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Attosecond Pulse Trains (APT) generated by high-harmonic generation (HHG) of high-intensity near-infrared (IR) laser pulses have proven valuable for studying the electronic dynamics of atomic and molecular species. However, the high intensities required for high-photon-energy, high-flux HHG usually limit the class of adequate laser systems to repetition rates below 10 kHz. Here, APT’s generated from the 100 kHz, 160 W, 40 fs laser system (HR-1) currently under commissioning at the extreme light infrastructure attosecond light pulse source (ELI-ALPS) are reconstructed using the reconstruction of attosecond beating by interference of two-photon Transitions (RABBIT) technique. These experiments constitute the first attosecond time-resolved photoelectron spectroscopy measurements with attosecond pulses performed at 100 kHz repetition rate and one of the first experiments performed at ELI-ALPS in the framework of projects commissioning its newly installed technologies. These RABBIT measurements were taken with an additional IR field temporally locked to the extreme-ultraviolet APT, resulting in an atypical ω beating. We show that the phase of the 2ω beating recorded under these conditions is strictly identical to that observed in standard RABBIT measurements within second-order perturbation theory. This work highlights an experimental simplification for future experiments based on attosecond interferometry (or RABBIT), which is particularly useful when lasers with high average powers are used. [ABSTRACT FROM AUTHOR]

Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB tyrosine kinase inhibitor with clinical activity in patients with ErbB2/HER2-positive breast cancer., Patients and Methods: Phase I of this open-label, phase I/II study investigated the maximum tolerated dose (MTD) of oral neratinib (160 or 240 mg/day) plus vinorelbine (25 mg/m2; days 1 and 8 of each 21-day cycle) in patients with solid tumors. Phase II assessed the safety, clinical activity, and pharmacokinetics of the combination in patients with HER2-positive metastatic breast cancer; the primary efficacy end point was objective response (OR)., Results: In phase I (n=12), neratinib (240 mg) plus vinorelbine (25 mg/m2) was established as the MTD. In phase II, 79 patients with HER2-positive metastatic breast cancer were treated at the MTD. The most common treatment-related adverse events were diarrhea (96%), neutropenia (54%), and nausea (50%). Three patients discontinued treatment due to diarrhea. No clinically important skin side-effects were observed. The OR rate in assessable phase II patients was 41% (no prior lapatinib) and 8% (prior lapatinib). There was no evidence of pharmacokinetic interaction between neratinib and vinorelbine., Conclusion: Neratinib plus vinorelbine showed promising antitumor activity and no unexpected toxic effects in HER2-positive metastatic breast cancer patients. Trial registration ClinicalTrials.gov #NCT00706030.

Patients with high-risk locally advanced/inflammatory and oligometastatic (≤3 sites) breast cancer frequently relapse or experience early progression. High-dose chemotherapy combined with peripheral stem cell rescue may prolong progression-free survival/relapse-free survival (PFS/RFS) and overall survival (OS). In this study, patients initiated high-dose chemotherapy with STAMP-V (carboplatin, thiotepa, and cyclophosphamide), ACT (doxorubicin, paclitaxel, and cyclophosphamide), or tandem melphalan and STAMP-V. Eighty-six patients were diagnosed with locally advanced/inflammatory (17 inflammatory) breast cancer, and 12 were diagnosed with oligometastatic breast cancer. Median follow-up was 84 months (range, 6-136 months) for patients with locally advanced cancer and 40 months (range, 24-62 months) for those with metastatic cancer. In the patients with locally advanced cancer, 5-year RFS and OS were 53% (95% CI, 41%-63%) and 71% (95% CI, 60%-80%), respectively, hormone receptors were positive in 74%, and HER2 overexpression was seen in 23%. In multivariate analysis, hormone receptor-positive disease and lower stage were associated with better 5-year RFS (60% for ER [estrogen receptor]/PR [progesterone receptor]-positive versus 30% for ER/PR-negative; P < .01) and OS (83% for ER/PR-positive versus 38% for ER/PR-negative; P < .001). In the patients with metastatic cancer, 3-year PFS and OS were 49% (95% CI, 19%-73%) and 73% (95% CI, 38%-91%), respectively. The favorable long-term RFS/PFS and OS for high-dose chemotherapy with peripheral stem cell rescue in this selected patient population reflect the relative safety of the procedure and warrant validation in defined subgroups through prospective, randomized, multi-institutional trials., (Copyright © 2012 American Society for Blood and Marrow Transplantation. All rights reserved.)

Inhibition of the HER-2 pathway via the monoclonal antibody trastuzumab has had a major impact in treatment of HER-2 positive breast cancer, but de novo or acquired resistance may reduce its effectiveness. The known interplay between the epidermal growth factor receptor (EGFR) and HER-2 receptors and pathways creates a rationale for combined anti-EGFR and anti-HER-2 therapy in HER-2 positive metastatic breast cancer (MBC), and toxicities associated with the use of multiple chemotherapeutic agents together with biological therapies may also be reduced. We conducted a prospective, single arm, phase I/II trial to determine the efficacy and toxicity of the combination of trastuzumab with the EGFR inhibitor gefitinib and docetaxel, in patients with HER-2 positive MBC. The maximum tolerated dose (MTD) was determined in the phase I portion. The primary end point of the phase II portion was progression-free survival (PFS). Immunohistochemical analysis of biomarker expression of the PKA-related proteins cAMP response element-binding protein (CREB), phospho-CREB and DARPP-32 (dopamine and cAMP-regulated phosphoprotein of 32 kDa) plus t-DARPP (the truncated isoform of DARPP-32); PTEN; p-p70 S6K; and EGFR was conducted on tissue from metastatic sites. Nine patients were treated in the phase I portion of the study and 22 in the phase II portion. The MTD was gefitinib 250 mg on days 2-14, trastuzumab 6 mg/kg, and docetaxel 60 mg/m(2) every 21 days. For the 29 patients treated at the MTD, median PFS was 12.7 months, with complete and partial response rates of 18 and 46%, and a stable disease rate of 29%. No statistically significant correlation was found between response and expression of any biomarkers. We conclude that the combination of gefitinib, trastuzumab, and docetaxel is feasible and effective. Expression of the biomarkers examined did not predict outcome in this sample of HER-2 overexpressing metastatic breast cancer.

We present exact results for the spectra of three fermionic atoms in a single well of an optical lattice. For the three lowest hyperfine states of 6Li atoms, we find a Borromean state across the region of the distinct pairwise Feshbach resonances. For 40K atoms, nearby Feshbach resonances are known for two of the pairs, and a bound three-body state develops towards the positive scattering-length side. In addition, we study the sensitivity of our results to atomic details. The predicted few-body phenomena can be realized in optical lattices in the limit of low tunneling.

GABA(A) receptors composed of alpha, beta and gamma subunits display a significantly higher single-channel conductance than receptors comprised of only alpha and beta subunits. The pore of GABA(A) receptors is lined by the second transmembrane region from each of its five subunits and includes conserved threonines at the 6', 10' and 13' positions. At the 2' position, however, a polar residue is present in the gamma subunit but not the alpha or beta subunits. As residues at the 2', 6' and 10' positions are exposed in the open channel and as such polar channel-lining residues may interact with permeant ions by substituting for water interactions, we compared both the single-channel conductance and the kinetic properties of wild-type alpha1beta1 and alpha1beta1gamma2S receptors with two mutant receptors, alphabetagamma(S2'A) and alphabetagamma(S2'V). We found that the single-channel conductance of both mutant alphabetagamma receptors was significantly decreased with respect to wild-type alphabetagamma, with the presence of the larger valine side chain having the greatest effect. However, the conductance of the mutant alphabetagamma receptors remained larger than wild-type alphabeta channels. This reduction in the conductance of mutant alphabetagamma receptors was observed at depolarized potentials only (E(Cl) = -1.8 mV), which revealed an asymmetry in the ion conduction pathway mediated by the gamma2' residue. The substitutions at the gamma2' serine residue also altered the gating properties of the channel in addition to the effects on the conductance with the open probability of the mutant channels being decreased while the mean open time increased. The data presented in this study show that residues at the 2' position in M2 of the gamma subunit affects both single-channel conductance and receptor kinetics.

The effective interaction problem in nuclear physics is believed to be highly nonperturbative, requiring extended high-momentum spaces for accurate solution. We trace this to difficulties that arise at both short and long distances when the included space is defined in terms of a basis of harmonic oscillator Slater determinants. We show, in the simplest case of the deuteron, that both difficulties can be circumvented, yielding highly perturbative results in the potential even for modest (approximately 4 variant Planck's over 2pi omega) included spaces.

Aotus monkeys received 4 doses of Plasmodium falciparum EBA-175 region II vaccine as plasmid DNA (Dv-Dv) or recombinant protein in adjuvant (Pv-Pv) or as 3 doses of DNA and 1 dose of protein (Dv-Pv). After 3 doses, antibody titers were approximately 10(4) in DNA-immunized monkeys and 10(6) in protein-immunized monkeys. A fourth dose did not significantly boost antibody responses in the Dv-Dv only or Pv-Pv only groups, but titers were boosted to approximately 10(6) in monkeys in the Dv-Pv group. Four weeks after the last immunization, the animals were challenged with 10(4) P. falciparum-parasitized erythrocytes. Peak levels of parasitemia were lower in the 16 monkeys that received region II-containing plasmids or proteins than in the 16 controls (geometric mean: 194,178 and 410,110 parasites/microL, respectively; P=.013, Student's t test). Three of 4 monkeys in the Dv-Pv group did not require treatment. These data demonstrate that immunization with EBA-175 region II induces a significant antiparasite effect in vivo.

EBA-175 of Plasmodium falciparum is a merozoite ligand that binds its receptor glycophorin A on erythrocytes during invasion. The ligand-receptor interaction is dependent on sialic acids as well as the protein backbone of glycophorin A. Region II (RII) of EBA-175 has been defined as the receptor-binding domain. RII is divided into regions F1 and F2, which contain duplicated cysteine motifs. We expressed RII in a baculovirus and show that RII binds erythrocytes with a specificity identical to that of the native protein. We found that, consistent with the binding of erythrocytes to COS cells expressing F2, recombinant baculovirus-expressed F2 bound erythrocytes. About 20% of all baculovirus-expressed RII is N-glycosylated, unlike native P. falciparum proteins that remain essentially unglycosylated. However, glycosylation of recombinant RII did not affect its immunogenicity. Antibodies raised against both glycosylated and unglycosylated baculovirus-expressed RII recognized P. falciparum schizonts in immunofluorescence assays and also gave similar enzyme-linked immunosorbent assay titers. Furthermore, these antibodies have similar abilities to block native EBA-175 binding to erythrocytes. These results allow the development of RII as a vaccine candidate for preclinical assessment.

We investigated the early diagnostic utility, including incremental value, of the serum cardiac markers creatine kinase (CK), CK-MB (mass and activity measurements), cardiac troponin T, and myoglobin in the diagnosis of acute myocardial infarction (AMI) in patients presenting to a major teaching hospital with chest pain and non-diagnostic electrocardiographs (ECG). The reference diagnosis of acute myocardial infarction was made by a single, independent cardiologist using World Health Organization criteria. CK and CK-MB mass were the only significant predictors of AMI at presentation to the Emergency Department. Logistic regression analysis revealed that CK did not significantly predict (P = 0.23) myocardial infarction once CK-MB mass was in the model. Using test results on follow up, in addition to presentation CK-MB mass, change in CK-MB mass was the only other significant independent predictor of AMI. Likelihood ratios for various levels of the significant markers in the logistic regression are given. In conclusion, CK-MB mass measurement was the only useful serum cardiac marker for the diagnosis of AMI in patients presenting with chest pain with non-diagnostic ECGs.

Production of multiple overlapping peptides is a key step in the identification of T-cell epitopes. A large number of peptides can be produced by using ABIMED's automated multiple peptide synthesizer. We report here considerable improvement in the software and chemistry of peptide synthesis by introducing a resin mixing step during coupling, when using this synthesizer. A comparison of two solvent systems for synthesis was performed. Six test peptides were synthesized by standard and modified methods. The purity of peptides, assessed by HPLC and mass spectrometry, showed a substantial improvement when automated resin mixing and mixed solvent system were used. These improvements enable us to produce 48 peptides within a week each of sufficient purity to be used for rapid screening of T-cell epitopes.

We have previously used laser Doppler technology to demonstrate that skin blood flow is reduced in Type 1 (insulin-dependent) diabetic patients. The possibility of using the skin as an extremely accessible indicator of diabetic microvascular disease is attractive. The streptozotocin diabetic rat is an appealing potential animal model. We performed measurements of skin blood flow in two rat species, nine Sprague Dawley (SD) rats and nine Wistar Kyoto (WKY) rats, observing early changes following the inception of diabetes. Four of the SD rats and five of the WKY rats were made diabetic, the rest serving as controls. There were no significant differences in skin blood flow between the two rat strains. As in man, there appear to be rat skin sites with primarily nutritive capillary supply and those with arteriovenous anastomotic predominance. The back and base of tail, both hair-covered areas, demonstrated low flow characteristics, consistent with nutritive perfusion. In contrast, the plantar surface of the paw behaved similarly to the finger or toe pulps in man, sites of arteriovenous perfusion, with high basal flow and a marked increment with thermal stimulation. In diabetic rats of both species, there was significantly lower flow at the back and base of tail than in non-diabetic animals. The differences were of the order of 30-40%. As a function of time, the decrease in blood flow at the base of tail parallelled the increase in glycohaemoglobin levels in the diabetic rats. In contrast, blood flow at the plantar surface of the paw was unchanged throughout the 3-month post-streptozotocin observation period.(ABSTRACT TRUNCATED AT 250 WORDS)

Using laser Doppler techniques in nine healthy volunteers, we contrasted the effect of increasing local skin temperature at the elbow, a skin site with nutritive microvasculature, and the finger pulp, with predominantly arteriovenous anastomic (AVA) perfusion). We also assessed flow at the finger dorsum, with contributions of both types of microvasculature. In parallel with the laser Doppler studies, we determined the effect of increasing temperature on the red cell deformability of our subjects, using the new technique of Cell Transit Time Analysis (CTTA). Thermal stimulation produced very large increases in skin blood flow at all three sites tested. However, the magnitude and the pattern of increase were different at the three sites. At the finger pulp, there was a linear approximately threefold increase in flow as temperature increased from the basal level to 44 degrees C. At the elbow, basal flow was considerably lower than at the finger pulp and increased very slowly until skin temperature reached 38 degrees C. From that point, flow increased sharply, reaching tenfold the basal level at 44 degrees C. The thermally induced increase at the finger dorsum was intermediate between the other two sites, with a pattern resembling the elbow more than the finger pulp. These differences among the sites were attributable to substantially different patterns of change in the two components of flow, microvascular volume and velocity. At the finger pulp, there was very little increase in microvascular volume with increasing temperature. The curve was practically flat from basal temperature to 44 degrees C. In contrast, there was a linear increase in red blood cell velocity of about 300%. At the elbow, both microvascular volume and red blood cell velocity exhibited a parallel curvilinear pattern of equivalent increase, on the order of 300% for each. There was only a small increase in both parameters until the temperature reached 38 degrees, at which point there was a sharp increase in both. At the finger dorsum, the situation was intermediate, again resembling the elbow more than the finger pulp. Cell Transit Time Analysis revealed a progressive decrease in red cell transit time (TT), from 3.28 ms at 28 degrees C to 2.48 m at 44 degrees C, an overall change of 24%. The decrease in TT was accompanied by an increase in transit frequency, measured as counts s-1 (C s-1), from 3.1 to 5.3, an overall change of 71%. The changes in both TT and C/S were essentially linear.(ABSTRACT TRUNCATED AT 400 WORDS)

Cell transit time analysis (CTTA) is a new filtrometric technique for assessing red blood cell deformability by measuring the conductivity change caused by passage of erythrocytes through a polycarbonate filter. Most reported studies to date using CTTA have focused on the transit time (TT), the duration of passage of an individual red cell through a micropore. Bulk flow rate has not been previously measured via CTTA. The use of new enzyme based cleaning solutions make it possible to reduce clogging in micropore filters. Therefore, valid measures of the number of red cell transits per unit time (counts/s: C/S) can now be obtained. We evaluated both parameters, TT and C/S, as indicators of red cell filterability. Our goal was to evaluate the effect of metabolic changes shown by alternative techniques to affect red cell deformability. The two best established factors are changes in intracellular [ATP] and [Ca2+]. ATP depletion produces a very small increase in TT but a very marked decrease in C/S. In contrast, the addition of low concentrations of calcium produces an increase in TT with minimal decrease in C/S. The effects of calcium appear to be complex. The substantial changes in intracellular calcium induced by the ionophore A23187 result in a curvilinear pattern of increase in transit times and reduction in counts per s. Lanthanum, which inhibits egress of intracellular calcium, causes an increase in TT with a drop in C/S. We conclude that CTTA demonstrates the same changes in red cell deformability measurable by alternative filtrometric techniques; however, CTTA furnishes two separate and independent parameters which may be used to evaluate red cell deformability.

This preliminary study was conducted to evaluate the effects of 0.02 mg/kg of epinephrine (E) on myocardial blood flow (MBF), myocardial oxygen consumption (MVO2), and delivery (MDO2) when administered during CPR after 10-min cardiopulmonary arrest. Five miniature swine were instrumented for MBF measurements using tracer microspheres. Ventricular fibrillation was induced. After 10 min, CPR was begun with a pneumatic compressor. Measurements of MBF, arterial, and coronary sinus blood gases were made. After 3 min of CPR, each animal received 0.02 mg/kg of E. The measurements were repeated and defibrillation was attempted. During CPR, MDO2 and MVO2 were 0.2 +/- 0.3 and 0.2 +/- 0.3 ml/min/100 g tissue, respectively. The myocardial oxygen extraction ratio (ER) was 94.2 +/- 3.0%. After 0.02 mg/kg of E, MDO2 was 1.1 +/- 1.4, MVO2 was 1.0 +/- 1.3, and ER was 93.9 +/- 0.7% (p greater than .05). There were no successful defibrillations. These data indicate that MDO2 improves slightly during CPR after 0.02 mg/kg of E, but it does not meet the oxygen demands of the fibrillating heart.

Recent studies in swine have shown that larger doses of epinephrine than those currently employed for cardiopulmonary resuscitation (CPR) significantly improve regional myocardial blood flow following prolonged cardiac arrest. The dose-response effect of a pure alpha-adrenergic agonist, methoxamine, on regional myocardial blood flow has not been investigated in this setting. This study compared the effect of high-dose epinephrine with graded doses of methoxamine on regional myocardial blood flow, oxygen delivery/utilization, and defibrillation rates during CPR. Twenty swine were instrumented for regional myocardial blood flow measurements using radiolabeled tracer microspheres. Measurements of regional myocardial blood flow, oxygen delivery, and oxygen consumption were made during normal sinus rhythm. Ventricular fibrillation was then induced. Following 10 minutes of ventricular fibrillation, CPR was initiated with a pneumatic compressor. Regional myocardial blood flow, oxygen delivery, and oxygen consumption were then measured during CPR. Following 3 minutes of CPR, the swine were allocated to one of four treatment groups (five per group): group I, epinephrine 0.2 mg/kg; group II, methoxamine 0.1 mg/kg; group III, methoxamine 1.0 mg/kg; and group IV, methoxamine 10.0 mg/kg. One minute after drug administration, regional myocardial blood flow, oxygen delivery, and oxygen consumption measurements again were made. Three and one half minutes after drug administration, defibrillation was attempted. Regional myocardial blood flow following drug administration was compared using an analysis of covariance. Epinephrine (0.2 mg/kg) significantly improved myocardial blood flow (P less than .002) for all tissues examined compared with all doses of methoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Our study compared the effect of high-dose epinephrine with the pure alpha-agonist phenylephrine on regional myocardial blood flow (MBF), myocardial oxygen delivery (MDO2), myocardial oxygen consumption (MVO2), and defibrillation rates during CPR. Fifteen swine weighing more than 15 kg were instrumented for measurement of regional MBF using radiolabeled tracer microspheres. Measurements of regional MBF, MDO2, and MVO2 were made during normal sinus rhythm. Ventricular fibrillation was induced and persisted for ten minutes. CPR was begun using a pneumatic compression device. Regional MBF, MDO2, and MVO2 were measured during CPR. Following three minutes of CPR, animals (N = 15) were allocated to one of three groups (n = 5): Group 1, epinephrine 0.2 mg/kg; Group 2, phenylephrine 0.1 mg/kg; or Group 3, phenylephrine 1.0 mg/kg. Measurements of regional MBF, MDO2, and MVO2 were repeated after drug administration. Extraction ratios, defined as MVO2/MDO2, were calculated during normal sinus rhythm, CPR, and after drug administration. Defibrillation was attempted 3 1/2 minutes after drug administration. There was no significant difference in MBF, MDO2, MVO2, and extraction ratio during normal sinus rhythm and CPR for any of the groups. Total MBF following drug administration was 67.2 +/- 49.4 mL/min/100 g for the group receiving epinephrine 0.2 mg/kg; 7.0 +/- 7.1 mL/min/100 g for the group receiving phenylephrine 0.1 mg/kg; and 36.7 +/- 21.1 mL/min/100 g for the group receiving phenylephrine 1.0 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

The use of simple off-the-shelf lenses as Fourier transform elements in an optical computer is considered. Several schemes for measuring those lens parameters that determine the performance of such simple lenses as Fourier transform elements are provided with emphasis on lens phase errors. It is assumed that no lens design data are available for the lens under test.

The effects of amplitude nonuniformities and phase errors on the accuracy of the optical Fourier transform are considered for the case of a simple lens. A quadratic phase model is derived, analyzed, and compared to experimental and point-by-point optical path difference data. The goal is to determine the lens specifications needed to produce an optical Fourier transform of given accuracy rather than the design of the lens itself.