Measuring the Berry phase of graphene from wavefront dislocations in Friedel oscillations.

Electronic band structures dictate the mechanical, optical and electrical properties of crystalline solids. Their experimental determination is therefore crucial for technological applications. Although the spectral distribution in energy bands is routinely measured by various techniques1, it is more difficult to access the topological properties of band structures such as the quantized Berry phase, γ, which is a gauge-invariant geometrical phase accumulated by the wavefunction along an adiabatic cycle2. In graphene, the quantized Berry phase γ = π accumulated by massless relativistic electrons along cyclotron orbits is evidenced by the anomalous quantum Hall effect4,5. It is usually thought that measuring the Berry phase requires the application of external electromagnetic fields to force the charged particles along closed trajectories3. Contradicting this belief, here we demonstrate that the Berry phase of graphene can be measured in the absence of any external magnetic field. We observe edge dislocations in oscillations of the charge density ρ (Friedel oscillations) that are formed at hydrogen atoms chemisorbed on graphene. Following Nye and Berry6 in describing these topological defects as phase singularities of complex fields, we show that the number of additional wavefronts in the dislocation is a real-space measure of the Berry phase of graphene. Because the electronic dispersion relation can also be determined from Friedel oscillations7, our study establishes the charge density as a powerful observable with which to determine both the dispersion relation and topological properties of wavefunctions. This could have profound consequences for the study of the band-structure topology of relativistic and gapped phases in solids.

Heisenberg-exchange-free nanoskyrmion mosaic.

Isotropic Heisenberg exchange naturally appears as the main interaction in magnetism, usually favouring long-range spin-ordered phases. The anisotropic Dzyaloshinskii-Moriya interaction arises from relativistic corrections and is a priori much weaker, even though it may sufficiently compete with the isotropic one to yield new spin textures. In this work, we challenge this well-established paradigm, and propose to explore a Heisenberg-exchange-free magnetic world. In this case, the Dzyaloshinskii-Moriya interaction induces magnetic frustration in two dimensions, from which the competition with an external magnetic field results in a new mechanism producing skyrmions of nanoscale size. A single nanoskyrmion can already be stabilized in a few-atom cluster, and may then be used as LEGO® block to build a large magnetic mosaic. The realization of such topological spin nanotextures in sp- and p -electron compounds or in ultracold atomic gases would open a new route toward robust and compact magnetic memories.

Efficacy and safety of midostaurin in patients with advanced systemic mastocytosis: 10-year median follow-up of a phase II trial.

Patients with advanced systemic mastocytosis (SM) (e.g. aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL)) have limited treatment options and exhibit reduced survival. Midostaurin is an oral multikinase inhibitor that inhibits D816V-mutated KIT, a primary driver of SM pathogenesis. We conducted a phase II trial of midostaurin 100 mg twice daily, administered as 28-day cycles, in 26 patients (ASM, n=3; SM-AHN, n= 17; MCL, n=6) with at least one sign of organ damage. During the first 12 cycles, the overall response rate was 69% (major/partial response: 50/19%) with clinical benefit in all advanced SM variants. With ongoing therapy, 2 patients achieved a complete remission of their SM. Midostaurin produced a ⩾50% reduction in bone marrow mast cell burden and serum tryptase level in 68% and 46% of patients, respectively. Median overall survival for the entire cohort was 40 months, and 18.5 months for MCL patients. Low-grade gastrointestinal side effects were common and manageable with antiemetics. The most frequent grade 3/4 nonhematologic and hematologic toxicities were asymptomatic hyperlipasemia (15%) and anemia (12%). With median follow-up of 10 years, no unexpected toxicities emerged. These data establish the durable activity and tolerability of midostaurin in advanced SM.

Dynamical and Reversible Control of Topological Spin Textures.

Recent observations of topological spin textures brought spintronics one step closer to new magnetic memories. Nevertheless, the existence of Skyrmions, as well as their stabilization, require very specific intrinsic magnetic properties which are usually fixed in magnets. Here we address the possibility to dynamically control their intrinsic magnetic interactions by varying the strength of a high-frequency laser field. It is shown that drastic changes can be induced in the antiferromagnetic exchange interactions and the latter can even be reversed to become ferromagnetic, provided the direct exchange is already non-negligible in equilibrium as predicted, for example, in Si doped with C, Sn, or Pb adatoms. In the presence of Dzyaloshinskii-Moriya interactions, this enables us to tune features of ferromagnetic Skyrmions such as their radius, making them easier to stabilize. Alternatively, such topological spin textures can occur in frustrated triangular lattices. Then, we demonstrate that a high-frequency laser field can induce dynamical frustration in antiferromagnets, where the degree of frustration can subsequently be tuned suitably to drive the material toward a Skyrmionic phase.

Target interaction profiling of midostaurin and its metabolites in neoplastic mast cells predicts distinct effects on activation and growth.

Proteomic-based drug testing is an emerging approach to establish the clinical value and anti-neoplastic potential of multikinase inhibitors. The multikinase inhibitor midostaurin (PKC412) is a promising new agent used to treat patients with advanced systemic mastocytosis (SM). We examined the target interaction profiles and the mast cell (MC)-targeting effects of two pharmacologically relevant midostaurin metabolites, CGP52421 and CGP62221. All three compounds, midostaurin and the two metabolites, suppressed IgE-dependent histamine secretion in basophils and MC with reasonable IC(50) values. Midostaurin and CGP62221 also produced growth inhibition and dephosphorylation of KIT in the MC leukemia cell line HMC-1.2, whereas the second metabolite, CGP52421, which accumulates in vivo, showed no substantial effects. Chemical proteomic profiling and drug competition experiments revealed that midostaurin interacts with KIT and several additional kinase targets. The key downstream regulator FES was recognized by midostaurin and CGP62221, but not by CGP52421 in MC lysates, whereas the IgE receptor downstream target SYK was recognized by both metabolites. Together, our data show that the clinically relevant midostaurin metabolite CGP52421 inhibits IgE-dependent histamine release, but is a weak inhibitor of MC proliferation, which may have clinical implications and may explain why mediator-related symptoms improve in SM patients even when disease progression occurs.

Phase IB study of the FLT3 kinase inhibitor midostaurin with chemotherapy in younger newly diagnosed adult patients with acute myeloid leukemia.

This phase 1b trial investigated several doses and schedules of midostaurin in combination with daunorubicin and cytarabine induction and high-dose cytarabine post-remission therapy in newly diagnosed patients with acute myeloid leukemia (AML). The discontinuation rate on the 50-mg twice-daily dose schedule was lower than 100 mg twice daily, and no grade 3/4 nausea or vomiting was seen. The complete remission rate for the midostaurin 50-mg twice-daily dose schedule was 80% (FMS-like tyrosine kinase 3 receptor (FLT3)-wild-type: 20 of 27 (74%), FLT3-mutant: 12 of 13 (92%)). Overall survival (OS) probabilities of patients with FLT3-mutant AML at 1 and 2 years (0.85 and 0.62, respectively) were similar to the FLT3-wild-type population (0.78 and 0.52, respectively). Midostaurin in combination with standard chemotherapy demonstrated high complete response and OS rates in newly diagnosed younger adults with AML, and was generally well tolerated at 50 mg twice daily for 14 days. A phase III prospective trial is ongoing (CALGB 10603, NCT00651261).

Safety and pharmacokinetics of paclitaxel and the oral mTOR inhibitor everolimus in advanced solid tumours.

Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m(-2) on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33-69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m(-2), warranting further clinical investigation.

Relative bioavailability of deferasirox tablets administered without dispersion and dispersed in various drinks.

UNLABELLED: Deferasirox (ExjadeA, ICL670) is a new, once-daily oral iron chelator, recently approved as first-line therapy in the treatment of iron overload resulting from blood transfusions. In registration studies, deferasirox tablets were dispersed in non-carbonated water prior to administration. In routine clinical practice, however, patients may prefer to take the tablet dispersed in a flavored drink rather than with water. OBJECTIVE: Stability and compatibility tests were performed to identify beverages suitable for the dispersion of tablets for further testing in man. This was followed by a pharmacokinetic study to assess the relative bioavailability of deferasirox tablets dispersed in two types of soft drinks, dispersed in water, and without dispersion. METHODS: An open-label, randomized, 4-period, crossover study was carried out with 28 healthy volunteers who received single 20 mg/kg oral doses of deferasirox without dispersion, dispersed in orange juice, dispersed in apple juice and dispersed in non-carbonated water (reference). Deferasirox and Fe-[deferasirox]2 were measured in plasma using liquid chromatography-mass spectrometry. Pharmacokinetic parameters were compared using standard bioequivalence tests. RESULTS: Mean deferasirox AUC0-t were 1,040 A+/- 530, 1,010 A+/- 278, 882 A+/- 252 and 996 A+/- 352 h x micromol/l when deferasirox tablets were administered without dispersion, dispersed in orange juice, dispersed in apple juice and dispersed in water, respectively, indicating that these forms of deferasirox administrations met bioequivalence criteria. Therefore, the oral bioavailability of deferasirox tablets was not affected neither by the degree of dispersion nor by the type of drink (orange or apple juice versus water) used for dispersion. CONCLUSIONS: This study shows that deferasirox bioavailability is unaltered when dispersed with orange or apple juice compared with dispersion in water. Thus, in addition to water, patients have the option of taking deferasirox tablets in orange or apple juice. The degree of dispersion did not affect deferasirox bioavailability. Therefore, deferasirox therapy will not be compromised if dispersion of the tablet is not fully complete; although the latter should be avoided.

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome p450 3A4 substrate, in patients with chronic myeloid leukaemia.

The inhibition by imatinib of the cytochrome p450 3A4 isoenzyme may reduce the CYP3A4-mediated metabolic clearance of clinically important coadministered drugs. The main purpose of this study was to evaluate the effect of the coadministration of imatinib on the pharmacokinetics of simvastatin, a probe CYP3A4 substrate. In total, 20 patients with chronic myeloid leukaemia received an oral dose of 40 mg of simvastatin on study day 1. On study days 2-7, each patient received 400 mg of imatinib once daily orally and on study day 8, 400 mg imatinib together with 40 mg of simvastatin was given. Blood levels of simvastatin were measured predose and for 24 h postdose on study days 1 and 8. Two additional blood samples were taken for imatinib pharmacokinetic (PK) assessment on day 8 before, and 24 h after, imatinib administration. Imatinib increased the mean maximum concentration (C(max)) value of simvastatin two-fold and the area under concentration-time curve (AUC ((0-inf))) value 3.5-fold (P<0.001) compared with simvastatin alone. There was a statistically significant decrease in total-body clearance of drug from the plasma (CL/F) with a mean reduction of 70% for simvastatin (P<0.001): the mean half-life of simvastatin was prolonged from 1.4-2.7 h when given together with imatinib. No changes in imatinib PK parameters were found when given concomitantly with simvastatin. In conclusion, the coadministration of imatinib at steady state with 40 mg simvastatin increases the exposure (C(max) and AUCs) of simvastatin significantly (P<0.001) by two-three-fold. Caution is therefore required when administering imatinib with CYP3A4 substrates with a narrow therapeutic window. The coadministration of simvastatin with imatinib (400 mg) was well tolerated and no major safety findings were reported in this study.

Phase I and pharmacokinetic study of PKC412, an inhibitor of protein kinase C.

PURPOSE: N-Benzoyl staurosporine (PKC412) is a protein kinase C inhibitor with antitumor activity in laboratory models. We determined the toxicity of oral PKC412 administered daily for repeat cycles of 28 days. PATIENTS AND METHODS: Thirty-two patients with advanced solid cancers were treated at seven dose levels (12.5 to 300 mg daily) for a total of 68 cycles. RESULTS: The most frequent treatment-related toxicities were nausea, vomiting, fatigue, and diarrhea. At the two top dose levels (225 and 300 mg/d), 15 of 16 patients experienced nausea/vomiting (common toxicity criteria [CTC], version 1), grade 2 in nine of 16 and grade 3 in three of 16 patients; and six of 16 patients developed CTC grade 2 diarrhea. After 1 month of treatment, there were significant reductions in circulating lymphocyte (P <.02) and monocyte (P <.01) counts in patients receiving doses > or = 100 mg/d. Nevertheless, only two patients developed myelosuppression (both grade 2). Of two patients with progressive cholangiocarcinoma, one attained stable disease lasting 4.5 months and one a partial response lasting 4 months. There was a linear relationship between PKC412 dose and area under the curve (0-24 hours) and maximum plasma concentration with marked interpatient variability. The estimated median elimination half-life was 1.6 days (range, 0.9 to 4.0 days), and a metabolite with a median half-life of 36 days was detected. Steady-state PKC412 plasma levels at the top three dose cohorts (150 to 300 mg) were five to 10 times the cellular 50% inhibitory concentration for PKC412 of 0.2 to 0.7 micromol/L. CONCLUSION: PKC412 can be safely administered by chronic oral therapy, and 150 mg/d is suitable for phase II studies. The pharmacokinetics and lack of conventional toxicity indicate that pharmacodynamic measures may be additionally needed to optimize the drug dose and schedule.