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  • 1
    Abstract: Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumors. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favoring tumorigenic and self-renewing properties. Conversely, H3.3 antagonizes self-renewal and promotes differentiation. We exploited these epigenetic states to rationally identify two small molecules that effectively curb cancer stem cell properties in a preclinical model. Our work uncovers a role for MLL5 and H3.3 in maintaining self-renewal hierarchies in adult GBM.
    Type of Publication: Journal article published
    PubMed ID: 26626085
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  • 2
    ISSN: 1573-8744
    Keywords: Bayesian ; compartment model ; discrete prior ; dose regimen design ; pharmacokinetics ; stochastic control
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In medical drug therapy, efficient dosage strategies are needed to maintain target drug concentrations. The relationship between the concentration of a drug and the dosages is often described by compartment models in which the parameters are unknown, although prior knowledge may be available and can be updated after blood samples are taken during the therapy. Currently MAP (maximum a posteriori) Bayesian is the most often used control strategy in this setting. We show by simulation in a one-compartment context that the performance of the MAP Bayesian strategy depends on the assumptions in prior distribution of the parameters as well as the cost function. We propose an alternative control strategy, VU, that outperforms and is more robust than the MAP Bayesian strategy in a variety of problem settings.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-8744
    Keywords: Bayesian ; compartment model ; dose regimen design ; pharmacokinetics ; pharmacodynamics ; stochastic control ; effect site
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract In drug therapy, effective dosage strategies are needed to maintain target drug effects. The relationship between drug dose and drug effect is often described by pharmacokinetic/pharmacodynamic (PK/PD) models where typically the PK model has a multicompartment form and the PD model is the sigmoidal Emax model. The parameters in the PK/PD model are generally unknown in the individual patient, although prior knowledge may be available and can be updated after measurements of drug effect are taken during the therapy. This fact, together with the complexity of the PK/PD model, makes the control problem complex. This paper investigates several control strategies in the framework of a three-compartment PK model plus an effect site with a PD model. Using computer simulations under different assumptions, we show that a MAP (maximum a posteriori) Bayesian type of strategy is effective, nevertheless in high-risk situations a stochastic control strategy hedging against estimation errors provides better performance at computational cost.
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    Springer
    The environmentalist 3 (1983), S. 59-63 
    ISSN: 1573-2991
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-2991
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    The environmentalist 3 (1983), S. 57-61 
    ISSN: 1573-2991
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    The environmentalist 5 (1985), S. 13-20 
    ISSN: 1573-2991
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Energy, Environment Protection, Nuclear Power Engineering
    Notes: Summary The area of tropical forest lands in high rainfall areas that is already degraded is great and growing rapidly. Rehabilitation of such lands is important so their biological productivity can support people and reduce pressures for degradation of additional tropical forest lands. While further knowledge and experience is needed, there is a sufficient basis for trial programs. The economic and social well-being is far better served by focusing on rehabilitation of degraded lands than by additional incursions into dwindling stocks of natural forest.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-5133
    Keywords: Elasmobranchs ; Holocephalans ; Neuropeptides ; Brain ; Immunohistochemistry ; Reproduction ; Vertebrates ; Evolution ; Chondrichthyes ; Sharks ; Skates ; Ratfish
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Synopsis Gonadotropin-releasing hormone (GnRH) is thought to play a fundamental role in the reproduction of cartilaginous fishes. The primary structures of the only form of GnRH in ratfish,Hydrolagus colliei, and one of four forms of GnRH in dogfish,Squalus acanthias, have recently been shown to be identical to a form originally isolated from birds (chicken GnRH-II). Phylogenetic studies indicate that this chicken GnRH-II molecule is the most highly conserved GnRH family member in vertebrates; it is present in animals from cartilaginous fishes to marsupials. However, the presence of four immunoreactive forms of GnRH inS. acanthias, but only one form inH. colliei suggests that the two subclasses of these species diverged a long time ago. Immunocytochemical localization of GnRH shows that it is found in the brains of all chondrichthyans examined to date. GnRH cell bodies and fibers were found in specific patterns throughout the brain in our studies of dogfish shark and black skate,Bathyraja kincaidii. The lack of immunoreactive GnRH fibers in the median eminence and the unique arrangement of the pituitary in Chondrichthyes suggest that transport of GnRH from the brain to the pituitary gonadotropes occurs in the systemic circulation. The use of this unconventional route is further supported by markedly higher levels of serum GnRH in ratfish compared with other vertebrates.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-5168
    Keywords: gonadotropin-releasing hormone ; GnRH ; hormone evolution ; primitive bony fishes ; fish ; peptides ; reproduction ; agnathans ; chondrichthyans ; osteichthyans
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract The presence of neuroendocrine hormones in extant agnathan fishes suggests that a method of control involving these hormones was operating 500–600 million years ago in emerging vertebrates. Data on a limited number of species show that several members of the GnRH family of peptides may have arisen in non-teleost fishes. Lamprey (Petromyzon marinus) GnRH has a unique composition and has not been detected in other vertebrates. It is not yet clear whether the chicken II GnRH-like molecule arose in cartilaginous fishes, but a chromatographically and immunologically similar molecule is found in dogfish (Squalus acanthias) and ratfish (Hydrolagus colliei). Finally, a mammalian GnRH-like molecule is detected in three primitive bony fish: sturgeon (Acipenser transmontanus), reed fish (Calamoichthys calabaricus), and alligator gar (Lepidosteus spatula). Minor forms are also present, but are not yet characterized. Clearly, the basic structure of GnRH peptides was established in primitive fish. In contrast, at least three other identified forms of GnRH have been detected in teleosts or tetrapods: Salmon I, catfish I, and chicken I GnRH. Evidence for the presence of members of the GnRH family and the neurohypophysial hormone family in primitive fishes argues for the importance of neuroendocrine control throughout the history of vertebrates.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1572-9338
    Source: Springer Online Journal Archives 1860-2000
    Topics: Mathematics , Economics
    Notes: Abstract A partially observed Markov decision process (POMDP) is a generalization of a Markov decision process that allows for incomplete information regarding the state of the system. The significant applied potential for such processes remains largely unrealized, due to an historical lack of tractable solution methodologies. This paper reviews some of the current algorithmic alternatives for solving discrete-time, finite POMDPs over both finite and infinite horizons. The major impediment to exact solution is that, even with a finite set of internal system states, the set of possible information states is uncountably infinite. Finite algorithms are theoretically available for exact solution of the finite horizon problem, but these are computationally intractable for even modest-sized problems. Several approximation methodologies are reviewed that have the potential to generate computationally feasible, high precision solutions.
    Type of Medium: Electronic Resource
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