Optimization of sub-relativistic co-propagating accelerating structures.

In this paper, novel optimization methodologies of sub-relativistic guided interaction structures for dielectric laser particle acceleration (DLA) are presented. In particular, we focus on co-propagating geometries based on slot waveguides in continuous wave (CW) operation, where the particle flow and the direction of propagation of the accelerating field are co-linear. Since the velocity of sub-relativistic particles varies along the acceleration path, proper tapering of the waveguide geometry is required to achieve an extended acceleration region, and, thus a large energy gain. The design of an optimal taper ensuring particle-wave synchronicity and maximum energy gain is pursued through a physics-based approach, and these results are compared, for validation, with the outcomes of a downhill simplex method searching algorithm. Additionally, the application of a simplified 2D model of the accelerating slot waveguide is investigated and profitably used to get qualitative results useful for fast structure optimization. Indeed, this approach can hold significant potential for the development of novel accelerating structures, as it enables a thorough and fast exploration of the design space.

The first measurement of plasma density in an ECRIS-like device by means of a frequency-sweep microwave interferometer.

The note presents the first plasma density measurements collected by a novel microwave interferometer in a compact Electron Cyclotron Resonance Ion Sources (ECRIS). The developed K-band (18.5 ÷ 26.5 GHz) microwave interferometry, based on the Frequency-Modulated Continuous-Wave method, has been able to discriminate the plasma signal from the spurious components due to the reflections at the plasma chamber walls, when working in the extreme unfavorable condition λp ≃ Lp ≃ Lc (λp, Lp, and Lc being the probing signal wavelength, the plasma dimension and the plasma chamber length, respectively). The note describes the experimental procedure when probing a high density plasma (ne > 1 ⋅ 1018 cm-3) produced by an ECRIS prototype operating at 3.75 GHz.

A new H2 (+) source: Conceptual study and experimental test of an upgraded version of the VIS-Versatile ion source.

The versatile ion source is an off-resonance microwave discharge ion source which produces a slightly overdense plasma at 2.45 GHz of pumping wave frequency extracting more than 60 mA proton beams and 50 mA He(+) beams. DAEδALUS and IsoDAR experiments require high intensities for H2 (+) beams to be accelerated by high power cyclotrons for neutrinos generation. In order to fulfill the new requirements, a new plasma chamber and injection system has been designed and manufactured for increasing the H2 (+) beam intensity. In this paper the studies for the increasing of the H2 (+)/p ratio and for the design of the new plasma chamber and injection system will be shown and discussed together with the experimental tests carried out at Istituto Nazionale di Fisica Nucleare-Laboratori Nazionali del Sud (INFN-LNS) and at Best Cyclotron Systems test-bench in Vancouver, Canada.

A double-layer based model of ion confinement in electron cyclotron resonance ion source.

The paper proposes a new model of ion confinement in ECRIS, which can be easily generalized to any magnetic configuration characterized by closed magnetic surfaces. Traditionally, ion confinement in B-min configurations is ascribed to a negative potential dip due to superhot electrons, adiabatically confined by the magneto-static field. However, kinetic simulations including RF heating affected by cavity modes structures indicate that high energy electrons populate just a thin slab overlapping the ECR layer, while their density drops down of more than one order of magnitude outside. Ions, instead, diffuse across the electron layer due to their high collisionality. This is the proper physical condition to establish a double-layer (DL) configuration which self-consistently originates a potential barrier; this "barrier" confines the ions inside the plasma core surrounded by the ECR surface. The paper will describe a simplified ion confinement model based on plasma density non-homogeneity and DL formation.

Heparin and suramin alter plitidepsin uptake via inhibition of GPCR coupled signaling.

Plitidepsin (Aplidin) is a novel antitumor agent, derived from the mediterranean tunicate Aplidium albicans, and is currently in phase ii clinical trials with evidence of activity in heavily pretreated multiple myeloma, renal cell carcinoma, melanoma and neuroblastoma patients. As compared to its parental compound didemnin B, plitidepsin has shown a better therapeutic index with less bone marrow toxicity, cardiotoxicity and neurotoxicity in patients and a more potent cytotoxic effect in several tumor cell lines. As sensitivity to the drug varies between cell lines and fresh leukemia samples, we performed studies on transport of plitidepsin in leukemia and lymphoma cell lines to determine the mechanism of uptake. The drug is taken up by an active transport process, i.e. the process is temperature and energy dependent, and has a high-affinity binding site with Kt =212 nM and Vmax = 15 pmoles/min. Importantly, once inside the cell, efflux of plitidepsin is minimum, suggesting that the drug is bound to intracellular macromolecules. Further work showed that plitidepsin binds to G-Protein Coupled Receptors (GPCRs), since GPCR and GRK (GPCR kinases) inhibitors suramin and heparin respectively, markedly reduce the drug uptake and its cytotoxic activity. Signaling via Jak/Stat pathway is inhibited by pharmacological concentrations of plitidepsin, further confirming the relationship between plitidepsin and GPCRs.

Single-mode and high power waveguide lasers fabricated by ion-exchange.

We report on a single-end diode-pumped waveguide laser providing output power in excess of 20 mW with 17% slope efficiency in robust single longitudinal and transverse mode operation at 1533.5 nm. The active medium was an Er:Yb-doped waveguide only 9-mm long fabricated by Ag-Na ion-exchange in a phosphate glass. The overall cavity length including butt-coupled fiber-Bragg-grating mirrors was <60 mm. We also report on high power waveguide lasers providing more than 160 mW output power and 46% slope efficiency in multimode operation. Feasibility of high power single mode waveguide lasers based on ion-exchange technology in phosphate glasses is also experimentally investigated by using a 50-mm long active waveguide specially designed for efficient single-end pumping.

Aplidin synergizes with cytosine arabinoside: functional relevance of mitochondria in Aplidin-induced cytotoxicity.

Aplidin (plitidepsin) is a novel marine-derived antitumor agent presently undergoing phase II clinical trials in hematological malignancies and solid tumors. Lack of bone marrow toxicity has encouraged further development of this drug for treatment of leukemia and lymphoma. Multiple signaling pathways have been shown to be involved in Aplidin-induced apoptosis and cell cycle arrest in G1 and G2 phase. However, the exact mechanism(s) of Aplidin action remains to be elucidated. Here we demonstrate that mitochondria-associated or -localized processes are the potential cellular targets of Aplidin. Whole genome gene-expression profiling (GEP) revealed that fatty acid metabolism, sterol biosynthesis and energy metabolism, including the tricarboxylic acid cycle and ATP synthesis are affected by Aplidin treatment. Moreover, mutant MOLT-4, human leukemia cells lacking functional mitochondria, were found to be resistant to Aplidin. Cytosine arabinoside (araC), which also generates oxidative stress but does not affect the ATP pool, showed synergism with Aplidin in our leukemia and lymphoma models in vitro and in vivo. These studies provide new insights into the mechanism of action of Aplidin. The efficacy of the combination of Aplidin and araC is currently being evaluated in clinical phase I/II program for the treatment of patients with relapsed leukemia and high-grade lymphoma.

Current understanding of methotrexate pharmacology and efficacy in acute leukemias. Use of newer antifolates in clinical trials.

BACKGROUND AND OBJECTIVES: Methotrexate (MTX) is a key drug in the curative regimen of children with acute lymphocytic leukemia. This drug is widely used not only in the treatment of neoplastic diseases such as leukemia, lymphoma, choriocarcinoma, head and neck cancer and osteogenic sarcoma, but also for various autoimmune diseases, e.g., rheumatoid arthritis and psoriasis, and for the prevention of graft-versus-host disease after transplantation. The development of drug resistance is the limiting factor in the use of MTX. This review will outline the mechanisms of acquired and natural resistance to MTX that have been studied in patients affected by acute lymphocytic leukemia and acute myelocytic leukemia and the cell cycle genes involved in MTX resistance. This information may improve the use of MTX or could lead to the development of better drugs. Moreover a short description of newer antifolates with their mechanisms of action is presented. EVIDENCE AND INFORMATION SOURCES: The authors of this review have a long-standing interest in the mechanism of action of and resistance to MTX and other antifolates. Information from journal articles covered by the Science Citation Index and Medline has been reviewed together with work performed by the authors. PERSPECTIVES: Antifolates continue to be an extremely important class of drugs for the treatment of non-neoplastic as well as neoplastic diseases. New inhibitors that target dihydrofolate reductase as well as other folate-dependent enzymes are being evaluated in the clinic, and show promise.

Suppression of intensity noise in a diode-pumped Tm-Ho:YAG laser.

We investigate the intensity noise induced by pump-power fluctuations in a diode-pumped single-frequency codoped Tm-Ho:YAG laser and we measure, in the frequency domain, the corresponding transfer function. Good agreement between the measured transfer functions and the theoretical prediction is found. A relative intensity-noise level of ~- 110 dB/Hz from ~1 kHz to the relaxation-oscillation frequency, with complete suppression of the relaxation-oscillation peak, is achieved by use of a suitable optoelectronic feedback circuit.

5-GHz repetition-rate dual-wavelength pulse-train generation from an intracavity frequency-modulated Er-Yb:glass laser.

We report the experimental demonstration of nearly transform-limited dual-wavelength pulse trains at a 5-GHz repetition rate that were generated by spectral filtering of an intracavity 2.5-GHz frequency-modulated Er-Yb bulk-glass laser operating at the 1533-nm wavelength. Highly stable dual-wavelength pulse trains with approximately 165-GHz frequency separation, approximately 48-ps pulse duration, and approximately 1-mW average single-mode fiber-coupled power were obtained.

5-GHz repetition-rate dual-wavelength pulse-train generation from an intracavity frequency-modulated Er-Yb:glass laser: errata.

In our recent Letter,(1) the affiliation of the authors was incorrect and should read as shown above. On p. 1549, in line 19 of the left-hand column the word "pulse" should be replaced with "trace." Finally, in Ref. 11 the name of the first author was misspelled. The correct reference should read as follows: