Sorafenib dose escalation is not uniformly associated with blood pressure elevations in normotensive patients with advanced malignancies.

Hypertension after treatment with vascular endothelial growth factor (VEGF) receptor inhibitors is associated with superior treatment outcomes for advanced cancer patients. To determine whether increased sorafenib doses cause incremental increases in blood pressure (BP), we measured 12-h ambulatory BP in 41 normotensive advanced solid tumor patients in a randomized dose-escalation study. After 7 days' treatment (400 mg b.i.d.), mean diastolic BP (DBP) increased in both study groups. After dose escalation, group A (400 mg t.i.d.) had marginally significant further increase in 12-h mean DBP (P = 0.053), but group B (600 mg b.i.d.) did not achieve statistically significant increases (P = 0.25). Within groups, individuals varied in BP response to sorafenib dose escalation, but these differences did not correlate with changes in steady-state plasma sorafenib concentrations. These findings in normotensive patients suggest BP is a complex pharmacodynamic biomarker of VEGF inhibition. Patients have intrinsic differences in sensitivity to sorafenib's BP-elevating effects

Genome scan of Diabrotica virgifera virgifera for genetic variation associated with crop rotation tolerance

Crop rotation has been a valuable technique for control of Diabrotica virgifera virgifera for almost a century. However, during the last two decades, crop rotation has ceased to be effective in an expanding area of the US corn belt. This failure appears to be due to a change in the insect's oviposition behaviour, which, in all probability, has an underlying genetic basis. A preliminary genome scan using 253 amplified fragment-length polymorphism (AFLP) markers sought to identify genetic variation associated with the circumvention of crop rotation. Samples of D. v. virgifera from east-central Illinois, where crop rotation is ineffective, were compared with samples from Iowa at locations that the behavioural variant has yet to reach. A single AFLP marker showed signs of having been influenced by selection for the circumvention of crop rotation. However, this marker was not diagnostic. The lack of markers strongly associated with the trait may be due to an insufficient density of marker coverage throughout the genome. A weak but significant general heterogeneity was observed between the Illinois and Iowa samples at microsatellite loci and AFLP markers. This has not been detected in previous population genetic studies of D. v. virgifera and may indicate a reduction in gene flow between variant and wild-type beetles

Embryonic Pattern Scaling Achieved by Oppositely Directed Morphogen Gradients

Morphogens are proteins, often produced in a localised region, whose concentrations spatially demarcate regions of differing gene expression in developing embryos. The boundaries of expression must be set accurately and in proportion to the size of the one-dimensional developing field; this cannot be accomplished by a single gradient. Here, we show how a pair of morphogens produced at opposite ends of a developing field can solve the pattern-scaling problem. In the most promising scenario, the morphogens effectively interact according to the annihilation reaction $A+B\to\emptyset$ and the switch occurs according to the absolute concentration of $A$ or $B$. In this case embryonic markers across the entire developing field scale approximately with system size; this cannot be achieved with a pair of non-interacting gradients that combinatorially regulate downstream genes. This scaling occurs in a window of developing-field sizes centred at a few times the morphogen decay length.Comment: 24 pages; 11 figures; uses iopar

Momento Económico (27)

En este número Temas de hoy, 2/ Reaganomics: Seis años despues, Elaine Levine, 3/ Las relaciones México-Estados Unidos: Hacia un replanteamiento de fondo, Ma. Teresa Gutiérrez Haces, 6/ El transporte en la ciudad de México: Su funcionamiento contradictorio, Bernardo Navarro B., 10/ Impuesto a la importación de petróleo en Estados Unidos, Miguel Ángel Flores, 13/ Comentarios a la Ley Simpson-Rodino, Mónica Verea C., 14

Treatment-resistant pediatric giant prolactinoma and multiple endocrine neoplasia type 1

Background Pediatric pituitary adenomas are rare, accounting for <3 % of all childhood intracranial tumors, the majority of which are prolactinomas. Consequently, they are often misdiagnosed as other suprasellar masses such as craniopharyngiomas in this age group. Whilst guidelines exist for the treatment of adult prolactinomas, the management of childhood presentations of these benign tumors is less clear, particularly when dopamine agonist therapy fails. Given their rarity, childhood-onset pituitary adenomas are more likely to be associated with a variety of genetic syndromes, the commonest being multiple endocrine neoplasia type 1 (MEN-1). Case description We present a case of an early-onset, treatment-resistant giant prolactinoma occurring in an 11-year-old peripubertal boy that was initially sensitive, but subsequently highly resistant to dopamine agonist therapy, ultimately requiring multiple surgical debulking procedures and proton beam irradiation. Our patient is now left with long-term tumor- and treatment-related neuroendocrine morbidities including blindness and panhypopituitarism. Only after multiple consultations and clinical data gained from 20-year-old medical records was a complex, intergenerationally consanguineous family history revealed, compatible with MEN-1, with a splice site mutation (c.784-9G > A) being eventually identified in intron 4 of the MEN1 gene, potentially explaining the difficulties in management of this tumor. Genetic counseling and screening has now been offered to the wider family. Conclusions This case emphasizes the need to consider pituitary adenomas in the differential diagnosis of all pediatric suprasellar tumors by careful endocrine assessment and measurement of at least a serum prolactin concentration. It also highlights the lack of evidence for the optimal management of pediatric drug-resistant prolactinomas. Finally, the case we describe demonstrates the importance of a detailed family history and the role of genetic testing for MEN1 and AIP mutations in all cases of pediatric pituitary adenoma

Closing the sea surface mixed layer temperature budget from in situ observations alone: Operation Advection during BoBBLE

Sea surface temperature (SST) is a fundamental driver of tropical weather systems such as monsoon rainfall and tropical cyclones. However, understanding of the factors that control SST variability is lacking, especially during the monsoons when in situ observations are sparse. Here we use a ground-breaking observational approach to determine the controls on the SST variability in the southern Bay of Bengal. We achieve this through the first full closure of the ocean mixed layer energy budget derived entirely from in situ observations during the Bay of Bengal Boundary Layer Experiment (BoBBLE). Locally measured horizontal advection and entrainment contribute more significantly than expected to SST evolution and thus oceanic variability during the observation period. These processes are poorly resolved by state-of-the-art climate models, which may contribute to poor representation of monsoon rainfall variability. The novel techniques presented here provide a blueprint for future observational experiments to quantify the mixed layer heat budget on longer time scales and to evaluate these processes in models

Weak lensing power spectra for precision cosmology: Multiple-deflection, reduced shear and lensing bias corrections

It is usually assumed that the ellipticity power spectrum measured in weak lensing observations can be expressed as an integral over the underlying matter power spectrum. This is true at second order in the gravitational potential. We extend the standard calculation, constructing all corrections to fourth order in the gravitational potential. There are four types of corrections: corrections to the lensing shear due to multiple-deflections; corrections due to the fact that shape distortions probe the reduced shear $\gamma/(1-\kappa)$ rather than the shear itself; corrections associated with the non-linear conversion of reduced shear to mean ellipticity; and corrections due to the fact that observational galaxy selection and shear measurement is based on galaxy brightnesses and sizes which have been (de)magnified by lensing. We show how the previously considered corrections to the shear power spectrum correspond to terms in our analysis, and highlight new terms that were not previously identified. All correction terms are given explicitly as integrals over the matter power spectrum, bispectrum, and trispectrum, and are numerically evaluated for the case of sources at z=1. We find agreement with previous works for the ${\mathcal O}(\Phi^3)$ terms. We find that for ambitious future surveys, the ${\mathcal O}(\Phi^4)$ terms affect the power spectrum at the ~ 1-5 $\sigma$ level; they will thus need to be accounted for, but are unlikely to represent a serious difficulty for weak lensing as a cosmological probe.Comment: 14 pages, 3 figures; matches A & A accepted versio