Targeted therapies and checkpoint inhibitors in sarcoma.

Sarcomas are defined as a group of mesenchymal malignancies with over 100 heterogeneous subtypes. As a rare and difficult to diagnose entity, micrometastasis is already present at the time of diagnosis in many cases. Current treatment practice of sarcomas consists mainly of surgery, (neo)adjuvant chemo- and/or radiotherapy. Although the past decade has shown that particular genetic abnormalities can promote the development of sarcomas, such as translocations, gain-of-function mutations, amplifications or tumor suppressor gene losses, these insights have not led to established alternative treatment strategies so far. Novel therapeutic concepts with immunotherapy at its forefront have experienced some remarkable success in different solid tumors while their impact in sarcoma remains limited. In this review, the most common immunotherapy strategies in sarcomas, such as immune checkpoint inhibitors, targeted therapy and cytokine therapy are concisely discussed. The programmed cell death (PD)-1/PD-1L axis and apoptosis-inducing cytokines, such as TNF-related apoptosis-inducing ligand (TRAIL), have not yielded the same success like in other solid tumors. However, in certain sarcoma subtypes, e.g. liposarcoma or undifferentiated pleomorphic sarcoma, encouraging results in some cases when employing immune checkpoint inhibitors in combination with other treatment options were found. Moreover, newer strategies such as the targeted therapy against the ancient cytokine macrophage migration inhibitory factor (MIF) may represent an interesting approach worth investigation in the future.

Interplay between Aggregation and Coalescence of Polymeric Particles: Experimental and Modeling Insights.

In the present work, the aggregation behavior of polymeric particles possessing different glass transition temperatures (i.e., different "softnesses") has been studied to shed light on the interplay between aggregation and coalescence. In particular, the time evolution of the clusters hydrodynamic and gyration radii as well as of their structure factor has been monitored. With the help of an ad hoc developed deterministic model, based on population balance equations, it was possible to establish a link between the experimentally obtained light scattering data and the predicted particle size distribution. The simplicity of the model, involving one single adjustable parameter based on the coalescence characteristic time, allowed us to obtain a good accordance between simulations and experimental results with little computational effort.

High numbers of mobilized CD34+ cells collected in AML in first remission are associated with high relapse risk irrespective of treatment with autologous peripheral blood SCT or autologous BMT.

The faster hematopoietic recovery after autologous peripheral blood SCT (APBSCT) in patients with AML may be offset by an increased relapse risk as compared with autologous BMT (ABMT). The EORTC and GIMEMA Leukemia Groups conducted a trial (AML-10) in which they compared, as second randomization, APBSCT and ABMT in first CR patients without an HLA compatible donor. A total of 292 patients were randomized. The 5-year DFS rate was 41% in the APBSCT arm and 46% in the ABMT arm with a hazard ratio (HR) of 1.17; 95% confidence interval=0.85-1.59; P=0.34. The 5-year cumulative relapse incidence was 56% vs 49% (P=0.26), and the 5-year OS 50% and 55% (P=0.6) in the APBSCT and ABMT groups, respectively. APBSCT was associated with significantly faster recovery of neutrophils and platelets, shorter duration of hospitalization, reduced need of transfusion packed RBC and less days of intravenous antibiotics. In both treatment groups, higher numbers of mobilized CD34+ cells were associated with a significantly higher relapse risk irrespective of the treatment given after the mobilization. Randomization between APBSCT and ABMT did not result in significantly different outcomes in terms of DFS, OS and relapse incidence.

EPO modulation in a 14-days undersea scuba dive.

Erythropoiesis is affected during deep saturation dives. The mechanism should be related to a downregulation of serum Erythropoietin (s-EPO) concentration or to a toxic effect of the hyperbaric hyperoxia. We evaluated s-EPO and other haematological parameters in 6 scuba divers before, during and after a 14-days guinness saturation dive (8-10 m). Athletes were breathing air at 1.8-2 ATA, under the control of a team of physicians. Serum parameters were measured before diving (T0) and: 7 days (T1), 14 days (T2) after the beginning of the dive and 2 h (T3) and 24 h (T4) after resurfacing. Hgb, and many other haematological parameters did not change whereas Ht, s-EPO, the ratio between s-EPO predicted and that observed and reticulocytes (absolute, percent) declined progressively from T0 to T3. At T4 a significant rise in s-EPO was observed. Hgb did not vary but erythropoiesis seemed to be affected as s-EPO and reticulocyte counts showed. All these changes were statistically significant. The experiment, conducted in realistic conditions of dive length, oxygen concentration and pressure, allows us to formulate some hypotheses about the role of prolonged hyperbarism on erythropoiesis. The s-EPO rise, 24 h after resurfacing, is clearly documented and related to the "Normobaric Oxygen Paradox". This evidence suggests interesting hypotheses for new clinical applications such as modulation of s-EPO production and Hgb content triggered by appropriate O2 administration in pre-surgical patients or in some anemic disease.

Density functional theory study of addition reactions of carbon-centered radicals to alkenes.

Addition reactions of carbon-centered radicals to unsaturated compounds have been studied using quantum chemistry. Following the review by Fischer and Radom (Angew. Chem., Int. Ed. 2001, 40, 1340.), the radicals were grouped in four different families, and the alkenes were selected from among those typical of polymer productions. All of the kinetic constants were calculated using density functional theory and classic transition state theory. Geometries of reactants, products, and transition states were determined at the B3LYP/6-311+G(d,p) level of theory, whereas reaction enthalpies, activation energies, and kinetic constants were estimated using different basis sets. By comparative evaluation of the results obtained with different basis sets, the best computational approach for each kinetic step was identified. As a result of this study, a computational methodology suitable for investigating a large number of kinetic pathways typical of free-radical polymerization processes is proposed.

Preparation of macroporous methacrylate-based monoliths for chromatographic applications by the Reactive Gelation Process.

Polymeric monoliths are a relatively new separation medium for chromatographic applications. The innovative approach to produce such monoliths, the Reactive Gelation Process, presented by Marti et al. [1] for polystyrene macroporous materials is applied to a methacrylate-based material. It is shown that it is possible to create a macroporous structure by Reactive Gelation also with this polymer even if the properties of the material are different. Besides the analysis of the material by SEM and BET, several chromatographic methods are used to analyze the material properties. The ISEC experiments showed a much smaller size exclusion effect than in conventional packed beds. The permeability of the material is comparable to a packed bed with 4.13 µm particles. The column efficiency is not changing for increasing flow rates. Because of the high efficiency of the material, shorter columns are needed and therefore the comparatively low permeability is compensated. The monolith also exhibits a significant adsorption capacity for hydrophobic interaction, which makes it suitable for chromatographic purification processes.

Enhancement of cytosine arabinoside-induced apoptosis in human myeloblastic leukemia cells by NF-kappa B/Rel- specific decoy oligodeoxynucleotides.

The activity of NF-kappa B/Rel nuclear factors is known to inhibit apoptosis in various cell types. We investigated whether the subtraction of NF-kappa B/Rel activity influenced the response of 11 AML (M1, M2 and M4) patients' cells to AraC. To this end we used a phosphorothioate double-stranded decoy oligodeoxynucleotide (ODN) carrying the NF-kappa B/Rel- consensus sequence. Cell incubation with this ODN, but not its mutated (scrambled) form used as a control, resulted in abating the NF-kappa B/Rel nuclear levels in these cells, as verified by electrophoretic mobility shift assay (EMSA) of cells' nuclear extracts. We incubated the leukemic cells with AraC (32 or 1 microM), in either the absence or presence of the decoy or the scrambled ODN, and analyzed cell apoptosis. The spontaneous cell apoptosis detectable in the absence of AraC (<25%) was not modulated by the oligonucleotide presence in cell cultures. On the other hand, in 10 of the 11 samples tested, the decoy kappa B, but not the scrambled ODN significantly (P < 0.01 in a Student's t test) enhanced cell apoptotic response to AraC. Such an effect was particularly remarkable at low AraC doses (1 microM). These findings indicate that NF-kappa B/Rel activity influences response to AraC in human primary myeloblastic cells, and suggests that the inhibition of NF-kappa B/Rel factors can improve the effect of chemotherapy in AML. Gene Therapy (2000) 7, 1234-1237.

Design of a simulated moving bed unit for sucrose-betaine separations.

The results of a series of pulse experiments carried out in a fixed bed column packed with a strongly acid ion-exchange resin and with reference to the separation of an aqueous sucrose-betaine mixture are presented. These data were used to evaluate equilibrium and diffusion parameters for both key components in the frame of linear chromatography theory. The estimated values were used to design a simulated moving bed plant aimed to separate betaine from sucrose in beet molasses.

Use of electron-trapping materials in optical signal processing. IV: Parallel incoherent image subtraction.

Novel electron trapping materials are inherently capable of performing subtraction over a wide dynamic range. The application of the electron trapping materials to parallel incoherent image subtraction is described in detail, and experimental results are presented.

Use of electron trapping materials in optical signal processing. 3: Modifiable Hopfield type neural networks.

Novel electron trapping materials are capable of performing optical formation of an interconnection matrix based on the Hopfield prescribed learning rule. The matrix is further modifiable when a memory is changed or added. An association is performed using the optically formed matrix. In addition, the construction of single liquid crystal display XOR and XNOR gates for the matrix formulation is described. The XOR operation of an electroluminescent lamp is demonstrated.

Use of electron trapping materials in optical signal processing. 2: two-dimensional associative memory.

The application of electron trapping materials to new optical architectures of associative memory based on space- and Fourier-domain inner products is described. Experimental results are presented.

Illumination-independent high-efficiency joint transform correlator.

A novel polarization-encoded two-channel joint transform correlator is described that can produce unity interference modulation, independent of the illumination of the target and the reference.

Use of electron trapping materials in optical signal processing. 1: Parallel Boolean logic.

Novel electron trapping materials capable of performing optical parallel Boolean logic operations are described. An application to binary full addition based on a parallel algorithm is discussed, and experimental results are presented.

Architecture for a ternary phase only processor using amplitude filters.

A novel technique is described to construct a ternary phase only filter using two binary amplitude filters.

Incoherent optical interconnects (perfect shuffle) based on shadow casting.

A simple method for an incoherent optical reconfigurable interconnection using shadow casting is presented. The implementation for perfect shuffle is discussed.

Noncoded shadow-casting logic array.

A new method is proposed to overcome the encoding problem that plagues optical shadow-casting logic processors.