Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase: a contributory factor to chemopotentiation in vivo?

Purpose: Poly(ADP-ribose) polymerase (PARP) plays an important role in DNA repair, and PARP inhibitors can enhance the activity of DNA-damaging agents in vitro and in vivo. AG014699 is a potent PARP inhibitor in phase II clinical development. However, the range of therapeutics with which AG014699 could interact via a DNA-repair based mechanism is limited. We aimed to investigate a novel, vascular-based activity of AG014699, underlying in vivo chemosensitization, which could widen its clinical application.

Experimental Design: Temozolomide response was analyzed in vitro and in vivo. Vessel dynamics were monitored using “mismatch” following the administration of perfusion markers and real-time analysis of fluorescently labeled albumin uptake in to tumors established in dorsal window chambers. Further mechanistic investigations used ex vivo assays of vascular smooth muscle relaxation, gut motility, and myosin light chain kinase (MLCK) inhibition.

Results: AG014699 failed to sensitize SW620 cells to temozolomide in vitro but induced pronounced enhancement in vivo. AG014699 (1 mg/kg) improved tumor perfusion comparably with the control agents nicotinamide (1 g/kg) and AG14361 (forerunner to AG014699; 10 mg/kg). AG014699 and AG14361 relaxed preconstricted vascular smooth muscle more potently than the standard agent, hydralazine, with no impact on gut motility. AG014699 inhibited MLCK at concentrations that relaxed isolated arteries, whereas AG14361 had no effect.

Conclusion: Increased vessel perfusion elicited by AG014699 could increase tumor drug accumulation and therapeutic response. Vasoactive concentrations of AG014699 do not cause detrimental side effects to gut motility and may increase the range of therapeutics with which AG014699 could be combined with for clinical benefit.

Stereotypes of Age Differences in Personality Traits: Universal and Accurate?

Age trajectories for personality traits are known to be similar across cultures. To address whether stereotypes of age groups reflect these age-related changes in personality, we asked participants in 26 countries (N = 3,323) to rate typical adolescents, adults, and old persons in their own country. Raters across nations tended to share similar beliefs about different age groups; adolescents were seen as impulsive, rebellious, undisciplined, preferring excitement and novelty, whereas old people were consistently considered lower on impulsivity, activity, antagonism, and Openness. These consensual age group stereotypes correlated strongly with published age differences on the five major dimensions of personality and most of 30 specific traits, using as criteria of accuracy both self-reports and observer ratings, different survey methodologies, and data from up to 50 nations. However, personal stereotypes were considerably less accurate, and consensual stereotypes tended to exaggerate differences across age groups.

Equação de regressão linear múltipla para estimativa do erro experimental

Este trabalho teve por objetivo estimar equações de regressão linear múltipla tendo, como variáveis explicativas, as demais características avaliadas em experimento de milho e, como variáveis principais, a diferença mínima significativa em percentagem da média (DMS%) e quadrado médio do erro (QMe), para peso de grãos. Com 610 experimentos conduzidos na Rede de Ensaios Nacionais de Competição de Cultivares de Milho, realizados entre 1986 e 1996 (522 experimentos) e em 1997 (88 experimentos), estimaram-se duas equações de regressão, com os 522 experimentos, validando estas pela análise de regressão simples entre os valores reais e os estimados pelas equações, com os 88 restantes, observando que, para a DMS% a equação não estimava o mesmo valor que a fórmula original e, para o QMe, a equação poderia ser utilizada na estimação. Com o teste de Lilliefors, verificou-se que os valores do QMe aderiam à distribuição normal padrão e foi construída uma tabela de classificação dos valores do QMe, baseada nos valores observados na análise da variância dos experimentos e nos estimados pela equação de regressão.

Adubação mineral com cobalto e molibdênio na cultura da soja

Altas produtividades de soja requerem grandes quantidades de nitrogênio, que podem ser obtidas principalmente, a partir da fixação simbiótica. No entanto, há possibilidade da eficiência desse processo biológico ser prejudicada pela deficiência de micronutrientes, especialmente de cobalto e molibdênio. Nesse contexto, objetivou-se com o presente trabalho avaliar a eficiência agronômica e a forma de aplicação de adubação mineral com cobalto e molibdênio na cultura da soja. Para tanto, a cultivar CD-206 foi submetida a diferentes tratamentos que consistiram da combinação entre aplicação de Co e Mo via tratamento de sementes e adubação foliar. As características agronômicas avaliadas foram o número de nódulos, massa seca da parte aérea, massa seca de raiz, número de vagens, número de grãos, massa de mil grãos e produção de grãos. A aplicação de molibdênio e cobalto via sementes e/ ou adubação foliar no estádio V4 (terceira folha trifoliolada completamente desenvolvida, quarto nó) promoveram incrementos significativos no rendimento da cultura. Respostas positivas ao cobalto e molibdênio também foram observadas no número de nódulos, vagens e grãos, com aumentos de até 240 kg ha-1 no rendimento da cultura. Os parâmetros agronômicos avaliados foram afetados positivamente pela aplicação de Co e Mo, principalmente quanto aplicado tanto via semente como foliar (TS + V4), inclusive para a produtividade de grãos. A forma de aplicação não foi significativamente distinta, ou seja, tanto a aplicação via semente como via foliar foram eficientes no fornecimento destes nutrientes para a cultura da soja.

Modified crop model estimation of depleted and potential soybean yield

Despite the great importance of soybeans in Brazil, there have been few applications of soybean crop modeling on Brazilian conditions. Thus, the objective of this study was to use modified crop models to estimate the depleted and potential soybean crop yield in Brazil. The climatic variable data used in the modified simulation of the soybean crop models were temperature, insolation and rainfall. The data set was taken from 33 counties (28 Sao Paulo state counties, and 5 counties from other states that neighbor São Paulo). Among the models, modifications in the estimation of the leaf area of the soybean crop, which includes corrections for the temperature, shading, senescence, CO2, and biomass partition were proposed; also, the methods of input for the model's simulation of the climatic variables were reconsidered. The depleted yields were estimated through a water balance, from which the depletion coefficient was estimated. It can be concluded that the adaptation soybean growth crop model might be used to predict the results of the depleted and potential yield of soybeans, and it can also be used to indicate better locations and periods of tillage.

Io volcano observer (IVO) integrated approach to optimizing system design for radiation challenges

One of the major challenges for a mission to the Jovian system is the radiation tolerance of the spacecraft (S/C) and the payload. Moreover, being able to achieve science observations with high signal to noise ratios (SNR), while passing through the high flux radiation zones, requires additional ingenuity on the part of the instrument provider. Consequently, the radiation mitigation is closely intertwined with the payload, spacecraft and trajectory design, and requires a systems-level approach. This paper presents a design for the Io Volcano Observer (IVO), a Discovery mission concept that makes multiple close encounters with Io while orbiting Jupiter. The mission aims to answer key outstanding questions about Io, especially the nature of its intense active volcanism and the internal processes that drive it. The payload includes narrow-angle and wide-angle cameras (NAC and WAC), dual fluxgate magnetometers (FGM), a thermal mapper (ThM), dual ion and neutral mass spectrometers (INMS), and dual plasma ion analyzers (PIA). The radiation mitigation is implemented by drawing upon experiences from designs and studies for missions such as the Radiation Belt Storm Probes (RBSP) and Jupiter Europa Orbiter (JEO). At the core of the radiation mitigation is IVO's inclined and highly elliptical orbit, which leads to rapid passes through the most intense radiation near Io, minimizing the total ionizing dose (177 krads behind 100 mils of Aluminum with radiation design margin (RDM) of 2 after 7 encounters). The payload and the spacecraft are designed specifically to accommodate the fast flyby velocities (e.g. the spacecraft is radioisotope powered, remaining small and agile without any flexible appendages). The science instruments, which collect the majority of the high-priority data when close to Io and thus near the peak flux, also have to mitigate transient noise in their detectors. The cameras use a combination of shielding and CMOS detectors with extremely fast readout to mi- imize noise. INMS microchannel plate detectors and PIA channel electron multipliers require additional shielding. The FGM is not sensitive to noise induced by energetic particles and the ThM microbolometer detector is nearly insensitive. Detailed SNR calculations are presented. To facilitate targeting agility, all of the spacecraft components are shielded separately since this approach is more mass efficient than using a radiation vault. IVO uses proven radiation-hardened parts (rated at 100 krad behind equivalent shielding of 280 mils of Aluminum with RDM of 2) and is expected to have ample mass margin to increase shielding if needed.

Neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with systemic chemotherapy in patients with breast cancer

BACKGROUND AND PURPOSE: This is the first study investigating neoadjuvant interstitial high-dose-rate (HDR) brachytherapy combined with chemotherapy in patients with breast cancer. The goal was to evaluate the type of surgical treatment, histopathologic response, side effects, local control, and survival. PATIENTS AND METHODS: 53 patients, who could not be treated with breast-conserving surgery due to initial tumor size (36/53) or due to an unfavorable breast-tumor ratio (17/53), were analyzed retrospectively. All but one were in an intermediate/high-risk group (St. Gallen criteria). The patients received a neoadjuvant protocol consisting of systemic chemotherapy combined with fractionated HDR brachytherapy (2 x 5 Gy/day, total dose 30 Gy). In cases, where breast-conserving surgery was performed, patients received additional external-beam radiotherapy (EBRT, 1.8 Gy/day, total dose 50.4 Gy). In patients, who underwent mastectomy but showed an initial tumor size of T3/T4 and/or more than three infiltrated lymph nodes, EBRT was also performed. RESULTS: In 30/53 patients (56.6%) breast-conserving surgery could be performed. The overall histopathologic response rate was 96.2% with a complete remission in 28.3% of patients. 49/53 patients were evaluable for follow-up. After a median of 58 months (45-72 months), one patient showed a mild fibrosis of the breast tissue, three patients had mild to moderate lymphatic edema of the arm. 6/49 (12.2%) patients died of distant metastases, 4/49 (8.2%) were alive with disease, and 39/49 (79.6%) were free from disease. Local recurrence was observed in only one case (2%) 40 months after primary therapy. After mastectomy, this patient is currently free from disease. CONCLUSION: The combination of interstitial HDR brachytherapy and chemotherapy is a well-tolerated and effective neoadjuvant treatment in patients with breast cancer. Compared to EBRT, treatment time is short. Postoperative EBRT of the whole breast -- if necessary -- is still possible after neoadjuvant brachytherapy. Even though the number of patients does not permit definite conclusions, the results are promising regarding survival and the very low rate of local recurrences.

Comparison of two non-bronchoscopic methods for evaluating inflammation in patients with acute hypoxaemic respiratory failure

INTRODUCTION: The simple bedside method for sampling undiluted distal pulmonary edema fluid through a normal suction catheter (s-Cath) has been experimentally and clinically validated. However, there are no data comparing non-bronchoscopic bronchoalveolar lavage (mini-BAL) and s-Cath for assessing lung inflammation in acute hypoxaemic respiratory failure. We designed a prospective study in two groups of patients, those with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and those with acute cardiogenic lung edema (ACLE), designed to investigate the clinical feasibility of these techniques and to evaluate inflammation in both groups using undiluted sampling obtained by s-Cath. To test the interchangeability of the two methods in the same patient for studying the inflammation response, we further compared mini-BAL and s-Cath for agreement of protein concentration and percentage of polymorphonuclear cells (PMNs). METHODS: Mini-BAL and s-Cath sampling was assessed in 30 mechanically ventilated patients, 21 with ALI/ARDS and 9 with ACLE. To analyse agreement between the two sampling techniques, we considered only simultaneously collected mini-BAL and s-Cath paired samples. The protein concentration and polymorphonuclear cell (PMN) count comparisons were performed using undiluted sampling. Bland-Altman plots were used for assessing the mean bias and the limits of agreement between the two sampling techniques; comparison between groups was performed by using the non-parametric Mann-Whitney-U test; continuous variables were compared by using the Student t-test, Wilcoxon signed rank test, analysis of variance or Student-Newman-Keuls test; and categorical variables were compared by using chi-square analysis or Fisher exact test. RESULTS: Using protein content and PMN percentage as parameters, we identified substantial variations between the two sampling techniques. When the protein concentration in the lung was high, the s-Cath was a more sensitive method; by contrast, as inflammation increased, both methods provided similar estimates of neutrophil percentages in the lung. The patients with ACLE showed an increased PMN count, suggesting that hydrostatic lung edema can be associated with a concomitant inflammatory process. CONCLUSIONS: There are significant differences between the s-Cath and mini-BAL sampling techniques, indicating that these procedures cannot be used interchangeably for studying the lung inflammatory response in patients with acute hypoxaemic lung injury.

The influence of recent major crater impacts on the surrounding surfaces of (21) Lutetia

We present 3-D simulations of impacts into Asteroid 21 Lutetia, the subject of a fly-by by the European Space Agency's Rosetta mission to Comet 67P/Churyumov-Gerasimenko. Using a 3-D shape model of the asteroid, impacts of sizes sufficient to reproduce the observed craters in Lutetia's North Polar Crater Cluster (NPCC) as observed by the OSIRIS experiment have been simulated using the Smoothed Particle Hydrodynamics technique. The asteroid itself has been modelled both as a homogeneous body and as a body with an iron core.

At surface behaviour of adult male southern elephant seals from King George Island from expedition JUB2000

Adult male southern elephant seals instrumented in 2000 on King George Island (n = 13), travelled both to the north (doi:10.1594/PANGAEA.231580, doi:10.1594/PANGAEA.231585) and to the east (doi:10.1594/PANGAEA.231571, doi:10.1594/PANGAEA.231579, doi:10.1594/PANGAEA.261708, doi:10.1594/PANGAEA.261709, doi:10.1594/PANGAEA.261710, doi:10.1594/PANGAEA.261711) of the Antarctic Peninsula. Five males (doi:10.1594/PANGAEA.231571, doi:10.1594/PANGAEA.231579, doi:10.1594/PANGAEA.231580, doi:10.1594/PANGAEA.261710, doi:10.1594/PANGAEA.231585) remained within 500 km of the island and focusing movements in the Bransfield Strait and around the Antarctic Peninsula. Sea-surface temperatures encountered by these animals showed little variation and they seemed to move about irrespective of sea ice cover, but frequented areas of shallow bathymetry. Three males (doi:10.1594/PANGAEA.261708, doi:10.1594/PANGAEA.261709, doi:10.1594/PANGAEA.261711) moved as far as 75°S to the east of the peninsula, into the Weddell Sea, with maximum distances of more than 1500 km from King George Island. They travelled into the Weddell Sea along the western continental shelf break until they reached the region of the Filchner Trough outflow. Here the bathymetry consists of canyons and ridges which support the intensive mixing between the warm saline waters of the Weddell Gyre and the very cold outflow waters with Ice Shelf water ingredients at the Antarctic Slope Front. Another five data sets were shorter then 40 days, and excluded from analyses (doi:10.1594/PANGAEA.231568, doi:10.1594/PANGAEA.231576, doi:10.1594/PANGAEA.231572, doi:10.1594/PANGAEA.231577, doi:10.1594/PANGAEA.264710). A computer animation was developed to visualize the animal movements in relation to the extent and concentration of sea ice (doi:10.1594/PANGAEA.509404). The need for re-instrumentation of adult males from King George Island is highlighted to investigate whether males continue to travel to similar areas and to obtain higher resolution data.