New therapies in multiple myeloma

The melphalan-prednisone regimen has been considered as standard therapy for patients with multiple myeloma (MM) for many years. Recently, high-dose chemotherapy with stem-cell support has extended progression-free survival and increased overall survival, and it is now considered conventional therapy in younger patients. However, most patients relapse and the salvage treatment is not very effective. New active drugs, including immunomodulatory agents, thalidomide (Thal) and lenalidomide, and the proteasome inhibitor bortezomib, have shown promising anti-myeloma activity. These novel treatments are aimed at overcoming resistance of tumour cells to conventional chemotherapy, acting both directly on myeloma cells and indirectly by blocking the interactions of myeloma cells with their local microenvironment and suppressing growth and survival signals induced by autocrine and paracrine loops in the bone marrow. Thal has been widely studied, mostly in combination regimens in patients with relapsed MM and, more recently, in front-line therapy, showing efficacy in terms of response rate and event-free survival. Bortezomib has been found to possess remarkable activity, especially in combination with other chemotherapeutic agents, in relapsed/refractory and newly diagnosed MM, as well as in patients presenting adverse prognostic factors. Lenalidomide, in combination with dexamethasone, is showing high overall response rates in relapsed and refractory MM and promising results also in first-line therapy. In this paper, the results of the most significant trials with Thal, bortezomib and lenalidomide are reported. Several ongoing clinical studies will hopefully allow the identification of the most active combinations capable of improving survival in patients with MM

CD20: A target antigen for immunotherapy of autoimmune diseases

This article reviews the role of CD20 antigen in B cell function and the effectiveness and limits of passive immunotherapy with anti-CD20 monoclonal antibody (Rituximab) in the treatment of autoimmune (or immune-mediated) diseases. Active immunotherapy is a more feasible way to control these chronic diseases. A peptide that mimics the CD20 epitope recognized by Rituximab is employed to stimulate the host immune response against CD20. (c) 2005 Elsevier B.V. All rights reserved

reactions of p coumaryl alcohol model compounds with dimethyl carbonate towards the upgrading of lignin building blocks

Cinnamyl alcohol 1 and 4-(3-hydroxypropyl)phenol 2, two compounds resembling the lignin building block p-coumaryl alcohol, can be selectively transformed into different products by catalytic methodologies based on dimethyl carbonate (DMC) as a green solvent/reagent. Selectivity can be tuned as a function of the reaction temperature and of the nature of the catalyst. Basic catalysts such as K2CO3, trioctylmethylphosphonium methylcarbonate ([P8881][CH3OCOO]), and CsF/αAl2O3 promote selective transesterification of the aliphatic hydroxyl group at 90 °C. However, amphoteric solids such as alkali metal-exchanged faujasites, NaX and NaY, selectively yield the corresponding alkyl ethers at higher temperatures (165–180 °C). The phenolic hydroxyl group of 2 can be methylated similarly with the faujasites at high temperatures. This preliminary screening for selectivity illustrates reactivity trends and delineates some of what might be among the most promising synthetic pathways to upgrade lignin-derived chemical building blocks

Bridging the gap of storage ring light sources and linac-driven free-electron lasers

High-gain free-electron lasers (FELs) are driven by short, high-charge density electron beams as only produced at dedicated single pass or recirculating linear accelerators. We describe new conceptual, technical, and modeling solutions to produce subpicosecond, up to 100 \u3bcJ energy extreme ultra-violet and soft x-ray FEL pulses at high- and tunable repetition rates, from diffraction-limited storage ring light source. In contrast to previously proposed schemes, we show that lasing can be simultaneous to the standard multibunch radiation emission from short insertion devices, and that it can be obtained with limited impact on the storage ring infrastructure. By virtue of the high-average power but moderate pulse energy, the storage ring-driven high-gain FEL would open the door to unprecedented accuracy in time-resolved spectroscopic analysis of matter in the linear response regime, in addition to inelastic scattering experiments

Synthesis of Methyl Carbamates from Primary Aliphatic Amines and Dimethyl Carbonate in Supercritical CO2: Effects of Pressure and Cosolvents and Chemoselectivity

At 130 °C, in the presence of CO2 (5-200 bar), primary aliphatic amines react with dimethyl carbonate (MeOCO2Me, DMC) to yield methyl carbamates (RNHCO2Me) and N-methylation sideproducts (RNHMe and RNMe2). The pressure of CO2 largely influences both the reaction conversion and the selectivity toward urethanes: in general, conversion goes through a maximum (70-80%) in the midrange (40 bar) and drops at lower and higher pressures, whereas selectivity is continuously improved (from 50% up to 90%) by an increase of the pressure. This is explained by the multiple role of CO2 in (i) the acid/base equilibrium with aliphatic amines, (ii) the reactivity/solubility of RNHCO2 - nucleophiles with/in DMC, and (iii) the inhibition of competitive N-methylation reaction of the substrates. Cosolvents also affect the reaction: in particular, a drop in selectivity is observed with polar protic media (i.e., MeOH), plausibly because of solvation effects (through H-bonds) of RNHCO2 - moieties. The reaction shows also a good chemoselectivity: bifunctional aliphatic amines bearing either aromatic NH2 or OH substituents [XC6H4(CH2)nNH2, X ) NH2, OH; n ) 1, 2], undergo methoxycarbonylation reactions exclusively at aliphatic amino groups and give the corresponding methyl carbamates [XC6H4(CH2)nNHCO2Me] in 39-65% isolated yields

Single-Step Methylation of Chitosan Using Dimethyl Carbonate as a Green Methylating Agent

N,N,N-Trimethyl chitosan (TMC) is one chitosan derivative that, because of its improved solubility, has been studied for industrial and pharmaceutic applications. Conventional methods for the synthesis of TMC involve the use of highly toxic and harmful reagents, such as methyl iodide and dimethyl sulfate (DMS). Although the methylation of dimethylated chitosan to TMC by dimethyl carbonate (DMC, a green and benign methylating agent) was reported recently, it involved a formaldehyde-based procedure. In this paper we report the single-step synthesis of TMC from chitosan using DMC in an ionic liquid. The TMC synthesised was characterised by 1H NMR spectroscopy and a functionally meaningful degree of quaternisation of 9% was demonstrated after a 12-h reaction time

Implications of quantitative susceptibility mapping at 7 Tesla MRI for microbleeds detection in cerebral small vessel disease

BACKGROUND: Cerebral microbleeds (MBs) are a hallmark of cerebral small vessel disease (CSVD) and can be found on T2*-weighted sequences on MRI. Quantitative susceptibility mapping (QSM) is a postprocessing method that also enables MBs identification and furthermore allows to differentiate them from calcifications. AIMS: We explored the implications of using QSM at submillimeter resolution for MBs detection in CSVD. METHODS: Both 3 and 7 Tesla (T) MRI were performed in elderly participants without MBs and patients with CSVD. MBs were quantified on T2*-weighted imaging and QSM. Differences in the number of MBs were assessed, and subjects were classified in CSVD subgroups or controls both on 3T T2*-weighted imaging and 7T QSM. RESULTS: 48 participants [mean age (SD) 70.9 (8.8) years, 48% females] were included: 31 were healthy controls, 6 probable cerebral amyloid angiopathy (CAA), 9 mixed CSVD, and 2 were hypertensive arteriopathy [HA] patients. After accounting for the higher number of MBs detected at 7T QSM (Median = Mdn; Mdn7T−QSM = 2.5; Mdn3T−T2 = 0; z = 4.90; p < 0.001) and false positive MBs (6.1% calcifications), most healthy controls (80.6%) demonstrated at least one MB and more MBs were discovered in the CSVD group. CONCLUSIONS: Our observations suggest that QSM at submillimeter resolution improves the detection of MBs in the elderly human brain. A higher prevalence of MBs than so far known in healthy elderly was revealed

Ferritin and C-reactive protein are predictive biomarkers of mortality and macrophage activation syndrome in adult onset Still's disease. Analysis of the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort

Objective To assess the predictive role of ferritin and C-reactive protein (CRP) on occurrence of macrophage activation syndrome (MAS) and mortality in patients with adult onset Still's disease (AOSD), a rare and severe disease, included in the multicentre Gruppo Italiano di Ricerca in Reumatologia Clinica e Sperimentale (GIRRCS) cohort. Methods The predictive role, at the time of diagnosis, of serum levels of ferritin and CRP on occurrence of MAS and mortality, was evaluated by logistic regression analyses and receiveroperating characteristic (ROC) curves were built to identify patients at high risk of MAS and mortality, respectively. Results In assessed 147 patients with AOSD, levels of ferritin were predictive of MAS (OR: 1.971; P: 0.002; CI 95%: 1.280-3.035). The ROC curve showed that the best cut-off for ferritin was 1225 ng/ml in predicting MAS (sensitivity 88%; specificity 57%). Levels of CRP were predictive of mortality in these patients (OR: 2.155; P: 0.007; CI 95%: 1.228-3.783). The ROC curve showed that the best cut-off for CRP was 68.7 mg/L in predicting mortality (sensitivity 80%; specificity of 65%). Conclusions We reported the predictive role of ferritin and CRP on MAS and mortality, respectively, in a large cohort of patients with AOSD, identifying subsets at higher risk of poor prognosis. Considering that the analysis of CRP and ferritin is widely available, these results could be readily transferable into clinical practice, thus improving the management of patients with AOSD