Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response.

BACKGROUND: Sunitinib prolongs progression-free survival (PFS) in patients with advanced pancreatic neuroendocrine tumours (pNET). Response Evaluation Criteria in Solid Tumors (RECIST)-defined partial responses (PR; classically defined as ⩾30% size decrease from baseline) are infrequent. METHODS: Individual data of pNET patients from the phase II [NCT00056693] and pivotal phase III [NCT00428597] trials of sunitinib were analysed in this investigator-initiated, post hoc study. The primary objective was to determine the optimal RECIST (v.1.0) response cut-off value to identify patients who were progression-free at 11 months (median PFS in phase III trial); and the most informative time-point (highest area under the curve (AUC) by receiver operating characteristic (ROC) analysis and logistic regression) for prediction of benefit (PFS) from sunitinib. RESULTS: Data for 237 patients (85 placebo; 152 sunitinib (n=66.50 mg \u274-weeks on/2-weeks off\u27 schedule; n=86 \u2737.5 mg continuous daily dosing (CDD)\u27)) and 788 scans were analysed. The median PFS for sunitinib and placebo were 9.3 months (95% CI 7.6-12.2) and 5.4 months (95% CI 3.5-6.01), respectively (hazard ratio (HR) 0.43 (95% CI 0.29-0.62); P CONCLUSIONS: A 10% reduction within marker lesions identifies pNET patients benefiting from sunitinib treatment with implications for maintenance of dose intensity and future trial design

The Late Pleistocene Po River lowstand wedge in the Adriatic Sea: Controls on architecture variability and sediment partitioning

Although facies and stratal geometries of continental margin successions can be defined in detail based on subsurface and outcrop studies, most studies lack the high-resolution age control needed to constrain the time scale of formation of such successions and infer their external forcing mechanisms. Our work on the Po River Lowstand Wedge (PRLW) indicates that deposition rates are surprisingly high with the entire 350-m-thick succession being deposited in less than 17,000 years, and with individual clinothems recording time periods ranging from 400 to 4700 years. The PRLW preserves a high-resolution record of stacked, deltaic shelf-edge clinothems deposited during the Last Glacial Maximum (31.8–14.4 ky BP) in the Adriatic basin (Mediterranean Sea). We investigated clinothem internal geometry, stacking patterns, and facies distributions to infer the main controls on their growth by integrating seismic reflection data with seismic facies attributes and paleoenvironmental proxies. The stratigraphic framework of the shelf-edge clinothems was then related to major paleoenvironmental shifts during the last glacial cycle and driven by eustatic and climatic changes. Within the PRLW, we recognized three distinctive types of 100's-m-high shelf-edge clinothems, type A, type B and type C, each with diagnostic topset geometries, shelf-edge trajectories, and associated distal basin-fill deposits. These elemental clinothem types stack into two Clinothem Sets. Clinothem Set 1, with essentially flat to slightly descending shelf-edge trajectory, is composed of stacked types A and B clinothems, and records the direct influence of river flux leading to dysoxic conditions on the bottom of the basin. In particular, clinothem accumulation rates were as much as 200 km3/ky in some of the type B clinothems. Clinothem Set 2, showing ascending shelf-edge trajectory, records an aggradational stacking coupled with a retreat of the river-entry points with benthic fauna assemblages that reflect the influence of peaks in freshwater discharge. Whereas Clinothem Set 1 developed under perturbations of river supply linked to the multi-scale waxing and waning of glaciers during an interval dominated by eustatic fall, Clinothem Set 2 reflects the main thawing of glaciers concomitant to the first phase of the eustatic rise. From a sequence stratigraphic perspective, Clinothem Set 1 is interpreted as staked high-frequency sequences, while Clinothem Set 2 represents a stack of high-frequency parasequences. The high-resolution age control from boreholes and seismic data enabled us to relate stratal character to independently constrained environmental proxies: this revealed how the evolution of a shelf-edge system intricately convolves the influences of both global (eustacy) and regional (climate-driven supply fluctuations) controls, both at sub-Milankovitch scales. Finally, the thickness, geometry, and stacking patterns of the centennial to millennial clinothems of the PRLW vary in systematic ways resulting in geometries that closely resemble those of ancient shelf-edge systems, and offering the PRLW as a sub-modern analogue. Our observations also reinforce the focus of the classic sequence-stratigraphic approach on analyzing surfaces and their geometric relations and not on time duration or formation mechanisms

CUDA compatible GPU cards as efficient hardware accelerators for Smith-Waterman sequence alignment

Background Searching for similarities in protein and DNA databases has become a routine procedure in Molecular Biology. The Smith-Waterman algorithm has been available for more than 25 years. It is based on a dynamic programming approach that explores all the possible alignments between two sequences; as a result it returns the optimal local alignment. Unfortunately, the computational cost is very high, requiring a number of operations proportional to the product of the length of two sequences. Furthermore, the exponential growth of protein and DNA databases makes the Smith-Waterman algorithm unrealistic for searching similarities in large sets of sequences. For these reasons heuristic approaches such as those implemented in FASTA and BLAST tend to be preferred, allowing faster execution times at the cost of reduced sensitivity. The main motivation of our work is to exploit the huge computational power of commonly available graphic cards, to develop high performance solutions for sequence alignment. Results In this paper we present what we believe is the fastest solution of the exact Smith-Waterman algorithm running on commodity hardware. It is implemented in the recently released CUDA programming environment by NVidia. CUDA allows direct access to the hardware primitives of the last-generation Graphics Processing Units (GPU) G80. Speeds of more than 3.5 GCUPS (Giga Cell Updates Per Second) are achieved on a workstation running two GeForce 8800 GTX. Exhaustive tests have been done to compare our implementation to SSEARCH and BLAST, running on a 3 GHz Intel Pentium IV processor. Our solution was also compared to a recently published GPU implementation and to a Single Instruction Multiple Data (SIMD) solution. These tests show that our implementation performs from 2 to 30 times faster than any other previous attempt available on commodity hardware. Conclusions The results show that graphic cards are now sufficiently advanced to be used as efficient hardware accelerators for sequence alignment. Their performance is better than any alternative available on commodity hardware platforms. The solution presented in this paper allows large scale alignments to be performed at low cost, using the exact Smith-Waterman algorithm instead of the largely adopted heuristic approaches

Integrated photonic quantum gates for polarization qubits

Integrated photonic circuits have a strong potential to perform quantum information processing. Indeed, the ability to manipulate quantum states of light by integrated devices may open new perspectives both for fundamental tests of quantum mechanics and for novel technological applications. However, the technology for handling polarization encoded qubits, the most commonly adopted approach, is still missing in quantum optical circuits. Here we demonstrate the first integrated photonic Controlled-NOT (CNOT) gate for polarization encoded qubits. This result has been enabled by the integration, based on femtosecond laser waveguide writing, of partially polarizing beam splitters on a glass chip. We characterize the logical truth table of the quantum gate demonstrating its high fidelity to the expected one. In addition, we show the ability of this gate to transform separable states into entangled ones and vice versa. Finally, the full accessibility of our device is exploited to carry out a complete characterization of the CNOT gate through a quantum process tomography.Comment: 6 pages, 4 figure

Accidental stability of dark matter

We propose that dark matter is stable as a consequence of an accidental Z2 that results from a flavour-symmetry group which is the double-cover group of the symmetry group of one of the regular geometric solids. Although model-dependent, the phenomenology resembles that of a generic Higgs portal dark matter scheme.Comment: 12 pages, final version, published in JHE

Clinical and molecular characterization of a cohort of patients with novel nucleotide alterations of the Dystrophin gene detected by direct sequencing

<p>Abstract</p> <p>Background</p> <p>Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements.</p> <p>Methods</p> <p>We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in <it>DMD </it>gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis.</p> <p>Results</p> <p>We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n = 10 patients), followed by TAG (n = 7) and TAA (n = 4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the <it>DMD </it>gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65.</p> <p>Conclusion</p> <p>The analysis of our patients' sample, carrying point mutations or complex rearrangements in <it>DMD </it>gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin functional domains. These data can have a prognostic relevance and can be useful in directing new therapeutic approaches, which rely on a precise definition of the genetic defects as well as their molecular consequences.</p

Towards Minimal S4 Lepton Flavor Model

We study lepton flavor models with the $S_4$ flavor symmetry. We construct simple models with smaller numbers of flavon fields and free parameters, such that we have predictions among lepton masses and mixing angles. The model with a $S_4$ triplet flavon is not realistic, but we can construct realistic models with two triplet flavons, or one triplet and one doublet flavons.Comment: 18 pages, 4 figures, references are adde

Ten-Year Mortality and Cardiovascular Morbidity in the Finnish Diabetes Prevention Study—Secondary Analysis of the Randomized Trial

The Finnish Diabetes Prevention Study (DPS) was a randomized controlled trial, which showed that it is possible to prevent type 2 diabetes by lifestyle changes. The aim of the present study was to examine whether the lifestyle intervention had an effect on the ten-year mortality and cardiovascular morbidity in the DPS participants originally randomized either into an intervention or control group. Furthermore, we compared these results with a population-based cohort comprising individuals of varying glucose tolerance states.Middle-aged, overweight people with IGT (n = 522) were randomized into intensive intervention (including physical activity, weight reduction and dietary counseling), or control "mini-intervention" group. Median length of the intervention period was 4 years and the mean follow-up was 10.6 years. The population-based reference study cohort included 1881 individuals (1570 with normal glucose tolerance, 183 with IGT, 59 with screen-detected type 2 diabetes, 69 with previously known type 2 diabetes) with the mean follow-up of 13.8 years. Mortality and cardiovascular morbidity data were collected from the national Hospital Discharge Register and Causes of Death Register. Among the DPS participants who consented for register linkage (n = 505), total mortality (2.2 vs. 3.8 per 1000 person years, hazard ratio HR = 0.57, 95% CI 0.21-1.58) and cardiovascular morbidity (22.9 vs. 22.0 per 1000 person years, HR = 1.04, 95% CI 0.72-1.51) did not differ significantly between the intervention and control groups. Compared with the population-based cohort with impaired glucose tolerance, adjusted HRs were 0.21 (95% CI 0.09-0.52) and 0.39 (95% CI 0.20-0.79) for total mortality, and 0.89 (95% CI 0.62-1.27) and 0.87 (0.60-1.27) for cardiovascular morbidity in the intervention and control groups of the DPS, respectively. The risk of death in DPS combined cohort was markedly lower than in FINRISK IGT cohort (adjusted HR 0.30, 95% CI 0.17-0.54), but there was no significant difference in the risk of CVD (adjusted HR 0.88, 95% CI 0.64-1.21).Lifestyle intervention among persons with IGT did not decrease cardiovascular morbidity during the first 10 years of follow-up. However, the statistical power may not be sufficient to detect small differences between the intervention and control groups. Low total mortality among participants of the DPS compared with individuals with IGT in the general population could be ascribed to a lower cardiovascular risk profile at baseline and regular follow-up.ClinicalTrials.gov NCT00518167

Evaluation of a Fotonovela to Increase Depression Knowledge and Reduce Stigma Among Hispanic Adults

Fotonovelas—small booklets that portray a dramatic story using photographs and captions— represent a powerful health education tool for low-literacy and ethnic minority audiences. This study evaluated the effectiveness of a depression fotonovela in increasing depression knowledge, decreasing stigma, increasing self-efficacy to recognize depression, and increasing intentions to seek treatment, relative to a text pamphlet. Hispanic adults attending a community adult school (N = 157, 47.5 % female, mean age = 35.8 years, 84 % immigrants, 63 % with less than high school education) were randomly assigned to read the fotonovela or a low-literacy text pamphlet about depression. They completed surveys before reading the material, immediately after reading the material, and 1 month later. The fotonovela and text pamphlet both produced significant improvements in depression knowledge and self-efficacy to identify depression, but the fotonovela produced significantly larger reductions in antidepressant stigma and mental health care stigma. The fotonovela also was more likely to be passed on to family or friends after the study, potentially increasing its reach throughout the community. Results indicate that fotonovelas can be useful for improving health literacy among underserved populations, which could reduce health disparities