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  • 1
    Publication Date: 2015-07-22
    Description: Cortney M. Bouldin, Alyssa J. Manning, Yu-Hsuan Peng, Gist H. Farr III, King L. Hung, Alice Dong, and David Kimelman Anterior to posterior growth of the vertebrate body is fueled by a posteriorly located population of bipotential neuro-mesodermal progenitor cells. These progenitors have a limited rate of proliferation and their maintenance is crucial for completion of the anterior-posterior axis. How they leave the progenitor state and commit to differentiation is largely unknown, in part because widespread modulation of factors essential for this process causes organism-wide effects. Using a novel assay, we show that zebrafish Tbx16 (Spadetail) is capable of advancing mesodermal differentiation cell-autonomously. Tbx16 locks cells into the mesodermal state by not only activating downstream mesodermal genes, but also by repressing bipotential progenitor genes, in part through a direct repression of sox2 . We demonstrate that tbx16 is activated as cells move from an intermediate Wnt environment to a high Wnt environment, and show that Wnt signaling activates the tbx16 promoter. Importantly, high-level Wnt signaling is able to accelerate mesodermal differentiation cell-autonomously, just as we observe with Tbx16. Finally, because our assay for mesodermal commitment is quantitative we are able to show that the acceleration of mesodermal differentiation is surprisingly incomplete, implicating a potential separation of cell movement and differentiation during this process. Together, our data suggest a model in which high levels of Wnt signaling induce a transition to mesoderm by directly activating tbx16 , which in turn acts to irreversibly flip a bistable switch, leading to maintenance of the mesodermal fate and repression of the bipotential progenitor state, even as cells leave the initial high-Wnt environment.
    Print ISSN: 0950-1991
    Electronic ISSN: 1477-9129
    Topics: Biology
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  • 2
    Publication Date: 2014-02-15
    Description: The vertebrate body forms from a multipotent stem cell-like progenitor population that progressively contributes newly differentiated cells to the most posterior end of the embryo. How the progenitor population balances proliferation and other cellular functions is unknown due to the difficulty of analyzing cell division in vivo. Here, we show that proliferation is compartmentalized at the posterior end of the embryo during early zebrafish development by the regulated expression of cdc25a , a key controller of mitotic entry. Through the use of a transgenic line that misexpresses cdc25a , we show that this compartmentalization is critical for the formation of the posterior body. Upon misexpression of cdc25a , several essential T-box transcription factors are abnormally expressed, including Spadetail/Tbx16, which specifically prevents the normal onset of myoD transcription, leading to aberrant muscle formation. Our results demonstrate that compartmentalization of proliferation during early embryogenesis is critical for both extension of the vertebrate body and differentiation of the multipotent posterior progenitor cells to the muscle cell fate.
    Print ISSN: 0890-9369
    Topics: Biology
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  • 3
    Publication Date: 2012-04-04
    Description: Context Leucovorin, fluorouracil, and oxaliplatin (FOLFOX) is the standard adjuvant therapy for resected stage III colon cancer. Adding cetuximab to FOLFOX benefits patients with metastatic wild-type KRAS but not mutated KRAS colon cancer. Objective To assess the potential benefit of cetuximab added to the modified sixth version of the FOLFOX regimen (mFOLFOX6) in patients with resected stage III wild-type KRAS colon cancer. Design, Setting, and Participants A randomized trial of 2686 patients aged 18 years or older at multiple institutions across North America enrolled following resection and informed consent between February 10, 2004, and November 25, 2009. The primary randomized comparison was 12 biweekly cycles of mFOLFOX6 with and without cetuximab. KRAS mutation status was centrally determined. The trial was halted after a planned interim analysis of 48% of predicted events (246/515) occurring in 1863 (of 2070 planned) patients with tumors having wild-type KRAS . A total of 717 patients with mutated KRAS and 106 with indeterminate KRAS were accrued. The 2070 patients with wild-type KRAS provided 90% power to detect a hazard ratio (HR) of 1.33 (2-sided α = .05), with planned interim efficacy analyses after 25%, 50%, and 75% of expected relapses. Main Outcome Measures Disease-free survival in patients with wild-type KRAS mutations. Secondary end points included overall survival and toxicity. Results Median (range) follow-up was 28 (0-68) months. The trial demonstrated no benefit when adding cetuximab. Three-year disease-free survival for mFOLFOX6 alone was 74.6% vs 71.5% with the addition of cetuximab (HR, 1.21; 95% CI, 0.98-1.49; P  = .08) in patients with wild-type KRAS , and 67.1% vs 65.0% (HR, 1.12; 95% CI, 0.86-1.46; P  = .38) in patients with mutated KRAS , with no significant benefit in any subgroups assessed. Among all patients, grade 3 or higher adverse events (72.5% vs 52.3%; odds ratio [OR], 2.4; 95% CI, 2.1-2.8; P  〈 .001) and failure to complete 12 cycles (33% vs 23%; OR, 1.6; 95% CI, 1.4-1.9; P  〈 .001) were significantly higher with cetuximab. Increased toxicity and greater detrimental differences in all outcomes were observed in patients aged 70 years or older. Conclusion Among patients with stage III resected colon cancer, the use of cetuximab with adjuvant mFOLFOX6 compared with mFOLFOX6 alone did not result in improved disease-free survival. Trial Registration clinicaltrials.gov Identifier: NCT00079274
    Keywords: Oncology, Colon Cancer, Surgery, Surgical Interventions, Colorectal Surgery, Randomized Controlled Trial, Prognosis/ Outcomes, Drug Therapy
    Print ISSN: 0098-7484
    Electronic ISSN: 1538-3598
    Topics: Medicine
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  • 4
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    Oxford University Press
    Publication Date: 2018-03-06
    Description: We develop a theory of minors for alternating dimaps—orientably embedded digraphs where, at each vertex, the incident edges (taken in the order given by the embedding) are directed alternately into, and out of, the vertex. We show that they are related by the triality relation of Tutte. They do not commute in general, though do in many circumstances, and we characterize the situations where they do. We give a characterization of alternating dimaps of at most a given genus, using a finite set of excluded minors. We also use the minor operations to define simple Tutte invariants for alternating dimaps and characterize them. We establish a connection with the Tutte polynomial, and pose the problem of characterizing universal Tutte-like invariants for alternating dimaps based on these minor operations.
    Print ISSN: 0033-5606
    Electronic ISSN: 1464-3847
    Topics: Mathematics
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science Ltd
    Alimentary pharmacology & therapeutics 20 (2004), S. 0 
    ISSN: 1365-2036
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Background : Insulin sensitizing agents may be useful in treatment of non-alcoholic fatty liver disease.Aim : A pilot study to evaluate the efficacy and safety of metformin in non-alcoholic fatty liver disease.Methods : In an open labelled study, patients with histologically confirmed non-alcoholic fatty liver disease were given metformin (20 mg/kg) for 1 year. Insulin resistance (by log homeostasis assessment model analysis for insulin resistance and Quantitative Insulin Sensitivity Check Index) and post-treatment hepatic histology were compared with pre-treatment histology.Results : Fifteen patients completed 1 year of treatment. During the initial 3 months, there was improvement in alanine aminotransferase and aspartate aminotransferase (P-value 0.01 and 0.02, respectively) along with improvement in insulin sensitivity. However, after 3 months, there was no further improvement in insulin sensitivity and there was gradual rise in aspartate aminotransferase and alanine aminotransferase back to pre-treatment levels. Among the 10 patients with post-treatment biopsy, three (33%), showed improvement in steatosis, two (20%) showed improvement in inflammation score and one (10%) showed improvement in fibrosis.Conclusion : Metformin treatment was associated with only a transient improvement in liver chemistries. A progressive, sustainable reduction in insulin sensitivity was not noted during treatment.
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Bulletin of environmental contamination and toxicology 57 (1996), S. 236 -241 
    ISSN: 1432-0800
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Advances in contraception 11 (1995), S. 23-24 
    ISSN: 1573-7195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Advances in contraception 13 (1997), S. 439-451 
    ISSN: 1573-7195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Male condoms made from synthetic materials offer an alternative to latexcondoms that may be more acceptable to users, thereby potentially resultingin more protected acts of intercourse. A prospective, noncomparativeclinical study was conducted to evaluate the safety of using certainpolyurethane materials to make condoms. Fifty-one healthy, contracepting,mutually monogamous couples were recruited between June 30 and November 24,1993 to use a prototype roll-on polyurethane condom developed by FamilyHealth International. Couples were to use the condoms for 10 consecutiveacts of vaginal intercourse over a 4-week period. Baseline and postexposuregenital examinations, including colposcopy for female participants, wereperformed. Fifty couples completed the study requirements and 517 acts ofintercourse occurred using the condoms. Two adverse events were reported:irritation of introitus in a female participant and a small irritatederythematous lesion on a male participant‘s penis. Neither event wasconsidered to be serious and both were resolved without treatment. Breakageand slippage rates were similar to those reported for latex condoms. Theseresults suggest that polyurethane condoms represent a safe, functional andacceptable alternative to latex condoms.
    Type of Medium: Electronic Resource
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  • 9
    Electronic Resource
    Electronic Resource
    Springer
    Advances in contraception 10 (1994), S. 137-149 
    ISSN: 1573-7195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resumé Les résultats cliniques des dispositifs intra-utériens (DIU) Copper T38OA (TCu380A) et Multiload 250 (MLCu250) ont été évalués pendant 12 mois chez un groupe de femmes qui portaient l'un ou l'autre de ces dispositifs. Les résultats proviennent d'un essai clinique randomisé, effectué en collaboration par quatre établissements de recherche dans trois pays en développement. Au terme de 12 mois, le taux brut cumulé de grossesses des tables de survie pour le dispositif TCu380A était significativement inférieur au taux correspondant pour le dispositif MLCu250 (0,5 et 1,2 respectivement,p〈0,01). Aucune différence statistiquement significative entre les deux dispositifs étudiés n'a été constatée du point de vue de l'expulsion du DIU ou de son retrait pour cause de microrragie/douleurs, pour des raisons personnelles ou médicales ou pour une grossesse planifiée. Les utilisatrices du TCu380A ont plus fréquemment signalé une dysménorrhée (p〈0,01) ou des douleurs pelviennes intermenstruelles (p〈0,01) que les utilisatrices du MLCu250. Peu nombreuses était cependant cells qui avaient, en raison de perturbations du flux menstruel ou de douleurs pelviennes intermenstruelles, abandonné l'usage du dispositif qui leur avait été assigné. Ces résultats indiquent que le dispositif TCu380A représente peut-être une meilleure solution que le dispositif MLCu250 pour les femmes recherchant à long terme une méthode hautement efficace de régulation des naissances, sans avoir recours aux méthodes hormonales.
    Abstract: Resumen El resultado clínico de los dispositivos intrauterinos (DIU) Copper T380A y Multiload 250 (MLCu250) se evaluó durante 12 meses en un grupo de mujeres a quienes se había colocado uno de los dos DIU. Los resultados corresponden a un ensayo clínico aleatorizado efectuado en cuatro emplazamientos de investigaciones en colaboración situados en tres países en desarrollo. La tasa bruta acumulativa de embarazo de las tablas de vida del DIU TCu380A fue significativamente inferior a la tasa correspondiente al DIU MLCu250 a los 12 meses (0,5 y 1,2, respectivamente,p〈0,01)). No hubo diferencias estadísticamente significativas entre los dos DIU del estudio con respecto a su expulsión o retiro debido a microrragia/dolor, razones personales, razones médicas o embarazo planificado. Era más probable que las usuarias del DIU TCu380A notificaran mayor dismenorrea (p〈0,01) o dolor pélvico intermenstrual (p〈0,01) que las usuarias del DIU MLCu250. Sin embargo, un número menor de este grupo de usuarias dejó de utilizar el DIU que le había sido asignado por haber experimentado trastornos menstruales de microrragia o dolor pélvico intermenstrual. Estos datos indican que el DIU TCu380A podría ser una mejor opción que el DIU MLCu250 para las mujeres que desean praticar un control de la natalidad a largo plaza altamente eficaz sin tener que recurrir a métodos hormonales.
    Notes: Abstract The clinical performance of the Copper T380A (TCu380A) and the Multiload 250 (MLCu250) intrauterine devices (IUDs) were evaluated for 12 months in a group of women who had one of the two IUDs inserted. Results are from a randomized clinical trial conducted at four collaborating research sites located in three developing countries. The gross cumulative life-table pregnancy rate of the TCu380A IUD was significantly lower than the rate with the MLCu250 IUD at 12 months (0.5 and 1.2, respectively,p〈0.01). No statistically significant differences between the two study IUDs were found with regard to IUD expulsion or IUD removal due to bleeding/pain, personal reasons, medical reasons, or planned pregnancy. TCu380A IUD users were more likely to report experiencing increased dysmenorrhea (p〈0.01) or intermenstrual pelvic pain (p〈0.01) than were MLCu250 IUD users. However, few of these users discontinued use of their assigned IUD because of having experienced menstrual bleeding disturbances or intermenstrual pelvic pain. These data indicate that the TCu380A IUD may be a better option than the MLCu250 IUD for women wishing to practice highly effective long-term birth control without having to resort to hormonal methods.
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Advances in contraception 10 (1994), S. 271-285 
    ISSN: 1573-7195
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Resumé Les essais cliniques ont invariablement montré que le DIU libérant chaque jour 20 μg de lévonorgestrel (LNG-IUD-20) a une utilité contraceptive comparable, sinon supérieure, à celle des dispositifs Copper T380 et Multiload Copper-375. Le présent article est axé non seulement sur les effets non contraceptifs du dispositif, ceux qui sont bénéfiques, tels qu'une réduction de la ménorragie, un effet thérapeutique sur la dysménorrhée, la prévention des grossesses ectopiques, mais aussi sur les effets délétères tels que l'aménorrhée, les microrragies et les pertes sanguines irrégulières, les effets hormonaux secondaires et les kystes fonctionnels ovariens. Y est examinée aussi la possibilité d'un effet préventif des maladies pelviennes inflammatories, les effets du DIU chez les femmes lors du post-partum et de la lactation, le retour à la fécondité après le retrait et d'autres aspects de sécurité. En général, les avantages non contraceptifs du LNG-IUD-20 sont considérables, ont d'importantes incidences médicales et en matière de santé publique, et compensent très largement les effets délétères du dispositif, lesquels sont soit bénins du point de vue médical soit passagers et peuvent en général être convenablement surmontés en demandant conseil. Une meilleure connaissance des effets, bénéfiques et délétères, de ce DIU libérant des hormones devrait permettre de mieux conseiller les patientes, ce qui devrait du même coup améliorer la qualité de la vie des utilisatrices, réduire au minimum les retraits inutiles du dispositif et maximaliser la poursuite de son utilisation.
    Abstract: Resumen Los ensayos clínicos realizados señalaron sistemáticamente que el DIU que descarga 20 μg de levonorgestrel diariamente (LNG-DIU-20) tiene una eficacia anticonceptiva similar o incluso superior a la de los DIU CuT380 y Multiload Cu375. Este examen se centra en los efectos no anticonceptivos del dispositivo, los benéficos, tales como la reducción de la menorragia, el efecto terapéutico sobre la dismenorrea y la prevención del embarazo ectópico, así como los perjudiciales, por ejemplo, la amenorrea, las pérdidas y el sangrado irregular, los efectos secundarios hormonales y los quistes ováricos funcionales. También se examina la posibilidad de un efecto preventivo de la enfermedad inflamatoria pélvica (PID), los efectos del DIU sobre mujeres de posparto/lactantes, el retorno de la fecundidad después del retiro y otras cuestiones de seguridad. En general, los beneficios no anticonceptivos de los LNG-DIU-20 son significativos, tienen importantes repercusiones médicas y de salud pública, y compensan con creces los efectos perjudiciales del dispositivo, que son médicamente ligeros o bien de naturaleza pasajera, y pueden ser manejados satisfactoriamente, en términos generales, mediante un asesoramiento adecuado. Una mejor comprensión de los efectos, tanto benéficos como perjudiciales, de estos DIU de descarga hormonal habrá de llevar a un mayor asesoramiento de pacientes, lo cual, a su vez, mejorará la calidad de vida de las usuarias, reducirá al mínimo los retiros innecesarios y aumentará al máximo la continuación del uso.
    Notes: Abstract Clinical trials have consistently shown that the IUD that releases 20 μg levonorgestrel daily (LNG-IUD-20) has a contraceptive efficacy comparable to, if not surpassing, the Copper T380 and the Multiload Copper-375 IUDs. The focus of this review is the device's non-contraceptive effects — the beneficial ones, such as reduction of menorrhagia, a therapeutic effect on dysmenorrhea, and prevention of ectopic pregnancy, as well as the deleterious ones, such as amenorrhea, spotting and irregular bleeding, hormonal side-effects, and functional ovarian cysts. Also discussed are the possibility of a preventive effect on pelvic inflammatory disease, the effects of the IUD on postpartum/lactating women, fertility return after removal and other safety issues. In general, the LNG-IUD-20's non-contraceptive benefits are substantive, carry important medical and public health implications, and far outweigh the device's deleterious effects, which are either medically mild or transient in nature, and can usually be managed satisfactorily by counseling. A better understanding of these effects, both beneficial and deleterious, of this hormone-releasing IUD should lead to more effective patient counseling, which, in turn, should improve user quality of life, minimize unnecessary removals, and maximize continuation of use.
    Type of Medium: Electronic Resource
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