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.
We present a measurement of angular observables and a test of lepton flavor universality in the B→K^{*}ℓ^{+}ℓ^{-} decay, where ℓ is either e or μ. The analysis is performed on a data sample ...corresponding to an integrated luminosity of 711 fb^{-1} containing 772×10^{6} BBover ¯ pairs, collected at the ϒ(4S) resonance with the Belle detector at the asymmetric-energy e^{+}e^{-} collider KEKB. The result is consistent with standard model (SM) expectations, where the largest discrepancy from a SM prediction is observed in the muon modes with a local significance of 2.6σ.
The H→ττ decays form a promising channel for tests of the CP invariance of Higgs boson couplings. A previous study has shown the viability of deep learning techniques for such a measurement. In this ...paper, the study is extended to consider potential sources of uncertainty. Effects due to the limited experimental resolution are discussed. Furthermore, systematics due to τ decay modeling for complex cascade decays to τ±→a1±ντ→ρ0π±ντ→3π±ντ are also addressed. Various parametrizations using low-energy collision data are considered.
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.
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.
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 report the first observation of the decay Λ_{c}^{+}→pK^{+}π^{-} using a 980 fb^{-1} data sample collected by the Belle detector at the KEKB asymmetric-energy e^{+}e^{-} collider. This is the ...first observation of a doubly Cabibbo-suppressed decay of a charmed baryon. We measure the branching ratio of this decay with respect to its Cabibbo-favored counterpart to be B(Λ_{c}^{+}→pK^{+}π^{-})/B(Λ_{c}^{+}→pK^{-}π^{+})=(2.35±0.27±0.21)×10^{-3}, where the uncertainties are statistical and systematic, respectively.
Abstract
We have performed measurements of sodium nuclear recoils in NaI:Tl crystals, following scattering by neutrons produced in a
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Li(p,n)
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Be reaction. Understanding the light output from such ...recoils, which is reduced relative to electrons of equivalent energy by the quenching factor, is critical to interpret dark matter experiments that search for nuclear scattering interactions. We have developed a spectrum-fitting methodology to extract the quenching factor from our measurements, and report quenching factors for nuclear recoil energies between 36 and 401 keV. Our results agree with other recent quenching factor measurements that use quasi-monoenergetic neutron sources. The new method will be applied in the future to the NaI:Tl crystals used in the SABRE experiment.
The direct detection of dark matter is a key problem in astroparticle physics that generally requires the use of deep-underground laboratories for a low-background environment where the rare signals ...from dark matter interactions can be observed. This work reports on the Stawell Underground Physics Laboratory – currently under construction and the first such laboratory in the Southern Hemisphere – and the associated research program. A particular focus will be given to ANU’s contribution to SABRE, a NaI:Tl dark matter, direct detection experiment that aims to confirm or refute the long-standing DAMA result. Preliminary measurements of the NaI:Tl quenching factor and characterisation of the SABRE liquid scintillator veto are reported.
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.
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