatively. Recent technological advances have the most potential for impacting a pilot in two areas: performance and mental workload. In an environment in which timing is critical, additional cognitive processing can cause performance decrements, and increase a pilot's perception of the mental workload involved. The effects of stimulus processing demands on motor response performance and subjective mental workload are examined, using different combinations of response selection and target acquisition tasks. The information processing demands of the response selection were varied (e.g., Sternberg memory set tasks, math equations, pattern matching), as was the difficulty of the response execution. Response latency as well as subjective workload ratings varied in accordance with the cognitive complexity of the task. Movement times varied according to the difficulty of the response execution task. Implications in terms of real-world flight situations are discussed.

Neural responses in the primary auditory cortex of freely behaving cats while discriminating fast and slow click-trains.

PubMed

Dong, Chao; Qin, Ling; Liu, Yongchun; Zhang, Xinan; Sato, Yu

2011-01-01

Repeated acoustic events are ubiquitous temporal features of natural sounds. To reveal the neural representation of the sound repetition rate, a number of electrophysiological studies have been conducted on various mammals and it has been proposed that both the spike-time and firing rate of primary auditory cortex (A1) neurons encode the repetition rate. However, previous studies rarely examined how the experimental animals perceive the difference in the sound repetition rate, and a caveat to these experiments is that they compared physiological data obtained from animals with psychophysical data obtained from humans. In this study, for the first time, we directly investigated acoustic perception and the underlying neural mechanisms in the same experimental animal by examining spike activities in the A1 of free-moving cats while performing a Go/No-go task to discriminate the click-trains at different repetition rates (12.5-200 Hz). As reported by previous studies on passively listening animals, A1 neurons showed both synchronized and non-synchronized responses to the click-trains. We further found that the neural performance estimated from the precise temporal information of synchronized units was good enough to distinguish all 16.7-200 Hz from the 12.5 Hz repetition rate; however, the cats showed declining behavioral performance with the decrease of the target repetition rate, indicating an increase of difficulty in discriminating two slower click-trains. Such behavioral performance was well explained by the firing rate of some synchronized and non-synchronized units. Trial-by-trial analysis indicated that A1 activity was not affected by the cat's judgment of behavioral response. Our results suggest that the main function of A1 is to effectively represent temporal signals using both spike timing and firing rate, while the cats may read out the rate-coding information to perform the task in this experiment.

Evaluative priming of naming and semantic categorization responses revisited: a mutual facilitation explanation.

PubMed

Schmitz, Melanie; Wentura, Dirk

2012-07-01

The evaluative priming effect (i.e., faster target responses following evaluatively congruent compared with evaluatively incongruent primes) in nonevaluative priming tasks (such as naming or semantic categorization tasks) is considered important for the question of how evaluative connotations are represented in memory. However, the empirical evidence is rather ambiguous: Positive effects as well as null results and negatively signed effects have been found. We tested the assumption that different processes are responsible for these results. In particular, we argue that positive effects are due to target-encoding facilitation (caused by a congruent prime), while negative effects are due to prime-activation maintenance (caused by a congruent target) and subsequent response conflict. In 4 experiments, we used a negative prime-target stimulus-onset asynchrony (SOA) to minimize target-encoding facilitation and maximize prime maintenance. In a naming task (Experiment 1), we found a negatively signed evaluative priming effect if prime and target competed for naming responses. In a semantic categorization task (i.e., person vs. animal; Experiments 2 and 3), response conflicts between prime and target were significantly larger in case of evaluative congruence compared with incongruence. These results corroborate the theory that a prime has more potential to interfere with the target response if its activation is maintained by an evaluatively congruent target. Experiment 4a/b indicated valence specificity of the effect. Implications for the memory representation of valence are discussed. 2012 APA, all rights reserved

Time dependency of temperature of a laser-irradiated infrared target pixel as a low-pass filter

NASA Technical Reports Server (NTRS)

Scholl, Marija S.; Scholl, James W.

1990-01-01

The thermal response of a surface layer of a pixel on an infrared target simulator is discussed. This pixel is maintained at a constant temperature by a rapidly scanning laser beam. An analytical model has been developed to describe the exact temperature dependence of a pixel as a function of time for different pixel refresh rates. The top layer of the pixel surface that generates the gray-body radiation shows the temperature dependence on time that is characteristic of a low-pass filter. The experimental results agree with the analytical predictions. The application of a pulsed laser beam to a noncontact, nondestructive diagnostic technique of surface characterization for the presence of microdefects is discussed.

Abnormal heart rate recovery and chronotropic incompetence on exercise in chronic obstructive pulmonary disease.

PubMed

Gupta, Mansi; Bansal, Vishal; Chhabra, Sunil K

2013-08-01

Chronotropic incompetence (CI; failure to reach the targeted heart rate (HR) on exercise) and a delayed HR recovery (HRR; ≤12 beats decline within the first minute after cessation) reflect autonomic dysfunction (AD) and predict adverse cardiac prognosis. As chronic obstructive pulmonary disease (COPD) is known to be associated with AD, we hypothesized that these patients may manifest these responses on exercise. The prevalence and predictors of these responses in COPD and their association with its severity have not been evaluated. Normoxemic, stable male patients with COPD (n = 39) and 11 healthy controls underwent lung function testing and incremental leg ergometry. HR responses were monitored during exercise and recovery to compute the HRR and CI. Of all the patients, 33 (84.6%) had at least one of the two exercise responses as abnormal, with the majority (23, 58.9%) having both an abnormal HRR and CI. The frequency of abnormal responses increased with increasing Global Initiative for Chronic Obstructive Lung Disease stage and body mass index, airflow obstruction, dyspnoea and exercise capacity index. After adjusting for smoking history and post-bronchodilator forced expiratory volume in 1 second, only a reduced diffusion capacity for carbon monoxide predicted abnormal HRR, though weakly. We concluded that abnormal HRR and CI are common in patients with COPD. These responses are observed with increasing frequency as the severity of disease increases.

The effects of moderate alcohol concentrations on driving and cognitive performance during ascending and descending blood alcohol concentrations.

PubMed

Starkey, Nicola J; Charlton, Samuel G

2014-07-01

Alcohol has an adverse effect on driving performance; however, the effects of moderate doses on different aspects of the driving task are inconsistent and differ across the intoxication curve. This research aimed to investigate driving and cognitive performance asymmetries (acute tolerance and acute protracted error) accompanying the onset and recovery from moderate alcohol consumption. Sixty-one participants received a placebo, medium (target blood alcohol concentration [BAC] 0.05 mg/ml) or high (target BAC 0.08 mg/ml) dose of alcohol. Participants completed a simulated drive, cognitive tests and subjective rating scales five times over a 3.5 h period. When ascending and descending BACs (0.05 and 0.09 mg/ml) were compared participants' self-ratings of intoxication and willingness to drive showed acute tolerance. Acute protracted errors were observed for response speed, maze learning errors, time exceeding the speed limit and exaggerated steering responses to hazards. Participants' estimates of their level of intoxication were poorly related to their actual BAC levels (and hence degree of impairment), and various aspects of driving and cognitive performance worsened during descending BACs. This indicates that drivers are not good at judging their fitness to drive after drinking only moderate amounts of alcohol and suggests an important focus for public education regarding alcohol and driving. Copyright © 2014 John Wiley & Sons, Ltd.

Pesticides and passive dispersal: acaricide- and starvation-induced take-off of the predatory mite Neoseiulus baraki.

PubMed

Monteiro, Vaneska Barbosa; Silva, Vanessa Farias; Lima, Debora Barbosa; Guedes, Raul Narciso Carvalho; Gondim, Manoel Guedes Correa

2018-06-01

An understanding of the causes and consequences of dispersal is vital for managing populations. Environmental contaminants, such as pesticides, provide potential environmental context-dependent stimuli for dispersal of targeted and non-targeted species, which may occur not only for active but also for passive dispersal, although such a possibility is frequently neglected. Here, we assessed the potential of food deprivation and acaricides to interfere with the take-off for passive (wind) dispersal of the predatory mite Neoseiulus baraki. Wind tunnel bioassays indicated that starvation favoured the take-off for wind dispersal by the mite predator, which also varied with wind velocity, and dispersal increased at higher velocities within the 1-7 (m s -1 ) range tested. For the acaricides tested, particularly the biopesticide azadirachtin but also abamectin and fenpyroximate, the rate of predator take-off for dispersal increased, and further increased with wind velocity up to 7 m/s. Such responses were associated with changes in the predator behavioural preparation for wind-mediated passive dispersal, with a greater incidence of the standing posture that permitted take-off. The rate of take-off for passive dispersal by N. baraki increased with food deprivation and exposure to the residues of agricultural acaricides. Azadirachtin exposure resulted in a particularly strong response, although abamectin and fenpyroximate also stimulated dispersal. © 2018 Society of Chemical Industry. © 2018 Society of Chemical Industry.

pH-Triggered Echogenicity and Contents Release from Liposomes

PubMed Central

2015-01-01

Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the cellular lysosomes has been successfully used to enhance the rate for releasing contents. However, imparting pH sensitivity to liposomes requires the synthesis of specialized lipids with structures that are substantially modified at a reduced pH. Herein, we report an alternative strategy to render liposomes pH sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at a reduced pH. The gas bubbles also render the liposomes echogenic, allowing ultrasound imaging. To demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells that overexpress the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents released from these liposomes are further enhanced by the application of continuous wave ultrasound (1 MHz), resulting in substantially reduced viability for the pancreatic cancer cells (14%). PMID:25271780

pH-triggered echogenicity and contents release from liposomes.

PubMed

Nahire, Rahul; Hossain, Rayat; Patel, Rupa; Paul, Shirshendu; Meghnani, Varsha; Ambre, Avinash H; Gange, Kara N; Katti, Kalpana S; Leclerc, Estelle; Srivastava, D K; Sarkar, Kausik; Mallik, Sanku

2014-11-03

Liposomes are representative lipid nanoparticles widely used for delivering anticancer drugs, DNA fragments, or siRNA to cancer cells. Upon targeting, various internal and external triggers have been used to increase the rate for contents release from the liposomes. Among the internal triggers, decreased pH within the cellular lysosomes has been successfully used to enhance the rate for releasing contents. However, imparting pH sensitivity to liposomes requires the synthesis of specialized lipids with structures that are substantially modified at a reduced pH. Herein, we report an alternative strategy to render liposomes pH sensitive by encapsulating a precursor which generates gas bubbles in situ in response to acidic pH. The disturbance created by the escaping gas bubbles leads to the rapid release of the encapsulated contents from the liposomes. Atomic force microscopic studies indicate that the liposomal structure is destroyed at a reduced pH. The gas bubbles also render the liposomes echogenic, allowing ultrasound imaging. To demonstrate the applicability of this strategy, we have successfully targeted doxorubicin-encapsulated liposomes to the pancreatic ductal carcinoma cells that overexpress the folate receptor on the surface. In response to the decreased pH in the lysosomes, the encapsulated anticancer drug is efficiently released. Contents released from these liposomes are further enhanced by the application of continuous wave ultrasound (1 MHz), resulting in substantially reduced viability for the pancreatic cancer cells (14%).

Predicting the sensitivity of populations from individual exposure to chemicals: the role of ecological interactions.

PubMed

Gabsi, Faten; Schäffer, Andreas; Preuss, Thomas G

2014-07-01

Population responses to chemical stress exposure are influenced by nonchemical, environmental processes such as species interactions. A realistic quantification of chemical toxicity to populations calls for the use of methodologies that integrate these multiple stress effects. The authors used an individual-based model for Daphnia magna as a virtual laboratory to determine the influence of ecological interactions on population sensitivity to chemicals with different modes of action on individuals. In the model, hypothetical chemical toxicity targeted different vital individual-level processes: reproduction, survival, feeding rate, or somatic growth rate. As for species interactions, predatory and competition effects on daphnid populations were implemented following a worst-case approach. The population abundance was simulated at different food levels and exposure scenarios, assuming exposure to chemical stress solely or in combination with either competition or predation. The chemical always targeted one vital endpoint. Equal toxicity-inhibition levels differently affected the population abundance with and without species interactions. In addition, population responses to chemicals were highly sensitive to the environmental stressor (predator or competitor) and to the food level. Results show that population resilience cannot be attributed to chemical stress only. Accounting for the relevant ecological interactions would reduce uncertainties when extrapolating effects of chemicals from individuals to the population level. Validated population models should be used for a more realistic risk assessment of chemicals. © 2014 SETAC.

Non-HLA Antibodies May Accelerate Immune Responses After Intestinal and Multivisceral Transplantation.

PubMed

Gerlach, Undine Ariane; Lachmann, Nils; Ranucci, Giuseppina; Sawitzki, Birgit; Schoenemann, Constanze; Pratschke, Johann; Dragun, Duska; Pascher, Andreas

2017-01-01

Non-HLA alloantibodies and autoantibodies are involved in allograft rejection in kidney and heart transplantation. Their role in intestinal transplantation has not yet been described. We examined the development of antiangiotensin II type I receptor antibodies (anti-AT1R) and antiendothelin type A receptor antibodies associated with the clinical course and histopathological findings of intestinal transplantation recipients. Thirty-seven patients underwent intestinal or multivisceral transplantation. Non-HLA antibodies (non-HLAabs) were screened in 29 transplant recipients. Antibody-levels greater than 12 U/L were considered positive and were evaluated retrospectively regarding rejection episodes. Twenty patients developed anti-AT1R and/or antiendothelin type A receptor antibodies (non-HLAabs group), 9 did not (control group). The non-HLAabs group had a higher rate of allograft rejection than controls (80% vs 55%), especially a higher rate of antibody-mediated rejections (55% vs 11%, P < 0.01) with detection of donor-specific anti-HLAabs. All rejection episodes in the non-HLAabs group appeared around the time of positive non-HLAabs detection. Five patients had acute cellular rejections at the time of non-HLAabs development, 4 had viral infections. Our data suggest that antibody-mediated mechanisms targeting antigens beyond HLA may trigger and accelerate immune responses. Given the possibility of pharmacologic targeting of non-HLA receptors, future studies will focus on the explanation of mechanisms how non-HLAabs may enhance rejection and affect long-term allograft survival.

Fertility preferences among Malaysian women: an analysis of responses to the new population policy.

PubMed

Khor, G L

1990-10-01

About 10% of 3887 ever-married women included in the 1984-85 Malaysian Population and Family Survey revealed that they were influenced by the new population policy to desire more children than they had originally wanted. These women were more likely to be rural Malays from the lower socioeconomic class. Ideal family size was more than four children. Children are desired for economic benefits and emotional support. The natality of the Malays has risen since 1980: their total fertility rate has increased while their contraceptive prevalence rate has dropped sharply. Coupled with a decline in the crude death rate, the present fertility preferences and behaviour of the Malays will render the target of the population policy more attainable than is reflected by the survey data.

Management of hepatitis C infection in the era of direct-acting antiviral therapy

NASA Astrophysics Data System (ADS)

Zain, L. H.; Sungkar, T.

2018-03-01

Hepatitis C viral infection globally affects millions of people and commonly results in debilitating complications and mortality. Initial mainstay therapy consisted of pegylated interferon α (pegIFNα) with additional ribavirin that showed unsatisfactory cure rate, common side effects and complicated dosing, contributing to high discontinuation rate. Over the last few years, newer antivirals have been extensively studied, that are Direct-Acting Antivirals (DAAs). Specifically targeting viral protein mainly during replication phase, DAAs showed greater cure rate (commonly measured as sustained virologic response), improved safety profile and shorter treatment duration compared to traditional interferon-ribavirin therapy. Current guidelines have also included Interferon-free, often ribavirin-free, DAAs combinations that suggest promising outcomes. The current review highlights development of rapidly growing hepatitis C treatment including DAAs recommendations.

An Action Learning Approach to the Question: Are Ambulance Response Time Targets Achievable?

ERIC Educational Resources Information Center

Slater, Alan

2017-01-01

In recent years, NHS Ambulance Trusts throughout the UK have consistently failed to achieve their response time targets for both actual and potential life-threatening calls. To avoid a media and public outcry, the NHS response has been to change the basic parameters upon which the response time targets are calculated. An action learning study,…

MUC1 and survivin combination tumor gene vaccine generates specific immune responses and anti-tumor effects in a murine melanoma model.

PubMed

Zhang, Haihong; Liu, Chenlu; Zhang, Fangfang; Geng, Fei; Xia, Qiu; Lu, Zhenzhen; Xu, Ping; Xie, Yu; Wu, Hui; Yu, Bin; Wu, Jiaxin; Yu, Xianghui; Kong, Wei

2016-05-23

MUC1 and survivin are ideal tumor antigens. Although many cancer vaccines targeting survivin or MUC1 have entered clinical trials, no vaccine combining MUC1 and survivin have been reported. Due to tumor heterogeneity, vaccines containing a combination of antigens may have improved efficacy and coverage of a broader spectrum of cancer targets. Here, cellular responses and anti-tumor activities induced by a combination of DNA vaccine targeting MUC1 and survivin (MS) were evaluated. Results showed that CTL activity and inhibition of tumor growth were obviously enhanced in mice immunized with the combined vaccine in a protection assay. However, in order to enhance the therapeutic effect in the treatment assay, a recombinant adenovirus (rAd) vaccine expressing MUC1 and survivin (Ad-MS) was used as a booster following the DNA vaccine prime. Meanwhile, IL-2 promoting T cell proliferation was used as an immunoadjuvant for the DNA vaccine. Results showed that the CTL activity response to the DNA vaccine was enhanced nearly 200% when boosted by the rAd vaccine and was further enhanced by nearly 60% when combined with the IL-2 adjuvant. Therefore, DNA prime combined with rAd boost and IL-2 (MS/IL2/Ad-MS) adjuvant was considered as the best strategy and further evaluated. Multiple cytokines promoting cellular immune responses were shown to be greatly enhanced in mice immunized with MS/IL2/Ad-MS. Moreover, in the treatment assay, the tumor inhibition rate of MS/IL2/Ad-MS reached up to 50.1%, which may be attributed to the enhancement of immune responses and reduction of immunosuppressive factors in tumor-bearing mice. These results suggested that immunization with the combination vaccine targeting MUC1 and survivin using a DNA prime-rAd boost strategy along with IL-2 adjuvant may be an effective method for breaking through immune tolerance to tumors expressing these antigens with potential therapeutic benefits in melanoma cancer. Copyright © 2016. Published by Elsevier Ltd.

Effect of viewing distance and location of the axis of head rotation on the monkey's vestibuloocular reflex. I. Eye movement responses.

PubMed

Snyder, L H; King, W M

1992-04-01

1. The vestibuloocular reflex (VOR) stabilizes images on the retina against movements of the head in space. Viewing distance, target eccentricity, and location of the axis of rotation may influence VOR responses because rotation of the head about most axes in space rotates and translates the eyes relative to visual targets. To study the VOR response to combined rotation and translation, monkeys were placed on a rate table and rotated briefly in the dark about a vertical axis that was located in front of or behind the eyes. The monkeys fixated a near or far visual target that was extinguished before the rotation. Eye movements were recorded from both eyes by the use of the search coil technique. 2. Peak eye velocity evoked by the VOR was linearly related to vergence angle for any axis of rotation. The percent change in the VOR with near target viewing relative to far target viewing at a vergence angle of 20 degrees was linearly related to the location of the axis of rotation. Axes located behind the eyes produced positive changes in VOR amplitude, and axes located in front of the eyes produced negative changes in VOR amplitude. An axis of rotation located in the coronal plane containing the centers of rotation of the eyes produced no modification of VOR amplitude. For any axis, the VOR compensated for approximately 90% of the translation of the eye relative to near targets. 3. The initial VOR response was not correct in magnitude but was refined by a series of three temporally delayed corrections of increasing complexity. The earliest VOR-evoked eye movement (10-20 ms after rotation onset) was independent of viewing distance and rotational axis location. In the next 100 ms, eye speed appeared to be sequentially modified three times: within 20 ms by viewing distance; within 30 ms by otolith translation; and within 100 ms by eye translation relative to the visual target. 4. These data suggest a formal model of the VOR consisting of four channels. Channel 1 conveys an unmodified head rotation signal with a pure delay of 10 ms. Channel 2 conveys an angular head velocity signal, modified by viewing distance with a pure delay of 20 ms, but invariant with respect to the location of the axis of rotation. Channel 3 conveys a linear head velocity signal, dependent on the location of the axis of rotation, that is modified by viewing distance with a pure delay of 30 ms.(ABSTRACT TRUNCATED AT 400 WORDS)

Dynamics of T cell, antigen-presenting cell, and pathogen interactions during recall responses in the lymph node.

PubMed

Chtanova, Tatyana; Han, Seong-Ji; Schaeffer, Marie; van Dooren, Giel G; Herzmark, Paul; Striepen, Boris; Robey, Ellen A

2009-08-21

Memory T cells circulate through lymph nodes where they are poised to respond rapidly upon re-exposure to a pathogen; however, the dynamics of memory T cell, antigen-presenting cell, and pathogen interactions during recall responses are largely unknown. We used a mouse model of infection with the intracellular protozoan parasite, Toxoplasma gondii, in conjunction with two-photon microscopy, to address this question. After challenge, memory T cells migrated more rapidly than naive T cells, relocalized toward the subcapsular sinus (SCS) near invaded macrophages, and engaged in prolonged interactions with infected cells. Parasite invasion of T cells occurred by direct transfer of the parasite from the target cell into the T cell and corresponded to an antigen-specific increase in the rate of T cell invasion. Our results provide insight into cellular interactions during recall responses and suggest a mechanism of pathogen subversion of the immune response.

Target weight achievement and ultrafiltration rate thresholds: potential patient implications.

PubMed

Flythe, Jennifer E; Assimon, Magdalene M; Overman, Robert A

2017-06-02

Higher ultrafiltration (UF) rates and extracellular hypo- and hypervolemia are associated with adverse outcomes among maintenance hemodialysis patients. The Centers for Medicare and Medicaid Services recently considered UF rate and target weight achievement measures for ESRD Quality Incentive Program inclusion. The dual measures were intended to promote balance between too aggressive and too conservative fluid removal. The National Quality Forum endorsed the UF rate measure but not the target weight measure. We examined the proposed target weight measure and quantified weight gains if UF rate thresholds were applied without treatment time (TT) extension or interdialytic weight gain (IDWG) reduction. Data were taken from the 2012 database of a large dialysis organization. Analyses considered 152,196 United States hemodialysis patients. We described monthly patient and dialysis facility target weight achievement patterns and examined differences in patient characteristics across target weight achievement status and differences in facilities across target weight measure scores. We computed the cumulative, theoretical 1-month fluid-related weight gain that would occur if UF rates were capped at 13 mL/h/kg without concurrent TT extension or IDWG reduction. Target weight achievement patterns were stable over the year. Patients who did not achieve target weight (post-dialysis weight ≥ 1 kg above or below target weight) tended to be younger, black and dialyze via catheter, and had shorter dialysis vintage, greater body weight, higher UF rate and more missed treatments compared with patients who achieved target weight. Facilities had, on average, 27.1 ± 9.7% of patients with average post-dialysis weight ≥ 1 kg above or below the prescribed target weight. In adjusted analyses, facilities located in the midwest and south and facilities with higher proportions of black and Hispanic patients and higher proportions of patients with shorter TTs were more likely to have unfavorable facility target weight measure scores. Without TT extension or IDWG reduction, UF rate threshold (13 mL/h/kg) implementation led to an average theoretical 1-month, fluid-related weight gain of 1.4 ± 3.0 kg. Target weight achievement patterns vary across clinical subgroups. Implementation of a maximum UF rate threshold without adequate attention to extracellular volume status may lead to fluid-related weight gain.

Interactions of task and subject variables among continuous performance tests.

PubMed

Denney, Colin B; Rapport, Mark D; Chung, Kyong-Mee

2005-04-01

Contemporary models of working memory suggest that target paradigm (TP) and target density (TD) should interact as influences on error rates derived from continuous performance tests (CPTs). The present study evaluated this hypothesis empirically in a typically developing, ethnically diverse sample of children. The extent to which scores based on different combinations of these task parameters showed different patterns of relationship to age, intelligence, and gender was also assessed. Four continuous performance tests were derived by combining two target paradigms (AX and repeated letter target stimuli) with two levels of target density (8.3% and 33%). Variations in mean omission (OE) and commission (CE) error rates were examined within and across combinations of TP and TD. In addition, a nested series of structural equation models was utilized to examine patterns of relationship among error rates, age, intelligence, and gender. Target paradigm and target density interacted as influences on error rates. Increasing density resulted in higher OE and CE rates for the AX paradigm. In contrast, the high density condition yielded a decline in OE rates accompanied by a small increase in CEs using the repeated letter CPT. Target paradigms were also distinguishable on the basis of age when using OEs as the performance measure, whereas combinations of age and intelligence distinguished between density levels but not target paradigms using CEs as the dependent measure. Different combinations of target paradigm and target density appear to yield scores that are conceptually and psychometrically distinguishable. Consequently, developmentally appropriate interpretation of error rates across tasks may require (a) careful analysis of working memory and attentional resources required for successful performance, and (b) normative data bases that are differently stratified with respect to combinations of age and intelligence.

Strategic Therapeutic Targeting to Overcome Venetoclax Resistance in Aggressive B-cell Lymphomas.

PubMed

Pham, Lan V; Huang, Shengjian; Zhang, Hui; Zhang, Jun; Bell, Taylor; Zhou, Shouhao; Pogue, Elizabeth; Ding, Zhiyong; Lam, Laura; Westin, Jason; Davis, R Eric; Young, Ken H; Medeiros, L Jeffrey; Ford, Richard J; Nomie, Krystle; Zhang, Leo; Wang, Michael

2018-04-17

Purpose: B-cell lymphoma-2 (BCL-2), an antiapoptotic protein often dysregulated in B-cell lymphomas, promotes cell survival and provides protection from stress. A recent phase I first-in-human study of the BCL-2 inhibitor venetoclax in non-Hodgkin lymphoma showed an overall response rate of 44%. These promising clinical results prompted our examination of the biological effects and mechanism of action underlying venetoclax activity in aggressive B-cell lymphoma, including mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL). Experimental Design: MCL and DLBCL cell lines, primary patient samples, and in vivo patient-derived xenograft (PDX) models were utilized to examine venetoclax efficacy. Furthermore, the mechanisms underlying venetoclax response and the development of venetoclax resistance were evaluated using proteomics analysis and Western blotting. Results: Potential biomarkers linked to venetoclax activity and targeted combination therapies that can augment venetoclax response were identified. We demonstrate that DLBCL and MCL cell lines, primary patient samples, and PDX mouse models expressing high BCL-2 levels are extremely sensitive to venetoclax treatment. Proteomics studies showed that venetoclax substantially alters the expression levels and phosphorylation status of key proteins involved in cellular processes, including the DNA damage response, cell metabolism, cell growth/survival, and apoptosis. Short- and long-term exposure to venetoclax inhibited PTEN expression, leading to enhanced AKT pathway activation and concomitant susceptibility to PI3K/AKT inhibition. Intrinsic venetoclax-resistant cells possess high AKT activation and are highly sensitive to PI3K/AKT inhibition. Conclusions: These findings demonstrate the on-target effect of venetoclax and offer potential mechanisms to overcome acquired and intrinsic venetoclax resistance through PI3K/AKT inhibition. Clin Cancer Res; 1-14. ©2018 AACR. ©2018 American Association for Cancer Research.

Personality trait inferences of Turkish immigrant and neutral targets: an experimental study.

PubMed

Sandal, Gro M; Bye, Hege H; Pallesen, Ståle

2012-12-01

The study investigated whether personality traits attributed to immigrant targets differ from personality inferences made for a neutral target, and whether trait attributions differ for assimilated and integrated immigrant targets. Participants (n = 340) were randomized to one of three conditions in which they read the same story about a person, but where the person was described as either: (a) an assimilated Turkish immigrant; (b) an integrated Turkish immigrant; or (c) neutral (no nationality or religious practice indicated). Subsequently, they rated the personality of the described person on the NEO-Five Factor Inventory (observer rating version) and completed the Balanced Inventory of Desirable Responding (Impression Management scale) with reference to themselves. Both immigrant targets were rated as significantly higher on extraversion and lower on neuroticism than the neutral target. The integrated target was rated as more open than the neutral target, and as higher than the assimilated target on neuroticism when controlling for impression management. © 2012 The Authors. Scandinavian Journal of Psychology © 2012 The Scandinavian Psychological Associations.

Tracking the Dissemination of a Culturally Targeted Brochure to Promote Awareness of Hereditary Breast and Ovarian Cancer among Black Women

PubMed Central

Scherr, Courtney Lynam; Bomboka, Linda; Nelson, Alison; Pal, Tuya; Vadaparampil, Susan Thomas

2016-01-01

Objective Black women have a higher rate of BRCA1 and BRCA2 (BRCA) mutations, compared with other populations, that increases their risk for hereditary breast and ovarian cancer (HBOC). However, Black women are less likely to know about HBOC and genetic testing. Based on a request from a community advisory panel of breast cancer survivors, community leaders and healthcare providers in the Black community, our team developed a culturally targeted educational brochure to promote awareness of HBOC among Black women. Methods To reach the target population we utilized a passive dissemination strategy. Using Diffusion of Innovations (DOI) as a framework, we traced dissemination of the brochure over a five year period using self-addressed postcards contained inside the brochure that included several open-ended questions about the utility of the brochure and a field for written comments. Closed-ended responses were analyzed using descriptive statistics and thematic analysis was conducted on the open-ended responses. Results DOI captured the proliferation of the brochure among Black women across the US. Practice Implications The use of passive dissemination strategies among pre-existing social networks proved to be a useful and sustainable method for increasing knowledge of HBOC among Black women. PMID:27866793

Antigen-specific T cell therapies for cancer

PubMed Central

Manzo, Teresa; Heslop, Helen E.; Rooney, Cliona M.

2015-01-01

Adoptively transferred antigen-specific T cells that recognize tumor antigens through their native receptors have many potential benefits as treatment for virus-associated diseases and malignancies, due to their ability to selectively recognize tumor antigens, expand and persist to provide long-term protection. Infusions of T cells targeting Epstein–Barr virus (EBV) antigens have shown encouraging response rates in patients with post-transplant lymphoproliferative disease as well as EBV-positive lymphomas and nasopharyngeal cancer, although a recent study also showed that human papilloma virus-reactive T cells can induce complete regression of metastatic cervical cancer. This strategy is also being evaluated to target non-viral tumor-associated antigens. Targeting these less immunogenic antigens is more challenging, as tumor antigens are generally weak, and high avidity T cells specific for self-antigens are deleted in the thymus, but tumor responses have been reported. Current research focusses on defining factors that promote in vivo persistence of transferred cells and ameliorate the immunosuppressive microenvironment. To this end, investigators are evaluating the effects of combining adoptive transfer of antigen-specific T cells with other immunotherapy moieties such as checkpoint inhibitors. Genetic modification of infused T cells may also be used to overcome tumor evasion mechanisms, and vaccines may be used to promote in vivo proliferation. PMID:26160910

Tracking the dissemination of a culturally targeted brochure to promote awareness of hereditary breast and ovarian cancer among Black women.

PubMed

Scherr, Courtney Lynam; Bomboka, Linda; Nelson, Alison; Pal, Tuya; Vadaparampil, Susan Thomas

2017-05-01

Black women have a higher rate of BRCA1 and BRCA2 (BRCA) mutations, compared with other populations, that increases their risk for hereditary breast and ovarian cancer (HBOC). However, Black women are less likely to know about HBOC and genetic testing. Based on a request from a community advisory panel of breast cancer survivors, community leaders and healthcare providers in the Black community, our team developed a culturally targeted educational brochure to promote awareness of HBOC among Black women. To reach the target population we utilized a passive dissemination strategy. Using Diffusion of Innovations (DOI) as a framework, we traced dissemination of the brochure over a five year period using self-addressed postcards contained inside the brochure that included several open-ended questions about the utility of the brochure, and a field for written comments. Closed-ended responses were analyzed using descriptive statistics and thematic analysis was conducted on the open-ended responses. DOI captured the proliferation of the brochure among Black women across the US. The use of passive dissemination strategies among pre-existing social networks proved to be a useful and sustainable method for increasing knowledge of HBOC among Black women. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Elucidation of the Ebola virus VP24 cellular interactome and disruption of virus biology through targeted inhibition of host-cell protein function.

PubMed

García-Dorival, Isabel; Wu, Weining; Dowall, Stuart; Armstrong, Stuart; Touzelet, Olivier; Wastling, Jonathan; Barr, John N; Matthews, David; Carroll, Miles; Hewson, Roger; Hiscox, Julian A

2014-11-07

Viral pathogenesis in the infected cell is a balance between antiviral responses and subversion of host-cell processes. Many viral proteins specifically interact with host-cell proteins to promote virus biology. Understanding these interactions can lead to knowledge gains about infection and provide potential targets for antiviral therapy. One such virus is Ebola, which has profound consequences for human health and causes viral hemorrhagic fever where case fatality rates can approach 90%. The Ebola virus VP24 protein plays a critical role in the evasion of the host immune response and is likely to interact with multiple cellular proteins. To map these interactions and better understand the potential functions of VP24, label-free quantitative proteomics was used to identify cellular proteins that had a high probability of forming the VP24 cellular interactome. Several known interactions were confirmed, thus placing confidence in the technique, but new interactions were also discovered including one with ATP1A1, which is involved in osmoregulation and cell signaling. Disrupting the activity of ATP1A1 in Ebola-virus-infected cells with a small molecule inhibitor resulted in a decrease in progeny virus, thus illustrating how quantitative proteomics can be used to identify potential therapeutic targets.

A novel small RNA S042 increases acid tolerance in Lactococcus lactis F44.

PubMed

Wu, Hao; Song, Shunyi; Tian, Kairen; Zhou, Dandan; Wang, Binbin; Liu, Jiaheng; Zhu, Hongji; Qiao, Jianjun

2018-06-07

Lactococcus lactis, a gram-positive bacterium, encounters various environmental stresses, especially acid stress, during fermentation. Small RNAs (sRNAs) that serve as regulators at post-transcriptional level play important roles in acid stress response. Here, a novel sRNA S042 was identified by RNA-Seq, RT-PCR and Northern blot. The transcription level of s042 was upregulated 2.29-fold under acid stress by Quantitative RT-PCR (qRT-PCR) analysis. Acid tolerance assay showed that overexpressing s042 increased the survival rate of L. lactis F44 and deleting s042 significantly inhibited the viability under acidic conditions. Moreover, the targets were predicted by online software and four genes were chosen as candidates. Among them, argR (arginine regulator) and accD (acetyl-CoA carboxylase carboxyl transferase subunit beta) were validated to be the direct targets activated by S042 through reporter fusion assay. The regulatory mechanism between S042 and its targets was further investigated through Bioinformatics and qRT-PCR. This study served to highlight the role of the novel sRNA S042 in acid resistance of L. lactis and provided new insights into the response mechanism of acid stress. Copyright © 2018 Elsevier Inc. All rights reserved.

Molecular biology of lung cancer: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines.

PubMed

Nana-Sinkam, Serge Patrick; Powell, Charles A

2013-05-01

Based on recent bench and clinical research, the treatment of lung cancer has been refined, with treatments allocated according to histology and specific molecular features. For example, targeting mutations such as epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors has been particularly successful as a treatment modality, demonstrating response rates in selected patients with adenocarcinoma tumors harboring EGFR mutations that are significantly higher than those for conventional chemotherapy. However, the development of new targeted therapies is, in part, highly dependent on an improved understanding of the molecular underpinnings of tumor initiation and progression, knowledge of the role of molecular aberrations in disease progression, and the development of highly reproducible platforms for high-throughput biomarker discovery and testing. In this article, we review clinically relevant research directed toward understanding the biology of lung cancer. The clinical purposes of this research are (1) to identify susceptibility variants and field molecular alterations that will promote the early detection of tumors and (2) to identify tumor molecular alterations that serve as therapeutic targets, prognostic biomarkers, or predictors of tumor response. We focus on research developments in the understanding of lung cancer somatic DNA mutations, chromosomal aberrations, epigenetics, and the tumor microenvironment, and how they can advance diagnostics and therapeutics.

Top-down deactivation of interference from irrelevant spatial or verbal stimulus features.

PubMed

Frings, Christian; Wühr, Peter

2014-11-01

The selective-attention model of Houghton and Tipper (1994) assumes top-down deactivation of (conflicting) distractor representations as a mechanism of visual attention. Deactivation should produce an inverted-U-shaped activation function for distractor representations. In a recent study, Frings, Wentura, and Wühr (2012) tested this prediction in a variant of the flanker task in which a cue sometimes required participants to respond to the distractors rather than to the target. When reaction times and error rates were plotted as a function of the target-cue stimulus onset asynchrony, a quadratic trend emerged, consistent with the notion of distractor deactivation. However, in the flanker task, an alternative explanation for the quadratic trend in terms of attentional zooming is possible. The present experiments tested the deactivation account against the attentional-zooming account with the Stroop and the Simon task, in which attentional zooming should have minimal effects on distractor processing, because the target and distractor are presented at the same spatial location. Both experiments replicated the quadratic trend in the performance functions for responses to incongruent distractors, and additionally showed linear trends in the performance functions for responses to congruent distractors. These results provide additional support for the notion of top-down deactivation of distractor representations as a mechanism of visual selective attention.

Perceptions of similarity and response to selected comparison targets in type 2 diabetes.

PubMed

Arigo, Danielle; Smyth, Joshua M; Suls, Jerry M

2015-01-01

Social comparisons (i.e. self-evaluations relative to others) may affect motivation for diabetes self-care behaviours. Comparisons can have either positive or negative effects, but it is not clear what differentiates these responses. This study tested the effect of a patient's perceived similarity to a comparison target on motivation for self-care. Individuals with type 2 diabetes (n = 180, MA1c = 7.59%) selected to read one of four brief descriptions of a patient with diabetes. Participants rated their motivation for self-care behaviours prior and subsequent to reading and reported the extent to which they focused on similarities between the self and the selected patient while reading. Perceived similarity moderated the effect of selection on motivation for self-care (p = .01, η2 = .06). Increased motivation was observed if participants focused on similarities with patients 'doing better' (i.e. high coping effectiveness/low symptom severity) and decreased motivation if they focused on similarities with patients 'doing worse' (low coping effectiveness/high symptom severity). Providing social comparison information in diabetes management (and perhaps other chronic diseases) may improve motivation for self-care among some patients. A subset of patients, however, may benefit from guidance to focus on similarities with certain targets.

Transient analysis mode participation for modal survey target mode selection using MSC/NASTRAN DMAP

NASA Technical Reports Server (NTRS)

Barnett, Alan R.; Ibrahim, Omar M.; Sullivan, Timothy L.; Goodnight, Thomas W.

1994-01-01

Many methods have been developed to aid analysts in identifying component modes which contribute significantly to component responses. These modes, typically targeted for dynamic model correlation via a modal survey, are known as target modes. Most methods used to identify target modes are based on component global dynamic behavior. It is sometimes unclear if these methods identify all modes contributing to responses important to the analyst. These responses are usually those in areas of hardware design concerns. One method used to check the completeness of target mode sets and identify modes contributing significantly to important component responses is mode participation. With this method, the participation of component modes in dynamic responses is quantified. Those modes which have high participation are likely modal survey target modes. Mode participation is most beneficial when it is used with responses from analyses simulating actual flight events. For spacecraft, these responses are generated via a structural dynamic coupled loads analysis. Using MSC/NASTRAN DMAP, a method has been developed for calculating mode participation based on transient coupled loads analysis results. The algorithm has been implemented to be compatible with an existing coupled loads methodology and has been used successfully to develop a set of modal survey target modes.

High-Speed Incoming Infrared Target Detection by Fusion of Spatial and Temporal Detectors

PubMed Central

Kim, Sungho

2015-01-01

This paper presents a method for detecting high-speed incoming targets by the fusion of spatial and temporal detectors to achieve a high detection rate for an active protection system (APS). The incoming targets have different image velocities according to the target-camera geometry. Therefore, single-target detector-based approaches, such as a 1D temporal filter, 2D spatial filter and 3D matched filter, cannot provide a high detection rate with moderate false alarms. The target speed variation was analyzed according to the incoming angle and target velocity. The speed of the distant target at the firing time is almost stationary and increases slowly. The speed varying targets are detected stably by fusing the spatial and temporal filters. The stationary target detector is activated by an almost zero temporal contrast filter (TCF) and identifies targets using a spatial filter called the modified mean subtraction filter (M-MSF). A small motion (sub-pixel velocity) target detector is activated by a small TCF value and finds targets using the same spatial filter. A large motion (pixel-velocity) target detector works when the TCF value is high. The final target detection is terminated by fusing the three detectors based on the threat priority. The experimental results of the various target sequences show that the proposed fusion-based target detector produces the highest detection rate with an acceptable false alarm rate. PMID:25815448

Mediators of compassionate goal intervention effects on human neuroendocrine responses to the Trier Social Stress Test.

PubMed

Erickson, Thane M; Mayer, Stefanie E; Lopez-Duran, Nestor L; Scarsella, Gina M; McGuire, Adam P; Crocker, Jennifer; Abelson, James L

2017-11-01

The hypothalamic-pituitary-adrenal (HPA) axis is thought to mediate the effects of stress on illness. Research has identified a limited number of psychological variables that modulate human HPA responses to stressors (e.g. perceived control and social support). Prosocial goals can reduce subjective stress, but have not been carefully examined in experimental settings where pathways of impact on biological stress markers may be traced. Recent work demonstrated that coaching individuals to strive to help others reduced HPA responses to the Trier Social Stress Test (TSST) relative to other cognitive interventions. However, identification of mediational pathways, which were not examined in the original study, is necessary to determine whether the HPA buffering effects were due to helping motivations (compassionate goals; CGs) rather than via previously identified variables such as control or support. In this new analysis, we combined the original cortisol data with novel observer ratings of interpersonal behavior and psychological variables during the stress task, and conducted new, theory-driven analyses to determine psychological mediators for the intervention's effect on cortisol responses (N = 54; 21 females, 33 males; 486 cortisol samples). Control, support, and task ego-threat failed to account for the effects of the intervention. As hypothesized, self and observer-rated CGs, as well as observer-rated perceptions of participants' interpersonal behavior as morally desirable (but not as dominant or affiliative) were significant mediators of neuroendocrine responses. The findings suggest that stress-reduction interventions based on prosocial behavior should target particular motivational and interpersonal features.

New Insights Into the Mechanism of COP9 Signalosome-Cullin-RING Ubiquitin-Ligase Pathway Deregulation in Urological Cancers.

PubMed

Gummlich, Linda; Kähne, Thilo; Naumann, Michael; Kilic, Ergin; Jung, Klaus; Dubiel, Wolfgang

2016-01-01

Urological cancers are a very common type of cancer worldwide and have alarming high incidence and mortality rates, especially in kidney cancers, illustrate the urgent need for new therapeutic targets. Recent publications point to a deregulated COP9 signalosome (CSN)-cullin-RING ubiquitin-ligase (CRL) pathway which is here considered and investigated as potential target in urological cancers with strong focus on renal cell carcinomas (RCC). The CSN forms supercomplexes with CRLs in order to preserve protein homeostasis and was found deregulated in several cancer types. Examination of selected CSN-CRL pathway components in RCC patient samples and four RCC cell lines revealed an interesting deregulated p27(Kip1)-Skp2-CAND1 axis and two p27(Kip1) point mutations in 786-O cells; p27(Kip1)V109G and p27(Kip1)I119T. The p27(Kip1) mutants were detected in patients with RCC and appear to be responsible for an accelerated growth rate in 786-O cells. The occurrence of p27(Kip1)V109G and p27(Kip1)I119T in RCC makes the CSN-CRL pathway an attractive therapeutic target. Copyright © 2016 Elsevier Inc. All rights reserved.

Thermal limits on MV x-ray production by bremsstrahlung targets in the context of novel linear accelerators.

PubMed

Wang, Jinghui; Trovati, Stefania; Borchard, Philipp M; Loo, Billy W; Maxim, Peter G; Fahrig, Rebecca

2017-12-01

To study the impact of target geometrical and linac operational parameters, such as target material and thickness, electron beam size, repetition rate, and mean current on the ability of the radiotherapy treatment head to deliver high-dose-rate x-ray irradiation in the context of novel linear accelerators capable of higher repetition rates/duty cycle than conventional clinical linacs. The depth dose in a water phantom without a flattening filter and heat deposition in an x-ray target by 10 MeV pulsed electron beams were calculated using the Monte-Carlo code MCNPX, and the transient temperature behavior of the target was simulated by ANSYS. Several parameters that affect both the dose distribution and temperature behavior were investigated. The target was tungsten with a thickness ranging from 0 to 3 mm and a copper heat remover layer. An electron beam with full width at half maximum (FWHM) between 0 and3 mm and mean current of 0.05-2 mA was used as the primary beam at repetition rates of 100, 200, 400, and 800 Hz. For a 10 MeV electron beam with FWHM of 1 mm, pulse length of 5 μs, by using a thin tungsten target with thickness of 0.2 mm instead of 1 mm, and by employing a high repetition rate of 800 Hz instead of 100 Hz, the maximum dose rate delivered can increase two times from 0.57 to 1.16 Gy/s. In this simple model, the limiting factor on dose rate is the copper heat remover's softening temperature, which was considered to be 500°C in our study. A high dose rate can be obtained by employing thin targets together with high repetition rate electron beams enabled by novel linac designs, whereas the benefit of thin targets is marginal at conventional repetition rates. Next generation linacs used to increase dose rate need different target designs compared to conventional linacs. © 2017 American Association of Physicists in Medicine.

26 CFR 1.430(h)(2)-1 - Interest rates used to determine present value.

Code of Federal Regulations, 2013 CFR

2013-04-01

... present value of the benefits that are included in the target normal cost and the funding target for the... of the benefits that are included in the target normal cost and the funding target for the plan is... target normal cost and the funding target for the plan is the second segment rate with respect to the...

26 CFR 1.430(h)(2)-1 - Interest rates used to determine present value.

Code of Federal Regulations, 2014 CFR

2014-04-01

... present value of the benefits that are included in the target normal cost and the funding target for the... of the benefits that are included in the target normal cost and the funding target for the plan is... target normal cost and the funding target for the plan is the second segment rate with respect to the...

Association Between Hospital Penalty Status Under the Hospital Readmission Reduction Program and Readmission Rates for Target and Non-Target Conditions

PubMed Central

Desai, Nihar R.; Ross, Joseph S.; Kwon, Ji Young; Herrin, Jeph; Dharmarajan, Kumar; Bernheim, Susannah M.; Krumholz, Harlan M.; Horwitz, Leora I.

2017-01-01

Importance Readmission rates declined after announcement of the Hospital Readmission Reduction Program (HRRP), which penalizes hospitals for excess readmissions for acute myocardial infarction (AMI), heart failure (HF), and pneumonia. Objective To compare trends in readmission rates for target and non-target conditions, stratified by hospital penalty status. Design, Setting, Participants Retrospective cohort study of 48,137,102 hospitalizations of 20,351,161 Medicare fee-for-service beneficiaries over 64 years discharged between January 1, 2008 and June 30, 2015 from 3,497 hospitals. Difference interrupted time series models were used to compare trends in readmission rates by condition and penalty status. Exposure Hospital penalty status or target condition under the HRRP. Outcome 30-day risk adjusted, all-cause unplanned readmission rates for target and non-target conditions. Results In January 2008, the mean readmission rates for AMI, HF, pneumonia and non-target conditions were 21.9%, 27.5%, 20.1%, and 18.4% respectively at hospitals later subject to financial penalties (n=2,189) and 18.7%, 24.2%, 17.4%, and 15.7% at hospitals not subject to penalties (n=1,283). Between January 2008 and March 2010, prior to HRRP announcement, readmission rates were stable across hospitals (except AMI at non-penalty hospitals). Following announcement of HRRP (March 2010), readmission rates for both target and non-target conditions declined significantly faster for patients at hospitals later subject to financial penalties compared with those at non-penalized hospitals (AMI, additional decrease of −1.24 (95% CI, −1.84, −0.65) percentage points per year relative to non-penalty discharges; HF, −1.25 (−1.64, −0.65); pneumonia, −1.37 (−0.95, −1.80); non-target, −0.27 (−0.38, −0.17); p<0.001 for all). For penalty hospitals, readmission rates for target conditions declined significantly faster compared with non-target conditions (AMI: additional decline of −0.49 (−0.81, −0.16) percentage points per year relative to non-target conditions, p=0.004; HF: −0.90 (−1.18, −0.62), p<0.001; pneumonia: −0.57 (−0.92,−0.23), p<0.001). By contrast, among non-penalty hospitals, readmissions for target conditions declined similarly or more slowly compared with non-target conditions (AMI: additional increase of 0.48 (0.01, 0.95) percentage points per year, p=0.05; HF: 0.08 (−0.30, 0.46), p=0.67; pneumonia: 0.53 (0.13, 0.93), p=0.01). After HRRP implementation in October 2012, the rate of change for readmission rates plateaued (p<0.05 for all except pneumonia at non-penalty hospitals) with the greatest relative change observed among hospitals subject to financial penalty. Conclusions Patients at hospitals subject to penalties had greater reductions in readmission rates compared with those at non-penalized hospitals. Changes were greater for target conditions at penalized hospitals, but not at non-penalized hospitals. PMID:28027367

Factors affecting emergency preparedness competency of public health inspectors: a cross-sectional study in northeastern China

PubMed Central

Ning, Ning; Kang, Zheng; Jiao, Mingli; Hao, Yanhua; Gao, Lijun; Sun, Hong; Wu, Qunhong

2014-01-01

Objectives To determine the emergency preparedness competency specific to public health inspectors (PHIs), preparedness limitations and needs of the workforce, as well as to identify important factors that affect the preparedness competency of PHIs. Setting Cross-sectional survey was conducted in Heilongjiang, a province in northeastern China. Participants A questionnaire was administered to a sample of 368 PHIs from 17 public health inspection agencies, chosen by stratified cluster sampling strategy. 9 PHIs and 6 agency's leaders were invited to participate in an in-depth interview. Outcome measures Self-rated preparedness competency in quantitative study was measured. Multivariate logistic regression model was used to test the associations between individual determinants and self-rated preparedness competency. Key themes relating to preparedness competency of PHIs in qualitative study were analysed. Results Although 82% of PHIs highly rated their general preparedness competency, there were significant differences among the assessment on specific domains of their competency. Comparing with attitude, the domains of skills and knowledge tend to be lower (p=0.000). Awareness on one's own responsibilities regarding emergency response work was identified as the most important factor associated with preparedness competency (adjusted OR=6.33, 95% CI 3.30 to 12.16). Lack of explicit national job requirements, overlapping responsibilities and poor collaboration among agencies, together with poor knowledge and skills level of personnel, led to an ambiguity of responsibility, and hindered the preparedness competency enhancement of PHIs furthermore. Conclusions Ambiguity responsibility in emergency response is still a prominent issue that hinders the further improvement on the preparedness competency for PHIs’ in China. Intensified capacity-building activities targeting at individuals’ weakness in specific knowledge and skills are urgently needed; in addition, capacity building at policy and system level as well as agency levels is of equal importance. PMID:24384897

Primate translational vestibuloocular reflexes. I. High-frequency dynamics and three-dimensional properties during lateral motion

NASA Technical Reports Server (NTRS)

Angelaki, D. E.; McHenry, M. Q.; Hess, B. J.

2000-01-01

The dynamics and three-dimensional (3-D) properties of the primate translational vestibuloocular reflex (trVOR) for high-frequency (4-12 Hz, +/-0.3-0.4 g) lateral motion were investigated during near-target viewing at center and eccentric targets. Horizontal response gains increased with frequency and depended on target eccentricity. The larger the horizontal and vertical target eccentricity, the steeper the dependence of horizontal response gain on frequency. In addition to horizontal eye movements, robust torsional response components also were present at all frequencies. During center-target fixation, torsional response phase was opposite (anticompensatory) to that expected for an "apparent" tilt response. Instead torsional response components depended systematically on vertical-target eccentricity, increasing in amplitude when looking down and reversing phase when looking up. As a result the trVOR eye velocity vector systematically tilted away from a purely horizontal direction, through an angle that increased with vertical eccentricity with a slope of approximately 0.7. This systematic dependence of torsional eye velocity tilt on vertical eye position suggests that the trVOR might follow the 3-D kinematic requirements that have been shown to govern visually guided eye movements and near-target fixation.

Pursuit Latency for Chromatic Targets

NASA Technical Reports Server (NTRS)

Mulligan, Jeffrey B.; Ellis, Stephen R. (Technical Monitor)

1998-01-01

The temporal dynamics of eye movement response to a change in direction of stimulus motion has been used to compare the processing speeds of different types of stimuli (Mulligan, ARVO '97). In this study, the pursuit response to colored targets was measured to test the hypothesis that the slow response of the chromatic system (as measured using traditional temporal sensitivity measures such as contrast sensitivity) results in increased eye movement latencies. Subjects viewed a small (0.4 deg) Gaussian spot which moved downward at a speed of 6.6 deg/sec. At a variable time during the trajectory, the dot's direction of motion changed by 30 degrees, either to the right or left. Subjects were instructed to pursue the spot. Eye movements were measured using a video ophthalmoscope with an angular resolution of approximately 1 arc min and a temporal sampling rate of 60 Hz. Stimuli were modulated in chrominance for a variety of hue directions, combined with a range of small luminance increments and decrements, to insure that some of the stimuli fell in the subjects' equiluminance planes. The smooth portions of the resulting eye movement traces were fit by convolving the stimulus velocity with an exponential having variable onset latency, time constant and amplitude. Smooth eye movements with few saccades were observed for all stimuli. Pursuit responses to stimuli having a significant luminance component are well-fit by exponentials having latencies and time constants on the order of 100 msec. Increases in pursuit response latency on the order of 100-200 msec are observed in response to certain stimuli, which occur in pairs of complementary hues, corresponding to the intersection of the stimulus section with the subjects' equiluminant plane. Smooth eye movements can be made in response to purely chromatic stimuli, but are slower than responses to stimuli with a luminance component.

ISDD: A computational model of particle sedimentation, diffusion and target cell dosimetry for in vitro toxicity studies

PubMed Central

2010-01-01

Background The difficulty of directly measuring cellular dose is a significant obstacle to application of target tissue dosimetry for nanoparticle and microparticle toxicity assessment, particularly for in vitro systems. As a consequence, the target tissue paradigm for dosimetry and hazard assessment of nanoparticles has largely been ignored in favor of using metrics of exposure (e.g. μg particle/mL culture medium, particle surface area/mL, particle number/mL). We have developed a computational model of solution particokinetics (sedimentation, diffusion) and dosimetry for non-interacting spherical particles and their agglomerates in monolayer cell culture systems. Particle transport to cells is calculated by simultaneous solution of Stokes Law (sedimentation) and the Stokes-Einstein equation (diffusion). Results The In vitro Sedimentation, Diffusion and Dosimetry model (ISDD) was tested against measured transport rates or cellular doses for multiple sizes of polystyrene spheres (20-1100 nm), 35 nm amorphous silica, and large agglomerates of 30 nm iron oxide particles. Overall, without adjusting any parameters, model predicted cellular doses were in close agreement with the experimental data, differing from as little as 5% to as much as three-fold, but in most cases approximately two-fold, within the limits of the accuracy of the measurement systems. Applying the model, we generalize the effects of particle size, particle density, agglomeration state and agglomerate characteristics on target cell dosimetry in vitro. Conclusions Our results confirm our hypothesis that for liquid-based in vitro systems, the dose-rates and target cell doses for all particles are not equal; they can vary significantly, in direct contrast to the assumption of dose-equivalency implicit in the use of mass-based media concentrations as metrics of exposure for dose-response assessment. The difference between equivalent nominal media concentration exposures on a μg/mL basis and target cell doses on a particle surface area or number basis can be as high as three to six orders of magnitude. As a consequence, in vitro hazard assessments utilizing mass-based exposure metrics have inherently high errors where particle number or surface areas target cells doses are believed to drive response. The gold standard for particle dosimetry for in vitro nanotoxicology studies should be direct experimental measurement of the cellular content of the studied particle. However, where such measurements are impractical, unfeasible, and before such measurements become common, particle dosimetry models such as ISDD provide a valuable, immediately useful alternative, and eventually, an adjunct to such measurements. PMID:21118529

Measuring elimination of podoconiosis, endemicity classifications, case definition and targets: an international Delphi exercise.

PubMed

Deribe, Kebede; Wanji, Samuel; Shafi, Oumer; Muheki Tukahebwa, Edridah; Umulisa, Irenee; Davey, Gail

2015-09-01

Podoconiosis is one of the major causes of lymphoedema in the tropics. Nonetheless, currently there are no endemicity classifications or elimination targets to monitor the effects of interventions. This study aimed at establishing case definitions and indicators that can be used to assess endemicity, elimination and clinical outcomes of podoconiosis. This paper describes the result of a Delphi technique used among 28 experts. A questionnaire outlining possible case definitions, endemicity classifications, elimination targets and clinical outcomes was developed. The questionnaire was distributed to experts working on podoconiosis and other neglected tropical diseases in two rounds. The experts rated the importance of case definitions, endemic classifications, elimination targets and the clinical outcome measures. Median and mode were used to describe the central tendency of expert responses. The coefficient of variation was used to describe the dispersals of expert responses. Consensus on definitions and indicators for assessing endemicity, elimination and clinical outcomes of podoconiosis directed at policy makers and health workers was achieved following the two rounds of Delphi approach among the experts. Based on the two Delphi rounds we discuss potential indicators and endemicity classification of this disabling disease, and the ongoing challenges to its elimination in countries with the highest prevalence. Consensus will help to increase effectiveness of podoconiosis elimination efforts and ensure comparability of outcome data. © The Author 2015. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.

Sensors, transmitters, and targets in mitochondrial oxygen shortage-a hypoxia-inducible factor relay story.

PubMed

Dehne, Nathalie; Brüne, Bernhard

2014-01-10

Cells sense and respond to a shortage of oxygen by activating the hypoxia-inducible transcription factors HIF-1 and HIF-2 and evoking adaptive responses. Mitochondria are at the center of a hypoxia sensing and responding relay system. Under normoxia, reactive oxygen species (ROS) and nitric oxide (NO) are HIF activators. As their individual flux rates determine their diffusion-controlled interaction, predictions how these radicals affect HIF appear context-dependent. Considering that the oxygen requirement for NO formation limits its role in activating HIF to conditions of ambient oxygen tension. Given the central role of mitochondrial complex IV as a NO target, especially under hypoxia, allows inhibition of mitochondrial respiration by NO to spare oxygen thus, raising the threshold for HIF activation. HIF targets seem to configure a feedback-signaling circuit aimed at gradually adjusting mitochondrial function. In hypoxic cancer cells, mitochondria redirect Krebs cycle intermediates to preserve their biosynthetic ability. Persistent HIF activation lowers the entry of electron-delivering compounds into mitochondria to reduce Krebs cycle fueling and β-oxidation, attenuates the expression of electron transport chain components, limits mitochondria biosynthesis, and provokes their removal by autophagy. Mitochondria can be placed central in a hypoxia sensing-hypoxia responding circuit. We need to determine to which extent and how mitochondria contribute to sense hypoxia, explore whether modulating their oxygen-consuming capacity redirects hypoxic responses in in vivo relevant disease conditions, and elucidate how the multiple HIF targets in mitochondria shape conditions of acute versus chronic hypoxia.