Lipid nanoparticles decorated with TNF-related aptosis-inducing ligand (TRAIL) are more cytotoxic than soluble recombinant TRAIL in sarcoma

Sarcomas are rare and heterogeneous cancers classically associated with a poor outcome. Sarcomas are 1% of the cancer but recent estimations indicate that sarcomas account for 2% of the estimated cancer-related deaths. Traditional treatment with surgery, radiotherapy, and chemotherapy has improved the outcome for some types of sarcomas. However, novel therapeutic strategies to treat sarcomas are necessary. TNF-related apoptosis-inducing ligand (TRAIL) is a death ligand initially described as capable of inducing apoptosis on tumor cell while sparing normal cells. Only few clinical trials have used TRAIL-based treatments in sarcoma, but they show only low or moderate efficacy of TRAIL. Consequently, novel TRAIL formulations with an improved TRAIL bioactivity are necessary. Our group has developed a novel TRAIL formulation based on tethering this death ligand on a lipid nanoparticle surface (LUV-TRAIL) resembling the physiological secretion of TRAIL as a trasmembrane protein inserted into the membrane of exosomes. We have already demonstrated that LUV-TRAIL shows an improved cytotoxic activity when compared to soluble recombinant TRAIL both in hematological malignancies and epithelial-derived cancers. In the present study, we have tested LUV-TRAIL in several human sarcoma tumor cell lines with different sensitivity to soluble recombinant TRAIL, finding that LUV-TRAIL was more efficient than soluble recombinant TRAIL. Moreover, combined treatment of LUV-TRAIL with distinct drugs proved to be especially effective, sensitizing even more resistant cell lines to TRAIL

Non-universal soft scalar masses in supersymmetric theories

The existence of non--universal soft masses is the most general situation in supersymmetric theories. We study the consecuences that this situation has for the low--energy sparticle spectrum. In particular, we analize in detail the contribution to the scalar mass renormalization group equations of the $U(1)_Y$ D--term. We obtain analytic expressions for the evolution of masses of the three generations and these allow us to show that such a contribution can produce important modifications on the spectrum. The necessity to avoid flavour changing neutral currents does not constrain this result. Finally, we discuss a realistic example in the context of string theory where the departure from universality is large.Comment: Latex, 13 pages + 3 figs.(avalaible upon request

Comparative proteomics of exosomes secreted by tumoral jurkat t cells and normal human t cell blasts unravels a potential tumorigenic role for valosin-containing protein

We have previously characterized that FasL and Apo2L/TRAIL are stored in their bioactive form inside human T cell blasts in intraluminal vesicles present in multivesicular bodies. These vesicles are rapidly released to the supernatant in the form of exosomes upon re-activation of T cells. In this study we have compared for the first time proteomics of exosomes produced by normal human T cell blasts with those produced by tumoral Jurkat cells, with the objective of identify proteins associated with tumoral exosomes that could have a previously unrecognized role in malignancy. We have identified 359 and 418 proteins in exosomes from T cell blasts and Jurkat cells, respectively. Interestingly, only 145 (around a 40%) are common. The major proteins in both cases are actin and tubulin isoforms and the common interaction nodes correspond to these cytoskeleton and related proteins, as well as to ribosomal and mRNA granule proteins. We detected 14 membrane proteins that were especially enriched in exosomes from Jurkat cells as compared with T cell blasts. The most abundant of these proteins was valosin-containing protein (VCP), a membrane ATPase involved in ER homeostasis and ubiquitination. In this work, we also show that leukemic cells are more sensitive to cell death induced by the VCP inhibitor DBeQ than normal T cells. Furthermore, VCP inhibition prevents functional exosome secretion only in Jurkat cells, but not in T cell blasts. These results suggest VCP targeting as a new selective pathway to exploit in cancer treatment to prevent tumoral exosome secretion

Strong Constraints on the Parameter Space of the MSSM from Charge and Color Breaking Minima

A complete analysis of all the potentially dangerous directions in the field-space of the minimal supersymmetric standard model is carried out. They are of two types, the ones associated with the existence of charge and color breaking minima in the potential deeper than the realistic minimum and the directions in the field-space along which the potential becomes unbounded from below. The corresponding new constraints on the parameter space are given in an analytic form, representing a set of necessary and sufficient conditions to avoid dangerous directions. They are very strong and, in fact, there are extensive regions in the parameter space that become forbidden. This produces important bounds, not only on the value of $A$, but also on the values of $B$ and $M_{1/2}$. Finally, the crucial issue of the one-loop corrections to the scalar potential has been taken into account in a proper way.Comment: 48 pages, LaTeX, 12 uuencoded postscript figures in additional file. Only a small comment about the m=0 (no-scale) limit has been included in sect.6 (Results) and sect.7 (Conclusions

High-order TRAIL oligomer formation in TRAIL-coated lipid nanoparticles enhances DR5 cross-linking and increases antitumour effect against colon cancer

During the last years, a great effort has been invested into developing new TRAIL formulations with increased bioactivity, trying to overcome the resistance to conventional soluble TRAIL (sTRAIL) exhibited by many primary tumours. In our group, we have generated artificial lipid nanoparticles decorated with sTRAIL (LUV-TRAIL), emulating the physiological TRAIL-containing exosomes by which T-cells release TRAIL upon activation. We already demonstrated that LUV-TRAIL has greater cytotoxicity against both chemoresistant haematologic tumour cells and epithelial carcinoma cells compared to a form of sTRAIL similar to that used in clinical trials. In this study we have tested LUV-TRAIL in several human colon cancer cell lines with different sensitivity to sTRAIL. LUV-TRAIL significantly improved sTRAIL cytotoxicity in all colon cancer cell lines tested. Trying to ascertain the molecular mechanism by which LUV-TRAIL exhibited improved cytotoxicity, we demonstrated that TRAIL-coated lipid nanoparticles were able to activate DR5 more efficiently than sTRAIL, and this relied on LUV-TRAIL ability to promote DR5 clustering on the cell surface. Moreover, we show that TRAIL molecules are arranged in higher order oligomers only in LUV-TRAIL, which may explain their enhanced DR5 clustering ability. Finally, LUV-TRAIL showed significantly better antitumour activity than sTRAIL in an in vivo model using HCT-116 xenograft tumours in nude mice, validating its potential clinical application

Flavour changing neutral currents and CP violating processes in generalized supersymmetric theories

We consider supersymmetric extensions of the standard model with general non-universal soft breaking terms. We analyse in a model-independent way the constraints on these terms at the electroweak energy scale coming from gluino mediated flavour (F) changing neutral current and CP-violating processes. We have computed the complete $\Delta F=1$ and $\Delta F=2$ effective hamiltonian for gluino mediated processes, including for the first time the effect of box diagrams in the evaluation of $\epsilon^{\prime}/\epsilon$. We present numerical results for the constraints on these non-universal soft breaking terms for different values of the parameters, extending the analysis also to the leptonic sector. A comparison with previous results in the literature is given.Comment: LaTeX, 17 pages, 3 uuencoded figure

Muon anomalous magnetic dipole moment in supersymmetric theories

We study the muon anomalous magnetic dipole moment in supersymmetric theories. The impact of the recent Brookhaven E821 experimental measurement on both model-independent and model-dependent supersymmetric parameter spaces is discussed in detail. We find that values of tan\beta as low as 3 can be obtained while remaining within the E821 one-sigma bound. This requires a light smuon; however, we show that, somewhat surprisingly, no model-independent bound can be placed on the mass of the lightest chargino for any tan\beta greater than or equal to 3. We also show that the maximum contributions to the anomalous magnetic moment are insensitive to CP-violating phases. We provide analyses of the supersymmetric contribution to the muon anomalous magnetic moment in dilaton-dominated supergravity models and gauge-mediated supersymmetry-breaking models. Finally, we discuss how other phenomena, such as $B(b\to s\gamma)$, relic abundance of the lightest superpartner, and the Higgs mass may be correlated with the anomalous magnetic moment, but do not significantly impact the viability of a supersymmetric explanation, or the mass limits obtainable on smuons and charginos.Comment: 28 page

Relaxed fine-tuning in models with non-universal gaugino masses

We study, in a bottom-up approach, the fine-tuning problem between soft SUSY breaking parameters and the $\mu$-term for the successful electroweak symmetry breaking in the minimal supersymmetric standard model. It is shown that certain nontrivial ratios between gaugino masses, that is non-universal gaugino masses, are necessary at the GUT scale, in order for the fine-tuning to be reduced above 10 % order. In addition, when all the gaugino masses should be regarded as independent ones in their origins, a small gluino mass $M_3 \lesssim 120$ GeV and a non-vanishing $A$-term $A_t \sim O(M_3)$ associated to top squarks are also required at the GUT scale as well as the non-universality. On the other hand, when we consider some UV theory, which fixes ratios of soft SUSY breaking parameters as certain values with the overall magnitude, heavier spectra are allowed. It is favored that the gluino and wino masses are almost degenerate at the weak scale, while wider region of bino mass is favorable.Comment: 17 pages, 29 figure

Flavor changing neutral current constraints on standard-like orbifold models

We examine for standard-like orbifold compactification models the constraints due to quarks and leptons generation non-universality of soft supersymmetry breaking interactions. We follow the approach initiated by Ibanez and Lust and developed by Brignole, Ibanez and Munoz. The breaking of supersymmetry is represented in terms of dilaton and moduli auxiliary field components and, consistently with a vanishing cosmological constant, is parametrized in terms of the dilaton-moduli mixing angle $\theta$ and the gravitino mass scale $m_g$. The soft breaking interactions (gaugino masses, squarks and sleptons mass matrices, scalars interactions A and B coupling constants) are calculable as a function of these parameters and of the discrete set of modular weight parameters specifying the modular transformation properties of the low-energy fields. We solve the renormalization group one-loop equations for the full set of gauge, Yukawa and supersymmetry breaking coupling constants.Comment: 32 page