Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. <br></br> EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. <br></br> RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients.<br></br> CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors.<br></br&gt

All-optical ion generation for ion trap loading

We have investigated the all-optical generation of ions by photo-ionisation of atoms generated by pulsed laser ablation. A direct comparison between a resistively heated oven source and pulsed laser ablation is reported. Pulsed laser ablation with 10 ns Nd:YAG laser pulses is shown to produce large calcium flux, corresponding to atomic beams produced with oven temperatures greater than 650 K. For an equivalent atomic flux, pulsed laser ablation is shown to produce a thermal load more than one order of magnitude smaller than the oven source. The atomic beam distributions obey Maxwell-Boltzmann statistics with most probable speeds corresponding to temperatures greater than 2200 K. Below a threshold pulse fluence between 280 mJ/cm^2 and 330 mJ/cm^2, the atomic beam is composed exclusively of ground state atoms. For higher fluences ions and excited atoms are generated.Comment: 7 pages, 9 figure

Allometric growth patterns in hatchery-reared larvae of the catfish Lophiosilurus alexandri (Pisces: Pseudopimelodidae)

The aim of the present study was to characterize the relationships that occur between morphometric variables of larvae of Lophiosilurus alexandri Steindachner, 1876 through their allometric growth analysis. Total length, head length and body height were correlated with standard length, head height and body height, as well as eye diameter and head height with head length. The results revealed allometric positive relation during the initial development, where the b coefficient varied between 1.10 and 2.81. The variable pre-anal distance in relation to the standard length and the snout length in relation to the head length revealed an allometric negative relation, where the b coefficient was 0.85 and 0.94, respectively

Kinetic Monte Carlo Simulation of Strained Heteroepitaxial Growth with Intermixing

An efficient method for the simulation of strained heteroepitaxial growth with intermixing using kinetic Monte Carlo is presented. The model used is based on a solid-on-solid bond counting formulation in which elastic effects are incorporated using a ball and spring model. While idealized, this model nevertheless captures many aspects of heteroepitaxial growth, including nucleation, surface diffusion, and long range effects due elastic interaction. The algorithm combines a fast evaluation of the elastic displacement field with an efficient implementation of a rejection-reduced kinetic Monte Carlo based on using upper bounds for the rates. The former is achieved by using a multigrid method for global updates of the displacement field and an expanding box method for local updates. The simulations show the importance of intermixing on the growth of a strained film. Further the method is used to simulate the growth of self-assembled stacked quantum dots

Background-free detection of trapped ions

We demonstrate a Doppler cooling and detection scheme for ions with low-lying D levels which almost entirely suppresses scattered laser light background, while retaining a high fluorescence signal and efficient cooling. We cool a single ion with a laser on the 2S1/2 to 2P1/2 transition as usual, but repump via the 2P3/2 level. By filtering out light on the cooling transition and detecting only the fluorescence from the 2P_3/2 to 2S1/2 decays, we suppress the scattered laser light background count rate to 1 per second while maintaining a signal of 29000 per second with moderate saturation of the cooling transition. This scheme will be particularly useful for experiments where ions are trapped in close proximity to surfaces, such as the trap electrodes in microfabricated ion traps, which leads to high background scatter from the cooling beam

Stringing Spins and Spinning Strings

We apply recently developed integrable spin chain and dilatation operator techniques in order to compute the planar one-loop anomalous dimensions for certain operators containing a large number of scalar fields in N =4 Super Yang-Mills. The first set of operators, belonging to the SO(6) representations [J,L-2J,J], interpolate smoothly between the BMN case of two impurities (J=2) and the extreme case where the number of impurities equals half the total number of fields (J=L/2). The result for this particular [J,0,J] operator is smaller than the anomalous dimension derived by Frolov and Tseytlin [hep-th/0304255] for a semiclassical string configuration which is the dual of a gauge invariant operator in the same representation. We then identify a second set of operators which also belong to [J,L-2J,J] representations, but which do not have a BMN limit. In this case the anomalous dimension of the [J,0,J] operator does match the Frolov-Tseytlin prediction. We also show that the fluctuation spectra for this [J,0,J] operator is consistent with the string prediction.Comment: 27 pages, 4 figures, LaTex; v2 reference added, typos fixe

The 2.4 Å cryo-EM structure of a heptameric light-harvesting 2 complex reveals two carotenoid energy transfer pathways

We report the 2.4 Ångström resolution structure of the light-harvesting 2 (LH2) complex from Marichromatium (Mch.) purpuratum determined by cryogenic electron microscopy. The structure contains a heptameric ring that is unique among all known LH2 structures, explaining the unusual spectroscopic properties of this bacterial antenna complex. We identify two sets of distinct carotenoids in the structure and describe a network of energy transfer pathways from the carotenoids to bacteriochlorophyll a molecules. The geometry imposed by the heptameric ring controls the resonant coupling of the long-wavelength energy absorption band. Together, these details reveal key aspects of the assembly and oligomeric form of purple bacterial LH2 complexes that were previously inaccessible by any technique

Long-term cardiometabolic morbidity in young adults with classic 21-hydroxylase deficiency congenital adrenal hyperplasia

Purpose To study the current practice for assessing comorbidity in adults with 21-hydroxylase CAH and to assess the prevalence of comorbidity in these adults. Methods A structured questionnaire was sent to 46 expert centres managing adults with CAH. Information collected included current therapy and surveillance practice with a particular focus on osteoporosis/osteopaenia, hyperlipidaemia, type 2 diabetes/hyperinsulinaemia, hypertension, CV disease, obesity. Results Of the 31 (67%) centres from 15 countries that completed the survey, 30 (97%) screened for hypertension by measuring blood pressure, 30 (97%) screened for obesity, 26 (84%) screened for abnormal glucose homoeostasis mainly by using Hb1Ac (73%), 25 (81%) screened for osteoporosis mainly by DXA (92%), 20 (65%) screened for hyperlipidaemia and 6 (19%) screened for additional CV disease. Of the 31 centres, 13 provided further information on the six co-morbidities in 244 patients with a median age of 33 yrs (range 19, 94). Of these, 126 (52%) were females and 174 (71%) received fludrocortisone in addition to glucocorticoids. Of the 244 adults, 73 (30%) were treated for at least one comorbidity and 15 (21%) for more than 2 co-morbidities. Of 73, the patients who were treated for osteoporosis/osteopaenia, hyperlipidaemia, type 2 diabetes/hyperinsulinaemia, hypertension, CV disease, obesity were 43 (59%), 17 (23%), 16 (22%), 10 (14%), 8 (11), 3 (4%) respectively. Conclusion Cardiometabolic and bone morbidities are not uncommon in adults with CAH. There is a need to standardise the screening for these morbidities from early adulthood and to explore optimal therapy through routine collection of standardised data