5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine

Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3–4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II–IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3–4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1–37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/106 cells/min) increased the risk of G3–4 adverse events (OR = 10.40 [95% IC: 1.48–7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3–4 toxicity occurrence (OR = 10.9 [95% IC 1.2–96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity

Scaling asymptotics for quantized Hamiltonian flows

In recent years, the near diagonal asymptotics of the equivariant components of the Szeg\"{o} kernel of a positive line bundle on a compact symplectic manifold have been studied extensively by many authors. As a natural generalization of this theme, here we consider the local scaling asymptotics of the Toeplitz quantization of a Hamiltonian symplectomorphism, and specifically how they concentrate on the graph of the underlying classical map

Local trace formulae and scaling asymptotics in Toeplitz quantization

A trace formula for Toeplitz operators was proved by Boutet de Monvel and Guillemin in the setting of general Toeplitz structures. Here we give a local version of this result for a class of Toeplitz operators related to continuous groups of symmetries on quantizable compact symplectic manifolds. The local trace formula involves certain scaling asymptotics along the clean fixed locus of the Hamiltonian flow of the symbol, reminiscent of the scaling asymptotics of the equivariant components of the Szeg\"o kernel along the diagonal

Instability statistics and mixing rates

We claim that looking at probability distributions of \emph{finite time} largest Lyapunov exponents, and more precisely studying their large deviation properties, yields an extremely powerful technique to get quantitative estimates of polynomial decay rates of time correlations and Poincar\'e recurrences in the -quite delicate- case of dynamical systems with weak chaotic properties.Comment: 5 pages, 5 figure

Vacuum Breakdown near a Black Hole Charged by Hypercritical Accretion

We consider a black hole accreting spherically from the surrounding medium. If accretion produces a luminosity close to the Eddington limit the hole acquires a net charge so that electrons and ions can fall with the same velocity. The condition for the electrostatic field to be large enough to break the vacuum near the hole horizon translates into an upper limit for the hole mass, $M\sim 6.6\times 10^{20} {\rm g}.$ The astrophysical conditions under which this phaenomenon can take place are rather extreme, but in principle they could be met by a mini black hole residing at the center of a star.Comment: 6 pages, accepted for publication in the Astrophysical Journa

Galaxy Orientations in the Coma Cluster

We have examined the orientations of early-type galaxies in the Coma cluster to see whether the well-established tendency for brightest cluster galaxies to share the same major axis orientation as their host cluster also extends to the rest of the galaxy population. We find no evidence of any preferential orientations of galaxies within Coma or its surroundings. The implications of this result for theories of the formation of clusters and galaxies (particularly the first-ranked members) are discussed.Comment: Accepted for publication in the Astrophysical Journal Letters. 4 pages, 4 figure

Construction and use of Plasmodium falciparum phage display libraries to identify host parasite interactions

BACKGROUND: The development of Plasmodium falciparum within human erythrocytes induces a wide array of changes in the ultrastructure, function and antigenic properties of the host cell. Numerous proteins encoded by the parasite have been shown to interact with the erythrocyte membrane. The identification of new interactions between human erythrocyte and P. falciparum proteins has formed a key area of malaria research. To circumvent the difficulties provided by conventional protein techniques, a novel application of the phage display technology was utilised. METHODS: P. falciparum phage display libraries were created and biopanned against purified erythrocyte membrane proteins. The identification of interacting and in-frame amino acid sequences was achieved by sequencing parasite cDNA inserts and performing bioinformatic analyses in the PlasmoDB database. RESULTS: Following four rounds of biopanning, sequencing and bioinformatic investigations, seven P. falciparum proteins with significant binding specificity toward human erythrocyte spectrin and protein 4.1 were identified. The specificity of these P. falciparum proteins were demonstrated by the marked enrichment of the respective in-frame binding sequences from a fourth round phage display library. CONCLUSION: The construction and biopanning of P. falciparum phage display expression libraries provide a novel approach for the identification of new interactions between the parasite and the erythrocyte membrane

Semiclassical almost isometry

Let M be a complex projective manifold, and L an Hermitian ample line bundle on it. A fundamental theorem of Gang Tian, reproved and strengthened by Zelditch, implies that the Khaeler form of L can be recovered from the asymptotics of the projective embeddings associated to large tensor powers of L. More precisely, with the natural choice of metrics the projective embeddings associated to the full linear series |kL| are asymptotically symplectic, in the appropriate rescaled sense. In this article, we ask whether and how this result extends to the semiclassical setting. Specifically, we relate the Weinstein symplectic structure on a given isodrastic leaf of half-weighted Bohr-Sommerfeld Lagrangian submanifolds of M to the asymptotics of the the pull-back of the Fubini-Study form under the semiclassical projective maps constructed by Borthwick, Paul and Uribe.Comment: exposition improve