A Bayesian seamless phase I-II trial design with two stages for cancer clinical trials with drug combinations

The use of drug combinations in clinical trials is increasingly common during the last years since a more favorable therapeutic response may be obtained by combining drugs. In phase I clinical trials, most of the existing methodology recommends a one unique dose combination as "optimal", which may result in a subsequent failed phase II clinical trial since other dose combinations may present higher treatment efficacy for the same level of toxicity. We are particularly interested in the setting where it is necessary to wait a few cycles of therapy to observe an efficacy outcome and the phase I and II population of patients are different with respect to treatment efficacy. Under these circumstances, it is common practice to implement two-stage designs where a set of maximum tolerated dose combinations is selected in a first stage, and then studied in a second stage for treatment efficacy. In this article we present a new two-stage design for early phase clinical trials with drug combinations. In the first stage, binary toxicity data is used to guide the dose escalation and set the maximum tolerated dose combinations. In the second stage, we take the set of maximum tolerated dose combinations recommended from the first stage, which remains fixed along the entire second stage, and through adaptive randomization, we allocate subsequent cohorts of patients in dose combinations that are likely to have high posterior median time to progression. The methodology is assessed with extensive simulations and exemplified with a real trial

Three Dimensional Quantum Geometry and Deformed Poincare Symmetry

We study a three dimensional non-commutative space emerging in the context of three dimensional Euclidean quantum gravity. Our starting point is the assumption that the isometry group is deformed to the Drinfeld double D(SU(2)). We generalize to the deformed case the construction of the flat Euclidean space as the quotient of its isometry group ISU(2) by SU(2). We show that the algebra of functions becomes the non-commutative algebra of SU(2) distributions endowed with the convolution product. This construction gives the action of ISU(2) on the algebra and allows the determination of plane waves and coordinate functions. In particular, we show that: (i) plane waves have bounded momenta; (ii) to a given momentum are associated several SU(2) elements leading to an effective description of an element in the algebra in terms of several physical scalar fields; (iii) their product leads to a deformed addition rule of momenta consistent with the bound on the spectrum. We generalize to the non-commutative setting the local action for a scalar field. Finally, we obtain, using harmonic analysis, another useful description of the algebra as the direct sum of the algebra of matrices. The algebra of matrices inherits the action of ISU(2): rotations leave the order of the matrices invariant whereas translations change the order in a way we explicitly determine.Comment: latex, 37 page

Modelling the impact of climate change on cereal yield in Morocco

To assess the impact of climate change different studies were conducted in several regions of Morocco. The assessment of climate change and its impacts involves the simulation of a range of different socio-economic and physical processes. Some of these processes are well known such temperature, rainfall, storms, etc.., others not. Hence for each modeling step researchers need to consider what is known, what is not known, and how climate change can be expressed.This paper is a contribution to research on climate change impact on cereal yield in the last 50 years. The application of the multiple linear regression model to a set of time series of yield, rainfall, temperature and storm has generated significant coefficients that can explain the relation between yield and the three climate variables. The model output confirms the results of the previous studies of yield variability. The positive effect of rainfall and the negative one of storm and temperature ware recorded. Above the three factors, temperature and storms have a negative effect on cereal yield. So more efforts on germplasm, crop management and agricultural policy measures are needed to alleviate the impact of climate change. An estimate coefficient of -4.943 for temperature is very indicating the high impact of temperature on yield. The R² is around 0.45indicates that more than 55% of total yield variability is explained by other factors than rain, temperature and storm

Theoretical study of a cold atom beam splitter

A theoretical model is presented for the study of the dynamics of a cold atomic cloud falling in the gravity field in the presence of two crossing dipole guides. The cloud is split between the two branches of this laser guide, and we compare experimental measurements of the splitting efficiency with semiclassical simulations. We then explore the possibilities of optimization of this beam splitter. Our numerical study also gives access to detailed information, such as the atom temperature after the splitting

Normal Bundles, Pfaffians and Anomalies

We deal with the problem of diffeomorphism anomaly in theories with branes. In particular we thoroughly analyze the problem of the residual chiral anomaly of a five-brane immersed in M-theory, paying attention to its global formulation in the five-brane world-volume. We conclude that the anomaly can be canceled by a {\it local} counterterm in the five-brane world-volume.Comment: 17 pages, Latex, sign convention changed, typos correcte

Linear connections on matrix geometries

A general definition of a linear connection in noncommutative geometry has been recently proposed. Two examples are given of linear connections in noncommutative geometries which are based on matrix algebras. They both possess a unique metric connection.Comment: 14p, LPTHE-ORSAY 94/9

Chemodiversity of dissolved organic matter in the Amazon Basin

Regions in the Amazon Basin have been associated with specific biogeochemical processes, but a detailed chemical classification of the abundant and ubiquitous dissolved organic matter (DOM), beyond specific indicator compounds and bulk measurements, has not yet been established. We sampled water from different locations in the Negro, Madeira/Jamari and Tapajós River areas to characterize the molecular DOM composition and distribution. Ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) combined with excitation emission matrix (EEM) fluorescence spectroscopy and parallel factor analysis (PARAFAC) revealed a large proportion of ubiquitous DOM but also unique area-specific molecular signatures. Unique to the DOM of the Rio Negro area was the large abundance of high molecular weight, diverse hydrogen-deficient and highly oxidized molecular ions deviating from known lignin or tannin compositions, indicating substantial oxidative processing of these ultimately plant-derived polyphenols indicative of these black waters. In contrast, unique signatures in the Madeira/Jamari area were defined by presumably labile sulfur- and nitrogen-containing molecules in this white water river system. Waters from the Tapajós main stem did not show any substantial unique molecular signatures relative to those present in the Rio Madeira and Rio Negro, which implied a lower organic molecular complexity in this clear water tributary, even after mixing with the main stem of the Amazon River. Beside ubiquitous DOM at average H ∕ C and O ∕ C elemental ratios, a distinct and significant unique DOM pool prevailed in the black, white and clear water areas that were also highly correlated with EEM-PARAFAC components and define the frameworks for primary production and other aspects of aquatic life

Covariant quantization of infinite spin particle models, and higher order gauge theories

Further properties of a recently proposed higher order infinite spin particle model are derived. Infinitely many classically equivalent but different Hamiltonian formulations are shown to exist. This leads to a condition of uniqueness in the quantization process. A consistent covariant quantization is shown to exist. Also a recently proposed supersymmetric version for half-odd integer spins is quantized. A general algorithm to derive gauge invariances of higher order Lagrangians is given and applied to the infinite spin particle model, and to a new higher order model for a spinning particle which is proposed here, as well as to a previously given higher order rigid particle model. The latter two models are also covariantly quantized.Comment: 38 pages, Late