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Brentuximab vedotin (BV) shows a high overall response rate (ORR) in relapsed/refractory (R/R) Hodgkin lymphoma (HL) after autologous transplant (ASCT). The aim of this multicenter study, conducted in nine Hematology Departments of Rete Ematologica Pugliese, was to retrospectively evaluate the efficacy and safety of BV as salvage therapy and as bridge regimen to ASCT or allogeneic transplant (alloSCT) in R/R HL patients. Seventy patients received BV. Forty-five patients (64%) were treated with BV as bridge to transplant:16 (23%) patients as bridge to ASCT and 29 (41%) as bridge to alloSCT. Twenty-five patients (36%), not eligible for transplant, received BV as salvage treatment. The ORR was 59% (CR 26%). The ORR in transplant naive patients was 75% (CR 31%). In patients treated with BV as bridge to alloSCT, the ORR was 62% (CR 24%). In a multivariate analysis, the ORR was lower in refractory patients (p

Inflammation plays a key role in the pathogenesis of several chronic diseases. The urokinase plasminogen activator receptor (uPAR) exerts a plethora of functions in both physiological and pathological processes, including inflammation. In this study, we evaluated the anti-inflammatory effect of a novel peptide ligand of uPAR, UPARANT, in different animal models of inflammation. Rats and mice were divided in different groups (n = 5) for single or repeated administration of vehicle (9% DMSO in 0.9% NaCl), UPARANT (6, 12 and 24 mg/kg) or dexamethasone (2 mg/kg). Animals were subjected to carrageenan-induced paw oedema or zymosan-induced peritonitis. UPARANT effects were tested on: (1) the carrageenan-induced paw oedema volume, (2) the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and the nitrite/nitrate (NOx) levels in the paw exudates, (3) cells recruitment into the peritoneal cavity after zymosan injection and (4) NOx levels in the peritoneal lavage. UPARANT (12 and 24 mg/kg) reduced inflammation in both experimental paradigms. Analysis of pro-inflammatory enzymes revealed that administration of UPARANT reduced iNOS, COX2 and NO over-production. Our study provides a solid evidence that UPARANT reduces the severity of inflammation in diverse animal models, thus representing a novel anti-inflammatory drug with potential advantages with respect to the typical steroidal agents.

Cationic antimicrobial peptides (CAMPs) are a promising alternative to treat multidrug-resistant bacteria, which have developed resistance to all the commonly used antimicrobial, and therefore represent a serious threat to human health. One of the major drawbacks of CAMPs is their sensitivity to proteases, which drastically limits their half-life. Here we describe the design and synthesis of three nine-residue CAMPs, which showed high stability in serum and broad spectrum antimicrobial activity. As for all peptides a very low selectivity between bacterial and eukaryotic cells was observed, we performed a detailed biophysical characterization of the interaction of one of these peptides with liposomes mimicking bacterial and eukaryotic membranes. Our results show a surface binding on the DPPC/DPPG vesicles, coupled with lipid domain formation, and, above a threshold concentration, a deep insertion into the bilayer hydrophobic core. On the contrary, mainly surface binding of the peptide on the DPPC bilayer was observed. These observed differences in the peptide interaction with the two model membranes suggest a divergence in the mechanisms responsible for the antimicrobial activity and for the observed high toxicity toward mammalian cell lines. These results could represent an important contribution to unravel some open and unresolved issues in the development of synthetic CAMPs.

Whilst there is an ever-growing literature on the economic and political aspects of ‘globalization,’ at present there are few studies analyzing how intergovernmental organizations have reacted to this phenomenon. This article aims to fill this gap by analyzing the response to globalization of UNESCO, one of the least studied organizations of the UN constellation. Addressing the global orientation of some of the current programs, this article shows how a recent re-evaluation of scientific humanism—the main philosophical framework contributing to the creation of UNESCO—has influenced both UNESCO’s self-understanding and its understanding of globalization. Scientific humanism is a philosophical utopia that couples the advance of scientific knowledge with the diffusion of a common philosophical framework and promotes a universal system of education in order to establish a global community. Based on the philosophical appeal of a culture of peace based on science, humanism and human rights, UNESCO’s representation of globalization represents an intriguing example of how our global future may be conceived and, to some extent, realized.

Haemopoietic stem cell therapy is an increasingly adopted procedure in the treatment of patients with malignant lymphoma. In this retrospective analysis, we evaluated 262 patients, 57 (22%) with Hodgkin's and 205 (78%) with non-Hodgkin's lymphomas (NHL), and 665 harvesting procedures in order to assess the impact of poor mobilization on survival and to determine the factors that may be predictive of CD34(+) poor mobilization. The mobilization chemotherapy regimens consisted of high-dose cyclophosphamide in 92 patients (35.1%) and a high-dose cytarabine-containing regimen (DHAP in 87 patients -(33.2%), MAD in 83 (31.7%)). The incidence of poor mobilizers (2 x 10(6) CD34(+) cells/kg) was 17.9% overall, with a 10% of very poor mobilizers (or = 1 x 10(6)/kg). Refractory disease status and chemotherapeutic load (3 regimens) before mobilization played a negative role and were associated with poor mobilization. Survival analysis of all harvested patients showed an overall survival at 3 years of 71% in good mobilizers vs 33% in poor mobilizers (P=0.002). The event-free survival at 3 years was 23% in poor mobilizers and 58% in good mobilizers (P=0.04). We conclude that in NHL patients, poor mobilization status is predictive of survival.

Our study analyzes the mobilization of hematopoietic stem cells after two chemotherapeutic regimens in non-Hodgkin's lymphoma (NHL) patients. The study included 72 patients with NHL (42 follicular and 30 large cells). The mean age was 37 years (range 17-60). Sixty-four patients (88.9%) had stage III-IV disease. Forty-eight patients (66.7%) had bone marrow involvement. Systemic B symptoms were present in 42 patients (58.3%). Mobilization chemotherapy regimens were randomly assigned as DHAP in 38 patients (52.7%) or cyclophosphamide (CPM) (5 g/m(2)) in 34 (47.2%) and the results of 132 procedures were analyzed. At the time of PBSC mobilization, 46 patients (63.9%) were considered to be responsive (complete remission, partial remission or sensitive relapse) and 26 (36.1%) not responsive (refractory relapse or refractory to therapy). Pre-apheresis CD34+ blood cell count and number of previous chemotherapy treatments were used to predict the total number of CD34+ cells in the apheresis product. The mobilizing regimens (CPM or DHAP) were similar in achieving the threshold CD34+ cell yield, for optimal engraftment. Since DHAP was very effective as salvage treatment, we suggest using DHAP as a mobilizing regimen in patients with active residual lymphoma at the time of stem cell collection.

Certain chemokines act as natural antagonists of human immunodeficiency virus (HIV) by blocking key viral coreceptors, such as CCR5 and CXCR4, on the surface of susceptible cells. Elucidating the structural determinants of the receptor-binding and HIV-inhibitory functions of these chemokines is essential for the rational design of derivative molecules of therapeutic value. Here, we identify the structural determinants of CCR5 recognition and antiviral activity of the CC chemokine RANTES, showing that critical residues form a solvent-exposed hydrophobic patch on the surface of the molecule. Moreover, we demonstrate that the biological function is critically dependent on dimerization, resulting in the exposure of a large ( approximately 180 A2), continuous hydrophobic surface. Relevant to the development of novel therapeutic approaches, we designed a retroinverted RANTES peptide mimetic that maintained both HIV- and chemotaxis-antagonistic functions.

Purpose: Over the past twenty years, GMOs have raised enormous expectations, passionate political controversies, and an on-going debate on how should these technologies be assessed. Current risk-assessment procedures generally assess GMOs in terms of their potential risk of negatively affecting human health and the environment. Yet, is this risk-benefit approach appropriate to a deliver a robust assessment of GMOs? In this paper, we question the validity of current risk-assessment from both a social and an ecological perspective, and we elaborate an alternative approach, namely in-context trajectory evaluation Methods: This paper combines frame analysis, context analysis and eco-social analysis to three different case studies. Results: Applying frame analysis to Syngenta´s recent campaign “Bring plant potential to life”, we first de-construct the techno-social imaginaries driving GMOs innovation, showing how the latter endorses the technological fix of socio-economic problems while reinforcing the neoliberal socio-political paradigm. Applying context analysis to biopharming in New Zealand, we then explore local practices, rules and formal and informal procedures, showing that to assess how safe is a technology it is necessary to address how “safe” is the context. Finally, drawing from the Italian case, we outline through eco-social analysis how the lack of long-term studies, further aggravated by current methodological deficiencies, prevent risk-assessment from considering not only how GMOs affect the environmental context but also, and most importantly, the way people live in, and interact with, this context. Conclusions: Whilst it emerges that there might be a number of socio-political reasons to support a moratorium on GMOs in Europe even if they come to be considered technically safe, these results suggest that the integration of in-context trajectory evaluation with traditional risk assessment procedures may help promoting social compatibility, political accountability and ecological sustainability.

A synthetic, terminally blocked homohexapeptide fromα-aminoisobutyric acid has been examined by single-crystal X-ray diffraction and the structure refined toR = 0.047. The compound is folded into almost two turns of a 310-helix, stabilized by four consecutive intramolecular N—H⋯·O=C H-bonds. An asymmetric covalent geometry for theα-aminoisobutyric acid residues, known to be responsible for the onset of the 310-helix in homopeptides from this Cα,α-dialkylatedα-aminoacid on the basis of a theoretrical conformational analysis, has been experimentally found also in this structure.

We previously identified the major structural determinants of CCR5 binding and HIV blockade in RANTES, describing linear RANTES-derived peptides with biological activity in the low micromolar range (Nardese et al., 2001). To deepen our understanding of RANTES structure-function relations and obtain more potent antiviral peptido-mimetics, we have extensively mutagenized the prototypic peptide, R11-29. This presents two clusters of hydrophobic residues at its termini, (corresponding to RANTES N-loop and b1-strand) connected by a positivelycharged linker. Single or multiple alanine substitutions within the Nor C-terminal hydrophobic clusters resulted in a dramatic loss of antiviral activity, whereas deletion of selected residues within the hydrophilic linker had no major functional consequences. Based on RANTES 3D structure, we designed a series of modified peptides, resulting in a progressive increase in specific antiviral activity. These peptides also displayed anti-inflammatory properties blocking RANTES-elicited lymphocyte chemotaxis. Through serial passages in culture in the presence of increasing concentrations of the most effective antiviral peptides, we have derived variants of the R5 HIV-1 isolate BaL resistant to the peptide inhibitory activity. Complete sequencing of the envelope genes from such variants is currently underway. Our results provide new insights into the structure of the receptor-binding region of RANTES and identify new antiviral peptides that may be instrumental in the development of effective HIV-1 entry inhibitors. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005

The objective of this study was to make a contribution to the debate on the cause-effect relationship between low-dose exposure to benzene and onset of hemopathies. We report the case of a coke plant worker suffering from aplastic anemia. Before being hired at the coke plant, he underwent a medical examination including a blood cell count: no disease or abnormalities of the blood crasis were found. For 3 years the patient was then exposed to gas containing-as measured in environmental investigation carried out at the coke plant-concentrations of benzene lower than TLV-TWA ACGIH (measured values 21-109 micrograms/m3). In the absence from the patient's history of any exposure to other myelotoxic agents and of any earlier pathology causing aplastic anemia, we assume there is a relationship between exposure to low levels of benzene and onset of the disease. However, it is very important to consider that exposure to low levels of benzene could promote myelotoxic reactions when the working environment contains other substances that may act synergistically or compete for the same metabolism sites, or when carcinogenic substances are present in the working environment.

Conformational energy computations of the monopeptides from three achiral α,α-dialkylated glycyl residues with acyclic side chains (namely α,α-dimethyl-; α,α-diethyl-; and α, α-di-n-propylglycines) are reported as a function of the relevant N-Cα-C′ bond angle. In parallel, experimental studies were performed in the solid state (infrared absorption and X-ray diffraction) and in solution (infrared absorption and proton magnetic resonance) on the corresponding protected homo-peptide series (the former series to the dodecamer, the other two series to the pentamers). The results obtained unequivocally indicate that the preference from a helical to a fully extended conformation increases as side-chain bulkiness increases. The longest homo-peptides from α,α-dimethylglycine form stable 310-helices. A picture of the mode of self-association of the helical structures has also been determined. The results of the theoretical analyses fit well with the experimentally observed conformational properties in the solid state and in chloroform solution.

Peptides from wheat gliadins, A-gliadin and prolamins from cereals toxic for coeliac patients agglutinate K 562(5) cells; they also damage in vitro cultured fetal rat intestine and atrophic coeliac mucosa. The largest common sequences among the in vitro active A-gliadin peptides were -Pro-Ser-Gln-Gln and -(Gln)3-Pro-. The following peptides all containing the aminoacid sequence -(Gln)3-Pro have been synthesized: the pentapeptide Tyr-(Gln)3-Pro, its dimer and tetramer and the epta-peptide Gln-Pro-Tyr-(Gln)3-Pro in their free and N-acetylated forms and the Pyro-glutamic derivate of the heptapeptide (Pyr 7). Pyr 7 agglutinated cells and inhibited the in vitro development of fetal rat intestine (medium's concentration 0.5-2 mg/ml); it was non toxic on the in vitro cultured coeliac atrophic mucosa. The N-acetylated form of the pentapeptide's tetramer (1 mg/ml) also damaged the atrophic coeliac mucosa in 3 cultured biopsies. These results suggest that the sequence -(Gln)3-Pro when part of a larger peptide may be toxic in vitro for the atrophic coeliac mucosa.

Peptides from wheat gliadlns, A-gliadin and prolamins from cereals toxic for coeliac patients agglutinate K 562(S) cells; they also damage in vitro cultured fetal rat intestine and atrophic coeliac mucosa. The largest common sequences among the in vitro active A-gliadin peptides were -Pro-Ser-Gln-Gln-and -(Gln)3 -Pro-. The following peptides all containing the aminoacid sequence -(Gln)3-Pro have been synthesized: the pentapeptide Tyr-(Gln) -Pro, its dimer and tetramer and the eptapeptide Gln-Pro-Tyr-(Gln)3-Pro in their free and N-acetylated forms and the Pyroglutamic derivate of the heptapeptlde (Pyr7). Pyr 7 agglutinated cells and inhibited the in vitro development of fetal rat intestine (medium's concentration 0.5-2mg/ml);it was non toxic on the in vitro cultured coeliac atrophic mucosa. The N-acetylated form of the pentapeptide's tetramer (1mg/ml) also damaged the atrophic coeliac mucosa in 4 cultured biopsies. These results suggest that the sequence -(Gln)3-Pro when part of a larger peptide may be toxic in vitro for the atrophic coeliac mucosa.