Although cytokine therapy is an attractive strategy to build a more robust immune response in tumors, cytokines have faced clinical failures due to toxicity. In particular, interleukin-12 has shown ...great clinical promise but was limited in translation because of systemic toxicity. In this study, we demonstrate an enhanced ability to reduce toxicity without affecting the efficacy of IL-12 therapy. We engineer the material properties of a NP to meet the enhanced demands for optimal cytokine delivery by using the layer-by-layer (LbL) approach. Importantly, using LbL, we demonstrate cell-level trafficking of NPs to preferentially localize to the cell’s outer surface and act as a drug depot, which is required for optimal payload activity on neighboring cytokine membrane receptors. LbL-NPs showed efficacy against a tumor challenge in both colorectal and ovarian tumors at doses that were not tolerated when administered carrier-free.
Ovarian cancer is especially deadly, challenging to treat, and has proven refractory to known immunotherapies. Cytokine therapy is an attractive strategy to drive a proinflammatory immune response in ...immunologically cold tumors such as many high grade ovarian cancers; however, this strategy has been limited in the past due to severe toxicity. We previously demonstrated the use of a layer‐by‐layer (LbL) nanoparticle (NP) delivery vehicle in subcutaneous flank tumors to reduce the toxicity of interleukin‐12 (IL‐12) therapy upon intratumoral injection. However, ovarian cancer cannot be treated by local injection as it presents as dispersed metastases. Herein, we demonstrate the use of systemically delivered LbL NPs using a cancer cell membrane‐binding outer layer to effectively target and engage the adaptive immune system as a treatment in multiple orthotopic ovarian tumor models, including immunologically cold tumors. IL‐12 therapy from systemically delivered LbL NPs shows reduced severe toxicity and maintained anti‐tumor efficacy compared to carrier‐free IL‐12 or layer‐free liposomal NPs leading to a 30% complete survival rate.
Nanoparticle surface chemistry is a fundamental engineering parameter that governs tumor-targeting activity. Electrostatic assembly generates controlled polyelectrolyte complexes through the process ...of adsorption and charge overcompensation utilizing synthetic polyions and natural biomacromolecules; it can yield films with distinctive hydration, charge, and presentation of functional groups. Here, we used electrostatic layer-by-layer (LbL) assembly to screen 10 different surface chemistries for their ability to preferentially target human ovarian cancer in vitro. Our screen identified that poly-l-aspartate, poly-l-glutamate, and hyaluronate-coated LbL nanoparticles have striking specificity for ovarian cancer, while sulfated poly(β-cyclodextrin) nanoparticles target noncancerous stromal cells. We validated top candidates for tumor-homing ability with a murine model of metastatic disease and with patient-derived ovarian cancer spheroids. Nanoparticle surface chemistry also influenced subcellular trafficking, indicating strategies to target the cell membrane, caveolae, and perinuclear vesicles. Our results confirm LbL is a powerful tool to systematically engineer nanoparticles and achieve specific targeting.
We investigate the impact of energy released from self-annihilating dark matter (DM) on heating of gas in the small, high-redshift DM haloes thought to host the first stars. A supersymmetric ...(SUSY)-neutralino-like particle is implemented as our DM candidate. The pythia code is used to model the final, stable particle distributions produced during the annihilation process. We use an analytic treatment in conjunction with the code medea2 to find the energy transfer and subsequent partition into heating, ionizing and Lyman α photon components. We consider a number of halo density models, DM particle masses and annihilation channels. We find that the injected energy from DM exceeds the binding energy of the gas within a 105–106 M⊙ halo at redshifts above 20, preventing star formation in early haloes in which primordial gas would otherwise cool. Thus we find that DM annihilation could delay the formation of the first galaxies.
Psoriasis is sustained by pro-inflammatory CD4+ T helper cells mainly belonging to the Th1, Th17 and Th22 lineage.
To identify whether treatment with the anti-tumour-necrosis-factor antagonist ...etanercept is able to induce significant modulations in transcription factor and cytokine mRNA gene expressions related to the different T cell immune response polarization (Th1, Th2, Th17 and regulatory T cells, Treg and to correlate them with clinical response.
The study population included 19 psoriasis patients treated with etanercept and 19 healthy subjects. Blood samples were collected at baseline and every 4 weeks during treatment. Taqman quantitative real-time polymerase chain reaction was applied to analyse the expression of: Stat-4, T-bet, IL-12p35 and IFN-γ (Th1-related); GATA-3, IL-4 (Th2-related); Stat-3, RORγt, IL-23p19 (Th17-related); Foxp3, IL-2 (Treg-related). Flow cytometry was applied to analyse CD4+CD25+(bright)Foxp3+ cells in peripheral blood.
Upregulation of Th1 and Th17 and downregulation of Treg subsets was found at baseline. The response to etanercept could be associated with a significant reversal of the Th1/Th17 activation, and a concomitant upregulation of Th2 and Treg subsets.
Our data may contribute to a better understanding of the mechanisms underlying the achievement of clinical response in psoriasis and could be helpful for the identification of early predictive markers of response.
Equal amounts of matter and antimatter are predicted to have been produced in the Big Bang, but our observable Universe is clearly matter-dominated. One of the prerequisites for understanding this ...elimination of antimatter is the nonconservation of charge-parity (CP) symmetry. So far, two types of CP violation have been observed in the neutral K meson (K0) and B meson (B0) systems: CP violation involving the mixing between K0 and its antiparticle (and likewise for B0 and ), and direct CP violation in the decay of each meson. The observed effects for both types of CP violation are substantially larger for the B0 meson system. However, they are still consistent with the standard model of particle physics, which has a unique source of CP violation that is known to be too small to account for the matter-dominated Universe. Here we report that the direct CP violation in charged B±→K± 0 decay is different from that in the neutral B0 counterpart. The direct CP-violating decay rate asymmetry, (that is, the difference between the number of observed B-→K- 0 event versus B+→K+ 0 events, normalized to the sum of these events) is measured to be about +7%, with an uncertainty that is reduced by a factor of 1.7 from a previous measurement. However, the asymmetry for versus B0→K+ - is at the -10% level. Although it is susceptible to strong interaction effects that need further clarification, this large deviation in direct CP violation between charged and neutral B meson decays could be an indication of new sources of CP violation-which would help to explain the dominance of matter in the Universe.
Summary
Background Transformation of mycosis fungoides (T‐MF) occurs in 8–55% of MF patients. Its early histopathological diagnosis is of tremendous importance to better define the management and to ...establish the prognosis. Recent studies have demonstrated that advanced‐stage MF at diagnosis of transformation is the predominant risk factor of poor outcome. The 5‐year survival rates for stage IIB and IV MF are 26·9% and 10·6%, respectively. The prognostic value of the immunophenotypic characterization of the infiltrate has not been thoroughly studied in the literature.
Objectives To retrieve clinical, histological and immunophenotypic features of T‐MF in our patient population and analyse their prognostic value.
Patients and methods A register‐based retrospective study was performed including all patients with cutaneous T‐cell lymphoma (CTCL) registered in our two departments from January 2000 to December 2005. Among 208 patients with CTCL, 17 patients with proven transformation of their MF were studied. Clinical features and staging as well as immunophenotypic and pathological findings at the time of the initial diagnosis of MF and of the diagnosis of T‐MF were analysed.
Results Our results, in accordance with previously published material, indicate that the main clinical prognostic factor in T‐MF is the stage of the initial disease at the time of the transformation. Patients with stage IIB–IV MF have a poor prognosis. In our study, strong expression of CD30 is linked to a better prognosis.
Conclusions We believe that pathological and immunopathological documentation of progressive MF is important in order to identify T‐MF early; however, the differential diagnosis is sometimes difficult. Aside from already acknowledged prognostic factors such as older age, advanced initial disease and short delay to transformation, the CD30 immunophenotype could be regarded as a useful additional prognostic marker in T‐MF.
The SABRE project and the SABRE Proof-of-Principle Antonello, M.; Barberio, E.; Baroncelli, T. ...
The European physical journal. C, Particles and fields,
04/2019, Letnik:
79, Številka:
4
Journal Article
Recenzirano
Odprti dostop
SABRE aims to directly measure the annual modulation of the dark matter interaction rate with NaI(Tl) crystals. A modulation compatible with the standard hypothesis, in which our Galaxy is immersed ...in a dark matter halo, has been measured by the DAMA experiment in the same target material. Other direct detection experiments, using different target materials, seem to exclude the interpretation of such modulation in the simplest scenario of WIMP-nucleon elastic scattering. The SABRE experiment aims to carry out an independent search with sufficient sensitivity to confirm or refute the DAMA claim. The goal of the SABRE experiment is to achieve the lowest background rate for a NaI(Tl) experiment (order of 0.1 cpd/kg/keV
ee
in the energy region of interest for dark matter). This challenging goal could be achievable by operating high-purity crystals inside a liquid scintillator veto for active background rejection. In addition, twin detectors will be located in the northern and southern hemispheres to identify possible contributions to the modulation from seasonal or site-related effects. The SABRE project includes an initial Proof-of-Principle phase at LNGS (Italy), to assess the radio-purity of the crystals and the efficiency of the liquid scintillator veto. This paper describes the general concept of SABRE and the expected sensitivity to WIMP annual modulation.
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