Pluronic polymer capped biocompatible mesoporous silica nanocarriers

A facile self-assembly method is described to prepare PEGylated silica nanocarriers using hydrophobic mesoporous silica nanoparticles and a pluronic F127 polymer. Pluronic capped nanocarriers revealed excellent dispersibility in biological media with cyto- and blood compatibilities. © 2013 The Royal Society of Chemistry

Design of a Gd-DOTA-Phthalocyanine Conjugate Combining MRI Contrast Imaging and Photosensitization Properties as a Potential Molecular Theranostic

Cataloged from PDF version of article.The design and synthesis of a phthalocyanine - Gd-DOTA conjugate is presented to open the way to novel molecular theranostics, combining the properties of MRI contrast imaging with photodynamic therapy. The rational design of the conjugate integrates isomeric purity of the phthalocyanine core substitution, suitable biocompatibility with the use of polyoxo water-solubilizing substituents, and a convergent synthetic strategy ended by the use of click chemistry to graft the Gd-DOTA moiety to the phthalocyanine. Photophysical and photochemical properties, contrast imaging experiments and preliminary in vitro investigations proved that such a combination is relevant and lead to a new type of potential theranostic agent

p53Psi is a transcriptionally inactive p53 isoform able to reprogram cells toward a metastatic-like state

Although much is known about the underlying mechanisms of p53 activity and regulation, the factors that influence the diversity and duration of p53 responses are not well understood. Here we describe a unique mode of p53 regulation involving alternative splicing of the TP53 gene. We found that the use of an alternative 3' splice site in intron 6 generates a unique p53 isoform, dubbed p53Psi. At the molecular level, p53Psi is unable to bind to DNA and does not transactivate canonical p53 target genes. However, like certain p53 gain-of-function mutants, p53Psi attenuates the expression of E-cadherin, induces expression of markers of the epithelial-mesenchymal transition, and enhances the motility and invasive capacity of cells through a unique mechanism involving the regulation of cyclophilin D activity, a component of the mitochondrial inner pore permeability. Hence, we propose that p53Psi encodes a separation-of-function isoform that, although lacking canonical p53 tumor suppressor/transcriptional activities, is able to induce a prometastatic program in a transcriptionally independent manner

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine: Brussels, Belgium. 15-18 March 2016.

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

VERITAS Search for VHE Gamma-ray Emission from Dwarf Spheroidal Galaxies

Indirect dark matter searches with ground-based gamma-ray observatories provide an alternative for identifying the particle nature of dark matter that is complementary to that of direct search or accelerator production experiments. We present the results of observations of the dwarf spheroidal galaxies Draco, Ursa Minor, Bootes 1, and Willman 1 conducted by VERITAS. These galaxies are nearby dark matter dominated objects located at a typical distance of several tens of kiloparsecs for which there are good measurements of the dark matter density profile from stellar velocity measurements. Since the conventional astrophysical background of very high energy gamma rays from these objects appears to be negligible, they are good targets to search for the secondary gamma-ray photons produced by interacting or decaying dark matter particles. No significant gamma-ray flux above 200 GeV was detected from these four dwarf galaxies for a typical exposure of ~20 hours. The 95% confidence upper limits on the integral gamma-ray flux are in the range 0.4-2.2x10^-12 photons cm^-2s^-1. We interpret this limiting flux in the context of pair annihilation of weakly interacting massive particles and derive constraints on the thermally averaged product of the total self-annihilation cross section and the relative velocity of the WIMPs. The limits are obtained under conservative assumptions regarding the dark matter distribution in dwarf galaxies and are approximately three orders of magnitude above the generic theoretical prediction for WIMPs in the minimal supersymmetric standard model framework. However significant uncertainty exists in the dark matter distribution as well as the neutralino cross sections which under favorable assumptions could further lower the limits.Comment: 21 pages, 2 figures, updated to reflect version published in ApJ. NOTE: M.D. Wood added as autho

Discovery of very high energy gamma rays from PKS 1424+240 and multiwavelength constraints on its redshift

We report the first detection of very-high-energy (VHE) gamma-ray emission above 140 GeV from PKS 1424+240, a BL Lac object with an unknown redshift. The photon spectrum above 140 GeV measured by VERITAS is well described by a power law with a photon index of 3.8 +- 0.5_stat +- 0.3_syst and a flux normalization at 200 GeV of (5.1 +- 0.9_stat +- 0.5_syst) x 10^{-11} TeV^-1 cm^-2 s^-1, where stat and syst denote the statistical and systematical uncertainty, respectively. The VHE flux is steady over the observation period between MJD 54881 and 55003 (2009 February 19 to June 21). Flux variability is also not observed in contemporaneous high energy observations with the Fermi Large Area Telescope (LAT). Contemporaneous X-ray and optical data were also obtained from the Swift XRT and MDM observatory, respectively. The broadband spectral energy distribution (SED) is well described by a one-zone synchrotron self-Compton (SSC) model favoring a redshift of less than 0.1. Using the photon index measured with Fermi in combination with recent extragalactic background light (EBL) absorption models it can be concluded from the VERITAS data that the redshift of PKS 1424+240 is less than 0.66.Comment: accepted for publication, Ap

Concurrent acute pancreatitis and pericardial effusion

While pleural effusion and ascites secondary to acute pancreatitis are common, clinically relevant pericardial effusion and cardiac tamponade are observed rarely. In a study by Pezzilli et al., pleural effusion was noted in 7 of the 21 patients with acute pancreatitis whereas the authors detected pericardial effusion development in only three. The authors asserted that pleural effusion was associated with severe acute pancreatitis, while pericardial effusion and the severity of acute pancreatitis were not significantly related

Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization

Objective: Lumican (LUM) is a major extracellular matrix glycoprotein in adult articular cartilage and its expression is known to be upregulated upon cartilage degeneration. LUM is associated with the pathogen-associated molecular pattern (PAMP) activation of the TLR4 signalling cascade, with TLR4 being highly associated with inflammation in rheumatic diseases. However, the main role of the LUM structural molecule in osteoarthritis (OA) remains elusive. The aim of this study was, therefore, to understand the role of LUM during TLR4-mediated activation in OA. Methods: After measuring LUM levels in synovial fluid (SF) of OA patients and lipopolysaccharide (LPS)-induced TLR4 activation, the role of LUM in the expression of pro-inflammatory molecules and cartilage degradation was assessed in vitro and ex vivo in a cartilage explant model. Primary macrophage activation and polarization were studied upon LUM co-stimulation with LPS. Results: We demonstrate that LUM is not only significantly upregulated in SF from OA patients compared to healthy controls, but also that LUM increases lipopolysaccharide (LPS)-induced TLR4 activation. Furthermore, we show that a pathophysiological level of LUM augments the LPS-induced TLR4 activation and expression of downstream pro-inflammatory molecules, resulting in extensive cartilage degradation. LUM co-stimulation with LPS also provided a pro-inflammatory stimulus, upregulating primary macrophage activation and polarization towards the M1-like phenotype. Conclusions: These findings strongly support the role of LUM as a mediator of PAMP-induced TLR4 activation of inflammation, cartilage degradation, and macrophage polarization in the OA joint and potentially other rheumatic diseases. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.Peer reviewe

Pancreatic cancer: Emerging field of regulatory B-cell-targeted immunotherapies

Pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer, is characterized by a high mortality rate and poor prognosis. Current treatments for PDAC, are ineffective due to a prominent immunosuppressive PDAC tumor microenvironment (TME). Although B lymphocytes are highly infiltrated into PDAC, the importance of B lymphocytes in tumorigenesis is largely neglected. B cells play a dual role in the PDAC tumor microenvironment, acting as either anti-tumorigenic or pro-tumorigenic depending on where they are localized. Tumor-infiltrating B cells, which reside in ectopic lymph nodes, namely tertiary lymphoid structures (TLS), produce anti-tumor antibodies and present tumor antigens to T cells to contribute to cancer immunosurveillance. Alternatively, regulatory B cells (Bregs), dispersed inside the TME, contribute to the dampening of anti-tumor immune responses by secreting anti-inflammatory cytokines (IL-10 and IL-35), which promote tumor growth and metastasis. Determining the role of Bregs in the PDAC microenvironment is thus becoming increasingly attractive for developing novel immunotherapeutic approaches. In this minireview, we shed light on the emerging role of B cells in PDAC development and progression, with an emphasis on regulatory B cells (Bregs). Furthermore, we discussed the potential link of Bregs to immunotherapies in PDAC. These current findings will help us in understanding the full potential of B cells in immunotherapy.ZS, IA, and BD acknowledges financial support by the The Scientific and Technological Research Council of Türkiye (TUBITAK- project no- 119S447)