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Sample records for early cytogenetic endpoints

  1. Evaluation of early efficacy endpoints for proof-of-concept trials.

    PubMed

    Chen, Cong; Sun, Linda; Li, Chih-Lin

    2013-03-11

    A Phase II proof-of-concept (POC) trial usually uses an early efficacy endpoint other than a clinical endpoint as the primary endpoint. Because of the advancement in bioscience and technology, which has yielded a number of new surrogate biomarkers, drug developers often have more candidate endpoints to choose from than they can handle. As a result, selection of endpoint and its effect size as well as choice of type I/II error rates are often at the center of heated debates in design of POC trials. While optimization of the trade-off between benefit and cost is the implicit objective in such a decision-making process, it is seldom explicitly accounted for in practice. In this research note, motivated by real examples from the oncology field, we provide practical measures for evaluation of early efficacy endpoints (E4) for POC trials. We further provide optimal design strategies for POC trials that include optimal Go-No Go decision criteria for initiation of Phase III and optimal resource allocation strategies for conducting multiple POC trials in a portfolio under fixed resources. Although oncology is used for illustration purpose, the same idea developed in this research note also applies to similar situations in other therapeutic areas or in early-stage drug development in that a Go-No Go decision has to rely on limited data from an early efficacy endpoint and cost-effectiveness is the main concern.

  2. The usefulness of cytogenetic parameters, level of p53 protein and endogenous glutathione as intermediate end-points in raw betel-nut genotoxicity.

    PubMed

    Kumpawat, K; Chatterjee, A

    2003-07-01

    Betel-nut (BN) chewing related oral mucosal lesions are potential hazards to a large population worldwide. Genotoxicity of betel alkaloids, polyphenol and tannin fractions have been reported. It has been shown earlier that BN ingredients altered the level of endogenous glutathione (GSH) which could modulate the host susceptibility to the action of other chemical carcinogens. The north-east Indian variety of BN, locally known as 'kwai', is raw, wet and consumed unprocessed with betel-leaf and slaked lime and contains higher alkaloids, polyphenol and tannins as compared to the dried one. Therefore, the purpose of this study was to investigate the extent of DNA damage, pattern of cell kinetics, the level of p53-protein and endogenous GSH in kwai chewers in the tribal population of Meghalaya state in the northeastern region of India with an aim to see whether these end-points could serve as biomarkers of genetic damage of relevance for genotoxic/carcinogenic process. The present data show higher DNA damage, delay in cell kinetics, p53 expression and lower GSH-level in heavy chewers (HC) than nonchewers (NC). The influence of bleomycin (BLM) on chromatid break induction in G2-phase of peripheral blood lymphocytes in NC and HC has been analysed to determine individual susceptibility to carcinogenic assaults. HC showed higher induction of chromatid breaks than NC. Risk assessment in this study suggests an interaction between carcinogen exposure and mutagen sensitivity measures, risk estimates being higher in those individuals who both consume kwai and express sensitivity to free radical oxygen damage in vitro. From this study it seems that besides cytogenetical parameters, the level of endogenous GSH and the level of p53 protein could act as effective biomarkers for kwai chewers.

  3. Swimming speed alteration in the early developmental stages of Paracentrotus lividus sea urchin as ecotoxicological endpoint.

    PubMed

    Morgana, Silvia; Gambardella, Chiara; Falugi, Carla; Pronzato, Roberto; Garaventa, Francesca; Faimali, Marco

    2016-04-01

    Behavioral endpoints have been used for decades to assess chemical impacts at concentrations unlikely to cause mortality. With recently developed techniques, it is possible to investigate the swimming behavior of several organisms under laboratory conditions. The aims of this study were: i) assessing for the first time the feasibility of swimming speed analysis of the early developmental stage sea urchin Paracentrotus lividus by an automatic recording system ii) investigating any Swimming Speed Alteration (SSA) on P. lividus early stages exposed to a chemical reference; iii) identifying the most suitable stage for SSA test. Results show that the swimming speed of all the developmental stages was easily recorded. The swimming speed was inhibited as a function of toxicant concentration. Pluteus were the most appropriate stage for evaluating SSA in P. lividus as ecotoxicological endpoint. Finally, swimming of sea urchin early stages represents a sensitive endpoint to be considered in ecotoxicological investigations. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Heavy Rare Earth Elements Affect Sphaerechinus granularis Sea Urchin Early Life Stages by Multiple Toxicity Endpoints.

    PubMed

    Gravina, Maria; Pagano, Giovanni; Oral, Rahime; Guida, Marco; Toscanesi, Maria; Siciliano, Antonietta; Di Nunzio, Aldo; Burić, Petra; Lyons, Daniel M; Thomas, Philippe J; Trifuoggi, Marco

    2018-05-01

    Heavy rare earth elements (HREEs) were tested for adverse effects to early life stages of the sea urchin Sphaerechinus granularis. Embryos were exposed to analytically measured HREE concentrations ranging from 10 -7 to 10 -5  M. No significant developmental defect (DD) increases were observed in embryos exposed to 10 -7  M HREEs, whereas 10 -5  M HREEs resulted in significant DD increase up to 96% for HoCl 3 versus 14% in controls. Embryos exposed to 10 -6  M HREEs showed the highest DD frequency in embryos exposed to 10 -6  M DyCl 3 and HoCl 3 . Cytogenetic analysis of HREE-exposed embryos revealed a significant decrease in mitotic activity, with increased mitotic aberrations. When S. granularis sperm were exposed to HREEs, the offspring of sperm exposed to 10 -5  M GdCl 3 and LuCl 3 showed significant DD increases. The results warrant investigations on HREEs in other test systems, and on REE-containing complex mixtures.

  5. Toward early safety alert endpoints: exploring biomarkers suggestive of microbicide failure.

    PubMed

    Mauck, Christine K; Lai, Jaim Jou; Weiner, Debra H; Chandra, Neelima; Fichorova, Raina N; Dezzutti, Charlene S; Hillier, Sharon L; Archer, David F; Creinin, Mitchell D; Schwartz, Jill L; Callahan, Marianne M; Doncel, Gustavo F

    2013-11-01

    Several microbicides, including nonoxynol-9 (N-9) and cellulose sulfate (CS), looked promising during early trials but failed in efficacy trials. We aimed to identify Phase I mucosal safety endpoints that might explain that failure. In a blinded, randomized, parallel trial, 60 healthy premenopausal sexually abstinent women applied Universal HEC placebo, 6% CS or 4% N-9 gel twice daily for 13½ days. Endpoints included immune biomarkers in cervicovaginal lavage (CVL) and endocervical cytobrushes, inflammatory infiltrates in vaginal biopsies, epithelial integrity by naked eye, colposcopy, and histology, CVL anti-HIV activity, vaginal microflora, pH, and adverse events. Twenty women enrolled per group. Soluble/cellular markers were similar with CS and placebo, except secretory leukocyte protease inhibitor (SLPI) levels decreased in CVL, and CD3(+) and CD45(+) cells increased in biopsies after CS use. Increases in interleukin (IL)-8, IL-1, IL-1RA, and myeloperoxidase (MPO) and decreases in SLPI were significant with N-9. CVL anti-HIV activity was significantly higher during CS use compared to N-9 or placebo. CS users tended to have a higher prevalence of intermediate Nugent score, Escherichia coli, and Enterococcus and fewer gram-negative rods. Most Nugent scores diagnostic for bacterial vaginosis were in N-9 users. All cases of histological inflammation or deep epithelial disruption occurred in N-9 users. While the surfactant N-9 showed obvious biochemical and histological signs of inflammation, more subtle changes, including depression of SLPI, tissue influx of CD45(+) and CD3(+) cells, and subclinical microflora shifts were associated with CS use and may help to explain the clinical failure of nonsurfactant microbicides.

  6. Linking tobacco control policies and practices to early cancer endpoints: surveillance as an agent for change.

    PubMed

    Hartman, Anne M; Thun, Michael J; Ballard-Barbash, Rachel

    2008-09-01

    State tobacco control programs provide an important laboratory for the development, implementation, and evaluation of comprehensive tobacco control interventions. Studies have shown that states and municipalities with aggressive tobacco control programs have experienced more rapid decreases in per capita cigarette sales, smoking prevalence, lung cancer, and heart disease than entities without such programs. Despite strong evidence that population-level interventions are critical in achieving large and sustained reductions in tobacco use, states do not fund tobacco control efforts at levels recommended by the Centers for Disease Control and Prevention. Research on the effectiveness and cost effectiveness of these activities is essential to inform and strengthen tobacco control at the state level. A workshop, co-organized by the American Cancer Society, the National Cancer Institute, the American Association for Cancer Research, and the Centers for Disease Control and Prevention, was held in Philadelphia in December, 2007, to discuss the topic "Linking tobacco control policies and practices to early cancer endpoints: surveillance as an agent for change." Participants represented three different disciplines. Tobacco surveillance researchers described the data currently collected on state-level tobacco control policies, protobacco countermeasures by the industry, public attitudes toward tobacco use, and measures of smoking prevalence and consumption. Cancer registry experts described the geographic coverage of high quality, population-based cancer registries. Mathematical modeling experts discussed various modeling approaches that can be used to relate upstream tobacco promotion and control activities to downstream measures such as public attitudes, changes in tobacco use, and trends in tobacco-related diseases. The most important recommendation of the Workshop was a call for national leadership to enhance the collection and integration of data from multiple sources as

  7. Early improvement with pregabalin predicts endpoint response in patients with generalized anxiety disorder: an integrated and predictive data analysis.

    PubMed

    Montgomery, Stuart A; Lyndon, Gavin; Almas, Mary; Whalen, Ed; Prieto, Rita

    2017-01-01

    Generalized anxiety disorder (GAD), a common mental disorder, has several treatment options including pregabalin. Not all patients respond to treatment; quickly determining which patients will respond is an important treatment goal. Patient-level data were pooled from nine phase II and III randomized, double-blind, short-term, placebo-controlled trials of pregabalin for the treatment of GAD. Efficacy outcomes included the change from baseline in the Hamilton Anxiety Scale (HAM-A) total score and psychic and somatic subscales. Predictive modelling assessed baseline characteristics and early clinical responses to determine those predictive of clinical improvement at endpoint. A total of 2155 patients were included in the analysis (1447 pregabalin, 708 placebo). Pregabalin significantly improved the HAM-A total score compared with the placebo at endpoint, treatment difference (95% confidence interval), -2.61 (-3.21 to -2.01), P<0.0001. Pregabalin significantly improved HAM-A psychic and somatic scores compared with placebo, -1.52 (-1.85 to -1.18), P<0.0001, and -1.10 (-1.41 to -0.80), P<0.0001, respectively. Response to pregabalin in the first 1-2 weeks (≥20 or ≥30% improvement in HAM-A total, psychic or somatic score) was predictive of an endpoint greater than or equal to 50% improvement in the HAM-A total score. Pregabalin is an effective treatment option for patients with GAD. Patients with early response to pregabalin are more likely to respond significantly at endpoint.

  8. Early analysis of surrogate endpoints for metastatic melanoma in immune checkpoint inhibitor trials.

    PubMed

    Petrelli, Fausto; Coinu, Andrea; Cabiddu, Mary; Borgonovo, Karen; Ghilardi, Mara; Lonati, Veronica; Barni, Sandro

    2016-06-01

    Recent major phase III trials led to the approval of immune checkpoint inhibitors (ipilimumab, pembrolizumab, and nivolumab) in metastatic malignant melanoma (MM). We aim to assess whether median progression-free survival, and 1 and 2-year overall survival (OS) rates are reliable surrogate endpoints for median OS through a meta-analysis of published trials involving immunotherapy. A systematic literature search in PubMed, EMBASE, Web of Science, and SCOPUS of published phase II to III trials with immunotherapy as the treatment for MM was conducted. Adjusted weighted linear regression was used to calculate Pearson correlations (R) between surrogates and median OS, and between treatment effects on surrogates and median OS. A total of 13 studies involving 3373 patients with MM were identified. The correlation of progression-free survival with OS was not significant (R = 0.45, P = .11). Conversely, the correlation between 1-year OS and median OS was very strong (R = 0.93, 95% confidence interval [CI] 0.84-0.96, P < .00001), as was the correlation between 2-year OS and OS (R = 0.79, 95% CI 0.51-0.91, P = .0001). The correlation between the treatment effects on 1-year OS and OS was also significant (R = -0.86, 95% CI -0.3 to 0.97, P = .01). Similar results were obtained for 2-year OS. According to the available study data, 1-year OS rate could be regarded as a potential surrogate for median OS in novel immunotherapy trials of metastatic MM. Waiting for ongoing studies (e.g., pembrolizumab), we suggest that this intermediate endpoint could be considered as a potential primary endpoint in future clinical trials.

  9. Two-stage phase II oncology designs using short-term endpoints for early stopping.

    PubMed

    Kunz, Cornelia U; Wason, James Ms; Kieser, Meinhard

    2017-08-01

    Phase II oncology trials are conducted to evaluate whether the tumour activity of a new treatment is promising enough to warrant further investigation. The most commonly used approach in this context is a two-stage single-arm design with binary endpoint. As for all designs with interim analysis, its efficiency strongly depends on the relation between recruitment rate and follow-up time required to measure the patients' outcomes. Usually, recruitment is postponed after the sample size of the first stage is achieved up until the outcomes of all patients are available. This may lead to a considerable increase of the trial length and with it to a delay in the drug development process. We propose a design where an intermediate endpoint is used in the interim analysis to decide whether or not the study is continued with a second stage. Optimal and minimax versions of this design are derived. The characteristics of the proposed design in terms of type I error rate, power, maximum and expected sample size as well as trial duration are investigated. Guidance is given on how to select the most appropriate design. Application is illustrated by a phase II oncology trial in patients with advanced angiosarcoma, which motivated this research.

  10. Confirmatory versus explorative endpoint analysis: Decision-making on the basis of evidence available from market authorization and early benefit assessment for oncology drugs.

    PubMed

    Niehaus, Ines; Dintsios, Charalabos-Markos

    2018-06-01

    The early benefit assessment of pharmaceuticals in Germany and their preceding market authorization pursue different objectives. This is reflected by the inclusion of varying confirmatory endpoints within the evaluation of oncology drugs in early benefit assessment versus market authorization, with both relying on the same evidence. Data from assessments up to July 2015 are used to estimate the impact of explorative in comparison to confirmatory endpoints on market authorization and early benefit assessment by contrasting the benefit-risk ratio of EMA and the benefit-harm balance of the HTA jurisdiction. Agreement between market authorization and early benefit assessment is examined by Cohen's kappa (k). 21 of 41 assessments were considered in the analysis. Market authorization is more confirmatory than early benefit assessment because it includes a higher proportion of primary endpoints. The latter implies a primary endpoint to be relevant for the benefit-harm balance in only 67% of cases (0.078). Explorative mortality endpoints reached the highest agreement regarding the mutual consideration for the risk-benefit ratio and the benefit-harm balance (0.000). For explorative morbidity endpoints (-0.600), quality of life (-0.600) and side effects (-0.949) no agreement is ascertainable. To warrant a broader confirmatory basis for decisions supported by HTA, closer inter-institutional cooperation of approval authorities and HTA jurisdictions by means of reliable joint advice for manufacturers regarding endpoint definition would be favorable. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Visual Function Metrics in Early and Intermediate Dry Age-related Macular Degeneration for Use as Clinical Trial Endpoints.

    PubMed

    Cocce, Kimberly J; Stinnett, Sandra S; Luhmann, Ulrich F O; Vajzovic, Lejla; Horne, Anupama; Schuman, Stefanie G; Toth, Cynthia A; Cousins, Scott W; Lad, Eleonora M

    2018-05-01

    To evaluate and quantify visual function metrics to be used as endpoints of age-related macular degeneration (AMD) stages and visual acuity (VA) loss in patients with early and intermediate AMD. Cross-sectional analysis of baseline data from a prospective study. One hundred and one patients were enrolled at Duke Eye Center: 80 patients with early AMD (Age-Related Eye Disease Study [AREDS] stage 2 [n = 33] and intermediate stage 3 [n = 47]) and 21 age-matched, normal controls. A dilated retinal examination, macular pigment optical density measurements, and several functional assessments (best-corrected visual acuity, macular integrity assessment mesopic microperimety, dark adaptometry, low-luminance visual acuity [LLVA] [standard using a log 2.0 neutral density filter and computerized method], and cone contrast test [CCT]) were performed. Low-luminance deficit (LLD) was defined as the difference in numbers of letters read at standard vs low luminance. Group comparisons were performed to evaluate differences between the control and the early and intermediate AMD groups using 2-sided significance tests. Functional measures that significantly distinguished between normal and intermediate AMD were standard and computerized (0.5 cd/m 2 ) LLVA, percent reduced threshold and average threshold on microperimetry, CCTs, and rod intercept on dark adaptation (P < .05). The intermediate group demonstrated deficits in microperimetry reduced threshhold, computerized LLD2, and dark adaptation (P < .05) relative to early AMD. Our study suggests that LLVA, microperimetry, CCT, and dark adaptation may serve as functional measures differentiating early-to-intermediate stages of dry AMD. Copyright © 2018 Elsevier Inc. All rights reserved.

  12. Cancer Cytogenetics: Methodology Revisited

    PubMed Central

    2014-01-01

    The Philadelphia chromosome was the first genetic abnormality discovered in cancer (in 1960), and it was found to be consistently associated with CML. The description of the Philadelphia chromosome ushered in a new era in the field of cancer cytogenetics. Accumulating genetic data have been shown to be intimately associated with the diagnosis and prognosis of neoplasms; thus, karyotyping is now considered a mandatory investigation for all newly diagnosed leukemias. The development of FISH in the 1980s overcame many of the drawbacks of assessing the genetic alterations in cancer cells by karyotyping. Karyotyping of cancer cells remains the gold standard since it provides a global analysis of the abnormalities in the entire genome of a single cell. However, subsequent methodological advances in molecular cytogenetics based on the principle of FISH that were initiated in the early 1990s have greatly enhanced the efficiency and accuracy of karyotype analysis by marrying conventional cytogenetics with molecular technologies. In this review, the development, current utilization, and technical pitfalls of both the conventional and molecular cytogenetics approaches used for cancer diagnosis over the past five decades will be discussed. PMID:25368816

  13. Improved Survival Endpoints With Adjuvant Radiation Treatment in Patients With High-Risk Early-Stage Endometrial Carcinoma

    SciTech Connect

    Elshaikh, Mohamed A., E-mail: melshai1@hfhs.org; Vance, Sean; Suri, Jaipreet S.

    2014-02-01

    Purpose/Objective(s): To determine the impact of adjuvant radiation treatment (RT) on recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) in patients with high-risk 2009 International Federation of Gynecology and Obstetrics stage I-II endometrial carcinoma. Methods and Materials: We identified 382 patients with high-risk EC who underwent hysterectomy. RFS, DSS, and OS were calculated from the date of hysterectomy by use of the Kaplan-Meier method. Cox regression modeling was used to explore the risks associated with various factors on survival endpoints. Results: The median follow-up time for the study cohort was 5.4 years. The median age was 71 years.more » All patients underwent hysterectomy and salpingo-oophorectomy, 93% had peritoneal cytology, and 85% underwent lymphadenectomy. Patients with endometrioid histology constituted 72% of the study cohort, serous in 16%, clear cell in 7%, and mixed histology in 4%. Twenty-three percent of patients had stage II disease. Adjuvant management included RT alone in 220 patients (57%), chemotherapy alone in 25 patients (7%), and chemoradiation therapy in 27 patients (7%); 110 patients (29%) were treated with close surveillance. The 5-year RFS, DSS, and OS were 76%, 88%, and 73%, respectively. On multivariate analysis, adjuvant RT was a significant predictor of RFS (P<.001) DSS (P<.001), and OS (P=.017). Lymphovascular space involvement was a significant predictor of RFS and DSS (P<.001). High tumor grade was a significant predictor for RFS (P=.038) and DSS (P=.025). Involvement of the lower uterine segment was also a predictor of RFS (P=.049). Age at diagnosis and lymphovascular space involvement were significant predictors of OS: P<.001 and P=.002, respectively. Conclusion: In the treatment of patients with high-risk features, our study suggests that adjuvant RT significantly improves recurrence-free, disease-specific, and overall survival in patients with early-stage endometrial

  14. Early Fungicidal Activity as a Candidate Surrogate Endpoint for All-Cause Mortality in Cryptococcal Meningitis: A Systematic Review of the Evidence.

    PubMed

    Montezuma-Rusca, Jairo M; Powers, John H; Follmann, Dean; Wang, Jing; Sullivan, Brigit; Williamson, Peter R

    2016-01-01

    Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality. In clinical trials evaluating treatments for CM, biomarkers of early fungicidal activity (EFA) in cerebrospinal fluid (CSF) have been proposed as candidate surrogate endpoints for all- cause mortality (ACM). However, there has been no systematic evaluation of the group-level or trial-level evidence for EFA as a candidate surrogate endpoint for ACM. We conducted a systematic review of randomized trials in treatment of CM to evaluate available evidence for EFA measured as culture negativity at 2 weeks/10 weeks and slope of EFA as candidate surrogate endpoints for ACM. We performed sensitivity analysis on superiority trials and high quality trials as determined by Cochrane measures of trial bias. Twenty-seven trials including 2854 patients met inclusion criteria. Mean ACM was 15.8% at 2 weeks and 27.0% at 10 weeks with no overall significant difference between test and control groups. There was a statistically significant group-level correlation between average EFA and ACM at 10 weeks but not at 2 weeks. There was also no statistically significant group-level correlation between CFU culture negativity at 2weeks/10weeks or average EFA slope at 10 weeks. A statistically significant trial-level correlation was identified between EFA slope and ACM at 2 weeks, but is likely misleading, as there was no treatment effect on ACM. Mortality remains high in short time periods in CM clinical trials. Using published data and Institute of Medicine criteria, evidence for use of EFA as a surrogate endpoint for ACM is insufficient and could provide misleading results from clinical trials. ACM should be used as a primary endpoint evaluating treatments for cryptococcal meningitis.

  15. The human autonomous karyotype and the origins of prenatal testing: children, pregnant women and early Down's syndrome cytogenetics, Madrid 1962-1975.

    PubMed

    Santesmases, María Jesús

    2014-09-01

    Through their ability to reveal and record abnormal chromosomes, whether inherited or accidentally altered, chromosomal studies, known as karyotyping, became the basis upon which medical genetics was constructed. The techniques involved became the visual evidence that confirmed a medical examination and were configured as a material culture for redefining health and disease, or the normal and the abnormal, in cytological terms. I will show that the study of foetal cells obtained by amniocentesis led to the stabilisation of karyotyping in its own right, while also keeping pregnant women under the vigilant medical eye. In the absence of any other examination, prenatal diagnosis by foetal karyotyping became autonomous from the foetal body. Although medical cytogenetics was practiced on an individual basis, data collected about patients over time contributed to the construction of population figures regarding birth defects. I study this complex trajectory by focussing on a Unit for Cytogenetics created in 1962 at the Clínica de la Concepción in Madrid. I incorporate the work and training of the clinicians who created the unit, and worked there as well as at other units in the large new hospitals of the national health care system built in Madrid during the mid-1960s and early 1970s. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. Mosquito cytogenetics

    PubMed Central

    Kitzmiller, James B.

    1963-01-01

    Although an intensified interest in mosquito cytogenetics in the past decade has produced a number of contributions to knowledge on this subject, the available information is still superficial and limited to a few mosquito species only. The author of this review summarizes the research done in this field between 1953 and 1962. The following are some of the achievements and some of the gaps that remain to be filled. Karyotypes of several species of Anopheles, Aedes and Culex conform to the general pattern 2n=6, with heterosomes distinguishable only in Anopheles. At least three different karyotypes are present in Anopheles. Salivary gland chromosome maps are now available for several anopheline species, but are still lacking for Culex and Aedes. No precise correlation may yet be made between the frequency of chromosomal aberrations and the degree of insecticide-resistance. Sexual differences in the salivary X-chromosomes have been reported for several species of Anopheles. Chromosomal polymorphism is common in some anophelines, but rare in others. Chromosomal mutation has been induced by means of X-rays. In his conclusions, the author stresses that prospects are especially good for evolutionary and genetic studies involving chromosomal polymorphism. PMID:14058227

  17. Dioxins and cytogenetic status of villagers after 40 years of agent Orange application in Vietnam.

    PubMed

    Sycheva, Lyudmila P; Umnova, Nataliya V; Kovalenko, Maria A; Zhurkov, Vjacheslav S; Shelepchikov, Andrey A; Roumak, Vladimir S

    2016-02-01

    We have examined cytogenetic status of the rural population living on dioxin-contaminated territories (DCT, TCDD in soil 2.6 ng/kg) compared to the villagers of the control area (TCDD in soil 0.18 ng kg(-1)). The examination took place almost 40 years after the war. The consequences of some confounding factors (years of residence in the region, farming, and aging) has been examined. Karyological analysis of buccal and nasal epitheliocytes among healthy adult males living on DCT and control area (26 and 35 persons) was conducted. A wide range of cytogenetic (micronuclei, nuclear protrusions), proliferative (binucleated cells and cells with doubled nucleus) and endpoints of cell death (cells with perinuclear vacuoles, with damaged nucleus membrane, condensed chromatin, pyknosis, karyorrhexis, karyolysis) had been analyzed. The frequent amount of cells with nuclear protrusions in both epithelia was slightly decreased in the DСT group. Biomarkers of early and late stages of nuclear destruction in buccal epithelium (cells with damaged nuclear membrane, karyolysis) were elevated significantly in DCT. Higher level of the same parameters was also identified in nasal epithelium. The cytogenetic status of healthy adult males on DCT had got "normalization" by present moment in comparison with our early data. Nevertheless, in exposed group some alteration of the cytogenetic status was being registered (mostly biomarkers of apoptosis). Years of residence (and exposure to dioxins) affected the cytogenetic status of DCT inhabitants, whereas no influence of farming factors (pesticides, fertilizers, etc.) had been discovered. Some biomarkers of proliferation and cell death were affected by aging. Copyright © 2015 Elsevier Ltd. All rights reserved.

  18. Cytogenetic and viability effects of petroleum aromatic and PCB hydrocarbons, temperature and salinity, on early development of the American oyster, Crassostrea virginica Gmelin

    SciTech Connect

    Stiles-Jewell, S.

    1994-01-01

    Fertilized eggs were exposed to 0.1, 10 and 100 mg/l of benzene, naphthalene and Aroclor 1254 individually and in combination in seawater at temperatures and salinities of 20 and 25. Toxicity was measured as frequencies of: (1) meiotic and mitotic abnormalities in 3-hour embryos; (2) total development to the 48-hour straight-hinge larval stage; (3) mortality and abnormality at the 48-hour larval stage; (4) mean size of larvae at 48 hours; and (5) cytogenetic and cytological abnormalities in 48-hour larvae. Dose-dependent responses were observed. Overall, naphthalene and aroclor at 100 mg/l had few embryos that survived to the stage where theymore » could be examined and scored for cytogenetic and cytological abnormality even by 3-hours post-fertilization. Abnormality of the few embryos available for examination was somewhat higher for aroclor but was significantly higher for naphthalene than for control embryos and those exposed to 0.1 mg/l. At the highest concentration of 100 mg/l, mortality was 100% by the larval stage for naphthalene and aroclor. Though total development and survival of embryos to the larval stage at the 10 mg/l dose were high, many of the larvae were dead or abnormal in the aroclor-exposed cultures. This mean incidence was significantly higher than for all other groups. Larvae developing in these cultures with 10 mg/l were also significantly smaller and cytological condition of the larvae was significantly worse. Higher temperature appeared to increase the frequency of deleterious effects, particularly for naphthalene and aroclor. Results with salinity were more variable. Overall, results showed that petroleum aromatic hydrocarbons and PCBs can have toxic effects on the development and survival of early life stages of oysters, as well as sublethal effects on growth and cytological condition, depending on dose and interactions with other compound and with environmental variables.« less

  19. Challenge of surrogate endpoints.

    PubMed

    Furgerson, James L; Hannah, William N; Thompson, Jennifer C

    2012-03-01

    Surrogate endpoints are biomarkers that are intended to substitute for clinical endpoints. They have been used to find novel therapeutic targets, improve the statistical power and shorten the duration of clinical trials, and control the cost of conducting research studies. The more generalized use of surrogate endpoints in clinical decision making can be hazardous and should be undertaken with great caution. This article reviews prior work with surrogate endpoints and highlights caveats and lessons learned from studies using surrogate endpoints.

  20. The history of human cytogenetics in India-A review.

    PubMed

    Dutta, Usha R

    2016-09-10

    It is 60years since the discovery of the correct number of chromosomes in 1956; the field of cytogenetics had evolved. The late evolution of this field with respect to other fields is primarily due to the underdevelopment of lenses and imaging techniques. With the advent of the new technologies, especially automation and evolution of advanced compound microscopes, cytogenetics drastically leaped further to greater heights. This review describes the historic events that had led to the development of human cytogenetics with a special attention about the history of cytogenetics in India, its present status, and future. Apparently, this review provides a brief account into the insights of the early laboratory establishments, funding, and the German collaborations. The details of the Indian cytogeneticists establishing their labs, promoting the field, and offering the chromosomal diagnostic services are described. The detailed study of chromosomes helps in increasing the knowledge of the chromosome structure and function. The delineation of the chromosomal rearrangements using cytogenetics and molecular cytogenetic techniques pays way in identifying the molecular mechanisms involved in the chromosomal rearrangement. Although molecular cytogenetics is greatly developing, the conventional cytogenetics still remains the gold standard in the diagnosis of various numerical chromosomal aberrations and a few structural aberrations. The history of cytogenetics and its importance even in the era of molecular cytogenetics are discussed. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. Flow cytogenetics and chromosome sorting.

    PubMed

    Cram, L S

    1990-06-01

    This review of flow cytogenetics and chromosome sorting provides an overview of general information in the field and describes recent developments in more detail. From the early developments of chromosome analysis involving single parameter or one color analysis to the latest developments in slit scanning of single chromosomes in a flow stream, the field has progressed rapidly and most importantly has served as an important enabling technology for the human genome project. Technological innovations that advanced flow cytogenetics are described and referenced. Applications in basic cell biology, molecular biology, and clinical investigations are presented. The necessary characteristics for large number chromosome sorting are highlighted. References to recent review articles are provided as a starting point for locating individual references that provide more detail. Specific references are provided for recent developments.

  2. Endpoints and surrogate endpoints in colorectal cancer: a review of recent developments.

    PubMed

    Piedbois, Pascal; Buyse, Marc

    2008-07-01

    The purpose of this review is to discuss recently published work on endpoints for early and advanced colorectal cancer, as well as the statistical approaches used to validate surrogate endpoints. Most attempts to validate surrogate endpoints have estimated the correlation between the surrogate and the true endpoint, and between the treatment effects on these endpoints. The correlation approach has made it possible to validate disease-free survival and progression-free survival as acceptable surrogates for overall survival in early and advanced disease, respectively. The search for surrogate endpoints will intensify over the coming years. In parallel, efforts to either standardize or extend the endpoints or both will improve the reliability and relevance of clinical trial results.

  3. Methods in molecular biology: plant cytogenetics

    USDA-ARS?s Scientific Manuscript database

    Cytogenetic studies have contributed greatly to our understanding of genetics, biology, reproduction, and evolution. From early studies in basic chromosome behavior the field has expanded enabling whole genome analysis to the manipulation of chromosomes and their organization. This book covers a ran...

  4. Cytogenetics of Festulolium (Festuca x Lolium hybrids).

    PubMed

    Kopecký, D; Lukaszewski, A J; Dolezel, J

    2008-01-01

    Grasses are the most important and widely cultivated crops. Among them, ryegrasses (Lolium spp.) and fescues (Festuca spp.) provide high quality fodder for livestock, are used for turf and amenity purposes, and play a fundamental role in environment protection. Species from the two genera display complementary agronomic characteristics and are often grown in mixtures. Breeding efforts to combine desired features in single entities culminated with the production of Festuca x Lolium hybrids. The so called Festuloliums enjoy a considerable commercial success with numerous cultivars registered all over the world. They are also very intriguing from a strictly cytogenetic point of view as the parental chromosomes recombine freely in hybrids. Until a decade ago this phenomenon was only known in general quantitative terms. The introduction of molecular cytogenetic tools such as FISH and GISH permitted detailed studies of intergeneric chromosome recombination and karyotyping of Festulolium cultivars. These tools were also invaluable in revealing the origin of polyploid fescues, and facilitated the development of chromosome substitution and introgression lines and physical mapping of traits of interest. Further progress in this area will require the development of a larger set of cytogenetic markers and high-resolution cytogenetic maps. It is expected that the Lolium-Festuca complex will continue providing opportunities for breeding superior grass cultivars and the complex will remain an attractive platform for fundamental research of the early steps of hybrid speciation and interaction of parental genomes, as well as the processes of chromosome pairing, elimination and recombination. 2008 S. Karger AG, Basel

  5. Antioxidant power as biochemical endpoint in bread for screening and early managing quality and toxicant-related safety anomalies in food production.

    PubMed

    Dragone, Roberto; Ermilov, Laura; Grasso, Gerardo; Maggioni, Silvia; Mantovani, Alberto; Frazzoli, Chiara

    2016-08-01

    Flaxseeds are both a food ingredient and a natural source of antioxidants (e.g. lignans, PUFAs) and pro-oxidant contaminants (e.g. cadmium): the variable mixture of anti- and pro-oxidant substances may impact on the redox homeostasis of flaxseed-enriched foods. The antioxidant power is studied here as biochemical activity of flaxseeds in white wheat bread and as endpoint for possible screening of anomalous variations of bioactive mixtures (antioxidants vs. prooxidants) in food matrices. A bioprobe assay based on the superoxide dismutase (SOD) enzyme (6 channels of the multiprobe bioelectronic platform BEST) was performed on white wheat bread with and without flaxseeds. Nine BEST channels were simultaneously used for validation and monitoring of measuring conditions (temperature, pH, conductivity). Findings were compared with quantitative analysis of antioxidants and pro-oxidant contaminants. Organic and aqueous extracts of both bread types were examined in parallel. The SOD-probe detected the difference in antioxidant power given by 10% flaxseed, thus supporting the use of antioxidant power detected by bioenzymatic screening as sensitive biochemical endpoint. Mixtures of bioactive molecules in foods generate biochemical activities that can be monitored as time-effective indicators of invariability, which is pivotal in the daily control of anomalies in food production and therefore in the protection of consumers' health. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies.

    PubMed

    Zhu, Rui; Lu, Dan; Chu, Yu-Waye; Chai, Akiko; Green, Michelle; Zhang, Nancy; Jin, Jin Yan

    2017-05-01

    Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R 2 ). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R 2  = 0.81, 95% confidence interval [CI] 0.51-0.96). Six-month PFS was strongly correlated with 3-year PFS (R 2  = 0.89, 95% CI 0.62-0.96) in FL and was moderately correlated with 2-year OS (R 2  = 0.69, 95% CI 0.40-0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13% ± 1.2% increase in 2-year OS in DLBCL, a 23% ± 1.1% increase in 3-year PFS in FL, or a 6.7% ± 1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R 2  = 0.66 (95% CI 0.52-0.98) and R 2  = 0.69 (95% CI 0.22-0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.

  7. Endpoint titration and immunotherapy.

    PubMed

    King, H C

    1985-11-01

    Inhalant allergy, or "atopy" as it is now termed, is the best understood form of allergy today. In some circles, it is the only recognized form of allergy. While an overall picture of its effects on the body and a reasonable approach to its treatment now exist, many problems remain to be solved and much improvement in its treatment will probably occur within the next several years. Many new approaches to treatment of aeroallergens are now available; however, all are compared with the skin test, which is and has been the baseline for testing and treatment. Endpoint titration provides a quantitative means for undertaking treatment of aeroallergen sensitivity. In no other way does it differ from the forms of skin testing that have been widely used for generations. The practitioners of endpoint titration feel that this difference is highly significant in simplifying, validating, and shortening the necessary period of therapy. While the concept of endpoint titration is not difficult, it is by definition a quantitative form of testing and requires a degree of expertise in performing it correctly. While a good understanding of the method may be gained from the literature, adequate hands-on experience should be obtained by any physician prior to instituting the technique as a treatment modality. Once mastered, it becomes a reliable baseline for all forms of inhalant allergy care.

  8. Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: effect on diabetic neuropathy related endpoints

    PubMed Central

    Yorek, Matthew S.; Obrosov, Alexander; Shevalye, Hanna; Coppey, Lawrence J.; Kardon, Randy H.; Yorek, Mark A.

    2017-01-01

    We have previously demonstrated that enalapril, α-lipoic acid and menhaden (fish) oil has potential as a treatment for diabetic peripheral neuropathy. In this study we sought to determine the efficacy of these treatments individually or in combination on multiple neuropathic endpoints in a high fat fed low dose streptozotocin treated mouse, a model of type 2 diabetes, following early or late intervention. Four or twelve weeks after the onset of hyperglycemia, diabetic mice were treated with enalapril, α-lipoic acid, menhaden oil or their combination for 12 weeks. Afterwards, endpoints including glucose tolerance, motor and sensory nerve conduction velocity, thermal nociception, and intraepidermal and cornea nerve fiber density was determined. Glucose clearance was impaired in diabetic mice and significantly improved only with combination treatment and early intervention. Diabetes caused steatosis, slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia and reduction in intraepidermal and cornea nerve fiber density. Treating diabetic mice with enalapril, α-lipoic acid or menhaden oil partially protected diabetic mice from these deficits, whereas the combination of these three treatments was more efficacious following early or late intervention. These studies suggest that a combination therapy may be more effective for treating neural complications of type 2 diabetes. PMID:28025096

  9. Early vs. late intervention of high fat/low dose streptozotocin treated C57Bl/6J mice with enalapril, α-lipoic acid, menhaden oil or their combination: Effect on diabetic neuropathy related endpoints.

    PubMed

    Yorek, Matthew S; Obrosov, Alexander; Shevalye, Hanna; Coppey, Lawrence J; Kardon, Randy H; Yorek, Mark A

    2017-04-01

    We have previously demonstrated that enalapril, α-lipoic acid and menhaden (fish) oil has potential as a treatment for diabetic peripheral neuropathy. In this study we sought to determine the efficacy of these treatments individually or in combination on multiple neuropathic endpoints in a high fat fed low dose streptozotocin treated mouse, a model of type 2 diabetes, following early or late intervention. Four or twelve weeks after the onset of hyperglycemia, diabetic mice were treated with enalapril, α-lipoic acid, menhaden oil or their combination for 12 weeks. Afterwards, endpoints including glucose tolerance, motor and sensory nerve conduction velocity, thermal nociception, and intraepidermal and cornea nerve fiber density was determined. Glucose clearance was impaired in diabetic mice and significantly improved only with combination treatment and early intervention. Diabetes caused steatosis, slowing of motor and sensory nerve conduction velocity, thermal hypoalgesia and reduction in intraepidermal and cornea nerve fiber density. Treating diabetic mice with enalapril, α-lipoic acid or menhaden oil partially protected diabetic mice from these deficits, whereas the combination of these three treatments was more efficacious following early or late intervention. These studies suggest that a combination therapy may be more effective for treating neural complications of type 2 diabetes. Published by Elsevier Ltd.

  10. Cytogenetic toxicity of vincristine.

    PubMed

    Choudhury, R C; Das, B; Misra, S; Jagdale, M B

    2000-01-01

    The anticancer drugs vincristine sulphate (VCR) and cyclophosphamide (CTX) were tested for their cytogenetic effects in the bone marrow cells of Swiss mice. The end points investigated were chromosomal aberrations and mitotic index at 24 hours posttreatment and micronuclei (MN) at 30 hours posttreatment in bone marrow cells of male and female mice after a single intraperitoneal exposure. The doses tested were VCR 0.25, 0.5, and 1.0 mg/kg and CTX 40 mg/kg b.w. of mice. Significant percentages of chromosomal aberrations and significant numbers of micronuclei per thousand polychromatic erythrocytes (PCEs) that were induced were recorded from bone marrow of each of the VCR-treated groups of mice. There were no significant differences between the percentages of dividing cells in the VCR-treated group and the vehicle control groups of mice. Peculiarly, in the chromosomal aberration study, the male mice were found to be more responsive to VCR than the females, and the aberrations per hundred metaphases were found to be decreased when the dose of VCR was increased. The percentage of dividing cells was also higher with the lowest dose of VCR tested. However, there was a dose-dependent, but nonlinear, increase in MN per thousand PCEs. The results were compared with the already available fragmentary and self-contradictory data on the genotoxicity of VCR in mice and in other mammalian test systems.

  11. [Structural endpoints for glaucoma studies].

    PubMed

    Popa-Cherechenau, A; Schmidl, D; Garhöfer, G; Schmetterer, L

    2018-03-06

    Structural endpoints have been discussed as surrogate endpoints for the approval of neuroprotective drugs in glaucoma. Is the evidence strong enough to establish structural endpoints as surrogate endpoints? Review of current understanding between structure and function in glaucoma. The introduction of optical coherence tomography has revolutionized imaging in glaucoma patients. Clinically either the nerve fiber layer thickness can be measured along a circle centered in the optic nerve head or the ganglion cell layer thickness can be assessed in the macular region, the latter being quantified in combination with other inner retinal layers. On a microscopic level there is a strong correlation between structural and functional loss but this relation can only partially be described with currently available clinical methods. This is particularly true for longitudinal course of the disease in glaucoma patients. Novel imaging techniques that are not yet used clinically may have the potential to increase our understanding between structure and function in glaucoma but further research in this field is required. The current evidence does not allow the establishment of structural endpoints as surrogate endpoints for phase 3 studies in glaucoma. Neuroprotective drugs have to be approved on the basis of visual field data because this is the patient-relevant endpoint. Structural endpoints can, however, play an important role in phase 2 and proof of concept studies.

  12. Prediction of outcome of bright light treatment in patients with seasonal affective disorder: Discarding the early response, confirming a higher atypical balance, and uncovering a higher body mass index at baseline as predictors of endpoint outcome.

    PubMed

    Dimitrova, Tzvetelina D; Reeves, Gloria M; Snitker, Soren; Lapidus, Manana; Sleemi, Aamar R; Balis, Theodora G; Manalai, Partam; Tariq, Muhammad M; Cabassa, Johanna A; Karim, Naila N; Johnson, Mary A; Langenberg, Patricia; Rohan, Kelly J; Miller, Michael; Stiller, John W; Postolache, Teodor T

    2017-11-01

    We tested the hypothesis that the early improvement in mood after the first hour of bright light treatment compared to control dim-red light would predict the outcome at six weeks of bright light treatment for depressed mood in patients with Seasonal Affective Disorder (SAD). We also analyzed the value of Body Mass Index (BMI) and atypical symptoms of depression at baseline in predicting treatment outcome. Seventy-eight adult participants were enrolled. The first treatment was controlled crossover, with randomized order, and included one hour of active bright light treatment and one hour of control dim-red light, with one-hour washout. Depression was measured on the Structured Interview Guide for the Hamilton Rating Scale for Depression-SAD version (SIGH-SAD). The predictive association of depression scores changes after the first session. BMI and atypical score balance with treatment outcomes at endpoint were assessed using multivariable linear and logistic regressions. No significant prediction by changes in depression scores after the first session was found. However, higher atypical balance scores and BMI positively predicted treatment outcome. Absence of a control intervention for the six-weeks of treatment (only the first session in the laboratory was controlled). Exclusion of patients with comorbid substance abuse, suicidality and bipolar I disorder, and patients on antidepressant medications, reducing the generalizability of the study. Prediction of outcome by early response to light treatment was not replicated, and the previously reported prediction of baseline atypical balance was confirmed. BMI, a parameter routinely calculated in primary care, was identified as a novel predictor, and calls for replication and then exploration of possible mediating mechanisms. Published by Elsevier B.V.

  13. Endpoint Model of Exclusive Processes

    NASA Astrophysics Data System (ADS)

    Dagaonkar, Sumeet; Jain, Pankaj; Ralston, John P.

    2018-07-01

    The endpoint model explains the scaling laws observed in exclusive hadronic reactions at large momentum transfer in all experimentally important regimes. The model, originally conceived by Feynman and others, assumes a single valence quark carries most of the hadron momentum. The quark wave function is directly related to the momentum transfer dependence of the reaction. After extracting the momentum dependence of the quark wave function from one process, it explains all the others. Endpoint quark-counting rules relate the number of quarks in a hadron to the power-law. A universal linear endpoint behavior explains the proton electromagnetic form factors F1 and F2, proton-proton scattering at fixed-angle, the t-dependence of proton-proton scattering at large s>> t, and Compton scattering at fixed t. The model appears to be the only comprehensive mechanism consistent with all experimental information.

  14. Comparative toxicities of selected rare earth elements: Sea urchin embryogenesis and fertilization damage with redox and cytogenetic effects

    SciTech Connect

    Pagano, Giovanni, E-mail: gbpagano@tin.it; Guida, Marco; Siciliano, Antonietta

    Background: Broad-ranging adverse effects are known for rare earth elements (REE), yet only a few studies tested the toxicity of several REE, prompting studies focusing on multi-parameter REE toxicity. Methods: Trichloride salts of Y, La, Ce, Nd, Sm, Eu and Gd were tested in Paracentrotus lividus sea urchin embryos and sperm for: (1) developmental defects in either REE-exposed larvae or in the offspring of REE-exposed sperm; (2) fertilization success; (3) mitotic anomalies in REE-exposed embryos and in the offspring of REE-exposed sperm, and (4) reactive oxygen species (ROS) formation, and malondialdehyde (MDA) and nitric oxide (NO) levels. Results: REEs affectedmore » P. lividus larvae with concentration-related increase in developmental defects, 10{sup −6} to 10{sup −4} M, ranking as: Gd(III)>Y(III)>La(III)>Nd(III)≅Eu(III)>Ce(III)≅Sm(III). Nominal concentrations of REE salts were confirmed by inductively coupled plasma mass spectrometry (ICP-MS). Significant increases in MDA levels, ROS formation, and NO levels were found in REE-exposed embryos. Sperm exposure to REEs (10{sup −5} to 10{sup −4} M) resulted in concentration-related decrease in fertilization success along with increase in offspring damage. Decreased mitotic activity and increased aberration rates were detected in REE-exposed embryos and in the offspring of REE-exposed sperm. Conclusion: REE-associated toxicity affecting embryogenesis, fertilization, cytogenetic and redox endpoints showed different activities of tested REEs. Damage to early life stages, along with redox and cytogenetic anomalies should be the focus of future REE toxicity studies. - Highlights: • Seven rare earth elements exerted different effects on sea urchin early life stages. • Embryo-, spermio- and mitotoxicity, and oxidative/ nitrosative stress were found. • Nominal vs. analytical REE concentrations were checked. • Comparative toxicities were evaluated for the different REE.« less

  15. Cytogenetic prognostication within medulloblastoma subgroups.

    PubMed

    Shih, David J H; Northcott, Paul A; Remke, Marc; Korshunov, Andrey; Ramaswamy, Vijay; Kool, Marcel; Luu, Betty; Yao, Yuan; Wang, Xin; Dubuc, Adrian M; Garzia, Livia; Peacock, John; Mack, Stephen C; Wu, Xiaochong; Rolider, Adi; Morrissy, A Sorana; Cavalli, Florence M G; Jones, David T W; Zitterbart, Karel; Faria, Claudia C; Schüller, Ulrich; Kren, Leos; Kumabe, Toshihiro; Tominaga, Teiji; Shin Ra, Young; Garami, Miklós; Hauser, Peter; Chan, Jennifer A; Robinson, Shenandoah; Bognár, László; Klekner, Almos; Saad, Ali G; Liau, Linda M; Albrecht, Steffen; Fontebasso, Adam; Cinalli, Giuseppe; De Antonellis, Pasqualino; Zollo, Massimo; Cooper, Michael K; Thompson, Reid C; Bailey, Simon; Lindsey, Janet C; Di Rocco, Concezio; Massimi, Luca; Michiels, Erna M C; Scherer, Stephen W; Phillips, Joanna J; Gupta, Nalin; Fan, Xing; Muraszko, Karin M; Vibhakar, Rajeev; Eberhart, Charles G; Fouladi, Maryam; Lach, Boleslaw; Jung, Shin; Wechsler-Reya, Robert J; Fèvre-Montange, Michelle; Jouvet, Anne; Jabado, Nada; Pollack, Ian F; Weiss, William A; Lee, Ji-Yeoun; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Leonard, Jeffrey R; Rubin, Joshua B; de Torres, Carmen; Lavarino, Cinzia; Mora, Jaume; Cho, Yoon-Jae; Tabori, Uri; Olson, James M; Gajjar, Amar; Packer, Roger J; Rutkowski, Stefan; Pomeroy, Scott L; French, Pim J; Kloosterhof, Nanne K; Kros, Johan M; Van Meir, Erwin G; Clifford, Steven C; Bourdeaut, Franck; Delattre, Olivier; Doz, François F; Hawkins, Cynthia E; Malkin, David; Grajkowska, Wieslawa A; Perek-Polnik, Marta; Bouffet, Eric; Rutka, James T; Pfister, Stefan M; Taylor, Michael D

    2014-03-20

    Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

  16. Cytogenetic Prognostication Within Medulloblastoma Subgroups

    PubMed Central

    Shih, David J.H.; Northcott, Paul A.; Remke, Marc; Korshunov, Andrey; Ramaswamy, Vijay; Kool, Marcel; Luu, Betty; Yao, Yuan; Wang, Xin; Dubuc, Adrian M.; Garzia, Livia; Peacock, John; Mack, Stephen C.; Wu, Xiaochong; Rolider, Adi; Morrissy, A. Sorana; Cavalli, Florence M.G.; Jones, David T.W.; Zitterbart, Karel; Faria, Claudia C.; Schüller, Ulrich; Kren, Leos; Kumabe, Toshihiro; Tominaga, Teiji; Shin Ra, Young; Garami, Miklós; Hauser, Peter; Chan, Jennifer A.; Robinson, Shenandoah; Bognár, László; Klekner, Almos; Saad, Ali G.; Liau, Linda M.; Albrecht, Steffen; Fontebasso, Adam; Cinalli, Giuseppe; De Antonellis, Pasqualino; Zollo, Massimo; Cooper, Michael K.; Thompson, Reid C.; Bailey, Simon; Lindsey, Janet C.; Di Rocco, Concezio; Massimi, Luca; Michiels, Erna M.C.; Scherer, Stephen W.; Phillips, Joanna J.; Gupta, Nalin; Fan, Xing; Muraszko, Karin M.; Vibhakar, Rajeev; Eberhart, Charles G.; Fouladi, Maryam; Lach, Boleslaw; Jung, Shin; Wechsler-Reya, Robert J.; Fèvre-Montange, Michelle; Jouvet, Anne; Jabado, Nada; Pollack, Ian F.; Weiss, William A.; Lee, Ji-Yeoun; Cho, Byung-Kyu; Kim, Seung-Ki; Wang, Kyu-Chang; Leonard, Jeffrey R.; Rubin, Joshua B.; de Torres, Carmen; Lavarino, Cinzia; Mora, Jaume; Cho, Yoon-Jae; Tabori, Uri; Olson, James M.; Gajjar, Amar; Packer, Roger J.; Rutkowski, Stefan; Pomeroy, Scott L.; French, Pim J.; Kloosterhof, Nanne K.; Kros, Johan M.; Van Meir, Erwin G.; Clifford, Steven C.; Bourdeaut, Franck; Delattre, Olivier; Doz, François F.; Hawkins, Cynthia E.; Malkin, David; Grajkowska, Wieslawa A.; Perek-Polnik, Marta; Bouffet, Eric; Rutka, James T.; Pfister, Stefan M.; Taylor, Michael D.

    2014-01-01

    Purpose Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. Patients and Methods Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. Results Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. Conclusion Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials. PMID

  17. Surrogate Endpoints in Suicide Research

    ERIC Educational Resources Information Center

    Wortzel, Hal S.; Gutierrez, Peter M.; Homaifar, Beeta Y.; Breshears, Ryan E.; Harwood, Jeri E.

    2010-01-01

    Surrogate endpoints frequently substitute for rare outcomes in research. The ability to learn about completed suicides by investigating more readily available and proximate outcomes, such as suicide attempts, has obvious appeal. However, concerns with surrogates from the statistical science perspective exist, and mounting evidence from…

  18. Bayesian Adaptive Trial Design for a Newly Validated Surrogate Endpoint

    PubMed Central

    Renfro, Lindsay A.; Carlin, Bradley P.; Sargent, Daniel J.

    2011-01-01

    Summary The evaluation of surrogate endpoints for primary use in future clinical trials is an increasingly important research area, due to demands for more efficient trials coupled with recent regulatory acceptance of some surrogates as ‘valid.’ However, little consideration has been given to how a trial which utilizes a newly-validated surrogate endpoint as its primary endpoint might be appropriately designed. We propose a novel Bayesian adaptive trial design that allows the new surrogate endpoint to play a dominant role in assessing the effect of an intervention, while remaining realistically cautious about its use. By incorporating multi-trial historical information on the validated relationship between the surrogate and clinical endpoints, then subsequently evaluating accumulating data against this relationship as the new trial progresses, we adaptively guard against an erroneous assessment of treatment based upon a truly invalid surrogate. When the joint outcomes in the new trial seem plausible given similar historical trials, we proceed with the surrogate endpoint as the primary endpoint, and do so adaptively–perhaps stopping the trial for early success or inferiority of the experimental treatment, or for futility. Otherwise, we discard the surrogate and switch adaptive determinations to the original primary endpoint. We use simulation to test the operating characteristics of this new design compared to a standard O’Brien-Fleming approach, as well as the ability of our design to discriminate trustworthy from untrustworthy surrogates in hypothetical future trials. Furthermore, we investigate possible benefits using patient-level data from 18 adjuvant therapy trials in colon cancer, where disease-free survival is considered a newly-validated surrogate endpoint for overall survival. PMID:21838811

  19. Contributions to the cytogenetics of the Neotropical fish fauna.

    PubMed

    Bertollo, Luiz Antônio Carlos; Cioffi, Marcelo de Bello; Galetti, Pedro Manoel; Filho, Orlando Moreira

    2017-01-01

    Brazilian fish cytogenetics started as early as the seventies in three pioneering research groups, located at the Universidade Estadual Paulista (UNESP, Botucatu, SP), Universidade Federal de São Carlos (UFSCar, São Carlos, SP) and Universidade de São Paulo (USP, São Paulo, SP). Investigations that have been conducted in these groups led to the discovery of a huge chromosomal and genomic biodiversity among Neotropical fishes. Besides, they also provided the expansion of this research area, with the genesis of several other South American research groups, in view of a number of dissertations and doctoral theses developed over years. The current authors were encouraged to make their thesis catalog accessible from a public source, in order to share informations on the taxa and subject matter analyzed. Some of the key contributions to evolutionary fish cytogenetics are also being highligthed.

  20. Contributions to the cytogenetics of the Neotropical fish fauna

    PubMed Central

    Bertollo, Luiz Antônio Carlos; Cioffi, Marcelo de Bello; Jr, Pedro Manoel Galetti; Filho, Orlando Moreira

    2017-01-01

    Abstract Brazilian fish cytogenetics started as early as the seventies in three pioneering research groups, located at the Universidade Estadual Paulista (UNESP, Botucatu, SP), Universidade Federal de São Carlos (UFSCar, São Carlos, SP) and Universidade de São Paulo (USP, São Paulo, SP). Investigations that have been conducted in these groups led to the discovery of a huge chromosomal and genomic biodiversity among Neotropical fishes. Besides, they also provided the expansion of this research area, with the genesis of several other South American research groups, in view of a number of dissertations and doctoral theses developed over years. The current authors were encouraged to make their thesis catalog accessible from a public source, in order to share informations on the taxa and subject matter analyzed. Some of the key contributions to evolutionary fish cytogenetics are also being highligthed. PMID:29114360

  1. Comparative toxicities of selected rare earth elements: Sea urchin embryogenesis and fertilization damage with redox and cytogenetic effects.

    PubMed

    Pagano, Giovanni; Guida, Marco; Siciliano, Antonietta; Oral, Rahime; Koçbaş, Fatma; Palumbo, Anna; Castellano, Immacolata; Migliaccio, Oriana; Thomas, Philippe J; Trifuoggi, Marco

    2016-05-01

    Broad-ranging adverse effects are known for rare earth elements (REE), yet only a few studies tested the toxicity of several REE, prompting studies focusing on multi-parameter REE toxicity. Trichloride salts of Y, La, Ce, Nd, Sm, Eu and Gd were tested in Paracentrotus lividus sea urchin embryos and sperm for: (1) developmental defects in either REE-exposed larvae or in the offspring of REE-exposed sperm; (2) fertilization success; (3) mitotic anomalies in REE-exposed embryos and in the offspring of REE-exposed sperm, and (4) reactive oxygen species (ROS) formation, and malondialdehyde (MDA) and nitric oxide (NO) levels. REEs affected P. lividus larvae with concentration-related increase in developmental defects, 10(-6) to 10(-4)M, ranking as: Gd(III)>Y(III)>La(III)>Nd(III)≅Eu(III)>Ce(III)≅Sm(III). Nominal concentrations of REE salts were confirmed by inductively coupled plasma mass spectrometry (ICP-MS). Significant increases in MDA levels, ROS formation, and NO levels were found in REE-exposed embryos. Sperm exposure to REEs (10(-5) to 10(-4)M) resulted in concentration-related decrease in fertilization success along with increase in offspring damage. Decreased mitotic activity and increased aberration rates were detected in REE-exposed embryos and in the offspring of REE-exposed sperm. REE-associated toxicity affecting embryogenesis, fertilization, cytogenetic and redox endpoints showed different activities of tested REEs. Damage to early life stages, along with redox and cytogenetic anomalies should be the focus of future REE toxicity studies. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Evaluating Candidate Principal Surrogate Endpoints

    PubMed Central

    Gilbert, Peter B.; Hudgens, Michael G.

    2009-01-01

    Summary Frangakis and Rubin (2002, Biometrics 58, 21–29) proposed a new definition of a surrogate endpoint (a “principal” surrogate) based on causal effects. We introduce an estimand for evaluating a principal surrogate, the causal effect predictiveness (CEP) surface, which quantifies how well causal treatment effects on the biomarker predict causal treatment effects on the clinical endpoint. Although the CEP surface is not identifiable due to missing potential outcomes, it can be identified by incorporating a baseline covariate(s) that predicts the biomarker. Given case–cohort sampling of such a baseline predictor and the biomarker in a large blinded randomized clinical trial, we develop an estimated likelihood method for estimating the CEP surface. This estimation assesses the “surrogate value” of the biomarker for reliably predicting clinical treatment effects for the same or similar setting as the trial. A CEP surface plot provides a way to compare the surrogate value of multiple biomarkers. The approach is illustrated by the problem of assessing an immune response to a vaccine as a surrogate endpoint for infection. PMID:18363776

  3. Application of cytogenetic endpoints and comet assay on human lymphocytes treated with atorvastatin in vitro.

    PubMed

    Gajski, Goran; Garaj-Vrhovac, Vera

    2008-01-01

    This study investigated the genotoxic potential of atorvastatin on human lymphocytes using comet assay, structural chromosome aberrations (CA) and sister-chromatid exchange (SCE) analysis. Lymphocyte cultures were treated with a single drug at a concentration of 30.21 ng/mL. For comet assay, cells exposed to atorvastatin for 24 h, 48 h and 72 h were embedded in agarose slides, lysed with alkaline lysis solution and exposed to an electric field. DNA migrated within the agarose and formed comets whose length depends on the amount of DNA damage. For analysis of structural CA, cells were grown on medium for 48 h and for SCE analysis for 72 h. Structural CA did not induce significant damage to the genome, although a higher CA frequency was observed in cells treated with atorvastatin for 3 h, 20 h and 48 h than in control samples. Results of the SCE analysis did show statistically significant differences in the mean SCE number between atorvastatin-exposed and control human lymphocytes and between different exposure times. Comet assay also showed increased DNA damage caused in atorvastatin-exposed human lymphocytes than in corresponding control cells for exposure times of 24 h, 48 h and 72 h for the tail length and for 72 h for the tail moment. Results obtained in this study point to the significance of biological indicators providing information on the primary genome damage after long-term exposure, which can help to establish drug therapeutic concentrations that do not put patients with high blood cholesterol to a greater treatment-related risk.

  4. A short introduction to cytogenetic studies in mammals with reference to the present volume.

    PubMed

    Graphodatsky, A; Ferguson-Smith, M A; Stanyon, R

    2012-01-01

    Genome diversity has long been studied from the comparative cytogenetic perspective. Early workers documented differences between species in diploid chromosome number and fundamental number. Banding methods allowed more detailed descriptions of between-species rearrangements and classes of differentially staining chromosome material. The infusion of molecular methods into cytogenetics provided a third revolution, which is still not exhausted. Chromosome painting has provided a global view of the translocation history of mammalian genome evolution, well summarized in the contributions to this special volume. More recently, FISH of cloned DNA has provided details on defining breakpoint and intrachromosomal marker order, which have helped to document inversions and centromere repositioning. The most recent trend in comparative molecular cytogenetics is to integrate sequencing information in order to formulate and test reconstructions of ancestral genomes and phylogenomic hypotheses derived from comparative cytogenetics. The integration of comparative cytogenetics and sequencing promises to provide an understanding of what drives chromosome rearrangements and genome evolution in general. We believe that the contributions in this volume, in no small way, point the way to the next phase in cytogenetic studies. Copyright © 2012 S. Karger AG, Basel.

  5. Establishing a group of endpoints to support collective operations without specifying unique identifiers for any endpoints

    DOEpatents

    Archer, Charles J.; Blocksom, Michael A.; Ratterman, Joseph D.; Smith, Brian E.; Xue, Hanghon

    2016-02-02

    A parallel computer executes a number of tasks, each task includes a number of endpoints and the endpoints are configured to support collective operations. In such a parallel computer, establishing a group of endpoints receiving a user specification of a set of endpoints included in a global collection of endpoints, where the user specification defines the set in accordance with a predefined virtual representation of the endpoints, the predefined virtual representation is a data structure setting forth an organization of tasks and endpoints included in the global collection of endpoints and the user specification defines the set of endpoints without a user specification of a particular endpoint; and defining a group of endpoints in dependence upon the predefined virtual representation of the endpoints and the user specification.

  6. Failure matters: unsuccessful cytogenetics and unperformed cytogenetics are associated with a poor prognosis in a population-based series of acute myeloid leukaemia.

    PubMed

    Lazarevic, Vladimir; Hörstedt, Ann-Sofi; Johansson, Bertil; Antunovic, Petar; Billström, Rolf; Derolf, Åsa; Lehmann, Sören; Möllgård, Lars; Peterson, Stefan; Stockelberg, Dick; Uggla, Bertil; Vennström, Lovisa; Wahlin, Anders; Höglund, Martin; Juliusson, Gunnar

    2015-05-01

    Unsuccessful cytogenetics (UC) in patients with acute myeloid leukaemia (AML) treated on different SWOG trials was recently reported to be associated with increased age and dismal outcome. To ascertain whether this holds true also in unselected patients with AML, we retrieved all cytogenetic reports in cases from the population-based Swedish AML Registry. Between 1997 and 2006, 1737 patients below 80 yr of age without myelosarcoma or acute promyelocytic leukaemia received intensive treatment. The frequencies of UC and unperformed cytogenetics (UPC) were 2.1% and 20%, respectively. The early death rates differed between the cytogenetic subgroups (P = 0.006) with the highest rates in patients with UC (14%) and UPC (12%) followed by high-risk (HR) AML, intermediate risk (IR) and standard risk (SR) cases successfully karyotyped (8.6%, 5.9%, and 5.8%, respectively). The complete remission rate was lower in UC and UPC and HR compared with the other risk groups (P < 0.001). The overall five-year survival rates were 25% for UC and 22% for UPC, whereas the corresponding frequencies for SR, IR and HR AML patients without UC and UPC were 64%, 31% and 15%, respectively. In conclusion, lack of cytogenetic data translates into a poor prognosis. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Pathophysiological Progression Model for Selected Toxicological Endpoints

    EPA Science Inventory

    The existing continuum paradigms are effective models to organize toxicological data associated with endpoints used in human health assessments. A compendium of endpoints characterized along a pathophysiological continuum would serve to: weigh the relative importance of effects o...

  8. Environmental genotoxicity evaluation using cytogenetic end points in wild rodents.

    PubMed Central

    de Souza Bueno, A M; de Bragança Pereira, C A; Rabello-Gay, M N

    2000-01-01

    We analyzed cytogenetic end points in three populations of two species of wild rodents--Akodon montensis and Oryzomys nigripes--living in an industrial, an agricultural, and a preservation area at the Itajaí Valley, state of Santa Catarina, Brazil. Our purpose was to evaluate the performance of the following end points in the establishment of a genotoxic profile of each area: the polychromatic/normochromatic cell ratio; the mitotic index; the frequency of micronucleated cells both in the bone marrow and peripheral blood; and the frequency of cells with chromosome aberrations in the bone marrow. Preparations were obtained using conventional cytogenetic techniques. The results showed a) the role of the end points used as biomarkers in the early detection of genotoxic agents and in the identification of species and populations at higher risk; b) the difference in sensitivity of the species selected as bioindicators in relation to the cytogenetic end points analyzed; c) the need to use at least two sympatric species to detect the presence of genotoxins in each locality; and d) the need to use several end points when trying to establish a genotoxic profile of an area. PMID:11133397

  9. Human molecular cytogenetics: From cells to nucleotides

    PubMed Central

    Riegel, Mariluce

    2014-01-01

    The field of cytogenetics has focused on studying the number, structure, function and origin of chromosomal abnormalities and the evolution of chromosomes. The development of fluorescent molecules that either directly or via an intermediate molecule bind to DNA has led to the development of fluorescent in situ hybridization (FISH), a technology linking cytogenetics to molecular genetics. This technique has a wide range of applications that increased the dimension of chromosome analysis. The field of cytogenetics is particularly important for medical diagnostics and research as well as for gene ordering and mapping. Furthermore, the increased application of molecular biology techniques, such as array-based technologies, has led to improved resolution, extending the recognized range of microdeletion/microduplication syndromes and genomic disorders. In adopting these newly expanded methods, cytogeneticists have used a range of technologies to study the association between visible chromosome rearrangements and defects at the single nucleotide level. Overall, molecular cytogenetic techniques offer a remarkable number of potential applications, ranging from physical mapping to clinical and evolutionary studies, making a powerful and informative complement to other molecular and genomic approaches. This manuscript does not present a detailed history of the development of molecular cytogenetics; however, references to historical reviews and experiments have been provided whenever possible. Herein, the basic principles of molecular cytogenetics, the technologies used to identify chromosomal rearrangements and copy number changes, and the applications for cytogenetics in biomedical diagnosis and research are presented and discussed. PMID:24764754

  10. Cytogenetic analysis in acute myeloid leukaemia.

    PubMed

    Campbell, Lynda J; White, Joanne S

    2011-01-01

    Cytogenetic analysis is an integral part of the diagnostic work-up of the patient with acute myeloid leukaemia. Conventional cytogenetic analysis relies on obtaining a good quality bone marrow specimen in a timely fashion and setting up at least two short-term cultures. A 15-24-h culture and a 48-h synchronised culture are routinely set up but as the cytogenetics result is often required urgently to determine the type of therapy to be administered, analysis is undertaken using the overnight culture in the first instance. Rapid and accurate analysis relies on obtaining high-quality G-banding. Knowledge of the conditions affecting banding is therefore essential.

  11. Biomarkers and surrogate endpoints in clinical trials.

    PubMed

    Fleming, Thomas R; Powers, John H

    2012-11-10

    One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function, and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures, and radiological tests, often are considered as replacement endpoints or 'surrogates' for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. Copyright © 2012 John Wiley & Sons, Ltd.

  12. Biomarkers and Surrogate Endpoints In Clinical Trials

    PubMed Central

    Fleming, Thomas R.; Powers, John H

    2012-01-01

    One of the most important considerations in designing clinical trials is the choice of outcome measures. These outcome measures could be clinically meaningful endpoints that are direct measures of how patients feel, function and survive. Alternatively, indirect measures, such as biomarkers that include physical signs of disease, laboratory measures and radiological tests, often are considered as replacement endpoints or “surrogates” for clinically meaningful endpoints. We discuss the definitions of clinically meaningful endpoints and surrogate endpoints, and provide examples from recent clinical trials. We provide insight into why indirect measures such as biomarkers may fail to provide reliable evidence about the benefit-to-risk profile of interventions. We also discuss the nature of evidence that is important in assessing whether treatment effects on a biomarker reliably predict effects on a clinically meaningful endpoint, and provide insights into why this reliability is specific to the context of use of the biomarker. . PMID:22711298

  13. Surrogate endpoints in randomized cardiovascular clinical trials.

    PubMed

    Domanski, Michael; Pocock, Stuart; Bernaud, Corine; Borer, Jeffrey; Geller, Nancy; Revkin, James; Zannad, Faiez

    2011-08-01

    Surrogate endpoints predict the occurrence and timing of a clinical endpoint of interest (CEI). Substitution of a surrogate endpoint for a CEI can dramatically reduce the time and cost necessary to complete a Phase III clinical trial. However, assurance that use of a surrogate endpoint will result in a correct conclusion regarding treatment effect on a CEI requires prior rigorous validation of the surrogate. Surrogate endpoints can also be of substantial use in Phase I and II studies to assess whether the intended therapeutic pathway is operative, thus providing assurance regarding the reasonableness of proceeding to a Phase III trial. This paper discusses the uses and validation of surrogate endpoints. © 2010 The Authors Fundamental and Clinical Pharmacology © 2010 Société Française de Pharmacologie et de Thérapeutique.

  14. The Cerrado (Brazil) plant cytogenetics database.

    PubMed

    Roa, Fernando; Telles, Mariana Pires de Campos

    2017-01-01

    Cerrado is a biodiversity hotspot that has lost ca. 50% of its original vegetation cover and hosts ca. 11,000 species belonging to 1,423 genera of phanerogams. For a fraction of those species some cytogenetic characteristics like chromosome numbers and C-value were available in databases, while other valuable information such as karyotype formula and banding patterns are missing. In order to integrate and share all cytogenetic information published for Cerrado species, including frequency of cytogenetic attributes and scientometrics aspects, Cerrado plant species were searched in bibliographic sources, including the 50 richest genera (with more than 45 taxa) and 273 genera with only one species in Cerrado. Determination of frequencies and the database website (http://cyto.shinyapps.io/cerrado) were developed in R. Studies were pooled by employed technique and decade, showing a rise in non-conventional cytogenetics since 2000. However, C-value estimation, heterochromatin staining and molecular cytogenetics are still not common for any family. For the richest and best sampled families, the following modal 2n counts were observed: Oxalidaceae 2n = 12, Lythraceae 2n = 30, Sapindaceae 2n = 24, Solanaceae 2n = 24, Cyperaceae 2n = 10, Poaceae 2n = 20, Asteraceae 2n = 18 and Fabaceae 2n = 26. Chromosome number information is available for only 16.1% of species, while there are genome size data for only 1.25%, being lower than the global percentages. In general, genome sizes were small, ranging from 2C = ca. 1.5 to ca. 3.5 pg. Intra-specific 2n number variation and higher 2n counts were mainly related to polyploidy, which relates to the prevalence of even haploid numbers above the mode of 2n in most major plant clades. Several orphan genera with almost no cytogenetic studies for Cerrado were identified. This effort represents a complete diagnosis for cytogenetic attributes of plants of Cerrado.

  15. The Cerrado (Brazil) plant cytogenetics database

    PubMed Central

    Roa, Fernando; Telles, Mariana Pires de Campos

    2017-01-01

    Abstract Cerrado is a biodiversity hotspot that has lost ca. 50% of its original vegetation cover and hosts ca. 11,000 species belonging to 1,423 genera of phanerogams. For a fraction of those species some cytogenetic characteristics like chromosome numbers and C-value were available in databases, while other valuable information such as karyotype formula and banding patterns are missing. In order to integrate and share all cytogenetic information published for Cerrado species, including frequency of cytogenetic attributes and scientometrics aspects, Cerrado plant species were searched in bibliographic sources, including the 50 richest genera (with more than 45 taxa) and 273 genera with only one species in Cerrado. Determination of frequencies and the database website (http://cyto.shinyapps.io/cerrado) were developed in R. Studies were pooled by employed technique and decade, showing a rise in non-conventional cytogenetics since 2000. However, C-value estimation, heterochromatin staining and molecular cytogenetics are still not common for any family. For the richest and best sampled families, the following modal 2n counts were observed: Oxalidaceae 2n = 12, Lythraceae 2n = 30, Sapindaceae 2n = 24, Solanaceae 2n = 24, Cyperaceae 2n = 10, Poaceae 2n = 20, Asteraceae 2n = 18 and Fabaceae 2n = 26. Chromosome number information is available for only 16.1% of species, while there are genome size data for only 1.25%, being lower than the global percentages. In general, genome sizes were small, ranging from 2C = ca. 1.5 to ca. 3.5 pg. Intra-specific 2n number variation and higher 2n counts were mainly related to polyploidy, which relates to the prevalence of even haploid numbers above the mode of 2n in most major plant clades. Several orphan genera with almost no cytogenetic studies for Cerrado were identified. This effort represents a complete diagnosis for cytogenetic attributes of plants of Cerrado. PMID:28919965

  16. Canine Cytogenetics - From band to basepair

    PubMed Central

    Breen, Matthew

    2008-01-01

    Humans and dogs have coexisted for thousands of years, during which time we have developed a unique bond, centered on companionship. Along the way, we have developed purebred dog breeds in a manner that has resulted unfortunately in many of them being affected by serious genetic disorders, including cancers. With serendipity and irony the unique genetic architecture of the 21st Century genome of Man's best friend may ultimately provide many of the keys to unlock some of nature's most intriguing biological puzzles. Canine cytogenetics has advanced significantly over the past 10 years, spurred on largely by the surge of interest in the dog as a biomedical model for genetic disease and the availability of advanced genomics resources. As such the role of canine cytogenetics has moved rapidly from one that served initially to define the gross genomic organization of the canine genome and provide a reliable means to determine the chromosomal location of individual genes, to one that enabled the assembled sequence of the canine genome to be anchored to the karyotype. Canine cytogenetics now presents the biomedical research community with a means to assist in our search for a greater understanding of how genome architectures altered during speciation and in our search for genes associated with cancers that affect both dogs and humans. The cytogenetics ‘toolbox’ for the dog is now loaded. This review aims to provide a summary of some of the recent advancements in canine cytogenetics. PMID:18467825

  17. [Cytogenetic, molecular cytogenetic, clinical and genealogical study of mothers of children with autism: a search for family genetic markers of autistic disorders].

    PubMed

    Vorsanova, S G; Voinova, V Iu; Iurov, I Iu; Kurinnaia, O S; Demidova, I A; Iurov, Iu B

    2009-01-01

    Using modern cytogenetic and molecular cytogenetic techniques towards the study of human chromosomes, an analysis of chromosomal abnormalities/chromosomal variations as well as clinical and genealogical data in mothers of children with autism has been performed. It has been shown that mothers of autistic children exhibit an increased incidence of chromosomal abnormalities (mainly mosaic forms involving chromosome X) and an increased occurrence of chromosomal variations compared to controls. The analysis of genotype-phenotype correlations revealed the increase in the frequency of cognitive disturbances and spontaneous abortions in mothers of children with autism as well as the higher frequency of mental retardation, early death and reproductive problems in the pedigrees. The high frequency of congenital malformations in the pedigrees of mothers with chromosomal variations was observed as well. Taking into account the data obtained, we have concluded that cytogenetic and molecular cytogenetic studies of mothers of children with autism are obligatory for detection of possible genetic causes of autism and genetic counseling of families with children affected with autistic disorders.

  18. [Immunological surrogate endpoints to evaluate vaccine efficacy].

    PubMed

    Jin, Pengfei; Li, Jingxin; Zhou, Yang; Zhu, Fengcai

    2015-12-01

    An immunological surrogate endpoints is a vaccine-induced immune response (either humoral or cellular immune) that predicts protection against clinical endpoints (infection or disease), and can be used to evaluate vaccine efficacy in clinical vaccine trials. Compared with field efficacy trials observing clinical endpoints, immunological vaccine trials could reduce the sample size or shorten the duration of a trial, which promote the license and development of new candidate vaccines. For these reasons, establishing immunological surrogate endpoints is one of 14 Grand Challenges of Global Health of the National Institutes of Health (NIH) and the Bill and Melinda Gates Foundation. From two parts of definition and statistical methods for evaluation of surrogate endpoints, this review provides a more comprehensive description.

  19. Angelman syndrome assessed by neurological and molecular cytogenetic investigations.

    PubMed

    Hou, J W; Wang, P J; Wang, T R

    1997-01-01

    Angelman syndrome (AS) is characterized by severe psychomotor retardation, speech impairment, happy disposition with bursts of laughter, ataxia, convulsions, and some distinct physical anomalies. Correct diagnosis of AS is important because of its clinical implications, and once the disease is confirmed, familial genetic counseling becomes crucial. We evaluated 22 patients with a putative diagnosis of AS by both clinical and molecular cytogenetic analysis. A deletion of the region 15q11-13 could be identified cytogenetically in 11 cases by high-resolution technique (group I). Four additional cases were confirmed by fluorescence in situ hybridization (FISH) study with D15S11, SNRPN, D15S10, and GABRB 3 [Prader-Willi syndrome (PWS)/AS region probes] (group II). The common deletion of GABRB 3 was documented in those AS cases (n = 15) by FISH. The other 7 cases exhibited no deletion over 15q11-13 at either the cytogenetic or molecular level (group III). We compared the following associated neurological disorders: convulsions and abnormal EEG, microcephaly, sleep and behavior problems, brain anomalies proved by image studies, sexual precocity with pineal tumor among the three groups, as well as other clinical conditions including congenital heart disease, obesity, scoliosis, and hypopigmentation. In the present study, the differences in neurological and facial characteristics were not distinct among these groups. However, the associated conditions were more frequently observed in the patients with deletion than in those without deletion. The EEG features of AS appear to be less sufficient in helping identify patients at an early age before the clinical features become obvious. Therefore, a region involved in the major As phenotypes may contain only one or more tightly contiguous genes around the GABRB 3 locus, which may explain the clinical heterogeneity in AS.

  20. Cytogenetics of melanoma and nonmelanoma skin cancer.

    PubMed

    Carless, Melanie A; Griffiths, Lyn R

    2014-01-01

    Cytogenetic analysis of melanoma and nonmelanoma skin cancers has revealed recurrent aberrations, the frequency of which is reflective of malignant potential. Highly aberrant karyotypes are seen in melanoma, squamous cell carcinoma, actinic keratosis, Merkel cell carcinoma and cutaneous lymphomas with more stable karyotypes seen in basal cell carcinoma, keratoacanthoma, Bowen's disease and dermatofibrosarcoma protuberans. Some aberrations are common among a number of skin cancer types including rearrangements and numerical abnormalities of chromosome 1, -3p, +3q, partial or entire trisomy 6, trisomy 7, +8q, -9p, +9q, partial or entire loss of chromosome 10, -17p, +17q and partial or entire gain of chromosome 20. Combination of cytogenetic analysis with other molecular genetic techniques has enabled the identification of not only aberrant chromosomal regions, but also the genes that contribute to a malignant phenotype. This review provides a comprehensive summary of the pertinent cytogenetic aberrations associated with a variety of melanoma and nonmelanoma skin cancers.

  1. 40 CFR 798.5375 - In vitro mammalian cytogenetics.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... mammalian cytogenetics. (a) Purpose. The in vitro cytogenetics test is a mutagenicity test system for the... first post-treatment mitosis and numerical aberrations require at least one cell division to be... chromatids. (c) Reference substances. Not applicable. (d) Test method—(1) Principle. In vitro cytogenetics...

  2. 42 CFR 493.1225 - Condition: Clinical cytogenetics.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 42 Public Health 5 2010-10-01 2010-10-01 false Condition: Clinical cytogenetics. 493.1225 Section... Testing § 493.1225 Condition: Clinical cytogenetics. If the laboratory provides services in the specialty of Clinical cytogenetics, the laboratory must meet the requirements specified in §§ 493.1230 through...

  3. Considerations in choosing a primary endpoint that measures durability of virological suppression in an antiretroviral trial.

    PubMed

    Gilbert, P B; Ribaudo, H J; Greenberg, L; Yu, G; Bosch, R J; Tierney, C; Kuritzkes, D R

    2000-09-08

    At present, many clinical trials of anti-HIV-1 therapies compare treatments by a primary endpoint that measures the durability of suppression of HIV-1 replication. Several durability endpoints are compared. Endpoints are compared by their implicit assumptions regarding surrogacy for clinical outcomes, sample size requirements, and accommodations for inter-patient differences in baseline plasma HIV-1-RNA levels and in initial treatment response. Virological failure is defined by the non-suppression of virus levels at a prespecified follow-up time T(early virological failure), or by relapse. A binary virological failure endpoint is compared with three time-to-virological failure endpoints: time from (i) randomization that assigns early failures a failure time of T weeks; (ii) randomization that extends the early failure time T for slowly responding subjects; and (iii) virological response that assigns non-responders a failure time of 0 weeks. Endpoint differences are illustrated with Agouron's trial 511. In comparing high with low-dose nelfinavir (NFV) regimens in Agouron 511, the difference in Kaplan-Meier estimates of the proportion not failing by 24 weeks is 16.7% (P = 0.048), 6.5% (P = 0.29) and 22.9% (P = 0.0030) for endpoints (i), (ii) and (iii), respectively. The results differ because NFV suppresses virus more quickly at the higher dose, and the endpoints weigh this treatment difference differently. This illustrates that careful consideration needs to be given to choosing a primary endpoint that will detect treatment differences of interest. A time from randomization endpoint is usually recommended because of its advantages in flexibility and sample size, especially at interim analyses, and for its interpretation for patient management.

  4. A cytogenetic view of sex chromosome evolution in plants.

    PubMed

    Armstrong, S J; Filatov, D A

    2008-01-01

    The recent origin of sex chromosomes in plant species provides an opportunity to study the early stages of sex chromosome evolution. This review focuses on the cytogenetic aspects of the analysis of sex chromosome evolution in plants and in particular, on the best-studied case, the sex chromosomes in Silene latifolia. We discuss the emerging picture of sex chromosome evolution in plants and the further work that is required to gain better understanding of the similarities and differences between the trends in animal and plant sex chromosome evolution. Similar to mammals, suppression of recombination between the X and Y in S. latifolia species has occurred in several steps, however there is little evidence that inversions on the S. latifolia Y chromosome have played a role in cessation of X/Y recombination. Secondly, in S. latifolia there is a lack of evidence for genetic degeneration of the Y chromosome, unlike the events documented in mammalian sex chromosomes. The insufficient number of genes isolated from this and other plant sex chromosomes does not allow us to generalize whether the trends revealed on S. latifolia Y chromosome are general for other dioecious plants. Isolation of more plant sex-linked genes and their cytogenetic mapping with fluorescent in situ hybridisation (FISH) will ultimately lead to a much better understanding of the processes driving sex chromosome evolution in plants. 2008 S. Karger AG, Basel

  5. CYTOGENETIC EFFECTS OF PHOSPHINE INHALATION BY RODENTS

    EPA Science Inventory

    Phosphine (PH3) is a highly toxic grain fumigant that can be produced from the reaction of metal phosphides with water. o determine the in vivo cytogenetic effects of inhalation of PH3, male CD-1 mice were exposed to either 0, 5, 10, or 15 ppm target concentrations of PH3 for 6 h...

  6. Cytogenetic characterization of a canine haemangiopericytoma.

    PubMed

    Mayr, B; Swidersky, W; Schleger, W; Reifinger, M

    1990-01-01

    A 15-year-old dachshund bitch developed a haemangiopericytoma in the perineal region. The cytogenetic evaluation of the tumour cells showed a chromosome number of 74. The following abnormalities were found: an intersitially deleted chromosome no. 1 and centric fusions 5/6, 5/14, 7/15 and 9/17.

  7. Comparing Laboratory and Field Measured Bioaccumulation Endpoints

    EPA Science Inventory

    The report presents an approach that allows comparisons of all laboratory and field bioaccumulation endpoints measurements. The approach will enable the inclusion of large amounts of field data into evaluations of bioaccumulation potential for legacy chemicals. Currently, these...

  8. Evaluation of Mysidopsis bahia fecundity endpoint

    SciTech Connect

    Griffin, D.; Wahl, E.; Krause, P.R.

    1995-12-31

    The M. bahia chronic toxicity test is commonly used to test estuarine and marine effluent discharges. The test evaluates three endpoints: survival, growth, and fecundity. The fecundity endpoint is often erratic over time and does not necessarily predict accurately other endpoints of effluent toxicity. Therefore, an analysis of the fecundity endpoint was performed to evaluate its use in compliance testing. The endpoint analysis was conducted in three phases: a literature search, analysis of M. bahia data from 24 separate testing events, and interviews with various policy makers, statisticians, and biologists. The literature search revealed a dozen publications, none of whichmore » evaluated fecundity using the EPA method. The literature suggested that evaluating fecundity was labor-intensive and inadequate for practical compliance testing applications. Analysis of the 24 tests revealed that fecundity was evaluated only half of the time (i.e. when at least 50% of the females in the control were fecund). There was a high coefficient of variation (C.V.) between replicates for fecundity (range = 9.--1209.3,x = 85.2%) as compared to survival (range = 0.0--24.0,x = 13.7 %) and growth (range = 7.5--43.9,x = 19.1%). The fecundity results were erratic and did not always follow a dose-response curve, due in part to the small sample size per replicate. Interviews showed that the fecundity endpoint was being evaluated differently by different laboratories. Some were using fecundity for compliance while others were not. Most people interviewed recognized there were inconsistencies with the endpoint. The conclusions drawn from the evaluation were that (1) fecundity does not lend itself for use as a compliance endpoint, (2) the fecundity evaluation process is time consuming and labor intensive, and (3) interpretation of the results is not consistent from laboratory to laboratory and from region to region.« less

  9. Biomarkers and surrogate endpoints in kidney disease.

    PubMed

    Hartung, Erum A

    2016-03-01

    Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. "Hard" endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value. Finding new biomarkers to serve as surrogate endpoints is therefore an important priority in kidney disease research and may help to accelerate nephrology clinical trials. In this paper, I first review key concepts related to the selection of clinical trial endpoints and discuss statistical and regulatory considerations related to the evaluation of biomarkers as surrogate endpoints. This is followed by a discussion of the challenges and opportunities in developing novel biomarkers and surrogate endpoints in three major areas of nephrology research: acute kidney injury, chronic kidney disease, and autosomal dominant polycystic kidney disease.

  10. Biomarkers and surrogate endpoints in kidney disease

    PubMed Central

    2015-01-01

    Kidney disease and its related comorbidities impose a large public health burden. Despite this, the number of clinical trials in nephrology lags behind many other fields. An important factor contributing to the relatively slow pace of nephrology trials is that existing clinical endpoints have significant limitations. “Hard” endpoints for chronic kidney disease, such as progression to end-stage renal disease, may not be reached for decades. Traditional biomarkers, such as serum creatinine in acute kidney injury, may lack sensitivity and predictive value. Finding new biomarkers to serve as surrogate endpoints is therefore an important priority in kidney disease research and may help to accelerate nephrology clinical trials. In this paper, I first review key concepts related to the selection of clinical trial endpoints and discuss statistical and regulatory considerations related to the evaluation of biomarkers as surrogate endpoints. This is followed by a discussion of the challenges and opportunities in developing novel biomarkers and surrogate endpoints in three major areas of nephrology research: acute kidney injury, chronic kidney disease, and autosomal dominant polycystic kidney disease. PMID:25980469

  11. Trial endpoints for drug approval in oncology: Chemoprevention.

    PubMed

    Beitz, J

    2001-04-01

    As with other drugs, new drug applications for marketing approval of chemopreventive drugs must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. This article summarizes the regulatory requirements for traditional marketing approval, as well as for approval under the accelerated approval regulations. Unlike traditional approval, accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefit. Discussions with the Food and Drug Administration (FDA) regarding the validity of trial endpoints that may serve as surrogates for clinical benefit for accelerated approval should take place as early as possible in drug development. Meetings with the FDA to discuss these issues may be requested throughout the clinical development of a new drug.

  12. Surrogate endpoints and emerging surrogate endpoints for risk reduction of cardiovascular disease.

    PubMed

    Rasnake, Crystal M; Trumbo, Paula R; Heinonen, Therese M

    2008-02-01

    This article reviews surrogate endpoints and emerging biomarkers that were discussed at the annual "Cardiovascular Biomarkers and Surrogate Endpoints" symposium cosponsored by the US Food and Drug Administration (FDA) and the Montreal Heart Institute. The FDA's Center for Food Safety and Applied Nutrition (CFSAN) uses surrogate endpoints in its scientific review of a substance/disease relationship for a health claim. CFSAN currently recognizes three validated surrogate endpoints: blood pressure, blood total cholesterol, and blood low-density lipoprotein (LDL) concentration in its review of a health claim for cardiovascular disease (CVD). Numerous potential surrogate endpoints of CVD are being evaluated as the pathophysiology of heart disease is becoming better understood. However, these emerging biomarkers need to be validated as surrogate endpoints before they are used by CFSAN in the evaluation of a CVD health claim.

  13. Establishing a group of endpoints in a parallel computer

    DOEpatents

    Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.; Xue, Hanhong

    2016-02-02

    A parallel computer executes a number of tasks, each task includes a number of endpoints and the endpoints are configured to support collective operations. In such a parallel computer, establishing a group of endpoints receiving a user specification of a set of endpoints included in a global collection of endpoints, where the user specification defines the set in accordance with a predefined virtual representation of the endpoints, the predefined virtual representation is a data structure setting forth an organization of tasks and endpoints included in the global collection of endpoints and the user specification defines the set of endpoints without a user specification of a particular endpoint; and defining a group of endpoints in dependence upon the predefined virtual representation of the endpoints and the user specification.

  14. Choice of saccade endpoint under risk

    PubMed Central

    Ackermann, John F.; Landy, Michael S.

    2013-01-01

    Eye movements function to bring detailed information onto the high-resolution region of the retina. Previous research has shown that human observers select fixation points that maximize information acquisition and minimize target location uncertainty. In this study, we ask whether human observers choose the saccade endpoint that maximizes gain when there are explicit rewards associated with correctly detecting the target. Observers performed an 8-alternative forced-choice detection task for a contrast-defined target in noise. After a single saccade, observers indicated the target location. Each potential target location had an associated reward that was known to the observer. In some conditions, the reward at one location was higher than at the other locations. We compared human saccade endpoints to those of an ideal observer that maximizes expected gain given the respective human observer's visibility map, i.e., d′ for target detection as a function of retinal location. Varying the location of the highest reward had a significant effect on human observers' distribution of saccade endpoints. Both human and ideal observers show a high density of saccades made toward the highest rewarded and actual target locations. But humans' overall spatial distributions of saccade endpoints differed significantly from the ideal observer as they made a greater number of saccade to locations far from the highest rewarded and actual target locations. Suboptimal choice of saccade endpoint, possibly in combination with suboptimal integration of information across saccades, had a significant effect on human observers' ability to correctly detect the target and maximize gain. PMID:24023277

  15. End-point sharpness in thermometric titrimetry.

    PubMed

    Tyrrell, H J

    1967-07-01

    It is shown that the sharpness of an end-point in a thermometric titration where the simple reaction A + B right harpoon over left harpoon AB takes place, depends on Kc(A') where K is the equilibrium constant for the reaction, and c(A') is the total concentration of the titrand (A) in the reaction mixture. The end-point is sharp if, (i) the enthalpy change in the reaction is not negligible, and (ii) Kc(A') > 10(3). This shows that it should, for example, be possible to titrate 0.1 M acid, pK(A) = 10, using a thennometric end-point. Some aspects of thermometric titrimetry when Kc(A') < 10(3) are also considered.

  16. Enabling communication concurrency through flexible MPI endpoints

    DOE PAGES

    Dinan, James; Grant, Ryan E.; Balaji, Pavan; ...

    2014-09-23

    MPI defines a one-to-one relationship between MPI processes and ranks. This model captures many use cases effectively; however, it also limits communication concurrency and interoperability between MPI and programming models that utilize threads. Our paper describes the MPI endpoints extension, which relaxes the longstanding one-to-one relationship between MPI processes and ranks. Using endpoints, an MPI implementation can map separate communication contexts to threads, allowing them to drive communication independently. Also, endpoints enable threads to be addressable in MPI operations, enhancing interoperability between MPI and other programming models. Furthermore, these characteristics are illustrated through several examples and an empirical study thatmore » contrasts current multithreaded communication performance with the need for high degrees of communication concurrency to achieve peak communication performance.« less

  17. Enabling communication concurrency through flexible MPI endpoints

    SciTech Connect

    Dinan, James; Grant, Ryan E.; Balaji, Pavan

    MPI defines a one-to-one relationship between MPI processes and ranks. This model captures many use cases effectively; however, it also limits communication concurrency and interoperability between MPI and programming models that utilize threads. Our paper describes the MPI endpoints extension, which relaxes the longstanding one-to-one relationship between MPI processes and ranks. Using endpoints, an MPI implementation can map separate communication contexts to threads, allowing them to drive communication independently. Also, endpoints enable threads to be addressable in MPI operations, enhancing interoperability between MPI and other programming models. Furthermore, these characteristics are illustrated through several examples and an empirical study thatmore » contrasts current multithreaded communication performance with the need for high degrees of communication concurrency to achieve peak communication performance.« less

  18. Enabling communication concurrency through flexible MPI endpoints

    SciTech Connect

    Dinan, James; Grant, Ryan E.; Balaji, Pavan

    MPI defines a one-to-one relationship between MPI processes and ranks. This model captures many use cases effectively; however, it also limits communication concurrency and interoperability between MPI and programming models that utilize threads. This paper describes the MPI endpoints extension, which relaxes the longstanding one-to-one relationship between MPI processes and ranks. Using endpoints, an MPI implementation can map separate communication contexts to threads, allowing them to drive communication independently. Endpoints also enable threads to be addressable in MPI operations, enhancing interoperability between MPI and other programming models. These characteristics are illustrated through several examples and an empirical study that contrastsmore » current multithreaded communication performance with the need for high degrees of communication concurrency to achieve peak communication performance.« less

  19. Pathology, genetics and cytogenetics of Wilms' tumour.

    PubMed

    Md Zin, Reena; Murch, Ashleigh; Charles, Adrian

    2011-06-01

    Wilms' tumour (WT) is an embryonal cancer of childhood and is thought to be derived from embryonic kidney precursor cells. The Knudson two hit model was initially thought to occur in WT, but findings emerging from genetic and cytogenetic studies in the past two decades have implicated several genetic events. Recent techniques in genetic analysis have improved our ability to characterise changes in genes involved in WT which include WT1, CTNNB1, IGF2 and WTX. These genetic events have not only provided insight into the pathobiology of this malignancy, but the recognition of these candidate genes may offer potential targets for novel therapies. In this review, we will provide an overview of the pathological, genetic and cytogenetic characteristics of WT.

  20. LIFE CYCLE IMPACT ASSESSMENT - MIDPOINTS VS. ENDPOINTS

    EPA Science Inventory

    The question of whether to use midpoints or endpoints or both in an LCIA framework is often dependent upon the goal and scope and the decision that is being supported by the LCIA. LCIAs for Enlightenment may not require an aggregation of impact categories and may be most useful ...

  1. Earlier Endpoints Are Required for Hemorrhagic Shock Trials among Severely Injured Patients

    PubMed Central

    Fox, Erin E.; Holcomb, John B.; Wade, Charles E.; Bulger, Eileen M.; Tilley, Barbara C.

    2016-01-01

    Background Choosing the appropriate endpoint for a trauma hemorrhage control trial can determine the likelihood of its success. Recent Phase 3 trials and observational studies have used 24-hour and/or 30-day all-cause mortality as the primary endpoint and some have not used exception from informed consent (EFIC), resulting in multiple failed trials. Five recent high-quality prospective studies among 4,064 hemorrhaging trauma patients provide new evidence to support earlier primary endpoints. Methods The goal of this project was to determine the optimal endpoint for hemorrhage control trials using existing literature and new analyses of previously published data. Results Recent studies among bleeding trauma patients show that hemorrhagic deaths occur rapidly, at a high rate, and in a consistent pattern. Early preventable deaths among trauma patients are largely due to hemorrhage and the median time to hemorrhagic death from admission is 2.0-2.6 hours. Approximately 85% of hemorrhagic deaths occur within 6 hours. The hourly mortality rate due to traumatic injury decreases rapidly after enrollment from 4.6% per hour at 1 hour post-enrollment to 1% per hour at 6 hours to <0.1% per hour by 9 hours and thereafter. Early primary endpoints (within 6 hours) have critically important benefits for hemorrhage control trials, including being congruent with the median time to hemorrhagic death, biologic plausibility, and enabling the use of all-cause mortality, which is definitive and objective. Conclusions Primary endpoints should be congruent with the timing of the disease process. Therefore, if a resuscitation/hemorrhage control intervention is under study, a primary endpoint of all-cause mortality evaluated within the first 6 hours is appropriate. Before choosing the timing of the primary endpoint for a large multicenter trial, we recommend performing a Phase 2 trial under EFIC to better understand the effects of the hemorrhage control intervention and distribution of time

  2. Cytogenetic Reconstruction of Gamma-Ray Doses Delivered to Atomic Bomb Survivors: Dealing with Wide Distributions of Photon Energies and Contributions from Hematopoietic Stem/Progenitor Cells.

    PubMed

    Nakamura, Nori; Hirai, Yuko; Kodama, Yoshiaki; Hamasaki, Kanya; Cullings, Harry M; Cordova, Kismet A; Awa, Akio

    2017-10-01

    Retrospective estimation of the doses received by atomic bomb (A-bomb) survivors by cytogenetic methods has been hindered by two factors: One is that the photon energies released from the bomb were widely distributed, and since the aberration yield varies depending on the energy, the use of monoenergetic 60 Co gamma radiation to construct a calibration curve may bias the estimate. The second problem is the increasing proportion of newly formed lymphocytes entering into the lymphocyte pool with increasing time intervals since the exposures. These new cells are derived from irradiated precursor/stem cells whose radiosensitivity may differ from that of blood lymphocytes. To overcome these problems, radiation doses to tooth enamel were estimated using the electron spin resonance (ESR; or EPR, electron paramagnetic resonance) method and compared with the cytogenetically estimated doses from the same survivors. The ESR method is only weakly dependent on the photon energy and independent of the years elapsed since an exposure. Both ESR and cytogenetic doses were estimated from 107 survivors. The latter estimates were made by assuming that although a part of the cells examined could be lymphoid stem or precursor cells at the time of exposure, all the cells had the same radiosensitivity as blood lymphocytes, and that the A-bomb gamma-ray spectrum was the same as that of the 60 Co gamma rays. Subsequently, ESR and cytogenetic endpoints were used to estimate the kerma doses using individual DS02R1 information on shielding conditions. The results showed that the two sets of kerma doses were in close agreement, indicating that perhaps no correction is needed in estimating atomic bomb gamma-ray doses from the cytogenetically estimated 60 Co gamma-ray equivalent doses. The present results will make it possible to directly compare cytogenetic doses with the physically estimated doses of the survivors, which would pave the way for testing whether or not there are any systematic

  3. [Familial retinoblastoma: cytogenetic study of the tumor].

    PubMed

    Robledo Batanero, M; Manzanal Martínez, A; Ayuso García, C; Benítez Ortiz, J

    1990-05-01

    We report a case of familiar retinoblastoma, in which both mother and daughter show bilateral retinoblastoma. The cytogenetic study, in both peripheral blood lymphocytes and tumoral tissue did not show alterations on the 13 chromosome, although we found a complex kariotype in tumoral tissue defined by three celular lines. In all of them appears a marker in which the 6 chromosome is involved (der 6). The derivated of 6 chromosome are markers highly characteristic of the retinoblastoma cases, and can be related with the aggressivity of tumor and the appearance of the second tumors.

  4. Improved Endpoints for Cancer Immunotherapy Trials

    PubMed Central

    Eggermont, Alexander M. M.; Janetzki, Sylvia; Hodi, F. Stephen; Ibrahim, Ramy; Anderson, Aparna; Humphrey, Rachel; Blumenstein, Brent; Wolchok, Jedd

    2010-01-01

    Unlike chemotherapy, which acts directly on the tumor, cancer immunotherapies exert their effects on the immune system and demonstrate new kinetics that involve building a cellular immune response, followed by changes in tumor burden or patient survival. Thus, adequate design and evaluation of some immunotherapy clinical trials require a new development paradigm that includes reconsideration of established endpoints. Between 2004 and 2009, several initiatives facilitated by the Cancer Immunotherapy Consortium of the Cancer Research Institute and partner organizations systematically evaluated an immunotherapy-focused clinical development paradigm and created the principles for redefining trial endpoints. On this basis, a body of clinical and laboratory data was generated that supports three novel endpoint recommendations. First, cellular immune response assays generate highly variable results. Assay harmonization in multicenter trials may minimize variability and help to establish cellular immune response as a reproducible biomarker, thus allowing investigation of its relationship with clinical outcomes. Second, immunotherapy may induce novel patterns of antitumor response not captured by Response Evaluation Criteria in Solid Tumors or World Health Organization criteria. New immune-related response criteria were defined to more comprehensively capture all response patterns. Third, delayed separation of Kaplan–Meier curves in randomized immunotherapy trials can affect results. Altered statistical models describing hazard ratios as a function of time and recognizing differences before and after separation of curves may allow improved planning of phase III trials. These recommendations may improve our tools for cancer immunotherapy trials and may offer a more realistic and useful model for clinical investigation. PMID:20826737

  5. Study to Understand Cervical Cancer Early Endpoints and Determinants (SUCCEED)

    Cancer.gov

    A study to comprehensively assess biomarkers of risk for progressive cervical neoplasia, and thus develop a new set of biomarkers that can distinguish those at highest risk of cervical cancer from those with benign infection

  6. Does the decision in a validation process of a surrogate endpoint change with level of significance of treatment effect? A proposal on validation of surrogate endpoints.

    PubMed

    Sertdemir, Y; Burgut, R

    2009-01-01

    In recent years the use of surrogate end points (S) has become an interesting issue. In clinical trials, it is important to get treatment outcomes as early as possible. For this reason there is a need for surrogate endpoints (S) which are measured earlier than the true endpoint (T). However, before a surrogate endpoint can be used it must be validated. For a candidate surrogate endpoint, for example time to recurrence, the validation result may change dramatically between clinical trials. The aim of this study is to show how the validation criterion (R(2)(trial)) proposed by Buyse et al. are influenced by the magnitude of treatment effect with an application using real data. The criterion R(2)(trial) proposed by Buyse et al. (2000) is applied to the four data sets from colon cancer clinical trials (C-01, C-02, C-03 and C-04). Each clinical trial is analyzed separately for treatment effect on survival (true endpoint) and recurrence free survival (surrogate endpoint) and this analysis is done also for each center in each trial. Results are used for standard validation analysis. The centers were grouped by the Wald statistic in 3 equal groups. Validation criteria R(2)(trial) were 0.641 95% CI (0.432-0.782), 0.223 95% CI (0.008-0.503), 0.761 95% CI (0.550-0.872) and 0.560 95% CI (0.404-0.687) for C-01, C-02, C-03 and C-04 respectively. The R(2)(trial) criteria changed by the Wald statistics observed for the centers used in the validation process. Higher the Wald statistic groups are higher the R(2)(trial) values observed. The recurrence free survival is not a good surrogate for overall survival in clinical trials with non significant treatment effects and moderate for significant treatment effects. This shows that the level of significance of treatment effect should be taken into account in validation process of surrogate endpoints.

  7. Molecular cytogenetics using fluorescence in situ hybridization

    SciTech Connect

    Gray, J.W.; Kuo, Wen-Lin; Lucas, J.

    1990-12-07

    Fluorescence in situ hybridization (FISH) with chromosome-specific probes enables several new areas of cytogenetic investigation by allowing visual determination of the presence and normality of specific genetic sequences in single metaphase or interphase cells. in this approach, termed molecular cytogenetics, the genetic loci to be analyzed are made microscopically visible in single cells using in situ hybridization with nucleic acid probes specific to these loci. To accomplish this, the DNA in the target cells is made single stranded by thermal denaturation and incubated with single-stranded, chemically modified probe under conditions where the probe will anneal only with DNA sequences tomore » which it has high DNA sequence homology. The bound probe is then made visible by treatment with a fluorescent reagent such as fluorescein that binds to the chemical modification carried by the probe. The DNA to which the probe does not bind is made visible by staining with a dye such as propidium iodide that fluoresces at a wavelength different from that of the reagent used for probe visualization. We show in this report that probes are now available that make this technique useful for biological dosimetry, prenatal diagnosis and cancer biology. 31 refs., 3 figs.« less

  8. Cytogenetic and molecular analysis in Angelman syndrome.

    PubMed

    Zackowski, J L; Nicholls, R D; Gray, B A; Bent-Williams, A; Gottlieb, W; Harris, P J; Waters, M F; Driscoll, D J; Zori, R T; Williams, C A

    1993-04-01

    We report on cytogenetic and molecular analyses of 29 Angelman syndrome (AS) individuals ascertained in 1990 through the first National Angelman Syndrome Conference. High resolution GTG- and GBG-banded chromosomes were studied. Standard molecular analysis with six 15q11q13 DNA sequences was used to analyze copy number and parental origin of 15q11q13. Concordance between molecular and cytogenetic data was excellent. The combined data showed that 23 of the 27 probands (85%) on whom we had definitive results have deletions of the chromosome 15q11q13 region. Two classes of deletion were detected molecularly: most patients were deleted for the 5 more proximal probes, but in 2 cases the deletion extended distally to include in sixth probe. In the 13 cases where the parental origin of the deleted chromosome 15 could be established, it was maternal. There were no cases of uniparental disomy. Cytological observations of the relative sizes of the heterochromatic regions of the short arm of chromosome 15 suggested that chromosomes with large heterochromatic blocks may be more prone to de novo deletion.

  9. Biomarkers and surrogate endpoints in glaucoma clinical trials

    PubMed Central

    Medeiros, Felipe A

    2015-01-01

    Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. PMID:25034049

  10. A quality-of-life-oriented endpoint for comparing therapies.

    PubMed

    Gelber, R D; Gelman, R S; Goldhirsch, A

    1989-09-01

    An endpoint, time without symptoms of disease and toxicity of treatment (TWiST), is defined to provide a single measure of length and quality of survival. Time with subjective side effects of treatment and time with unpleasant symptoms of disease are subtracted from overall survival time to calculate TWiST for each patient. The purpose of this paper is to describe the construction of this endpoint, and to elaborate on its interpretation for patient care decision-making. Estimating the distribution of TWiST using actuarial methods is shown by simulation studies to be biased as a result of induced dependency between TWiST and its censoring distribution. Considering the distribution of TWiST accumulated within a specified time from start of therapy, L, allows one to reduce this bias by substituting estimated TWiST for censored values and provides a method to evaluate the "payback" period for early toxic effects. Quantile distance plots provide graphical representations for treatment comparisons. The analysis of Ludwig Trial III evaluating toxic adjuvant therapies versus a no-treatment control group for postmenopausal women with node-positive breast cancer illustrates the methodology.

  11. Ecosystem Services as Assessment Endpoints in Ecological Risk Assessment

    EPA Science Inventory

    The focus of ecological risk assessment (ERA) is on assessment endpoints, explicit expressions of environmental values to be protected. Traditionally, the ecological entities identified in assessment endpoints have been components of ecosystems deemed by risk assessors to be impo...

  12. Immunohistochemical, cytogenetic, and molecular cytogenetic characterization of both components of a dedifferentiated liposarcoma: implications for histogenesis.

    PubMed

    Nishio, Jun; Iwasaki, Hiroshi; Nabeshima, Kazuki; Naito, Masatoshi

    2015-01-01

    Dedifferentiated liposarcoma (DDLS) is a malignant adipocytic tumor showing transition from an atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLS) to a non-lipogenic sarcoma of variable histological grades. We present the immunohistochemical, cytogenetic, and molecular cytogenetic findings of DDLS arising in the right chest wall of a 76-year-old man. Magnetic resonance imaging exhibited a large mass composed of two components with heterogeneous signal intensities, suggesting the coexistence of a fatty area and another soft tissue component. The grossly heterogeneous mass was histologically composed of an ALT/WDLS component transitioning abruptly into a dedifferentiated component. Immunohistochemistry was positive for murine double-minute 2 (MDM2), cyclin-dependent kinase 4 (CDK4), and p16 in both components, although a more strong and diffuse staining was found in the dedifferentiated area. The MIB-1 labeling index was extremely higher in the dedifferentiated area compared to the ALT/WDLS area. Cytogenetic analysis of the ALT/WDLS component revealed the following karyotype: 46,X,-Y,+r. Notably, cytogenetic analysis of the dedifferentiated component revealed a similar but more complex karyotype. Spectral karyotyping demonstrated that the ring chromosome was entirely composed of material from chromosome 12. Interphase fluorescence in situ hybridization analysis revealed amplification of MDM2 and CDK4 in both components. These findings suggest that multiple abnormal clones derived from a single precursor cell would be present in DDLS, with one or more containing supernumerary rings or giant marker chromosomes. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  13. Comparing biomarkers as principal surrogate endpoints.

    PubMed

    Huang, Ying; Gilbert, Peter B

    2011-12-01

    Recently a new definition of surrogate endpoint, the "principal surrogate," was proposed based on causal associations between treatment effects on the biomarker and on the clinical endpoint. Despite its appealing interpretation, limited research has been conducted to evaluate principal surrogates, and existing methods focus on risk models that consider a single biomarker. How to compare principal surrogate value of biomarkers or general risk models that consider multiple biomarkers remains an open research question. We propose to characterize a marker or risk model's principal surrogate value based on the distribution of risk difference between interventions. In addition, we propose a novel summary measure (the standardized total gain) that can be used to compare markers and to assess the incremental value of a new marker. We develop a semiparametric estimated-likelihood method to estimate the joint surrogate value of multiple biomarkers. This method accommodates two-phase sampling of biomarkers and is more widely applicable than existing nonparametric methods by incorporating continuous baseline covariates to predict the biomarker(s), and is more robust than existing parametric methods by leaving the error distribution of markers unspecified. The methodology is illustrated using a simulated example set and a real data set in the context of HIV vaccine trials. © 2011, The International Biometric Society.

  14. Helicopter EMS: Research Endpoints and Potential Benefits

    PubMed Central

    Thomas, Stephen H.; Arthur, Annette O.

    2012-01-01

    Patients, EMS systems, and healthcare regions benefit from Helicopter EMS (HEMS) utilization. This article discusses these benefits in terms of specific endpoints utilized in research projects. The endpoint of interest, be it primary, secondary, or surrogate, is important to understand in the deployment of HEMS resources or in planning further HEMS outcomes research. The most important outcomes are those which show potential benefits to the patients, such as functional survival, pain relief, and earlier ALS care. Case reports are also important “outcomes” publications. The benefits of HEMS in the rural setting is the ability to provide timely access to Level I or Level II trauma centers and in nontrauma, interfacility transport of cardiac, stroke, and even sepsis patients. Many HEMS crews have pharmacologic and procedural capabilities that bring a different level of care to a trauma scene or small referring hospital, especially in the rural setting. Regional healthcare and EMS system's benefit from HEMS by their capability to extend the advanced level of care throughout a region, provide a “backup” for areas with limited ALS coverage, minimize transport times, make available direct transport to specialized centers, and offer flexibility of transport in overloaded hospital systems. PMID:22203905

  15. The Role of Ecological Endpoints in Watershed Management

    EPA Science Inventory

    Landscape change and pollution in watersheds affect ecological endpoints in receiving water bodies. Therefore, these endpoints are useful in watershed management. Fish and benthic macro invertebrates are often used as endpoints, since they are easily measured in the field and int...

  16. Recent Developments in Whole Sediment Toxicity Identification Evaluations: Innovations in Manipulations and Endpoints

    EPA Science Inventory

    Whole sediment Toxicity Identification Evaluation (TIE) methods were developed primarily in the late 1990s and early 2000s in research programs dedicated to developing manipulations and endpoints to characterize and identify causes of toxicity to benthic freshwater and marine org...

  17. Ultrasound and radiology surrogate endpoints in pharmacological studies.

    PubMed

    Agewall, S; DeGroot, E; Marcos-Alberca, P; Zamorano, J L; Barrero, A A; Badano, L P; Perrone-Filardi, P

    2012-09-01

    Cardiovascular studies investigating therapeutic intervention with clinical endpoints are costly due to the need for considerable duration and large number of patients, or both. Therefore, for evaluation of novel cardiovascular drug efficacy, surrogate endpoints are used. Cardiovascular imaging endpoints have proven their worth. Sometimes the relevance of imaging is questioned and other methods are suggested instead. There is also some confusion about the strengths of imaging endpoints. The aim of the present paper is to review ultrasound and radiology imaging techniques as surrogate endpoints in pharmacological trials. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Advanced topics in evidence-based urologic oncology: surrogate endpoints.

    PubMed

    Lavallée, Luke T; Montori, Victor M; Canfield, Stephen E; Breau, Rodney H

    2011-01-01

    Clinical trials often report surrogate endpoint data. A surrogate endpoint is a biological marker or clinical sign that can be substituted for a patient-important outcome. Using surrogate endpoints correctly may facilitate and expedite clinical trials and may improve medical decisions. However, rigorous criteria must be met for an endpoint to be considered a valid surrogate. The purpose of this article is to review the topic of surrogate endpoints in the context of a urologic encounter. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Analytical cytology applied to detection of induced cytogenetic abnormalities

    SciTech Connect

    Gray, J.W.; Lucas, J.; Straume, T.

    1987-08-06

    Radiation-induced biological damage results in formation of a broad spectrum of cytogenetic changes such as translocations, dicentrics, ring chromosomes, and acentric fragments. A battery of analytical cytologic techniques are now emerging that promise to significantly improve the precision and ease with which these radiation induced cytogenetic changes can be quantified. This report summarizes techniques to facilitate analysis of the frequency of occurrence of structural and numerical aberrations in control and irradiated human cells. 14 refs., 2 figs.

  20. Use of nutrigenomics endpoints in dietary interventions.

    PubMed

    Hendriks, Henk F J

    2013-08-01

    In this paper, the nutrigenomics approach is discussed as a research tool to study the physiological effects of nutrition and consequently how nutrition affects health and disease (endpoints). Nutrigenomics is the study of the effects of foods and food constituents on gene expression; the analyses include analysis of mRNA, proteins and metabolites. Nutrigenomics may be useful in dealing with the challenges that nutrition research is facing; by integrating the description of numerous active genes and metabolic pathways stronger evidence and new biomarkers for subtle nutritional effects may be obtained. Also, a new definition of disease and health may be needed. The use of tests challenging homoeostasis is being proposed to help define health. Challenge tests may be able to demonstrate in a better way subtle beneficial effects of nutrition on health. The paper describes some basic concepts relevant to nutrition research as well as some of the possibilities that are offered by nutrigenomics technology. Some of its applications are described.

  1. Development and Application of Camelid Molecular Cytogenetic Tools

    PubMed Central

    Avila, Felipe; Das, Pranab J.; Kutzler, Michelle; Owens, Elaine; Perelman, Polina; Rubes, Jiri; Hornak, Miroslav; Johnson, Warren E.

    2014-01-01

    Cytogenetic chromosome maps offer molecular tools for genome analysis and clinical cytogenetics and are of particular importance for species with difficult karyotypes, such as camelids (2n = 74). Building on the available human–camel zoo-fluorescence in situ hybridization (FISH) data, we developed the first cytogenetic map for the alpaca (Lama pacos, LPA) genome by isolating and identifying 151 alpaca bacterial artificial chromosome (BAC) clones corresponding to 44 specific genes. The genes were mapped by FISH to 31 alpaca autosomes and the sex chromosomes; 11 chromosomes had 2 markers, which were ordered by dual-color FISH. The STS gene mapped to Xpter/Ypter, demarcating the pseudoautosomal region, whereas no markers were assigned to chromosomes 14, 21, 22, 28, and 36. The chromosome-specific markers were applied in clinical cytogenetics to identify LPA20, the major histocompatibility complex (MHC)-carrying chromosome, as a part of an autosomal translocation in a sterile male llama (Lama glama, LGL; 2n = 73,XY). FISH with LPAX BACs and LPA36 paints, as well as comparative genomic hybridization, were also used to investigate the origin of the minute chromosome, an abnormally small LPA36 in infertile female alpacas. This collection of cytogenetically mapped markers represents a new tool for camelid clinical cytogenetics and has applications for the improvement of the alpaca genome map and sequence assembly. PMID:23109720

  2. An information-theoretic approach to surrogate-marker evaluation with failure time endpoints.

    PubMed

    Pryseley, Assam; Tilahun, Abel; Alonso, Ariel; Molenberghs, Geert

    2011-04-01

    Over the last decades, the evaluation of potential surrogate endpoints in clinical trials has steadily been growing in importance, not only thanks to the availability of ever more potential markers and surrogate endpoints, also because more methodological development has become available. While early work has been devoted, to a large extent, to Gaussian, binary, and longitudinal endpoints, the case of time-to-event endpoints is in need of careful scrutiny as well, owing to the strong presence of such endpoints in oncology and beyond. While work had been done in the past, it was often cumbersome to use such tools in practice, because of the need for fitting copula or frailty models that were further embedded in a hierarchical or two-stage modeling approach. In this paper, we present a methodologically elegant and easy-to-use approach based on information theory. We resolve essential issues, including the quantification of "surrogacy" based on such an approach. Our results are put to the test in a simulation study and are applied to data from clinical trials in oncology. The methodology has been implemented in R.

  3. Arsenate (As V) in water: quantitative sensitivity relationships among biomarker, ecotoxicity and genotoxicity endpoints.

    PubMed

    Silva, Valéria C; Almeida, Sônia M; Resgalla, Charrid; Masfaraud, Jean-François; Cotelle, Sylvie; Radetski, Claudemir M

    2013-06-01

    It is useful to test ecotoxicity and genotoxicity endpoints in the environmental impact assessment. Here, we compare and discuss ecotoxicity and genotoxicity effects in organisms in response to exposure to arsenate (As V) in solution. Eco(geno)toxicity responses in Aliivibrio fischeri, Lytechinus variegatus, Daphnia magna, Skeletonema costatum and Vicia faba were analyzed by assessing different endpoints: biomass growth, peroxidase activity, mitotic index, micronucleus frequency, and lethality in accordance with the international protocols. Quantitative sensitivity relationships (QSR) between these endpoints were established in order to rank endpoint sensitivity. The results for the QSR values based on the lowest observed effect concentration (LOEC) ratios varied from 2 (for ratio of root peroxidase activity to leaf peroxidase activity) to 2286 (for ratio of higher plant biomass growth to root peroxidase activity). The QSR values allowed the following sensitivity ranking to be established: higher plant enzymatic activity>daphnids≈echinoderms>bacteria≈algae>higher plant biomass growth. The LOEC values for the mitotic index and micronucleus frequency (LOEC=0.25mgAsL(-1)) were similar to the lowest LOEC values observed in aquatic organisms. This approach to the QSR of different endpoints could form the basis for monitoring and predicting early effects of pollutants before they give rise to significant changes in natural community structures. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Biomarkers and surrogate endpoints in glaucoma clinical trials.

    PubMed

    Medeiros, Felipe A

    2015-05-01

    Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. This article reviews the general requirements for validating surrogate endpoints and provides a critical assessment of the use of intraocular pressure (IOP), visual fields, and structural measurements of the optic nerve as surrogate endpoints in glaucoma clinical trials. A valid surrogate endpoint must be able to predict the clinically relevant endpoint and fully capture the effect of an intervention on that endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has ever been conducted for any class of IOP-lowering treatments. Evidence has accumulated with regard to the role of imaging measurements of optic nerve damage as surrogate endpoints in glaucoma. These measurements are predictive of functional losses in the disease and may explain, at least in part, treatment effects on clinically relevant endpoints. The use of composite endpoints in glaucoma trials may overcome weaknesses of the use of structural or functional endpoints in isolation. Unless research is dedicated to fully develop and validate suitable endpoints that can be used in glaucoma clinical trials, we run the risk of inappropriate judgments about the value of new therapies. 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.

  5. The intermediate endpoint effect in logistic and probit regression

    PubMed Central

    MacKinnon, DP; Lockwood, CM; Brown, CH; Wang, W; Hoffman, JM

    2010-01-01

    Background An intermediate endpoint is hypothesized to be in the middle of the causal sequence relating an independent variable to a dependent variable. The intermediate variable is also called a surrogate or mediating variable and the corresponding effect is called the mediated, surrogate endpoint, or intermediate endpoint effect. Clinical studies are often designed to change an intermediate or surrogate endpoint and through this intermediate change influence the ultimate endpoint. In many intermediate endpoint clinical studies the dependent variable is binary, and logistic or probit regression is used. Purpose The purpose of this study is to describe a limitation of a widely used approach to assessing intermediate endpoint effects and to propose an alternative method, based on products of coefficients, that yields more accurate results. Methods The intermediate endpoint model for a binary outcome is described for a true binary outcome and for a dichotomization of a latent continuous outcome. Plots of true values and a simulation study are used to evaluate the different methods. Results Distorted estimates of the intermediate endpoint effect and incorrect conclusions can result from the application of widely used methods to assess the intermediate endpoint effect. The same problem occurs for the proportion of an effect explained by an intermediate endpoint, which has been suggested as a useful measure for identifying intermediate endpoints. A solution to this problem is given based on the relationship between latent variable modeling and logistic or probit regression. Limitations More complicated intermediate variable models are not addressed in the study, although the methods described in the article can be extended to these more complicated models. Conclusions Researchers are encouraged to use an intermediate endpoint method based on the product of regression coefficients. A common method based on difference in coefficient methods can lead to distorted

  6. Prolonged treatment with imatinib mesylate in patients with advanced chronic myeloid leukemia causes a reduction of bcr/abl mRNA levels independent of cytogenetic response.

    PubMed

    Cariani, E; Capucci, M; Micheletti, M; Spalenza, F; Zanella, I; Albertini, A; Rossi, G

    2003-06-01

    Bcr/abl mRNA levels were monitored in 13 patients with chronic myeloid leukemia receiving imatinib mesylate over a period of 78 weeks. During treatment median bcr/abl mRNA levels progressively declined from 77.2 normalized dose (nD) at baseline to 11.28 nD after 13 weeks ( P<0.05) and to 1.28 nD after 78 weeks ( P<0.05). After 13 weeks, bcr/abl mRNA levels were significantly lower in cytogenetic responders compared to nonresponders ( P<0.05), but subsequent decrease in the transcript levels caused the loss of any correlation to the cytogenetic status. These results suggest that bcr/abl mRNA levels may reflect cytogenetic response only during the early phases of imatinib therapy.

  7. The Use of a Binary Composite Endpoint and Sample Size Requirement: Influence of Endpoints Overlap.

    PubMed

    Marsal, Josep-Ramon; Ferreira-González, Ignacio; Bertran, Sandra; Ribera, Aida; Permanyer-Miralda, Gaietà; García-Dorado, David; Gómez, Guadalupe

    2017-05-01

    Although composite endpoints (CE) are common in clinical trials, the impact of the relationship between the components of a binary CE on the sample size requirement (SSR) has not been addressed. We performed a computational study considering 2 treatments and a CE with 2 components: the relevant endpoint (RE) and the additional endpoint (AE). We assessed the strength of the components' interrelation by the degree of relative overlap between them, which was stratified into 5 groups. Within each stratum, SSR was computed for multiple scenarios by varying the events proportion and the effect of the therapy. A lower SSR using CE was defined as the best scenario for using the CE. In 25 of 66 scenarios the degree of relative overlap determined the benefit of using CE instead of the RE. Adding an AE with greater effect than the RE leads to lower SSR using the CE regardless of the AE proportion and the relative overlap. The influence of overlapping decreases when the effect on RE increases. Adding an AE with lower effect than the RE constitutes the most uncertain situation. In summary, the interrelationship between CE components, assessed by the relative overlap, can help to define the SSR in specific situations and it should be considered for SSR computation. © The Author 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  8. Cytogenetic investigations of chronic lymphocytic leukemia.

    PubMed

    Wren, Catherine; Moriarty, Helen; Marsden, Katherine; Tegg, Elizabeth

    2010-04-15

    This study aimed to determine which culture method would yield the highest culture success rate, mitotic index, banding resolution, and abnormality rate in investigation of patients with chronic lymphocytic leukemia (CLL). A range of culture techniques for conventional cytogenetic (CC) analyses was compared: 24-hour unstimulated, 72 hours incubation with additional fetal calf serum, 72 hours stimulation with interleukin 4, 72 hours stimulation with lipopolysaccharide (LPS), 72 hours stimulation with TPA (12-O-tetradecanoylphorbol 13-acetate), and 72 hours stimulation with CpG-oligonucleotide DSP30 + Interleukin-2 (IL-2). CC abnormality rates were also compared to fluorescence in situ hybridization (FISH) results using probes for CLL (LSI D13S319/13q34/CEP 12: LSI ATM/p53). Forty-five samples from 24 patients (consisting of 11 newly diagnosed and 13 previously diagnosed patients) were included. For CC, a 100.0% culture success rate was achieved (n = 45) by means of an EDTA (ethylenediaminetetraacetic acid) peripheral blood sample with an associated 62.5% CC abnormality rate (n = 24). FISH detected an abnormality rate of 75.0% (n = 24). The combined CC and FISH abnormality rate was 87.5% (n = 24). This study demonstrates that CC that uses TPA and DSP30 + IL-2 on EDTA peripheral blood is effective in the investigation of CLL and may be used as a supplement to FISH studies. Copyright 2010 Elsevier Inc. All rights reserved.

  9. Sample size determination for equivalence assessment with multiple endpoints.

    PubMed

    Sun, Anna; Dong, Xiaoyu; Tsong, Yi

    2014-01-01

    Equivalence assessment between a reference and test treatment is often conducted by two one-sided tests (TOST). The corresponding power function and sample size determination can be derived from a joint distribution of the sample mean and sample variance. When an equivalence trial is designed with multiple endpoints, it often involves several sets of two one-sided tests. A naive approach for sample size determination in this case would select the largest sample size required for each endpoint. However, such a method ignores the correlation among endpoints. With the objective to reject all endpoints and when the endpoints are uncorrelated, the power function is the production of all power functions for individual endpoints. With correlated endpoints, the sample size and power should be adjusted for such a correlation. In this article, we propose the exact power function for the equivalence test with multiple endpoints adjusted for correlation under both crossover and parallel designs. We further discuss the differences in sample size for the naive method without and with correlation adjusted methods and illustrate with an in vivo bioequivalence crossover study with area under the curve (AUC) and maximum concentration (Cmax) as the two endpoints.

  10. Automatic Detection of Mitosis and Nuclei From Cytogenetic Images by CellProfiler Software for Mitotic Index Estimation.

    PubMed

    González, Jorge Ernesto; Radl, Analía; Romero, Ivonne; Barquinero, Joan Francesc; García, Omar; Di Giorgio, Marina

    2016-12-01

    Mitotic Index (MI) estimation expressed as percentage of mitosis plays an important role as quality control endpoint. To this end, MI is applied to check the lot of media and reagents to be used throughout the assay and also to check cellular viability after blood sample shipping, indicating satisfactory/unsatisfactory conditions for the progression of cell culture. The objective of this paper was to apply the CellProfiler open-source software for automatic detection of mitotic and nuclei figures from digitized images of cultured human lymphocytes for MI assessment, and to compare its performance to that performed through semi-automatic and visual detection. Lymphocytes were irradiated and cultured for mitosis detection. Sets of images from cultures were analyzed visually and findings were compared with those using CellProfiler software. The CellProfiler pipeline includes the detection of nuclei and mitosis with 80% sensitivity and more than 99% specificity. We conclude that CellProfiler is a reliable tool for counting mitosis and nuclei from cytogenetic images, saves considerable time compared to manual operation and reduces the variability derived from the scoring criteria of different scorers. The CellProfiler automated pipeline achieves good agreement with visual counting workflow, i.e. it allows fully automated mitotic and nuclei scoring in cytogenetic images yielding reliable information with minimal user intervention. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  11. Cytogenetic and molecular characterization of 57 individuals with the Parder-Willi syndrome

    SciTech Connect

    Butler, M.G.; Forrest, K.B.; Miller, L.K.

    Prader-Willi syndrome (PWS) is characterized by hypotonia, early childhood obesity, mental deficiency, hypogonadism and an interstitial deletion of 15q11q13 of paternal origin in 50-70% of patients. The remaining patients have either submicroscopic deletions, maternal disomy or other anomalies of chromosome 15. We have undertaken cytogenetic and molecular genetic studies of 57 individuals presenting with features consistent with PWS (28 males and 29 females; age range of 3 months to 38 years), 25 with recognizable 15q11q13 deletions (44%), 28 with normal appearing chromosomes (49%), and four patients with other chromosome 15 anomalies (7%). High resolution chromosome analysis and PCR amplification weremore » performed utilizing 17 STRs from 15q11q13 region, quantitative Southern hybridization using seven 15q11q13 probes, and fluorescence in situ hybridization (FISH) using four 15q11q13 probes (4-3R, SNRPN, 3-21, and GABRB3). The cytogenetic deletion was paternal in all PWS families studied but the deletion varied in size in 10 patients. Parental DNA studies from 20 of 28 non-deletion patients showed maternal disomy in 7 patients and biparental inheritance in 13 non-deletion patients. In order to evaluate for submicroscopic deletions, PCR amplification with several loci in the area of the PWS minimal critical region, FISH using SNRPN and quantitative hybridization using a PCR product generated from primers of exons E and H of the SNRPN gene were undertaken on the non-deletion patients. Quantitative hybridization and FISH using SNRPN from 3 of 11 non-deletion patients (excluding maternal disomy cases) showed a submicroscopic deletion. One of these patients also showed a paternal deletion of D15S128 and MN1. We furthur support the use of both cytogenetic and molecular genetic methods for determining the genetic status of PWS patients.« less

  12. Metaphase and interphase cytogenetics in fibroadenomas of the breast.

    PubMed

    Rizou, Helen; Bardi, Georgia; Arnaourti, Maria; Apostolikas, Nikiforos; Sfikas, Kostas; Charlaftis, Antonios; Polichronis, Athanassios; Agnantis, Niki J; Pandis, Nikos

    2004-01-01

    Short-term cultures of fifty-two samples of fibroadenomas were cytogenetically analyzed. Thirty-three of the successfully karyotyped fibroadenomas were further investigated for the presence of amplifications in the CCND1, c-MYC and HER/2-neu genes by means of FISH analysis. Compared to carcinomas, fibroadenomas seem to have less complex cytogenetic rearrangements and limited alterations on HER-2/neu, CCND1 and c-MYC loci. A cytogenetic subgroup of fibroadenomas with hyperdiploid karyotypes and only numerical changes was observed. Amplification of CCND1 seems to play a more substantial role in benign tumor progression. These findings confirm that fibroadenomas do have genetic alterations and support the hypothesis that a fibroadenoma subset displays changes also found in carcinomas, thus indicating that patients belonging to this group might have an increased risk for subsequent breast cancer.

  13. 40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

  14. 40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

  15. 40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

  16. 40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

  17. 40 CFR 798.5385 - In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... cytogenetics tests: Chromosomal analysis. 798.5385 Section 798.5385 Protection of Environment ENVIRONMENTAL... Genetic Toxicity § 798.5385 In vivo mammalian bone marrow cytogenetics tests: Chromosomal analysis. (a) Purpose. The in vivo bone marrow cytogenetic test is a mutagenicity test for the detection of structural...

  18. Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma

    PubMed Central

    Medeiros, Felipe A.

    2017-01-01

    With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes. Valid surrogate endpoints must be able to predict a clinically relevant endpoint, such as loss of vision or decrease in quality of life. In addition, the effect of a proposed treatment on the surrogate must capture the effect of the treatment on the clinically relevant endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has yet been conducted for any class of IOP-lowering treatments. Although strong evidence has accumulated about imaging measurements as predictors of relevant functional outcomes in glaucoma, there is still insufficient evidence to support their use as valid surrogate endpoints. However, imaging biomarkers could potentially be used as part of composite endpoints in glaucoma trials, overcoming weaknesses of the use of structural or functional endpoints in isolation. Efforts should be taken to properly design and conduct studies that can provide proper validation of potential biomarkers in glaucoma clinical trials. PMID:28475699

  19. Biomarkers and Surrogate Endpoints: Lessons Learned From Glaucoma.

    PubMed

    Medeiros, Felipe A

    2017-05-01

    With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes. Valid surrogate endpoints must be able to predict a clinically relevant endpoint, such as loss of vision or decrease in quality of life. In addition, the effect of a proposed treatment on the surrogate must capture the effect of the treatment on the clinically relevant endpoint. Despite its widespread use in clinical trials, no proper validation of IOP as a surrogate endpoint has yet been conducted for any class of IOP-lowering treatments. Although strong evidence has accumulated about imaging measurements as predictors of relevant functional outcomes in glaucoma, there is still insufficient evidence to support their use as valid surrogate endpoints. However, imaging biomarkers could potentially be used as part of composite endpoints in glaucoma trials, overcoming weaknesses of the use of structural or functional endpoints in isolation. Efforts should be taken to properly design and conduct studies that can provide proper validation of potential biomarkers in glaucoma clinical trials.

  20. Utilization of optical emission endpoint in photomask dry etch processing

    NASA Astrophysics Data System (ADS)

    Faure, Thomas B.; Huynh, Cuc; Lercel, Michael J.; Smith, Adam; Wagner, Thomas

    2002-03-01

    Use of accurate and repeatable endpoint detection during dry etch processing of photomask is very important for obtaining good mask mean-to-target and CD uniformity performance. It was found that the typical laser reflectivity endpoint detecting system used on photomask dry etch systems had several key limitations that caused unnecessary scrap and non-optimum image size performance. Consequently, work to develop and implement use of a more robust optical emission endpoint detection system for chrome dry etch processing of photomask was performed. Initial feasibility studies showed that the emission technique was sensitive enough to monitor pattern loadings on contact and via level masks down to 3 percent pattern coverage. Additional work was performed to further improve this to 1 percent pattern coverage by optimizing the endpoint detection parameters. Comparison studies of mask mean-to-target performance and CD uniformity were performed with the use of optical emission endpoint versus laser endpoint for masks built using TOK IP3600 and ZEP 7000 resist systems. It was found that an improvement in mean-to-target performance and CD uniformity was realized on several types of production masks. In addition, part-to-part endpoint time repeatability was found to be significantly improved with the use of optical emission endpoint.

  1. Useful pharmacodynamic endpoints in children: selection, measurement, and next steps

    PubMed Central

    Kelly, Lauren E; Sinha, Yashwant; Barker, Charlotte I S; Standing, Joseph F; Offringa, Martin

    2018-01-01

    Pharmacodynamic (PD) endpoints are essential for establishing the benefit-to-risk ratio for therapeutic interventions in children and neonates. This article discusses the selection of an appropriate measure of response, the PD endpoint, which is a critical methodological step in designing pediatric efficacy and safety studies. We provide an overview of existing guidance on the choice of PD endpoints in pediatric clinical research. We identified several considerations relevant to the selection and measurement of PD endpoints in pediatric clinical trials, including the use of biomarkers, modeling, compliance, scoring systems, and validated measurement tools. To be useful, PD endpoints in children need to be clinically relevant, responsive to both treatment and/or disease progression, reproducible, and reliable. In most pediatric disease areas, this requires significant validation efforts. We propose a minimal set of criteria for useful PD endpoint selection and measurement. We conclude that, given the current heterogeneity of pediatric PD endpoint definitions and measurements, both across and within defined disease areas, there is an acute need for internationally agreed, validated, and condition-specific pediatric PD endpoints that consider the needs of all stakeholders, including healthcare providers, policy makers, patients, and families. PMID:29667952

  2. Cytogenetic profile of aplastic anaemia in Indian children

    PubMed Central

    Gupta, Vineeta; Kumar, Akash; Saini, Isha; Saxena, Ajit Kumar

    2013-01-01

    Background & objectives: Aplastic anaemia is a rare haematological disorder characterized by pancytopenia with a hypocellular bone marrow. It may be inherited/genetic or acquired. Acquired aplastic anaemia has been linked to many drugs, chemicals and viruses. Cytogenetic abnormalities have been reported infrequently with acquired aplastic anaemia. Majority of the studies are in adult patients from the West. We report here cytogenetic studies on paediatric patients with acquired aplastic anaemia seen in a tertiary care hospital in north India. Methods: Patients (n=71, age 4-14 yr) were diagnosed according to the guidelines of International Agranulocytosis and Aplastic Anaemia Study. Conventional cytogenetics with Giemsa Trypsin Giemsa (GTG) banding was performed. Karyotyping was done according to the International System for Human Cytogenetics Nomenclature (ISCN). Results: Of the 71 patients, 42 had successful karyotyping where median age was 9 yr; of these 42, 27 (64.3%) patients had severe, nine (21.4%) had very severe and six (14.3%) had non severe aplastic anaemia. Five patients had karyotypic abnormalities with trisomy 12 (1), trisomy 8 (1) and monosomy 7 (1). Two patients had non numerical abnormalities with del 7 q - and t (5:12) in one each. Twenty nine patients had uninformative results. There was no difference in the clinical and haematological profile of patients with normal versus abnormal cytogenetics although the number of patients was small in the two groups. Interpretation & conclusions: Five (11.9%) patients with acquired aplastic anaemia had chromosomal abnormalities. Trisomy was found to be the commonest abnormality. Cytogenetic abnormalities may be significant in acquired aplastic anaemia although further studies on a large sample are required to confirm the findings. PMID:23640556

  3. Cytogenetic profile of aplastic anaemia in Indian children.

    PubMed

    Gupta, Vineeta; Kumar, Akash; Saini, Isha; Saxena, Ajit Kumar

    2013-03-01

    Aplastic anaemia is a rare haematological disorder characterized by pancytopenia with a hypocellular bone marrow. It may be inherited/genetic or acquired. Acquired aplastic anaemia has been linked to many drugs, chemicals and viruses. Cytogenetic abnormalities have been reported infrequently with acquired aplastic anaemia. Majority of the studies are in adult patients from the West. We report here cytogenetic studies on paediatric patients with acquired aplastic anaemia seen in a tertiary care hospital in north India. Patients (n=71, age 4-14 yr) were diagnosed according to the guidelines of International Agranulocytosis and Aplastic Anaemia Study. Conventional cytogenetics with Giemsa Trypsin Giemsa (GTG) banding was performed. Karyotyping was done according to the International System for Human Cytogenetics Nomenclature (ISCN). Of the 71 patients, 42 had successful karyotyping where median age was 9 yr; of these 42, 27 (64.3%) patients had severe, nine (21.4%) had very severe and six (14.3%) had non severe aplastic anaemia. Five patients had karyotypic abnormalities with trisomy 12 (1), trisomy 8 (1) and monosomy 7 (1). Two patients had non numerical abnormalities with del 7 q - and t (5:12) in one each. Twenty nine patients had uninformative results. There was no difference in the clinical and haematological profile of patients with normal versus abnormal cytogenetics although the number of patients was small in the two groups. Five (11.9%) patients with acquired aplastic anaemia had chromosomal abnormalities. Trisomy was found to be the commonest abnormality. Cytogenetic abnormalities may be significant in acquired aplastic anaemia although further studies on a large sample are required to confirm the findings.

  4. Cytogenetic study is not essential in patients with aplastic anemia

    PubMed Central

    Dutta, Atreyee; De, Rajib; Dolai, Tuphan K; Mitra, Pradip K; Halder, Ajanta

    2017-01-01

    Depending on contemporary treatment approach of aggressive immunosuppression, Aplastic Anemia (AA) is caused by immunological destruction of otherwise normal hematopoietic stem cells. The aim was to summarize the cytogenetic abnormalities in AA patients and the frequency of Fanconi Anemia (FA) in morphologically normal AA patients in eastern India. Ethical clearances were obtained from both institutions involved in this study. Out of 72800 patients attending the outpatient department, 520 pancytopenia patients were screened for AA after Bone marrow (BM) aspiration and biopsy. Samples were collected from 117 cases in 3 phases. 51 peripheral venous blood (PVB) samples in the first phase, 19 BM & PVB paired samples in the second phase and 47 BM samples in third phase were collected followed by leukocyte and/or BM stem cell culture. Next GTG banding and karyotyping were performed. PVB was collected from 63 (< 50 years) AA patients and stress cytogenetics was done to diagnose FA. In the first phase of the study, out of 51 PVB samples, 1 (1.96%) showed a unique chromosomal abnormality, i.e. 45,XY,rob(14:21)(p10:q10)[20]. In the second phase of study, among 19 BM & PVB paired samples, 1 (5.26%) showed abnormal karyotype i.e. 45,X,-Y[3]/46,XY[47]. In the third phase of the study, 47 BM samples showed normal karyotype. Only 6 (9.52%) cases were found positive for stress cytogenetics. A negligible percentage showing cytogenetic abnormality in such a considerable number of AA cases indicates that routine cytogenetic analysis of AA patient is not essential. A significant percentage was positive for stress cytogenetics; suggestive for FA, even the patients were morphologically normal. PMID:29181263

  5. Molecular cytogenetic analysis of Xq critical regions in premature ovarian failure

    PubMed Central

    2013-01-01

    Background One of the frequent reasons for unsuccessful conception is premature ovarian failure/primary ovarian insufficiency (POF/POI) that is defined as the loss of functional follicles below the age of 40 years. Among the genetic causes the most common one involves the X chromosome, as in Turner syndrome, partial X deletion and X-autosome translocations. Here we report a case of a 27-year-old female patient referred to genetic counselling because of premature ovarian failure. The aim of this case study to perform molecular genetic and cytogenetic analyses in order to identify the exact genetic background of the pathogenic phenotype. Results For premature ovarian failure disease diagnostics we performed the Fragile mental retardation 1 gene analysis using Southern blot technique and Repeat Primed PCR in order to identify the relationship between the Fragile mental retardation 1 gene premutation status and the premature ovarion failure disease. At this early onset, the premature ovarian failure affected patient we detected one normal allele of Fragile mental retardation 1 gene and we couldn’t verify the methylated allele, therefore we performed the cytogenetic analyses using G-banding and fluorescent in situ hybridization methods and a high resolution molecular cytogenetic method, the array comparative genomic hybridization technique. For this patient applying the G-banding, we identified a large deletion on the X chromosome at the critical region (ChrX q21.31-q28) which is associated with the premature ovarian failure phenotype. In order to detect the exact breakpoints, we used a special cytogenetic array ISCA plus CGH array and we verified a 67.355 Mb size loss at the critical region which include total 795 genes. Conclusions We conclude for this case study that the karyotyping is definitely helpful in the evaluation of premature ovarian failure patients, to identify the non submicroscopic chromosomal rearrangement, and using the array CGH technique we can

  6. Proof of concept demonstration of optimal composite MRI endpoints for clinical trials.

    PubMed

    Edland, Steven D; Ard, M Colin; Sridhar, Jaiashre; Cobia, Derin; Martersteck, Adam; Mesulam, M Marsel; Rogalski, Emily J

    2016-09-01

    Atrophy measures derived from structural MRI are promising outcome measures for early phase clinical trials, especially for rare diseases such as primary progressive aphasia (PPA), where the small available subject pool limits our ability to perform meaningfully powered trials with traditional cognitive and functional outcome measures. We investigated a composite atrophy index in 26 PPA participants with longitudinal MRIs separated by two years. Rogalski et al . [ Neurology 2014;83:1184-1191] previously demonstrated that atrophy of the left perisylvian temporal cortex (PSTC) is a highly sensitive measure of disease progression in this population and a promising endpoint for clinical trials. Using methods described by Ard et al . [ Pharmaceutical Statistics 2015;14:418-426], we constructed a composite atrophy index composed of a weighted sum of volumetric measures of 10 regions of interest within the left perisylvian cortex using weights that maximize signal-to-noise and minimize sample size required of trials using the resulting score. Sample size required to detect a fixed percentage slowing in atrophy in a two-year clinical trial with equal allocation of subjects across arms and 90% power was calculated for the PSTC and optimal composite surrogate biomarker endpoints. The optimal composite endpoint required 38% fewer subjects to detect the same percent slowing in atrophy than required by the left PSTC endpoint. Optimal composites can increase the power of clinical trials and increase the probability that smaller trials are informative, an observation especially relevant for PPA, but also for related neurodegenerative disorders including Alzheimer's disease.

  7. Impaired Cytogenetic Damage Repair and Cell Cycle Regulation in Response to Ionizing Radiation in Human Fibroblast Cells with Individual Knock-down of 25 Genes

    NASA Technical Reports Server (NTRS)

    Zhang, Ye; Rohde, Larry; Emami, Kamal; Hammond, Dianne; Casey, Rachael; Mehta, Satish; Jeevarajan, Antony; Pierson, Duane; Wu, Honglu

    2008-01-01

    Changes of gene expression profile are one of the most important biological responses in living cells after ionizing radiation (IR) exposure. Although some studies have demonstrated that genes with upregulated expression induced by IR may play important roles in DNA damage sensing, cell cycle checkpoint and chromosomal repair, the relationship between the regulation of gene expression by IR and its impact on cytogenetic responses to ionizing radiation has not been systematically studied. In our present study, the expression of 25 genes selected based on their transcriptional changes in response to IR or from their known DNA repair roles were individually knocked down by siRNA transfection in human fibroblast cells. Chromosome aberrations (CA) and micronuclei (MN) formation were measured as the cytogenetic endpoints. Our results showed that the yield of MN and/or CA formation were significantly increased by suppressed expression of 5 genes that included Ku70 in the DSB repair pathway; XPA in the NER pathway; RPA1 in the MMR pathway; RAD17 and RBBP8 in cell cycle control. Knocked-down expression of 4 genes including MRE11A, RAD51 in the DSB pathway, and SESN1 and SUMO1 showed significant inhibition of cell cycle progression, possibly because of severe impairment of DNA damage repair. Furthermore, loss of XPA, p21 and MLH1 expression resulted in both enhanced cell cycle progression and significantly higher yield of cytogenetic damage, indicating the involvement of these gene products in both cell cycle control and DNA damage repair. Of these 11 genes that affected the cytogenetic response, 9 were up-regulated in the cells exposed to gamma radiation, suggesting that genes transcriptionally modulated by IR were critical to regulating the biological consequences after IR. Failure to express these IR-responsive genes, such as by gene mutation, could seriously change the outcome of the post IR scenario and lead to carcinogenesis.

  8. Evaluation of clinical and cytogenetic parameters in rheumatoid arthritis patients for effective diagnosis.

    PubMed

    Chandirasekar, R; Kumar, B Lakshman; Jayakumar, R; Uthayakumar, V; Jacob, Raichel; Sasikala, K

    2015-01-15

    Rheumatoid arthritis is the commonest inflammatory joint disease, affecting nearly 1% of the adult population worldwide. Early and accurate diagnosis and prognosis of rheumatoid arthritis (RA) have become increasingly important. In the present study, we aimed to elucidate the relationships between hematological, biochemical, immunological and cytogenetic parameters in rheumatoid arthritis patients and healthy normal controls. The study group comprised of 126 RA patients and equal number of healthy normal control subjects. The blood was collected and analyzed for biochemical, immunological, enzymatic and cytogenetic parameters. Results of the present study indicated that 20% of RA patient's hematological, 31% of biochemical and 70% immunological parameters had a significant difference from the controls and reference range. The RF and anti-CCP antibody levels were also positive in 70% of RA patients. A significant increase in minor chromosomal abnormalities was also observed in patients as compared to controls. The knowledge about autoimmune diseases is very low among the South Indian population. The present study has thus helped in understanding the RA disease in a better way based on a pattern of various clinical markers of the disease condition which might help in planning therapeutic intervention strategies and create awareness about the disease management among RA patients of the population studied. Copyright © 2014. Published by Elsevier B.V.

  9. Validated surrogate endpoints needed for peri-implantitis.

    PubMed

    Lee, Dong Won

    2011-01-01

    Pubmed, Cochrane and Lilac databases, Google, Google Scholar, hand searching of websites of major dental journals. The reference list of five recently published systematic reviews on peri-implantitis treatment were also screened for potential studies. Randomised controlled trials and non-randomised studies in English, German, French, Spanish and Italian on peri-implantitis treatment in humans were included. Case series, case reports and cross sectional or non-therapy studies were excluded from the assessment of endpoints. No minimum follow up time was set for studies that were included. Data were extracted in duplicate by two reviewers and disagreements were resolved by consensus. True endpoints for peri-implantitis treatment were considered only if they provided evidence of tangible benefit to the patient. The outcome variables regarded as true endpoints were implant failure, aesthetic assessment and variables related to quality of life, but these were only considered if they were clearly identified as an objective of the research, not as an outcome of treatment. Surrogate endpoints were considered as those measurements of clinical outcomes such as probing pocket depth and clinical attachment level. Fourteen studies were included in this review with data on implant failure presented solely as consequence of peri-implantitis therapy. No true endpoint was described for any study on peri-implantitis. Mean pocket probing depth, clinical attachment level and bleeding on probing were the three surrogate endpoints cited most often in the literature. All endpoints used in the trials reviewed are surrogates of clinical events, such as implant failure. Clinical surrogate endpoints should be validated to assess the real effect of these measures on true endpoints.

  10. Equipment management risk rating system based on engineering endpoints.

    PubMed

    James, P J

    1999-01-01

    The equipment management risk ratings system outlined here offers two significant departures from current practice: risk classifications are based on intrinsic device risks, and the risk rating system is based on engineering endpoints. Intrinsic device risks are categorized as physical, clinical and technical, and these flow from the incoming equipment assessment process. Engineering risk management is based on verification of engineering endpoints such as clinical measurements or energy delivery. This practice eliminates the ambiguity associated with ranking risk in terms of physiologic and higher-level outcome endpoints such as no significant hazards, low significance, injury, or mortality.

  11. Ecosystem services as assessment endpoints for ecological risk assessment.

    PubMed

    Munns, Wayne R; Rea, Anne W; Suter, Glenn W; Martin, Lawrence; Blake-Hedges, Lynne; Crk, Tanja; Davis, Christine; Ferreira, Gina; Jordan, Steve; Mahoney, Michele; Barron, Mace G

    2016-07-01

    Ecosystem services are defined as the outputs of ecological processes that contribute to human welfare or have the potential to do so in the future. Those outputs include food and drinking water, clean air and water, and pollinated crops. The need to protect the services provided by natural systems has been recognized previously, but ecosystem services have not been formally incorporated into ecological risk assessment practice in a general way in the United States. Endpoints used conventionally in ecological risk assessment, derived directly from the state of the ecosystem (e.g., biophysical structure and processes), and endpoints based on ecosystem services serve different purposes. Conventional endpoints are ecologically important and susceptible entities and attributes that are protected under US laws and regulations. Ecosystem service endpoints are a conceptual and analytical step beyond conventional endpoints and are intended to complement conventional endpoints by linking and extending endpoints to goods and services with more obvious benefit to humans. Conventional endpoints can be related to ecosystem services even when the latter are not considered explicitly during problem formulation. To advance the use of ecosystem service endpoints in ecological risk assessment, the US Environmental Protection Agency's Risk Assessment Forum has added generic endpoints based on ecosystem services (ES-GEAE) to the original 2003 set of generic ecological assessment endpoints (GEAEs). Like conventional GEAEs, ES-GEAEs are defined by an entity and an attribute. Also like conventional GEAEs, ES-GEAEs are broadly described and will need to be made specific when applied to individual assessments. Adoption of ecosystem services as a type of assessment endpoint is intended to improve the value of risk assessment to environmental decision making, linking ecological risk to human well-being, and providing an improved means of communicating those risks. Integr Environ Assess Manag

  12. Practical Instruction in Tissue Culture and Cytogenetics for Sandwich Students.

    ERIC Educational Resources Information Center

    Williams, D. C.; Bishun, N. P.

    1973-01-01

    Describes the training and practical techniques taught to students involved in a sandwich course at the Tissue Culture and Cytogenetics Unit of the Marie Curie Memorial Foundation, Surrey, England. Students spend a minimum of six months involved in the sandwich course before returning to university for a final academic year. (JR)

  13. Cytogenetic studies of three triazine herbicides. I. In vitro studies

    EPA Science Inventory

    Atrazine, simazine, and cyanazine are widely used pre-emergence and post-emergence triazine herbicides that have made their way into the potable water supply of many agricultural communities. Because of this and the prevalence of contradictory cytogenetic studies in the literatur...

  14. Molecular cytogenetics: an indispensable tool for cancer diagnosis.

    PubMed

    Wan, Thomas Sk; Ma, Edmond Sk

    2012-01-01

    Cytogenetic aberrations may escape detection or recognition in traditional karyotyping. The past decade has seen an explosion of methodological advances in molecular cytogenetics technology. These cytogenetics techniques add color to the black and white world of conventional banding. Fluorescence in-situ hybridization (FISH) study has emerged as an indispensable tool for both basic and clinical research, as well as diagnostics, in leukemia and cancers. FISH can be used to identify chromosomal abnormalities through fluorescent labeled DNA probes that target specific DNA sequences. Subsequently, FISH-based tests such as multicolor karyotyping, comparative genomic hybridization (CGH) and array CGH have been used in emerging clinical applications as they enable resolution of complex karyotypic aberrations and whole global scanning of genomic imbalances. More recently, crossspecies array CGH analysis has also been employed in cancer gene identification. The clinical impact of FISH is pivotal, especially in the diagnosis, prognosis and treatment decisions for hematological diseases, all of which facilitate the practice of personalized medicine. This review summarizes the methodology and current utilization of these FISH techniques in unraveling chromosomal changes and highlights how the field is moving away from conventional methods towards molecular cytogenetics approaches. In addition, the potential of the more recently developed FISH tests in contributing information to genetic abnormalities is illustrated.

  15. Cytogenetic variation between four cases of feline fibrosarcoma.

    PubMed

    Mayr, B; Bockstahler, B; Loupal, G; Reifinger, M; Schleger, W

    1996-11-01

    Short term cultures of four feline fibrosarcomas were analysed cytogenetically. There was marked genetic heterogeneity between the four cats, each showing a different clonal abnormality. The aberrations detected were one deleted B2, one marker F1 and two reciprocal translocations, t (A2q; E3q) and t (A1q; B4p).

  16. Surrogate endpoints for cancer screening trials: general principles and an illustration using the UK Flexible Sigmoidoscopy Screening Trial.

    PubMed

    Cuzick, Jack; Cafferty, Fay H; Edwards, Robert; Møller, Henrik; Duffy, Stephen W

    2007-01-01

    Cancer screening is aimed primarily at reducing deaths. Thus, site-specific cancer mortality is the appropriate endpoint for evaluating screening interventions. However, it is also the most demanding endpoint, requiring follow-up and a large numbers of patients order to have adequate power. Therefore, it is highly desirable to have surrogate endpoints that can reliably predict mortality reductions many years earlier. We here review a range of surrogate markers in terms of their potential advantages and pitfalls, and argue that a measure which weights incident cancers according to their predicted mortality has many advantages over other measures and should be used more routinely. Application to the UK Flexible Sigmoidoscopy Screening Trial data suggests that predicted colorectal cancer mortality, based on stage-specific incidence, is a more powerful endpoint than actual mortality and could advance the analysis time by about three years. Total colorectal cancer incidence as a surrogate endpoint provides little advance in the analysis time over actual mortality. The approach requires reliable prognostic data, (e.g. stage), for both the study cohort and a representative sample of the whole population. The routine collection of such data should be a priority for cancer registries. Surrogate endpoints should not replace a long-term analysis based directly on mortality, but can provide reliable early indicators which can be useful both for monitoring ongoing screening programmes and for making policy decisions.

  17. Mixed response and time-to-event endpoints for multistage single-arm phase II design.

    PubMed

    Lai, Xin; Zee, Benny Chung-Ying

    2015-06-04

    The objective of phase II cancer clinical trials is to determine if a treatment has sufficient activity to warrant further study. The efficiency of a conventional phase II trial design has been the object of considerable debate, particularly when the study regimen is characteristically cytostatic. At the time of development of a phase II cancer trial, we accumulated clinical experience regarding the time to progression (TTP) for similar classes of drugs and for standard therapy. By considering the time to event (TTE) in addition to the tumor response endpoint, a mixed-endpoint phase II design may increase the efficiency and ability of selecting promising cytotoxic and cytostatic agents for further development. We proposed a single-arm phase II trial design by extending the Zee multinomial method to fully use mixed endpoints with tumor response and the TTE. In this design, the dependence between the probability of response and the TTE outcome is modeled through a Gaussian copula. Given the type I and type II errors and the hypothesis as defined by the response rate (RR) and median TTE, such as median TTP, the decision rules for a two-stage phase II trial design can be generated. We demonstrated through simulation that the proposed design has a smaller expected sample size and higher early stopping probability under the null hypothesis than designs based on a single-response endpoint or a single TTE endpoint. The proposed design is more efficient for screening new cytotoxic or cytostatic agents and less likely to miss an effective agent than the alternative single-arm design.

  18. Automatic streak endpoint localization from the cornerness metric

    NASA Astrophysics Data System (ADS)

    Sease, Brad; Flewelling, Brien; Black, Jonathan

    2017-05-01

    Streaked point sources are a common occurrence when imaging unresolved space objects from both ground- and space-based platforms. Effective localization of streak endpoints is a key component of traditional techniques in space situational awareness related to orbit estimation and attitude determination. To further that goal, this paper derives a general detection and localization method for streak endpoints based on the cornerness metric. Corners detection involves searching an image for strong bi-directional gradients. These locations typically correspond to robust structural features in an image. In the case of unresolved imagery, regions with a high cornerness score correspond directly to the endpoints of streaks. This paper explores three approaches for global extraction of streak endpoints and applies them to an attitude and rate estimation routine.

  19. Comprehensive Review on the Surrogate Endpoints of Efficacy Proposed or Hypothesized in the Scientific Community Today.

    PubMed

    von Minckwitz, Gunter; Fontanella, Caterina

    2015-05-01

    An intermediate endpoint is a surrogate marker of treatment efficacy assessed earlier than the true outcome of interest. A suitable intermediate endpoint in neoadjuvant trials of specific breast cancer subtypes is pathological complete response (pCR) rate, defined as no invasive (+/-noninvasive) residual cancer in breast and nodes at surgery. On the basis of available evidence, Food and Drug Administration the US allowed to use of pCR as a surrogate endpoint for accelerated approval process. However, surrogacy to long-term outcome remains an unresolved issue. Literature data provide indications that triple-negative, HER2-positive, and high-grade hormone receptor-positive breast cancer subtypes achieved the highest pCR rate; the prognostic impact of pCR on survival is established only for these aggressive subtypes. In the German experience, early response after two to four cycles of neoadjuvant treatment strongly correlated with both pCR rate and long-term outcome. Therefore, early response may be considered a predictive marker for pCR and used for driving clinical trial design. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. Surrogate and Intermediate Endpoints in Randomized Trials: What's the Goal?

    PubMed

    Korn, Edward L; Freidlin, Boris

    2018-05-15

    Establishing trial-level surrogacy of an intermediate endpoint for predicting survival benefit in future trials is extremely challenging because of the extrapolations required, but there are other useful drug development and patient management applications of intermediate endpoints. Clin Cancer Res; 24(10); 2239-40. ©2018 AACR See related article by Mushti et al., p. 2268 . ©2018 American Association for Cancer Research.

  1. 21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 7 2014-04-01 2014-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

  2. 21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 7 2013-04-01 2013-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

  3. 21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 7 2012-04-01 2012-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

  4. 21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 7 2011-04-01 2010-04-01 true Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

  5. 21 CFR 601.41 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 7 2010-04-01 2010-04-01 false Approval based on a surrogate endpoint or on an... Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or... uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical...

  6. Efficient estimation of the distribution of time to composite endpoint when some endpoints are only partially observed

    PubMed Central

    Daniel, Rhian M.; Tsiatis, Anastasios A.

    2014-01-01

    Two common features of clinical trials, and other longitudinal studies, are (1) a primary interest in composite endpoints, and (2) the problem of subjects withdrawing prematurely from the study. In some settings, withdrawal may only affect observation of some components of the composite endpoint, for example when another component is death, information on which may be available from a national registry. In this paper, we use the theory of augmented inverse probability weighted estimating equations to show how such partial information on the composite endpoint for subjects who withdraw from the study can be incorporated in a principled way into the estimation of the distribution of time to composite endpoint, typically leading to increased efficiency without relying on additional assumptions above those that would be made by standard approaches. We describe our proposed approach theoretically, and demonstrate its properties in a simulation study. PMID:23722304

  7. [Cytogenetic status of the residents of the Gydansky Peninsula (Gydan)].

    PubMed

    Shinkaruk, E V; Agbalyan, E V

    The relevance of the study on the Gydansky Peninsula lies in poor knowledge and inaccessibility of the territory, planned intensive industrial development of the Gydansky Peninsula, in 2011 there were received licenses for the exploration of license areas at the peninsula up to 2031. Industrial development will inevitably lead to certain environmental shifts, emission of the harmful substances into biosphere, the accumulation of anthropogenic pollutants in soil and water sources. The proposed development of the territory of the Peninsula Gydan sets the task of assessment of the impact of gas and oil production in conditions of the far North on health, as well indigenous persons as employees recruited to this of the region. One of the informative approaches to the assessment of population health is the assessment of the cytogenetic status with the use of noninvasive analysis of buccal epithelium. The aim of the study is to determine the cytogenetic status of the inhabitants of the village of Antipayuta of the Yamal-Nenets Autonomous Okrug for the assessment of the impact of environmental factors on the health of the population at the present stage of the industrial development of the territory. Samples of buccal epithelium of 81 alien and indigenous people of the Yamal-Nenets Autonomous district were the object of the investigation. There was performed the analysis of indices of cells of buccal epithelium of the residents living in the village in comparison with the control group. The analysis of samples was performed on a Nikon Eclipse E100 microscope. For the assessment of the cytogenetic status of the individual there was used the proposed by Sycheva L. P. (2012-Index of accumulation of cytogenetic damages (Iac). It is shown that the frequency of occurrence of micronucleus and nuclear protrusions does not exceed the performance of the control group. The index of accumulation of cytogenetic damage for the population of the village is 0.78±0.07% and corresponds to

  8. Transient myeloproliferative disease of the newborn: case report with placental, cytogenetic, and flow cytometric findings.

    PubMed

    de Tar, M W; Dittman, W; Gilbert, J

    2000-03-01

    Transient myeloproliferative disease (TMD) of the newborn is a rare hematologic abnormality associated with trisomy 21. It is frequently difficult to distinguish the disorder from true congenital leukemia (TCL). Unlike leukemia, which has a clinically aggressive course, TMD generally resolves within weeks to months. We present a case of TMD of the newborn diagnosed on the basis of peripheral blood studies and describe the pertinent pathological findings within the placenta. Flow cytometric analysis of the blasts in the peripheral blood showed phenotypic heterogeneity with features consistent with megakaryocytic differentiation. Cytogenetic studies showed trisomy 21 within the blastic cells. The placenta showed villous dysmaturity with associated chorangiosis and prominent intravascular aggregates of primitive-appearing cells with focal, early vascular wall invasion. The neonate recovered fully and shows no evidence of disease at 2 years of age.

  9. [The chiral mutagens: cytogenetic effects on higher plants].

    PubMed

    Morgun, V V; Larchenko, E A; Kostianovskiĭ, R G; Keterinchuk, A M

    2011-01-01

    The paper covers investigation of cytogenetic activity of chiral mutagens and their specific effects on the plant cells chromosomes of soft winter wheat (Triticum aestivum L.). Comparative analysis of cytogenetic activity of chiral NEU: S(+)1-N-nitroso- 1-N-methyl-3-N-sec-buthylureas (S(+)NMsBU) and R(-)1-N-nitroso- 1N-methyl-3-Nsec-buthylureas (R(-)NMsBU) on winter wheat was performed. As it was shown by the frequency of chromosomal aberrations the S(+) stereoisomer was twice more active than R(-). In addition to typical anaphase aberrations (fragments, bridges, lagging chromosomes) the numerous mitosis pathologies were revealed - K-mitoses, hyperspiralization and despiralization of chromosomes, unequal allocation of chromosomes between the daughter nuclei, mass fragmentation, nondisjunction and chromosome adhesion, three-pole mitoses, etc. Neither of the mentioned pathologies was observed under the action of NEU and gamma-rays.

  10. Evaluation of LOINC for Representing Constitutional Cytogenetic Test Result Reports

    PubMed Central

    Heras, Yan Z.; Mitchell, Joyce A.; Williams, Marc S.; Brothman, Arthur R.; Huff, Stanley M.

    2009-01-01

    Genetic testing is becoming increasingly important to medical practice. Integrating genetics and genomics data into electronic medical records is crucial in translating genetic discoveries into improved patient care. Information technology, especially Clinical Decision Support Systems, holds great potential to help clinical professionals take full advantage of genomic advances in their daily medical practice. However, issues relating to standard terminology and information models for exchanging genetic testing results remain relatively unexplored. This study evaluates whether the current LOINC standard is adequate to represent constitutional cytogenetic test result reports using sample result reports from ARUP Laboratories. The results demonstrate that current standard terminology is insufficient to support the needs of coding cytogenetic test results. The terminology infrastructure must be developed before clinical information systems will be able to handle the high volumes of genetic data expected in the near future. PMID:20351857

  11. Evaluation of LOINC for representing constitutional cytogenetic test result reports.

    PubMed

    Heras, Yan Z; Mitchell, Joyce A; Williams, Marc S; Brothman, Arthur R; Huff, Stanley M

    2009-11-14

    Genetic testing is becoming increasingly important to medical practice. Integrating genetics and genomics data into electronic medical records is crucial in translating genetic discoveries into improved patient care. Information technology, especially Clinical Decision Support Systems, holds great potential to help clinical professionals take full advantage of genomic advances in their daily medical practice. However, issues relating to standard terminology and information models for exchanging genetic testing results remain relatively unexplored. This study evaluates whether the current LOINC standard is adequate to represent constitutional cytogenetic test result reports using sample result reports from ARUP Laboratories. The results demonstrate that current standard terminology is insufficient to support the needs of coding cytogenetic test results. The terminology infrastructure must be developed before clinical information systems will be able to handle the high volumes of genetic data expected in the near future.

  12. Comparative cytogenetic and cytologic study in malignant lymphomas.

    PubMed

    Răileanu-Motoiu, I; Gociu, M; Leahu, S; Berceanu, S

    1976-01-01

    The possibility of a cytogenetic-cytologic correlation with implications in the diagnosis, evolutivity and prognosis of malignant lymphomas was studied. Cytogenetic investigations were carried out comparatively in the lymph node and spleen lymphoid cells from 25 patients with malignant lymphomas and in normal subjects or patients with malignant tumors. The dominant malignant cellular type was found to correspond genotypically to the abnormal clone. In lymphomas with more differentiated cells the chormosomal abnormalities were limited to a single chromosomal group, while in those with less differentiated cells there were many clonal chromozomal abnormalities. The pathogenic significance of an extra-chromosome in the C-group (observed in most of the cases) is discussed.

  13. [From conventional cytogenetics to microarrays. Fifty years of Philadelphia chromosome].

    PubMed

    Hernández, Jesús M; Granada, Isabel; Solé, Francesc

    2011-07-23

    In 1960 Ph-chromosome was found associated with the presence of chronic myelogenous leukemia. In these 50 years an increasing number of cytogenetic abnormalities have been found associated with hematological malignancies. The presence of these abnormalities is not only important for the diagnosis of the patient, but it also contributes to the prognosis of patients with leukemia or lymphoma. For this reason the WHO classification of hematological disease has included these studies for the correct characterization of leukemias and lymphomas. In addition, the use of FISH and micromatrix methodologies have refined the genetic lesions present in these malignancies. The cytogenetic changes observed also provide further information in relation to the therapy. Copyright © 2010 Elsevier España, S.L. All rights reserved.

  14. Comparative cytogenetics of Auchenorrhyncha (Hemiptera, Homoptera): a review

    PubMed Central

    Kuznetsova, Valentina; Aguin-Pombo, Dora

    2015-01-01

    Abstract A comprehensive review of cytogenetic features is provided for the large hemipteran suborder Auchenorrhyncha, which currently contains approximately 42,000 valid species. This review is based on the analysis of 819 species, 483 genera, and 31 families representing all presently recognized Auchenorrhyncha superfamilies, e.i. Cicadoidea (cicadas), Cercopoidea (spittle bugs), Membracoidea (leafhoppers and treehoppers), Myerslopioidea (ground-dwelling leafhoppers), and Fulgoroidea (planthoppers). History and present status of chromosome studies are described, as well as the structure of chromosomes, chromosome counts, trends and mechanisms of evolution of karyotypes and sex determining systems, their variation at different taxonomic levels and most characteristic (modal) states, occurrence of parthenogenesis, polyploidy, B-chromosomes and chromosome rearrangements, and methods used for cytogenetic analysis of Auchenorrhyncha. PMID:26807037

  15. Cytogenetic biodosimetry: what it is and how we do it.

    PubMed

    Wong, K F; Siu, Lisa L P; Ainsbury, E; Moquet, J

    2013-04-01

    Dicentric assay is the international gold standard for cytogenetic biodosimetry after radiation exposure, despite being very labour-intensive, time-consuming, and highly expertise-dependent. It involves the identification of centromeres and structure of solid-stained chromosomes and the enumeration of dicentric chromosomes in a large number of first-division metaphases of cultured T lymphocytes. The dicentric yield is used to estimate the radiation exposure dosage according to a statistically derived and predetermined dose-response curve. It can be used for population triage after large-scale accidental over-exposure to ionising radiation or with a view to making clinical decisions for individual patients receiving substantial radiation. In this report, we describe our experience in the establishment of a cytogenetic biodosimetry laboratory in Queen Elizabeth Hospital, Hong Kong. This was part of the contingency plan for emergency measures against radiation accidents at nuclear power stations.

  16. [Strategies to identify supernumerary chromosomal markers in constitutional cytogenetics].

    PubMed

    Douet-Guilbert, N; Basinko, A; Le Bris, M-J; Herry, A; Morel, F; De Braekeleer, M

    2008-09-01

    Supernumerary marker chromosomes (SMCs) are defined as extrastructurally abnormal chromosomes which origin and composition cannot be determined by conventional cytogenetics. SMCs are an heterogeneous group of abnormalities concerning all chromosomes with variable structure and size and are associated with phenotypic heterogeneity. The characterisation of SMCs is of utmost importance for genetic counselling. Different molecular techniques are used to identify chromosomal material present in markers such as 24-colour FISH (MFISH, SKY), centromere specific multicolour FISH (cenMFISH) and derivatives (acroMFISH, subcenMFISH), comparative genomic hybridisation (CGH), arrayCGH, and targeted FISH techniques (banding techniques, whole chromosome painting...). Based on the morphology of SMC with conventional cytogenetic and clinical data, we tried to set up different molecular strategies with all available techniques.

  17. LS-CAP: an algorithm for identifying cytogenetic aberrations in hepatocellular carcinoma using microarray data.

    PubMed

    He, Xianmin; Wei, Qing; Sun, Meiqian; Fu, Xuping; Fan, Sichang; Li, Yao

    2006-05-01

    Biological techniques such as Array-Comparative genomic hybridization (CGH), fluorescent in situ hybridization (FISH) and affymetrix single nucleotide pleomorphism (SNP) array have been used to detect cytogenetic aberrations. However, on genomic scale, these techniques are labor intensive and time consuming. Comparative genomic microarray analysis (CGMA) has been used to identify cytogenetic changes in hepatocellular carcinoma (HCC) using gene expression microarray data. However, CGMA algorithm can not give precise localization of aberrations, fails to identify small cytogenetic changes, and exhibits false negatives and positives. Locally un-weighted smoothing cytogenetic aberrations prediction (LS-CAP) based on local smoothing and binomial distribution can be expected to address these problems. LS-CAP algorithm was built and used on HCC microarray profiles. Eighteen cytogenetic abnormalities were identified, among them 5 were reported previously, and 12 were proven by CGH studies. LS-CAP effectively reduced the false negatives and positives, and precisely located small fragments with cytogenetic aberrations.

  18. [Cytogenetic characteristics of the uterine cervical epithelium in inflammatory diseases].

    PubMed

    Aleksieienko, O I

    2011-01-01

    Functional status of epithelial cells at inflammatory cervical pathologies has been studied with the use of cytogenetic method of detection of chromosome nucleolar organizer regions. The highest level of rRNA proliferation and synthesis has been detected in cylindrical epithelial cells using the indexes of compact and transitional nucleolonemic types of nucleolar organizer regions, a higher level--in squamous cells of intermediate type, and the lowest one in squamous epithelium of superficial type.

  19. The role of imperfect surrogate endpoint information in drug approval and reimbursement decisions.

    PubMed

    Bognar, Katalin; Romley, John A; Bae, Jay P; Murray, James; Chou, Jacquelyn W; Lakdawalla, Darius N

    2017-01-01

    Approval of new drugs is increasingly reliant on "surrogate endpoints," which correlate with but imperfectly predict clinical benefits. Proponents argue surrogate endpoints allow for faster approval, but critics charge they provide inadequate evidence. We develop an economic framework that addresses the value of improvement in the predictive power, or "quality," of surrogate endpoints, and clarifies how quality can influence decisions by regulators, payers, and manufacturers. For example, the framework shows how lower-quality surrogates lead to greater misalignment of incentives between payers and regulators, resulting in more drugs that are approved for use but not covered by payers. Efficient price-negotiation in the marketplace can help align payer incentives for granting access based on surrogates. Higher-quality surrogates increase manufacturer profits and social surplus from early access to new drugs. Since the return on better quality is shared between manufacturers and payers, private incentives to invest in higher-quality surrogates are inefficiently low. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

  20. Meeting Report: Measuring Endocrine-Sensitive Endpoints within the First Years of Life

    PubMed Central

    Arbuckle, Tye E.; Hauser, Russ; Swan, Shanna H.; Mao, Catherine S.; Longnecker, Matthew P.; Main, Katharina M.; Whyatt, Robin M.; Mendola, Pauline; Legrand, Melissa; Rovet, Joanne; Till, Christine; Wade, Mike; Jarrell, John; Matthews, Stephen; Van Vliet, Guy; Bornehag, Carl-Gustaf; Mieusset, Roger

    2008-01-01

    An international workshop titled “Assessing Endocrine-Related Endpoints within the First Years of Life” was held 30 April–1 May 2007, in Ottawa, Ontario, Canada. Representatives from a number of pregnancy cohort studies in North America and Europe presented options for measuring various endocrine-sensitive endpoints in early life and discussed issues related to performing and using those measures. The workshop focused on measuring reproductive tract developmental endpoints [e.g., anogenital distance (AGD)], endocrine status, and infant anthropometry. To the extent possible, workshop participants strove to develop or recommend standardized measurements that would allow comparisons and pooling of data across studies. The recommended outcomes include thigh fat fold, breast size, vaginal cytology, AGD, location of the testis, testicular size, and growth of the penis, with most of the discussion focusing on the genital exam. Although a number of outcome measures recommended during the genital exam have been associated with exposure to endocrine-disrupting chemicals, little is known about how predictive these effects are of later reproductive health or other chronic health conditions. PMID:18629319

  1. Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial

    PubMed Central

    Chen, Yu-Pei; Chen, Yong; Zhang, Wen-Na; Liang, Shao-Bo; Zong, Jing-Feng; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Guo, Ying; Lin, Ai-Hua; Liu, Meng-Zhong; Sun, Ying; Ma, Jun

    2015-01-01

    The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice’s four criteria. The Spearman’s rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice’s second criterion. Being consistent with all Prentice’s criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival. PMID:26219568

  2. Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial.

    PubMed

    Chen, Yu-Pei; Chen, Yong; Zhang, Wen-Na; Liang, Shao-Bo; Zong, Jing-Feng; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Guo, Ying; Lin, Ai-Hua; Liu, Meng-Zhong; Sun, Ying; Ma, Jun

    2015-07-29

    The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice's four criteria. The Spearman's rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice's second criterion. Being consistent with all Prentice's criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival.

  3. Patients' preferences for selection of endpoints in cardiovascular clinical trials.

    PubMed

    Chow, Robert D; Wankhedkar, Kashmira P; Mete, Mihriye

    2014-01-01

    To reduce the duration and overall costs of cardiovascular trials, use of the combined endpoints in trial design has become commonplace. Though this methodology may serve the needs of investigators and trial sponsors, the preferences of patients or potential trial subjects in the trial design process has not been studied. To determine the preferences of patients in the design of cardiovascular trials. Participants were surveyed in a pilot study regarding preferences among various single endpoints commonly used in cardiovascular trials, preference for single vs. composite endpoints, and the likelihood of compliance with a heart medication if patients similar to them participated in the trial design process. One hundred adult English-speaking patients, 38% male, from a primary care ambulatory practice located in an urban setting. Among single endpoints, participants rated heart attack as significantly more important than death from other causes (4.53 vs. 3.69, p=0.004) on a scale of 1-6. Death from heart disease was rated as significantly more important than chest pain (4.73 vs. 2.47, p<0.001), angioplasty/PCI/CABG (4.73 vs. 2.43, p<0.001), and stroke (4.73 vs. 2.43, p<0.001). Participants also expressed a slight preference for combined endpoints over single endpoint (43% vs. 57%), incorporation of the opinions of the study patient population into the design of trials (48% vs. 41% for researchers), and a greater likelihood of medication compliance if patient preferences were considered during trial design (67% indicated a significant to major effect). Patients are able to make judgments and express preferences regarding trial design. They prefer that the opinions of the study population rather than the general population be incorporated into the design of the study. This novel approach to study design would not only incorporate patient preferences into medical decision making, but it also has the potential to improve compliance with cardiovascular medications.

  4. Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition

    PubMed Central

    Gilbert, Peter B.; Gabriel, Erin E.; Huang, Ying; Chan, Ivan S.F.

    2015-01-01

    A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the “principal effects” or “causal effect predictiveness (CEP)” surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the “surrogate paradox”). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of

  5. Surrogate Endpoint Evaluation: Principal Stratification Criteria and the Prentice Definition.

    PubMed

    Gilbert, Peter B; Gabriel, Erin E; Huang, Ying; Chan, Ivan S F

    2015-09-01

    A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. Within the principal stratification framework for addressing this problem based on data from a single randomized clinical efficacy trial, a variety of definitions and criteria for a good surrogate endpoint have been proposed, all based on or closely related to the "principal effects" or "causal effect predictiveness (CEP)" surface. We discuss CEP-based criteria for a useful surrogate endpoint, including (1) the meaning and relative importance of proposed criteria including average causal necessity (ACN), average causal sufficiency (ACS), and large clinical effect modification; (2) the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and (3) the relationship between these criteria and the consistency criterion (i.e., assurance against the "surrogate paradox"). This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata sub-populations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect

  6. Influence of heavy ions on cell survival, cytogenetic damage and mitochondrial function of human endothelial cells

    NASA Astrophysics Data System (ADS)

    Ritter, Sylvia; Helm, Alexander; Lee, Ryonfa; Pollet, Dieter; Durante, Marco

    There is increasing evidence that there is an elevated risk of cardiovascular disease among atomic bomb survivors and radiotherapy patients, typically developing with a long latency. However, essentially no information is available on the potential cardiovascular risks associated with space radiation, in particular heavy ions. To address this issue, we have chosen human umbilical vein endothelial cells (HUVEC) as a model system. Cells at an early passage number were irradiated with 0.1 to 4 Gy of either 9.8 MeV/u C-ions (LET=170 keV/µm), 91 MeV/u C-ions (LET=29 keV/µm) or 250 kV X-rays. Cells were regularly subcultured up to 40 days (20 population doublings) post-irradiation. Immediately after exposure cell inactivation was deter-mined by the colony forming assay. Furthermore, at selected time-points cytogenetic damage (formation of micronuclei in binucleated cells) and the mitochondrial membrane potential ΨM (flow cytometric analysis following JC-1 staining) were assessed. Measurement of the directly induced radiation damage showed that 9.8 MeV/u and 91 MeV/u C-ions were more effective than X-rays (i.e. about 3 and 2 times, respectively) with respect to cell inactivation or the in-duction of cytogenetic damage. At the subsequent days in the irradiated cultures the number of cells with micronuclei declined to the control level (3-5Altogether our data indicate that under the applied radiation conditions the integrity of mitochondria which play a significant role in the regulation of cardiovascular cell function is not impaired. With respect to directly induced genetic damage C-ions are more effective than X-rays as observed in other cell systems. If the effectiveness of charged particles for the occurrence of late chromosomal damage in endothelial cells is higher than that of sparsely ionizing radiation needs further clarification. The data obtained up to now indicate that sophisticated cytogenetic techniques have to be applied in order to draw any firm

  7. Clinical endpoints for developing pharmaceuticals to manage patients with sporadic or genetic risk of colorectal cancer

    PubMed Central

    Rial, Nathaniel S.; Zell, Jason A.; Cohen, Alfred M.; Gerner, Eugene W.

    2013-01-01

    To reduce the morbidity and mortality from colorectal cancer, current clinical practice focuses on screening for early detection and polypectomy as a form of secondary prevention, complemented with surgical interventions when appropriate. No pharmaceutical agent is currently approved for use in clinical practice for the management of patients with risk of colorectal cancer. This article will review earlier attempts to develop pharmaceuticals for use in managing patients with sporadic or genetic risk of colorectal cancer. It will also discuss therapeutic endpoints under evaluation in current efforts to develop drugs for treating colorectal cancer risk factors. PMID:22928902

  8. Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists.

    PubMed

    Methy, Nicolas; Bedenne, Laurent; Bonnetain, Franck

    2010-06-10

    Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion.Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS.DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first, with a frequency of more than 69

  9. Surrogate endpoints for overall survival in digestive oncology trials: which candidates? A questionnaires survey among clinicians and methodologists

    PubMed Central

    2010-01-01

    Background Overall survival (OS) is the gold standard for the demonstration of a clinical benefit in cancer trials. Replacement of OS by a surrogate endpoint allows to reduce trial duration. To date, few surrogate endpoints have been validated in digestive oncology. The aim of this study was to draw up an ordered list of potential surrogate endpoints for OS in digestive cancer trials, by way of a survey among clinicians and methodologists. Secondary objective was to obtain their opinion on surrogacy and quality of life (QoL). Methods In 2007 and 2008, self administered sequential questionnaires were sent to a panel of French clinicians and methodologists involved in the conduct of cancer clinical trials. In the first questionnaire, panellists were asked to choose the most important characteristics defining a surrogate among six proposals, to give advantages and drawbacks of the surrogates, and to answer questions about their validation and use. Then they had to suggest potential surrogate endpoints for OS in each of the following tumour sites: oesophagus, stomach, liver, pancreas, biliary tract, lymphoma, colon, rectum, and anus. They finally gave their opinion on QoL as surrogate endpoint. In the second questionnaire, they had to classify the previously proposed candidate surrogates from the most (position #1) to the least relevant in their opinion. Frequency at which the endpoints were chosen as first, second or third most relevant surrogates was calculated and served as final ranking. Results Response rate was 30% (24/80) in the first round and 20% (16/80) in the second one. Participants highlighted key points concerning surrogacy. In particular, they reminded that a surrogate endpoint is expected to predict clinical benefit in a well-defined therapeutic situation. Half of them thought it was not relevant to study QoL as surrogate for OS. DFS, in the neoadjuvant settings or early stages, and PFS, in the non operable or metastatic settings, were ranked first

  10. [Clinical manifestation and cytogenetic analysis of 607 patients with Turner syndrome].

    PubMed

    Zheng, Jiemei; Liu, Zhiying; Xia, Pei; Lai, Yi; Wei, Yangjun; Liu, Yanyan; Chen, Jiurong; Qin, Li; Xie, Liangyu; Wang, He

    2017-02-10

    To explore the correlation between cytogenetic findings and clinical manifestations of Turner syndrome. 607 cases of cytogenetically diagnosed Turner syndrome, including those with a major manifestation of Turner syndrome, were analyzed with conventional G-banding. Correlation between the karyotypes and clinical features were analyzed. Among the 607 cases, there were 154 cases with monosomy X (25.37%). Mosaicism monosomy X was found in 240 patients (39.54%), which included 194 (80.83%) with a low proportion of 45,X (3 ≤ the number of 45, X ≤5, while the normal cells ≥ 30). Structural X chromosome abnormalities were found in 173 patients (28.50%). A supernumerary marker chromosome was found in 40 cases (6.59%). Most patients with typical manifestations of Turner syndrome were under 11 years of age and whose karyotypes were mainly 45,X. The karyotype of patients between 11 and 18 years old was mainly 45,X, 46,X,i(X)(q10) and mos45,X/46,X,i(X)(q10), which all had primary amenorrhea in addition to the typical clinical manifestations. The karyotype of patients over 18 years of age were mainly mosaicism with a low proportion of 45,X, whom all had primary infertility. 53 patients had a history of pregnancy, which included 48 with non-structural abnormalities of X chromosome and 5 with abnormal structure of X chromosome. Generally, the higher proportion of cells with an abnormal karyotype, the more severe were the clinical symptoms and the earlier clinical recognition. Karyotyping analysis can provide guidance for the early diagnosis of Turner syndrome, especially those with a low proportion of 45,X.

  11. Comparison and Evaluation of Laboratory and Field Measured Bioaccumulation Endpoints

    EPA Science Inventory

    Evaluation of bioaccumulation endpoints on a fugacity basis allows provides a framework to assess the biomagnification potential of a chemical and assess data deficiencies, i.e., uncertainties and lack of data. In addition, it is suggested that additional guidance is needed in o...

  12. Is Suicide Ideation a Surrogate Endpoint for Geriatric Suicide?

    ERIC Educational Resources Information Center

    Links, Paul S.; Heisel, Marnin J.; Quastel, Adam

    2005-01-01

    The present study explored the validity of treating suicide ideation as a surrogate endpoint that can serve as a proxy for suicide in clinical intervention research with suicidal seniors. Two criteria; that suicide ideation is modulated by the proposed intervention and that modulation of suicide ideation leads to a quantitative reduction in…

  13. ECOLOGICAL ENDPOINT MODELING: EFFECTS OF SEDIMENT ON FISH POPULATIONS

    EPA Science Inventory

    Sediment is one of the main stressors of concern for TMDLs (Total Maximum Daily Loads) for streams, and often it is a concern because of its impact on biological endpoints. The National Research Council (NRC) has recommended that the EPA promote the development of models that ca...

  14. Developing a Cognition Endpoint for Traumatic Brain Injury Clinical Trials

    PubMed Central

    Crane, Paul K.; Dams-O'Connor, Kristen; Holdnack, James; Ivins, Brian J.; Lange, Rael T.; Manley, Geoffrey T.; McCrea, Michael; Iverson, Grant L.

    2017-01-01

    Abstract Cognitive impairment is a core clinical feature of traumatic brain injury (TBI). After TBI, cognition is a key determinant of post-injury productivity, outcome, and quality of life. As a final common pathway of diverse molecular and microstructural TBI mechanisms, cognition is an ideal endpoint in clinical trials involving many candidate drugs and nonpharmacological interventions. Cognition can be reliably measured with performance-based neuropsychological tests that have greater granularity than crude rating scales, such as the Glasgow Outcome Scale-Extended, which remain the standard for clinical trials. Remarkably, however, there is no well-defined, widely accepted, and validated cognition endpoint for TBI clinical trials. A single cognition endpoint that has excellent measurement precision across a wide functional range and is sensitive to the detection of small improvements (and declines) in cognitive functioning would enhance the power and precision of TBI clinical trials and accelerate drug development research. We outline methodologies for deriving a cognition composite score and a research program for validation. Finally, we discuss regulatory issues and the limitations of a cognition endpoint. PMID:27188248

  15. [The endpoint detection of cough signal in continuous speech].

    PubMed

    Yang, Guoqing; Mo, Hongqiang; Li, Wen; Lian, Lianfang; Zheng, Zeguang

    2010-06-01

    The endpoint detection of cough signal in continuous speech has been researched in order to improve the efficiency and veracity of manual recognition or computer-based automatic recognition. First, using the short time zero crossing ratio(ZCR) for identifying the suspicious coughs and getting the threshold of short time energy based on acoustic characteristics of cough. Then, the short time energy is combined with short time ZCR in order to implement the endpoint detection of cough in continuous speech. To evaluate the effect of the method, first, the virtual number of coughs in each recording was identified by two experienced doctors using the graphical user interface (GUI). Second, the recordings were analyzed by automatic endpoint detection program under Matlab7.0. Finally, the comparison between these two results showed: The error rate of undetected cough is 2.18%, and 98.13% of noise, silence and speech were removed. The way of setting short time energy threshold is robust. The endpoint detection program can remove most speech and noise, thus maintaining a lower rate of error.

  16. Predictive Modeling of Apical Toxicity Endpoints Using Data ...

    EPA Pesticide Factsheets

    The US EPA and other regulatory agencies face a daunting challenge of evaluating potential toxicity for tens of thousands of environmental chemicals about which little is currently known. The EPA’s ToxCast program is testing a novel approach to this problem by screening compounds using a variety of in vitro assays and using the results to prioritize chemicals for further, more detailed testing. Phase I of ToxCast is testing 320 chemicals (mainly pesticide active ingredients) against ~400 cell-based and biochemical assays. In order to anchor these studies, we are using in vivo guideline study data for subchronic, chronic, cancer, reproductive and developmental endpoints. This data is compiled in the EPA toxicity reference database, ToxRefDB. The main goal of ToxCast is the discovery and validation of “signatures” linking in vitro assay data to in vivo toxicity endpoints. These signatures will be collections of assays that are correlated with particular endpoints. These assay collections should also help define molecular-and cellular-level mechanisms of toxicity. This talk will discuss our strategy to use a combination of statistical and machine learning methods, coupled with biochemical network or systems biology approaches. Our initial examples will focus signatures for endpoints from 2 year rodent cancer bioassays. Most of the data we have analyzed is in dose or concentration response series, so to effectively use this data we have developed novel appro

  17. Modeling hard clinical end-point data in economic analyses.

    PubMed

    Kansal, Anuraag R; Zheng, Ying; Palencia, Roberto; Ruffolo, Antonio; Hass, Bastian; Sorensen, Sonja V

    2013-11-01

    The availability of hard clinical end-point data, such as that on cardiovascular (CV) events among patients with type 2 diabetes mellitus, is increasing, and as a result there is growing interest in using hard end-point data of this type in economic analyses. This study investigated published approaches for modeling hard end-points from clinical trials and evaluated their applicability in health economic models with different disease features. A review of cost-effectiveness models of interventions in clinically significant therapeutic areas (CV diseases, cancer, and chronic lower respiratory diseases) was conducted in PubMed and Embase using a defined search strategy. Only studies integrating hard end-point data from randomized clinical trials were considered. For each study included, clinical input characteristics and modeling approach were summarized and evaluated. A total of 33 articles (23 CV, eight cancer, two respiratory) were accepted for detailed analysis. Decision trees, Markov models, discrete event simulations, and hybrids were used. Event rates were incorporated either as constant rates, time-dependent risks, or risk equations based on patient characteristics. Risks dependent on time and/or patient characteristics were used where major event rates were >1%/year in models with fewer health states (<7). Models of infrequent events or with numerous health states generally preferred constant event rates. The detailed modeling information and terminology varied, sometimes requiring interpretation. Key considerations for cost-effectiveness models incorporating hard end-point data include the frequency and characteristics of the relevant clinical events and how the trial data is reported. When event risk is low, simplification of both the model structure and event rate modeling is recommended. When event risk is common, such as in high risk populations, more detailed modeling approaches, including individual simulations or explicitly time-dependent event rates

  18. Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

    PubMed Central

    Plewes, Katherine; Maude, Richard J.; Hanson, Josh; Herdman, M. Trent; Leopold, Stije J.; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M. Mahtab Uddin; Fanello, Caterina I.; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P. J.; White, Nicholas J.; Dondorp, Arjen M.

    2017-01-01

    Background Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Methods Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African ‘AQUAMAT’ trial comparing artesunate and quinine (children), and the Vietnamese ‘AQ’ study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Results Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the ‘AQUAMAT’ study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. Conclusions The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid

  19. Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.

    PubMed

    Jeeyapant, Atthanee; Kingston, Hugh W; Plewes, Katherine; Maude, Richard J; Hanson, Josh; Herdman, M Trent; Leopold, Stije J; Ngernseng, Thatsanun; Charunwatthana, Prakaykaew; Phu, Nguyen Hoan; Ghose, Aniruddha; Hasan, M Mahtab Uddin; Fanello, Caterina I; Faiz, Md Abul; Hien, Tran Tinh; Day, Nicholas P J; White, Nicholas J; Dondorp, Arjen M

    2017-01-01

    Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.

  20. Biomechanical constraints on the feedforward regulation of endpoint stiffness.

    PubMed

    Hu, Xiao; Murray, Wendy M; Perreault, Eric J

    2012-10-01

    Although many daily tasks tend to destabilize arm posture, it is still possible to have stable interactions with the environment by regulating the multijoint mechanics of the arm in a task-appropriate manner. For postural tasks, this regulation involves the appropriate control of endpoint stiffness, which represents the stiffness of the arm at the hand. Although experimental studies have been used to evaluate endpoint stiffness control, including the orientation of maximal stiffness, the underlying neural strategies remain unknown. Specifically, the relative importance of feedforward and feedback mechanisms has yet to be determined due to the difficulty separately identifying the contributions of these mechanisms in human experiments. This study used a previously validated three-dimensional musculoskeletal model of the arm to quantify the degree to which the orientation of maximal endpoint stiffness could be changed using only steady-state muscle activations, used to represent feedforward motor commands. Our hypothesis was that the feedforward control of endpoint stiffness orientation would be significantly constrained by the biomechanical properties of the musculoskeletal system. Our results supported this hypothesis, demonstrating substantial biomechanical constraints on the ability to regulate endpoint stiffness throughout the workspace. The ability to regulate stiffness orientation was further constrained by additional task requirements, such as the need to support the arm against gravity or exert forces on the environment. Together, these results bound the degree to which slowly varying feedforward motor commands can be used to regulate the orientation of maximum arm stiffness and provide a context for better understanding conditions in which feedback control may be needed.

  1. Utilization of cytogenetic biomarkers as a tool for assessment of radiation injury and evaluation of radiomodulatory effects of various medicinal plants - a review.

    PubMed

    Samarth, Ravindra M; Samarth, Meenakshi; Matsumoto, Yoshihisa

    2015-01-01

    Systematic biological measurement of "cytogenetic endpoints" has helped phenomenally in assessment of risks associated with radiation exposure. There has been a surge in recent times for the usage of radioactive materials in health care, agriculture, industrial, and nuclear power sectors. The likelihood of radiation exposure from accidental or occupational means is always higher in an overburdened ecosystem that is continuously challenged to meet the population demands. Risks associated with radiation exposure in this era of modern industrial growth are minimal as international regulations for maintaining the safety standards are stringent and strictly adhered to, however, a recent disaster like "Fukushima" impels us to think beyond. The major objective of radiobiology is the development of an orally effective radio-modifier that provides protection from radiation exposure. Once available for mass usage, these compounds will not only be useful for providing selective protection against accidental and occupational radiation exposure but also help to permit use of higher doses of radiation during treatment of various malignancies curtailing unwarranted adverse effects imposed on normal tissues. Bio-active compounds isolated from natural sources enriched with antioxidants possess unique immune-modulating properties, thus providing a double edged benefit over synthetic radioprotectors. We aim to provide here a comprehensive overview of the various agents originating from plant sources that portrayed promising radioprotection in various experimental models with special emphasis on studies that used cytogenetic biomarkers. The agents will include crude extracts of various medicinal plants, purified fractions, and herbal preparations.

  2. 21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

  3. 21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

  4. 21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

  5. 21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Approval based on a surrogate endpoint or on an... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on... the drug product has an effect on a surrogate endpoint that is reasonably likely, based on...

  6. 21 CFR 314.510 - Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. 314.510 Section 314.510 Food... Serious or Life-Threatening Illnesses § 314.510 Approval based on a surrogate endpoint or on an effect on...

  7. Sensitivity of submersed freshwater macrophytes and endpoints in laboratory toxicity tests.

    PubMed

    Arts, Gertie H P; Belgers, J Dick M; Hoekzema, Conny H; Thissen, Jac T N M

    2008-05-01

    The toxicological sensitivity and variability of a range of macrophyte endpoints were statistically tested with data from chronic, non-axenic, macrophyte toxicity tests. Five submersed freshwater macrophytes, four pesticides/biocides and 13 endpoints were included in the statistical analyses. Root endpoints, reflecting root growth, were most sensitive in the toxicity tests, while endpoints relating to biomass, growth and shoot length were less sensitive. The endpoints with the lowest coefficients of variation were not necessarily the endpoints, which were toxicologically most sensitive. Differences in sensitivity were in the range of 10-1000 for different macrophyte-specific endpoints. No macrophyte species was consistently the most sensitive. Criteria to select endpoints in macrophyte toxicity tests should include toxicological sensitivity, variance and ecological relevance. Hence, macrophyte toxicity tests should comprise an array of endpoints, including very sensitive endpoints like those relating to root growth.

  8. Methylphenidate and Amphetamine Do Not Induce Cytogenetic Damage in Lymphocytes of Children with ADHD

    ERIC Educational Resources Information Center

    Witt, Kristine L.; Shelby, Michael D.; Itchon-Ramos, Nilda; Faircloth, Melissa; Kissling, Grace E.; Chrisman, Allan K.; Ravi, Hima; Murli, Hemalatha; Mattison, Donald R.; Kollins, Scott H.

    2008-01-01

    The inducement of chromosomal damage in lymphocytes among children with attention deficit hyperactivity disorder receiving treatment with methylphenidate- or amphetamine-based drugs is investigated. Findings did not reveal significant increases in cytogenetic damage related to the treatment. The risk for cytogenetic damage posed by such products…

  9. Cytogenetic Profile of Down Syndrome Cases Seen by a General Genetics Outpatient Service in Brazil

    ERIC Educational Resources Information Center

    Biselli, Joice; Goloni-Bertollo, Eny; Ruiz, Mariangela; Pavarino-Bertelli, Erika

    2009-01-01

    Down syndrome or trisomy 21 can be caused by three types of chromosomal abnormalities: free trisomy 21, translocation or mosaicism. The cytogenetic diagnosis, made through karyotypic examination, is important mainly to determine recurrence risks to assist genetic counselling. The object of this work was to carry out a cytogenetic profile of…

  10. A new approach for modeling patient overall radiosensitivity and predicting multiple toxicity endpoints for breast cancer patients.

    PubMed

    Mbah, Chamberlain; De Ruyck, Kim; De Schrijver, Silke; De Sutter, Charlotte; Schiettecatte, Kimberly; Monten, Chris; Paelinck, Leen; De Neve, Wilfried; Thierens, Hubert; West, Catharine; Amorim, Gustavo; Thas, Olivier; Veldeman, Liv

    2018-05-01

    Evaluation of patient characteristics inducing toxicity in breast radiotherapy, using simultaneous modeling of multiple endpoints. In 269 early-stage breast cancer patients treated with whole-breast irradiation (WBI) after breast-conserving surgery, toxicity was scored, based on five dichotomized endpoints. Five logistic regression models were fitted, one for each endpoint and the effect sizes of all variables were estimated using maximum likelihood (MLE). The MLEs are improved with James-Stein estimates (JSEs). The method combines all the MLEs, obtained for the same variable but from different endpoints. Misclassification errors were computed using MLE- and JSE-based prediction models. For associations, p-values from the sum of squares of MLEs were compared with p-values from the Standardized Total Average Toxicity (STAT) Score. With JSEs, 19 highest ranked variables were predictive of the five different endpoints. Important variables increasing radiation-induced toxicity were chemotherapy, age, SATB2 rs2881208 SNP and nodal irradiation. Treatment position (prone position) was most protective and ranked eighth. Overall, the misclassification errors were 45% and 34% for the MLE- and JSE-based models, respectively. p-Values from the sum of squares of MLEs and p-values from STAT score led to very similar conclusions, except for the variables nodal irradiation and treatment position, for which STAT p-values suggested an association with radiosensitivity, whereas p-values from the sum of squares indicated no association. Breast volume was ranked as the most significant variable in both strategies. The James-Stein estimator was used for selecting variables that are predictive for multiple toxicity endpoints. With this estimator, 19 variables were predictive for all toxicities of which four were significantly associated with overall radiosensitivity. JSEs led to almost 25% reduction in the misclassification error rate compared to conventional MLEs. Finally, patient

  11. Molecular cytogenetic of the Amoy croaker, Argyrosomus amoyensis (Teleostei, Sciaenidae)

    NASA Astrophysics Data System (ADS)

    Liao, Mengxiang; Zheng, Jiao; Wang, Zhiyong; Wang, Yilei; Zhang, Jing; Cai, Mingyi

    2017-08-01

    The family Sciaenidae is remarkable for its species richness and economic importance. However, the cytogenetic data available in this fish group are still limited, especially those obtained using fluorescence in situ hybridization (FISH). In the present study, the chromosome characteristics of a sciaenid species, Argyrosomus amoyensis, were examined with several cytogenetic methods, including dual-FISH with 18S and 5S rDNA probes, and a self-genomic in situ hybridization procedure (Self-GISH). The karyotype of A. amoyensis comprised 2n=48 acrocentric chromosomes. A single pair of nucleolar organizer regions (NORs) was located at the proximal position of chromosome 1, which was positive for silver nitrate impregnation (AgNO3) staining and denaturation-propidium iodide (DPI) staining but negative for Giemsa staining and 4',6-diamidino-2-phenylindole (DAPI) staining, and was confirmed by FISH with 18S rDNA probes. The 5S rDNA sites were located at the centromeric region of chromosome 3. Telomeric FISH signals were detected at all chromosome ends with different intensities, but internal telomeric sequences (ITSs) were not found. Self-GISH resulted in strong signals distributed at the centromeric regions of all chromosomes. C-banding revealed not only centromeric heterochromatin, but also heterochromatin that located on NORs, in interstitial and distal telomeric regions of specific chromosomes. These results suggest that the karyotype of Amoy croaker was relatively conserved and primitive. By comparison with the reported cytogenetic data of other sciaenids, it can be deduced that although the karyotypic macrostructure and chromosomal localization of 18S rDNA are conserved, the distribution of 5S rDNA varies dynamically among sciaenid species. Thus, the 5S rDNA sites may have different evolutionary dynamics in relation to other chromosomal regions, and have the potential to be effective cytotaxonomic markers in Sciaenidae.

  12. Cytogenetic analyses of four solid tumours in dogs.

    PubMed

    Mayr, B; Reifinger, M; Weissenböck, H; Schleger, W; Eisenmenger, E

    1994-07-01

    Four solid tumours (one haemangiopericytoma, one haemangioendothelioma, one spindle-cell sarcoma and one mammary carcinoma) in dogs were analysed cytogenetically. In the haemangiopericytoma, an additional small chromosomal segment was present. Very complex changes including centric fusions and symmetric meta-centrics 1, 6, 10 and 12 were conspicuous in the highly unbalanced karyotype of the haemangioendothelioma. Complex changes, particularly many centric fusions and a tandem translocation 4/14, were features of the spindle-cell sarcoma. One centric fusion and a symmetric metacentric 13 were present in the mammary carcinoma.

  13. Chronic radiation exposure modifies temporal dynamics of cytogenetic but not reproductive indicators in Scots pine populations.

    PubMed

    Geras'kin, Stanislav; Oudalova, Alla; Kuzmenkov, Alexey; Vasiliyev, Denis

    2018-04-18

    Over a period of 13 years (2003-2015), reproductive and cytogenetic effects are investigated in Scots pine populations growing in the Bryansk region of Russia radioactively contaminated as a result of the Chernobyl accident. In reference populations, the frequencies of cytogenetic abnormalities are shown to change with time in a cyclic manner. In chronically exposed populations, the cyclic patterns in temporal dynamics of cytogenetic abnormalities appear to be disturbed. In addition, a tendency to decrease in the frequencies of cytogenetic abnormalities with time as well as an increase in their variability with dose rate is revealed. In contrast, no significant impact of chronic radiation exposure on the time dynamics of reproductive indexes is detected. Finally, long-term observations on chronically exposed Scots pine populations revealed qualitative differences in the temporal dynamics of reproductive and cytogenetic indicators. Copyright © 2018 Elsevier Ltd. All rights reserved.

  14. Value of amniocentesis versus fetal tissue for cytogenetic analysis in cases of fetal demise.

    PubMed

    Bryant Borders, Ann E; Greenberg, Jessica; Plaga, Stacey; Shepard-Hinton, Megan; Yates, Carin; Elias, Sherman; Shulman, Lee P

    2009-01-01

    Use of fetal tissue for cytogenetic analysis in cases of second- and third-trimester fetal demise frequently results in unacceptably high failure rates. We reviewed our ongoing use of amniocentesis prior to uterine evacuation to determine if this provided a better source of cells for cytogenetic analysis. We compared cytogenetic results using fetal tissues obtained following uterine evacuation to our ongoing use of amniotic fluid cell obtained by transabdominal amniocentesis prior to uterine evacuation from 2003 to 2008. In 49 of the 63 cases evaluated by fetal tissue biopsies performed after uterine evacuation, a karyotypic analysis was obtained (77.8%). Among the 38 cases evaluated by amniocentesis, an amniotic fluid sample and fetal cytogenetic results were obtained in all 38 (100%) cases. Our findings indicate that amniocentesis is a more reliable source of cytogenetic information than fetal tissue in cases of second- and third-trimester fetal demise.

  15. Changing the endpoints for determining effective obesity management.

    PubMed

    Ross, Robert; Blair, Steve; de Lannoy, Louise; Després, Jean-Pierre; Lavie, Carl J

    2015-01-01

    Health authorities worldwide recommend weight loss as a primary endpoint for effective obesity management. Despite a growing public awareness of the importance of weight loss and the spending of billions of dollars by Americans in attempts to lose weight, obesity prevalence continues to rise. In this report we argue that effective obesity management in today's environment will require a shift in focus from weight loss as the primary endpoint, to improvements in the causal behaviors; diet and exercise/physical activity (PA). We reason that increases in PA combined with a balanced diet are associated with improvement in many of the intermediate risk factors including cardiorespiratory fitness (CRF) associated with obesity despite minimal or no weight loss. Consistent with this notion, we suggest that a focus on healthy behaviors for the prevention of additional weight gain may be an effective way of managing obesity in the short term. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. The endpoint detection technique for deep submicrometer plasma etching

    NASA Astrophysics Data System (ADS)

    Wang, Wei; Du, Zhi-yun; Zeng, Yong; Lan, Zhong-went

    2009-07-01

    The availability of reliable optical sensor technology provides opportunities to better characterize and control plasma etching processes in real time, they could play a important role in endpoint detection, fault diagnostics and processes feedback control and so on. The optical emission spectroscopy (OES) method becomes deficient in the case of deep submicrometer gate etching. In the newly developed high density inductively coupled plasma (HD-ICP) etching system, Interferometry endpoint (IEP) is introduced to get the EPD. The IEP fringe count algorithm is investigated to predict the end point, and then its signal is used to control etching rate and to call end point with OES signal in over etching (OE) processes step. The experiment results show that IEP together with OES provide extra process control margin for advanced device with thinner gate oxide.

  17. Sperm count as a surrogate endpoint for male fertility control.

    PubMed

    Benda, Norbert; Gerlinger, Christoph

    2007-11-30

    When assessing the effectiveness of a hormonal method of fertility control in men, the classical approach used for the assessment of hormonal contraceptives in women, by estimating the pregnancy rate or using a life-table analysis for the time to pregnancy, is difficult to apply in a clinical development program. The main reasons are the dissociation of the treated unit, i.e. the man, and the observed unit, i.e. his female partner, the high variability in the frequency of male intercourse, the logistical cost and ethical concerns related to the monitoring of the trial. A reasonable surrogate endpoint of the definite endpoint time to pregnancy is sperm count. In addition to the avoidance of the mentioned problems, trials that compare different treatments are possible with reasonable sample sizes, and study duration can be shorter. However, current products do not suppress sperm production to 100 per cent in all men and the sperm count is only observed with measurement error. Complete azoospermia might not be necessary in order to achieve an acceptable failure rate compared with other forms of male fertility control. Therefore, the use of sperm count as a surrogate endpoint must rely on the results of a previous trial in which both the definitive- and surrogate-endpoint results were assessed. The paper discusses different estimation functions of the mean pregnancy rate (corresponding to the cumulative hazard) that are based on the results of sperm count trial and a previous trial in which both sperm count and time to pregnancy were assessed, as well as the underlying assumptions. Sample size estimations are given for pregnancy rate estimation with a given precision.

  18. Misspecification of Cox regression models with composite endpoints

    PubMed Central

    Wu, Longyang; Cook, Richard J

    2012-01-01

    Researchers routinely adopt composite endpoints in multicenter randomized trials designed to evaluate the effect of experimental interventions in cardiovascular disease, diabetes, and cancer. Despite their widespread use, relatively little attention has been paid to the statistical properties of estimators of treatment effect based on composite endpoints. We consider this here in the context of multivariate models for time to event data in which copula functions link marginal distributions with a proportional hazards structure. We then examine the asymptotic and empirical properties of the estimator of treatment effect arising from a Cox regression model for the time to the first event. We point out that even when the treatment effect is the same for the component events, the limiting value of the estimator based on the composite endpoint is usually inconsistent for this common value. We find that in this context the limiting value is determined by the degree of association between the events, the stochastic ordering of events, and the censoring distribution. Within the framework adopted, marginal methods for the analysis of multivariate failure time data yield consistent estimators of treatment effect and are therefore preferred. We illustrate the methods by application to a recent asthma study. Copyright © 2012 John Wiley & Sons, Ltd. PMID:22736519

  19. Exposing the cancer genome atlas as a SPARQL endpoint

    PubMed Central

    Deus, Helena F.; Veiga, Diogo F.; Freire, Pablo R.; Weinstein, John N.; Mills, Gordon B.; Almeida, Jonas S.

    2011-01-01

    The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to characterize several types of cancer. Datasets from biomedical domains such as TCGA present a particularly challenging task for those interested in dynamically aggregating its results because the data sources are typically both heterogeneous and distributed. The Linked Data best practices offer a solution to integrate and discover data with those characteristics, namely through exposure of data as Web services supporting SPARQL, the Resource Description Framework query language. Most SPARQL endpoints, however, cannot easily be queried by data experts. Furthermore, exposing experimental data as SPARQL endpoints remains a challenging task because, in most cases, data must first be converted to Resource Description Framework triples. In line with those requirements, we have developed an infrastructure to expose clinical, demographic and molecular data elements generated by TCGA as a SPARQL endpoint by assigning elements to entities of the Simple Sloppy Semantic Database (S3DB) management model. All components of the infrastructure are available as independent Representational State Transfer (REST) Web services to encourage reusability, and a simple interface was developed to automatically assemble SPARQL queries by navigating a representation of the TCGA domain. A key feature of the proposed solution that greatly facilitates assembly of SPARQL queries is the distinction between the TCGA domain descriptors and data elements. Furthermore, the use of the S3DB management model as a mediator enables queries to both public and protected data without the need for prior submission to a single data source. PMID:20851208

  20. Cytogenetically confirmed primary Ewing's sarcoma of the pancreas.

    PubMed

    Golhar, Ankush; Ray, Samrat; Haugk, Beate; Singhvi, Suresh Kumar

    2017-05-04

    Ewing's sarcoma is a highly aggressive malignant tumour most commonly affecting long bones in children and adolescents. It is part of the Ewing's sarcoma family of tumours (ESFTs) that also include peripheral primitive neuroectodermal tumour and Askin's tumours. ESFTs share common cytogenetic aberrations, antigenic profiles and proto-oncogene expression with an overall similar clinical course. In 99% of ESFTs, genetic translocation with molecular fusion involves the EWSR1 gene on 22q12. Approximately 30% of ESFTs are extraosseous, most commonly occurring in the soft tissues of extremities, pelvis, retroperitoneum and chest wall. Primary presentation in solid organs is very rare but has been described in multiple sites including the pancreas. Accurate diagnosis of a Ewing's sarcoma in a solid organ is critical in facilitating correct treatment. We report the case of a 17-year-old girl with cytogenetically confirmed primary pancreatic Ewing's sarcoma and provide a brief review of the published literature. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  1. Molecular Cytogenetic Characterization of Tenosynovial Giant Cell Tumors

    PubMed Central

    Brandal, Petter; Bjerkehagen, Bodil; Heim, Sverre

    2004-01-01

    Abstract Tenosynovial giant cell tumor (TSGCT) is a disease of disputed etiology and pathogenesis. Some investigations indicate a neoplastic origin of the tumors; others indicate that they are polyclonal and inflammatory. The cytogenetic and molecular genetic features of TSGCTs are largely unknown, as only some 20 localized and 30 diffuse tumors with cytogenetic aberrations have been reported. The most common karyotypic aberrations have been trisomy for chromosomes 5 and 7 and translocations involving chromosomal area 1p11-13. We decided to screen the genomes of TSGCTs by comparative genomic hybridization (CGH) to perform interphase fluorescence in situ hybridization (IP-FISH), looking for numerical aberrations of chromosomes 1, 5, and 7, and to analyze the tumors for microsatellite instability. Except for two diffuse TSGCTs that came fresh to us, and which, by karyotyping, exhibited t(1;22)(p13;q12) and a t(1;1)(q21;p11) and +7, respectively, all studies had to be performed on formalin-fixed, paraffin-embedded material. DNA was extracted from 51 localized and nine diffuse TSGCTs. CGH was successful for 24 tumors, but none of them showed copy number changes. The IP-FISH studies showed trisomy 7 in 56% of the tumors (15/27), whereas chromosomes 1 and 5 seemed to be disomic in all TSGCTs. All informative tumors were wild-type by microsatellite instability analysis. PMID:15548367

  2. Cytogenetic effects of cadmium accumulation on water hyacinth (Eichhornia crassipes)

    SciTech Connect

    Rosas, I.; Carbajal, M.E.; Gomez-Arroyo, S.

    1984-04-01

    Cadmium was bioassayed to observe cytogenetic effects in the water hyacinth (Eichhornia crassipes). Plants were exposed for 96 hr to freshwater containing 0.01, 0.05, 0.10, 1, 5, and 10 mg/liter of cadmium. Metal concentrations in tissues were determined by atomic absorption spectrophotometry. The highest level was found in roots, thus root-tip cells were used for cytogenetic studies; after 24 hr of exposure, micronuclei, c-mitotic effects, and pycnosis were detected and after 48 hr polyploidy was observed. A linear relationship between frequencies of micronuclei and cadmium concentrations was found; at 1, 5, and 10 mg/liter micronuclei numbers were always the lowest.more » The inhibition of cell proliferation, shown by the low mitotic index, was proportional to the concentration and time of exposure. From the results presented in this paper it may be concluded that water hyacinth is a good sensor, due to its fast rate of metal accumulation, which allows an easy way to determine the presence of potential mutagenic compounds in water. 63 references.« less

  3. Cytogenetic Biodosimetry Using the Blood Lymphocytes of Astronauts

    NASA Technical Reports Server (NTRS)

    George, Kerry; Rhone, J.; Chappell, L. J.; Cucinotta, F. A.

    2010-01-01

    Cytogenetic analysis of blood lymphocytes remains the most sensitive and reliable method available for in vivo assessment of the biological effects of exposure to radiation and provides the most informative measurement of radiation induced health risks. To date chromosome damage has been assessed in lymphocytes from more than 30 astronauts before and after they participated in long-duration space missions of three months or more on board the International Space Station. For all individuals, the frequency of chromosome damage measured within a month of return from space was higher than their prefight yield and biodosimetry estimates lie within the range expected from physical dosimetry. Biodosimetry data provides a direct measurement of space radiation damage, which takes into account individual radiosensitivity in the presence of confounding factors such as microgravity and other stress conditions. In contrast to physical measurements, which are external to body and require multiple devices to detect all radiation types all of which have poor sensitivity to neutrons, biodosimetry is internal and includes the effects of shielding provided by the body itself plus chromosome damage shows excellent sensitivity to protons, heavy ions, and neutrons. In addition, chromosome damage is reflective of cancer risk and biodosimetry values can therefore be used to validate and develop risk assessment models that can be used to characterize excess health risk incurred by crewmembers. A review of astronaut biodosimetry data will be presented along with recent findings on the persistence of space radiation induced chromosome damage and the cytogenetic effects of repeat long duration missions

  4. Cytogenetic map of common bean (Phaseolus vulgaris L.)

    PubMed Central

    Fonsêca, Artur; Ferreira, Joana; dos Santos, Tiago Ribeiro Barros; Mosiolek, Magdalena; Bellucci, Elisa; Kami, James; Gepts, Paul; Geffroy, Valérie; Schweizer, Dieter; dos Santos, Karla G. B.

    2010-01-01

    A cytogenetic map of common bean was built by in situ hybridization of 35 bacterial artificial chromosomes (BACs) selected with markers mapping to eight linkage groups, plus two plasmids for 5S and 45S ribosomal DNA and one bacteriophage. Together with three previously mapped chromosomes (chromosomes 3, 4, and 7), 43 anchoring points between the genetic map and the cytogenetic map of the species are now available. Furthermore, a subset of four BAC clones was proposed to identify the 11 chromosome pairs of the standard cultivar BAT93. Three of these BACs labelled more than a single chromosome pair, indicating the presence of repetitive DNA in their inserts. A repetitive distribution pattern was observed for most of the BACs; for 38% of them, highly repetitive pericentromeric or subtelomeric signals were observed. These distribution patterns corresponded to pericentromeric and subtelomeric heterochromatin blocks observed with other staining methods. Altogether, the results indicate that around half of the common bean genome is heterochromatic and that genes and repetitive sequences are intermingled in the euchromatin and heterochromatin of the species. Electronic supplementary material The online version of this article (doi:10.1007/s10577-010-9129-8) contains supplementary material, which is available to authorized users. PMID:20449646

  5. An in vivo cytogenetic analysis of human oral squamous cell carcinoma

    PubMed Central

    Mohanta, Abhimanyu; Mohanty, Prafulla K.; Parida, Gadadhar

    2015-01-01

    Background: Oral cancer ranks in the top three of all cancers in India, which accounts for over 30% of all cancers reported in the country. The micronucleus test (MNT) is one of the most widely applied short term tests used in genetic toxicology to evaluate the mutagenicity and carcinogenicity. Aims: The present study aims at an in vivo cytogenetic analysis of human oral squamous cell carcinoma and to assess the applicability of MNT in diagnosing early detection of oral carcinoma. Materials and Methods: Exfoliated scrape smears were collected from the clinically diagnosed 136 patients suffering from oral precancerous and cancerous lesions. The wet fixed smears were stained by adopting Papanicolaou's staining protocol and counter-stained with Giemsa's solution. Results: The frequency of micronucleated cells has been observed to be in increasing order with the increase of the age-groups and from control to precancerous to cancerous cases significantly in both sexes. Conclusion: Micronucleus formation in the oral mucosa could be a biomarker of genetic damage and also a potential onco-indicator in the long run of oral carcinogenesis. Therefore, MNT can be applied for the early detection of oral carcinoma in the human being. PMID:26942142

  6. Cytogenetic characterization of three Balistoidea fish species from the Atlantic with inferences on chromosomal evolution in the families Monacanthidae and Balistidae

    PubMed Central

    de Lima, Lorena Corina Bezerra; Martinez, Pablo Ariel; Molina, Wagner Franco

    2011-01-01

    Abstract The Tetraodontiformes are the most derived group of teleostean fish. Among other apomorphies, they are characterized by a high degree of fusions or significant bone loss in the head and body. In the early phylogenetic proposals presented for this order, the families Balistidae and Monacanthidae have been unanimously considered to be closely related. Although they have moderate species diversity, they are scarcely known in cytogenetic aspect and chromosomal pattern comparisons between these groups have yet to be established. The species Cantherhines macrocerus (Hollard,1853), Cantherhines pullus (Ranzani, 1842) (Monacanthidae) and Melichthys niger (Bloch, 1786) (Balistidae) were cytogenetically analyzed using conventional (Ag-impregnation, C-banding, CMA3- and DAPI-fluorescence) and molecular (FISH with an 18S rDNA probe) cytogenetic protocols. The karyotypes of all three species were very similar possessing diploid chromosome numbers 2n = 40 and composed exclusively of acrocentric chromosomes. Single NOR-bearing pair as well as positive heterochromatic blocks at pericentromeric regions were identified in the karyotypes of the three species studied. NOR-bearing sites were positively labeled after Ag-impregnation, C-banding, CMA3-fluorescence and FISH with an 18S rDNA probe but were negative after DAPI-fluorescence. Such remarkable shared conspicuous chromosomal characters corroborate either close phylogenetic relationship of these families, previously established by morphological and molecular data, or rather conservative nature of karyotype differentiation processes. The later hypothesis, however, appears less probable due to centric or in tandem fusions documented for another Balistoidea species. PMID:24260619

  7. Dosimetric quality endpoints for low-dose-rate prostate brachytherapy using biological effective dose (bed) vs. conventional dose

    SciTech Connect

    Singh, Rachana; Al-Hallaq, Hania; Pelizzari, Charles A.

    2003-12-31

    The purpose of this study was to compare conventional low-dose-rate prostate brachytherapy dosimetric quality parameters with their biological effective dose (BED) counterparts. To validate a model for transformation from conventional dose to BED, the postimplant plans of 31 prostate brachytherapy patients were evaluated using conventional dose-volume histogram (DVH) quality endpoints and analogous BED-DVH endpoints. Based on CT scans obtained 4 weeks after implantation, DVHs were computed and standard dosimetric endpoints V100 (volume receiving 100% of the prescribed dose), V150, V200, HI (1-[V150/V100]), and D90 (dose that 90% of the target volume received) were obtained for quality analysis. Using known andmore » reported transformations, dose grids were transformed to BED-early ({alpha}/{beta} = 10 Gy) and BED-late ({alpha}/{beta} = 3 Gy) grids, and the same dosimetric endpoints were analyzed. For conventional, BED-early and BED-late DVHs, no differences in V100 were seen (0.896, 0.893, and 0.894, respectively). However, V150 and V200 were significantly higher for both BED-early (0.582 and 0.316) and BED-late (0.595 and 0.337), compared with the conventional (0.539 and 0.255) DVHs. D90 was significantly lower for the BED-early (103.1 Gy) and BED-late transformations (106.9 Gy) as compared with the conventional (119.5 Gy) DVHs. The conventional prescription parameter V100 is the same for the corresponding BED-early and BED-late transformed DVHs. The toxicity parameters V150 and V200 are slightly higher using the BED transformations, suggesting that the BED doses are somewhat higher than predicted using conventional DVHs. The prescription/quality parameter D90 is slightly lower, implying that target coverage is lower than predicted using conventional DVHs. This methodology can be applied to analyze BED dosimetric endpoints to improve clinical outcome and reduce complications of prostate brachytherapy.« less

  8. Safety and Efficacy Endpoints for Mesenchymal Stromal Cell Therapy in Renal Transplant Recipients.

    PubMed

    Bank, J R; Rabelink, T J; de Fijter, J W; Reinders, M E J

    2015-01-01

    Despite excellent short-term graft survival after renal transplantation, the long-term graft outcome remains compromised. It has become evident that a combination of sustained alloreactivity and calcineurin-inhibitor- (CNI-) related nephrotoxicity results in fibrosis and consequently dysfunction of the graft. New immunosuppressive regimens that can minimize or eliminate side effects, while maintaining efficacy, are required to improve long-term graft survival. In this perspective mesenchymal stromal cells (MSCs) are an interesting candidate, since MSCs have immunosuppressive and regenerative properties. The first clinical trials with MSCs in renal transplantation showed safety and feasibility and displayed promising results. Recently, the first phase II studies have been started. One of the most difficult and challenging aspects in those early phase trials is to define accurate endpoints that can measure safety and efficacy of MSC treatment. Since both graft losses and acute rejection rates declined, alternative surrogate markers such as renal function, histological findings, and immunological markers are used to measure efficacy and to provide mechanistic insight. In this review, we will discuss the current status of MSCs in renal transplantation with a focus on the endpoints used in the different experimental and clinical studies.

  9. Exposing the cancer genome atlas as a SPARQL endpoint.

    PubMed

    Deus, Helena F; Veiga, Diogo F; Freire, Pablo R; Weinstein, John N; Mills, Gordon B; Almeida, Jonas S

    2010-12-01

    The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to characterize several types of cancer. Datasets from biomedical domains such as TCGA present a particularly challenging task for those interested in dynamically aggregating its results because the data sources are typically both heterogeneous and distributed. The Linked Data best practices offer a solution to integrate and discover data with those characteristics, namely through exposure of data as Web services supporting SPARQL, the Resource Description Framework query language. Most SPARQL endpoints, however, cannot easily be queried by data experts. Furthermore, exposing experimental data as SPARQL endpoints remains a challenging task because, in most cases, data must first be converted to Resource Description Framework triples. In line with those requirements, we have developed an infrastructure to expose clinical, demographic and molecular data elements generated by TCGA as a SPARQL endpoint by assigning elements to entities of the Simple Sloppy Semantic Database (S3DB) management model. All components of the infrastructure are available as independent Representational State Transfer (REST) Web services to encourage reusability, and a simple interface was developed to automatically assemble SPARQL queries by navigating a representation of the TCGA domain. A key feature of the proposed solution that greatly facilitates assembly of SPARQL queries is the distinction between the TCGA domain descriptors and data elements. Furthermore, the use of the S3DB management model as a mediator enables queries to both public and protected data without the need for prior submission to a single data source. Copyright © 2010 Elsevier Inc. All rights reserved.

  10. Directional constraint of endpoint force emerges from hindlimb anatomy.

    PubMed

    Bunderson, Nathan E; McKay, J Lucas; Ting, Lena H; Burkholder, Thomas J

    2010-06-15

    Postural control requires the coordination of force production at the limb endpoints to apply an appropriate force to the body. Subjected to horizontal plane perturbations, quadruped limbs stereotypically produce force constrained along a line that passes near the center of mass. This phenomenon, referred to as the force constraint strategy, may reflect mechanical constraints on the limb or body, a specific neural control strategy or an interaction among neural controls and mechanical constraints. We used a neuromuscular model of the cat hindlimb to test the hypothesis that the anatomical constraints restrict the mechanical action of individual muscles during stance and constrain the response to perturbations to a line independent of perturbation direction. In a linearized neuromuscular model of the cat hindlimb, muscle lengthening directions were highly conserved across 10,000 different muscle activation patterns, each of which produced an identical, stance-like endpoint force. These lengthening directions were closely aligned with the sagittal plane and reveal an anatomical structure for directionally constrained force responses. Each of the 10,000 activation patterns was predicted to produce stable stance based on Lyapunov stability analysis. In forward simulations of the nonlinear, seven degree of freedom model under the action of 200 random muscle activation patterns, displacement of the endpoint from its equilibrium position produced restoring forces, which were also biased toward the sagittal plane. The single exception was an activation pattern based on minimum muscle stress optimization, which produced destabilizing force responses in some perturbation directions. The sagittal force constraint increased during simulations as the system shifted from an inertial response during the acceleration phase to a viscoelastic response as peak velocity was obtained. These results qualitatively match similar experimental observations and suggest that the force

  11. Directional constraint of endpoint force emerges from hindlimb anatomy

    PubMed Central

    Bunderson, Nathan E.; McKay, J. Lucas; Ting, Lena H.; Burkholder, Thomas J.

    2010-01-01

    Postural control requires the coordination of force production at the limb endpoints to apply an appropriate force to the body. Subjected to horizontal plane perturbations, quadruped limbs stereotypically produce force constrained along a line that passes near the center of mass. This phenomenon, referred to as the force constraint strategy, may reflect mechanical constraints on the limb or body, a specific neural control strategy or an interaction among neural controls and mechanical constraints. We used a neuromuscular model of the cat hindlimb to test the hypothesis that the anatomical constraints restrict the mechanical action of individual muscles during stance and constrain the response to perturbations to a line independent of perturbation direction. In a linearized neuromuscular model of the cat hindlimb, muscle lengthening directions were highly conserved across 10,000 different muscle activation patterns, each of which produced an identical, stance-like endpoint force. These lengthening directions were closely aligned with the sagittal plane and reveal an anatomical structure for directionally constrained force responses. Each of the 10,000 activation patterns was predicted to produce stable stance based on Lyapunov stability analysis. In forward simulations of the nonlinear, seven degree of freedom model under the action of 200 random muscle activation patterns, displacement of the endpoint from its equilibrium position produced restoring forces, which were also biased toward the sagittal plane. The single exception was an activation pattern based on minimum muscle stress optimization, which produced destabilizing force responses in some perturbation directions. The sagittal force constraint increased during simulations as the system shifted from an inertial response during the acceleration phase to a viscoelastic response as peak velocity was obtained. These results qualitatively match similar experimental observations and suggest that the force

  12. Variability in the reporting of renal function endpoints in immunosuppression trials in renal transplantation: time for consensus?

    PubMed

    Knight, Simon R; Hussain, Samia

    2016-12-01

    Early measures of graft function are increasingly used to assess efficacy in clinical trials of kidney transplant immunosuppression. This study aimed to assess the variability and quality of reporting of these endpoints in contemporary trials. Data regarding renal function endpoints were extracted from 213 reports from randomized controlled trials comparing immunosuppressive interventions in renal transplant recipients published between 2010 and 2014. A total of 174 (81.7%) reports included a measure of renal function; in 44 (20.7%), this was the primary endpoint. A total of 103 manuscripts (48.4%) reported serum creatinine, 142 (66.6%) reported estimated glomerular filtration rate (eGFR), and 26 (12.2%) reported measured GFR. Formulas used for GFR estimation were modification of diet in renal disease (42.3%), Cockroft-Gault (23.5%), Nankivell (15.0%), and CKD-EPI (0.9%). Six studies (2.8%) did not report the formula used to estimate GFR. A total of 13.9% of endpoints had missing data. In 10 studies, disagreement was found in the significance of findings using different measures of renal function. There is a great deal of variability in the reporting of renal function endpoints, with a significant proportion of studies using underperforming or inappropriate estimates. There is a need for consensus as to the best tool for monitoring and reporting renal function post-transplant, and in particular for use in clinical trials and registries. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Endpoint-based parallel data processing in a parallel active messaging interface of a parallel computer

    DOEpatents

    Archer, Charles J; Blocksome, Michael E; Ratterman, Joseph D; Smith, Brian E

    2014-02-11

    Endpoint-based parallel data processing in a parallel active messaging interface ('PAMI') of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes coupled for data communications through the PAMI, including establishing a data communications geometry, the geometry specifying, for tasks representing processes of execution of the parallel application, a set of endpoints that are used in collective operations of the PAMI including a plurality of endpoints for one of the tasks; receiving in endpoints of the geometry an instruction for a collective operation; and executing the instruction for a collective opeartion through the endpoints in dependence upon the geometry, including dividing data communications operations among the plurality of endpoints for one of the tasks.

  14. Idiopathic Pulmonary Fibrosis: Clinically Meaningful Primary Endpoints in Phase 3 Clinical Trials

    PubMed Central

    Collard, Harold R.; Anstrom, Kevin J.; Flaherty, Kevin R.; Fleming, Thomas R.; King, Talmadge E.; Martinez, Fernando J.; Brown, Kevin K.

    2012-01-01

    Definitive evidence of clinical efficacy in a Phase 3 trial is best shown by a beneficial impact on a clinically meaningful endpoint—that is, an endpoint that directly measures how a patient feels (symptoms), functions (the ability to perform activities in daily life), or survives. In idiopathic pulmonary fibrosis (IPF), we believe the endpoints that best meet these criteria are all-cause mortality and all-cause nonelective hospitalization. There are no validated measures of symptoms or broader constructs such as health status or funtional status in IPF. A surrogate endpoint is defined as an indirect measure that is intended to substitute for a clinically meaningful endpoint. Surrogate endpoints can be appropriate outcome measures if validated. However, validation requires substantial evidence that the effect of an intervention on a clinically meaningful endpoint is reliably predicted by the effect of an intervention on the surrogate endpoint. For patients with IPF, there are currently no validated surrogate endpoints. PMID:22505745

  15. Endpoint-based parallel data processing in a parallel active messaging interface of a parallel computer

    DOEpatents

    Archer, Charles J.; Blocksome, Michael A.; Ratterman, Joseph D.; Smith, Brian E.

    2014-08-12

    Endpoint-based parallel data processing in a parallel active messaging interface (`PAMI`) of a parallel computer, the PAMI composed of data communications endpoints, each endpoint including a specification of data communications parameters for a thread of execution on a compute node, including specifications of a client, a context, and a task, the compute nodes coupled for data communications through the PAMI, including establishing a data communications geometry, the geometry specifying, for tasks representing processes of execution of the parallel application, a set of endpoints that are used in collective operations of the PAMI including a plurality of endpoints for one of the tasks; receiving in endpoints of the geometry an instruction for a collective operation; and executing the instruction for a collective operation through the endpoints in dependence upon the geometry, including dividing data communications operations among the plurality of endpoints for one of the tasks.

  16. Micropropagation and cytogenetic assessment of Zingiber species of Northeast India.

    PubMed

    Das, Archana; Kesari, Vigya; Rangan, Latha

    2013-12-01

    An improved micropropagation protocol was developed for Zingiber moran and Z. zerumbet, two wild species of the genus Zingiber, found in Northeast India. The effects of growth regulators, sugar concentrations, and nutrients were tested on the rate of shoot initiation and multiplication. An increase in proliferation and multiplication occurred in modified Murashige and Skoog (MS) medium supplemented with benzyladenine and kinetin. About 2 % sucrose and 0.7 % agar were found to be the optimum for shoot multiplication and regeneration. Naphthalene acetic acid at 0.5 mg/L produced the best rooting response for both the species. Regenerated plantlets were acclimatized successfully and cytogenetic stability was confirmed by RAPD profiling and ploidy checks.

  17. Plant genotoxicity: a molecular cytogenetic approach in plant bioassays.

    PubMed

    Maluszynska, Jolanta; Juchimiuk, Jolanta

    2005-06-01

    It is important for the prevention of DNA changes caused by environment to understand the biological consequences of DNA damages and their molecular modes of action that lead to repair or alterations of the genetic material. Numerous genotoxicity assay systems have been developed to identify DNA reactive compounds. The available data show that plant bioassays are important tests in the detection of genotoxic contamination in the environment and the establishment of controlling systems. Plant system can detect a wide range of genetic damage, including gene mutations and chromosome aberrations. Recently introduced molecular cytogenetic methods allow analysis of genotoxicity, both at the chromosomal and DNA level. FISH gives a new possibility of the detection and analysis of chromosomal rearrangements in a great detail. DNA fragmentation can be estimated using the TUNEL test and the single cell gel electrophoresis (Comet assay).

  18. Cytogenetic investigation of subjects professionally exposed to radiofrequency radiation.

    PubMed

    Maes, Annemarie; Van Gorp, Urbain; Verschaeve, Luc

    2006-03-01

    Nowadays, virtually everybody is exposed to radiofrequency radiation (RFR) from mobile phone base station antennas or other sources. At least according to some scientists, this exposure can have detrimental health effects. We investigated cytogenetic effects in peripheral blood lymphocytes from subjects who were professionally exposed to mobile phone electromagnetic fields in an attempt to demonstrate possible RFR-induced genetic effects. These subjects can be considered well suited for this purpose as their RFR exposure is 'normal' though rather high, and definitely higher than that of the 'general population'. The alkaline comet assay, sister chromatid exchange (SCE) and chromosome aberration tests revealed no evidence of RFR-induced genetic effects. Blood cells were also exposed to the well known chemical mutagen mitomycin C in order to investigate possible combined effects of RFR and the chemical. No cooperative action was found between the electromagnetic field exposure and the mutagen using either the comet assay or SCE test.

  19. Discrepancy of cytogenetic analysis in Western and eastern Taiwan.

    PubMed

    Chang, Yu-Hsun; Chen, Pui-Yi; Li, Tzu-Ying; Yeh, Chung-Nan; Li, Yi-Shian; Chu, Shao-Yin; Lee, Ming-Liang

    2013-06-01

    This study aimed at investigating the results of second-trimester amniocyte karyotyping in western and eastern Taiwan, and identifying any regional differences in the prevalence of fetal chromosomal anomalies. From 2004 to 2009, pregnant women who underwent amniocentesis in their second trimester at three hospitals in western Taiwan and at four hospitals in eastern Taiwan were included. All the cytogenetic analyses of cultured amniocytes were performed in the cytogenetics laboratory of the Genetic Counseling Center of Hualien Buddhist Tzu Chi General Hospital. We used the chi-square test, Student t test, and Mann-Whitney U test to evaluate the variants of clinical indications, amniocyte karyotyping results, and prevalence and types of chromosomal anomalies in western and eastern Taiwan. During the study period, 3573 samples, 1990 (55.7%) from western Taiwan and 1583 (44.3%) from eastern Taiwan, were collected and analyzed. The main indication for amniocyte karyotyping was advanced maternal age (69.0% in western Taiwan, 67.1% in eastern Taiwan). The detection rates of chromosomal anomalies by amniocyte karyotyping in eastern Taiwan (45/1582, 2.8%) did not differ significantly from that in western Taiwan (42/1989, 2.1%) (p = 1.58). Mothers who had abnormal ultrasound findings and histories of familial hereditary diseases or chromosomal anomalies had higher detection rates of chromosomal anomalies (9.3% and 7.2%, respectively). The detection rate of autosomal anomalies was higher in eastern Taiwan (93.3% vs. 78.6%, p = 0.046), but the detection rate of sex-linked chromosomal anomalies was higher in western Taiwan (21.4% vs. 6.7%, p = 0.046). We demonstrated regional differences in second-trimester amniocyte karyotyping results and established a database of common chromosomal anomalies that could be useful for genetic counseling, especially in eastern Taiwan. Copyright © 2012. Published by Elsevier B.V.

  20. Comparative molecular cytogenetic characterization of seven Deschampsia (Poaceae) species

    PubMed Central

    Bolsheva, Nadezhda L.; Zoshchuk, Svyatoslav A.; Twardovska, Maryana O.; Yurkevich, Olga Yu; Andreev, Igor O.; Samatadze, Tatiana E.; Badaeva, Ekaterina D.; Kunakh, Viktor A.; Muravenko, Olga V.

    2017-01-01

    The genus Deschampsia P. Beauv (Poaceae) involves a group of widespread polymorphic species. Some of them are highly tolerant to stressful and variable environmental conditions, and D. antarctica is one of the only two vascular plants growing in Antarctic. This species is a source of useful for selection traits and a valuable model for studying an environmental stress tolerance in plants. Genome diversity and comparative chromosomal phylogeny within the genus have not been studied yet as karyotypes of most Deschampsia species are poorly investigated. We firstly conducted a comparative molecular cytogenetic analysis of D. antarctica (Antarctic Peninsula) and related species from various localities (D. cespitosa, D. danthonioides, D. elongata, D. flexuosa (= Avenella flexuosa), D. parvula and D. sukatschewii by fluorescence in situ hybridization with 45S and 5S rDNA, DAPI-banding and sequential rapid in situ hybridization with genomic DNA of D. antarctica, D. cespitosa, and D. flexuosa. Based on patterns of distribution of the examined markers, chromosomes of the studied species were identified. Within these species, common features as well as species peculiarities in their karyotypic structure and chromosomal distribution of molecular cytogenetic markers were characterized. Different chromosomal rearrangements were detected in D. antarctica, D. flexuosa, D. elongata and D. sukatschewii. In karyotypes of D. antarctica, D. cespitosa, D. elongata and D. sukatschewii, 0–3 B chromosomes possessed distinct DAPI-bands were observed. Our findings suggest that the genome evolution of the genus Deschampsia involved polyploidy and also different chromosomal rearrangements. The obtained results will help clarify the relationships within the genus Deschampsia, and can be a basis for the further genetic and biotechnological studies as well as for selection of plants tolerant to extreme habitats. PMID:28407010

  1. Molecular Cytogenetic Analysis of Deschampsia antarctica Desv. (Poaceae), Maritime Antarctic.

    PubMed

    Amosova, Alexandra V; Bolsheva, Nadezhda L; Samatadze, Tatiana E; Twardovska, Maryana O; Zoshchuk, Svyatoslav A; Andreev, Igor O; Badaeva, Ekaterina D; Kunakh, Viktor A; Muravenko, Olga V

    2015-01-01

    Deschampsia antarctica Desv. (Poaceae) (2n = 26) is one of the two vascular plants adapted to the harshest environment of the Antarctic. Although the species is a valuable model for study of environmental stress tolerance in plants, its karyotype is still poorly investigated. We firstly conducted a comprehensive molecular cytogenetic analysis of D. antarctica collected on four islands of the Maritime Antarctic. D. antarctica karyotypes were studied by Giemsa C- and DAPI/C-banding, Ag-NOR staining, multicolour fluorescence in situ hybridization with repeated DNA probes (pTa71, pTa794, telomere repeats, pSc119.2, pAs1) and the GAA simple sequence repeat probe. We also performed sequential rapid in situ hybridization with genomic DNA of D. caespitosa. Two chromosome pairs bearing transcriptionally active 45S rDNA loci and five pairs with 5S rDNA sites were detected. A weak intercalary site of telomere repeats was revealed on the largest chromosome in addition to telomere hybridization signals at terminal positions. This fact confirms indirectly the hypothesis that chromosome fusion might have been the cause of the unusual for cereals chromosome number in this species. Based on patterns of distribution of the examined molecular cytogenetic markers, all chromosomes in karyotypes were identified, and chromosome idiograms of D. antarctica were constructed. B chromosomes were found in most karyotypes of plants from Darboux Island. A mixoploid plant with mainly triploid cells bearing a Robertsonian rearrangement was detected among typical diploid specimens from Great Jalour Island. The karyotype variability found in D. antarctica is probably an expression of genome instability induced by environmental stress factors. The differences in C-banding patterns and in chromosome distribution of rDNA loci as well as homologous highly repeated DNA sequences detected between genomes of D. antarctica and its related species D. caespitosa indicate that genome reorganization involving

  2. Molecular Cytogenetic Analysis of Deschampsia antarctica Desv. (Poaceae), Maritime Antarctic

    PubMed Central

    Amosova, Alexandra V.; Bolsheva, Nadezhda L.; Samatadze, Tatiana E.; Twardovska, Maryana O.; Zoshchuk, Svyatoslav A.; Andreev, Igor O.; Badaeva, Ekaterina D.; Kunakh, Viktor A.; Muravenko, Olga V.

    2015-01-01

    Deschampsia antarctica Desv. (Poaceae) (2n = 26) is one of the two vascular plants adapted to the harshest environment of the Antarctic. Although the species is a valuable model for study of environmental stress tolerance in plants, its karyotype is still poorly investigated. We firstly conducted a comprehensive molecular cytogenetic analysis of D. antarctica collected on four islands of the Maritime Antarctic. D. antarctica karyotypes were studied by Giemsa C- and DAPI/C-banding, Ag-NOR staining, multicolour fluorescence in situ hybridization with repeated DNA probes (pTa71, pTa794, telomere repeats, pSc119.2, pAs1) and the GAA simple sequence repeat probe. We also performed sequential rapid in situ hybridization with genomic DNA of D. caespitosa. Two chromosome pairs bearing transcriptionally active 45S rDNA loci and five pairs with 5S rDNA sites were detected. A weak intercalary site of telomere repeats was revealed on the largest chromosome in addition to telomere hybridization signals at terminal positions. This fact confirms indirectly the hypothesis that chromosome fusion might have been the cause of the unusual for cereals chromosome number in this species. Based on patterns of distribution of the examined molecular cytogenetic markers, all chromosomes in karyotypes were identified, and chromosome idiograms of D. antarctica were constructed. B chromosomes were found in most karyotypes of plants from Darboux Island. A mixoploid plant with mainly triploid cells bearing a Robertsonian rearrangement was detected among typical diploid specimens from Great Jalour Island. The karyotype variability found in D. antarctica is probably an expression of genome instability induced by environmental stress factors. The differences in C-banding patterns and in chromosome distribution of rDNA loci as well as homologous highly repeated DNA sequences detected between genomes of D. antarctica and its related species D. caespitosa indicate that genome reorganization involving

  3. Comparative molecular cytogenetic characterization of seven Deschampsia (Poaceae) species.

    PubMed

    Amosova, Alexandra V; Bolsheva, Nadezhda L; Zoshchuk, Svyatoslav A; Twardovska, Maryana O; Yurkevich, Olga Yu; Andreev, Igor O; Samatadze, Tatiana E; Badaeva, Ekaterina D; Kunakh, Viktor A; Muravenko, Olga V

    2017-01-01

    The genus Deschampsia P. Beauv (Poaceae) involves a group of widespread polymorphic species. Some of them are highly tolerant to stressful and variable environmental conditions, and D. antarctica is one of the only two vascular plants growing in Antarctic. This species is a source of useful for selection traits and a valuable model for studying an environmental stress tolerance in plants. Genome diversity and comparative chromosomal phylogeny within the genus have not been studied yet as karyotypes of most Deschampsia species are poorly investigated. We firstly conducted a comparative molecular cytogenetic analysis of D. antarctica (Antarctic Peninsula) and related species from various localities (D. cespitosa, D. danthonioides, D. elongata, D. flexuosa (= Avenella flexuosa), D. parvula and D. sukatschewii by fluorescence in situ hybridization with 45S and 5S rDNA, DAPI-banding and sequential rapid in situ hybridization with genomic DNA of D. antarctica, D. cespitosa, and D. flexuosa. Based on patterns of distribution of the examined markers, chromosomes of the studied species were identified. Within these species, common features as well as species peculiarities in their karyotypic structure and chromosomal distribution of molecular cytogenetic markers were characterized. Different chromosomal rearrangements were detected in D. antarctica, D. flexuosa, D. elongata and D. sukatschewii. In karyotypes of D. antarctica, D. cespitosa, D. elongata and D. sukatschewii, 0-3 B chromosomes possessed distinct DAPI-bands were observed. Our findings suggest that the genome evolution of the genus Deschampsia involved polyploidy and also different chromosomal rearrangements. The obtained results will help clarify the relationships within the genus Deschampsia, and can be a basis for the further genetic and biotechnological studies as well as for selection of plants tolerant to extreme habitats.

  4. Ideal discrimination of discrete clinical endpoints using multilocus genotypes.

    PubMed

    Hahn, Lance W; Moore, Jason H

    2004-01-01

    Multifactor Dimensionality Reduction (MDR) is a method for the classification and prediction of discrete clinical endpoints using attributes constructed from multilocus genotype data. Empirical studies with both real and simulated data suggest that MDR has good power for detecting gene-gene interactions in the absence of independent main effects. The purpose of this study is to develop an objective, theory-driven approach to evaluate the strengths and limitations of MDR. To accomplish this goal, we borrow concepts from ideal observer analysis used in visual perception to evaluate the theoretical limits of classifying and predicting discrete clinical endpoints using multilocus genotype data. We conclude that MDR ideally discriminates between low risk and high risk subjects using attributes constructed from multilocus genotype data. We also how that the classification approach used once a multilocus attribute is constructed is similar to that of a naive Bayes classifier. This study provides a theoretical foundation for the continued development, evaluation, and application of the MDR as a data mining tool in the domain of statistical genetics and genetic epidemiology.

  5. Verification of models for ballistic movement time and endpoint variability.

    PubMed

    Lin, Ray F; Drury, Colin G

    2013-01-01

    A hand control movement is composed of several ballistic movements. The time required in performing a ballistic movement and its endpoint variability are two important properties in developing movement models. The purpose of this study was to test potential models for predicting these two properties. Twelve participants conducted ballistic movements of specific amplitudes using a drawing tablet. The measured data of movement time and endpoint variability were then used to verify the models. This study was successful with Hoffmann and Gan's movement time model (Hoffmann, 1981; Gan and Hoffmann 1988) predicting more than 90.7% data variance for 84 individual measurements. A new theoretically developed ballistic movement variability model, proved to be better than Howarth, Beggs, and Bowden's (1971) model, predicting on average 84.8% of stopping-variable error and 88.3% of aiming-variable errors. These two validated models will help build solid theoretical movement models and evaluate input devices. This article provides better models for predicting end accuracy and movement time of ballistic movements that are desirable in rapid aiming tasks, such as keying in numbers on a smart phone. The models allow better design of aiming tasks, for example button sizes on mobile phones for different user populations.

  6. Time-dependent efficacy of longitudinal biomarker for clinical endpoint.

    PubMed

    Kolamunnage-Dona, Ruwanthi; Williamson, Paula R

    2018-06-01

    Joint modelling of longitudinal biomarker and event-time processes has gained its popularity in recent years as they yield more accurate and precise estimates. Considering this modelling framework, a new methodology for evaluating the time-dependent efficacy of a longitudinal biomarker for clinical endpoint is proposed in this article. In particular, the proposed model assesses how well longitudinally repeated measurements of a biomarker over various time periods (0,t) distinguish between individuals who developed the disease by time t and individuals who remain disease-free beyond time t. The receiver operating characteristic curve is used to provide the corresponding efficacy summaries at various t based on the association between longitudinal biomarker trajectory and risk of clinical endpoint prior to each time point. The model also allows detecting the time period over which a biomarker should be monitored for its best discriminatory value. The proposed approach is evaluated through simulation and illustrated on the motivating dataset from a prospective observational study of biomarkers to diagnose the onset of sepsis.

  7. Challenges in translating endpoints from trials to observational cohort studies in oncology

    PubMed Central

    Ording, Anne Gulbech; Cronin-Fenton, Deirdre; Ehrenstein, Vera; Lash, Timothy L; Acquavella, John; Rørth, Mikael; Sørensen, Henrik Toft

    2016-01-01

    Clinical trials are considered the gold standard for examining drug efficacy and for approval of new drugs. Medical databases and population surveillance registries are valuable resources for post-approval observational research, which are increasingly used in studies of benefits and risk of new cancer drugs. Here, we address the challenges in translating endpoints from oncology trials to observational studies. Registry-based cohort studies can investigate real-world safety issues – including previously unrecognized concerns – by examining rare endpoints or multiple endpoints at once. In contrast to clinical trials, observational cohort studies typically do not exclude real-world patients from clinical practice, such as old and frail patients with comorbidity. The observational cohort study complements the clinical trial by examining the effectiveness of interventions applied in clinical practice and by providing evidence on long-term clinical outcomes, which are often not feasible to study in a clinical trial. Various endpoints can be included in clinical trials, such as hard endpoints, soft endpoints, surrogate endpoints, and patient-reported endpoints. Each endpoint has it strengths and limitations for use in research studies. Endpoints used in oncology trials are often not applicable in observational cohort studies which are limited by the setting of standard clinical practice and by non-standardized endpoint determination. Observational studies can be more helpful moving research forward if they restrict focus to appropriate and valid endpoints. PMID:27354827

  8. New drugs and patient-centred end-points in old age: setting the wheels in motion.

    PubMed

    Mangoni, Arduino A; Pilotto, Alberto

    2016-01-01

    Older patients with various degrees of frailty and disability, a key population target of pharmacological interventions in acute and chronic disease states, are virtually neglected in pre-marketing studies assessing the efficacy and safety of investigational drugs. Moreover, aggressively pursuing established therapeutic targets in old age, e.g. blood pressure, serum glucose or cholesterol concentrations, is not necessarily associated with the beneficial effects, and the acceptable safety, reported in younger patient cohorts. Measures of self-reported health and functional status might represent additional, more meaningful, therapeutic end-points in the older population, particularly in patients with significant frailty and relatively short life expectancy, e.g. in the presence of cancer and/or neurodegenerative disease conditions. Strategies enhancing early knowledge about key pharmacological characteristics of investigational drugs targeting older adults are discussed, together with the rationale for incorporating non-traditional, patient-centred, end-points in this ever-increasing group.

  9. Impact of copula directional specification on multi-trial evaluation of surrogate endpoints

    PubMed Central

    Renfro, Lindsay A.; Shang, Hongwei; Sargent, Daniel J.

    2014-01-01

    Evaluation of surrogate endpoints using patient-level data from multiple trials is the gold standard, where multi-trial copula models are used to quantify both patient-level and trial-level surrogacy. While limited consideration has been given in the literature to copula choice (e.g., Clayton), no prior consideration has been given to direction of implementation (via survival versus distribution functions). We demonstrate that evenwith the “correct” copula family, directional misspecification leads to biased estimates of patient-level and trial-level surrogacy. We illustrate with a simulation study and a re-analysis of disease-free survival as a surrogate for overall survival in early stage colon cancer. PMID:24905465

  10. Progression-free survival as a primary endpoint in clinical trials of metastatic colorectal cancer

    PubMed Central

    Gill, S.; Berry, S.; Biagi, J.; Butts, C.; Buyse, M.; Chen, E.; Jonker, D.; Mărginean, C.; Samson, B.; Stewart, J.; Thirlwell, M.; Wong, R.; Maroun, J.A.

    2011-01-01

    In recent years, significant advances have been made in the management of metastatic colorectal cancer. Traditionally, an improvement in overall survival has been considered the “gold standard”—the most convincing measure of efficacy. However, overall survival requires larger patient numbers and longer follow-up and may often be confounded by other factors, including subsequent therapies and crossover. Given the number of active therapies for potential investigation, demand for rapid evaluation and early availability of new therapies is growing. Progression-free survival is regarded as an important measure of treatment benefit and, compared with overall survival, can be evaluated earlier, with fewer patients and no confounding by subsequent lines of therapy. The present paper reviews the advantages, limitations, and relevance of progression-free survival as a primary endpoint in randomized trials of metastatic colorectal cancer. PMID:21969810

  11. A maximum likelihood algorithm for genome mapping of cytogenetic loci from meiotic configuration data.

    PubMed Central

    Reyes-Valdés, M H; Stelly, D M

    1995-01-01

    Frequencies of meiotic configurations in cytogenetic stocks are dependent on chiasma frequencies in segments defined by centromeres, breakpoints, and telomeres. The expectation maximization algorithm is proposed as a general method to perform maximum likelihood estimations of the chiasma frequencies in the intervals between such locations. The estimates can be translated via mapping functions into genetic maps of cytogenetic landmarks. One set of observational data was analyzed to exemplify application of these methods, results of which were largely concordant with other comparable data. The method was also tested by Monte Carlo simulation of frequencies of meiotic configurations from a monotelodisomic translocation heterozygote, assuming six different sample sizes. The estimate averages were always close to the values given initially to the parameters. The maximum likelihood estimation procedures can be extended readily to other kinds of cytogenetic stocks and allow the pooling of diverse cytogenetic data to collectively estimate lengths of segments, arms, and chromosomes. Images Fig. 1 PMID:7568226

  12. Comparative cytogenetic analysis of sex chromosomes in several Canidae species using zoo-FISH.

    PubMed

    Bugno-Poniewierska, Monika; Sojecka, Agnieszka; Pawlina, Klaudia; Jakubczak, Andrzej; Jezewska-Witkowska, Grazyna

    2012-01-01

    Sex chromosome differentiation began early during mammalian evolution. The karyotype of almost all placental mammals living today includes a pair of heterosomes: XX in females and XY in males. The genomes of different species may contain homologous synteny blocks indicating that they share a common ancestry. One of the tools used for their identification is the Zoo-FISH technique. The aim of the study was to determine whether sex chromosomes of some members of the Canidae family (the domestic dog, the red fox, the arctic fox, an interspecific hybrid: arctic fox x red fox and the Chinese raccoon dog) are evolutionarily conservative. Comparative cytogenetic analysis by Zoo-FISH using painting probes specific to domestic dog heterosomes was performed. The results show the presence of homologous synteny covering the entire structures of the X and the Y chromosomes. This suggests that sex chromosomes are conserved in the Canidae family. The data obtained through Zoo-FISH karyotype analysis append information obtained using other comparative genomics methods, giving a more complete depiction of genome evolution.

  13. Impact of the track structure of heavy charged particles on cytogenetic damage in human blood lymphocytes

    NASA Astrophysics Data System (ADS)

    Lee, Ryonfa; Nasonova, Elena; Sommer, Sylwetster; Hartel, Carola; Durante, Marco; Ritter, Sylvia

    -ions). Furthermore, the aberration yield increased linearly with Fe-ion fluence. When aberrations were analyzed in first cycle G2 -PCC cells to account for the prolonged G2 arrest of damaged cells, the same trend was detected. However, the increase in the aberration yield with time and the saturation effect were less pronounced compared to metaphase samples. Altogether, these data show that the aberration analysis with multiple samplings is necessary for a reliable estimate of cytogenetic damage induced by charged particles. In particular, when damage is measured at one early time-point the effectiveness of low energy particles will be considerably underestimated. When the aberration spectrum induced by low energy C-ions and high en-ergy Fe-ions was compared, we did not find a difference. Preliminary data obtained with the high resolution mFISH-technique confirm this observation. (Work supported by BMBF, Bonn, under contract 02S8497)

  14. Cytogenetics and fluorescence in-situ hybridization in detection of hematological malignancies.

    PubMed

    Frenny, V J; Antonella, Z; Luisa, A; Shah, A D; Sheth, J J; Rocchi, M

    2003-01-01

    The technique of Fluorescence In-Situ Hybridization (FISH), a hybrid of cytogenetics and molecular biology has increased the resolution and application of cytogenetics in various neoplastic processes. In various types of leukemias, primary investigation by conventional cytogenetic [CC] technique followed by FISH has increased our understanding of the abnormal clonal formation involving different gene region. Present study is aimed to use different kinds of in-house FISH probes in various hematological malignancies and its correlation with conventional cytogenetic finding. Cytogenetic study was carried out in 360 patients either from peripheral blood or from bone marrow cells suspected for various types of leukemias. Four of 360 cases were further selected for FISH study by using different types of in-house probes, such as BAC [Bacterial Artificial Chromosome], PAC [Phague Artificial Chromosome], alphoid, PCP [Partial Chromosome Paint] and WCP [Whole Chromosome paint]. The results confirmed breakpoints of inversion 16 and del 16 in case 2 and 3 respectively. Whereas, case 1 did not confirm the cytogenetic findings of t(15;17) by PML/RARa fusion signals as multiple cell lines were involved in the patients. PCP and WCP were helpful in the identification of the marker chromosome in case 1. Telomeric and centromeric probes confirmed the cytogenetic findings of t(5;7) in case 4. We observe from this study that, in addition to the conventional cytogenetic study, FISH study provide further confirmation of chromosomal rearrangements. This facilitates our understanding of the neoplastic process more precisely for the better prognostication of the patient.

  15. Multicenter validation study of a transplantation-specific cytogenetics grouping scheme for patients with myelodysplastic syndromes.

    PubMed

    Armand, P; Deeg, H J; Kim, H T; Lee, H; Armistead, P; de Lima, M; Gupta, V; Soiffer, R J

    2010-05-01

    Cytogenetics is an important prognostic factor for patients with myelodysplastic syndromes (MDS). However, existing cytogenetics grouping schemes are based on patients treated with supportive care, and may not be optimal for patients undergoing allo-SCT. We proposed earlier an SCT-specific cytogenetics grouping scheme for patients with MDS and AML arising from MDS, based on an analysis of patients transplanted at the Dana-Farber Cancer Institute/Brigham and Women's Hospital. Under this scheme, abnormalities of chromosome 7 and complex karyotype are considered adverse risk, whereas all others are considered standard risk. In this retrospective study, we validated this scheme on an independent multicenter cohort of 546 patients. Adverse cytogenetics was the strongest prognostic factor for outcome in this cohort. The 4-year relapse-free survival and OS were 42 and 46%, respectively, in the standard-risk group, vs 21 and 23% in the adverse group (P<0.0001 for both comparisons). This grouping scheme retained its prognostic significance irrespective of patient age, disease type, earlier leukemogenic therapy and conditioning intensity. Therapy-related disease was not associated with increased mortality in this cohort, after taking cytogenetics into account. We propose that this SCT-specific cytogenetics grouping scheme be used for patients with MDS or AML arising from MDS who are considering or undergoing SCT.

  16. Comprehensive 5-Year Study of Cytogenetic Aberrations in 668 Infertile Men

    PubMed Central

    Yatsenko, Alexander N.; Yatsenko, Svetlana A.; Weedin, John W.; Lawrence, Amy E.; Patel, Ankita; Peacock, Sandra; Matzuk, Martin M.; Lamb, Dolores J.; Cheung, Sau Wai; Lipshultz, Larry I.

    2010-01-01

    Purpose The causes of male infertility are heterogeneous but more than 50% of cases have a genetic basis. Specific genetic defects have been identified in less than 20% of infertile males and, thus, most causes remain to be elucidated. The most common cytogenetic defects associated with nonobstructive azoospermia are numerical and structural chromosome abnormalities, including Klinefelter syndrome (47,XXY) and Y chromosome microdeletions. To refine the incidence and nature of chromosomal aberrations in males with infertility we reviewed cytogenetic results in 668 infertile men with oligozoospermia and azoospermia. Materials and Methods High resolution Giemsa banding chromosome analysis and/or fluorescence in situ hybridization were done in 668 infertile males referred for routine cytogenetic analysis between January 2004 and March 2009. Results The overall incidence of chromosomal abnormalities was about 8.2%. Of the 55 patients with abnormal cytogenetic findings sex chromosome aneuploidies were observed in 29 (53%), including Klinefelter syndrome in 27 (49%). Structural chromosome abnormalities involving autosomes (29%) and sex chromosomes (18%) were detected in 26 infertile men. Abnormal cytogenetic findings were observed in 35 of 264 patients (13.3%) with azoospermia and 19 of 365 (5.2%) with oligozoospermia. Conclusions Structural chromosomal defects and low level sex chromosome mosaicism are common in oligozoospermia cases. Extensive cytogenetic assessment and fluorescence in situ hybridization may improve the detection rate in males with oligozoospermia. These findings highlight the need for efficient genetic testing in infertile men so that couples may make informed decisions on assisted reproductive technologies to achieve parenthood. PMID:20172548

  17. Surrogate and clinical endpoints for studies in peripheral artery occlusive disease: Are statistics the brakes?

    PubMed

    Waliszewski, Matthias W; Redlich, Ulf; Breul, Victor; Tautenhahn, Jörg

    2017-04-30

    The aim of this review is to present the available clinical and surrogate endpoints that may be used in future studies performed in patients with peripheral artery occlusive disease (PAOD). Importantly, we describe statistical limitations of the most commonly used endpoints and offer some guidance with respect to study design for a given sample size. The proposed endpoints may be used in studies using surgical or interventional revascularization and/or drug treatments. Considering recently published study endpoints and designs, the usefulness of these endpoints for reimbursement is evaluated. Based on these potential study endpoints and patient sample size estimates with different non-inferiority or tests for difference hypotheses, a rating relative to their corresponding reimbursement values is attempted. As regards the benefit for the patients and for the payers, walking distance and the ankle brachial index (ABI) are the most feasible endpoints in a relatively small study samples given that other non-vascular impact factors can be controlled. Angiographic endpoints such as minimal lumen diameter (MLD) do not seem useful from a reimbursement standpoint despite their intuitiveness. Other surrogate endpoints, such as transcutaneous oxygen tension measurements, have yet to be established as useful endpoints in reasonably sized studies with patients with critical limb ischemia (CLI). From a reimbursement standpoint, WD and ABI are effective endpoints for a moderate study sample size given that non-vascular confounding factors can be controlled.

  18. Multiple critical endpoints in magnetized three flavor quark matter

    NASA Astrophysics Data System (ADS)

    Ferreira, Márcio; Costa, Pedro; Providência, Constança

    2018-01-01

    The magnetized phase diagram for three-flavor quark matter is studied within the Polyakov extended Nambu-Jona-Lasinio model. The order parameters are analyzed with special emphasis on the strange quark condensate. We show that the presence of an external magnetic field induces several critical endpoints (CEPs) in the strange sector, which arise due to the multiple phase transitions that the strange quark undergoes. The spinodal and binodal regions of the phase transitions are shown to increase with external magnetic field strength. The influence of strong magnetic fields on the isentropic trajectories around the several CEPs is analyzed. A focusing effect is observed on the region towards the CEPs that are related with the strange quark phase transitions. Compared to the chiral transitions, the deconfinement transition turns out to be less sensitive to the external magnetic field and the crossover nature is preserved over the whole phase diagram.

  19. Regulatory considerations on endpoints in ovarian cancer drug development.

    PubMed

    Balasubramaniam, Sanjeeve; Kim, Geoffrey S; McKee, Amy E; Pazdur, Richard

    2017-07-15

    Ovarian cancer remains a disease entity that is responsible for considerable morbidity and mortality among women worldwide. Modern drug research pipelines and accelerated drug development timelines applied to other disease entities have begun to make an impact on treatment options for patients with advanced ovarian cancer, as exemplified by the recent accelerated approval of 2 agents for this disease as the forerunners of a growing number of registrational trials. Regulatory flexibility for this serious and life-threatening condition spurs the consideration of intermediate endpoints for regulatory trial design, including potential applications in the development of newer therapeutic classes such as targeted therapies and immunotherapies for patients with advanced ovarian cancer. Cancer 2017;123:2604-8. © 2017 American Cancer Society. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

  20. Mouse handling limits the impact of stress on metabolic endpoints.

    PubMed

    Ghosal, Sriparna; Nunley, Amanda; Mahbod, Parinaz; Lewis, Alfor G; Smith, Eric P; Tong, Jenny; D'Alessio, David A; Herman, James P

    2015-10-15

    Studies focused on end-points that are confounded by stress are best performed under minimally stressful conditions. The objective of this study was to demonstrate the impact of handling designed to reduce animal stress on measurements of glucose tolerance. A cohort of mice (CD1.C57BL/6) naïve to any specific handling was subjected to either a previously described "cup" handling method, or a "tail-picked" method in which the animals were picked up by the tail (as is common for metabolic studies). Following training, an elevated plus maze (EPM) test was performed followed by measurement of blood glucose and plasma corticosterone. A second cohort (CD1.C57BL/6) was rendered obese by exposure to a high fat diet, handled with either the tail-picked or cup method and subjected to an intraperitoneal glucose tolerance test. A third cohort of C57BL/6 mice was exposed to a cup regimen that included a component of massage and was subjected to tests of anxiety-like behavior, glucose homeostasis, and corticosterone secretion. We found that the cup mice showed reduced anxiety-like behaviors in the EPM coupled with a reduction in blood glucose levels compared to mice handled by the tail-picked method. Additionally, cup mice on the high fat diet exhibited improved glucose tolerance compared to tail-picked controls. Finally, we found that the cup/massage group showed lower glucose levels following an overnight fast, and decreased anxiety-like behaviors associated with lower stress-induced plasma corticosterone concentration compared to tail-picked controls. These data demonstrate that application of handling methods that reduce anxiety-like behaviors in mice mitigates the confounding contribution of stress to interpretation of metabolic endpoints (such as glucose tolerance). Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Mouse Handling Limits the Impact of Stress on Metabolic Endpoints

    PubMed Central

    Ghosal, Sriparna; Nunley, Amanda; Mahbod, Parinaz; Lewis, Alfor G.; Smith, Eric P.; Tong, Jenny; D’Alessio, David A.; Herman, James P.

    2015-01-01

    Studies focused on end-points that are confounded by stress are best performed under minimally stressful conditions. The objective of this study was to demonstrate the impact of handling designed to reduce animal stress on measurements of glucose tolerance. A cohort of mice (CD1.C57BL/6) naïve to any specific handling were subjected to either a previously described “cup” handling method, or a “tail-picked” method in which the animals were picked up by the tail (as is common for metabolic studies). Following training, an elevated plus maze (EPM) test was performed followed by measurement of blood glucose and plasma corticosterone. A second cohort (CD1.C57BL/6) was rendered obese by exposure to a high fat diet, handled with either the tail-picked or cup method and subjected to an intraperitoneal glucose tolerance test. A third cohort of C57BL/6 mice was exposed to a cup regimen that included a component of massage and was subjected to tests of anxiety-like behavior, glucose homeostasis, and corticosterone secretion. We found that the cup mice showed reduced anxiety-like behaviors in the EPM coupled with a reduction in blood glucose levels compared to mice handled by the tail-picked method. Additionally, cup mice on the high fat diet exhibited improved glucose tolerance compared to tail-picked controls. Finally, we found that the cup/massage group showed lower glucose levels following an overnight fast, and decreased anxiety-like behaviors associated with lower stress-induced plasma corticosterone concentration compared to tail-picked controls. These data demonstrate that application of handling methods that reduce anxiety-like behaviors in mice mitigates the confounding contribution of stress to interpretation of metabolic endpoints (such as glucose tolerance). PMID:26079207

  2. Trends in Utilization of Surrogate Endpoints in Contemporary Cardiovascular Clinical Trials.

    PubMed

    Patel, Ravi B; Vaduganathan, Muthiah; Samman-Tahhan, Ayman; Kalogeropoulos, Andreas P; Georgiopoulou, Vasiliki V; Fonarow, Gregg C; Gheorghiade, Mihai; Butler, Javed

    2016-06-01

    Surrogate endpoints facilitate trial efficiency but are variably linked to clinical outcomes, and limited data are available exploring their utilization in cardiovascular clinical trials over time. We abstracted data regarding primary clinical, intermediate, and surrogate endpoints from all phase II to IV cardiovascular clinical trials from 2001 to 2012 published in the 8 highest Web of Science impact factor journals. Two investigators independently classified the type of primary endpoint. Of the 1,224 trials evaluated, 677 (55.3%) primary endpoints were clinical, 165 (13.5%) intermediate, and 382 (31.2%) surrogate. The relative proportions of these endpoints remained constant over time (p = 0.98). Trials using surrogate endpoints were smaller (187 vs 1,028 patients) and enrolled patients more expeditiously (1.4 vs 0.9 patients per site per month) compared with trials using clinical endpoints (p <0.001 for both comparisons). Surrogate endpoint trials were independently more likely to meet their primary endpoint compared to trials with clinical endpoints (adjusted odds ratio 1.56, 95% CI 1.05 to 2.34; p = 0.03). Rates of positive results in clinical endpoint trials have decreased over time from 66.1% in 2001 to 2003 to 47.2% in 2010 to 2012 (p = 0.001), whereas these rates have remained stable over the same period for surrogate (72.0% to 69.3%, p = 0.27) and intermediate endpoints (74.4% to 71.4%, p = 0.98). In conclusion, approximately a third of contemporary cardiovascular trials use surrogate endpoints. These trials are completed more expeditiously and are more likely to meet their primary outcomes. The overall scientific contribution of these surrogate endpoint trials requires further attention given their variable association with definitive outcomes. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. A Bayesian prediction model between a biomarker and the clinical endpoint for dichotomous variables.

    PubMed

    Jiang, Zhiwei; Song, Yang; Shou, Qiong; Xia, Jielai; Wang, William

    2014-12-20

    Early biomarkers are helpful for predicting clinical endpoints and for evaluating efficacy in clinical trials even if the biomarker cannot replace clinical outcome as a surrogate. The building and evaluation of an association model between biomarkers and clinical outcomes are two equally important concerns regarding the prediction of clinical outcome. This paper is to address both issues in a Bayesian framework. A Bayesian meta-analytic approach is proposed to build a prediction model between the biomarker and clinical endpoint for dichotomous variables. Compared with other Bayesian methods, the proposed model only requires trial-level summary data of historical trials in model building. By using extensive simulations, we evaluate the link function and the application condition of the proposed Bayesian model under scenario (i) equal positive predictive value (PPV) and negative predictive value (NPV) and (ii) higher NPV and lower PPV. In the simulations, the patient-level data is generated to evaluate the meta-analytic model. PPV and NPV are employed to describe the patient-level relationship between the biomarker and the clinical outcome. The minimum number of historical trials to be included in building the model is also considered. It is seen from the simulations that the logit link function performs better than the odds and cloglog functions under both scenarios. PPV/NPV ≥0.5 for equal PPV and NPV, and PPV + NPV ≥1 for higher NPV and lower PPV are proposed in order to predict clinical outcome accurately and precisely when the proposed model is considered. Twenty historical trials are required to be included in model building when PPV and NPV are equal. For unequal PPV and NPV, the minimum number of historical trials for model building is proposed to be five. A hypothetical example shows an application of the proposed model in global drug development. The proposed Bayesian model is able to predict well the clinical endpoint from the observed biomarker

  4. Cytogenetic, molecular-cytogenetic, and clinical-genealogical studies of the mothers of children with autism: a search for familial genetic markers for autistic disorders.

    PubMed

    Vorsanova, S G; Voinova, V Yu; Yurov, I Yu; Kurinnaya, O S; Demidova, I A; Yurov, Yu B

    2010-09-01

    State-of-the-art cytogenetic and molecular-cytogenetic methods for studying human chromosomes were used to analyze chromosomal anomalies and variants in mothers of children with autistic disorders and the results were compared with clinical-genealogical data. These investigations showed that these mothers, as compared with a control group, showed increases in the frequencies of chromosomal anomalies (mainly mosaic forms involving chromosome X) and chromosomal heteromorphisms. Analysis of correlations of genotypes and phenotypes revealed increases in the frequencies of cognitive impairments and spontaneous abortions in the mothers of children with autism with chromosomal anomalies, as well as increases in the frequencies of mental retardation, death in childhood, and impairments to reproductive function in the pedigrees of these women. There was a high incidence of developmental anomalies in the pedigrees of mothers with chromosomal variants. These results lead to the conclusion that cytogenetic and molecular-cytogenetic studies of mothers and children with autism should be regarded as obligatory in terms of detecting possible genetic causes of autism and for genetic counseling of families with autistic children.

  5. Cytogenetic effects in workers occupationally exposed to tobacco dust.

    PubMed

    Umadevi, B; Swarna, M; Padmavathi, P; Jyothi, A; Reddy, P P

    2003-03-03

    Tobacco dust mainly contains nitrosamines, which are readily absorbed by the body tissues like skin, respiratory epithelium, and mucous membrane of mouth, nose and intestines. Exposure to tobacco dust is known to affect the respiratory tracts in humans. In the present study, cytogenetic effects of exposure to tobacco dust are evaluated in 154 male tobacco factory workers and 138 age and sex matched controls by analysing chromosomal aberrations in their peripheral blood lymphocytes. The workers were in the age group of 20-55 years and were employed in the tobacco processing factory for 1-32 years. Heparinised blood samples were collected from workers and control subjects and lymphocyte cultures were carried out by using standard technique. Slides were prepared and 150 metaphases were screened for each sample for various structural and numerical types of abnormalities. A statistically significant increase was observed in the frequencies of chromosomal aberrations in non-smoking and smoking exposed groups when compared to the respective controls. An increase in the frequencies of chromosomal aberrations was also observed with increase in years of service in the exposed subjects.

  6. Prenatal identification of i(Yp) by molecular cytogenetic analysis

    SciTech Connect

    Wang, B.T.; Peng, W.; Williams, J. III

    1994-09-01

    An isochromosome derived from the short arm of the Y chromosome, i(Yp), is a rare marker chromosome. Its de novo presence prenatally represents a diagnostic dilemna since its impact on fetal development is difficult to predict. We present a case of 46,X,+i(Yp) de novo detected in an amniotic fluid specimen received for karyotype analysis. Fluorescence in situ hybridization (FISH) studies using a panel of Y-specific biotinylated DNA probes including a Y-centromere probe, a Y whole chromosome painting probe, and a lambda HAM2 probe containing 19 kb of AMG-Y sequence, located to Yp11.2, have identified the marker chromosome as i(Yp). Themore » breakpoint on this marker chromosome is tentatively assigned to Yq11.1 which is close to the centromere. The present report illustrates the importance of FISH techniques as a complement to cytogenetic methods for accurate identification of chromosome rearrangements in prenatal diagnosis and genetic counseling.« less

  7. Recommendations for the development of rare disease drugs using the accelerated approval pathway and for qualifying biomarkers as primary endpoints.

    PubMed

    Kakkis, Emil D; O'Donovan, Mary; Cox, Gerald; Hayes, Mark; Goodsaid, Federico; Tandon, P K; Furlong, Pat; Boynton, Susan; Bozic, Mladen; Orfali, May; Thornton, Mark

    2015-02-10

    For rare serious and life-threatening disorders, there is a tremendous challenge of transforming scientific discoveries into new drug treatments. This challenge has been recognized by all stakeholders who endorse the need for flexibility in the regulatory review process for novel therapeutics to treat rare diseases. In the United States, the best expression of this flexibility was the creation of the Accelerated Approval (AA) pathway. The AA pathway is critically important for the development of treatments for diseases with high unmet medical need and has been used extensively for drugs used to treat cancer and infectious diseases like HIV.In 2012, the AA provisions were amended to enhance the application of the AA pathway to expedite the development of drugs for rare disorders under the Food and Drug Administration Safety and Innovation Act (FDASIA). FDASIA, among many provisions, requires the development of a more relevant FDA guidance on the types of evidence that may be acceptable in support of using a novel surrogate endpoint. The application of AA to rare diseases requires more predictability to drive greater access to appropriate use of AA for more rare disease treatments that might not be developed otherwise.This white paper proposes a scientific framework for assessing biomarker endpoints to enhance the development of novel therapeutics for rare and devastating diseases currently without adequate treatment and is based on the opinions of experts in drug development and rare disease patient groups. Specific recommendations include: 1) Establishing regulatory rationale for increased AA access in rare disease programs; 2) Implementing a Biomarker Qualification Request Process to provide the opportunity for an early determination of biomarker acceptance; and 3) A proposed scientific framework for qualifying biomarkers as primary endpoints. The paper's final section highlights case studies of successful examples that have incorporated biomarker endpoints into

  8. Improving the analysis of composite endpoints in rare disease trials.

    PubMed

    McMenamin, Martina; Berglind, Anna; Wason, James M S

    2018-05-22

    Composite endpoints are recommended in rare diseases to increase power and/or to sufficiently capture complexity. Often, they are in the form of responder indices which contain a mixture of continuous and binary components. Analyses of these outcomes typically treat them as binary, thus only using the dichotomisations of continuous components. The augmented binary method offers a more efficient alternative and is therefore especially useful for rare diseases. Previous work has indicated the method may have poorer statistical properties when the sample size is small. Here we investigate small sample properties and implement small sample corrections. We re-sample from a previous trial with sample sizes varying from 30 to 80. We apply the standard binary and augmented binary methods and determine the power, type I error rate, coverage and average confidence interval width for each of the estimators. We implement Firth's adjustment for the binary component models and a small sample variance correction for the generalized estimating equations, applying the small sample adjusted methods to each sub-sample as before for comparison. For the log-odds treatment effect the power of the augmented binary method is 20-55% compared to 12-20% for the standard binary method. Both methods have approximately nominal type I error rates. The difference in response probabilities exhibit similar power but both unadjusted methods demonstrate type I error rates of 6-8%. The small sample corrected methods have approximately nominal type I error rates. On both scales, the reduction in average confidence interval width when using the adjusted augmented binary method is 17-18%. This is equivalent to requiring a 32% smaller sample size to achieve the same statistical power. The augmented binary method with small sample corrections provides a substantial improvement for rare disease trials using composite endpoints. We recommend the use of the method for the primary analysis in relevant rare

  9. Benchmarking outcomes in the Neonatal Intensive Care Unit: Cytogenetic and molecular diagnostic rates in a retrospective cohort.

    PubMed

    Malam, Faheem; Hartley, Taila; Gillespie, Meredith K; Armour, Christine M; Bariciak, Erika; Graham, Gail E; Nikkel, Sarah M; Richer, Julie; Sawyer, Sarah L; Boycott, Kym M; Dyment, David A

    2017-05-09

    Genetic disease and congenital anomalies continue to be a leading cause of neonate mortality and morbidity. A genetic diagnosis in the neonatal intensive care unit (NICU) can be a challenge given the associated genetic heterogeneity and early stage of a disease. We set out to evaluate the outcomes of Medical Genetics consultation in the NICU in terms of cytogenetic and molecular diagnostic rates and impact on management. We retrospectively reviewed 132 charts from patients admitted to the NICU who received a Medical Genetics diagnostic evaluation over a 2 year period. Of the 132 patients reviewed, 26% (34/132) received a cytogenetic or molecular diagnosis based on the Medical Genetics diagnostic evaluation; only 10% (13/132) received a diagnosis during their admission. The additional 16% (21 patients) received their diagnosis following NICU discharge, but based on a genetic test initiated during hospital-stay. Mean time from NICU admission to confirmed diagnosis was 24 days. For those who received a genetic diagnosis, the information was considered beneficial for clinical management in all, and a direct change to medical management occurred for 12% (4/32). For those non-diagnosed infants seen in out-patient follow-up clinic, diagnoses were made in 8% (3/37). The diagnoses made post-discharge from the NICU comprised a greater number of Mendelian disorders and represent an opportunity to improve genetic care. The adoption of diagnostic tools, such as exome sequencing, used in parallel with traditional approaches will improve rate of diagnoses and will have a significant impact, in particular when the differential diagnosis is broad. © 2017 Wiley Periodicals, Inc.

  10. SpEnD: Linked Data SPARQL Endpoints Discovery Using Search Engines

    NASA Astrophysics Data System (ADS)

    Yumusak, Semih; Dogdu, Erdogan; Kodaz, Halife; Kamilaris, Andreas; Vandenbussche, Pierre-Yves

    In this study, a novel metacrawling method is proposed for discovering and monitoring linked data sources on the Web. We implemented the method in a prototype system, named SPARQL Endpoints Discovery (SpEnD). SpEnD starts with a "search keyword" discovery process for finding relevant keywords for the linked data domain and specifically SPARQL endpoints. Then, these search keywords are utilized to find linked data sources via popular search engines (Google, Bing, Yahoo, Yandex). By using this method, most of the currently listed SPARQL endpoints in existing endpoint repositories, as well as a significant number of new SPARQL endpoints, have been discovered. Finally, we have developed a new SPARQL endpoint crawler (SpEC) for crawling and link analysis.

  11. Threshold Collision Energy of the QCD Phase Diagram Tricritical Endpoint

    NASA Astrophysics Data System (ADS)

    Bugaev, K. A.; Emaus, R.; Sagun, V. V.; Ivanytskyi, A. I.; Bravina, L. V.; Blaschke, D. B.; Nikonov, E. G.; Taranenko, A. V.; Zabrodin, E. E.; Zinovjev, G. M.

    2018-05-01

    Using the most advanced formulation of the hadron resonance gas model we analyze the two sets of irregularities found at chemical freeze-out of central nuclear-nuclear collisions at the center of mass energies 3.8-4.9 GeV and 7.6-9.2 GeV. In addition to previously reported irregularities at the collision energies 4.9 and 9.2 GeV we found sharp peaks of baryonic charge density. Also we analyze the collision energy dependence of the modified Wroblewski factor and the strangeness suppression factor. Based on the thermostatic properties of the mixed phase of a 1st order phase transition and the ones of the Hagedorn mass spectrum we explain, respectively, the reason of observed chemical equilibration of strangeness at the collision energy 4.9 GeV and above 8.7 GeV. It is argued that the both sets of irregularities possibly evidence for two phase transitions, namely, the 1st order transition at lower energy range and the 2nd order transition at higher one. In combination with a recent analysis of the light nuclei number fluctuations we conclude that the center of mass collision energy range 8.8-9.2 GeV may be in the nearest vicinity of the QCD tricritical endpoint. The properties of the phase existing between two phase transitions are revealed and discussed.

  12. Chromosomal mutagenesis in human somatic cells: 30-year cytogenetic monitoring after Chornobyl accident.

    PubMed

    Pilinska, M A; Shemetun, G M; Shemetun, O V; Dybsky, S S; Dybska, O B; Talan, O O; Pedan, L R; Kurinnyi, D А

    2016-12-01

    In the lecture we have generalized and analyzed the data of cytogenetic laboratory of National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine on 30-year selective cytogenetic monitoring among the priority contingents of different ages exposed to radiation after Chornobyl accident in Ukraine. It is highlighted that not only targeted but also untargeted radiation-induced cytogenetic effects should be explored, especially in delayed terms following radiation exposure. The new methodical approaches for studying "bystander effect", individual radiosensitivity, and various forms of radiation-induced chromosomal instability (delayed, hidden, transmissible) have been proposed. These approaches proved to be advantageous for analyzing cytogenetic patterns of induction and persistence of chromosomal instability in human somatic cells because of "bystander effect" and "bystander type effect". The phenomenon of positive "reverse" bystander effect has been found. The possibility of modifying the inherited individual human susceptibility to mutagenic exposure by ionizing radiation has been estimated. Finally, the association between hypersensitivity to radiation exposure and realization of oncopathology in exposed individuals has been revealed. The increased intensity of human somatic chromosomal mutagenesis was confirmed not only in the nearest but in the delayed terms following Chornobyl accident as a result of radiation-induced both targeted and untargeted cytogenetic effects. Such effects can be considered as risk factors for malignant transformation of cells, hereditary diseases, birth defects, and multifactorial somatic pathology. This article is a part of a Special Issue entitled "The Chornobyl Nuclear Accident: Thirty Years After".

  13. Cytogenetic studies of 1232 patients with different sexual development abnormalities from the Sultanate of Oman.

    PubMed

    Al-Alawi, Intisar; Goud, Tadakal Mallana; Al-Harasi, Salma; Rajab, Anna

    2016-02-01

    The aim of this study was to evaluate cytogenetic findings in Omani patients who had been referred for suspicion of sex chromosome abnormalities that resulted in different clinical disorders. Furthermore, it sought to examine the frequency of chromosomal anomalies in these patients and to compare the obtained results with those reported elsewhere. Cytogenetic analysis was performed on 1232 cases with variant characteristics of sexual development disorders who had been referred to the cytogenetic department, National Genetic Centre, Ministry of Health, from different hospitals in the Sultanate of Oman between 1999 and 2014. The karyotype results demonstrated chromosomal anomalies in 24.2% of the cases, where 67.5% of abnormalities were identified in referral females, whereas only 32.6% were in referral males. Of all sex chromosome anomalies detected, Turner syndrome was the most frequent (38.2%) followed by Klinefelter syndrome (24.9%) and XY phenotypic females (16%). XXX syndrome and XX phenotypic males represented 6.8% and 3.8% of all sex chromosome anomalies, respectively. Cytogenetic analysis of patients referred with various clinical suspicions of chromosomal abnormalities revealed a high rate of chromosomal anomalies. This is the first broad cytogenetic study reporting combined frequencies of sex chromosome anomalies in sex development disorders in Oman. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  14. Cytogenetic correlates of TET2 mutations in 199 patients with myeloproliferative neoplasms

    PubMed Central

    Hussein, Kebede; Abdel-Wahab, Omar; Lasho, Terra L.; Van Dyke, Daniel L.; Levine, Ross L.; Hanson, Curtis A.; Pardanani, Animesh; Tefferi, Ayalew

    2015-01-01

    TET2 is a putative tumor suppressor gene located at chromosome 4q24. TET2 mutations were recently described in several myeloid neoplasms but correlations with cytogenetic findings have not been studied. Among a recently described cohort of patients with myeloproliferative neoplasms (MPN) who underwent TET2 mutation analysis, 199 had information on karyotype at diagnosis or time of TET2 testing: 71 polycythemia vera (PV), 55 primary myelofibrosis (PMF), 43 essential thrombocythemia (ET), 13 post-PV MF, 7 post-ET MF, and 10 blast phase MPN. Forty eight patients (24%) exhibited abnormal karyotype: 15 favorable (sole 20q-, 13q-, or +9), 8 unfavorable (complex karyotype or sole +8), and 25 “other” cytogenetic abnormalities. We found no significant difference either in the incidence or type of cytogenetic abnormalities between TET2 mutated (n = 25) and unmutated (n = 174) cases. Seventy nine patients, including 14 with TET2 mutations, underwent follow-up cytogenetic testing and the findings were again not affected by TET2 mutational status. We conclude that TET2 mutated MPN patients are not cytogenetically different than their TET2 unmutated counterparts. PMID:19957346

  15. Synergistic cytogenetic and antineoplastic effects by the combined action of esteric steroidal derivatives of nitrogen mustards.

    PubMed

    Mourelatos, Constantinos; Nikolaropoulos, Sotiris; Fousteris, Manolis; Pairas, Georgios; Argyraki, Maria; Kareli, Dimitra; Dafa, Evaggelia; Mourelatos, Dionisios; Lialiaris, Theodore

    2012-06-01

    We studied the effect of five newly synthesized steroidal derivatives of nitrogen mustards. These derivatives have as alkylators either P-N, N-bis(2-chloroethyl)aminophenyl-butyrate (CHL) or P-N, N-bis(2-chloroethyl)aminophenyl-acetate (PHE) groups esterified with different modified steroidal nuclei. We examined them alone or in combination, on sister chromatid exchange rates and on human lymphocyte proliferation kinetics. The antitumor activity of these compounds, alone or in combination, was also tested on Leukemia P388-bearing mice. A pronounced cytogenetic and antineoplastic action was demonstrated by the compounds that contain either PHE or CHL as alkylators and are esterified with a steroidal nucleus having added a cholestene group in the 17 position of the D-ring. The exocyclical insertion of an -NHCO- group in the D-ring of the steroidal nucleus esterified with PHE (amide ester of PHE) yielded a compound demonstrating a distinct cytogenetic and antineoplastic effect. In contrast, the ketone group in the D-ring being inserted endocyclically in the steroidal nucleus (androstene) esterified with either CHL or with PHE gave negative cytogenetic and antineoplastic effects. However, the combined action of cholestene esterified with either CHL or with PHE in combination with either the androstene ester of PHE or with the androstene ester of CHL, respectively, gave synergistic cytogenetic and antineoplastic effects. Also the amide ester of PHE in combination with the androstene ester of CHL gave distinct cytogenetic and antineoplastic effects in a synergistic manner.

  16. Hermes III endpoint energy calculation from photonuclear activation of 197Au and 58Ni foils

    SciTech Connect

    Parzyck, Christopher Thomas

    2014-09-01

    A new process has been developed to characterize the endpoint energy of HERMES III on a shot-to-shot basis using standard dosimetry tools from the Sandia Radiation Measurements Laboratory. Photonuclear activation readings from nickel and gold foils are used in conjunction with calcium fluoride thermoluminescent dosimeters to derive estimated electron endpoint energies for a series of HERMES shots. The results are reasonably consistent with the expected endpoint voltages on those shots.

  17. Individual and Composite Study Endpoints: Separating the Wheat from the Chaff

    PubMed Central

    Goldberg, Robert; Gore, Joel M.; Barton, Bruce; Gurwitz, Jerry

    2014-01-01

    We provide an overview of the individual and combined clinical endpoints and patient reported outcomes typically used in clinical trials and prospective epidemiological investigations. We discuss the strengths and limitations associated with the utilization of aggregated study endpoints and surrogate measures of important clinical endpoints and patient-centered outcomes. We hope that the points raised in this overview will lead to the collection of clinically rich, relevant, measurable, and cost-efficient study outcomes. PMID:24486289

  18. Anatomy of an experimental two-link flexible manipulator under end-point control

    NASA Technical Reports Server (NTRS)

    Oakley, Celia M.; Cannon, Robert H., Jr.

    1990-01-01

    The design and experimental implementation of an end-point controller for two-link flexible manipulators are presented. The end-point controller is based on linear quadratic Gaussian (LQG) theory and is shown to exhibit significant improvements in trajectory tracking over a conventional controller design. To understand the behavior of the manipulator structure under end-point control, a strobe sequence illustrating the link deflections during a typical slew maneuver is included.

  19. Equilibrium-Based Movement Endpoints Elicited from Primary Motor Cortex Using Repetitive Microstimulation

    PubMed Central

    Van Acker, Gustaf M.; Amundsen, Sommer L.; Messamore, William G.; Zhang, Hongyu Y.; Luchies, Carl W.

    2014-01-01

    High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being used to deduce how the brain encodes coordinated muscle activity and movement. However, the full movement repertoire that can be elicited from the forelimb representation of primary motor cortex (M1) using this method has not been systematically determined. Our goal was to acquire a comprehensive M1 forelimb representational map of movement endpoints elicited with HFLD-ICMS, using stimulus parameters optimal for evoking stable forelimb spatial endpoints. The data reveal a 3D forelimb movement endpoint workspace that is represented in a patchwork fashion on the 2D M1 cortical surface. Although cortical maps of movement endpoints appear quite disorderly with respect to movement space, we show that the endpoint locations in the workspace evoked with HFLD-ICMS of two adjacent cortical points are closer together than would be expected if the organization were random. Although there were few obvious consistencies in the endpoint maps across the two monkeys tested, one notable exception was endpoints bringing the hand to the mouth, which was located at the boundary between the hand and face representation. Endpoints at the extremes of the monkey's workspace and locations above the head were largely absent. Our movement endpoints are best explained as resulting from coactivation of agonist and antagonist muscles driving the joints toward equilibrium positions determined by the length–tension relationships of the muscles. PMID:25411500

  20. Equilibrium-based movement endpoints elicited from primary motor cortex using repetitive microstimulation.

    PubMed

    Van Acker, Gustaf M; Amundsen, Sommer L; Messamore, William G; Zhang, Hongyu Y; Luchies, Carl W; Cheney, Paul D

    2014-11-19

    High-frequency, long-duration intracortical microstimulation (HFLD-ICMS) is increasingly being used to deduce how the brain encodes coordinated muscle activity and movement. However, the full movement repertoire that can be elicited from the forelimb representation of primary motor cortex (M1) using this method has not been systematically determined. Our goal was to acquire a comprehensive M1 forelimb representational map of movement endpoints elicited with HFLD-ICMS, using stimulus parameters optimal for evoking stable forelimb spatial endpoints. The data reveal a 3D forelimb movement endpoint workspace that is represented in a patchwork fashion on the 2D M1 cortical surface. Although cortical maps of movement endpoints appear quite disorderly with respect to movement space, we show that the endpoint locations in the workspace evoked with HFLD-ICMS of two adjacent cortical points are closer together than would be expected if the organization were random. Although there were few obvious consistencies in the endpoint maps across the two monkeys tested, one notable exception was endpoints bringing the hand to the mouth, which was located at the boundary between the hand and face representation. Endpoints at the extremes of the monkey's workspace and locations above the head were largely absent. Our movement endpoints are best explained as resulting from coactivation of agonist and antagonist muscles driving the joints toward equilibrium positions determined by the length-tension relationships of the muscles. Copyright © 2014 the authors 0270-6474/14/3415722-13$15.00/0.

  1. Impact of weighted composite compared to traditional composite endpoints for the design of randomized controlled trials.

    PubMed

    Bakal, Jeffrey A; Westerhout, Cynthia M; Armstrong, Paul W

    2015-12-01

    Composite endpoints are commonly used in cardiovascular clinical trials. When using a composite endpoint a subject is considered to have an event when the first component endpoint has occurred. The use of composite endpoints offers the ability to incorporate several clinically important endpoint events thereby augmenting the event rate and increasing statistical power for a given sample size. One assumption of the composite is that all component events are of equal clinical importance. This assumption is rarely achieved given the diversity of component endpoints included. One means of adjusting for this diversity is to adjust the outcomes using severity weights determined a priori. The use of a weighted endpoint also allows for the incorporation of multiple endpoints per patient. Although weighting the outcomes lowers the effective number of events, it offers additional information that reduces the variance of the estimate. We created a series of simulation studies to examine the effect on power as the individual components of a typical composite were changed. In one study, we noted that the weighted composite was able to offer discriminative power when the component outcomes were altered, while the traditional method was not. In the other study, we noted that the weighted composite offered a similar level of power to the traditional composite when the change was driven by the more severe endpoints. © The Author(s) 2011.

  2. Determining the Primary Endpoint for a Stimulant Abuse Trial: Lessons Learned from STRIDE (CTN 0037)

    PubMed Central

    Trivedi, Madhukar H.; Greer, Tracy L.; Potter, Jennifer Sharpe; Grannemann, Bruce D.; Nunes, Edward V.; Rethorst, Chad; Warden, Diane; Ring, Kolette M.; Somoza, Eugene

    2012-01-01

    Background No consensus is available for identifying the best primary outcome for substance abuse trials. While abstinence is the most desirable outcome for substance use interventions, a wide variety of other endpoints have been used to evaluate efficacy trials. Objectives This report provides a framework for determining an optimal primary endpoint and the relevant measurement approach for substance use disorder treatment trials. The framework was developed based on a trial for stimulant abuse using exercise as an augmentation treatment, delivered within the NIDA Clinical Trials Network. The use of a common primary endpoint across trials will facilitate comparisons of treatment efficacy. Methods Primary endpoint options in existing substance abuse studies were evaluated. This evaluation included surveys of the literature for endpoints and measurement approaches, followed by assessment of endpoint choices against study design issues, population characteristics, tests of sensitivity and tests of clinical meaningfulness. Conclusion We concluded that the best current choice for a primary endpoint is percent days abstinent, as measured by the Time Line Follow Back (TLFB) interview conducted three times a week with recall aided by a take-home Substance Use Diary. To further improve the accuracy of the self-reported drug use, an algorithm will be applied to reconcile the results from the TLFB with the results of qualitative urine drug screens. Scientific Significance There is a need for a standardized endpoint in this field to allow for comparison across treatment studies, and we suggest that the recommended endpoint be considered for use in this field. PMID:21854276

  3. Nonparametric Discrete Survival Function Estimation with Uncertain Endpoints Using an Internal Validation Subsample

    PubMed Central

    Zee, Jarcy; Xie, Sharon X.

    2015-01-01

    Summary When a true survival endpoint cannot be assessed for some subjects, an alternative endpoint that measures the true endpoint with error may be collected, which often occurs when obtaining the true endpoint is too invasive or costly. We develop an estimated likelihood function for the situation where we have both uncertain endpoints for all participants and true endpoints for only a subset of participants. We propose a nonparametric maximum estimated likelihood estimator of the discrete survival function of time to the true endpoint. We show that the proposed estimator is consistent and asymptotically normal. We demonstrate through extensive simulations that the proposed estimator has little bias compared to the naïve Kaplan-Meier survival function estimator, which uses only uncertain endpoints, and more efficient with moderate missingness compared to the complete-case Kaplan-Meier survival function estimator, which uses only available true endpoints. Finally, we apply the proposed method to a dataset for estimating the risk of developing Alzheimer's disease from the Alzheimer's Disease Neuroimaging Initiative. PMID:25916510

  4. Translocation (16;20)(p11.2;q13). sole cytogenetic abnormality in a unicameral bone cyst.

    PubMed

    Richkind, Kathleen E; Mortimer, Errol; Mowery-Rushton, Patricia; Fraire, Armando

    2002-09-01

    We report the results of cytogenetic analysis of a case of unicameral bone cyst with a t(16;20(p11.2;q13) present as the sole abnormality. To our knowledge, this is only the second report of a cytogenetically characterized tumor of this type.

  5. Cytogenetics of small cell carcinoma of the lung.

    PubMed

    Wurster-Hill, D H; Cannizzaro, L A; Pettengill, O S; Sorenson, G D; Cate, C C; Maurer, L H

    1984-12-01

    Nineteen cell lines derived from various malignant tissues of 15 patients with small cell carcinoma of the lung (SCCL) have been studied. The results showed heterogeneity in all cell lines, with no one consistent abnormality among them. Cell lines from 11 of the patients had minute and double minute chromosomes, and cell lines from 2 patients had abnormally banding regions, designated as ABRs, as distinguished from homogeneously staining regions (HSRs). The latter 2 and several of the former cell lines were derived from specimens taken before the patients were placed on therapy. All but 2 of the cell lines had a constant marker load, consisting of 24%-35% of the complement. Some markers remained stable through months and years of culture life, while other markers came and went. Chromosomes #1, #6 and #11 were most frequently involved in marker formation in the cell lines, and these were compared to similar markers in direct bone marrow preparations. Chromosome #1 markers were of variable structure, whereas #6 and #11 most often took the form of 6q- and 11p+ markers, with breakpoints most frequently at 6q23-25 and 11p11-12. A 3p- marker was found in a minority of cell lines. All of these markers were also found in direct marrow preparations from some patients with SCCL. Nonmonoclonal tumors arose from inoculation of bimodal cell lines into nude mice, but population selection by undetermined mechanism was evident. Cytogenetic parameters showed no positive correlation with hormone production by these cell lines.

  6. Induction and repair of HZE induced cytogenetic damage

    NASA Technical Reports Server (NTRS)

    Brooks, A. L.; Bao, S.; Rithidech, K.; Chrisler, W. B.; Couch, L. A.; Braby, L. A.

    2001-01-01

    Wistar rats were exposed to high-mass, high energy (HZE) 56Fe particles (1000 GeV/AMU) using the Alternating Gradient Synchrotron (AGS). The animals were sacrificed at 1-5 hours or after a 30-day recovery period. The frequency of micronuclei in the tracheal and the deep lung epithelial cells were evaluated. The relative effectiveness of 56Fe, for the induction of initial chromosome damage in the form of micronuclei, was compared to damage produced in the same biological system exposed to other types of high and low-LET radiation. It was demonstrated that for animals sacrificed at short times after exposure, the tracheal and lung epithelial cells, the 56Fe particles were 3.3 and 1.3 times as effective as 60Co in production of micronuclei, respectively. The effectiveness was also compared to that for exposure to inhaled radon. With this comparison, the 56Fe exposure of the tracheal epithelial cells and the lung epithelial cells were only 0.18 and 0.20 times as effective as radon in the production of the initial cytogenetic damage. It was suggested that the low relative effectiveness was related to potential for 'wasted energy' from the core of the 56Fe particles. When the animals were sacrificed after 30 days, the slopes of the dose-response relationships, which reflect the remaining level of damage, decreased by a factor of 10 for both the tracheal and lung epithelial cells. In both cases, the slope of the dose-response lines were no longer significantly different from zero, and the r2 values were very high. Lung epithelial cells, isolated from the animals sacrificed hours after exposure, were maintained in culture, and the micronuclei frequency evaluated after 4 and 6 subcultures. These cells were harvested at 24 and 36 days after the exposure. There was no dose-response detected in these cultures and no signs of genomic instability at either sample time.

  7. Low educational level but not low income impairs the achievement of cytogenetic remission in chronic myeloid leukemia patients treated with imatinib in Brazil.

    PubMed

    Rego, Monica Napoleão Fortes; Metze, Konradin; Lorand-Metze, Irene

    2015-05-01

    In Brazil, imatinib mesylate is supplied as the first-line therapy for chronic myeloid leukemia in the chronic phase through the public universal healthcare program, Sistema Único de Saúde (SUS). We studied the socio-demographic factors that influenced therapy success in a population in the northeast region of Brazil. Patients with chronic myeloid leukemia from the state of Piauí were treated in only one reference center. Diagnosis was based on WHO 2008 criteria. Risk was assessed by Sokal, Hasford and EUTOS scores. Patients received 400 mg imatinib daily. We studied the influence of the following factors on the achievement of complete cytogenetic response within one year of treatment: age, clinical risk category, time interval between diagnosis and the start of imatinib treatment, geographic distance from the patient's home to the hospital, years of formal education and monthly income. Among 103 patients studied, the median age was 42 years; 65% of the patients had 2-9 years of formal education, and the median monthly income was approximately 100 US$. Imatinib was started in the first year after diagnosis (early chronic phase) in 69 patients. After 12 months of treatment, 68 patients had a complete cytogenetic response. The Hasford score, delay to start imatinib and years of formal education influenced the attainment of a complete cytogenetic response, whereas income and the distance from the home to the healthcare facility did not. Patients require additional healthcare information to better understand the importance of long-term oral anticancer treatment and to improve their compliance with the treatment.

  8. Customized laboratory information management system for a clinical and research leukemia cytogenetics laboratory.

    PubMed

    Bakshi, Sonal R; Shukla, Shilin N; Shah, Pankaj M

    2009-01-01

    We developed a Microsoft Access-based laboratory management system to facilitate database management of leukemia patients referred for cytogenetic tests in regards to karyotyping and fluorescence in situ hybridization (FISH). The database is custom-made for entry of patient data, clinical details, sample details, cytogenetics test results, and data mining for various ongoing research areas. A number of clinical research laboratoryrelated tasks are carried out faster using specific "queries." The tasks include tracking clinical progression of a particular patient for multiple visits, treatment response, morphological and cytogenetics response, survival time, automatic grouping of patient inclusion criteria in a research project, tracking various processing steps of samples, turn-around time, and revenue generated. Since 2005 we have collected of over 5,000 samples. The database is easily updated and is being adapted for various data maintenance and mining needs.

  9. A cytogenetics study of Hydrodroma despiciens (Müller, 1776) (Acari: Hydrachnellae: Hydrodromidae).

    PubMed

    Onrat, Serap Tutgun; Aşçi, Ferruh; Ozkan, Muhlis

    2006-06-30

    The karyotypes of water mites (Acari: Hydrachnellae: Hydrodromidae) are largely unknown. The present investigation is the first report of a study designed to characterize the chromosomes of water mites. The study was carried out with specimens of Hydrodroma despiciens collected from Eber Lake in Afyon, Turkey. Several different methods were tried to obtain chromosomes of this species. However, somatic cell culture proved to be the most effective for the preparation of chromosomes. In the present study, we determined the diploid chromosome number of Hydrodroma despiciens to be 2n = 16. However, a large metacentric chromosome was found in each metaphase, which we believed to be the X chromosome. We could not determine the sex chromosomes of this species. This study is the first approach to the cytogenetic characterization of this water mite group. Furthermore, these cytogenetic data will contribute to the understanding of the phylogenetic relationship among water mites. To our knowledge, this is the first report on the cytogenetics of water mites.

  10. Cytogenetic studies of Brazilian pediatric myelodysplastic syndrome cases: challenges and difficulties in a large and emerging country

    PubMed Central

    Velloso, E.D.R.P.; Chauffaille, M.L.; Peliçario, L.M.; Tanizawa, R.S.S.; Toledo, S.R.C.; Gaiolla, R.D.; Lopes, L.F.

    2013-01-01

    Myelodysplastic syndromes (MDS) and juvenile myelomonocytic leukemia (JMML) are rare hematopoietic stem cell diseases affecting children. Cytogenetics plays an important role in the diagnosis of these diseases. We report here the experience of the Cytogenetic Subcommittee of the Brazilian Cooperative Group on Pediatric Myelodysplastic Syndromes (BCG-MDS-PED). We analyzed 168 cytogenetic studies performed in 23 different cytogenetic centers; 84 of these studies were performed in patients with confirmed MDS (primary MDS, secondary MDS, JMML, and acute myeloid leukemia/MDS+Down syndrome). Clonal abnormalities were found in 36.9% of the MDS cases and cytogenetic studies were important for the detection of constitutional diseases and for differential diagnosis with other myeloid neoplasms. These data show the importance of the Cooperative Group for continuing education in order to avoid a late or wrong diagnosis. PMID:23314345

  11. Acute myeloid leukaemia: expression of MYC protein and its association with cytogenetic risk profile and overall survival.

    PubMed

    Mughal, Muhammad Kashif; Akhter, Ariz; Street, Lesley; Pournazari, Payam; Shabani-Rad, Meer-Taher; Mansoor, Adnan

    2017-09-01

    Acute myeloid leukaemia (AML) is a clinically aggressive disease with marked genetic heterogeneity. Cytogenetic abnormalities provide the basis for risk stratification into clinically favourable, intermediate, and unfavourable groups. There are additional genetic mutations, which further influence the prognosis of patients with AML. Most of these result in molecular aberrations whose downstream target is MYC. It is therefore logical to study the relationship between MYC protein expression and cytogenetic risk groups. We studied MYC expression by immunohistochemistry in a large cohort (n = 199) of AML patients and correlated these results with cytogenetic risk profile and overall survival (OS). We illustrated differential expression of MYC protein across various cytogenetic risk groups (p = 0.03). Highest expression of MYC was noted in AML patients with favourable cytogenetic risk group. In univariate analysis, MYC expression showed significant negative influence of OS in favourable and intermediate cytogenetic risk group (p = 0.001). Interestingly, MYC expression had a protective effect in the unfavourable cytogenetic risk group. In multivariate analysis, while age and cytogenetic risk group were significant factors influencing survival, MYC expression by immunohistochemistry methods also showed some marginal impact (p = 0.069). In conclusion, we have identified differential expression of MYC protein in relation to cytogenetic risk groups in AML patients and documented its possible impact on OS in favourable and intermediate cytogenetic risk groups. These preliminary observations mandate additional studies to further investigate the routine clinical use of MYC protein expression in AML risk stratification. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  12. Surrogate endpoints and competing risk of death in cardiac arrest research.

    PubMed

    McCredie, Victoria A; Scales, Damon C

    2016-06-29

    We urgently need new therapies to improve outcomes after cardiac arrest. Initial studies typically target surrogate endpoints, and these studies help to inform subsequent larger trials that are powered to measure more patient-orientated clinical outcomes such as survival. The competing risk of death and premature assessment of neurological prognosis pose significant challenges to measuring these surrogate endpoints after cardiac arrest.

  13. Statistical evaluation of surrogate endpoints with examples from cancer clinical trials.

    PubMed

    Buyse, Marc; Molenberghs, Geert; Paoletti, Xavier; Oba, Koji; Alonso, Ariel; Van der Elst, Wim; Burzykowski, Tomasz

    2016-01-01

    A surrogate endpoint is intended to replace a clinical endpoint for the evaluation of new treatments when it can be measured more cheaply, more conveniently, more frequently, or earlier than that clinical endpoint. A surrogate endpoint is expected to predict clinical benefit, harm, or lack of these. Besides the biological plausibility of a surrogate, a quantitative assessment of the strength of evidence for surrogacy requires the demonstration of the prognostic value of the surrogate for the clinical outcome, and evidence that treatment effects on the surrogate reliably predict treatment effects on the clinical outcome. We focus on these two conditions, and outline the statistical approaches that have been proposed to assess the extent to which these conditions are fulfilled. When data are available from a single trial, one can assess the "individual level association" between the surrogate and the true endpoint. When data are available from several trials, one can additionally assess the "trial level association" between the treatment effect on the surrogate and the treatment effect on the true endpoint. In the latter case, the "surrogate threshold effect" can be estimated as the minimum effect on the surrogate endpoint that predicts a statistically significant effect on the clinical endpoint. All these concepts are discussed in the context of randomized clinical trials in oncology, and illustrated with two meta-analyses in gastric cancer. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Restoration for the future: endpoints, targets, and indicators of progress and success

    Treesearch

    Daniel C. Dey; Callie Jo. Schweitzer

    2014-01-01

    Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly described and quantitative endpoints and intermediary targets are needed to...

  15. Restoration for the future: Setting endpoints and targets and selecting indicators of progress and success

    Treesearch

    Daniel C. Dey; Callie Jo Schweitzer; John M. Kabrick

    2014-01-01

    Setting endpoints and targets in forest restoration is a complicated task that is best accomplished in cooperative partnerships that account for the ecology of the system, production of desired ecosystem goods and services, economics and well-being of society, and future environments. Clearly written and quantitative endpoints and intermediary targets need to be...

  16. 77 FR 49447 - Endpoints for Clinical Trials in Kidney Transplantation; Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-16

    ...] Endpoints for Clinical Trials in Kidney Transplantation; Public Workshop AGENCY: Food and Drug... public workshop to discuss the endpoints for clinical trials of drugs and therapeutic biologics in kidney... trials of kidney transplantation. The meeting will include a discussion of measure of patient and graft...

  17. Fixed and equilibrium endpoint problems in uneven-aged stand management

    Treesearch

    Robert G. Haight; Wayne M. Getz

    1987-01-01

    Studies in uneven-aged management have concentrated on the determination of optimal steady-state diameter distribution harvest policies for single and mixed species stands. To find optimal transition harvests for irregular stands, either fixed endpoint or equilibrium endpoint constraints can be imposed after finite transition periods. Penalty function and gradient...

  18. Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications

    PubMed Central

    Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M.; Leufkens, Hubert

    2015-01-01

    Background. Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy’s clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. Materials and Methods. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Results. Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Conclusion. Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Implications for Practice: Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many

  19. Observations on Three Endpoint Properties and Their Relationship to Regulatory Outcomes of European Oncology Marketing Applications.

    PubMed

    Liberti, Lawrence; Stolk, Pieter; McAuslane, James Neil; Schellens, Jan; Breckenridge, Alasdair M; Leufkens, Hubert

    2015-06-01

    Guidance and exploratory evidence indicate that the type of endpoints and the magnitude of their outcome can define a therapy's clinical activity; however, little empirical evidence relates specific endpoint properties with regulatory outcomes. We explored the relationship of 3 endpoint properties to regulatory outcomes by assessing 50 oncology marketing authorization applications (MAAs; reviewed from 2009 to 2013). Overall, 16 (32%) had a negative outcome. The most commonly used hard endpoints were overall survival (OS) and the duration of response or stable disease. OS was a component of 91% approved and 63% failed MAAs. The most commonly used surrogate endpoints were progression-free survival (PFS), response rate, and health-related quality of life assessments. There was no difference (p = .3801) between the approved and failed MAA cohorts in the proportion of hard endpoints used. A mean of slightly more than four surrogate endpoints were used per approved MAA compared with slightly more than two for failed MAAs. Longer OS and PFS duration outcomes were generally associated with approvals, often when not statistically significant. The approved cohort was associated with a preponderance of statistically significant (p < .05) improvements in primary endpoints (p < .0001 difference between the approved and failed groups). Three key endpoint properties (type of endpoint [hard/surrogate], magnitude of an endpoint outcome, and its statistical significance) are consistent with the European Medicines Agency guidance and, notwithstanding the contribution of unique disease-specific circumstances, are associated with a predictable positive outcome for oncology MAAs. Regulatory decisions made by the European Medicines Agency determine which new medicines will be available to European prescribers and for which therapeutic indications. Regulatory success or failure can be influenced by many factors. This study assessed three key properties of endpoints used in

  20. Defining the end-point of mastication: A conceptual model.

    PubMed

    Gray-Stuart, Eli M; Jones, Jim R; Bronlund, John E

    2017-10-01

    properties define the end-point texture and enduring sensory perception of the food. © 2017 Wiley Periodicals, Inc.

  1. In vitro developmental neurotoxicity (DNT) testing: relevant models and endpoints.

    PubMed

    Bal-Price, Anna K; Hogberg, Helena T; Buzanska, Leonora; Lenas, Petros; van Vliet, Erwin; Hartung, Thomas

    2010-09-01

    Environmental chemicals have a potential impact on children's health as the developing brain is much more vulnerable to injury caused by different classes of chemicals than the adult brain. This vulnerability is partly due to the fact that very complex processes of cell development and maturation take place within a tightly controlled time frame. So different stages of brain development are susceptible to toxic effects at different time points. Additionally the adult brain is well protected against chemicals by the blood brain barrier (BBB) whereas the placenta only partially protects against harmful chemical exposure. Many metals easily cross the placenta and BBB barrier since even after the birth BBB is not entirely differentiated (until about 6 months after birth). Additionally, the susceptibility of infants and children is due to increased exposure, augmented absorption rates, and less efficient ability of defense mechanism in comparison to adults. The In Vitro Session during the 12th International Neurotoxicology Association meeting (Jerusalem, June, 2009) provided the opportunity to discuss the new challenges that have to be faced to create new type of safety assessments for regulatory requirements. The integration of various tests into testing strategies as well as combination of information-rich approaches with bioinformatics was discussed. Furthermore relevant models and endpoints for developmental neurotoxicity (DNT) evaluation using in vitro approach were presented. The primary neuronal cultures of cerebellar granule cells (CGCs) as well as 3D aggregate model and the possible application of human embryonic and adult stem cells was discussed pointing out the potential of these models to be used for DNT testing. The presented systems are relevant for DNT evaluation as the key processes of brain development such cell proliferation, migration and neuronal/glial differentiation are present. Furthermore, emerging technologies such as gene expression

  2. OPERA models for predicting physicochemical properties and environmental fate endpoints.

    PubMed

    Mansouri, Kamel; Grulke, Chris M; Judson, Richard S; Williams, Antony J

    2018-03-08

    The collection of chemical structure information and associated experimental data for quantitative structure-activity/property relationship (QSAR/QSPR) modeling is facilitated by an increasing number of public databases containing large amounts of useful data. However, the performance of QSAR models highly depends on the quality of the data and modeling methodology used. This study aims to develop robust QSAR/QSPR models for chemical properties of environmental interest that can be used for regulatory purposes. This study primarily uses data from the publicly available PHYSPROP database consisting of a set of 13 common physicochemical and environmental fate properties. These datasets have undergone extensive curation using an automated workflow to select only high-quality data, and the chemical structures were standardized prior to calculation of the molecular descriptors. The modeling procedure was developed based on the five Organization for Economic Cooperation and Development (OECD) principles for QSAR models. A weighted k-nearest neighbor approach was adopted using a minimum number of required descriptors calculated using PaDEL, an open-source software. The genetic algorithms selected only the most pertinent and mechanistically interpretable descriptors (2-15, with an average of 11 descriptors). The sizes of the modeled datasets varied from 150 chemicals for biodegradability half-life to 14,050 chemicals for logP, with an average of 3222 chemicals across all endpoints. The optimal models were built on randomly selected training sets (75%) and validated using fivefold cross-validation (CV) and test sets (25%). The CV Q 2 of the models varied from 0.72 to 0.95, with an average of 0.86 and an R 2 test value from 0.71 to 0.96, with an average of 0.82. Modeling and performance details are described in QSAR model reporting format and were validated by the European Commission's Joint Research Center to be OECD compliant. All models are freely available as an open

  3. Multi-Toxic Endpoints of the Foodborne Mycotoxins in Nematode Caenorhabditis elegans

    PubMed Central

    Yang, Zhendong; Xue, Kathy S.; Sun, Xiulan; Tang, Lili; Wang, Jia-Sheng

    2015-01-01

    Aflatoxins B1 (AFB1), deoxynivalenol (DON), fumonisin B1 (FB1), T-2 toxin (T-2), and zearalenone (ZEA) are the major foodborne mycotoxins of public health concerns. In the present study, the multiple toxic endpoints of these naturally-occurring mycotoxins were evaluated in Caenorhabditis elegans model for their lethality, toxic effects on growth and reproduction, as well as influence on lifespan. We found that the lethality endpoint was more sensitive for T-2 toxicity with the EC50 at 1.38 mg/L, the growth endpoint was relatively sensitive for AFB1 toxic effects, and the reproduction endpoint was more sensitive for toxicities of AFB1, FB1, and ZEA. Moreover, the lifespan endpoint was sensitive to toxic effects of all five tested mycotoxins. Data obtained from this study may serve as an important contribution to knowledge on assessment of mycotoxin toxic effects, especially for assessing developmental and reproductive toxic effects, using the C. elegans model. PMID:26633509

  4. Endpoints and cutpoints in head and neck oncology trials: methodical background, challenges, current practice and perspectives.

    PubMed

    Hezel, Marcus; von Usslar, Kathrin; Kurzweg, Thiemo; Lörincz, Balazs B; Knecht, Rainald

    2016-04-01

    This article reviews the methodical and statistical basics of designing a trial, with a special focus on the process of defining and choosing endpoints and cutpoints as the foundations of clinical research, and ultimately that of evidence-based medicine. There has been a significant progress in the treatment of head and neck cancer in the past few decades. Currently available treatment options can have a variety of different goals, depending e.g. on tumor stage, among other factors. The outcome of a specific treatment in clinical trials is measured using endpoints. Besides classical endpoints, such as overall survival or organ preservation, other endpoints like quality of life are becoming increasingly important in designing and conducting a trial. The present work is based on electronic research and focuses on the solid methodical and statistical basics of a clinical trial, on the structure of study designs and on the presentation of various endpoints.

  5. Cytogenetic and morphologic typing of 58 papillary renal cell carcinomas: evidence for a cytogenetic evolution of type 2 from type 1 tumors.

    PubMed

    Gunawan, Bastian; von Heydebreck, Anja; Fritsch, Thekla; Huber, Wolfgang; Ringert, Rolf-Hermann; Jakse, Gerhard; Füzesi, László

    2003-10-01

    We evaluated clinical characteristics, patient outcome (mean follow-up, 47 months), and cytogenetic abnormalities in the largest as yet reported cytogenetic series of 47 primary and 11 secondary papillary renal cell carcinomas for differences between the recently proposed type 1 and type 2 subtypes. Secondary tumors were more often of type 2 morphology (P = 0.02), whereas primary type 2 tumors were associated with higher clinical stage (P = 0.001) and worse patient outcome (P = 0.02). Although both subtypes had at least one of the primary chromosomal gains at 17q, 7, and 16q, type 2 tumors had moderately lower frequencies of primary gains at 17p (61 versus 94%; P = 0.007) and 17q (72 versus 97%; P = 0.02). On the other hand, type 2 tumors overall had more chromosomal alterations than type 1 tumors (P = 0.01), particularly gains of 1q (28 versus 3%; P = 0.02) and losses of 8p (33 versus 0%; P = 0.001), 11 (28 versus 3%; P = 0.02), and 18 (44 versus 9%; P = 0.01). Hierarchical clustering suggested cytogenetic patterns common but not restricted to type 2 morphology, one characterized by multiple additional gains, and another predominantly showing additional losses. These findings provide genetic evidence that type 1 and type 2 tumors arise from common cytogenetic pathways and that type 2 tumors evolve from type 1 tumors. Independently of type, losses of 9p were statistically correlated with advanced disease (P = 0.0008) and may serve as a potential adverse prognostic marker in papillary renal cell carcinomas.

  6. A data-driven weighting scheme for multivariate phenotypic endpoints recapitulates zebrafish developmental cascades

    SciTech Connect

    Zhang, Guozhu, E-mail: gzhang6@ncsu.edu

    Zebrafish have become a key alternative model for studying health effects of environmental stressors, partly due to their genetic similarity to humans, fast generation time, and the efficiency of generating high-dimensional systematic data. Studies aiming to characterize adverse health effects in zebrafish typically include several phenotypic measurements (endpoints). While there is a solid biomedical basis for capturing a comprehensive set of endpoints, making summary judgments regarding health effects requires thoughtful integration across endpoints. Here, we introduce a Bayesian method to quantify the informativeness of 17 distinct zebrafish endpoints as a data-driven weighting scheme for a multi-endpoint summary measure, called weightedmore » Aggregate Entropy (wAggE). We implement wAggE using high-throughput screening (HTS) data from zebrafish exposed to five concentrations of all 1060 ToxCast chemicals. Our results show that our empirical weighting scheme provides better performance in terms of the Receiver Operating Characteristic (ROC) curve for identifying significant morphological effects and improves robustness over traditional curve-fitting approaches. From a biological perspective, our results suggest that developmental cascade effects triggered by chemical exposure can be recapitulated by analyzing the relationships among endpoints. Thus, wAggE offers a powerful approach for analysis of multivariate phenotypes that can reveal underlying etiological processes. - Highlights: • Introduced a data-driven weighting scheme for multiple phenotypic endpoints. • Weighted Aggregate Entropy (wAggE) implies differential importance of endpoints. • Endpoint relationships reveal developmental cascade effects triggered by exposure. • wAggE is generalizable to multi-endpoint data of different shapes and scales.« less

  7. Cytogenetic and molecular characterization of plutonium-induced rat osteosarcomas.

    PubMed

    Roch-Lefevre, Sandrine; Daino, Kazuhiro; Altmeyer-Morel, Sandrine; Guilly, Marie-Noëlle; Chevillard, Sylvie

    2010-01-01

    The association between ionizing radiation and the subsequent development of osteosarcoma has been well described, but little is known about the cytogenetic and molecular events, which could be involved in the formation of radiation-induced osteosarcomas. Here, we performed comparative genomic hybridization (CGH) to detect chromosomal copy number changes in a series of 16 rat osteosarcomas induced by injection of plutonium-238. Recurrent gains/amplifications were observed at chromosomal regions 3p12-q12, 3q41-qter, 4q41-qter, 6q12-q16, 7q22-q34, 8q11-q23, 9q11-q22, 10q32.1-qter, and 12q, whereas recurrent losses were observed at 1p, 1q, 3q23-q35, 5q21-q33, 8q24-q31, 10q22-q25, 15p, 15q, and 18q. The gained region at 7q22-q34 was homologous to human chromosome bands 12q13-q15/8q24/22q11-q13, including the loci of Mdm2, Cdk4, c-Myc and Pdgf-b genes. The lost regions at 5q21-q33, 10q22-q25 and 15q contained tumor suppressor genes such as p16INK4a/p19ARF, Tp53 and Rb1. To identify potential target gene(s) for the chromosomal aberrations, we compared the expression levels of several candidate genes, located within the regions of frequent chromosomal aberrations, between the tumors and normal osteoblasts by using quantitative RT-PCR analysis. The Cdk4, c-Myc, Pdgf-b and p57KIP2 genes were thought to be possible target genes for the frequent chromosomal gain at 7q22-34 and loss at 1q in the tumors, respectively. In addition, mutations of the Tp53 gene were found in 27% (4 of 15) osteosarcomas. Our data may contribute to further understanding of the molecular mechanisms underlying osteosarcomas induced by ionizing radiation in human.

  8. Center-Within-Trial Versus Trial-Level Evaluation of Surrogate Endpoints.

    PubMed

    Renfro, Lindsay A; Shi, Qian; Xue, Yuan; Li, Junlong; Shang, Hongwei; Sargent, Daniel J

    2014-10-01

    Evaluation of candidate surrogate endpoints using individual patient data from multiple clinical trials is considered the gold standard approach to validate surrogates at both patient and trial levels. However, this approach assumes the availability of patient-level data from a relatively large collection of similar trials, which may not be possible to achieve for a given disease application. One common solution to the problem of too few similar trials involves performing trial-level surrogacy analyses on trial sub-units (e.g., centers within trials), thereby artificially increasing the trial-level sample size for feasibility of the multi-trial analysis. To date, the practical impact of treating trial sub-units (centers) identically to trials in multi-trial surrogacy analyses remains unexplored, and conditions under which this ad hoc solution may in fact be reasonable have not been identified. We perform a simulation study to identify such conditions, and demonstrate practical implications using a multi-trial dataset of patients with early stage colon cancer.

  9. Center-Within-Trial Versus Trial-Level Evaluation of Surrogate Endpoints

    PubMed Central

    Renfro, Lindsay A.; Shi, Qian; Xue, Yuan; Li, Junlong; Shang, Hongwei; Sargent, Daniel J.

    2014-01-01

    Evaluation of candidate surrogate endpoints using individual patient data from multiple clinical trials is considered the gold standard approach to validate surrogates at both patient and trial levels. However, this approach assumes the availability of patient-level data from a relatively large collection of similar trials, which may not be possible to achieve for a given disease application. One common solution to the problem of too few similar trials involves performing trial-level surrogacy analyses on trial sub-units (e.g., centers within trials), thereby artificially increasing the trial-level sample size for feasibility of the multi-trial analysis. To date, the practical impact of treating trial sub-units (centers) identically to trials in multi-trial surrogacy analyses remains unexplored, and conditions under which this ad hoc solution may in fact be reasonable have not been identified. We perform a simulation study to identify such conditions, and demonstrate practical implications using a multi-trial dataset of patients with early stage colon cancer. PMID:25061255

  10. Chronic radioisotope effects on residents of the Techa River (Russia) region: cytogenetic analysis more than 50 years after onset of exposure.

    PubMed

    Vozilova, A V; Shagina, N B; Degteva, M O; Akleyev, A V

    2013-08-30

    This paper presents the results of a cytogenetic study conducted among residents of the Techa Riverside communities (Southern Urals, Russia) exposed in the early 1950s as a result of releases of liquid radioactive wastes from the Mayak plutonium-production facility. The study was performed 50-60 years after the beginning of the exposure for those individuals who were predominantly exposed to strontium radioisotopes ((89,90)Sr) through drinking contaminated river water and consumption of local foodstuff. Standard cytogenetic methods were used for evaluation of the frequency of unstable chromosome aberrations in exposed persons as well as in persons from the control group who were of similar age and sex, living in similar socio-economic conditions in non-contaminated territories of the Southern Urals. The exposure doses were reconstructed for the studied donors using the Techa River Dosimetry System developed in 2009. The doses of internal exposure from ingested radionuclides were evaluated using individual or family in vivo measurements of (90)Sr-body burden. Individual cumulative absorbed doses in red bone marrow (RBM) in the studied persons varied in the range of 0.01-4.4Gy. A significantly higher level of unstable chromosome aberrations (UCA) in T-cells was observed in the group of exposed individuals as compared to control group. The highest UCA level was detected in the individuals who were suspected of having chronic radiation syndrome. Copyright © 2013 Elsevier B.V. All rights reserved.

  11. Cytogenetic analysis of 750 spontaneous abortions with the direct-preparation method of chorionic villi and its implications for studying genetic causes of pregnancy wastage

    PubMed Central

    Eiben, Bernd; Bartels, Iris; Bähr-Porsch, Susan; Borgmann, Sabine; Gatz, Gudrun; Gellert, Gaby; Goebel, Richard; Hammans, Wilhelm; Hentemann, Martha; Osmers, Rüdiger; Rauskolb, Rüdiger; Hansmann, Ingo

    1990-01-01

    Altogether, 750 cases of spontaneous abortion between the fifth and 25th week of gestation were analyzed cytogenetically by the direct-preparation method using chorionic villi. The majority of cases (68%) were derived from early abortions before the 12th week of gestation. The frequency of abnormal karyotypes was 50.1%; trisomy was predominant (62.1%), followed by triploidy (12.4%), monosomy X (10.5%), tetraploidy (9.2%), and structural chromosome anomalies (4.7%). Among trisomies, chromosomes 16 (21.8%), 22 (17.9%), and 21 (10.0%) were prevalent. The frequency of chromosomally abnormal abortions increased with maternal age but only because of an increase of trisomy. Polyploidy and monosomy X, however, decreased. Mean maternal age was significantly increased for trisomies 16, 21, and 22 and was highest for trisomies 18 and 20. The results obtained are within the range of variability reported earlier from tissue culture–type studies. A consistent feature during our study is the excess of females in chromosomally normal abortions (male:female sex ratio 0.71). According to the methodology applied, maternal cell contamination and undetected 46,XX molar samples cannot have influenced the sex ratio. However, a bias introduced by social status or maternal age cannot be excluded. With the more rapid and convenient direct preparation of chorionic villi, reliable cytogenetic data on causes of spontaneous abortions can be obtained. PMID:2220806

  12. Enabling Live Internet Broadcasting Using an Application Endpoint Architecture

    DTIC Science & Technology

    2005-05-09

    students and staff members in the ESM project: Aditya Ganjam , Eugene Ng, Kunwadee Sripanidkulchai, and Jibin Zhan. Much of the work in Chapter 3 is...dissertation. Chapter 2 is joint work with fellow student Sanjay Rao. Chapter 3 is joint work with Aditya Ganjam , Eugene Ng, Sanjay Rao, Kunwadee...Networked Systems (PINS), August 2004. [16] Y. Chu, A. Ganjam , T. Ng, S. Rao, K. Sripanidkulchai, J. Zhan, and H. Zhang. Early Experi- ence with an

  13. The reality of cancer treatment in a developing country: the effects of delayed TKI treatment on survival, cytogenetic and molecular responses in chronic myeloid leukaemia patients.

    PubMed

    Kurtovic-Kozaric, Amina; Hasic, Azra; Radich, Jerald P; Bijedic, Vildan; Nefic, Hilada; Eminovic, Izet; Kurtovic, Sabira; Colakovic, Ferida; Kozaric, Mirza; Vranic, Semir; Bovan, Nada S

    2016-02-01

    Cancer patients in developing and low-income countries have limited access to target therapies. For example, tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukaemia patients (CML) is often delayed. In Bosnia, 16% of patients received immediate TKI treatment (<3 months of diagnosis), while 66% of patients received therapy after a median 14-month wait period. To assess the effect of delayed treatment on outcome, three patient groups were studied according to the time they received TKI treatment (0-5 months, 6-12 months and >13 months delay). The primary endpoints were complete cytogenetic (CCyR) and major molecular response (MMR) at 12 months. At 12 months of therapy, CCyR and MMR rates on imatinib decreased significantly: CCyR was achieved in 67% of patients in the immediate imatinib treatment group, 18% of patients in 6-12 months group and 15% of patients in >13 months wait group. MMR rates at 12 months occurred in 10% of patients with immediate treatment, 6% of those in 6-12 months group and 0% of patients in >13 months wait group. However, CCyR and MMR rates in patients on nilotinib were not associated with duration of treatment delay. Our data suggests that the deleterious effect of a prolonged TKI therapy delay may be ameliorated by the more active TKI nilotinib. © 2015 John Wiley & Sons Ltd.

  14. Prognostic discrimination for early chronic phase chronic myeloid leukemia in imatinib era: comparison of Sokal, Euro, and EUTOS scores in Korean population.

    PubMed

    Yahng, Seung-Ah; Jang, Eun-Jung; Choi, Soo-Young; Lee, Sung-Eun; Kim, Soo-Hyun; Kim, Dong-Wook

    2014-08-01

    Beyond the conventional Sokal and Euro scores, a new prognostic risk classification, based on the European Treatment Outcome Study (EUTOS), has been developed to predict the outcome of treatment with tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML). In the present study, each risk score was validated by various endpoints in 206 Korean patients with early chronic-phase CML treated with up-front standard dose imatinib. In our analysis, all three scores were found to be valid. The 5-year event-free survival (EFS) was significantly discriminated using Sokal (P = 0.002), Euro (P = 0.003), and EUTOS (P = 0.029), with the worst probability by Euro high-risk (62 vs. 49 vs. 67 %) and better EFS in Sokal low-risk (89 vs. 86 vs. 82 %). Combining all scores identified 6 % of all patients having homogeneous high-risk with distinctively worse outcomes (5-year EFS of 41 %, cumulative complete cytogenetic response rate of 56 %, and cumulative major molecular response rate of 27 %), whereas the group of discordance in risk scores (60 %) had similar results to those of intermediate-risk groups of Sokal and Euro scores. Combining all risk scores for baseline risk assessment may be useful in clinical practice for identifying groups of patients who may benefit from treatment initiation with a more potent TKI among the currently available first-line TKIs.

  15. The use of molecular and cytogenetic methods as a valuable tool in the detection of chromosomal abnormalities in horses: a case of sex chromosome chimerism in a Spanish purebred colt.

    PubMed

    Demyda-Peyrás, S; Membrillo, A; Bugno-Poniewierska, M; Pawlina, K; Anaya, G; Moreno-Millán, M

    2013-01-01

    Chromosomal abnormalities associated to sex chromosomes are reported as a problem more common than believed to be in horses. Most of them remain undiagnosed due to the complexity of the horse karyotype and the lack of interest of breeders and veterinarians in this type of diagnosis. Approximately 10 years ago, the Spanish Purebred Breeders Association implemented a DNA paternity test to evaluate the pedigree of every newborn foal. All candidates who showed abnormal or uncertain results are routinely submitted to cytogenetical analysis to evaluate the presence of chromosomal abnormalities. We studied the case of a foal showing 3 and even 4 different alleles in several loci in the short tandem repeat (STR) -based DNA parentage test. To confirm these results, a filiation test was repeated using follicular hair DNA showing normal results. A complete set of conventional and molecular cytogenetic analysis was performed to determine their chromosomal complements. C-banding and FISH had shown that the foal presents a sex chimerism 64,XX/64,XY with a cellular percentage of approximately 70/30, diagnosed in blood samples. The use of a diagnostic approach combining routine parentage QF-PCR-based STR screening tested with classical or molecular cytogenetic analysis could be a powerful tool that allows early detection of foals that will have a poor or even no reproductive performance due to chromosomal abnormalities, saving time, efforts and breeders' resources. Copyright © 2013 S. Karger AG, Basel.

  16. CYTOGENETIC STUDIES IN MICE TREATED WITH THE JET FUELS, JET-A AND JP-8

    EPA Science Inventory

    Cytogenetic studies in mice treated with the jet fuels, Jet-A and JP-8
    Abstract
    The genotoxic potential of the jet fuels, Jet-A and JP-8, were examined in mice treated on the skin with a single dose of 240 ug/mouse. Peripheral blood smears were prepared at the start of the ...

  17. Cytogenetic Profile of de novo Acute Myeloid Leukemia Patients in Malaysia.

    PubMed

    Meng, Chin Yuet; Noor, Puteri J; Ismail, Azli; Ahid, Mohd Fadly Md; Zakaria, Zubaidah

    2013-03-01

    Acute myeloid leukemia (AML) is a heterogeneous disease in terms of cytogenetics and molecular genetics. AML is the most common acute leukemia in adults and its incidence increases with age. Diagnostic cytogenetics is an important prognostic indicator for predicting outcome of AML. We examined the karyotypic patterns of 480 patients with de novo AML seen at government hospitals throughout the country and evaluated the association of chromosome aberrations with the age of patient. Chromosome abnormalities were detected in 146 (30.4%) patients. The most common cytogenetic abnormality was balanced translocation t (8; 21), followed by trisomy 8 (as sole abnormality) and t (15; 17). The age of our Malaysian patients at diagnosis ranged from four months to 81 years, with a median age of 39 years. The normal karyotype was found mainly in patients aged 15-30 years. About 75% of patients with t (8; 21) were below 40 years of age, and the complex karyotype was found with the highest frequently (34.3%) in elderly patients (age above 60 years). More than half of the patients with complex karyotype were above 50 years of age. The deletion 5q was detected only in patients aged above 50 years. Different cytogenetic abnormalities in AML show different frequencies with increasing age. Probably different genetic mechanisms are involved in the pathogenesis of AML and these mechanisms might occur at different frequencies over lifetime.

  18. Xp11.2 Translocation Renal Cell Carcinoma Diagnosed by Immunohistochemistry and Cytogenetics.

    PubMed

    Dey, Biswajit; Badhe, Bhawana; Govindarajan, Krishna Kumar; Ramesh, Ranjith Arumbakkam

    2016-01-01

    Xp11.2 translocation renal cell carcinomas (TRCCs) are a group of neoplasms with distinct clinical, histopathological appearance, immunohistochemical, and cytogenetic profile. We report a case of Xp11.2 translocation TRCC in an 11-year-old male diagnosed based on immunohistochemistry and fluorescence in situ hybridization.

  19. Xp11.2 Translocation Renal Cell Carcinoma Diagnosed by Immunohistochemistry and Cytogenetics

    PubMed Central

    Dey, Biswajit; Badhe, Bhawana; Govindarajan, Krishna Kumar; Ramesh, Ranjith Arumbakkam

    2016-01-01

    Xp11.2 translocation renal cell carcinomas (TRCCs) are a group of neoplasms with distinct clinical, histopathological appearance, immunohistochemical, and cytogenetic profile. We report a case of Xp11.2 translocation TRCC in an 11-year-old male diagnosed based on immunohistochemistry and fluorescence in situ hybridization. PMID:27365924

  20. Describing sequencing results of structural chromosome rearrangements with a suggested next-generation cytogenetic nomenclature.

    PubMed

    Ordulu, Zehra; Wong, Kristen E; Currall, Benjamin B; Ivanov, Andrew R; Pereira, Shahrin; Althari, Sara; Gusella, James F; Talkowski, Michael E; Morton, Cynthia C

    2014-05-01

    With recent rapid advances in genomic technologies, precise delineation of structural chromosome rearrangements at the nucleotide level is becoming increasingly feasible. In this era of "next-generation cytogenetics" (i.e., an integration of traditional cytogenetic techniques and next-generation sequencing), a consensus nomenclature is essential for accurate communication and data sharing. Currently, nomenclature for describing the sequencing data of these aberrations is lacking. Herein, we present a system called Next-Gen Cytogenetic Nomenclature, which is concordant with the International System for Human Cytogenetic Nomenclature (2013). This system starts with the alignment of rearrangement sequences by BLAT or BLAST (alignment tools) and arrives at a concise and detailed description of chromosomal changes. To facilitate usage and implementation of this nomenclature, we are developing a program designated BLA(S)T Output Sequence Tool of Nomenclature (BOSToN), a demonstrative version of which is accessible online. A standardized characterization of structural chromosomal rearrangements is essential both for research analyses and for application in the clinical setting. Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  1. Blood Specimens From Patients Referred for Cytogenetic Analysis: Vanderbilt University Experience From 1985 to 1992

    PubMed Central

    BUTLER, MERLIN G.; HAMILL, TRACY

    2017-01-01

    Cytogenetic records were examined from consecutive nononcology blood specimens from 2,821 patients referred for cytogenetic services to Vanderbilt University Medical Center, Nashville, Tenn, from January 1985 to December 1992. We grouped the records according to reasons for referral and diagnoses. The most common reasons for referral were history of multiple abortions/miscarriages (23.3%), possibility of chromosomal abnormality (18.8%), and possible presence of the fragile X syndrome (15.6%). Overall, 2,418 (85.7%) patients were found to have normal chromosomes, and 403 (14.3%) patients were diagnosed with a cytogenetic abnormality. For example, 20 (5.4%) of the 373 males referred for the fragile X syndrome, or 1.4% of all males (20 of 1,428) excluding those with ambiguous genitalia, were diagnosed with this syndrome while 8 (2.1%) of the 373 males had a chromosome abnormality other than the fragile X chromosome. In addition, 85 (70.2%) of 121 males referred for Down syndrome had this syndrome, and only 53 (40.8%) of 130 females referred for Down syndrome had this diagnosis. This study should assist physicians in middle Tennessee and surrounding areas by increasing their awareness of the types and frequencies of cytogenetic diseases and by providing figures for comparison with other regions of the country. PMID:7886528

  2. Minimal residual disease evaluation by flow cytometry is a complementary tool to cytogenetics for treatment decisions in acute myeloid leukaemia.

    PubMed

    Vidriales, María-Belén; Pérez-López, Estefanía; Pegenaute, Carlota; Castellanos, Marta; Pérez, José-Juan; Chandía, Mauricio; Díaz-Mediavilla, Joaquín; Rayón, Consuelo; de Las Heras, Natalia; Fernández-Abellán, Pascual; Cabezudo, Miguel; de Coca, Alfonso García; Alonso, Jose M; Olivier, Carmen; Hernández-Rivas, Jesús M; Montesinos, Pau; Fernández, Rosa; García-Suárez, Julio; García, Magdalena; Sayas, María-José; Paiva, Bruno; González, Marcos; Orfao, Alberto; San Miguel, Jesús F

    2016-01-01

    The clinical utility of minimal residual disease (MRD) analysis in acute myeloid leukaemia (AML) is not yet defined. We analysed the prognostic impact of MRD level at complete remision after induction therapy using multiparameter flow cytometry in 306 non-APL AML patients. First, we validated the prognostic value of MRD-thresholds we have previously proposed (≥ 0.1%; ≥ 0.01-0.1%; and <0.01), with a 5-year RFS of 38%, 50% and 71%, respectively (p=0.002). Cytogenetics is the most relevant prognosis factor in AML, however intermediate risk cytogenetics represent a grey zone that require other biomarkers for risk stratification, and we show that MRD evaluation discriminate three prognostic subgroups (p=0.03). Also, MRD assessments yielded relevant information on favourable and adverse cytogenetics, since patients with favourable cytogenetics and high MRD levels have poor prognosis and patients with adverse cytogenetics but undetectable MRD overcomes the adverse prognosis. Interestingly, in patients with intermediate or high MRD levels, intensification with transplant improved the outcome as compared with chemotherapy, while the type of intensification therapy did not influenced the outcome of patients with low MRD levels. Multivariate analysis revealed age, MRD and cytogenetics as independent variables. Moreover, a scoring system, easy in clinical practice, was generated based on MRD level and cytogenetics. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Case-control cytogenetic study in offspring of mothers treated with bromocriptine during early pregnancy.

    PubMed

    Czeizel, A; Kiss, R; Rácz, K; Mohori, K; Gláz, E

    1989-01-01

    The distribution of modal and non-modal karyotypes was examined in mitoses of lymphocyte cultures of 31 children who had been exposed to bromocriptine in utero, and in 31 matched controls. No mosaicism was diagnosed. Furthermore, no more hypomodal cells occurred in the study group than in the control group.

  4. Meta-analyses evaluating surrogate endpoints for overall survival in cancer randomized trials: A critical review.

    PubMed

    Savina, Marion; Gourgou, Sophie; Italiano, Antoine; Dinart, Derek; Rondeau, Virginie; Penel, Nicolas; Mathoulin-Pelissier, Simone; Bellera, Carine

    2018-03-01

    In cancer randomized controlled trials (RCT), alternative endpoints are increasingly being used in place of overall survival (OS) to reduce sample size, duration and cost of trials. It is necessary to ensure that these endpoints are valid surrogates for OS. Our aim was to identify meta-analyses that evaluated surrogate endpoints for OS and assess the strength of evidence for each meta-analysis (MA). We performed a systematic review to identify MA of cancer RCTs assessing surrogate endpoints for OS. We evaluated the strength of the association between the endpoints based on (i) the German Institute of Quality and Efficiency in Health Care guidelines and (ii) the Biomarker-Surrogate Evaluation Schema. Fifty-three publications reported on 164 MA, with heterogeneous statistical methods Disease-free survival (DFS) and progression-free survival (PFS) showed good surrogacy properties for OS in colorectal, lung and head and neck cancers. DFS was highly correlated to OS in gastric cancer. The statistical methodology used to evaluate surrogate endpoints requires consistency in order to facilitate the accurate interpretation of the results. Despite the limited number of clinical settings with validated surrogate endpoints for OS, there is evidence of good surrogacy for DFS and PFS in tumor types that account for a large proportion of cancer cases. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. A comparison of chemoembolization endpoints using angiographic versus transcatheter intraarterial perfusion/MR imaging monitoring.

    PubMed

    Lewandowski, Robert J; Wang, Dingxin; Gehl, James; Atassi, Bassel; Ryu, Robert K; Sato, Kent; Nemcek, Albert A; Miller, Frank H; Mulcahy, Mary F; Kulik, Laura; Larson, Andrew C; Salem, Riad; Omary, Reed A

    2007-10-01

    Transcatheter arterial chemoembolization (TACE) is an established treatment for unresectable liver cancer. This study was conducted to test the hypothesis that angiographic endpoints during TACE are measurable and reproducible by comparing subjective angiographic versus objective magnetic resonance (MR) endpoints of TACE. The study included 12 consecutive patients who presented for TACE for surgically unresectable HCC or progressive hepatic metastases despite chemotherapy. All procedures were performed with a dedicated imaging system. Angiographic series before and after TACE were reviewed independently by three board-certified interventional radiologists. A subjective angiographic chemoembolization endpoint (SACE) classification scheme, modified from an established angiographic grading system in the cardiology literature, was designed to assist in reproducibly classifying angiographic endpoints. Reproducibility in SACE classification level was compared among operators, and MR imaging perfusion reduction was compared with SACE levels for each observer. Twelve patients successfully underwent 15 separate TACE sessions. SACE levels ranged from I through IV. There was moderate agreement in SACE classification (kappa = 0.46 +/- 0.12). There was no correlation between SACE level and MR perfusion reduction (r = 0.16 for one operator and 0.02 for the other two). Angiographic endpoints during TACE vary widely, have moderate reproducibility among operators, and do not correlate with functional MR imaging perfusion endpoints. Future research should aim to determine ideal angiographic and functional MR imaging endpoints for TACE according to outcome measures such as imaging response, pathologic response, and survival.

  6. A step towards standardization: A method for end-point titer determination by fluorescence index of an automated microscope. End-point titer determination by fluorescence index.

    PubMed

    Carbone, Teresa; Gilio, Michele; Padula, Maria Carmela; Tramontano, Giuseppina; D'Angelo, Salvatore; Pafundi, Vito

    2018-05-01

    Indirect Immunofluorescence (IIF) is widely considered the Gold Standard for Antinuclear Antibody (ANA) screening. However, the high inter-reader variability remains the major disadvantage associated with ANA testing and the main reason for the increasing demand of the computer-aided immunofluorescence microscope. Previous studies proposed the quantification of the fluorescence intensity as an alternative for the classical end-point titer evaluation. However, the different distribution of bright/dark light linked to the nature of the self-antigen and its location in the cells result in different mean fluorescence intensities. The aim of the present study was to correlate Fluorescence Index (F.I.) with end-point titers for each well-defined ANA pattern. Routine serum samples were screened for ANA testing on HEp-2000 cells using Immuno Concepts Image Navigator System, and positive samples were serially diluted to assign the end-point titer. A comparison between F.I. and end-point titers related to 10 different staining patterns was made. According to our analysis, good technical performance of F.I. (97% sensitivity and 94% specificity) was found. A significant correlation between quantitative reading of F.I. and end-point titer groups was observed using Spearman's test and regression analysis. A conversion scale of F.I. in end-point titers for each recognized ANA-pattern was obtained. The Image Navigator offers the opportunity to improve worldwide harmonization of ANA test results. In particular, digital F.I. allows quantifying ANA titers by using just one sample dilution. It could represent a valuable support for the routine laboratory and an effective tool to reduce inter- and intra-laboratory variability. Copyright © 2018. Published by Elsevier B.V.

  7. Sublethal Toxicity Endpoints of Heavy Metals to the Nematode Caenorhabditis elegans

    PubMed Central

    Wu, Yue; Wang, Qiang; Li, Huixin

    2016-01-01

    Caenorhabditis elegans, a free-living nematode, is commonly used as a model organism in ecotoxicological studies. The current literatures have provided useful insight into the relative sensitivity of several endpoints, but few direct comparisons of multiple endpoints under a common set of experimental conditions. The objective of this study was to determine appropriate sublethal endpoints to develop an ecotoxicity screening and monitoring system. C. elegans was applied to explore the sublethal toxicity of four heavy metals (copper, zinc, cadmium and chromium). Two physiological endpoints (growth and reproduction), three behavioral endpoints (head thrash frequency, body bend frequency and feeding) and two enzymatic endpoints (acetylcholine esterase [AChE] and superoxide dismutase [SOD]) were selected for the assessment of heavy metal toxicity. The squared correlation coefficients (R2) between the responses observed and fitted by Logit function were higher than 0.90 and the RMSE were lower than 0.10, indicating a good significance statistically. There was no significant difference among the half effect concentration (EC50) endpoints in physiological and behavioral effects of the four heavy metals, indicating similar sensitivity of physiological and behavioral effects. AChE enzyme was more sensitive to copper, zinc, and cadmium than to other physiological and behavioral effects, and SOD enzyme was most sensitive to chromium. The EC50 of copper, zinc, and cadmium, to the AChE enzyme in the nematodes were 0.68 mg/L, 2.76 mg/L, and 0.92 mg/L respectively and the EC50 of chromium to the SOD enzyme in the nematode was 1.58 mg/L. The results of this study showed that there was a good concentration-response relationship between all four heavy metals and the sublethal toxicity effects to C. elegans. Considering these sublethal endpoints in terms of simplicity, accuracy, repeatability and costs of the experiments, feeding is the relatively ideal sublethal toxicity endpoint of

  8. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper.

    PubMed

    Herzog, Thomas J; Armstrong, Deborah K; Brady, Mark F; Coleman, Robert L; Einstein, Mark H; Monk, Bradley J; Mannel, Robert S; Thigpen, J Tate; Umpierre, Sharee A; Villella, Jeannine A; Alvarez, Ronald D

    2014-01-01

    To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies

  9. Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper

    PubMed Central

    Herzog, Thomas J.; Armstrong, Deborah K.; Brady, Mark F.; Coleman, Robert L.; Einstein, Mark H.; Monk, Bradley J.; Mannel, Robert S.; Thigpen, J. Tate; Umpierre, Sharee A.; Villella, Jeannine A.; Alvarez, Ronald D.

    2015-01-01

    Objective To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. Methods A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. Results Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. Conclusions Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect

  10. Reliability of a Manual Procedure for Marking the EZ Endpoint Location in Patients with Retinitis Pigmentosa

    PubMed Central

    Ramachandran, Rithambara; Cai, Cindy X.; Lee, Dongwon; Epstein, Benjamin C.; Locke, Kirsten G.; Birch, David G.; Hood, Donald C.

    2016-01-01

    Purpose We developed and evaluated a training procedure for marking the endpoints of the ellipsoid zone (EZ), also known as the inner segment/outer segment (IS/OS) border, on frequency domain optical coherence tomography (fdOCT) scans from patients with retinitis pigmentosa (RP). Methods A manual for marking EZ endpoints was developed and used to train 2 inexperienced graders. After training, an experienced grader and the 2 trained graders marked the endpoints on fdOCT horizontal line scans through the macula from 45 patients with RP. They marked the endpoints on these same scans again 1 month later. Results Intragrader agreement was excellent. The intraclass correlation coefficient (ICC) was 0.99, the average difference of endpoint locations (19.6 μm) was close to 0 μm, and the 95% limits were between −284 and 323 μm, approximately ±1.1°. Intergrader agreement also was excellent. The ICC values were 0.98 (time 1) and 0.97 (time 2), the average difference among graders was close to zero, and the 95% limits of these differences was less than 350 μm, approximately 1.2°, for both test times. Conclusions While automated algorithms are becoming increasingly accurate, EZ endpoints still have to be verified manually and corrected when necessary. With training, the inter- and intragrader agreement of manually marked endpoints is excellent. Translational Relevance For clinical studies, the EZ endpoints can be marked by hand if a training procedure, including a manual, is used. The endpoint confidence intervals, well under ±2.0°, are considerably smaller than the 6° spacing for the typically used static visual field. PMID:27226930

  11. Gene expression profiles in auricle skin as a possible additional endpoint for determination of sensitizers: A multi-endpoint evaluation of the local lymph node assay.

    PubMed

    Tsuchiyama, Hiromi; Maeda, Akihisa; Nakajima, Mayumi; Kitsukawa, Mika; Takahashi, Kei; Miyoshi, Tomoya; Mutsuga, Mayu; Asaoka, Yoshiji; Miyamoto, Yohei; Oshida, Keiyu

    2017-10-05

    The murine local lymph node assay (LLNA) is widely used to test chemicals to induce skin sensitization. Exposure of mouse auricle skin to a sensitizer results in proliferation of local lymph node T cells, which has been measured by in vivo incorporation of H 3 -methyl thymidine or 5-bromo-2'-deoxyuridine (BrdU). The stimulation index (SI), the ratio of the mean proliferation in each treated group to that in the concurrent vehicle control group, is frequently used as a regulatory-authorized endpoint for LLNA. However, some non-sensitizing irritants, such as sodium dodecyl sulfate (SDS) or methyl salicylate (MS), have been reported as false-positives by this endpoint. In search of a potential endpoint to enhance the specificity of existing endpoints, we evaluated 3 contact sensitizers; (hexyl cinnamic aldehyde [HCA], oxazolone [OXA], and 2,4-dinitrochlorobenzene [DNCB]), 1 respiratory sensitizer (toluene 2,4-diisocyanate [TDI]), and 2 non-sensitizing irritants (MS and SDS) by several endpoints in LLNA. Each test substance was applied to both ears of female CBA/Ca mice daily for 3 consecutive days. The ears and auricle lymph node cells were analyzed on day 5 for endpoints including the SI value, lymph node cell count, cytokine release from lymph node cells, and histopathological changes and gene expression profiles in auricle skin. The SI values indicated that all the test substances induced significant proliferation of lymph node cells. The lymph node cell counts showed no significant changes by the non-sensitizers assessed. The inflammatory findings of histopathology were similar among the auricle skins treated by sensitizers and irritants. Gene expression profiles of cytokines IFN-γ, IL-4, and IL-17 in auricle skin were similar to the cytokine release profiles in draining lymph node cells. In addition, the gene expression of the chemokine CXCL1 and/or CXCL2 showed that it has the potential to discriminate sensitizers and non-sensitizing irritants. Our results

  12. Role of cytogenetic biomarkers in management of chronic kidney disease patients: A review.

    PubMed

    Khan, Zeba; Pandey, Manoj; Samartha, Ravindra M

    2016-10-01

    Chronic kidney disease (CKD) is much more common than people recognize, and habitually goes undetected and undiagnosed until the disease is well advanced or when their kidney functions is down to 25% of normal function. Genetic and non-genetic factors contribute to cause CKD. Non-genetic factors include hypertension, High level of DNA damage due to the production of reactive oxygen species and nucleic acid oxidation has been reported in CKD patients. Main genetic factor which causes CKD is diabetic nephropathy. A three- to nine-fold greater risk of End Stage Renal Disease (ESRD) is observed in individuals with a family history of ESRD. This greater risk have led researchers to search for genes linked to diabetic and other forms of nephropathy for the management of CKD. Multicenter consortia are currently recruiting large numbers of multiplex diabetic families with index cases having nephropathy for linkage and association analyses using various cytogenetic techniques. In addition, large-scale screening studies are underway, with the goals of better defining the overall prevalence of chronic kidney disease, as well as educating the population about risk factors for nephropathy, including family history. Cytogenetic biomarkers play an imperative role for the linkage study using G banding and detection of genomic instability in CKD patients. Classical and molecular cytogenetic tools with cytogenetic biomarkers provide remarkable findings in CKD patients. The aim of the present review is to draw outline of classical and molecular cytogenetic findings in CKD patients and their possible role in management to reduce genomic instability in CKD patients.

  13. [From cytogenetics to cytogenomics of dermatofibrosarcoma protuberans family of tumors].

    PubMed

    Bianchini, Laurence; Maire, Georges; Pedeutour, Florence

    2007-02-01

    Dermatofibrosarcoma protuberans (DP) is a rare, slow growing dermal neoplasm of intermediate malignancy. It is made of spindle-shaped tumor cells in a storiform pattern often positive for CD34. The preferred treatment for DP is a surgical wide excision with pathologically sane margins of 3 cm. At the cytogenetic level, DP cells are characterized by either supernumerary ring chromosomes composed of sequences derived from chromosomes 17 and 22 or more rarely of translocations t(17;22). Rings have been mainly observed in adults whereas translocations have been reported in all pediatric cases. These chromosomal rearrangements lead to the formation of a specific fusion gene : COL1A1-PDGFB detected in rings as well as in translocations. DP is therefore a unique example of tumor in which the same molecular event occurs either on rings or linear translocation derivatives and the chromosomal abnormalities display an age-related pattern. So far, the COL1A1-PDGFB fusion gene remains the only fusion gene identified in this tumor. It is also present in variant forms of DP such as giant cell fibroblastoma, Bednar tumor, adult superficial fibrosarcoma and the granular cell variant of DP demonstrating that these tumors are not distinct entities but morphological variants of DP. The breakpoint localization in PDGFB was found to be remarkably constant, placing exon 2 of PDGFB under the control of the COL1A1 promoter. In contrast, the COL1A1 breakpoint was found to be variably located within the exons of the alpha-helical coding region (exons 7-47). No correlation between the breakpoint location in COL1A1 and the age of the patient or any clinical or histological particularity has been established. Moreover, no preferential breakpoint appears to be more particularly linked to one or another variant of DP. The COL1A1-PDGFB fusion gene is detectable either by multiplex RT-PCR with a combination of forward primers designed from a variety of COL1A1 exons and one reverse primer for PDGFB

  14. The Brief Pain Inventory and its "pain at its worst in the last 24 hours" item: clinical trial endpoint considerations.

    PubMed

    Atkinson, Thomas M; Mendoza, Tito R; Sit, Laura; Passik, Steven; Scher, Howard I; Cleeland, Charles; Basch, Ethan

    2010-03-01

    In 2006, the United States Food and Drug Administration (FDA) released a draft Guidance for Industry on the use of patient-reported outcomes (PRO) Measures in Medical Product Development to Support Labeling Claims. This draft guidance outlines psychometric aspects that should be considered when designing a PRO measure, including conceptual framework, content validity, construct validity, reliability, and the ability to detect clinically meaningful score changes. When finalized, it may provide a blueprint for evaluations of PRO measures that can be considered by sponsors and investigators involved in PRO research and drug registration trials. In this review we examine the short form of the Brief Pain Inventory (BPI) and particularly the "pain at its worst in the last 24 hours" item in the context of the FDA draft guidance, to assess its utility in clinical trials that include pain as a PRO endpoint. After a systematic evaluation of the psychometric aspects of the BPI, we conclude that the BPI and its "pain at its worst in the last 24 hours" item generically satisfy most key recommendations outlined in the draft guidance for assessing a pain-reduction treatment effect. Nonetheless, when the BPI is being considered for assessment of pain endpoints in a registration trial, sponsors and investigators should consult with the appropriate FDA division early during research design to discuss whether there is sufficient precedent to use the instrument in the population of interest or whether additional evaluations of measurement properties are advisable.

  15. Approving cancer treatments based on endpoints other than overall survival: an analysis of historical data using the PACE Continuous Innovation Indicators™ (CII).

    PubMed

    Brooks, Neon; Campone, Mario; Paddock, Silvia; Shortenhaus, Scott; Grainger, David; Zummo, Jacqueline; Thomas, Samuel; Li, Rose

    2017-01-01

    There is an active debate about the role that endpoints other than overall survival (OS) should play in the drug approval process. Yet the term 'surrogate endpoint' implies that OS is the only critical metric for regulatory approval of cancer treatments. We systematically analyzed the relationship between U.S. Food and Drug Administration (FDA) approval and publication of OS evidence to understand better the risks and benefits of delaying approval until OS evidence is available. Using the PACE Continuous Innovation Indicators (CII) platform, we analyzed the effects of cancer type, treatment goal, and year of approval on the lag time between FDA approval and publication of first significant OS finding for 53 treatments approved between 1952 and 2016 for 10 cancer types (n = 71 approved indications). Greater than 59% of treatments were approved before significant OS data for the approved indication were published. Of the drugs in the sample, 31% had lags between approval and first published OS evidence of 4 years or longer. The average number of years between approval and first OS evidence varied by cancer type and did not reliably predict the eventual amount of OS evidence accumulated. Striking the right balance between early access and minimizing risk is a central challenge for regulators worldwide. We illustrate that endpoints other than OS have long helped to provide timely access to new medicines, including many current standards of care. We found that many critical drugs are approved many years before OS data are published, and that OS may not be the most appropriate endpoint in some treatment contexts. Our examination of approved treatments without significant OS data suggests contexts where OS may not be the most relevant endpoint and highlights the importance of using a wide variety of fit-for-purpose evidence types in the approval process.

  16. An entropy-based nonparametric test for the validation of surrogate endpoints.

    PubMed

    Miao, Xiaopeng; Wang, Yong-Cheng; Gangopadhyay, Ashis

    2012-06-30

    We present a nonparametric test to validate surrogate endpoints based on measure of divergence and random permutation. This test is a proposal to directly verify the Prentice statistical definition of surrogacy. The test does not impose distributional assumptions on the endpoints, and it is robust to model misspecification. Our simulation study shows that the proposed nonparametric test outperforms the practical test of the Prentice criterion in terms of both robustness of size and power. We also evaluate the performance of three leading methods that attempt to quantify the effect of surrogate endpoints. The proposed method is applied to validate magnetic resonance imaging lesions as the surrogate endpoint for clinical relapses in a multiple sclerosis trial. Copyright © 2012 John Wiley & Sons, Ltd.

  17. Selecting surrogate endpoints for estimating pesticide effects on avian reproductive success.

    PubMed

    Bennett, Richard S; Etterson, Matthew A

    2013-10-01

    A Markov chain nest productivity model (MCnest) has been developed for projecting the effects of a specific pesticide-use scenario on the annual reproductive success of avian species of concern. A critical element in MCnest is the use of surrogate endpoints, defined as measured endpoints from avian toxicity tests that represent specific types of effects possible in field populations at specific phases of a nesting attempt. In this article, we discuss the attributes of surrogate endpoints and provide guidance for selecting surrogates from existing avian laboratory tests as well as other possible sources. We also discuss some of the assumptions and uncertainties related to using surrogate endpoints to represent field effects. The process of explicitly considering how toxicity test results can be used to assess effects in the field helps identify uncertainties and data gaps that could be targeted in higher-tier risk assessments. © 2013 SETAC.

  18. Predicting Treatment Effect from Surrogate Endpoints and Historical Trials | Division of Cancer Prevention

    Cancer.gov

    By Stuart G. Baker, 2017 Introduction This software fits a zero-intercept random effects linear model to data on surrogate and true endpoints in previous trials. Requirement:  Mathematica Version 11 or later. |

  19. PREDICTING TOXICOLOGICAL ENDPOINTS OF CHEMICALS USING QUANTITATIVE STRUCTURE-ACTIVITY RELATIONSHIPS (QSARS)

    EPA Science Inventory

    Quantitative structure-activity relationships (QSARs) are being developed to predict the toxicological endpoints for untested chemicals similar in structure to chemicals that have known experimental toxicological data. Based on a very large number of predetermined descriptors, a...

  20. 78 FR 46351 - Trial Designs and Endpoints for Liver Disease Secondary to Nonalcoholic Steatohepatitis; Public...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-07-31

    ...- associated liver disease, and FDA, will be engaged to address challenging issues related to selection of... for endpoints will be explored. The state of knowledge of the natural history of NAFLD will also be...

  1. Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

    PubMed

    Waliszewski, Matthias; Rittger, Harald

    2016-10-01

    Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300-700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit further thoughts and explorations

  2. Surrogate and clinical endpoints in interventional cardiology: are statistics the brakes?

    PubMed Central

    Waliszewski, Matthias; Rittger, Harald

    2016-01-01

    Background: Randomized controlled trials are the gold standard for demonstrating safety and efficacy of coronary devices with or without accompanying drug treatments in interventional cardiology. With the advent of last-generation drug-eluting stents having enhanced technical attributes and long-term clinical benefits, the proof of incremental angiographic or long-term clinical efficacy becomes more challenging. The purpose of this review is to provide an overview of the most common and alternative study endpoints in interventional cardiology and their potential reimbursement value. Moreover, we intend to describe the statistical limitations in order to demonstrate differences between potential treatment groups. Furthermore, careful endpoint recommendations for a given patient number are offered for future study designs. Methods: The number of patients per treatment group was estimated for various study designs such as noninferiority test hypotheses with hard clinical endpoints and various surrogate endpoints. To test for differences in various surrogate endpoint scenarios, the corresponding patient group sizes were explored. To evaluate these endpoints in terms of their reimbursement impact, preferred endpoints for technical appraisals in interventional cardiology at the National Institute of Health and Care Excellence (NICE) were used. Results: Even with the most stringent experimental control to reduce bias-introducing factors, studies with hard primary clinical endpoints such as the occurrence of major adverse cardiac events (MACE) or target-lesion revascularization (TLR) rates remain the gold standard, with numbers reaching into the 300–700 patient range per group. Study designs using loss in fractional-flow reserve (FFR) or stent-strut-coverage rates can be statistically formulated; however, the clinical ramifications for the patient remain to be discussed. Nonrandomized study designs with intrapatient angiographic controls in nontarget vessels may merit

  3. End-point controller design for an experimental two-link flexible manipulator using convex optimization

    NASA Technical Reports Server (NTRS)

    Oakley, Celia M.; Barratt, Craig H.

    1990-01-01

    Recent results in linear controller design are used to design an end-point controller for an experimental two-link flexible manipulator. A nominal 14-state linear-quadratic-Gaussian (LQG) controller was augmented with a 528-tap finite-impulse-response (FIR) filter designed using convex optimization techniques. The resulting 278-state controller produced improved end-point trajectory tracking and disturbance rejection in simulation and experimentally in real time.

  4. Implications of the Institute of Medicine Report: Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease.

    PubMed

    Wagner, J A; Ball, J R

    2015-07-01

    The Institute of Medicine (IOM) released a groundbreaking 2010 report, Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Key recommendations included a harmonized scientific process and a general framework for biomarker evaluation with three interrelated steps: (1) Analytical validation -- is the biomarker measurement accurate? (2) Qualification -- is the biomarker associated with the clinical endpoint of concern? (3) Utilization -- what is the specific context of the proposed use? © 2015 American Society for Clinical Pharmacology and Therapeutics.

  5. The art and science of choosing efficacy endpoints for rare disease clinical trials.

    PubMed

    Cox, Gerald F

    2018-04-01

    An important challenge in rare disease clinical trials is to demonstrate a clinically meaningful and statistically significant response to treatment. Selecting the most appropriate and sensitive efficacy endpoints for a treatment trial is part art and part science. The types of endpoints should align with the stage of development (e.g., proof of concept vs. confirmation of clinical efficacy). The patient characteristics and disease stage should reflect the treatment goal of improving disease manifestations or preventing disease progression. For rare diseases, regulatory approval requires demonstration of clinical benefit, defined as how a patient, feels, functions, or survives, in at least one adequate and well-controlled pivotal study conducted according to Good Clinical Practice. In some cases, full regulatory approval can occur using a validated surrogate biomarker, while accelerated, or provisional, approval can occur using a biomarker that is likely to predict clinical benefit. Rare disease studies are small by necessity and require the use of endpoints with large effect sizes to demonstrate statistical significance. Understanding the quantitative factors that determine effect size and its impact on powering the study with an adequate sample size is key to the successful choice of endpoints. Interpreting the clinical meaningfulness of an observed change in an efficacy endpoint can be justified by statistical methods, regulatory precedence, and clinical context. Heterogeneous diseases that affect multiple organ systems may be better accommodated by endpoints that assess mean change across multiple endpoints within the same patient rather than mean change in an individual endpoint across all patients. © 2018 Wiley Periodicals, Inc.

  6. The Use of Surrogate Endpoints in Regulating Medicines for Cardio-Renal Disease: Opinions of Stakeholders

    PubMed Central

    Schievink, Bauke; Lambers Heerspink, Hiddo; Leufkens, Hubert; De Zeeuw, Dick; Hoekman, Jarno

    2014-01-01

    Aim There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. Methods We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. Results Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9) or when there is an unmet clinical need (mean score: 3.8, SD: 1.2). Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP), HbA1c, albuminuria, CRP) for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1). Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. Conclusion Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them. PMID:25268242

  7. Evaluating surrogate endpoints, prognostic markers, and predictive markers: Some simple themes.

    PubMed

    Baker, Stuart G; Kramer, Barnett S

    2015-08-01

    A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the unobserved true endpoint. A prognostic marker is a marker for predicting the risk of an event given a control treatment; it informs treatment decisions when there is information on anticipated benefits and harms of a new treatment applied to persons at high risk. A predictive marker is a marker for predicting the effect of treatment on outcome in a subgroup of patients or study participants; it provides more rigorous information for treatment selection than a prognostic marker when it is based on estimated treatment effects in a randomized trial. We organized our discussion around a different theme for each topic. "Fundamentally an extrapolation" refers to the non-statistical considerations and assumptions needed when using surrogate endpoints to evaluate a new treatment. "Decision analysis to the rescue" refers to use the use of decision analysis to evaluate an additional prognostic marker because it is not possible to choose between purely statistical measures of marker performance. "The appeal of simplicity" refers to a straightforward and efficient use of a single randomized trial to evaluate overall treatment effect and treatment effect within subgroups using predictive markers. The simple themes provide a general guideline for evaluation of surrogate endpoints, prognostic markers, and predictive markers. © The Author(s) 2014.

  8. Biomarkers and Surrogate Endpoints in Drug Development: A European Regulatory View.

    PubMed

    Wickström, Kerstin; Moseley, Jane

    2017-05-01

    To give a European regulatory overview of the requirements on and the use of biomarkers or surrogate endpoints in the development of drugs for ocular disease. Definitions, methods to validate new markers, and circumstances where surrogate endpoints can be appropriate are summarized. The key endpoints that have been used in registration studies so far are based on visual acuity, signs, and symptoms, or on surrogate endpoints. In some ocular conditions, established outcome measures such as those based on visual acuity or visual field are not feasible (as with slowly progressing diseases), or lack relevance (e.g., when central visual acuity may be preserved even though the patient is legally blind owing to a severely restricted visual field, or vice versa). There are several ocular conditions for which there is an unmet medical need. In some of these conditions, surrogate endpoints as well as new clinical endpoints are needed to help speed up patient access to new medicines. Interaction with European regulators through the pathway specific for the development of biomarkers or novel methods is encouraged.

  9. Evaluating surrogate endpoints, prognostic markers, and predictive markers — some simple themes

    PubMed Central

    Baker, Stuart G.; Kramer, Barnett S.

    2014-01-01

    Background A surrogate endpoint is an endpoint observed earlier than the true endpoint (a health outcome) that is used to draw conclusions about the effect of treatment on the unobserved true endpoint. A prognostic marker is a marker for predicting the risk of an event given a control treatment; it informs treatment decisions when there is information on anticipated benefits and harms of a new treatment applied to persons at high risk. A predictive marker is a marker for predicting the effect of treatment on outcome in a subgroup of patients or study participants; it provides more rigorous information for treatment selection than a prognostic marker when it is based on estimated treatment effects in a randomized trial. Methods We organized our discussion around a different theme for each topic. Results “Fundamentally an extrapolation” refers to the non-statistical considerations and assumptions needed when using surrogate endpoints to evaluate a new treatment. “Decision analysis to the rescue” refers to use the use of decision analysis to evaluate an additional prognostic marker because it is not possible to choose between purely statistical measures of marker performance. “The appeal of simplicity” refers to a straightforward and efficient use of a single randomized trial to evaluate overall treatment effect and treatment effect within subgroups using predictive markers. Conclusion The simple themes provide a general guideline for evaluation of surrogate endpoints, prognostic markers, and predictive markers. PMID:25385934

  10. The use of surrogate endpoints in regulating medicines for cardio-renal disease: opinions of stakeholders.

    PubMed

    Schievink, Bauke; Lambers Heerspink, Hiddo; Leufkens, Hubert; De Zeeuw, Dick; Hoekman, Jarno

    2014-01-01

    There is discussion whether medicines can be authorized on the market based on evidence from surrogate endpoints. We assessed opinions of different stakeholders on this topic. We conducted an online questionnaire that targeted various stakeholder groups (regulatory agencies, pharmaceutical industry, academia, relevant public sector organisations) and medical specialties (cardiology or nephrology vs. other). Participants were enrolled through purposeful sampling. We inquired for conditions under which surrogate endpoints can be used, the validity of various cardio-renal biomarkers and new approaches for biomarker use. Participants agreed that surrogate endpoints can be used when the surrogate is scientifically valid (5-point Likert response format, mean score: 4.3, SD: 0.9) or when there is an unmet clinical need (mean score: 3.8, SD: 1.2). Industry participants agreed to a greater extent than regulators and academics. However, out of four proposed surrogates (blood pressure (BP), HbA1c, albuminuria, CRP) for cardiovascular outcomes or end-stage renal disease, only use of BP for cardiovascular outcomes was deemed moderately accurate (mean: 3.6, SD: 1.1). Specialists in cardiology or nephrology tended to be more positive about the use of surrogate endpoints. Stakeholders in drug development do not oppose to the use of surrogate endpoints in drug marketing authorization, but most surrogates are not considered valid. To solve this impasse, increased efforts are required to validate surrogate endpoints and to explore alternative ways to use them.

  11. A quantitative analysis of statistical power identifies obesity endpoints for improved in vivo preclinical study design

    PubMed Central

    Selimkhanov, Jangir; Thompson, W. Clayton; Guo, Juen; Hall, Kevin D.; Musante, Cynthia J.

    2017-01-01

    The design of well-powered in vivo preclinical studies is a key element in building knowledge of disease physiology for the purpose of identifying and effectively testing potential anti-obesity drug targets. However, as a result of the complexity of the obese phenotype, there is limited understanding of the variability within and between study animals of macroscopic endpoints such as food intake and body composition. This, combined with limitations inherent in the measurement of certain endpoints, presents challenges to study design that can have significant consequences for an anti-obesity program. Here, we analyze a large, longitudinal study of mouse food intake and body composition during diet perturbation to quantify the variability and interaction of key metabolic endpoints. To demonstrate how conclusions can change as a function of study size, we show that a simulated pre-clinical study properly powered for one endpoint may lead to false conclusions based on secondary endpoints. We then propose guidelines for endpoint selection and study size estimation under different conditions to facilitate proper power calculation for a more successful in vivo study design. PMID:28392555

  12. Clinical Trial Principles and Endpoint Definitions for Paravalvular Leaks in Surgical Prosthesis: An Expert Statement.

    PubMed

    Ruiz, Carlos E; Hahn, Rebecca T; Berrebi, Alain; Borer, Jeffrey S; Cutlip, Donald E; Fontana, Greg; Gerosa, Gino; Ibrahim, Reda; Jelnin, Vladimir; Jilaihawi, Hasan; Jolicoeur, E Marc; Kliger, Chad; Kronzon, Itzhak; Leipsic, Jonathon; Maisano, Francesco; Millan, Xavier; Nataf, Patrick; O'Gara, Patrick T; Pibarot, Philippe; Ramee, Stephen R; Rihal, Charanjit S; Rodes-Cabau, Josep; Sorajja, Paul; Suri, Rakesh; Swain, Julie A; Turi, Zoltan G; Tuzcu, E Murat; Weissman, Neil J; Zamorano, Jose L; Serruys, Patrick W; Leon, Martin B

    2017-04-25

    The VARC (Valve Academic Research Consortium) for transcatheter aortic valve replacement set the standard for selecting appropriate clinical endpoints reflecting safety and effectiveness of transcatheter devices, and defining single and composite clinical endpoints for clinical trials. No such standardization exists for circumferentially sutured surgical valve paravalvular leak (PVL) closure. This document seeks to provide core principles, appropriate clinical endpoints, and endpoint definitions to be used in clinical trials of PVL closure devices. The PVL Academic Research Consortium met to review evidence and make recommendations for assessment of disease severity, data collection, and updated endpoint definitions. A 5-class grading scheme to evaluate PVL was developed in concordance with VARC recommendations. Unresolved issues in the field are outlined. The current PVL Academic Research Consortium provides recommendations for assessment of disease severity, data collection, and endpoint definitions. Future research in the field is warranted. Copyright © 2017 American College of Cardiology Foundation and European Society of Cardiology. Published by Elsevier Inc. All rights reserved.

  13. Clinical endpoints in allogeneic hematopoietic stem cell transplantation studies: the cost of freedom.

    PubMed

    Kim, Haesook T; Armand, Philippe

    2013-06-01

    When designing a study for allogeneic hematopoietic stem cell transplantation (HSCT), many choices must be made, including conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prevention method. For each of these, there are a growing number of options, which can be combined into a bewildering number of possible HSCT protocols. To properly interpret the results of a given strategy and compare them with others, it is essential that there be agreement on the definitions and estimation methods of HSCT endpoints. We report a survey of the recent HSCT literature that confirms the heterogeneity of endpoint definitions and estimation methods used. Unfortunately, this heterogeneity may lead to significant biases in the estimates of key endpoints, including nonrelapse mortality, relapse, GVHD, or engraftment. This can preclude adequate comparisons among studies, even though such comparisons are the major tool with which to improve HSCT outcome. In the context of our survey, we discuss some of the statistical issues that arise when dealing with HSCT endpoints and the ramifications of the choice of endpoint definition, when the endpoint occurs in the context of competing risks. Our hope is to generate discussion and motivate a search for consensus among those who perform transplantations and statisticians. Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  14. The use of intermediate endpoints in the design of type 1 diabetes prevention trials.

    PubMed

    Krischer, Jeffrey P

    2013-09-01

    This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials.

  15. The use of intermediate endpoints in the design of type 1 diabetes prevention trials

    PubMed Central

    Krischer, Jeffrey P.

    2013-01-01

    Aims/hypothesis This paper presents a rationale for the selection of intermediate endpoints to be used in the design of type 1 diabetes prevention clinical trials. Methods Relatives of individuals diagnosed with type 1 diabetes were enrolled on the TrialNet Natural History Study and screened for diabetes-related autoantibodies. Those with two or more such autoantibodies were analysed with respect to increased HbA1c, decreased C-peptide following an OGTT, or abnormal OGTT values as intermediate markers of disease progression. Results Over 2 years, a 10% increase in HbA1c, and a 20% or 30% decrease in C-peptide from baseline, or progression to abnormal OGTT, occurred with a frequency between 20% and 41%. The 3- to 5-year risk of type 1 diabetes following each intermediate endpoint was high, namely 47% to 84%. The lower the incidence of the endpoint being reached, the higher the risk of diabetes. A diabetes prevention trial using these intermediate endpoints would require a 30% to 50% smaller sample size than one using type 1 diabetes as the endpoint. Conclusions/interpretation The use of an intermediate endpoint in diabetes prevention is based on the generally held view of disease progression from initial occurrence of autoantibodies through successive immunological and metabolic changes to manifest type 1 diabetes. Thus, these markers are suitable for randomised phase 2 trials, which can more rapidly screen promising new therapies, allowing them to be subsequently confirmed in definitive phase 3 trials. PMID:23744306

  16. Physiological and lavage fluid cytological and biochemical endpoints of toxicity in the rat

    SciTech Connect

    Lehnert, B.E.

    1992-01-01

    Exposure of the respiratory tract to toxic materials can result in a variety of physiologic disturbances that can serve as endpoints of toxicity. In addition to a brief review of commonly assessed physiologic endpoints, attention is given in the first component of this report to the use of both nose breathing and mouth'' breathing rats in toxicity studies that involve measurements of ventilatory functional changes in response to test atmospheres. Additionally, the usefulness of maximum oxygen consumption, or VO[sub 2max], as a physiologic endpoint of toxicity that uses exercising rats after exposure to test atmospheres is described, along with anmore » introduction to post-exposure exercise as an important behavioral activity that can markedly impact on the severity of acute lung injury caused by pneumoedematogenic materials. The second component of this report focuses on bronchoalveolar lavage and cytological and biochemical endpoints that can be assessed in investigations of the toxicities of test materials. As will be shown herein, some of the biochemical endpoints of toxicity, especially, can sensitively detect subtle injury to the lower respiratory tract that may escape detection by changes in some other conventional endpoints of toxicity, including lung gravimetric increases and histopathological alterations.« less

  17. Physiological and lavage fluid cytological and biochemical endpoints of toxicity in the rat

    SciTech Connect

    Lehnert, B.E.

    1992-12-31

    Exposure of the respiratory tract to toxic materials can result in a variety of physiologic disturbances that can serve as endpoints of toxicity. In addition to a brief review of commonly assessed physiologic endpoints, attention is given in the first component of this report to the use of both nose breathing and ``mouth`` breathing rats in toxicity studies that involve measurements of ventilatory functional changes in response to test atmospheres. Additionally, the usefulness of maximum oxygen consumption, or VO{sub 2max}, as a physiologic endpoint of toxicity that uses exercising rats after exposure to test atmospheres is described, along with anmore » introduction to post-exposure exercise as an important behavioral activity that can markedly impact on the severity of acute lung injury caused by pneumoedematogenic materials. The second component of this report focuses on bronchoalveolar lavage and cytological and biochemical endpoints that can be assessed in investigations of the toxicities of test materials. As will be shown herein, some of the biochemical endpoints of toxicity, especially, can sensitively detect subtle injury to the lower respiratory tract that may escape detection by changes in some other conventional endpoints of toxicity, including lung gravimetric increases and histopathological alterations.« less

  18. Development of Cardiovascular and Neurodevelopmental Metrics as Sublethal Endpoints for the Fish Embryo Toxicity Test.

    PubMed

    Krzykwa, Julie C; Olivas, Alexis; Jeffries, Marlo K Sellin

    2018-06-19

    The fathead minnow fish embryo toxicity (FET) test has been proposed as a more humane alternative to current toxicity testing methods, as younger organisms are thought to experience less distress during toxicant exposure. However, the FET test protocol does not include endpoints that allow for the prediction of sublethal adverse outcomes, limiting its utility relative to other test types. Researchers have proposed the development of sublethal endpoints for the FET test to increase its utility. The present study 1) developed methods for previously unmeasured sublethal metrics in fathead minnows (i.e., spontaneous contraction frequency and heart rate) and 2) investigated the responsiveness of several sublethal endpoints related to growth (wet weight, length, and growth-related gene expression), neurodevelopment (spontaneous contraction frequency, and neurodevelopmental gene expression), and cardiovascular function and development (pericardial area, eye size and cardiovascular related gene expression) as additional FET test metrics using the model toxicant 3,4-dichloroaniline. Of the growth, neurological and cardiovascular endpoints measured, length, eye size and pericardial area were found to more responsive than the other endpoints, respectively. Future studies linking alterations in these endpoints to longer-term adverse impacts are needed to fully evaluate the predictive power of these metrics in chemical and whole effluent toxicity testing. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  19. 76 FR 35450 - Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-17

    ...] Draft Guidance for Industry on Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer... entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Drugs and Biologics... draft guidance for industry entitled ``Clinical Trial Endpoints for the Approval of Non-Small Cell Lung...

  20. Identification of novel cytogenetic markers with prognostic significance in a series of 968 patients with primary myelodysplastic syndromes.

    PubMed

    Solé, Francesc; Luño, Elisa; Sanzo, Carmen; Espinet, Blanca; Sanz, Guillermo F; Cervera, José; Calasanz, María José; Cigudosa, Juan Cruz; Millà, Fuensanta; Ribera, Josep Maria; Bureo, Encarna; Marquez, Maria Luisa; Arranz, Eva; Florensa, Lourdes

    2005-09-01

    The main prognostic factors in myelodysplastic syndromes (MDS) are chromosomal abnormalities, the proportion of blasts in bone marrow and number and degree of cytopenias. A consensus-defined International Prognostic Scoring System (IPSS) for predicting outcome and planning therapy in MDS has been developed, but its prognostic value in a large and independent series remains unproven. Furthermore, the intermediate-risk cytogenetic subgroup defined by the IPSS includes a miscellaneous number of different single abnormalities of uncertain prognostic significance at present. The main aim of the present study was to identify chromosomal abnormalities with a previously unrecognized good or poor prognosis in order to find new cytogenetic markers with predictive value. We report the cytogenetic findings in a series of 968 patients with primary MDS from the Spanish Cytogenetics Working Group, Grupo Cooperativo Español de Citogenética Hematológica (GCECGH). In this series of 968 MDS patients, we found various cytogenetic aberrations with a new prognostic impact. Complex karyotype, -7/7q- and i(17q) had a poor prognosis; normal karyotype, loss of Y chromosome, deletion 11q, deletion 12p and deletion 20q as single alterations had a good prognosis. Intermediate prognosis aberrations were rearrangements of 3q21q26, trisomy 8, trisomy 9, translocations of 11q and del(17p). Finally, a new group of single or double cytogenetic abnormalities, most of which are considered rare cytogenetic events and are usually included in the intermediate category of the IPSS, showed a trend to poor prognosis. This study suggests that some specific chromosomal abnormalities could be segregated from the IPSS intermediate-risk cytogenetic prognostic subgroup and included in the low risk or in the poor risk groups.

  1. A web-based endpoint adjudication system for interim analyses in clinical trials.

    PubMed

    Nolen, Tracy L; Dimmick, Bill F; Ostrosky-Zeichner, Luis; Kendrick, Amy S; Sable, Carole; Ngai, Angela; Wallace, Dennis

    2009-02-01

    A data monitoring committee (DMC) is often employed to assess trial progress and review safety data and efficacy endpoints throughout a trail. Interim analyses performed for the DMC should use data that are as complete and verified as possible. Such analyses are complicated when data verification involves subjective study endpoints or requires clinical expertise to determine each subject's status with respect to the study endpoint. Therefore, procedures are needed to obtain adjudicated data for interim analyses in an efficient manner. In the past, methods for handling such data included using locally reported results as surrogate endpoints, adjusting analysis methods for unadjudicated data, or simply performing the adjudication as rapidly as possible. These methods all have inadequacies that make their sole usage suboptimal. For a study of prophylaxis for invasive candidiasis, adjudication of both study eligibility criteria and clinical endpoints prior to two interim analyses was required. Because the study was expected to enroll at a moderate rate and the sponsor required adjudicated endpoints to be used for interim analyses, an efficient process for adjudication was required. We created a web-based endpoint adjudication system (WebEAS) that allows for expedited review by the endpoint adjudication committee (EAC). This system automatically identifies when a subject's data are complete, creates a subject profile from the study data, and assigns EAC reviewers. The reviewers use the WebEAS to review the subject profile and submit their completed review form. The WebEAS then compares the reviews, assigns an additional review as a tiebreaker if needed, and stores the adjudicated data. The study for which this system was originally built was administratively closed after 10 months with only 38 subjects enrolled. The adjudication process was finalized and the WebEAS system activated prior to study closure. Some website accessibility issues presented initially. However

  2. Genetic and cytogenetic analysis of the fruit fly Rhagoletis cerasi (Diptera: Tephritidae).

    PubMed

    Kounatidis, Ilias; Papadopoulos, Nikolaos; Bourtzis, Kostas; Mavragani-Tsipidou, Penelope

    2008-07-01

    The European cherry fruit fly, Rhagoletis cerasi, is a major agricultural pest for which biological, genetic, and cytogenetic information is limited. We report here a cytogenetic analysis of 4 natural Greek populations of R. cerasi, all of them infected with the endosymbiotic bacterium Wolbachia pipientis. The mitotic karyotype and detailed photographic maps of the salivary gland polytene chromosomes of this pest species are presented here. The mitotic metaphase complement consists of 6 pairs of chromosomes, including one pair of heteromorphic sex chromosomes, with the male being the heterogametic sex. The analysis of the salivary gland polytene complement has shown a total of 5 long chromosomes (10 polytene arms) that correspond to the 5 autosomes of the mitotic nuclei and a heterochromatic mass corresponding to the sex chromosomes. The most prominent landmarks of each polytene chromosome, the "weak points", and the unusual asynapsis of homologous pairs of polytene chromosomes at certain regions of the polytene elements are also presented and discussed.

  3. [Cytogenetic characteristics of seed progeny of trees under condition of antropogenic contamination in Voronezh town].

    PubMed

    Butorina, A K; Kalaev, V N; Vostrikova, T V; Miagkova, O E

    2000-01-01

    It has been shown that in seed progeny of Quercus robur L., Pinus sylvestris L. and Betula pendula Roth. some cytogenetical characteristics vary under conditions of contamination. Such changes may be common or specific type. Thus, the frequency of pathological mitosis increases under such conditions in all the investigated species of trees. Inhibition of mitosis was found in the progeny of the pine, and variability in the number of nucleoli was detected in the pine and oak. However, in some cases the level of pathological mitosis in the oak progeny did not differ from the control, but the mitotic activity was higher due to the presence of much more cells being at the prophase stage. In the birch progeny under conditions of contamination the mitotic index increased, with a simultaneous shifts in the peaks of mitotic activity. The possibility of using these cytological characteristics for the aims of cytogenetical monitoring is considered.

  4. Case report: Concomitant Chronic Lymphocytic Leukaemia and Cytogenetically Normal de novo Acute Leukaemia in a Patient.

    PubMed

    Kajtár, Béla; Rajnics, Péter; Egyed, Miklós; Alizadeh, Hussain

    2015-01-01

    The simultaneous occurrence of acute myeloid leukaemia with untreated chronic lymphocytic leukemia is extremely rare. We report a case of a 74-year-old man who was evaluated for macrocytic anaemia. Based on the morphology and immunophenotyping analysis of peripheral blood, a diagnosis of chronic lymphocytic leukemia was established. Subsequently, the bone marrow examination revealed the presence of two distinct, coexisting CLL and AML clones. Cytogenetic and molecular genetic analysis detected deletion 13q14.3 and unmutated immunoglobulin variable heavy-chain in the CLL clone, only. The AML and CLL clones did not share clonality, and the AML did not involve the peripheral blood. A diagnosis of cytogenetically normal de novo AML occurring concurrently with untreated CLL has not been reported previously in English literature. © 2015 by the Association of Clinical Scientists, Inc.

  5. Comparative Cytogenetic Study on the Toxicity of Magnetite and Zinc Ferrite Nanoparticles in Sunflower Root Cells

    NASA Astrophysics Data System (ADS)

    Foca-nici, Ecaterina; Capraru, Gabriela; Creanga, Dorina

    2010-12-01

    In this experimental study the authors present their results regarding the cellular division rate and the percentage of chromosomal aberrations in the root meristematic cells of Helianthus annuus cultivated in the presence of different volume fractions of magnetic nanoparticle suspensions, ranging between 20 and 100 microl/l. The aqueous magnetic colloids were prepared from chemically co-precipitated ferrites coated in sodium oleate. Tissue samples from the root meristeme of 2-3 day old germinated seeds were taken to prepare microscope slides following Squash method combined with Fuelgen techniques. Microscope investigation (cytogenetic tests) has resulted in the evaluation of mitotic index and chromosomal aberration index that appeared diminished and respectively increased following the addition of magnetic nanoparticles in the culture medium of the young seedlings. Zinc ferrite toxic influence appeared to be higher than that of magnetite, according to both cytogenetic parameters.

  6. [Cytogenetic effects in Koeleria gracilis Pers. populations from the Semipalatinsk proving ground].

    PubMed

    Geras'kin, S A; Mozolin, E M; Dikarev, V G; Udalova, A A; Dikareva, N S; Spiridonov, S I; Teten'kin, V L

    2009-01-01

    The proliferative activity and the frequency of cytogenetic disturbances in apical meristem of coleoptile sprouts at germination of seeds collected from crested hairgrass populations inhabiting contrast in level of radioactive contamination sites of the Semipalatinsk test site (Kazakhstan) are studied. Sampling of biological material and soil was carrying out during three years (2005-2007). The absorbed dose to critical organs of crested hairgrass vary depending on a site from 2.8 up to 262.2 mGy/year. A sognificant correlation between the frequency of cytogenetic disturbances in apical meristem and dose absorbed in crested hairgrass critical organs is found. Devere aberrations such as single and double bridges make the main contribution to spectrum of structural mutations as well as lagging chromosomes. In spite of the fact that the crested hairgrass populations have occupied the sites with a high level of radioactive contamination for a long time, the data analysis fails to reveal radio-adaptation effect.

  7. Cytogenetic biomonitoring carried out in a village (Dolon) adjacent to the Semipalatinsk nuclear weapon test site.

    PubMed

    Testa, A; Stronati, L; Ranaldi, R; Spanò, M; Steinhäusler, F; Gastberger, M; Hubmer, A; Ptitskaya, L; Akhmetov, M

    2001-06-01

    The Semipalatinsk region (Kazakhstan Republic) has been affected by extensive radioactive contamination due to more than 450 nuclear tests of which almost 100 were exploded in the atmosphere. The present results refer to cytogenetic assessments in a study cohort of the population of Dolon, a settlement located on the NE boundary of the nuclear weapon test site, which was exposed to elevated doses of ionising radiation primarily due to the first Soviet nuclear test in 1949. Conventional cytogenetic analyses were carried out on 21 blood samples from individuals (more than 50 years old) living in Dolon since the very beginning of nuclear testing. A matched control group included 20 individuals living in non-contaminated areas. Higher frequencies of chromosome aberrations were found in the Dolon cohort compared to the control group, even though they remain within the range of the background levels reported for large normal human population studies on elderly individuals.

  8. Platinum(II) and palladium(II) complexes with 2-acetylpyridine thiosemicarbazone: cytogenetic and antineoplastic effects.

    PubMed

    Lakovidou, Z; Papageorgiou, A; Demertzis, M A; Mioglou, E; Mourelatos, D; Kotsis, A; Yadav, P N; Kovala-Demertzi, D

    2001-01-01

    The effect of three novel complexes of Pt(II) and three complexes of Pd(II) with 2-acetylpyridine thiosemicarbazone (HAcTsc) on sister chromatid exchange (SCE) rates and human lymphocyte proliferation kinetics on a molar basis was studied. Also, the effect of Pt(II) and Pd(II) complexes against leukemia P388 was investigated. Among these compounds, the most effective in inducing antitumor and cytogenetic effects were the complexes [Pt(AcTsc)2] x H2O and [Pd(AcTsc)2] while the rest, i.e. (HAcTsc), [Pt(AcTsc)Cl], [Pt(HAcTsc)2]Cl2 x 2H2O, [Pd(AcTsc)Cl] and [Pd(HAcTsc)2]Cl2, displayed marginal cytogenetic and antitumor effects.

  9. Two Decades of Cardiovascular Trials With Primary Surrogate Endpoints: 1990-2011.

    PubMed

    Bikdeli, Behnood; Punnanithinont, Natdanai; Akram, Yasir; Lee, Ike; Desai, Nihar R; Ross, Joseph S; Krumholz, Harlan M

    2017-03-21

    Surrogate endpoint trials test strategies more efficiently but are accompanied by uncertainty about the relationship between changes in surrogate markers and clinical outcomes. We identified cardiovascular trials with primary surrogate endpoints published in the New England Journal of Medicine , Lancet , and JAMA: Journal of the American Medical Association from 1990 to 2011 and determined the trends in publication of surrogate endpoint trials and the success of the trials in meeting their primary endpoints. We tracked for publication of clinical outcome trials on the interventions tested in surrogate trials. We screened 3016 articles and identified 220 surrogate endpoint trials. From the total of 220 surrogate trials, 157 (71.4%) were positive for their primary endpoint. Only 59 (26.8%) surrogate trials had a subsequent clinical outcomes trial. Among these 59 trials, 24 outcomes trial results validated the positive surrogates, whereas 20 subsequent outcome trials were negative following positive results on a surrogate. We identified only 3 examples in which the surrogate trial was negative but a subsequent outcomes trial was conducted and showed benefit. Findings were consistent in a sample cohort of 383 screened articles inclusive of 37 surrogate endpoint trials from 6 other high-impact journals. Although cardiovascular surrogate outcomes trials frequently show superiority of the tested intervention, they are infrequently followed by a prominent outcomes trial. When there was a high-profile clinical outcomes study, nearly half of the positive surrogate trials were not validated. Cardiovascular surrogate outcome trials may be more appropriate for excluding benefit from the patient perspective than for identifying it. © 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

  10. Computational fluid dynamics endpoints to characterize obstructive sleep apnea syndrome in children

    PubMed Central

    Luo, Haiyan; Persak, Steven C.; Sin, Sanghun; McDonough, Joseph M.; Isasi, Carmen R.; Arens, Raanan

    2013-01-01

    Computational fluid dynamics (CFD) analysis may quantify the severity of anatomical airway restriction in obstructive sleep apnea syndrome (OSAS) better than anatomical measurements alone. However, optimal CFD model endpoints to characterize or assess OSAS have not been determined. To model upper airway fluid dynamics using CFD and investigate the strength of correlation between various CFD endpoints, anatomical endpoints, and OSAS severity, in obese children with OSAS and controls. CFD models derived from magnetic resonance images were solved at subject-specific peak tidal inspiratory flow; pressure at the choanae was set by nasal resistance. Model endpoints included airway wall minimum pressure (Pmin), flow resistance in the pharynx (Rpharynx), and pressure drop from choanae to a minimum cross section where tonsils and adenoids constrict the pharynx (dPTAmax). Significance of endpoints was analyzed using paired comparisons (t-test or Wilcoxon signed rank test) and Spearman correlation. Fifteen subject pairs were analyzed. Rpharynx and dPTAmax were higher in OSAS than control and most significantly correlated to obstructive apnea-hypopnea index (oAHI), r = 0.48 and r = 0.49, respectively (P < 0.01). Airway minimum cross-sectional correlation to oAHI was weaker (r = −0.39); Pmin was not significantly correlated. CFD model endpoints based on pressure drops in the pharynx were more closely associated with the presence and severity of OSAS than pressures including nasal resistance, or anatomical endpoints. This study supports the usefulness of CFD to characterize anatomical restriction of the pharynx and as an additional tool to evaluate subjects with OSAS. PMID:24265282

  11. Comparing three novel endpoints for developmental osteotoxicity in the embryonic stem cell test

    SciTech Connect

    Nieden, Nicole I. zur, E-mail: nicole.zurnieden@ucr.ed; Department of Cell Biology and Neuroscience and Stem Cell Center, University of California Riverside, Riverside, CA 92521; Fraunhofer Institute for Cell Therapy and Immunology, Perlickstrasse 1, 04103 Leipzig

    Birth defects belong to the most serious side effects of pharmaceutical compounds or environmental chemicals. In vivo, teratogens most often affect the normal development of bones, causing growth retardation, limb defects or craniofacial malformations. The embryonic stem cell test (EST) is one of the most promising models that allow the in vitro prediction of embryotoxicity, with one of its endpoints being bone tissue development. The present study was designed to describe three novel inexpensive endpoints to assess developmental osteotoxicity using the model compounds penicillin G (non-teratogenic), 5-fluorouracil (strong teratogen) and all-trans retinoic acid (bone teratogen). These three endpoints were: quantificationmore » of matrix incorporated calcium by (1) morphometric analysis and (2) measurement of calcium levels as well as (3) activity of alkaline phosphatase, an enzyme involved in matrix calcification. To evaluate our data, we have compared the concentration curves and resulting ID{sub 50}s of the new endpoints with mRNA expression for osteocalcin. Osteocalcin is an exclusive marker found only in mineralized tissues, is regulated upon compound treatment and reliably predicts the potential of a chemical entity acting as a bone teratogen. By comparing the new endpoints to quantitative expression of osteocalcin, which we previously identified as suitable to detect developmental osteotoxicity, we were ultimately able to illustrate IMAGE analysis and Ca{sup 2+} deposition assays as two reliable novel endpoints for the EST. This is of particular importance for routine industrial assessment of novel compounds as these two new endpoints may substitute previously used molecular read-out methods, which are often costly and time-consuming.« less

  12. Cytogenetic data on the threatened leafcutter ant Atta robusta Borgmeier, 1939 (Formicidae: Myrmicinae: Attini).

    PubMed

    Barros, Luísa Antônia Campos; Aguiar, Hilton Jeferson Alves Cardoso de; Teixeira, Gisele Amaro; Mariano, Cléa Dos Santos Ferreira; Teixeira, Marcos da Cunha; Delabie, Jacques Hubert Charles; Pompolo, Silvia das Graças

    2015-10-01

    The karyotype of the threatened ant species Atta robusta is described so as to establish the evolutionary relationships of this taxon with other leafcutter ants. Standard Giemsa staining, C-banding, NOR banding, fluorochromes CMA3/DAPI, Hsc-FA technique and Fluorescence in situ Hybridization (FISH) using 18S rDNA probe were conducted on a population from Aracruz, state of Espírito Santo, Brazil, allowing for comparisons with data available on Atta and other fungus-growing ant species. The diploid chromosome number observed for A. robusta was 2n=22, and the karyotypic formula was 18m+2sm+2st. Heterochromatic blocks were observed in the centromeric region of most chromosomes, where one pair of metacentric chromosomes is characterized by a GC-rich heterochromatic band in the interstitial region of its long arm. The detection of 18S rDNA using FISH confirmed the presence of single NOR for A. robusta. This is the first report of rDNA 18S detection using FISH for leafcutter ants. The cytogenetic results of this study confirm the information available for Atta and allow us to confirm the conserved chromosome number, morphology and banding pattern within the genus for the taxa studied to date, which included species from three out of the four groups of Atta indicated by molecular data. The accumulation of cytogenetic data on fungus-growing ants enhances the understanding of the genomic evolutionary patterns of Atta, since it belongs to a group of recent origin between the most well studied ants. Cytogenetic data does not indicate restrictions in relocation or reintroduction in areas where populations were extinct due to the conserved karyotype. This study allows for cytogenetic comparison of A. robusta with other ants of Atta, emphasizing the importance of chromosomal information for species conservation. Copyright © 2015 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  13. Modification of cytogenetic and physiological effects of space flight factors by biologically active compounds

    NASA Technical Reports Server (NTRS)

    Aliyev, A. A.; Mekhti-Zade, E. R.; Mashinskiy, A. L.; Alekperov, U. K.

    1986-01-01

    Physiological and cytogenetic changes in the Welsh onion plants induced by a short (82 days) and long term (522 days) space flight are expressed in decrease of seed germination, inhibition of stem growth, depression of cell division in root meristem, and increase in the number of structural chromosome rearrangements. The treatment of such plants with solutions of a-tocopherol, auxin, and kinetin decreased the level of chromosome aberrations to the control one and normalized cell divisions and growth partly or completely.

  14. [Cytogenetic analysis of genotoxic effects in subjects employed in heat power industry].

    PubMed

    Savchenko, Ia A; Druzhinin, V G; Minina, V I; Glushkov, A N; Akhmat'ianova, V R; Ostaptseva, A V; Shibaldin, A V; Vetrova, I V

    2008-06-01

    Chromosomal aberration rate has been estimated in peripheral blood lymphocytes of subjects occupationally exposed to a set of hazardous factors (employees of the Kemerovo Heat Power Plant). The frequency of metaphases with aberrations in the workers (3.23 +/- 0.26%, N = 104) is significantly higher than in control subjects (2.11 +/- 0.28%, N = 70). The cytogenetic aberrations did not depend on the sex, age, duration of employment, or smoking.

  15. Comparative cytogenetics among populations of Astyanax altiparanae (Characiformes, Characidae, Incertae sedis)

    PubMed Central

    2009-01-01

    Cytogenetic data are presented for Astyanax altiparanae populations from three Brazilian hydrographic systems. The chromosomal data obtained in A. altiparanae support the hypothesis of diploid number conservation. However, small differences in the karyotype formula and number of nucleolar organizer regions were observed in these populations. The apparent karyotypical similarity among the studied populations strongly suggests a close relationship among them with some chromosomal divergences due to gene flow restriction. PMID:21637456

  16. Advances in cytogenetics of Brazilian rodents: cytotaxonomy, chromosome evolution and new karyotypic data

    PubMed Central

    Di-Nizo, Camilla Bruno; Banci, Karina Rodrigues da Silva; Sato-Kuwabara, Yukie; Silva, Maria José de J.

    2017-01-01

    Abstract Rodents constitute one of the most diversified mammalian orders. Due to the morphological similarity in many of the groups, their taxonomy is controversial. Karyotype information proved to be an important tool for distinguishing some species because some of them are species-specific. Additionally, rodents can be an excellent model for chromosome evolution studies since many rearrangements have been described in this group.This work brings a review of cytogenetic data of Brazilian rodents, with information about diploid and fundamental numbers, polymorphisms, and geographical distribution. We point out that, even with the recent efforts on cytogenetic studies in this group, many species lack karyotypic data. Moreover, we describe for the first time the karyotype of Carterodon sulcidens (Lund, 1838) (Family Echimyidae), a new fundamental number for an undescribed species of Neacomys Thomas, 1900 (Family Cricetidae, Subfamily Sigmodontinae), and illustrate the karyotype of a Brazilian specimen of Mus musculus Linnaeus, 1758 (Family Muridae). This review compiles the cytogenetic data on Brazilian rodents reported in the last three decades, after the last revision published in 1984, including synonyms, chromosomal variations, and geographic distribution. Additionally, it also reinforces that Brazilian biodiversity is still poorly known, considering the new data reported here. PMID:29362668

  17. Transcervical embryoscopic and cytogenetic findings reveal distinctive differences in primary and secondary recurrent pregnancy loss.

    PubMed

    Feichtinger, Michael; Wallner, Elisabeth; Hartmann, Beda; Reiner, Angelika; Philipp, Thomas

    2017-01-01

    To assess the cytogenetic and embryoscopic characteristics of primary and secondary recurrent pregnancy loss. Clinical prospective descriptive study. Tertiary care center. Nine hundred and eighty-four women affected by first-trimester pregnancy loss; 145 patients with recurrent pregnancy loss (RPL) and 839 patients with nonrecurrent pregnancy loss as controls. Transcervical embryoscopic examination of the embryo before uterine evacuation, and cytogenetic analysis of the chorionic villi by standard G-banding cytogenetic techniques. Aneuploidy frequency in the primary and secondary RPL group and the nonrecurrent pregnancy loss (non-RPL) control group. Patients with RPL showed statistically significantly fewer aneuploid pregnancy losses (odds ratio [OR] 0.596; 95% confidence interval [CI], 0.40-0.88). Primary RPL was associated with lower aneuploidy rates compared with the non-RPL group (OR 0.423; 95% CI, 0.27-0.66) while secondary RPL was not (OR 1.414; 95% CI, 0.67-2.99). Patients with primary RPL had statistically significantly more morphologically normal embryos compared with non-RPL and secondary RPL. Patients' embryos after primary and secondary RPL show distinctive differences in aneuploidy and morphologic defect rates. These findings suggest different treatment approaches for the patients with primary and secondary RPL. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  18. Canadian Cytogenetic Emergency network (CEN) for biological dosimetry following radiological/nuclear accidents.

    PubMed

    Miller, Susan M; Ferrarotto, Catherine L; Vlahovich, Slavica; Wilkins, Ruth C; Boreham, Douglas R; Dolling, Jo-Anna

    2007-07-01

    To test the ability of the cytogenetic emergency network (CEN) of laboratories, currently under development across Canada, to provide rapid biological dosimetry using the dicentric assay for triage assessment, that could be implemented in the event of a large-scale radiation/nuclear emergency. A workshop was held in May 2004 in Toronto, Canada, to introduce the concept of CEN and recruit clinical cytogenetic laboratories at hospitals across the country. Slides were prepared for dicentric assay analysis following in vitro irradiation of blood to a range of gamma-ray doses. A minimum of 50 metaphases per slide were analyzed by 41 people at 22 different laboratories to estimate the exposure level. Dose estimates were calculated based on a dose response curve generated at Health Canada. There were a total of 104 dose estimates and 96 (92.3%) of them fell within the expected range using triage scoring criteria. Half of the laboratories analyzed 50 metaphases in cytogenetic networks.

  19. Clinical relevance of cytogenetics to pediatric practice. Postnatal findings of Patau syndrome - Review of 5 cases.

    PubMed

    Plaiasu, Vasilica; Ochiana, Diana; Motei, Gabriela; Anca, Ioana; Georgescu, Adrian

    2010-07-01

    Patau syndrome (trisomy 13) is one of the most common chromosomal anomalies clinically characterized by the presence of numerous malformations with a limited survival rate for most cases. Babies are usually identified at birth and the diagnosis is confirmed with genetic testing. In this review we outline the clinical and cytogenetic aspects of trisomy 13 and associated phenotypes for 5 cases analyzed in the last 3 years, referred to our Clinical Genetics Department. For each child cytogenetic analysis was performed to determine the genetic variant; also, the patients were investigated for other associated malformations (cardiac, cerebral, renal, ocular anomalies). All 5 cases presented multiple malformations, including some but not all signs of the classical clinical triad suggestive of Patau syndrome. The cytogenetic investigation confirmed for each case the suspected diagnosis and also indicated the specific genetic variant, this being a valuable information for the genetic counselling of the families. The application of genetic analysis can increase diagnosis and prognosis accuracy and have an impact on clinical management.

  20. The impact of the condenser on cytogenetic image quality in digital microscope system.

    PubMed

    Ren, Liqiang; Li, Zheng; Li, Yuhua; Zheng, Bin; Li, Shibo; Chen, Xiaodong; Liu, Hong

    2013-01-01

    Optimizing operational parameters of the digital microscope system is an important technique to acquire high quality cytogenetic images and facilitate the process of karyotyping so that the efficiency and accuracy of diagnosis can be improved. This study investigated the impact of the condenser on cytogenetic image quality and system working performance using a prototype digital microscope image scanning system. Both theoretical analysis and experimental validations through objectively evaluating a resolution test chart and subjectively observing large numbers of specimen were conducted. The results show that the optimal image quality and large depth of field (DOF) are simultaneously obtained when the numerical aperture of condenser is set as 60%-70% of the corresponding objective. Under this condition, more analyzable chromosomes and diagnostic information are obtained. As a result, the system shows higher working stability and less restriction for the implementation of algorithms such as autofocusing especially when the system is designed to achieve high throughput continuous image scanning. Although the above quantitative results were obtained using a specific prototype system under the experimental conditions reported in this paper, the presented evaluation methodologies can provide valuable guidelines for optimizing operational parameters in cytogenetic imaging using the high throughput continuous scanning microscopes in clinical practice.

  1. The Impact of the Condenser on Cytogenetic Image Quality in Digital Microscope System

    PubMed Central

    Ren, Liqiang; Li, Zheng; Li, Yuhua; Zheng, Bin; Li, Shibo; Chen, Xiaodong; Liu, Hong

    2013-01-01

    Background: Optimizing operational parameters of the digital microscope system is an important technique to acquire high quality cytogenetic images and facilitate the process of karyotyping so that the efficiency and accuracy of diagnosis can be improved. OBJECTIVE: This study investigated the impact of the condenser on cytogenetic image quality and system working performance using a prototype digital microscope image scanning system. Methods: Both theoretical analysis and experimental validations through objectively evaluating a resolution test chart and subjectively observing large numbers of specimen were conducted. Results: The results show that the optimal image quality and large depth of field (DOF) are simultaneously obtained when the numerical aperture of condenser is set as 60%–70% of the corresponding objective. Under this condition, more analyzable chromosomes and diagnostic information are obtained. As a result, the system shows higher working stability and less restriction for the implementation of algorithms such as autofocusing especially when the system is designed to achieve high throughput continuous image scanning. Conclusions: Although the above quantitative results were obtained using a specific prototype system under the experimental conditions reported in this paper, the presented evaluation methodologies can provide valuable guidelines for optimizing operational parameters in cytogenetic imaging using the high throughput continuous scanning microscopes in clinical practice. PMID:23676284

  2. An integrated molecular cytogenetic map of Cucumis sativus L. chromosome 2.

    PubMed

    Han, Yonghua; Zhang, Zhonghua; Huang, Sanwen; Jin, Weiwei

    2011-01-27

    Integration of molecular, genetic and cytological maps is still a challenge for most plant species. Recent progress in molecular and cytogenetic studies created a basis for developing integrated maps in cucumber (Cucumis sativus L.). In this study, eleven fosmid clones and three plasmids containing 45S rDNA, the centromeric satellite repeat Type III and the pericentriomeric repeat CsRP1 sequences respectively were hybridized to cucumber metaphase chromosomes to assign their cytological location on chromosome 2. Moreover, an integrated molecular cytogenetic map of cucumber chromosomes 2 was constructed by fluorescence in situ hybridization (FISH) mapping of 11 fosmid clones together with the cucumber centromere-specific Type III sequence on meiotic pachytene chromosomes. The cytogenetic map was fully integrated with genetic linkage map since each fosmid clone was anchored by a genetically mapped simple sequence repeat marker (SSR). The relationship between the genetic and physical distances along chromosome was analyzed. Recombination was not evenly distributed along the physical length of chromosome 2. Suppression of recombination was found in centromeric and pericentromeric regions. Our results also indicated that the molecular markers composing the linkage map for chromosome 2 provided excellent coverage of the chromosome.

  3. Evaluation of cytogenetic and DNA damage in human lymphocytes treated with adrenaline in vitro.

    PubMed

    Djelić, Ninoslav; Radaković, Milena; Spremo-Potparević, Biljana; Zivković, Lada; Bajić, Vladan; Stevanović, Jevrosima; Stanimirović, Zoran

    2015-02-01

    Catechol groups can be involved in redox cycling accompanied by generation of reactive oxygen species (ROS) which may lead to oxidative damage of cellular macromolecules including DNA. The objective of this investigation was to evaluate possible genotoxic effects of a natural catecholamine adrenaline in cultured human lymphocytes using cytogenetic (sister chromatid exchange and micronuclei) and the single cell gel electrophoresis (Comet) assay. In cytogenetic tests, six experimental concentrations of adrenaline were used in a range from 0.01-500 μM. There were no indications of genotoxic effects of adrenaline in sister chromatid exchange and micronucleus tests. However, at four highest concentrations of adrenaline (5 μM, 50 μM, 150 μM and 300 μM) we observed a decreased mitotic index and cell-cycle delay. In addition, in the Comet assay we used adrenaline in a range from 0.0005-500 μM, at two treatment times: 15 min or 60 min. In contrast to cytogenetic analysis, there was a dose-dependent increase of DNA damage detected in the Comet assay. These effects were significantly reduced by concomitant treatment with quercetin or catalase. Therefore, the obtained results indicate that adrenaline may exhibit genotoxic effects in cultured human lymphocytes, most likely due to production of reactive oxygen species. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective.

    PubMed

    Piedbois, Pascal; Miller Croswell, Jennifer

    2008-10-01

    Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. This activity has largely been driven by the promise surrogate endpoints appear to hold: the potential to get new therapies to seriously ill patients more rapidly. However, uncertainties abound. Even agreeing upon a definition of a "valid" surrogate endpoint has not been a straightforward exercise; this article begins by highlighting differences in how this term has been previously captured and applied, as well as laying out the basic criteria essential for its application in advanced colorectal cancer. Ideally, these elements include (but are not limited to) ease of measurement, rapid indication of treatment effect, and, most importantly, reliable and consistent prediction of the true impact of a treatment on the ultimate outcome of interest: overall survival. The strengths and weaknesses of current potential surrogate endpoints in advanced colorectal cancer, including performance status, carcinoembryonic antigen plasma level, overall response rate, time to progression, and disease-free survival, are each considered in turn. Finally, limitations of surrogate endpoints in the clinical setting, including challenges in extrapolation to new therapies, and the incomplete provision of information about potential adverse effects, are discussed. Work remains to be done between physicians and statisticians to bridge the gap between that which is statistically demonstrable and that which will be clinically useful.The term ;surrogate endpoint' was virtually unknown by most oncologists 15 years ago. A search in PubMed [http://www.ncbi.nlm.nih.gov] based on the words ;surrogate and cancer' shows that more than 2000 papers were published in medical journals in the last 20 years, with a dramatic increase of interest in the last five years. Interestingly, the same trend is observed when the words ;surrogate and heart' are entered into PubMed, suggesting that the

  5. Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology.

    PubMed

    Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

    2012-01-01

    Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types.

  6. A new proportion measure of the treatment effect captured by candidate surrogate endpoints.

    PubMed

    Kobayashi, Fumiaki; Kuroki, Manabu

    2014-08-30

    The use of surrogate endpoints is expected to play an important role in the development of new drugs, as they can be used to reduce the sample size and/or duration of randomized clinical trials. Biostatistical researchers and practitioners have proposed various surrogacy measures; however, (i) most of these surrogacy measures often fall outside the range [0,1] without any assumptions, (ii) these surrogacy measures do not provide a cut-off value for judging a surrogacy level of candidate surrogate endpoints, and (iii) most surrogacy measures are highly variable; thus, the confidence intervals are often unacceptably wide. In order to solve problems (i) and (ii), we propose a new surrogacy measure, a proportion of the treatment effect captured by candidate surrogate endpoints (PCS), on the basis of the decomposition of the treatment effect into parts captured and non-captured by the candidate surrogate endpoints. In order to solve problem (iii), we propose an estimation method based on the half-range mode method with the bootstrap distribution of the estimated surrogacy measures. Finally, through numerical experiments and two empirical examples, we show that the PCS with the proposed estimation method overcomes these difficulties. The results of this paper contribute to the reliable evaluation of how much of the treatment effect is captured by candidate surrogate endpoints. Copyright © 2014 John Wiley & Sons, Ltd.

  7. A unified framework for the evaluation of surrogate endpoints in mental-health clinical trials.

    PubMed

    Molenberghs, Geert; Burzykowski, Tomasz; Alonso, Ariel; Assam, Pryseley; Tilahun, Abel; Buyse, Marc

    2010-06-01

    For a number of reasons, surrogate endpoints are considered instead of the so-called true endpoint in clinical studies, especially when such endpoints can be measured earlier, and/or with less burden for patient and experimenter. Surrogate endpoints may occur more frequently than their standard counterparts. For these reasons, it is not surprising that the use of surrogate endpoints in clinical practice is increasing. Building on the seminal work of Prentice(1) and Freedman et al.,(2) Buyse et al. (3) framed the evaluation exercise within a meta-analytic setting, in an effort to overcome difficulties that necessarily surround evaluation efforts based on a single trial. In this article, we review the meta-analytic approach for continuous outcomes, discuss extensions to non-normal and longitudinal settings, as well as proposals to unify the somewhat disparate collection of validation measures currently on the market. Implications for design and for predicting the effect of treatment in a new trial, based on the surrogate, are discussed. A case study in schizophrenia is analysed.

  8. Considerations for development of surrogate endpoints for antifracture efficacy of new treatments in osteoporosis: a perspective.

    PubMed

    Bouxsein, Mary L; Delmas, Pierre D

    2008-08-01

    Because of the broad availability of efficacious osteoporosis therapies, conduct of placebo-controlled trials in subjects at high risk for fracture is becoming increasing difficult. Alternative trial designs include placebo-controlled trials in patients at low risk for fracture or active comparator studies, both of which would require enormous sample sizes and associated financial resources. Another more attractive alternative is to develop and validate surrogate endpoints for fracture. In this perspective, we review the concept of surrogate endpoints as it has been developed in other fields of medicine and discuss how it could be applied in clinical trials of osteoporosis. We outline a stepwise approach and possible study designs to qualify a biomarker as a surrogate endpoint in osteoporosis and review the existing data for several potential surrogate endpoints to assess their success in meeting the proposed criteria. Finally, we suggest a research agenda needed to advance the development of biomarkers as surrogate endpoints for fracture in osteoporosis trials. To ensure optimal development and best use of biomarkers to accelerate drug development, continuous dialog among the health professionals, industry, and regulators is of paramount importance.

  9. Surrogate endpoints for overall survival in lung cancer trials: a review.

    PubMed

    Fiteni, Frédéric; Westeel, Virginie; Bonnetain, Franck

    2017-05-01

    Intermediate endpoints are often used as primary endpoints instead of overall survival (OS) in lung cancer trials but they are not systematically validated as surrogate endpoints for OS. Areas covered: The aim of the study was to review the studies which assessed potential surrogate endpoints for OS in lung cancer trials. Expert commentary: Twenty studies were identified. In operable non-small cell lung cancer (NSCLC) (adjuvant trials) and locally advanced NSCLC (radiotherapy trials), one individual-patient data meta-analysis found a high correlation of disease-free survival (DFS) and progression-free survival (PFS) with OS at patient and trial level. In trials of adjuvant chemotherapy, correlation between disease-free survival DFS and OS were 0.83 at the individual level (95% CI 0.83-0.83) and 0.92 at trial level (95% CI 0.88-0.95). In locally advanced disease, correlation between PFS and OS was 0.77 to 0.85 at the individual level, and 0.89 to 0.97 at trial level. This study provides a 'proof' of the surrogacy of PFS and DFS on OS according to the IQWiG framework and the surrogacy of PFS and DFS on OS was classified level 2 according to Fleming hierarchy. In all the other setting, no endpoint was judged to be valid surrogate for OS.

  10. Review of meta-analyses evaluating surrogate endpoints for overall survival in oncology

    PubMed Central

    Sherrill, Beth; Kaye, James A; Sandin, Rickard; Cappelleri, Joseph C; Chen, Connie

    2012-01-01

    Overall survival (OS) is the gold standard in measuring the treatment effect of new drug therapies for cancer. However, practical factors may preclude the collection of unconfounded OS data, and surrogate endpoints are often used instead. Meta-analyses have been widely used for the validation of surrogate endpoints, specifically in oncology. This research reviewed published meta-analyses on the types of surrogate measures used in oncology studies and examined the extent of correlation between surrogate endpoints and OS for different cancer types. A search was conducted in October 2010 to compile available published evidence in the English language for the validation of disease progression-related endpoints as surrogates of OS, based on meta-analyses. We summarize published meta-analyses that quantified the correlation between progression-based endpoints and OS for multiple advanced solid-tumor types. We also discuss issues that affect the interpretation of these findings. Progression-free survival is the most commonly used surrogate measure in studies of advanced solid tumors, and correlation with OS is reported for a limited number of cancer types. Given the increased use of crossover in trials and the availability of second-/third-line treatment options available to patients after progression, it will become increasingly more difficult to establish correlation between effects on progression-free survival and OS in additional tumor types. PMID:23109809

  11. [Selection of "surrogate" and "endpoints" evaluation of the efficacy of medical interventions].

    PubMed

    Lazebnik, L B; Gusein-Zade, M G; Efremov, L I

    2011-01-01

    With the advent of new medical technologies and medicines, as well as due to changes in disease patterns and demographic problems rises the need for continued increases in health spending. Increased costs can be totally inadequate, if it has been done without studying the effectiveness of medical interventions, based on the results of evidence-based medicine and economic of their feasibility. To evaluate the clinical effectiveness of medical interventions have been recently used specific criteria, so called points of clinical efficacy (surrogate and endpoints), that allow to conclude feasibility or harmfulness of the introduction or application of the intervention in clinical practice. The endpoint is reliable indicator the effectiveness of medical intervention. Surrogate point--is a biomarker that is intended to replace the endpoint and is a predictor of the effectiveness of medical intervention. The use of surrogate points has several advantages such as simple in identification and measurement, as well as more higher in compare with endpoints the vents frequency, that can significantly reduce the size of the selection and duration and cost of clinical trials, respectively. Finally, the surrogate points allow to evaluate treatment effect in situations where the use of endpoints is difficult or is unethical.

  12. The effects of repeated nitroglycerin administrations in rats; modeling migraine-related endpoints and chronification.

    PubMed

    Harris, Hannah M; Carpenter, Jessica M; Black, Jonathan R; Smitherman, Todd A; Sufka, Kenneth J

    2017-06-01

    Rodent models typically use a single nitroglycerin injection to induce migraine, yet migraine in clinical populations presents as recurrent episodes. Further, these models quantify behavioral endpoints that do not align with the clinical features of episodic migraine or migraine chronification and therefore may limit translational relevance. Rats received 5 nitroglycerin (10mg/kg/2ml), propylene glycol/ethanol vehicle, or saline injections every third day over 15days. Behavioral endpoints were assessed 110min post nitroglycerin administration and included time spent light/dark chambers for photophobia as well as activity, facial pain expressions, and tactile allodynia. Animals administered nitroglycerin displayed photophobia, decreased activity, and increased facial pain expression. Similar alterations in photophobia and activity were seen in the vehicle treated animals, but these tended to diminish by the 4th or 5th injection. The presentation of spontaneous tactile allodynia was observed in the nitroglycerin group by the 5th episode. Most NTG migraine models entail a single NTG administration and quantification of evoked allodynia. This paradigm employs recurring NTG episodes and clinically-relevant measures of photophobia, hypoactivity and facial grimace endpoints as well as introduces a novel arena apparatus to quantify spontaneous allodynia. This repeated NTG procedure and endpoint measures aligns with the frequency and clinical presentation of episodic migraine and its chronification, respectively. Further, propylene glycol ethanol vehicle contributes to migraine endpoints. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Endpoint in plasma etch process using new modified w-multivariate charts and windowed regression

    NASA Astrophysics Data System (ADS)

    Zakour, Sihem Ben; Taleb, Hassen

    2017-09-01

    Endpoint detection is very important undertaking on the side of getting a good understanding and figuring out if a plasma etching process is done in the right way, especially if the etched area is very small (0.1%). It truly is a crucial part of supplying repeatable effects in every single wafer. When the film being etched has been completely cleared, the endpoint is reached. To ensure the desired device performance on the produced integrated circuit, the high optical emission spectroscopy (OES) sensor is employed. The huge number of gathered wavelengths (profiles) is then analyzed and pre-processed using a new proposed simple algorithm named Spectra peak selection (SPS) to select the important wavelengths, then we employ wavelet analysis (WA) to enhance the performance of detection by suppressing noise and redundant information. The selected and treated OES wavelengths are then used in modified multivariate control charts (MEWMA and Hotelling) for three statistics (mean, SD and CV) and windowed polynomial regression for mean. The employ of three aforementioned statistics is motivated by controlling mean shift, variance shift and their ratio (CV) if both mean and SD are not stable. The control charts show their performance in detecting endpoint especially W-mean Hotelling chart and the worst result is given by CV statistic. As the best detection of endpoint is given by the W-Hotelling mean statistic, this statistic will be used to construct a windowed wavelet Hotelling polynomial regression. This latter can only identify the window containing endpoint phenomenon.

  14. Pollutant threshold concentration determination in marine ecosystems using an ecological interaction endpoint.

    PubMed

    Wang, Changyou; Liang, Shengkang; Guo, Wenting; Yu, Hua; Xing, Wenhui

    2015-09-01

    The threshold concentrations of pollutants are determined by extrapolating single-species effect data to community-level effects. This assumes the most sensitive endpoint of the life cycle of individuals and the species sensitivity distribution from single-species toxic effect tests, thus, ignoring the ecological interactions. The uncertainties due to this extrapolation can be partially overcome using the equilibrium point of a customized ecosystem. This method incorporates ecological interactions and integrates the effects on growth, survival, and ingestion into a single effect measure, the equilibrium point excursion in the customized ecosystem, in order to describe the toxic effects on plankton. A case study showed that the threshold concentration of copper calculated with the endpoint of the equilibrium point was 10 μg L(-1), which is significantly different from the threshold calculated with a single-species endpoint. The endpoint calculated using this method provides a more relevant measure of the ecological impact than any single individual-level endpoint. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Feeding Behavior of an Aquatic Snail as a Simple Endpoint to Assess the Exposure to Cadmium.

    PubMed

    Alonso, Álvaro; Valle-Torres, Guillermo

    2018-01-01

    One of the aims of ecotoxicology is the assessment of the effects of chemicals on the ecosystems. Bioassays assessing lethality are frequently used in ecotoxicology, however they usually employ supra-environmental toxic concentrations. Toxicity tests employing behavioral endpoints may present a balance between simplicity (i.e., laboratory bioassays) and complexity (i.e., relevant ecological effects). The aim of this study was to develop a feeding behavioral bioassay with the aquatic snail, Potamopyrgus antipodarum, which included a 2 days exposure to cadmium, followed by a 9 days post-exposure observational period. Several behavioral feeding endpoints were monitored, including percentage of actively feeding animals, percentage of animals in food quadrants and a mobility index. The percentage of actively feeding animals was reduced by the four cadmium treatments (0.009, 0.026, 0.091 and 0.230 mg Cd/L) with the stronger effect in the highest concentration. The two highest cadmium concentrations significantly reduced the percentage of animals in food quadrants and the mobility index. Therefore, the percentage of actively feeding animals was the most sensitive endpoint to cadmium toxicity as the four cadmium concentrations caused a significant decrease in this endpoint. It is concluded that feeding behavior is a useful endpoint to detect the exposure of aquatic snails to cadmium.

  16. Cytogenetics in the management of multiple myeloma: an update by the Groupe francophone de cytogénétique hématologique (GFCH).

    PubMed

    Daudignon, Agnès; Quilichini, Benoît; Ameye, Geneviève; Poirel, Hélène; Bastard, Christian; Terré, Christine

    2016-10-01

    Cytogenetics of multiple myeloma has evolved in recent years by the emergence of Interphasic fluorescence in situ hybridization (FISH) performed on sorted plasma cells detecting abnormalities independently of a proliferative and infiltrative index. Cytogenetic analysis plays a major part in the risk stratification of myeloma diagnosis due to prognostic impact of various cytogenetic abnormalities as well as to the association between emerging therapeutic approaches in MM. Thus, practice guidelines now recommend interphasic FISH or alternative molecular technics as the initial analysis for multiple myeloma. The Groupe francophone de cytogénétique hématologique (GFCH) proposes in this issue an update of managing multiple myeloma cytogenetics.

  17. Sample size determination in group-sequential clinical trials with two co-primary endpoints

    PubMed Central

    Asakura, Koko; Hamasaki, Toshimitsu; Sugimoto, Tomoyuki; Hayashi, Kenichi; Evans, Scott R; Sozu, Takashi

    2014-01-01

    We discuss sample size determination in group-sequential designs with two endpoints as co-primary. We derive the power and sample size within two decision-making frameworks. One is to claim the test intervention’s benefit relative to control when superiority is achieved for the two endpoints at the same interim timepoint of the trial. The other is when the superiority is achieved for the two endpoints at any interim timepoint, not necessarily simultaneously. We evaluate the behaviors of sample size and power with varying design elements and provide a real example to illustrate the proposed sample size methods. In addition, we discuss sample size recalculation based on observed data and evaluate the impact on the power and Type I error rate. PMID:24676799

  18. Effect of pre-fixation delay and freezing on mink testicular endpoints for environmental research.

    PubMed

    Spörndly-Nees, Ellinor; Ekstedt, Elisabeth; Magnusson, Ulf; Fakhrzadeh, Azadeh; Luengo Hendriks, Cris L; Holm, Lena

    2015-01-01

    There is growing interest in using wild animals to monitor the real-life cocktail effect of environmental chemicals on male reproduction. However, practical difficulties, such as long distances to the laboratory, generally prolong the time between euthanisation and specimen handling. For instance, tissue fixation is often performed on frozen material or on material where deterioration has started, which may affect tissue morphology. This study examined the effect of pre-fixation delay and freezing on mink testicular endpoints in order to determine robust endpoints in suboptimally handled specimens. Sexually mature farmed mink (n=30) selected at culling were divided into six groups and subjected to different time intervals between euthanisation and fixation or freezing: 0 hours (fixed immediately post mortem), 6 hours, 18 hours, 30 hours, 42 hours, or frozen 6 hours post mortem and thawed overnight. Unaffected endpoints when pre-fixation storage was extended to 30 hours included: area and diameter of the seminiferous tubules, length and weight of the testes, and acrosomes marked with Gata-4. Epithelial height, Sertoli cells marked with Gata-4 and cell morphology were affected endpoints after 6 hours of storage. Freezing the tissue prior to fixation severely altered cell morphology and reduced testicular weight, tubular diameter and area. Morphological changes seen after 6 hours included shredded germ cells and excess cytoplasm in seminiferous tubular lumen, chromatin rearrangements and increased germ cell death. Extended delay before fixation and freezing affected many endpoints in the mink testicular tissue. Some of these endpoints may mimic chemically induced effects, which is important to consider when evaluating specimens from wild animals for environmental toxicity.

  19. Potential surrogate endpoints for prostate cancer survival: analysis of a phase III randomized trial.

    PubMed

    Ray, Michael E; Bae, Kyounghwa; Hussain, Maha H A; Hanks, Gerald E; Shipley, William U; Sandler, Howard M

    2009-02-18

    The identification of surrogate endpoints for prostate cancer-specific survival may shorten the length of clinical trials for prostate cancer. We evaluated distant metastasis and general clinical treatment failure as potential surrogates for prostate cancer-specific survival by use of data from the Radiation Therapy and Oncology Group 92-02 randomized trial. Patients (n = 1554 randomly assigned and 1521 evaluable for this analysis) with locally advanced prostate cancer had been treated with 4 months of neoadjuvant and concurrent androgen deprivation therapy with external beam radiation therapy and then randomly assigned to no additional therapy (control arm) or 24 additional months of androgen deprivation therapy (experimental arm). Data from landmark analyses at 3 and 5 years for general clinical treatment failure (defined as documented local disease progression, regional or distant metastasis, initiation of androgen deprivation therapy, or a prostate-specific antigen level of 25 ng/mL or higher after radiation therapy) and/or distant metastasis were tested as surrogate endpoints for prostate cancer-specific survival at 10 years by use of Prentice's four criteria. All statistical tests were two-sided. At 3 years, 1364 patients were alive and contributed data for analysis. Both distant metastasis and general clinical treatment failure at 3 years were consistent with all four of Prentice's criteria for being surrogate endpoints for prostate cancer-specific survival at 10 years. At 5 years, 1178 patients were alive and contributed data for analysis. Although prostate cancer-specific survival was not statistically significantly different between treatment arms at 5 years (P = .08), both endpoints were consistent with Prentice's remaining criteria. Distant metastasis and general clinical treatment failure at 3 years may be candidate surrogate endpoints for prostate cancer-specific survival at 10 years. These endpoints, however, must be validated in other datasets.

  20. Bayesian meta-analytical methods to incorporate multiple surrogate endpoints in drug development process.

    PubMed

    Bujkiewicz, Sylwia; Thompson, John R; Riley, Richard D; Abrams, Keith R

    2016-03-30

    A number of meta-analytical methods have been proposed that aim to evaluate surrogate endpoints. Bivariate meta-analytical methods can be used to predict the treatment effect for the final outcome from the treatment effect estimate measured on the surrogate endpoint while taking into account the uncertainty around the effect estimate for the surrogate endpoint. In this paper, extensions to multivariate models are developed aiming to include multiple surrogate endpoints with the potential benefit of reducing the uncertainty when making predictions. In this Bayesian multivariate meta-analytic framework, the between-study variability is modelled in a formulation of a product of normal univariate distributions. This formulation is particularly convenient for including multiple surrogate endpoints and flexible for modelling the outcomes which can be surrogate endpoints to the final outcome and potentially to one another. Two models are proposed, first, using an unstructured between-study covariance matrix by assuming the treatment effects on all outcomes are correlated and second, using a structured between-study covariance matrix by assuming treatment effects on some of the outcomes are conditionally independent. While the two models are developed for the summary data on a study level, the individual-level association is taken into account by the use of the Prentice's criteria (obtained from individual patient data) to inform the within study correlations in the models. The modelling techniques are investigated using an example in relapsing remitting multiple sclerosis where the disability worsening is the final outcome, while relapse rate and MRI lesions are potential surrogates to the disability progression. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  1. One universal common endpoint in mouse models of amyotrophic lateral sclerosis.

    PubMed

    Solomon, Jesse A; Tarnopolsky, Mark A; Hamadeh, Mazen J

    2011-01-01

    There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean ± SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS?

  2. Comparison of RNA-seq and microarray-based models for clinical endpoint prediction.

    PubMed

    Zhang, Wenqian; Yu, Ying; Hertwig, Falk; Thierry-Mieg, Jean; Zhang, Wenwei; Thierry-Mieg, Danielle; Wang, Jian; Furlanello, Cesare; Devanarayan, Viswanath; Cheng, Jie; Deng, Youping; Hero, Barbara; Hong, Huixiao; Jia, Meiwen; Li, Li; Lin, Simon M; Nikolsky, Yuri; Oberthuer, André; Qing, Tao; Su, Zhenqiang; Volland, Ruth; Wang, Charles; Wang, May D; Ai, Junmei; Albanese, Davide; Asgharzadeh, Shahab; Avigad, Smadar; Bao, Wenjun; Bessarabova, Marina; Brilliant, Murray H; Brors, Benedikt; Chierici, Marco; Chu, Tzu-Ming; Zhang, Jibin; Grundy, Richard G; He, Min Max; Hebbring, Scott; Kaufman, Howard L; Lababidi, Samir; Lancashire, Lee J; Li, Yan; Lu, Xin X; Luo, Heng; Ma, Xiwen; Ning, Baitang; Noguera, Rosa; Peifer, Martin; Phan, John H; Roels, Frederik; Rosswog, Carolina; Shao, Susan; Shen, Jie; Theissen, Jessica; Tonini, Gian Paolo; Vandesompele, Jo; Wu, Po-Yen; Xiao, Wenzhong; Xu, Joshua; Xu, Weihong; Xuan, Jiekun; Yang, Yong; Ye, Zhan; Dong, Zirui; Zhang, Ke K; Yin, Ye; Zhao, Chen; Zheng, Yuanting; Wolfinger, Russell D; Shi, Tieliu; Malkas, Linda H; Berthold, Frank; Wang, Jun; Tong, Weida; Shi, Leming; Peng, Zhiyu; Fischer, Matthias

    2015-06-25

    Gene expression profiling is being widely applied in cancer research to identify biomarkers for clinical endpoint prediction. Since RNA-seq provides a powerful tool for transcriptome-based applications beyond the limitations of microarrays, we sought to systematically evaluate the performance of RNA-seq-based and microarray-based classifiers in this MAQC-III/SEQC study for clinical endpoint prediction using neuroblastoma as a model. We generate gene expression profiles from 498 primary neuroblastomas using both RNA-seq and 44 k microarrays. Characterization of the neuroblastoma transcriptome by RNA-seq reveals that more than 48,000 genes and 200,000 transcripts are being expressed in this malignancy. We also find that RNA-seq provides much more detailed information on specific transcript expression patterns in clinico-genetic neuroblastoma subgroups than microarrays. To systematically compare the power of RNA-seq and microarray-based models in predicting clinical endpoints, we divide the cohort randomly into training and validation sets and develop 360 predictive models on six clinical endpoints of varying predictability. Evaluation of factors potentially affecting model performances reveals that prediction accuracies are most strongly influenced by the nature of the clinical endpoint, whereas technological platforms (RNA-seq vs. microarrays), RNA-seq data analysis pipelines, and feature levels (gene vs. transcript vs. exon-junction level) do not significantly affect performances of the models. We demonstrate that RNA-seq outperforms microarrays in determining the transcriptomic characteristics of cancer, while RNA-seq and microarray-based models perform similarly in clinical endpoint prediction. Our findings may be valuable to guide future studies on the development of gene expression-based predictive models and their implementation in clinical practice.

  3. Degree of target utilization influences the location of movement endpoint distributions.

    PubMed

    Slifkin, Andrew B; Eder, Jeffrey R

    2017-03-01

    According to dominant theories of motor control, speed and accuracy are optimized when, on the average, movement endpoints are located at the target center and when the variability of the movement endpoint distributions is matched to the width of the target (viz., Meyer, Abrams, Kornblum, Wright, & Smith, 1988). The current study tested those predictions. According to the speed-accuracy trade-off, expanding the range of variability to the amount permitted by the limits of the target boundaries allows for maximization of movement speed while centering the distribution on the target center prevents movement errors that would have occurred had the distribution been off center. Here, participants (N=20) were required to generate 100 consecutive targeted hand movements under each of 15 unique conditions: There were three movement amplitude requirements (80, 160, 320mm) and within each there were five target widths (5, 10, 20, 40, 80mm). According to the results, it was only at the smaller target widths (5, 10mm) that movement endpoint distributions were centered on the target center and the range of movement endpoint variability matched the range specified by the target boundaries. As target width increased (20, 40, 80mm), participants increasingly undershot the target center and the range of movement endpoint variability increasingly underestimated the variability permitted by the target region. The degree of target center undershooting was strongly predicted by the difference between the size of the target and the amount of movement endpoint variability, i.e., the amount of unused space in the target. The results suggest that participants have precise knowledge of their variability relative to that permitted by the target, and they use that knowledge to systematically reduce the travel distance to targets. The reduction in travel distance across the larger target widths might have resulted in greater cost savings than those associated with increases in speed

  4. A systematic comparison of recurrent event models for application to composite endpoints.

    PubMed

    Ozga, Ann-Kathrin; Kieser, Meinhard; Rauch, Geraldine

    2018-01-04

    Many clinical trials focus on the comparison of the treatment effect between two or more groups concerning a rarely occurring event. In this situation, showing a relevant effect with an acceptable power requires the observation of a large number of patients over a long period of time. For feasibility issues, it is therefore often considered to include several event types of interest, non-fatal or fatal, and to combine them within a composite endpoint. Commonly, a composite endpoint is analyzed with standard survival analysis techniques by assessing the time to the first occurring event. This approach neglects that an individual may experience more than one event which leads to a loss of information. As an alternative, composite endpoints could be analyzed by models for recurrent events. There exists a number of such models, e.g. regression models based on count data or Cox-based models such as the approaches of Andersen and Gill, Prentice, Williams and Peterson or, Wei, Lin and Weissfeld. Although some of the methods were already compared within the literature there exists no systematic investigation for the special requirements regarding composite endpoints. Within this work a simulation-based comparison of recurrent event models applied to composite endpoints is provided for different realistic clinical trial scenarios. We demonstrate that the Andersen-Gill model and the Prentice- Williams-Petersen models show similar results under various data scenarios whereas the Wei-Lin-Weissfeld model delivers effect estimators which can considerably deviate under commonly met data scenarios. Based on the conducted simulation study, this paper helps to understand the pros and cons of the investigated methods in the context of composite endpoints and provides therefore recommendations for an adequate statistical analysis strategy and a meaningful interpretation of results.

  5. Cardiac magnetic resonance imaging parameters as surrogate endpoints in clinical trials of acute myocardial infarction

    PubMed Central

    2011-01-01

    Cardiac magnetic resonance (CMR) offers a variety of parameters potentially suited as surrogate endpoints in clinical trials of acute myocardial infarction such as infarct size, myocardial salvage, microvascular obstruction or left ventricular volumes and ejection fraction. The present article reviews each of these parameters with regard to the pathophysiological basis, practical aspects, validity, reliability and its relative value (strengths and limitations) as compared to competitive modalities. Randomized controlled trials of acute myocardial infarction which have used CMR parameters as a primary endpoint are presented. PMID:21917147

  6. Comparison of methods for accurate end-point detection of potentiometric titrations

    NASA Astrophysics Data System (ADS)

    Villela, R. L. A.; Borges, P. P.; Vyskočil, L.

    2015-01-01

    Detection of the end point in potentiometric titrations has wide application on experiments that demand very low measurement uncertainties mainly for certifying reference materials. Simulations of experimental coulometric titration data and consequential error analysis of the end-point values were conducted using a programming code. These simulations revealed that the Levenberg-Marquardt method is in general more accurate than the traditional second derivative technique used currently as end-point detection for potentiometric titrations. Performance of the methods will be compared and presented in this paper.

  7. QSAR modeling of cumulative environmental end-points for the prioritization of hazardous chemicals.

    PubMed

    Gramatica, Paola; Papa, Ester; Sangion, Alessandro

    2018-01-24

    The hazard of chemicals in the environment is inherently related to the molecular structure and derives simultaneously from various chemical properties/activities/reactivities. Models based on Quantitative Structure Activity Relationships (QSARs) are useful to screen, rank and prioritize chemicals that may have an adverse impact on humans and the environment. This paper reviews a selection of QSAR models (based on theoretical molecular descriptors) developed for cumulative multivariate endpoints, which were derived by mathematical combination of multiple effects and properties. The cumulative end-points provide an integrated holistic point of view to address environmentally relevant properties of chemicals.

  8. Responsiveness of efficacy endpoints in clinical trials with over the counter analgesics for headache.

    PubMed

    Aicher, Bernhard; Peil, Hubertus; Peil, Barbara; Diener, Hans-Christoph

    2012-10-01

    To quantify and compare the responsiveness within the meaning of clinical relevance of efficacy endpoints in a clinical trial with over the counter (OTC) analgesics for headache. Efficacy endpoints and observed differences in clinical trials need to be clinically meaningful and mirror the change in the clinical status of a patient. This must be demonstrated for the specific disease indication and the particular patient population based on the application of treatments with proven efficacy. Patient's global efficacy assessment during two study phases (pre-phase and treatment phase) was used to classify patients as satisfied or non-satisfied with the efficacy of their medication. The analysis is based on 1734 patients included in the efficacy analysis of a randomized, placebo-controlled, double-blind, multi-centre parallel group trial with six treatment arms. Based on this classification and the pain intensity recorded by the patients on a 100 mm visual analogue scale, group differences by assessment categories and receiver operating characteristic (ROC) curve methods were used to quantify responsiveness of the efficacy endpoints 'time to 50% pain relief', 'time until reduction of pain intensity to 10 mm', 'weighted sum of pain intensity difference' (%SPIDweighted), 'pain intensity difference (PID) relative to baseline at 2 hours', and 'pain-free at 2 hours'. Clinically relevant differences between patients satisfied and non-satisfied with the treatment were observed for all efficacy endpoints. Patients with the highest rating of efficacy had the fastest and strongest pain relief. In comparison, patients assessing efficacy as 'less good' reached a 50% pain relief on average nearly an hour later than those scoring efficacy as at least 'good'. Simultaneously, their extent of pain relief was only half as great 2 hours after medication intake. Patients scoring efficacy as 'poor' experienced practically no pain relief within the 4 hour observation interval. ROC curve

  9. Health-related quality-of-life as co-primary endpoint in randomized clinical trials in oncology.

    PubMed

    Fiteni, Frédéric; Pam, Alhousseiny; Anota, Amélie; Vernerey, Dewi; Paget-Bailly, Sophie; Westeel, Virginie; Bonnetain, Franck

    2015-01-01

    Overall survival (OS) has been considered as the most relevant primary endpoint but trials using OS often require large numbers of patients and long-term follow-up. Therefore composite endpoints, which are assessed earlier, are frequently used as primary endpoint but suffer from important limitations specially a lack of validation as surrogate of OS. Therefore, Health-related quality of life (HRQoL) could be considered as an outcome to judge efficacy of a treatment. An alternative approach would be to combine HRQoL with composite endpoints as co-primary endpoint to ensure a clinical benefit for patients of a new therapy. The decision rules of such design, the procedure to control the Type I error and the determination of sample size remain questions to debate. Here, we discusses HRQoL as co-primary endpoints in randomized clinical trials in oncology and provide some solutions to promote such design.

  10. Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints

    PubMed Central

    Thompson, John R; Spata, Enti; Abrams, Keith R

    2015-01-01

    We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing–remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions. PMID:26271918

  11. Uncertainty in the Bayesian meta-analysis of normally distributed surrogate endpoints.

    PubMed

    Bujkiewicz, Sylwia; Thompson, John R; Spata, Enti; Abrams, Keith R

    2017-10-01

    We investigate the effect of the choice of parameterisation of meta-analytic models and related uncertainty on the validation of surrogate endpoints. Different meta-analytical approaches take into account different levels of uncertainty which may impact on the accuracy of the predictions of treatment effect on the target outcome from the treatment effect on a surrogate endpoint obtained from these models. A range of Bayesian as well as frequentist meta-analytical methods are implemented using illustrative examples in relapsing-remitting multiple sclerosis, where the treatment effect on disability worsening is the primary outcome of interest in healthcare evaluation, while the effect on relapse rate is considered as a potential surrogate to the effect on disability progression, and in gastric cancer, where the disease-free survival has been shown to be a good surrogate endpoint to the overall survival. Sensitivity analysis was carried out to assess the impact of distributional assumptions on the predictions. Also, sensitivity to modelling assumptions and performance of the models were investigated by simulation. Although different methods can predict mean true outcome almost equally well, inclusion of uncertainty around all relevant parameters of the model may lead to less certain and hence more conservative predictions. When investigating endpoints as candidate surrogate outcomes, a careful choice of the meta-analytical approach has to be made. Models underestimating the uncertainty of available evidence may lead to overoptimistic predictions which can then have an effect on decisions made based on such predictions.

  12. Correlates of protection for rotavirus vaccines: Possible alternative trial endpoints, opportunities, and challenges.

    PubMed

    Angel, Juana; Steele, A Duncan; Franco, Manuel A

    2014-01-01

    Rotavirus (RV) is a major vaccine-preventable killer of young children worldwide. Two RV vaccines are globally commercially available and other vaccines are in different stages of development. Due to the absence of a suitable correlate of protection (CoP), all RV vaccine efficacy trials have had clinical endpoints. These trials represent an important challenge since RV vaccines have to be introduced in many different settings, placebo-controlled studies are unethical due to the availability of licensed vaccines, and comparator assessments for new vaccines with clinical endpoints are very large, complex, and expensive to conduct. A CoP as a surrogate endpoint would allow predictions of vaccine efficacy for new RV vaccines and enable a regulatory pathway, contributing to the more rapid development of new RV vaccines. The goal of this review is to summarize experiences from RV natural infection and vaccine studies to evaluate potential CoP for use as surrogate endpoints for assessment of new RV vaccines, and to explore challenges and opportunities in the field.

  13. 77 FR 46444 - Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT); Public Workshop

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-03

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001] Gastroenterology Regulatory Endpoints and the Advancement of Therapeutics (GREAT); Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public workshop. SUMMARY: The Food and Drug Administration...

  14. ECOLOGICAL ENDPOINT MODELING FOR TMDLS: EFFECTS OF SEDIMENT ON FISH POPULATIONS

    EPA Science Inventory

    Sediment is one of the primary stressors of concern for Total Maximum Daily Loads (TMDLs) for streams, and often it is a concern because of its impact on ecological endpoints. A modeling approach relating sediment to stream fish population dynamics is presented. Equations are d...

  15. Selecting surrogate endpoints for estimating pesticide effects on avian reproductive success

    EPA Science Inventory

    A Markov chain nest productivity model (MCnest) has been developed for projecting the effects of a specific pesticide-use scenario on the annual reproductive success of avian species of concern. A critical element in MCnest is the use of surrogate endpoints, defined as measured ...

  16. Weighted analysis of composite endpoints with simultaneous inference for flexible weight constraints.

    PubMed

    Duc, Anh Nguyen; Wolbers, Marcel

    2017-02-10

    Composite endpoints are widely used as primary endpoints of randomized controlled trials across clinical disciplines. A common critique of the conventional analysis of composite endpoints is that all disease events are weighted equally, whereas their clinical relevance may differ substantially. We address this by introducing a framework for the weighted analysis of composite endpoints and interpretable test statistics, which are applicable to both binary and time-to-event data. To cope with the difficulty of selecting an exact set of weights, we propose a method for constructing simultaneous confidence intervals and tests that asymptotically preserve the family-wise type I error in the strong sense across families of weights satisfying flexible inequality or order constraints based on the theory of χ¯2-distributions. We show that the method achieves the nominal simultaneous coverage rate with substantial efficiency gains over Scheffé's procedure in a simulation study and apply it to trials in cardiovascular disease and enteric fever. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd. © 2016 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.

  17. Shape and Steepness of Toxicological Dose-Response Relationships of Continuous Endpoints

    EPA Science Inventory

    A re-analysis of a large number of historical dose-response data for continuous endpoints indicates that an exponential or a Hill model with four parameters both adequately describe toxicological dose-responses. The four parameters relate to the background response, the potency o...

  18. Endpoint regularity of discrete multisublinear fractional maximal operators associated with [Formula: see text]-balls.

    PubMed

    Liu, Feng

    2018-01-01

    In this paper we investigate the endpoint regularity of the discrete m -sublinear fractional maximal operator associated with [Formula: see text]-balls, both in the centered and uncentered versions. We show that these operators map [Formula: see text] into [Formula: see text] boundedly and continuously. Here [Formula: see text] represents the set of functions of bounded variation defined on [Formula: see text].

  19. EFFECTS OF COPPER ON COMMUNITY, FUNCTIONAL, AND BEHAVIORAL ENDPOINTS IN AN ARTIFICIAL STREAM STUDY

    EPA Science Inventory

    A study of the effects of copper on biota and behavioral endpoints was carried out at the U.S. EPA's Experimental Stream Facility (ESF), Milford OH. The objective of the study was to identify relationships between structural (macrobenthos and periphyton indices), functional (inte...

  20. Developing ecosystem services-based assessment endpoints for determining ecological risks to estuarine environments

    EPA Science Inventory

    Current U.S. EPA ecological risk assessment (ERA) guidance defines an assessment endpoint (AE) as an explicit expression of the environmental value that is to be protected, and recommends that AEs are selected based on ecological relevance, susceptibility to known or potential st...

  1. QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP (QSAR) MODELS TO PREDICT CHEMICAL TOXICITY FOR VARIOUS HEALTH ENDPOINTS

    EPA Science Inventory

    Although ranking schemes based on exposure and toxicity have been developed to aid in the prioritization of research funds for identifying chemicals of regulatory concern, there are significant gaps in the availability of experimental toxicity data for most health endpoints. Pred...

  2. LIFE CYCLE IMPACT ASSESSMENT WORKSHOP SUMMARY - MIDPOINTS VERSUS ENDPOINTS: THE SACRIFICES AND BENEFITS

    EPA Science Inventory

    On 5/25-26/2000 in Brighton, England, the third international workshop was held under the umbrella of UNEP addressing issues in Life Cycle Impact Assessment (LCIA). The workshop provided a forum for experts to discuss midpoint vs. endpoint modeling. Midpoints are considered to be...

  3. Can joint sound assess soft and hard endpoints of the Lachman test?: A preliminary study.

    PubMed

    Hattori, Koji; Ogawa, Munehiro; Tanaka, Kazunori; Matsuya, Ayako; Uematsu, Kota; Tanaka, Yasuhito

    2016-05-12

    The Lachman test is considered to be a reliable physical examination for anterior cruciate ligament (ACL) injury. Patients with a damaged ACL demonstrate a soft endpoint feeling. However, examiners judge the soft and hard endpoints subjectively. The purpose of our study was to confirm objective performance of the Lachman test using joint auscultation. Human and porcine knee joints were examined. Knee joint sound during the Lachman test (Lachman sound) was analyzed by fast Fourier transformation. As quantitative indices of Lachman sound, the peak sound as the maximum relative amplitude (acoustic pressure) and its frequency were used. The mean Lachman peak sound for healthy volunteer knees was 86.9 ± 12.9 Hz in frequency and -40 ± 2.5 dB in acoustic pressure. The mean Lachman peak sound for intact porcine knees was 84.1 ± 9.4 Hz and -40.5 ± 1.7 dB. Porcine knees with ACL deficiency had a soft endpoint feeling during the Lachman test. The Lachman peak sounds of porcine knees with ACL deficiency were dispersed into four distinct groups, with center frequencies of around 40, 160, 450, and 1600. The Lachman peak sound was capable of assessing soft and hard endpoints of the Lachman test objectively.

  4. Predictive Signatures from ToxCast Data for Chronic, Developmental and Reproductive Toxicity Endpoints

    EPA Science Inventory

    The EPA ToxCast program is using in vitro assay data and chemical descriptors to build predictive models for in vivo toxicity endpoints. In vitro assays measure activity of chemicals against molecular targets such as enzymes and receptors (measured in cell-free and cell-based sys...

  5. Coulometric Titration of Ethylenediaminetetraacetate (EDTA) with Spectrophotometric Endpoint Detection: An Experiment for the Instrumental Analysis Laboratory

    ERIC Educational Resources Information Center

    Williams, Kathryn R.; Young, Vaneica Y.; Killian, Benjamin J.

    2011-01-01

    Ethylenediaminetetraacetate (EDTA) is commonly used as an anticoagulant in blood-collection procedures. In this experiment for the instrumental analysis laboratory, students determine the quantity of EDTA in commercial collection tubes by coulometric titration with electrolytically generated Cu[superscript 2+]. The endpoint is detected…

  6. Population modelling to compare chronic external radiotoxicity between individual and population endpoints in four taxonomic groups.

    PubMed

    Alonzo, Frédéric; Hertel-Aas, Turid; Real, Almudena; Lance, Emilie; Garcia-Sanchez, Laurent; Bradshaw, Clare; Vives I Batlle, Jordi; Oughton, Deborah H; Garnier-Laplace, Jacqueline

    2016-02-01

    In this study, we modelled population responses to chronic external gamma radiation in 12 laboratory species (including aquatic and soil invertebrates, fish and terrestrial mammals). Our aim was to compare radiosensitivity between individual and population endpoints and to examine how internationally proposed benchmarks for environmental radioprotection protected species against various risks at the population level. To do so, we used population matrix models, combining life history and chronic radiotoxicity data (derived from laboratory experiments and described in the literature and the FREDERICA database) to simulate changes in population endpoints (net reproductive rate R0, asymptotic population growth rate λ, equilibrium population size Neq) for a range of dose rates. Elasticity analyses of models showed that population responses differed depending on the affected individual endpoint (juvenile or adult survival, delay in maturity or reduction in fecundity), the considered population endpoint (R0, λ or Neq) and the life history of the studied species. Among population endpoints, net reproductive rate R0 showed the lowest EDR10 (effective dose rate inducing 10% effect) in all species, with values ranging from 26 μGy h(-1) in the mouse Mus musculus to 38,000 μGy h(-1) in the fish Oryzias latipes. For several species, EDR10 for population endpoints were lower than the lowest EDR10 for individual endpoints. Various population level risks, differing in severity for the population, were investigated. Population extinction (predicted when radiation effects caused population growth rate λ to decrease below 1, indicating that no population growth in the long term) was predicted for dose rates ranging from 2700 μGy h(-1) in fish to 12,000 μGy h(-1) in soil invertebrates. A milder risk, that population growth rate λ will be reduced by 10% of the reduction causing extinction, was predicted for dose rates ranging from 24 μGy h(-1) in mammals to 1800 μGy h(-1) in

  7. Improvement in latent variable indirect response joint modeling of a continuous and a categorical clinical endpoint in rheumatoid arthritis.

    PubMed

    Hu, Chuanpu; Zhou, Honghui

    2016-02-01

    Improving the quality of exposure-response modeling is important in clinical drug development. The general joint modeling of multiple endpoints is made possible in part by recent progress on the latent variable indirect response (IDR) modeling for ordered categorical endpoints. This manuscript aims to investigate, when modeling a continuous and a categorical clinical endpoint, the level of improvement achievable by joint modeling in the latent variable IDR modeling framework through the sharing of model parameters for the individual endpoints, guided by the appropriate representation of drug and placebo mechanism. This was illustrated with data from two phase III clinical trials of intravenously administered mAb X for the treatment of rheumatoid arthritis, with the 28-joint disease activity score (DAS28) and 20, 50, and 70% improvement in the American College of Rheumatology (ACR20, ACR50, and ACR70) disease severity criteria were used as efficacy endpoints. The joint modeling framework led to a parsimonious final model with reasonable performance, evaluated by visual predictive check. The results showed that, compared with the more common approach of separately modeling the endpoints, it is possible for the joint model to be more parsimonious and yet better describe the individual endpoints. In particular, the joint model may better describe one endpoint through subject-specific random effects that would not have been estimable from data of this endpoint alone.

  8. SEMICONDUCTOR TECHNOLOGY A signal processing method for the friction-based endpoint detection system of a CMP process

    NASA Astrophysics Data System (ADS)

    Chi, Xu; Dongming, Guo; Zhuji, Jin; Renke, Kang

    2010-12-01

    A signal processing method for the friction-based endpoint detection system of a chemical mechanical polishing (CMP) process is presented. The signal process method uses the wavelet threshold denoising method to reduce the noise contained in the measured original signal, extracts the Kalman filter innovation from the denoised signal as the feature signal, and judges the CMP endpoint based on the feature of the Kalman filter innovation sequence during the CMP process. Applying the signal processing method, the endpoint detection experiments of the Cu CMP process were carried out. The results show that the signal processing method can judge the endpoint of the Cu CMP process.

  9. CHROMOSOME 11 ABERRATIONS IN SMALL COLONY L5178Y TK-/-MUTANTS EARLY IN THEIR CLONAL HISTORY

    EPA Science Inventory

    The authors have developed a cytogenetic technique that allows observation of chromosome rearrangements associated with TK-/- mutagenesis of the L5178Y/TK+/-3.7.2C cell line early in mutant clonal history. For a series of mutagenic treatments they show that the major proportion (...

  10. The Impact of Chemoembolization Endpoints on Survival in Hepatocellular Carcinoma Patients

    PubMed Central

    Jin, Brian; Wang, Dingxin; Lewandowski, Robert J.; Riaz, Ahsun; Ryu, Robert K.; Sato, Kent T.; Larson, Andrew C.; Salem, Riad; Omary, Reed A.

    2010-01-01

    OBJECTIVE To investigate the relationship between angiographic embolic endpoints of transarterial chemoembolization (TACE) and survival in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS This study retrospectively assessed 105 patients with surgically unresectable HCC who underwent TACE. Patients were classified according to a previously established subjective angiographic chemoembolization endpoint (SACE) scale. Only one patient was classified as SACE level 1 and thus excluded from all subsequent analysis. Survival was evaluated with Kaplan-Meier analysis. Multivariate analysis with Cox’s proportional hazard regression model was used to determine independent prognostic risk factors of survival. RESULTS Overall median survival was 21.1 months (95% confidence interval [CI], 15.9–26.4). Patients embolized to SACE levels 2 and 3 were aggregated and had a significantly higher median survival (25.6 months; 95% CI, 16.2–35.0) than patients embolized to SACE level 4 (17.1 months; 95% CI, 13.3–20.9) (p = 0.035). Multivariate analysis indicated that SACE level 4 (Hazard ratio [HR], 2.49; 95% CI, 1.41–4.42; p = 0.002), European Cooperative Oncology Group performance status > 0 (HR, 1.97; 95% CI, 1.15–3.37; p = 0.013), American Joint Committee on Cancer stage 3 or 4 (HR, 2.42; 95% CI, 1.27–4.60; p = 0.007), and Child-Pugh class B (HR, 1.94; 95% CI, 1.09–3.46; p = 0.025) were all independent negative prognostic indicators of survival. CONCLUSION Embolization to an intermediate, sub-stasis endpoint (SACE levels 2 and 3) during TACE improves survival compared to embolization to a higher, stasis endpoint (SACE level 4). Interventional oncologists should consider targeting these intermediate, sub-stasis angiographic endpoints during TACE. PMID:21427346

  11. Alternative Endpoints and Approaches Selected for the Remediation of Contaminated Groundwater at Complex Sites

    NASA Astrophysics Data System (ADS)

    Deeb, R. A.; Hawley, E.

    2011-12-01

    This presentation will focus on findings, statistics, and case studies from a recently-completed report for the Department of Defense's Environmental Security Technology Certification Program (ESTCP) (Project ER-0832) on alternative endpoints and alternative remedial strategies for groundwater remediation under a variety of Federal and state cleanup programs, including technical impracticability (TI) and other Applicable or Relevant and Appropriate Requirement (ARAR) waivers, state and local designations such as groundwater management zones, Alternate Concentration Limits (ACLs), use of monitored natural attenuation (MNA) over long timeframes, and more. The primary objective of the project was to provide environmental managers and regulators with tools, metrics, and information needed to evaluate alternative endpoints for groundwater remediation at complex sites. A statistical analysis of Comprehensive Environmental Response, Compensation and Liability Act (CERCLA) sites receiving TI waivers will be presented as well as case studies of other types of alternative endpoints and alternative remedial strategies to illustrate the variety of approaches used at complex sites and the technical analyses used to predict and document cost, timeframe, and potential remedial effectiveness. Case studies provide examples of the flexible, site-specific, application of alternative endpoints and alternative remedial strategies that have been used in the past to manage and remediate groundwater contamination at complex sites. For example, at least 13 states consider some designation for groundwater containment in their corrective action policies, such as groundwater management zones, containment zones, and groundwater classification exemption areas. These designations typically indicate that groundwater contamination is present above permissible levels. Soil and groundwater within these zones are managed to protect human health and the environment. Lesson learned for the analyses

  12. Weighting Composite Endpoints in Clinical Trials: Essential Evidence for the Heart Team

    PubMed Central

    Tong, Betty C.; Huber, Joel C.; Ascheim, Deborah D.; Puskas, John D.; Ferguson, T. Bruce; Blackstone, Eugene H.; Smith, Peter K.

    2013-01-01

    Background Coronary revascularization trials often use a composite endpoint of major adverse cardiac and cerebrovascular events (MACCE). The usual practice in analyzing data with a composite endpoint is to assign equal weights to each of the individual MACCE elements. Non-inferiority margins are used to offset effects of presumably less important components, but their magnitudes are subject to bias. This study describes the relative importance of MACCE elements from a patient perspective. Methods A discrete choice experiment was conducted. Survey respondents were presented with a scenario that would make them eligible for the SYNTAX 3-Vessel Disease cohort. Respondents chose among pairs of procedures that differed on the 3-year probability of MACCE, potential for increased longevity, and procedure/recovery time. Conjoint analysis derived relative weights for these attributes. Results In all, 224 respondents completed the survey. The attributes did not have equal weight. Risk of death was most important (relative weight 0.23), followed by stroke (.18), potential increased longevity and recovery time (each 0.17), MI (0.14) and risk of repeat revascularization (0.11). Applying these weights to the SYNTAX 3-year endpoints resulted in a persistent, but decreased margin of difference in MACCE favoring CABG compared to PCI. When labeled only as “Procedure A” and “B,” 87% of respondents chose CABG over PCI. When procedures were labeled as “Coronary Stent” and “Coronary Bypass Surgery,” only 73% chose CABG. Procedural preference varied with demographics, gender and familiarity with the procedures. Conclusions MACCE elements do not carry equal weight in a composite endpoint, from a patient perspective. Using a weighted composite endpoint increases the validity of statistical analyses and trial conclusions. Patients are subject to bias by labels when considering coronary revascularization. PMID:22795064

  13. "Holostei versus Halecostomi" Problem: Insight from Cytogenetics of Ancient Nonteleost Actinopterygian Fish, Bowfin Amia calva.

    PubMed

    Majtánová, Zuzana; Symonová, Radka; Arias-Rodriguez, Lenin; Sallan, Lauren; Ráb, Petr

    2017-11-01

    Bowfin belongs to an ancient lineage of nonteleost ray-finned fishes (actinopterygians) and is the only extant survivor of a once diverged group, the Halecomorphi or Amiiformes. Owing to the scarcity of extant nonteleost ray-finned lineages, also referred as "living fossils," their phylogenetic interrelationships have been the target of multiple hypotheses concerning their sister group relationships. Molecular and morphological data sets have produced controversial results; bowfin is considered as either the sister group to genome-duplicated teleosts (together forming the group of Halecostomi) or to gars (Lepisosteiformes; together forming the group of Holostei). However, any detailed cytogenetic analysis of bowfin chromosomes has never been performed to address this issue. Here we examined bowfin chromosomes by conventional (Giemsa-staining, C-banding, base-specific fluorescence and silver staining) and molecular (FISH with rDNA probes) cytogenetic protocols. We identified diploid chromosome number 2n = 46 with a middle-sized submetacentric chromosome pair as the major ribosomal DNA-bearing (45S rDNA), GC-positive and silver-positive element. The minor rDNA (5S rDNA) sites were localized in the pericentromeric region of one middle-sized acrocentric chromosome pair. Comparison with available cytogenetic data of other nonteleost actinopterygians (bichirs, sturgeons, gars) and teleost species including representative of basally branching lineages showed bowfin chromosomal characteristics more similar to the teleost type than to any other nonteleosts. Particularly striking differences were identified between bowfin and gars, the latter of which were found to mimic mammalian AT/GC genomic organisation. Such conclusion however contradicts the most recent phylogenomic results and raises the question what states are ancestral and what are derived. © 2017 Wiley Periodicals, Inc.

  14. Spontaneous abortion and recurrent miscarriage: A comparison of cytogenetic diagnosis in 250 cases.

    PubMed

    Choi, Tae Yeong; Lee, Hye Min; Park, Won Kyoung; Jeong, So Yeong; Moon, Hwa Sook

    2014-11-01

    The purpose of this study was to determine the frequency and distribution of cytogenetically abnormal miscarriages in couples with spontaneous abortions (SA) or recurrent miscarriages (RM). Karyotyping of specimens from 164 abortuses with SA and 86 abortuses with RM was successfully performed according to the standard cytogenetic methods using G-banding technique. Among the total 164 cases of SA group, 81 (49.4%) were euploid and the rest (83, 50.6%) showed chromosomal abnormalities. In RM(≥2) and RM(≥3) group, 31 (36.0%)/27 (34.6%) cases were euploid and 55 (64.0%)/51(65.4%) cases were abnormal, respectively. A statistically significant difference was found in the rate of cytogenetic abnormality between SA and RM groups (P<0.05). In all groups, women with advanced maternal age (≥35 years) had a higher rate of chromosome anomalies compared with women younger than age 35 (normal:abnormal = 32.4%:67.6% for ≥35 years and 53.8%:46.2% for <35 years in SA; 19.2%:80.8%/21.7%:78.3% for ≥35 years and 43.3%:56.7%/40.0%:60.0% for <35 years in RM(≥2) and RM(≥3), respectively; P<0.05). In SA group, an increase of normal karyotypes was noted with increased gestational age (<10 week, 38.0%; 10-15 week, 53.5%; 16-20 week, 65.7%). In RM group, most of cases were in <10 week and the frequency of trisomies with chromosomes 1 to 10 were increased compared with that of SA. There was a statistically significant difference in the frequency and distribution of chromosomal abnormalities between SA and RM groups. Our results will provide useful information for diagnosis and genetic counseling of patients with SA or RM.

  15. Molecular cytogenetic map of the central bearded dragon, Pogona vitticeps (Squamata: Agamidae).

    PubMed

    Young, M J; O'Meally, D; Sarre, S D; Georges, A; Ezaz, T

    2013-07-01

    Reptiles, as the sister group to birds and mammals, are particularly valuable for comparative genomic studies among amniotes. The Australian central bearded dragon (Pogona vitticeps) is being developed as a reptilian model for such comparisons, with whole-genome sequencing near completion. The karyotype consists of 6 pairs of macrochromosomes and 10 pairs microchromosomes (2n = 32), including a female heterogametic ZW sex microchromosome pair. Here, we present a molecular cytogenetic map for P. vitticeps comprising 87 anchor bacterial artificial chromosome clones that together span each macro- and microchromosome. It is the first comprehensive cytogenetic map for any non-avian reptile. We identified an active nucleolus organizer region (NOR) on the sub-telomeric region of 2q by mapping 18S rDNA and Ag-NOR staining. We identified interstitial telomeric sequences in two microchromosome pairs and the W chromosome, indicating that microchromosome fusion has been a mechanism of karyotypic evolution in Australian agamids within the last 21 to 19 million years. Orthology searches against the chicken genome revealed an intrachromosomal rearrangement of P. vitticeps 1q, identified regions orthologous to chicken Z on P. vitticeps 2q, snake Z on P. vitticeps 6q and the autosomal microchromosome pair in P. vitticeps orthologous to turtle Pelodiscus sinensis ZW and lizard Anolis carolinensis XY. This cytogenetic map will be a valuable reference tool for future gene mapping studies and will provide the framework for the work currently underway to physically anchor genome sequences to chromosomes for this model Australian squamate.

  16. Metastatic neuroblastoma of the mandible: a cytogenetic and molecular genetic study.

    PubMed

    Manor, Esther; Kapelushnik, Joseph; Joshua, Ben-Zion; Bodner, Lipa

    2012-08-01

    Neuroblastoma (NB) jaw metastases are rare. Here, we report on cytogenetic and genetic studies on metastatic NB to the mandible. A 7-year-old boy, with an abdominal neuroblastoma, presented with a mass of the left body of the mandible. Cytogenetic analysis of the original tumor and the mandibular lesion biopsies revealed similar heterogenous subclones with 42 ~ 47,XY,+der(1)(q11 → qter),-2,del(7)(q21.1 → qter),-8,-9,-10,-11,del(11)(q13.3 → qter),-13,-14,-15,-17, + 18-18,der(18)(?),+21,+m1,+m2,+m3,+m4,+m5,+m6,+m7[cp25]. The different markers were identified by SKY analysis. Most of the cells carried 3-6 of these translocations: der(1;21), der(2;9;17), der(2;15;18), der(2;15;Y), der(8;10), der(10;17). Molecular examination using Neuroblastoma MLPA kit (MRC-Holland) revealed gain of 1q25, 1q42, 2q33, 2p23, 2p24 (N-myc), and 21q22, and loss of 11q22, 11q23, 17p13, and 17q11. FISH analysis using N-myc probe showed high amplification levels of N-myc. The cytogenetic and molecular genetic work-ups revealed that the mandibular lesion is a metastasis of the original abdominal tumor and not a second primary caused by the aggressive treatment. Clinical parameters such as : patient's age, site of primary tumor and the mandibular metastasis, together with poor prognosis genetic markers explain the patient's short-term survival.

  17. Ozone Inhalation Leads to a Dose-Dependent Increase of Cytogenetic Damage in Human Lymphocytes

    PubMed Central

    Holland, Nina; Davé, Veronica; Venkat, Subha; Wong, Hofer; Donde, Aneesh; Balmes, John R; Arjomandi, Mehrdad

    2014-01-01

    Ozone is an important constituent of ambient air pollution and represents a major public health concern. Oxidative injury due to ozone inhalation causes the generation of reactive oxygen species and can be genotoxic. To determine whether ozone exposure causes genetic damage in peripheral blood lymphocytes, we employed a well-validated cytokinesis-block micronucleus Cytome assay. Frequencies of micronuclei (MN) and nucleoplasmic bridges (NB) were used as indicators of cytogenetic damage. Samples were obtained from 22 non-smoking healthy subjects immediately before and 24-hr after controlled 4-hr exposures to filtered air, 100 ppb, and 200 ppb ozone while exercising in a repeated-measure study design. Inhalation of ozone at different exposure levels was associated with a significant dose-dependent increase in MN frequency (P < 0.0001) and in the number of cells with more than 1 MN per cell (P < 0.0005). Inhalation of ozone also caused an increase in the number of apoptotic cells (P = 0.002). Airway neutrophilia was associated with an increase in MN frequency (P = 0.033) independent of the direct effects of ozone exposure (P < 0.0001). We also observed significant increases in both MN and NB frequencies after exercise in filtered air, suggesting that physical activity is also an important inducer of oxidative stress. These results corroborate our previous findings that cytogenetic damage is associated with ozone exposure, and show that damage is dose-dependent. Further study of ozone-induced cytogenetic damage in airway epithelial cells could provide evidence for the role of oxidative injury in lung carcinogenesis, and help to address the potential public health implications of exposures to oxidant environments. PMID:25451016

  18. Movement trajectory smoothness is not associated with the endpoint accuracy of rapid multi-joint arm movements in young and older adults

    PubMed Central

    Poston, Brach; Van Gemmert, Arend W.A.; Sharma, Siddharth; Chakrabarti, Somesh; Zavaremi, Shahrzad H.; Stelmach, George

    2013-01-01

    The minimum variance theory proposes that motor commands are corrupted by signal-dependent noise and smooth trajectories with low noise levels are selected to minimize endpoint error and endpoint variability. The purpose of the study was to determine the contribution of trajectory smoothness to the endpoint accuracy and endpoint variability of rapid multi-joint arm movements. Young and older adults performed arm movements (4 blocks of 25 trials) as fast and as accurately as possible to a target with the right (dominant) arm. Endpoint accuracy and endpoint variability along with trajectory smoothness and error were quantified for each block of trials. Endpoint error and endpoint variance were greater in older adults compared with young adults, but decreased at a similar rate with practice for the two age groups. The greater endpoint error and endpoint variance exhibited by older adults were primarily due to impairments in movement extent control and not movement direction control. The normalized jerk was similar for the two age groups, but was not strongly associated with endpoint error or endpoint variance for either group. However, endpoint variance was strongly associated with endpoint error for both the young and older adults. Finally, trajectory error was similar for both groups and was weakly associated with endpoint error for the older adults. The findings are not consistent with the predictions of the minimum variance theory, but support and extend previous observations that movement trajectories and endpoints are planned independently. PMID:23584101

  19. Cytogenetic characterization of a fibroma and three haemangiopericytomas in domestic dogs.

    PubMed

    Mayr, B; Scheller, M; Reifinger, M; Loupal, G

    1995-01-01

    Cytogenetic evaluation of tumour cells taken from an 11-year-old mixed breed birth with a fibroma, showed trisomy 1 (2n = 79) and often the presence of a third copy of chromosome 4. In a 13-year-old mixed breed Boxer bitch with a haemangiopericytoma, trisomy 9 (2n = 79) was present. In contrast, another haemangiopericytoma (in a 15-year-old rough-haired Dachshund bitch) showed a deleted chromosome 1, several centric fusions and trisomy 2. Trisomy 2 and trisomy 29 were detected in a third haemangiopericytoma from an 11-year-old rough-haired Dachshund bitch.

  20. Changes in cytogenetics and molecular genetics in acute myeloid leukemia from childhood to adult age groups.

    PubMed

    Creutzig, Ursula; Zimmermann, Martin; Reinhardt, Dirk; Rasche, Mareike; von Neuhoff, Christine; Alpermann, Tamara; Dworzak, Michael; Perglerová, Karolína; Zemanova, Zuzana; Tchinda, Joelle; Bradtke, Jutta; Thiede, Christian; Haferlach, Claudia

    2016-12-15

    To obtain better insight into the biology of acute myeloid leukemia (AML) in various age groups, this study focused on the genetic changes occurring during a lifetime. This study analyzed the relation between age and genetics from birth to 100 years in 5564 patients with de novo AML diagnosed from 1998 to 2012 (1192 patients from nationwide pediatric studies [AML Berlin-Frankfurt-Münster studies 98 and 2004] and 4372 adults registered with the Munich Leukemia Laboratory). The frequencies of cytogenetic subgroups were age-dependent. Favorable subtypes (t(8;21), inv(16)/t(16;16), and t(15;17)) decreased in general from the pediatric age group (2 to < 18 years; 33%) to the oldest groups (<5% for > 70 years; P < .0001). Unfavorable cytogenetics (-7/del(7), -5/del(5q) or 5p, inv(3)/t(3;3), t(6;9), complex karyotype, 12p, 17p, and 11q23/mixed-lineage leukemia aberrations, excluding t(9;11)) were frequent (42%) in infants (<2 years), had a low frequency in children and young adults (<22%), and increased in frequency up to 36% in patients older than 85 years (P = .01). This was even more significant for complex karyotypes (P ≤ .0001), which also showed a strong increase in the absolute age-specific incidence with age. Interestingly, the frequency of 11q23 abnormalities decreased from infants to older patients. The proportion of clinically relevant molecular aberrations of CCAAT/enhancer binding protein α, nucleophosmin (NPM1), and NPM1/fms-related tyrosine kinase 3-internal tandem duplication increased with age. Altogether, with the exclusion of infants, a significant decrease in the proportion of favorable cytogenetic subtypes and an increase in unfavorable cytogenetics were observed with increasing age. These findings indicate different mechanisms for the pathogenesis of AML; these different mechanisms also suggest directions for etiological research and contribute to the more unfavorable prognosis with increasing age. Cancer 2016;122:3821-3830.

  1. No short-term cytogenetic consequences of Hungarian red mud catastrophe.

    PubMed

    Gundy, Sarolta; Farkas, Gyöngyi; Székely, Gábor; Kásler, Miklós

    2013-01-01

    Red mud is an industrial waste produced in the process of alumina extraction from bauxite with concentrated NaOH. When the red mud-containing reservoir collapsed in Ajka Alumina Plant Hungary in October 2010, the most serious immediate effects were caused by the high alkalinity (pH ≥ 13) of the flood. Many persons suffered burn-like damage to tissues and contact with caustic desiccated ultra-fine dust with traces of toxic metals also caused irritation of upper respiratory tract and eyes. This catastrophe was unique from the point of view of genotoxic effects as well. Therefore cytogenetic examinations were carried out on inhabitants, either with burns (17 persons) or on those inhaling desiccated caustic dust (42 persons). Chromosomal aberration (CA) analysis and bleomycin (BLM)-sensitivity assays, as possible markers of effects, were studied in peripheral blood lymphocytes of persons within 4-6 weeks following the catastrophe. Controls were matched for age, sex and smoking habits, and also places of residence with different constituents of air pollution either from rural (59 persons), or from urban environments (59 persons). Neither spontaneous rate of CAs (1.47% vs. 1.69%) nor BLM-induced in vitro chromosomal breakage (0.79 vs. 0.83 break/cell) showed elevated rates when cytogenetic biomarkers of genotoxicity were compared between controls and exposed persons. Time spent in cleaning did not affect cytogenetic changes either (R(2) = 0.04). BLM-induced mutagen sensitivity was similar in exposed and control persons (27.1% vs. 30.5%). It seems that the red mud exposure does not appear to pose an immediate genotoxic hazard on residents when measured with cytogenetic methods. We recommend, however, that those involved in clean-up activities should be followed closely not only for overall health, but also for further genotoxic risk assessment, because the long-term hazards of ultra-fine fugitive dust particles with alkalinity of residual NaOH in red mud are still

  2. Imputation of a true endpoint from a surrogate: application to a cluster randomized controlled trial with partial information on the true endpoint.

    PubMed

    Nixon, Richard M; Duffy, Stephen W; Fender, Guy R K

    2003-09-24

    The Anglia Menorrhagia Education Study (AMES) is a randomized controlled trial testing the effectiveness of an education package applied to general practices. Binary data are available from two sources; general practitioner reported referrals to hospital, and referrals to hospital determined by independent audit of the general practices. The former may be regarded as a surrogate for the latter, which is regarded as the true endpoint. Data are only available for the true end point on a sub set of the practices, but there are surrogate data for almost all of the audited practices and for most of the remaining practices. The aim of this paper was to estimate the treatment effect using data from every practice in the study. Where the true endpoint was not available, it was estimated by three approaches, a regression method, multiple imputation and a full likelihood model. Including the surrogate data in the analysis yielded an estimate of the treatment effect which was more precise than an estimate gained from using the true end point data alone. The full likelihood method provides a new imputation tool at the disposal of trials with surrogate data.

  3. American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation

    PubMed Central

    Shaffer, Lisa G.

    2005-01-01

    The following are the recommendations of the American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee, which was convened to assist health care professionals in making decisions regarding cytogenetic diagnostic testing and counseling for mental retardation (MR) and developmental delay (DD). This document reviews available evidence concerning the value of conventional and molecular cytogenetic testing for the identification of chromosomal anomalies that play a role in the etiology of MR/DD, and, based on this evidence, specific recommendations for each method of testing are provided. PMID:16301868

  4. Surrogate endpoints for clinical trials in primary sclerosing cholangitis: Review and results from an International PSC Study Group consensus process.

    PubMed

    Ponsioen, Cyriel Y; Chapman, Roger W; Chazouillères, Olivier; Hirschfield, Gideon M; Karlsen, Tom H; Lohse, Ansgar W; Pinzani, Massimo; Schrumpf, Erik; Trauner, Michael; Gores, Gregory J

    2016-04-01

    Primary sclerosing cholangitis (PSC) is a rare, but serious, cholestatic disease for which, to date, no effective therapy exists to halt disease progression toward end-stage liver disease. Clinical trial design to study drugs that improve prognosis is hampered by the relatively low event rate of clinically relevant endpoints. To overcome this shortcoming, there is an urgent need to identify appropriate surrogate endpoints. At present, there are no established surrogate endpoints. This article provides a critical review and describes the results of a consensus process initiated by the International PSC Study Group to delineate appropriate candidate surrogate endpoints at present for clinical trials in this frequently dismal disease. The consensus process resulted in a shortlist of five candidates as surrogate endpoints for measuring disease progression: alkaline phosphatase (ALP); transient elastography (TE); histology; combination of ALP+histology; and bilirubin. Of these, histology, ALP, and TE came out as the most promising. However, the expert panel concluded that no biomarker currently exceeds level 3 validation. Combining multiple endpoints is advisable. At present, there are insufficient data to support level 2 validation for any surrogate endpoint in PSC. Concerted efforts by all stakeholders are highly needed. Novel, promising noninvasive biomarkers are under study and should be incorporated as exploratory endpoints in clinical trials. © 2015 by the American Association for the Study of Liver Diseases.

  5. The Genomic Landscape of Balanced Cytogenetic Abnormalities Associated with Human Congenital Anomalies

    PubMed Central

    Redin, Claire; Brand, Harrison; Collins, Ryan L.; Kammin, Tammy; Mitchell, Elyse; Hodge, Jennelle C.; Hanscom, Carrie; Pillalamarri, Vamsee; Seabra, Catarina M.; Abbott, Mary-Alice; Abdul-Rahman, Omar A.; Aberg, Erika; Adley, Rhett; Alcaraz-Estrada, Sofia L.; Alkuraya, Fowzan S.; An, Yu; Anderson, Mary-Anne; Antolik, Caroline; Anyane-Yeboa, Kwame; Atkin, Joan F.; Bartell, Tina; Bernstein, Jonathan A.; Beyer, Elizabeth; Blumenthal, Ian; Bongers, Ernie M.H.F.; Brilstra, Eva H.; Brown, Chester W.; Brüggenwirth, Hennie T.; Callewaert, Bert; Chiang, Colby; Corning, Ken; Cox, Helen; Cuppen, Edwin; Currall, Benjamin B.; Cushing, Tom; David, Dezso; Deardorff, Matthew A.; Dheedene, Annelies; D’Hooghe, Marc; de Vries, Bert B.A.; Earl, Dawn L.; Ferguson, Heather L.; Fisher, Heather; FitzPatrick, David R.; Gerrol, Pamela; Giachino, Daniela; Glessner, Joseph T.; Gliem, Troy; Grady, Margo; Graham, Brett H.; Griffis, Cristin; Gripp, Karen W.; Gropman, Andrea L.; Hanson-Kahn, Andrea; Harris, David J.; Hayden, Mark A.; Hill, Rosamund; Hochstenbach, Ron; Hoffman, Jodi D.; Hopkin, Robert J.; Hubshman, Monika W.; Innes, A. Micheil; Irons, Mira; Irving, Melita; Jacobsen, Jessie C.; Janssens, Sandra; Jewett, Tamison; Johnson, John P.; Jongmans, Marjolijn C.; Kahler, Stephen G.; Koolen, David A.; Korzelius, Jerome; Kroisel, Peter M.; Lacassie, Yves; Lawless, William; Lemyre, Emmanuelle; Leppig, Kathleen; Levin, Alex V.; Li, Haibo; Li, Hong; Liao, Eric C.; Lim, Cynthia; Lose, Edward J.; Lucente, Diane; Macera, Michael J.; Manavalan, Poornima; Mandrile, Giorgia; Marcelis, Carlo L.; Margolin, Lauren; Mason, Tamara; Masser-Frye, Diane; McClellan, Michael W.; Zepeda Mendoza, Cinthya J.; Menten, Björn; Middelkamp, Sjors; Mikami, Liya R.; Moe, Emily; Mohammed, Shehla; Mononen, Tarja; Mortenson, Megan E.; Moya, Graciela; Nieuwint, Aggie W.; Ordulu, Zehra; Parkash, Sandhya; Pauker, Susan P.; Pereira, Shahrin; Perrin, Danielle; Phelan, Katy; Piña Aguilar, Raul E.; Poddighe, Pino J.; Pregno, Giulia; Raskin, Salmo; Reis, Linda; Rhead, William; Rita, Debra; Renkens, Ivo; Roelens, Filip; Ruliera, Jayla; Rump, Patrick; Schilit, Samantha L.P.; Shaheen, Ranad; Sparkes, Rebecca; Spiegel, Erica; Stevens, Blair; Stone, Matthew R.; Tagoe, Julia; Thakuria, Joseph V.; van Bon, Bregje W.; van de Kamp, Jiddeke; van Der Burgt, Ineke; van Essen, Ton; van Ravenswaaij-Arts, Conny M.; van Roosmalen, Markus J.; Vergult, Sarah; Volker-Touw, Catharina M.L.; Warburton, Dorothy P.; Waterman, Matthew J.; Wiley, Susan; Wilson, Anna; Yerena-de Vega, Maria de la Concepcion A.; Zori, Roberto T.; Levy, Brynn; Brunner, Han G.; de Leeuw, Nicole; Kloosterman, Wigard P.; Thorland, Erik C.; Morton, Cynthia C.; Gusella, James F.; Talkowski, Michael E.

    2017-01-01

    Despite their clinical significance, characterization of balanced chromosomal abnormalities (BCAs) has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and revealed complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. This study proposes that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements, and provides insight into novel pathogenic mechanisms such as altered regulation due to changes in chromosome topology. PMID:27841880

  6. CytoBayesJ: software tools for Bayesian analysis of cytogenetic radiation dosimetry data.

    PubMed

    Ainsbury, Elizabeth A; Vinnikov, Volodymyr; Puig, Pedro; Maznyk, Nataliya; Rothkamm, Kai; Lloyd, David C

    2013-08-30

    A number of authors have suggested that a Bayesian approach may be most appropriate for analysis of cytogenetic radiation dosimetry data. In the Bayesian framework, probability of an event is described in terms of previous expectations and uncertainty. Previously existing, or prior, information is used in combination with experimental results to infer probabilities or the likelihood that a hypothesis is true. It has been shown that the Bayesian approach increases both the accuracy and quality assurance of radiation dose estimates. New software entitled CytoBayesJ has been developed with the aim of bringing Bayesian analysis to cytogenetic biodosimetry laboratory practice. CytoBayesJ takes a number of Bayesian or 'Bayesian like' methods that have been proposed in the literature and presents them to the user in the form of simple user-friendly tools, including testing for the most appropriate model for distribution of chromosome aberrations and calculations of posterior probability distributions. The individual tools are described in detail and relevant examples of the use of the methods and the corresponding CytoBayesJ software tools are given. In this way, the suitability of the Bayesian approach to biological radiation dosimetry is highlighted and its wider application encouraged by providing a user-friendly software interface and manual in English and Russian. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. Cytogenetics of two species of Paratelmatobius (Anura: Leptodactylidae), with phylogenetic comments.

    PubMed

    Lourenço, L B; Garcia, P C; Recco-Pimentel, S M

    2000-01-01

    In this paper we provide a cytogenetic analysis of Paratelmatobius cardosoi and Paratelmatobius poecilogaster. The karyotypes of both species showed a diploid number of 24 chromosomes and shared some similarity in the morphology of some pairs. On the other hand, pairs 4 and 6 widely differed between these complements. These karyotypes also differed in their NOR number and location. Size heteromorphism was seen in all NOR-bearing chromosomes of the two karyotypes. In addition, both karyotypes showed small centromeric C-bands and a conspicuous heterochromatic band in the short arm of chromosome 1, although with a different size in each species. The P. cardosoi complement also showed other strongly stained non-centromeric C-bands, with no counterparts in the P. cardosoi karyotype. Chromosome staining with fluorochromes revealed heterogeneity in the base composition of two of the non-centromeric C-bands of P. cardosoi. Comparison of the chromosomal morphology of these Paratelmatobius karyotypes with that of P. lutzii showed that the P. poecilogaster karyotype is more similar to that of P. lutzii than P. cardosoi. These cytogenetic results agree with the proposed species arrangements in the P. cardosoi and P. lutzii groups based on morphological and ecological data.

  8. Cytogenetics of Hylodes and Crossodactylus species (Anura, Leptodactylidae) with comments on Hylodinae/Dendrobatidae relationships.

    PubMed

    Aguiar Júnior, Odair; Carvalho, Klélia Aparecida; Giaretta, Ariovaldo Antônio; Recco-Pimentel, Shirlei Maria

    2004-05-01

    The karyotype, nucleolar organizer region (NOR) location and C-banding pattern of two species of Hylodes (H. phyllodes and H. asper) and two of Crossodactylus (Crossodactylus sp. n. and Crossodactylus cf. caramaschi) were studied. All species had a diploid number of 2n = 26, with differences in the chromosomal morphology of the Hylodes species while the two Crossodactylus species were cytogenetically indistinguishable. The NOR was located on pair 1 in both species of Hylodes, and on pair 8 in the Crossodactylus species. In the latter, the NOR was heteromorphic between the homologues. The NOR was coincident with a secondary constriction in the four species. Except to H. phyllodes, such secondary constrictions were clearly seen strongly stained after C-banding treatment. The C-banding pattern varied between the two species of Hylodes, but was identical in the Crossodactylus species. The results from conventionally stained karyotypes confirmed the uniformity within the genus Crossodactylus, and the relatively conserved karyotypes within Hylodes, in agreement with other literature reports. We conclude that the cytogenetic data do not provide further evidence which could be useful to corroborate the supposed relationships between the hylodines and dendrobatids since there are no unambiguous homeologies between the karyotypes of these groups.

  9. Highly distinct chromosomal structures in cowpea (Vigna unguiculata), as revealed by molecular cytogenetic analysis.

    PubMed

    Iwata-Otsubo, Aiko; Lin, Jer-Young; Gill, Navdeep; Jackson, Scott A

    2016-05-01

    Cowpea (Vigna unguiculata (L.) Walp) is an important legume, particularly in developing countries. However, little is known about its genome or chromosome structure. We used molecular cytogenetics to characterize the structure of pachytene chromosomes to advance our knowledge of chromosome and genome organization of cowpea. Our data showed that cowpea has highly distinct chromosomal structures that are cytologically visible as brightly DAPI-stained heterochromatic regions. Analysis of the repetitive fraction of the cowpea genome present at centromeric and pericentromeric regions confirmed that two retrotransposons are major components of pericentromeric regions and that a 455-bp tandem repeat is found at seven out of 11 centromere pairs in cowpea. These repeats likely evolved after the divergence of cowpea from common bean and form chromosomal structure unique to cowpea. The integration of cowpea genetic and physical chromosome maps reveals potential regions of suppressed recombination due to condensed heterochromatin and a lack of pairing in a few chromosomal termini. This study provides fundamental knowledge on cowpea chromosome structure and molecular cytogenetics tools for further chromosome studies.

  10. Cytogenetic and molecular markers for detecting Aegilops uniaristata chromosomes in a wheat background.

    PubMed

    Gong, Wenping; Li, Guangrong; Zhou, Jianping; Li, Genying; Liu, Cheng; Huang, Chengyan; Zhao, Zhendong; Yang, Zujun

    2014-09-01

    Aegilops uniaristata has many agronomically useful traits that can be used for wheat breeding. So far, a Triticum turgidum - Ae. uniaristata amphiploid and one set of Chinese Spring (CS) - Ae. uniaristata addition lines have been produced. To guide Ae. uniaristata chromatin transformation from these lines into cultivated wheat through chromosome engineering, reliable cytogenetic and molecular markers specific for Ae. uniaristata chromosomes need to be developed. Standard C-banding shows that C-bands mainly exist in the centromeric regions of Ae. uniaristata but rarely at the distal ends. Fluorescence in situ hybridization (FISH) using (GAA)8 as a probe showed that the hybridization signal of chromosomes 1N-7N are different, thus (GAA)8 can be used to identify all Ae. uniaristata chromosomes in wheat background simultaneously. Moreover, a total of 42 molecular markers specific for Ae. uniaristata chromosomes were developed by screening expressed sequence tag - sequence tagged site (EST-STS), expressed sequence tag - simple sequence repeat (EST-SSR), and PCR-based landmark unique gene (PLUG) primers. The markers were subsequently localized using the CS - Ae. uniaristata addition lines and different wheat cultivars as controls. The cytogenetic and molecular markers developed herein will be helpful for screening and identifying wheat - Ae. uniaristata progeny.

  11. Employment of Oligodeoxynucleotide plus Interleukin-2 Improves Cytogenetic Analysis in Splenic Marginal Zone Lymphoma

    PubMed Central

    Bardi, Antonella; Cavazzini, Francesco; Rigolin, Gian Matteo; Tammiso, Elisa; Volta, Eleonora; Pezzolo, Elisa; Formigaro, Luca; Sofritti, Olga; Daghia, Giulia; Ambrosio, Cristina; Rizzotto, Lara; Abass, Awad E.; D'Auria, Fiorella; Musto, Pellegrino; Cuneo, Antonio

    2011-01-01

    To compare the efficiency of novel mitogenic agents and traditional mitosis inductors, 18 patients with splenic marginal zone lymphoma (SMZL) were studied. Three cultures using oligodeoxynucleotide (ODN) plus interleukin-2 (IL-2), or TPA, or LPS were setup in each patient. Seventeen/18 cases with ODN + IL2 had moderate/good proliferation (94, 4%) as compared with 10/18 cases with TPA and LPS (55%) (P = .015); 14/18 (77, 7%) cases with ODN + IL2 had sufficient good quality of banding as compared with 8/18 cases (44, 4%) with TPA and LPS. The karyotype could be defined from ODN + IL2-stimulated cultures in all 18 patients, 14 of whom (77, 7%) had a cytogenetic aberration, whereas clonal aberrations could be documented in 9 and in 3 cases by stimulation with LPS and TPA, respectively. Recurrent chromosome aberrations in our series were represented by aberrations of chromosome 14q in 5 patients, by trisomy 12 and 7q deletion in 4 cases each, and by abnormalities involving 11q and 13q in two cases each. These findings show that stimulation with ODN + IL2 offers more mitotic figures of better quality and results in an increased rate of clonal aberrations in SMZL, making this method ideal for prospective studies aiming at the definition of the prognostic impact of cytogenetic aberrations in this disorder. PMID:21629757

  12. Cytogenetic analysis in Thoracocharax stellatus (Kner, 1858) (Characiformes, Gasteropelecidae) from Paraguay River Basin, Mato Grosso, Brazil

    PubMed Central

    da Silva, Edson Lourenço; de Borba, Rafael Splendore; Centofante, Liano; Miyazawa, Carlos Suetoshi; Parise-Maltempi, Patrícia Pasquali

    2012-01-01

    Abstract Thoracocharax stellatus (Characiformes, Gasteropelecidae) is a small Neotropical species of fish, widely distributed in several rivers of South America. Evidence for karyotype heteromorphysm in populations from different geographical regions has been reported for this species. In this way, populations of Thoracocharax stellatus from the Paraguay River basin were cytogenetically characterized and the results were compared with other studies performed in the same species but from different basins. The results showed a diploid number of 2n = 54 for Thoracocharax stellatus, with chromosomes arranged in 6 metacentric (m), 6 submetacentric (sm), 2 subtelocentric (st) and 40 acrocentric (a), for both sexes, with a simple Nucleolus Organiser Region (NOR) system reported by the techniques of silver nitrate impregnation and fluorescent in situ hybridisation (FISH) using 18S rDNA sequences as probe. The distribution of constitutive heterochromatin, observed by the C-band technique and Chromomycin A3 staining showed great similarity among the analyzed populations and consists mainly of discrete blocks in the pericentromeric and telomeric regions of most chromosomes. The presence of female heterogamety was also observed indicating a ZZ/ZW system with W chromosome almost totally heterochromatic. The results also show cytogenetic diversity of the group and are useful to understand the mechanisms of karyotype evolution of the family. PMID:24260672

  13. Pre-pregnancy cytogenetic analysis of general couples in eastern China.

    PubMed

    Yang, Yan; Wang, Hexi; Gao, Min; Xu, Shuangshan; Xu, Xiaofen; Cao, Xinyu; Tao, Ying

    2014-11-27

    The aim of this study was to investigate the contribution of chromosomal anomalies and the frequency of particular types of aberrations in general couples preparing for pregnancy and make recommendations for pregnancy on the basis of the medical literature. A total of 6,198 general couples were included in the present study. The karyotypes were generated from the peripheral blood lymphocyte cultures and the cytogenetic analysis was performed using G-banding. In 12,396 cases, chromosomal anomalies were detected in 59 cases (0.48%, 59/12,396). Among of them, the frequency of translocation was 0.35% (n = 43). Sex chromosomal anomalies accounted for 0.07% (n = 9), including Klinefelter syndrome (KS) (n = 4), Turner syndrome (TS) (n = 4), and XYY syndrome (n = 1). The others, including inversions (n = 6) and deletion (n = 1), accounted for 0.06%. Our study indicates that clinically important chromosomal defects are present at a remarkable frequency in the general couples in eastern China, suggesting pre-pregnancy cytogenetic analysis should be routinely performed among general couples in this area so that informed decision can be made, which will help to improve the quality of the pregnancy.

  14. [Comparative analysis of cytogenetic examination of control groups of subjects carried out in different Russian laboratories].

    PubMed

    Sevan'kaev, A V; Khvostunov, I K; Snigireva, G P; Novitskaia, N N; Antoshchina, M M; Fesenko, E V; Vorobtsova, I E; Neronova, E G; Domracheva, E V; Nugis, V Iu; Govorun, R D; Handogina, E K

    2013-01-01

    The incidence of unstable chromosome aberrations in peripheral blood lymphocytes from unirradiated control subjects was analyzed using cytogenetic data obtained from 9 cytogenetic laboratories located in Moscow, St.-Petersburg, Obninsk, and Dubna (Russia). The objective of this study was to estimate the level and spectrum of spontaneous chromosome aberrations in human lymphocytes. 1140 blood samples were taken from 1112 subjects (594 men and 546 women) aged 1 to 72. The total metaphase number was 466795. The uniform Giemsa method for peripheral blood lymphocyte cultures was used. After counting 466795 metaphases, 4288 chromosomal aberrations of various types were classified. The most frequent types of aberrations were acentrics and chromatid deletions. They made up 90% of the total number of aberrations. The remaining 10% were exchange aberrations. The number of chromosome exchanges (dicentrics and centric rings) was twice the number of chromatid exchanges. Overall, the portion ofcells with chromosomal or (and) chromatid aberrations was 0.89 +/- 0.01%; the frequency of acentrics was 0.29 +/- 0.01; the frequency of dicentrics was 0.046 +/- 0.003; the frequency of unstable chromosome aberrations was 0.35 +/- 0.01; and the frequency of chromatid aberrations was 0.57 +/- 0.01 per 100 cells.

  15. Cytogenetic Diversity of Simple Sequences Repeats in Morphotypes of Brassica rapa ssp. chinensis

    PubMed Central

    Zheng, Jin-shuang; Sun, Cheng-zhen; Zhang, Shu-ning; Hou, Xi-lin; Bonnema, Guusje

    2016-01-01

    A significant fraction of the nuclear DNA of all eukaryotes is comprised of simple sequence repeats (SSRs). Although these sequences are widely used for studying genetic variation, linkage mapping and evolution, little attention had been paid to the chromosomal distribution and cytogenetic diversity of these sequences. In this paper, we report the distribution characterization of mono-, di-, and tri-nucleotide SSRs in Brassica rapa ssp. chinensis. Fluorescence in situ hybridization was used to characterize the cytogenetic diversity of SSRs among morphotypes of B. rapa ssp. chinensis. The proportion of different SSR motifs varied among morphotypes of B. rapa ssp. chinensis, with tri-nucleotide SSRs being more prevalent in the genome of B. rapa ssp. chinensis. We determined the chromosomal locations of mono-, di-, and tri-nucleotide repeat loci. The results showed that the chromosomal distribution of SSRs in the different morphotypes is non-random and motif-dependent, and allowed us to characterize the relative variability in terms of SSR numbers and similar chromosomal distributions in centromeric/peri-centromeric heterochromatin. The differences between SSR repeats with respect to abundance and distribution indicate that SSRs are a driving force in the genomic evolution of B. rapa species. Our results provide a comprehensive view of the SSR sequence distribution and evolution for comparison among morphotypes B. rapa ssp. chinensis. PMID:27507974

  16. Cytogenetic Diversity of Simple Sequences Repeats in Morphotypes of Brassica rapa ssp. chinensis.

    PubMed

    Zheng, Jin-Shuang; Sun, Cheng-Zhen; Zhang, Shu-Ning; Hou, Xi-Lin; Bonnema, Guusje

    2016-01-01

    A significant fraction of the nuclear DNA of all eukaryotes is comprised of simple sequence repeats (SSRs). Although these sequences are widely used for studying genetic variation, linkage mapping and evolution, little attention had been paid to the chromosomal distribution and cytogenetic diversity of these sequences. In this paper, we report the distribution characterization of mono-, di-, and tri-nucleotide SSRs in Brassica rapa ssp. chinensis. Fluorescence in situ hybridization was used to characterize the cytogenetic diversity of SSRs among morphotypes of B. rapa ssp. chinensis. The proportion of different SSR motifs varied among morphotypes of B. rapa ssp. chinensis, with tri-nucleotide SSRs being more prevalent in the genome of B. rapa ssp. chinensis. We determined the chromosomal locations of mono-, di-, and tri-nucleotide repeat loci. The results showed that the chromosomal distribution of SSRs in the different morphotypes is non-random and motif-dependent, and allowed us to characterize the relative variability in terms of SSR numbers and similar chromosomal distributions in centromeric/peri-centromeric heterochromatin. The differences between SSR repeats with respect to abundance and distribution indicate that SSRs are a driving force in the genomic evolution of B. rapa species. Our results provide a comprehensive view of the SSR sequence distribution and evolution for comparison among morphotypes B. rapa ssp. chinensis.

  17. Classical and molecular cytogenetic characterization of Agonostomus monticola, a primitive species of Mugilidae (Mugiliformes).

    PubMed

    Nirchio, Mauro; Oliveira, Claudio; Ferreira, Irani A; Martins, Cesar; Rossi, Anna Rita; Sola, Luciana

    2009-01-01

    This study reports the first description of the karyotype of Agonostomus monticola, a species belonging to a genus which is considered to be the most primitive among living mugilid fish. Specimens from Panama and Venezuela were cytogenetically analysed by conventional chromosome banding (Ag and base-specific-fluorochrome staining, C-banding) and by fluorescent in situ hybridization (FISH). Agonostomus monticola showed a chromosome complement of 2n = 48, composed of 23 acrocentric and one subtelocentric chromosome pairs and a pericentromeric distribution of the C-positive heterochromatin in all chromosomes. Major ribosomal genes were found to be located on the short arms of the subtelocentric chromosome pair number 24 and minor ribosomal genes in a paracentromeric position of a single medium-sized chromosome pair. All these observed cytogenetic features are similar to those previously described in four representatives of two genera, Liza and Chelon, which are considered to be among the most advanced in the family. Thus, this karyotypic form might represent the plesiomorphic condition for the mullets. This hypothesis regarding the plesiomorphic condition, if confirmed, would shed new light on the previously inferred cytotaxonomic relationships for the studied species of Mugilidae, because the karyotype with 48 acrocentric chromosomes, which has been so far regarded as primitive for the family, would have to be considered as derived.

  18. Comparative Cytogenetics between Two Important Songbird, Models: The Zebra Finch and the Canary

    PubMed Central

    dos Santos, Michelly da Silva; Kretschmer, Rafael; Frankl-Vilches, Carolina; Bakker, Antje; Gahr, Manfred; O´Brien, Patricia C. M.; Ferguson-Smith, Malcolm A.

    2017-01-01

    Songbird species (order Passeriformes, suborder Oscines) are important models in various experimental fields spanning behavioural genomics to neurobiology. Although the genomes of some songbird species were sequenced recently, the chromosomal organization of these species is mostly unknown. Here we focused on the two most studied songbird species in neuroscience, the zebra finch (Taeniopygia guttata) and the canary (Serinus canaria). In order to clarify these issues and also to integrate chromosome data with their assembled genomes, we used classical and molecular cytogenetics in both zebra finch and canary to define their chromosomal homology, localization of heterochromatic blocks and distribution of rDNA clusters. We confirmed the same diploid number (2n = 80) in both species, as previously reported. FISH experiments confirmed the occurrence of multiple paracentric and pericentric inversions previously found in other species of Passeriformes, providing a cytogenetic signature for this order, and corroborating data from in silico analyses. Additionally, compared to other Passeriformes, we detected differences in the zebra finch karyotype concerning the morphology of some chromosomes, in the distribution of 5S rDNA clusters, and an inversion in chromosome 1. PMID:28129381

  19. Molecular Cytogenetics Guides Massively Parallel Sequencing of a Radiation-Induced Chromosome Translocation in Human Cells.

    PubMed

    Cornforth, Michael N; Anur, Pavana; Wang, Nicholas; Robinson, Erin; Ray, F Andrew; Bedford, Joel S; Loucas, Bradford D; Williams, Eli S; Peto, Myron; Spellman, Paul; Kollipara, Rahul; Kittler, Ralf; Gray, Joe W; Bailey, Susan M

    2018-05-11

    Chromosome rearrangements are large-scale structural variants that are recognized drivers of oncogenic events in cancers of all types. Cytogenetics allows for their rapid, genome-wide detection, but does not provide gene-level resolution. Massively parallel sequencing (MPS) promises DNA sequence-level characterization of the specific breakpoints involved, but is strongly influenced by bioinformatics filters that affect detection efficiency. We sought to characterize the breakpoint junctions of chromosomal translocations and inversions in the clonal derivatives of human cells exposed to ionizing radiation. Here, we describe the first successful use of DNA paired-end analysis to locate and sequence across the breakpoint junctions of a radiation-induced reciprocal translocation. The analyses employed, with varying degrees of success, several well-known bioinformatics algorithms, a task made difficult by the involvement of repetitive DNA sequences. As for underlying mechanisms, the results of Sanger sequencing suggested that the translocation in question was likely formed via microhomology-mediated non-homologous end joining (mmNHEJ). To our knowledge, this represents the first use of MPS to characterize the breakpoint junctions of a radiation-induced chromosomal translocation in human cells. Curiously, these same approaches were unsuccessful when applied to the analysis of inversions previously identified by directional genomic hybridization (dGH). We conclude that molecular cytogenetics continues to provide critical guidance for structural variant discovery, validation and in "tuning" analysis filters to enable robust breakpoint identification at the base pair level.

  20. A comprehensive whole-genome integrated cytogenetic map for the alpaca (Lama pacos).

    PubMed

    Avila, Felipe; Baily, Malorie P; Perelman, Polina; Das, Pranab J; Pontius, Joan; Chowdhary, Renuka; Owens, Elaine; Johnson, Warren E; Merriwether, David A; Raudsepp, Terje

    2014-01-01

    Genome analysis of the alpaca (Lama pacos, LPA) has progressed slowly compared to other domestic species. Here, we report the development of the first comprehensive whole-genome integrated cytogenetic map for the alpaca using fluorescence in situ hybridization (FISH) and CHORI-246 BAC library clones. The map is comprised of 230 linearly ordered markers distributed among all 36 alpaca autosomes and the sex chromosomes. For the first time, markers were assigned to LPA14, 21, 22, 28, and 36. Additionally, 86 genes from 15 alpaca chromosomes were mapped in the dromedary camel (Camelus dromedarius, CDR), demonstrating exceptional synteny and linkage conservation between the 2 camelid genomes. Cytogenetic mapping of 191 protein-coding genes improved and refined the known Zoo-FISH homologies between camelids and humans: we discovered new homologous synteny blocks (HSBs) corresponding to HSA1-LPA/CDR11, HSA4-LPA/CDR31 and HSA7-LPA/CDR36, and revised the location of breakpoints for others. Overall, gene mapping was in good agreement with the Zoo-FISH and revealed remarkable evolutionary conservation of gene order within many human-camelid HSBs. Most importantly, 91 FISH-mapped markers effectively integrated the alpaca whole-genome sequence and the radiation hybrid maps with physical chromosomes, thus facilitating the improvement of the sequence assembly and the discovery of genes of biological importance. © 2015 S. Karger AG, Basel.

  1. Cytogenetic risks and possible adverse health effects by narcotic substances dependent.

    PubMed

    Movafagh, Abolfazl; Haeri, Ali; Kolahi, Ali Asghar; Hassani-Moghadam, Hossein

    2012-09-01

    Illicit drug abuse has crossed social, economic, and geographical borders, and remains one of the major health problems that modern society is facing worldwide. The role of multiple drug abuse as a basic for chromosome damage has been overlooked and it is important to determine its possible adverse health effects. This study aimed to compare the frequency of chromosomal damages between drug addicts and free drug controls. Cytogenetic study was obtained from 146 illicit drug-users and 200 free drug controls. Subjects were grouped into three categories depending on main drug of dependence. Cytogenetic studies on cultured lymphocytes showed an increase the frequency of chromosomal damages among addicts including opiate (5.89%), heroin (7.65%), and crystal (4.9%) when compared with drug free controls (1.45%). The frequency of chromosomal abnormalities was breaks, gaps, marker, and acentric, respectively. Our findings are also important as they are among the first to suggest here, illicit drug addiction continue to be significant public health problems in Iran.

  2. Prognostic significance of cytogenetic abnormalities in patients with chronic myelogenous leukemia.

    PubMed

    Przepiorka, D; Thomas, E D

    1988-03-01

    The cytogenetic data for 126 patients with Ph-positive chronic myelogenous leukemia (CML) in accelerated phase or blast crisis were analysed for clonal chromosomal abnormalities in addition to the standard Ph prior to allogeneic or syngeneic bone marrow transplantation (BMT). Additional clonal abnormalities were found in 84%, and 14% had a variant Ph (VPh). In decreasing order of frequency, the most common clonal abnormalities were a second Ph, +8, i(17q), -Y and +19. A second Ph, VPh or +8 occurred more frequently in patients who relapsed following BMT than in those who survived disease-free for at least 1 1/2 years. The presence of an i(17q) alone did not correlate with relapse. The patients with a second Ph, VPh or +8 had a median time to relapse of 19 months, and the risk of relapse at 3 years was 73%. Those with other or no additional clonal abnormalities had not reached a median time to relapse and had a 3-year risk of relapse of 31% (p = 0.002). This analysis suggests that specific cytogenetic abnormalities may be useful indicators of resistance to therapy for CML and should be included in proportional hazard models to predict outcome after BMT.

  3. Proposed Standardized Neurological Endpoints for Cardiovascular Clinical Trials: An Academic Research Consortium Initiative.

    PubMed

    Lansky, Alexandra J; Messé, Steven R; Brickman, Adam M; Dwyer, Michael; Bart van der Worp, H; Lazar, Ronald M; Pietras, Cody G; Abrams, Kevin J; McFadden, Eugene; Petersen, Nils H; Browndyke, Jeffrey; Prendergast, Bernard; Ng, Vivian G; Cutlip, Donald E; Kapadia, Samir; Krucoff, Mitchell W; Linke, Axel; Scala Moy, Claudia; Schofer, Joachim; van Es, Gerrit-Anne; Virmani, Renu; Popma, Jeffrey; Parides, Michael K; Kodali, Susheel; Bilello, Michel; Zivadinov, Robert; Akar, Joseph; Furie, Karen L; Gress, Daryl; Voros, Szilard; Moses, Jeffrey; Greer, David; Forrest, John K; Holmes, David; Kappetein, Arie P; Mack, Michael; Baumbach, Andreas

    2018-05-14

    Surgical and catheter-based cardiovascular procedures and adjunctive pharmacology have an inherent risk of neurological complications. The current diversity of neurological endpoint definitions and ascertainment methods in clinical trials has led to uncertainties in the neurological risk attributable to cardiovascular procedures and inconsistent evaluation of therapies intended to prevent or mitigate neurological injury. Benefit-risk assessment of such procedures should be on the basis of an evaluation of well-defined neurological outcomes that are ascertained with consistent methods and capture the full spectrum of neurovascular injury and its clinical effect. The Neurologic Academic Research Consortium is an international collaboration intended to establish consensus on the definition, classification, and assessment of neurological endpoints applicable to clinical trials of a broad range of cardiovascular interventions. Systematic application of the proposed definitions and assessments will improve our ability to evaluate the risks of cardiovascular procedures and the safety and effectiveness of preventive therapies.

  4. Selection and quantification of infection endpoints for trials of vaccines against intestinal helminths

    PubMed Central

    Alexander, Neal; Cundill, Bonnie; Sabatelli, Lorenzo; Bethony, Jeffrey M.; Diemert, David; Hotez, Peter; Smith, Peter G.; Rodrigues, Laura C.; Brooker, Simon

    2011-01-01

    Vaccines against human helminths are being developed but the choice of optimal parasitological endpoints and effect measures to assess their efficacy has received little attention. Assuming negative binomial distributions for the parasite counts, we rank the statistical power of three measures of efficacy: ratio of mean parasite intensity at the end of the trial, the odds ratio of infection at the end of the trial, and the rate ratio of incidence of infection during the trial. We also use a modelling approach to estimate the likely impact of trial interventions on the force of infection, and hence statistical power. We conclude that (1) final mean parasite intensity is a suitable endpoint for later phase vaccine trials, and (2) mass effects of trial interventions are unlikely to appreciably reduce the force of infection in the community – and hence statistical power – unless there is a combination of high vaccine efficacy and a large proportion of the population enrolled. PMID:21435404

  5. Free Energy, Enthalpy and Entropy from Implicit Solvent End-Point Simulations.

    PubMed

    Fogolari, Federico; Corazza, Alessandra; Esposito, Gennaro

    2018-01-01

    Free energy is the key quantity to describe the thermodynamics of biological systems. In this perspective we consider the calculation of free energy, enthalpy and entropy from end-point molecular dynamics simulations. Since the enthalpy may be calculated as the ensemble average over equilibrated simulation snapshots the difficulties related to free energy calculation are ultimately related to the calculation of the entropy of the system and in particular of the solvent entropy. In the last two decades implicit solvent models have been used to circumvent the problem and to take into account solvent entropy implicitly in the solvation terms. More recently outstanding advancement in both implicit solvent models and in entropy calculations are making the goal of free energy estimation from end-point simulations more feasible than ever before. We review briefly the basic theory and discuss the advancements in light of practical applications.

  6. Development of drugs for celiac disease: review of endpoints for Phase 2 and 3 trials

    PubMed Central

    Gottlieb, Klaus; Dawson, Jill; Hussain, Fez; Murray, Joseph A.

    2015-01-01

    Celiac disease is a lifelong disorder for which there is currently only one known, effective treatment: a gluten-free diet. New treatment approaches have recently emerged; several drugs are in Phase 2 trials and results appear promising; however, discussion around regulatory endpoints is in its infancy. We will briefly discuss the drugs that are under development and then shift our attention to potential trial endpoints, such as patient-reported outcomes, histology, serology, gene expression analysis and other tests. We will outline the differing requirements for proof-of-concept Phase 2 trials and Phase 3 registration trials, with a particular emphasis on current thinking in regulatory agencies. We conclude our paper with recommendations and a glossary of regulatory terms, to enable readers who are less familiar with regulatory language to take maximum advantage of this review. PMID:25725041

  7. Detection of Bordetella pertussis from Clinical Samples by Culture and End-Point PCR in Malaysian Patients.

    PubMed

    Ting, Tan Xue; Hashim, Rohaidah; Ahmad, Norazah; Abdullah, Khairul Hafizi

    2013-01-01

    Pertussis or whooping cough is a highly infectious respiratory disease caused by Bordetella pertussis. In vaccinating countries, infants, adolescents, and adults are relevant patients groups. A total of 707 clinical specimens were received from major hospitals in Malaysia in year 2011. These specimens were cultured on Regan-Lowe charcoal agar and subjected to end-point PCR, which amplified the repetitive insertion sequence IS481 and pertussis toxin promoter gene. Out of these specimens, 275 were positive: 4 by culture only, 6 by both end-point PCR and culture, and 265 by end-point PCR only. The majority of the positive cases were from ≤3 months old patients (77.1%) (P < 0.001). There was no significant association between type of samples collected and end-point PCR results (P > 0.05). Our study showed that the end-point PCR technique was able to pick up more positive cases compared to culture method.

  8. Development of Pain Endpoint Models for Use in Prostate Cancer Clinical Trials and Drug Approval

    DTIC Science & Technology

    2016-10-01

    consensus meeting, with input from investigators in the Prostate Cancer Clinical Trials Consortium, FDA Office of Oncology Drug Products, FDA Study...Cancer Clinical Trials Consortium, FDA Office of Oncology Drug Products, FDA Study Endpoint and Label Development Team, and FDA Division of...Abstract. American Society of Clinical Oncology . Chicago IL, June 1-5, 2013. INVENTIONS, PATENTS AND LICENSES None 11 REPORTABLE OUTCOMES

  9. Muscle Synergies Heavily Influence the Neural Control of Arm Endpoint Stiffness and Energy Consumption

    PubMed Central

    Inouye, Joshua M.; Valero-Cuevas, Francisco J.

    2016-01-01

    Much debate has arisen from research on muscle synergies with respect to both limb impedance control and energy consumption. Studies of limb impedance control in the context of reaching movements and postural tasks have produced divergent findings, and this study explores whether the use of synergies by the central nervous system (CNS) can resolve these findings and also provide insights on mechanisms of energy consumption. In this study, we phrase these debates at the conceptual level of interactions between neural degrees of freedom and tasks constraints. This allows us to examine the ability of experimentally-observed synergies—correlated muscle activations—to control both energy consumption and the stiffness component of limb endpoint impedance. In our nominal 6-muscle planar arm model, muscle synergies and the desired size, shape, and orientation of endpoint stiffness ellipses, are expressed as linear constraints that define the set of feasible muscle activation patterns. Quadratic programming allows us to predict whether and how energy consumption can be minimized throughout the workspace of the limb given those linear constraints. We show that the presence of synergies drastically decreases the ability of the CNS to vary the properties of the endpoint stiffness and can even preclude the ability to minimize energy. Furthermore, the capacity to minimize energy consumption—when available—can be greatly affected by arm posture. Our computational approach helps reconcile divergent findings and conclusions about task-specific regulation of endpoint stiffness and energy consumption in the context of synergies. But more generally, these results provide further evidence that the benefits and disadvantages of muscle synergies go hand-in-hand with the structure of feasible muscle activation patterns afforded by the mechanics of the limb and task constraints. These insights will help design experiments to elucidate the interplay between synergies and the

  10. Impact of acute antibiotic therapy on the pulmonary exacerbation endpoint in cystic fibrosis clinical trials.

    PubMed

    Mayer-Hamblett, Nicole; Saiman, Lisa; Lands, Larry C; Anstead, Michael; Rosenfeld, Margaret; Kloster, Margaret; Fisher, Leigh; Ratjen, Felix

    2013-09-01

    In a chronic disease setting such as cystic fibrosis (CF), antibiotics are often prescribed for emergent symptoms and it is unclear whether this affects endpoints in a clinical trial. Pulmonary exacerbations (PEs) are defined episodes of acute worsening and a key clinical efficacy measure in CF. Our hypothesis was that acute antibiotics given for illnesses not meeting the PE definition may alter estimates of treatment effect that do not account for this antibiotic use. A randomized, placebo-controlled trial of azithromycin (AZ) including 260 participants with CF was utilized for this study. PEs were defined using a priori criteria. Physician initiated antibiotic therapy (PIT) not meeting the PE endpoint was characterized and its impact on treatment effect assessed. 40% (104/260) of participants were prescribed 188 courses of PIT in the absence of a PE; 19% (25/129) of placebo and 10% (13/131) of AZ participants received ≥2 courses of PIT and never fulfilled the PE definition (9% difference, 95% confidence interval: 1%, 18%, p = 0.04). Accounting for PIT through use of a composite endpoint including time to PE or need for repeated PIT altered treatment effect estimates (a 56% reduction in the event rate comparing AZ to placebo [p < 0.0001] as compared to a 50% reduction not accounting for PIT [p = 0.003]). PIT is common in CF and may impact treatment effect estimates. Optimization of the PE endpoint to include meaningful events necessitating treatment may improve our ability to conduct efficient trials by reducing the sample size 30-50%, ultimately enabling rapid evaluation of new therapies. Copyright © 2013 Elsevier Inc. All rights reserved.

  11. Kinetic titration with differential thermometric determination of the end-point.

    PubMed

    Sajó, I

    1968-06-01

    A method has been described for the determination of concentrations below 10(-4)M by applying catalytic reactions and using thermometric end-point determination. A reference solution, identical with the sample solution except for catalyst, is titrated with catalyst solution until the rates of reaction become the same, as shown by a null deflection on a galvanometer connected via bridge circuits to two opposed thermistors placed in the solutions.

  12. Testing for qualitative heterogeneity: An application to composite endpoints in survival analysis.

    PubMed

    Oulhaj, Abderrahim; El Ghouch, Anouar; Holman, Rury R

    2017-01-01

    Composite endpoints are frequently used in clinical outcome trials to provide more endpoints, thereby increasing statistical power. A key requirement for a composite endpoint to be meaningful is the absence of the so-called qualitative heterogeneity to ensure a valid overall interpretation of any treatment effect identified. Qualitative heterogeneity occurs when individual components of a composite endpoint exhibit differences in the direction of a treatment effect. In this paper, we develop a general statistical method to test for qualitative heterogeneity, that is to test whether a given set of parameters share the same sign. This method is based on the intersection-union principle and, provided that the sample size is large, is valid whatever the model used for parameters estimation. We propose two versions of our testing procedure, one based on a random sampling from a Gaussian distribution and another version based on bootstrapping. Our work covers both the case of completely observed data and the case where some observations are censored which is an important issue in many clinical trials. We evaluated the size and power of our proposed tests by carrying out some extensive Monte Carlo simulations in the case of multivariate time to event data. The simulations were designed under a variety of conditions on dimensionality, censoring rate, sample size and correlation structure. Our testing procedure showed very good performances in terms of statistical power and type I error. The proposed test was applied to a data set from a single-center, randomized, double-blind controlled trial in the area of Alzheimer's disease.

  13. Establishing Good Practices for Exposure–Response Analysis of Clinical Endpoints in Drug Development

    PubMed Central

    Overgaard, RV; Ingwersen, SH; Tornøe, CW

    2015-01-01

    This tutorial aims at promoting good practices for exposure–response (E-R) analyses of clinical endpoints in drug development. The focus is on practical aspects of E-R analyses to assist modeling scientists with a process of performing such analyses in a consistent manner across individuals and projects and tailored to typical clinical drug development decisions. This includes general considerations for planning, conducting, and visualizing E-R analyses, and how these are linked to key questions. PMID:26535157

  14. Quantitative 4D Transcatheter Intraarterial Perfusion MR Imaging as a Method to Standardize Angiographic Chemoembolization Endpoints

    PubMed Central

    Jin, Brian; Wang, Dingxin; Lewandowski, Robert J.; Ryu, Robert K.; Sato, Kent T.; Larson, Andrew C.; Salem, Riad; Omary, Reed A.

    2011-01-01

    PURPOSE We aimed to test the hypothesis that subjective angiographic endpoints during transarterial chemoembolization (TACE) of hepatocellular carcinoma (HCC) exhibit consistency and correlate with objective intraprocedural reductions in tumor perfusion as determined by quantitative four dimensional (4D) transcatheter intraarterial perfusion (TRIP) magnetic resonance (MR) imaging. MATERIALS AND METHODS This prospective study was approved by the institutional review board. Eighteen consecutive patients underwent TACE in a combined MR/interventional radiology (MR-IR) suite. Three board-certified interventional radiologists independently graded the angiographic endpoint of each procedure based on a previously described subjective angiographic chemoembolization endpoint (SACE) scale. A consensus SACE rating was established for each patient. Patients underwent quantitative 4D TRIP-MR imaging immediately before and after TACE, from which mean whole tumor perfusion (Fρ) was calculated. Consistency of SACE ratings between observers was evaluated using the intraclass correlation coefficient (ICC). The relationship between SACE ratings and intraprocedural TRIP-MR imaging perfusion changes was evaluated using Spearman’s rank correlation coefficient. RESULTS The SACE rating scale demonstrated very good consistency among all observers (ICC = 0.80). The consensus SACE rating was significantly correlated with both absolute (r = 0.54, P = 0.022) and percent (r = 0.85, P < 0.001) intraprocedural perfusion reduction. CONCLUSION The SACE rating scale demonstrates very good consistency between raters, and significantly correlates with objectively measured intraprocedural perfusion reductions during TACE. These results support the use of the SACE scale as a standardized alternative method to quantitative 4D TRIP-MR imaging to classify patients based on embolic endpoints of TACE. PMID:22021520

  15. Polysilicon planarization and plug recess etching in a decoupled plasma source chamber using two endpoint techniques

    NASA Astrophysics Data System (ADS)

    Kaplita, George A.; Schmitz, Stefan; Ranade, Rajiv; Mathad, Gangadhara S.

    1999-09-01

    The planarization and recessing of polysilicon to form a plug are processes of increasing importance in silicon IC fabrication. While this technology has been developed and applied to DRAM technology using Trench Storage Capacitors, the need for such processes in other IC applications (i.e. polysilicon studs) has increased. Both planarization and recess processes usually have stringent requirements on etch rate, recess uniformity, and selectivity to underlying films. Additionally, both processes generally must be isotropic, yet must not expand any seams that might be present in the polysilicon fill. These processes should also be insensitive to changes in exposed silicon area (pattern factor) on the wafer. A SF6 plasma process in a polysilicon DPS (Decoupled Plasma Source) reactor has demonstrated the capability of achieving the above process requirements for both planarization and recess etch. The SF6 process in the decoupled plasma source reactor exhibited less sensitivity to pattern factor than in other types of reactors. Control of these planarization and recess processes requires two endpoint systems to work sequentially in the same recipe: one for monitoring the endpoint when blanket polysilicon (100% Si loading) is being planarized and one for monitoring the recess depth while the plug is being recessed (less than 10% Si loading). The planarization process employs an optical emission endpoint system (OES). An interferometric endpoint system (IEP), capable of monitoring lateral interference, is used for determining the recess depth. The ability of using either or both systems is required to make these plug processes manufacturable. Measuring the recess depth resulting from the recess process can be difficult, costly and time- consuming. An Atomic Force Microscope (AFM) can greatly alleviate these problems and can serve as a critical tool in the development of recess processes.

  16. Energy metabolism and biotransformation as endpoints to pre-screen hepatotoxicity using a liver spheroid model

    SciTech Connect

    Xu Jinsheng; Purcell, Wendy M.

    2006-10-15

    The current study investigated liver spheroid culture as an in vitro model to evaluate the endpoints relevant to the status of energy metabolism and biotransformation after exposure to test toxicants. Mature rat liver spheroids were exposed to diclofenac, galactosamine, isoniazid, paracetamol, m-dinitrobenzene (m-DNB) and 3-nitroaniline (3-NA) for 24 h. Pyruvate uptake, galactose biotransformation, lactate release and glucose secretion were evaluated after exposure. The results showed that pyruvate uptake and lactate release by mature liver spheroids in culture were maintained at a relatively stable level. These endpoints, together with glucose secretion and galactose biotransformation, were related to and could reflect themore » status of energy metabolism and biotransformation in hepatocytes. After exposure, all of the test agents significantly reduced glucose secretion, which was shown to be the most sensitive endpoint of those evaluated. Diclofenac, isoniazid, paracetamol and galactosamine reduced lactate release (P < 0.01), but m-DNB increased lactate release (P < 0.01). Diclofenac, isoniazid and paracetamol also reduced pyruvate uptake (P < 0.01), while galactosamine had little discernible effect. Diclofenac, galactosamine, paracetamol and m-DNB also reduced galactose biotransformation (P < 0.01), by contrast, isoniazid did not. The metabolite of m-DNB, 3-NA, which served as a negative control, did not cause significant changes in lactate release, pyruvate uptake or galactose biotransformation. It is concluded that pyruvate uptake, galactose biotransformation, lactate release and glucose secretion can be used as endpoints for evaluating the status of energy metabolism and biotransformation after exposure to test agents using the liver spheroid model to pre-screen hepatotoxicity.« less

  17. Muscle Synergies Heavily Influence the Neural Control of Arm Endpoint Stiffness and Energy Consumption.

    PubMed

    Inouye, Joshua M; Valero-Cuevas, Francisco J

    2016-02-01

    Much debate has arisen from research on muscle synergies with respect to both limb impedance control and energy consumption. Studies of limb impedance control in the context of reaching movements and postural tasks have produced divergent findings, and this study explores whether the use of synergies by the central nervous system (CNS) can resolve these findings and also provide insights on mechanisms of energy consumption. In this study, we phrase these debates at the conceptual level of interactions between neural degrees of freedom and tasks constraints. This allows us to examine the ability of experimentally-observed synergies--correlated muscle activations--to control both energy consumption and the stiffness component of limb endpoint impedance. In our nominal 6-muscle planar arm model, muscle synergies and the desired size, shape, and orientation of endpoint stiffness ellipses, are expressed as linear constraints that define the set of feasible muscle activation patterns. Quadratic programming allows us to predict whether and how energy consumption can be minimized throughout the workspace of the limb given those linear constraints. We show that the presence of synergies drastically decreases the ability of the CNS to vary the properties of the endpoint stiffness and can even preclude the ability to minimize energy. Furthermore, the capacity to minimize energy consumption--when available--can be greatly affected by arm posture. Our computational approach helps reconcile divergent findings and conclusions about task-specific regulation of endpoint stiffness and energy consumption in the context of synergies. But more generally, these results provide further evidence that the benefits and disadvantages of muscle synergies go hand-in-hand with the structure of feasible muscle activation patterns afforded by the mechanics of the limb and task constraints. These insights will help design experiments to elucidate the interplay between synergies and the mechanisms

  18. Impact of confinement housing on study end-points in the calf model of cryptosporidiosis.

    PubMed

    Graef, Geneva; Hurst, Natalie J; Kidder, Lance; Sy, Tracy L; Goodman, Laura B; Preston, Whitney D; Arnold, Samuel L M; Zambriski, Jennifer A

    2018-04-01

    Diarrhea is the second leading cause of death in children < 5 years globally and the parasite genus Cryptosporidium is a leading cause of that diarrhea. The global disease burden attributable to cryptosporidiosis is substantial and the only approved chemotherapeutic, nitazoxanide, has poor efficacy in HIV positive children. Chemotherapeutic development is dependent on the calf model of cryptosporidiosis, which is the best approximation of human disease. However, the model is not consistently applied across research studies. Data collection commonly occurs using two different methods: Complete Fecal Collection (CFC), which requires use of confinement housing, and Interval Collection (IC), which permits use of box stalls. CFC mimics human challenge model methodology but it is unknown if confinement housing impacts study end-points and if data gathered via this method is suitable for generalization to human populations. Using a modified crossover study design we compared CFC and IC and evaluated the impact of housing on study end-points. At birth, calves were randomly assigned to confinement (n = 14) or box stall housing (n = 9), or were challenged with 5 x 107 C. parvum oocysts, and followed for 10 days. Study end-points included fecal oocyst shedding, severity of diarrhea, degree of dehydration, and plasma cortisol. Calves in confinement had no significant differences in mean log oocysts enumerated per gram of fecal dry matter between CFC and IC samples (P = 0.6), nor were there diurnal variations in oocyst shedding (P = 0.1). Confinement housed calves shed significantly more oocysts (P = 0.05), had higher plasma cortisol (P = 0.001), and required more supportive care (P = 0.0009) than calves in box stalls. Housing method confounds study end-points in the calf model of cryptosporidiosis. Due to increased stress data collected from calves in confinement housing may not accurately estimate the efficacy of chemotherapeutics targeting C. parvum.

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

    PubMed

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

    2016-03-15

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

  20. Idaho National Laboratory Test Area North: Application of Endpoints to Guide Adaptive Remediation at a Complex Site: INL Test Area North: Application of Endpoints

    SciTech Connect

    Lee, M. Hope; Truex, Mike; Freshley, Mark

    Complex sites are defined as those with difficult subsurface access, deep and/or thick zones of contamination, large areal extent, subsurface heterogeneities that limit the effectiveness of remediation, or where long-term remedies are needed to address contamination (e.g., because of long-term sources or large extent). The Test Area North at the Idaho National Laboratory, developed for nuclear fuel operations and heavy metal manufacturing, is used as a case study. Liquid wastes and sludge from experimental facilities were disposed in an injection well, which contaminated the subsurface aquifer located deep within fractured basalt. The wastes included organic, inorganic, and low-level radioactive constituents,more » with the focus of this case study on trichloroethylene. The site is used as an example of a systems-based framework that provides a structured approach to regulatory processes established for remediation under existing regulations. The framework is intended to facilitate remedy decisions and implementation at complex sites where restoration may be uncertain, require long timeframes, or involve use of adaptive management approaches. The framework facilitates site, regulator, and stakeholder interactions during the remedial planning and implementation process by using a conceptual model description as a technical foundation for decisions, identifying endpoints, which are interim remediation targets or intermediate decision points on the path to an ultimate end, and maintaining protectiveness during the remediation process. At the Test Area North, using a structured approach to implementing concepts in the endpoint framework, a three-component remedy is largely functioning as intended and is projected to meet remedial action objectives by 2095 as required. The remedy approach is being adjusted as new data become available. The framework provides a structured process for evaluating and adjusting the remediation approach, allowing site owners, regulators

  1. [Online endpoint detection algorithm for blending process of Chinese materia medica].

    PubMed

    Lin, Zhao-Zhou; Yang, Chan; Xu, Bing; Shi, Xin-Yuan; Zhang, Zhi-Qiang; Fu, Jing; Qiao, Yan-Jiang

    2017-03-01

    Blending process, which is an essential part of the pharmaceutical preparation, has a direct influence on the homogeneity and stability of solid dosage forms. With the official release of Guidance for Industry PAT, online process analysis techniques have been more and more reported in the applications in blending process, but the research on endpoint detection algorithm is still in the initial stage. By progressively increasing the window size of moving block standard deviation (MBSD), a novel endpoint detection algorithm was proposed to extend the plain MBSD from off-line scenario to online scenario and used to determine the endpoint in the blending process of Chinese medicine dispensing granules. By online learning of window size tuning, the status changes of the materials in blending process were reflected in the calculation of standard deviation in a real-time manner. The proposed method was separately tested in the blending processes of dextrin and three other extracts of traditional Chinese medicine. All of the results have shown that as compared with traditional MBSD method, the window size changes according to the proposed MBSD method (progressively increasing the window size) could more clearly reflect the status changes of the materials in blending process, so it is suitable for online application. Copyright© by the Chinese Pharmaceutical Association.

  2. The current role and limitations of surrogate endpoints in advanced prostate cancer.

    PubMed

    Gomella, Leonard G; Oliver Sartor, A

    2014-01-01

    The identification of appropriate surrogate endpoints for evaluating cancer therapeutics has been of ongoing interest across various tumor types. Metastatic castrate-resistant prostate cancer (mCRPC) has been a particularly challenging area. As more targeted and novel therapies are being developed in this disease space, an urgent need exists to identify surrogate endpoints in mCRPC. The ability to discern patient benefit in the absence of patient death or other complications would facilitate both drug development and more appropriate patient care. We reviewed the available literature and guidelines used in the development and approval of recent agents for mCRPC. The majority of regulatory approvals of new medications have relied on overall survival (OS) or prevention of complications such as skeletal related events (SRE's). Progression-free survival measures, such as bone scans, computed tomography scans, and prostate-specific antigen related changes, have not been validated nor uniformly accepted as outcome surrogates. All of the successful recent pivotal Phase III trials designed to achieve regulatory approval in mCRPC have used either OS or SRE's as the primary endpoint. There are significant problematic issues that exist associated with defining and implementing surrogate markers in mCRPC beyond survival and complications. Suggestions are made as to how the current situation might be improved. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Surrogate Endpoints and Risk Adaptive Strategies in Previously Untreated Follicular Lymphoma.

    PubMed

    Narkhede, Mayur S; Cheson, Bruce D

    2018-05-05

    Follicular lymphoma is the second most common subtype of non-Hodgkin lymphoma with an estimated 3.18 cases per 100,000 people. Despite the prolongation of survival with chemoimmunotherapy, variability in response to initial treatment and outcome still exists. Whereas prolonging overall survival is important, it is generally an unreasonable primary endpoint in the front-line setting. The long follow-up needed and the influence of subsequent therapies creates a potential bias. Thus, clinical trials require approximately 5 to 8 years from activation to completion and analysis of outcomes. This duration results in enormous cost and a delay in developing newer therapies. Thus, there is a need to identify markers or surrogate endpoints that can be used in clinical trials to expedite the development of new treatments. This review will discuss various clinical, radiologic, and laboratory measures used to assess outcomes and overall survival in patients with untreated follicular lymphoma, and gauge their utility in clinical trials as surrogate endpoints. Copyright © 2018 Elsevier Inc. All rights reserved.

  4. Hard, harder, hardest: principal stratification, statistical identifiability, and the inherent difficulty of finding surrogate endpoints.

    PubMed

    Wolfson, Julian; Henn, Lisa

    2014-01-01

    In many areas of clinical investigation there is great interest in identifying and validating surrogate endpoints, biomarkers that can be measured a relatively short time after a treatment has been administered and that can reliably predict the effect of treatment on the clinical outcome of interest. However, despite dramatic advances in the ability to measure biomarkers, the recent history of clinical research is littered with failed surrogates. In this paper, we present a statistical perspective on why identifying surrogate endpoints is so difficult. We view the problem from the framework of causal inference, with a particular focus on the technique of principal stratification (PS), an approach which is appealing because the resulting estimands are not biased by unmeasured confounding. In many settings, PS estimands are not statistically identifiable and their degree of non-identifiability can be thought of as representing the statistical difficulty of assessing the surrogate value of a biomarker. In this work, we examine the identifiability issue and present key simplifying assumptions and enhanced study designs that enable the partial or full identification of PS estimands. We also present example situations where these assumptions and designs may or may not be feasible, providing insight into the problem characteristics which make the statistical evaluation of surrogate endpoints so challenging.

  5. Statistical Validation of Surrogate Endpoints: Another Look at the Prentice Criterion and Other Criteria.

    PubMed

    Saraf, Sanatan; Mathew, Thomas; Roy, Anindya

    2015-01-01

    For the statistical validation of surrogate endpoints, an alternative formulation is proposed for testing Prentice's fourth criterion, under a bivariate normal model. In such a setup, the criterion involves inference concerning an appropriate regression parameter, and the criterion holds if the regression parameter is zero. Testing such a null hypothesis has been criticized in the literature since it can only be used to reject a poor surrogate, and not to validate a good surrogate. In order to circumvent this, an equivalence hypothesis is formulated for the regression parameter, namely the hypothesis that the parameter is equivalent to zero. Such an equivalence hypothesis is formulated as an alternative hypothesis, so that the surrogate endpoint is statistically validated when the null hypothesis is rejected. Confidence intervals for the regression parameter and tests for the equivalence hypothesis are proposed using bootstrap methods and small sample asymptotics, and their performances are numerically evaluated and recommendations are made. The choice of the equivalence margin is a regulatory issue that needs to be addressed. The proposed equivalence testing formulation is also adopted for other parameters that have been proposed in the literature on surrogate endpoint validation, namely, the relative effect and proportion explained.

  6. Hard, harder, hardest: principal stratification, statistical identifiability, and the inherent difficulty of finding surrogate endpoints

    PubMed Central

    2014-01-01

    In many areas of clinical investigation there is great interest in identifying and validating surrogate endpoints, biomarkers that can be measured a relatively short time after a treatment has been administered and that can reliably predict the effect of treatment on the clinical outcome of interest. However, despite dramatic advances in the ability to measure biomarkers, the recent history of clinical research is littered with failed surrogates. In this paper, we present a statistical perspective on why identifying surrogate endpoints is so difficult. We view the problem from the framework of causal inference, with a particular focus on the technique of principal stratification (PS), an approach which is appealing because the resulting estimands are not biased by unmeasured confounding. In many settings, PS estimands are not statistically identifiable and their degree of non-identifiability can be thought of as representing the statistical difficulty of assessing the surrogate value of a biomarker. In this work, we examine the identifiability issue and present key simplifying assumptions and enhanced study designs that enable the partial or full identification of PS estimands. We also present example situations where these assumptions and designs may or may not be feasible, providing insight into the problem characteristics which make the statistical evaluation of surrogate endpoints so challenging. PMID:25342953

  7. An evaluation of motor evoked potential surrogate endpoints during intracranial vascular procedures.

    PubMed

    Holdefer, R N; MacDonald, D B; Guo, L; Skinner, S A

    2016-02-01

    MEPs are used as surrogate endpoints to predict the effectiveness of interventions, made in response to MEP deterioration, in avoiding new postoperative deficits. MEP performance in capturing intervention effects on these outcomes was investigated. A meta-analysis of studies using MEPs during intracranial vascular surgeries between 2003 and 2014 was performed. MEP diagnostic performance and relative risk of new postoperative deficits for reversible compared with irreversible MEP changes were determined. Intervention efficacy in reversing MEP deterioration and postoperative outcomes was compared across studies. MEP diagnostic performance compared favorably with that of other tests used in medicine, with all likelihood ratios >10. The summary relative risk comparing reversible and irreversible changes was 0.40, indicating a 60% decrease in new deficits for reversible MEP changes. The proportion of MEP deteriorations which recovered was negatively correlated with the proportion of new postoperative deficits (r=-0.81, p<.005). The effectiveness of interventions in recovering an MEP decline was predictive of preserved neurologic status. MEPs are provisionally qualified as surrogate endpoints given potentially major harms to the patient if they are not used, compared to the minimal harms and costs associated with their use. The performance of MEPs as substitute, or surrogate, endpoints during intracranial vascular surgeries for new deficits in motor strength in the immediate postoperative period was directly assessed for ten recent studies. Copyright © 2015 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  8. Wound Blush Obtainment Is the Most Important Angiographic Endpoint for Wound Healing.

    PubMed

    Utsunomiya, Makoto; Takahara, Mitsuyoshi; Iida, Osamu; Yamauchi, Yasutaka; Kawasaki, Daizo; Yokoi, Yoshiaki; Soga, Yoshimistu; Ohura, Norihiko; Nakamura, Masato

    2017-01-23

    This study aimed to assess the optimal angiographic endpoint of endovascular therapy (EVT) for wound healing. Several reports have demonstrated acceptable patency and limb salvage rates following infrapopliteal interventions for the treatment of critical limb ischemia (CLI). However, the optimal angiographic endpoint of EVT remains unclear. We conducted a subanalysis of the prospective multicenter OLIVE (Endovascular Treatment for Infrainguinal Vessels in Patients with Critical Limb Ischemia) registry investigation assessing patients who received infrainguinal EVT for CLI. We analyzed data from 185 limbs with ischemic ulcerations classified as Rutherford class 5 or 6, managed with EVT alone (i.e., not undergoing bypass surgery). The wound healing rate after EVT was estimated by the Kaplan-Meier method. The association between final angiographic data and wound healing was assessed employing a Cox proportional hazards model. The overall wound healing rate was 73.5%. The probabilities of wound healing in patients with wound blush obtainment was significantly higher than that of those without wound blush (79.6% vs. 46.5%; p = 0.01). In the multivariate analysis, wound blush obtainment was an independent predictor of wound healing. The presence of wound blush after EVT is significantly associated with wound healing. Wound blush as an angiographic endpoint for EVT may serve as a novel predictor of wound healing in patients with CLI. Copyright © 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  9. Individuals versus organisms versus populations in the definition of ecological assessment endpoints.

    PubMed

    Suter, Glenn W; Norton, Susan B; Fairbrother, Anne

    2005-11-01

    Discussions and applications of the policies and practices of the U.S. Environmental Protection Agency (USEPA) in ecological risk assessment will benefit from continued clarification of the concepts of assessment endpoints and of levels of biological organization. First, assessment endpoint entities and attributes can be defined at different levels of organization. Hence, an organism-level attribute, such as growth or survival, can be applied collectively to a population-level entity such as the brook trout in a stream. Second, assessment endpoints for ecological risk assessment are often mistakenly described as "individual level," which leads to the idea that such assessments are intended to protect individuals. Finally, populations play a more important role in risk assessments than is generally recognized. Organism-level attributes are used primarily for population-level assessments. In addition, the USEPA and other agencies already are basing management decisions on population or community entities and attributes such as production of fisheries, abundance of migratory bird populations, and aquatic community composition.

  10. Clinically relevant behavioral endpoints in a recurrent nitroglycerin migraine model in rats.

    PubMed

    Sufka, Kenneth J; Staszko, Stephanie M; Johnson, Ainslee P; Davis, Morgan E; Davis, Rachel E; Smitherman, Todd A

    2016-01-01

    This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan. Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.3 and 1.0 mg/kg/ml] rescue. Behavioral endpoints were assessed 2 h after final NTG administration and included time in light/dark chambers for photophobia and activity, pain facial ratings, and cool (5 °C) and warm (46 °C) tail dip. The first two experiments demonstrated that repeated (n = 5) but not single NTG injections produced photophobia, decreased activity, and yielded less weight gain than saline injections. Experiment 3 showed that sumatriptan attenuated hypoactivity, reduced facial expressions of pain, and reversed weight alterations in a dose-dependent manner. These findings identify numerous clinical homologies of a recurrent NTG rat migraine model that may be useful for screening novel pharmacotherapies.

  11. Reduction of animal suffering in rabies vaccine potency testing by introduction of humane endpoints.

    PubMed

    Takayama-Ito, Mutsuyo; Lim, Chang-Kweng; Nakamichi, Kazuo; Kakiuchi, Satsuki; Horiya, Madoka; Posadas-Herrera, Guillermo; Kurane, Ichiro; Saijo, Masayuki

    2017-03-01

    Potency controls of inactivated rabies vaccines for human use are confirmed by the National Institutes of Health challenge test in which lethal infection with severe neurological symptoms should be observed in approximately half of the mice inoculated with the rabies virus. Weight loss, decreased body temperature, and the presence of rabies-associated neurological signs have been proposed as humane endpoints. The potential for reduction of animal suffering by introducing humane endpoints in the potency test for inactivated rabies vaccine for human use was investigated. The clinical signs were scored and body weight was monitored. The average times to death following inoculation were 10.49 and 10.99 days post-inoculation (dpi) by the potency and challenge control tests, respectively, whereas the average times to showing Score-2 signs (paralysis, trembling, and coma) were 6.26 and 6.55 dpi, respectively. Body weight loss of more than 15% appeared at 5.82 and 6.42 dpi. The data provided here support the introduction of obvious neuronal signs combined with a body weight loss of ≥15% as a humane endpoint to reduce the time of animal suffering by approximately 4 days. Copyright © 2017 International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  12. A New Test Unit for Disintegration End-Point Determination of Orodispersible Films.

    PubMed

    Low, Ariana; Kok, Si Ling; Khong, Yuet Mei; Chan, Sui Yung; Gokhale, Rajeev

    2015-11-01

    No standard time or pharmacopoeia disintegration test method for orodispersible films (ODFs) exists. The USP disintegration test for tablets and capsules poses significant challenges for end-point determination when used for ODFs. We tested a newly developed disintegration test unit (DTU) against the USP disintegration test. The DTU is an accessory to the USP disintegration apparatus. It holds the ODF in a horizontal position, allowing top-view of the ODF during testing. A Gauge R&R study was conducted to assign relative contributions of the total variability from the operator, sample or the experimental set-up. Precision was compared using commercial ODF products in different media. Agreement between the two measurement methods was analysed. The DTU showed improved repeatability and reproducibility compared to the USP disintegration system with tighter standard deviations regardless of operator or medium. There is good agreement between the two methods, with the USP disintegration test giving generally longer disintegration times possibly due to difficulty in end-point determination. The DTU provided clear end-point determination and is suitable for quality control of ODFs during product developmental stage or manufacturing. This may facilitate the development of a standardized methodology for disintegration time determination of ODFs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  13. Infant lung function tests as endpoints in the ISIS multicenter clinical trial in cystic fibrosis.

    PubMed

    Davis, Stephanie D; Ratjen, Felix; Brumback, Lyndia C; Johnson, Robin C; Filbrun, Amy G; Kerby, Gwendolyn S; Panitch, Howard B; Donaldson, Scott H; Rosenfeld, Margaret

    2016-05-01

    The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilize infant pulmonary function tests (iPFTs) as an endpoint. Secondary analysis of ISIS data was conducted in order to assess feasibility of iPFT measures and their associations with respiratory symptoms. Standard deviations were calculated to aid in power calculations for future clinical trials. Seventy-three participants enrolled, 70 returned for the final visit; 62 (89%) and 45 (64%) had acceptable paired functional residual capacity (FRC) and raised volume measurements, respectively. Mean baseline FEV0.5, FEF75 and FRC z-scores were 0.3 (SD: 1.2), -0.2 (SD: 2.0), and 1.8 (SD: 2.0). iPFTs are not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. Raised volume measures have potential to serve as secondary endpoints in future clinical CF trials. Copyright © 2015 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

  14. Differences in end-point force trajectories elicited by electrical stimulation of individual human calf muscles

    PubMed Central

    Giordano, S B; Segal, R L; Abelew, T A

    2009-01-01

    The purpose of this study was to investigate the end-point force trajectories of the fibularis longus (FIB), lateral gastrocnemius (LG) and medial gastrocnemius (MG) muscles. Most information about individual muscle function has come from studies which use models based on electromyographic (EMG) recordings. In this study (N=20 subjects) we used electrical stimulation (20Hz) to elicit activity in individual muscles, recorded the end-point forces at the foot and verified the selectivity of stimulation by using magnetic resonance imaging. Unexpectedly, no significant differences were found between LG and MG force directions. Stimulation of LG and MG resulted in downward and medial or lateral forces depending on the subject. We found FIB end-point forces to be significantly different than those of LG and MG. In all subjects, stimulation of FIB resulted in downward and lateral forces. Based on our results, we suggest that there are multiple factors determining when and whether LG or MG will produce a medial or lateral force and FIB consistently plays a significant role in eversion/abduction and plantarflexion. We suggest that the inter-subject variability we found is not simply an artifact of experimental or technical error but is functionally relevant and should be addressed in future studies and models. PMID:20095454

  15. Combining SVM and flame radiation to forecast BOF end-point

    NASA Astrophysics Data System (ADS)

    Wen, Hongyuan; Zhao, Qi; Xu, Lingfei; Zhou, Munchun; Chen, Yanru

    2009-05-01

    Because of complex reactions in Basic Oxygen Furnace (BOF) for steelmaking, the main end-point control methods of steelmaking have insurmountable difficulties. Aiming at these problems, a support vector machine (SVM) method for forecasting the BOF steelmaking end-point is presented based on flame radiation information. The basis is that the furnace flame is the performance of the carbon oxygen reaction, because the carbon oxygen reaction is the major reaction in the steelmaking furnace. The system can acquire spectrum and image data quickly in the steelmaking adverse environment. The structure of SVM and the multilayer feed-ward neural network are similar, but SVM model could overcome the inherent defects of the latter. The model is trained and forecasted by using SVM and some appropriate variables of light and image characteristic information. The model training process follows the structure risk minimum (SRM) criterion and the design parameter can be adjusted automatically according to the sampled data in the training process. Experimental results indicate that the prediction precision of the SVM model and the executive time both meet the requirements of end-point judgment online.

  16. Probabilistic neural networks modeling of the 48-h LC50 acute toxicity endpoint to Daphnia magna.

    PubMed

    Niculescu, S P; Lewis, M A; Tigner, J

    2008-01-01

    Two modeling experiments based on the maximum likelihood estimation paradigm and targeting prediction of the Daphnia magna 48-h LC50 acute toxicity endpoint for both organic and inorganic compounds are reported. The resulting models computational algorithms are implemented as basic probabilistic neural networks with Gaussian kernel (statistical corrections included). The first experiment uses strictly D. magna information for 971 structures as training/learning data and the resulting model targets practical applications. The second experiment uses the same training/learning information plus additional data on another 29 compounds whose endpoint information is originating from D. pulex and Ceriodaphnia dubia. It only targets investigation of the effect of mixing strictly D. magna 48-h LC50 modeling information with small amounts of similar information estimated from related species, and this is done as part of the validation process. A complementary 81 compounds dataset (involving only strictly D. magna information) is used to perform external testing. On this external test set, the Gaussian character of the distribution of the residuals is confirmed for both models. This allows the use of traditional statistical methodology to implement computation of confidence intervals for the unknown measured values based on the models predictions. Examples are provided for the model targeting practical applications. For the same model, a comparison with other existing models targeting the same endpoint is performed.

  17. Use of Zebrafish Larvae as a Multi-Endpoint Platform to Characterize the Toxicity Profile of Silica Nanoparticles.

    PubMed

    Pham, Duc-Hung; De Roo, Bert; Nguyen, Xuan-Bac; Vervaele, Mattias; Kecskés, Angela; Ny, Annelii; Copmans, Daniëlle; Vriens, Hanne; Locquet, Jean-Pierre; Hoet, Peter; de Witte, Peter A M

    2016-11-22

    Nanomaterials are being extensively produced and applied in society. Human and environmental exposures are, therefore, inevitable and so increased attention is being given to nanotoxicity. While silica nanoparticles (NP) are one of the top five nanomaterials found in consumer and biomedical products, their toxicity profile is poorly characterized. In this study, we investigated the toxicity of silica nanoparticles with diameters 20, 50 and 80 nm using an in vivo zebrafish platform that analyzes multiple endpoints related to developmental, cardio-, hepato-, and neurotoxicity. Results show that except for an acceleration in hatch