Functionalized nanoparticles targeting tumor-associated macrophages as cancer therapy

The tumor microenvironment (TME) plays a central role in regulating antitumor immune responses. As an important part of the TME, alternatively activated type 2 (M2) macrophages drive the development of primary and secondary tumors by promoting tumor cell proliferation, tumor angiogenesis, extracellular matrix remodeling and overall immunosuppression. Immunotherapy approaches targeting tumor-associated macrophages (TAMs) in order to reduce the immunosuppressive state in the TME have received great attention. Although these methods hold great potential for the treatment of several cancers, they also face some limitations, such as the fast degradation rate of drugs and drug-induced cytotoxicity of organs and tissues. Nanomedicine formulations that prevent TAM signaling and recruitment to the TME or deplete M2 TAMs to reduce tumor growth and metastasis represent encouraging novel strategies in cancer therapy. They allow the specific delivery of antitumor drugs to the tumor area, thereby reducing side effects associated with systemic application. In this review, we give an overview of TAM biology and the current state of nanomedicines that target M2 macrophages in the course of cancer immunotherapy, with a specific focus on nanoparticles (NPs). We summarize how different types of NPs target M2 TAMs, and how the physicochemical properties of NPs (size, shape, charge and targeting ligands) influence NP uptake by TAMs in vitro and in vivo in the TME. Furthermore, we provide a comparative analysis of passive and active NP-based TAM-targeting strategies and discuss their therapeutic potential.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Nanocarriers as a tool for the treatment of colorectal cancer

Experimentele farmacotherapi

Ceramide and palmitic acid inhibit macrophage-mediated epithelial-mesenchymal transition in colorectal cancer

Accumulating evidence indicates that ceramide (Cer) and palmitic acid (PA) possess the ability to modulate switching of macrophage phenotypes and possess anti-tumorigenic effects; however, the underlying molecular mechanisms are largely unknown. The aim of the present study was to investigate whether Cer and PA could induce switching of macrophage polarization from the tumorigenic M2- towards the pro-inflammatory M1-phenotype, and whether this consequently altered the potential of colorectal cancer cells to undergo epithelial-mesenchymal transition (EMT), a hallmark of tumor progression. Our study showed that Cer- and PA-treated macrophages increased expression of the macrophage 1 (M1)-marker CD68 and secretion of IL-12 and attenuated expression of the macrophage 2 (M2)-marker CD163 and IL-10 secretion. Moreover, Cer and PA abolished M2 macrophage-induced EMT and migration of colorectal cancer cells. At the molecular level, this coincided with inhibition of SNAI1 and vimentin expression and upregulation of E-cadherin. Furthermore, Cer and PA attenuated expression levels of IL-10 in colorectal cancer cells co-cultured with M2 macrophages and downregulated STAT3 and NF-kappa B expression. For the first time, our findings suggest the presence of an IL-10-STAT3-NF-kappa B signaling axis in colorectal cancer cells co-cultured with M2 macrophages, mimicking the tumor microenvironment. Importantly, PA and Cer were powerful inhibitors of this signaling axis and, consequently, EMT of colorectal cancer cells. These results contribute to our understanding of the immunological mechanisms that underlie the anti-tumorigenic effects of lipids for future combination with drugs in the therapy of colorectal carcinoma.Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Ceramide and palmitic acid inhibit macrophage-mediated epithelial-mesenchymal transition in colorectal cancer (vol 468, pg 153, 2020)

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas

Using data mining algorithms to predict the bond strength of NSM FRP systems in concrete

This paper presents the effectiveness of soft computing algorithms in analyzing the bond behavior of fiber reinforced polymer (FRP) systems inserted in the cover of concrete elements, commonly known as the near-surface mounted (NSM) technique. It focuses on the use of Data Mining (DM) algorithms as an alternative to the existing guidelines’ models to predict the bond strength of NSM FRP systems. To ease and spread the use of DM algorithms, a web-based tool is presented. This tool was developed to allow an easy use of the DM prediction models presented in this work, where the user simply provides the values of the input variables, the same as those used by the guidelines, in order to get the predictions. The results presented herein show that the DM based models are robust and more accurate than the guidelines’ models and can be considered as a relevant alternative to those analytical methods

Benzene with Alkyl Chains Is a Universal Scaffold for Multivalent Virucidal Antivirals.

Most viruses start their invasion by binding to glycoproteins' moieties on the cell surface (heparan sulfate proteoglycans [HSPG] or sialic acid [SA]). Antivirals mimicking these moieties multivalently are known as broad-spectrum multivalent entry inhibitors (MEI). Due to their reversible mechanism, efficacy is lost when concentrations fall below an inhibitory threshold. To overcome this limitation, we modify MEIs with hydrophobic arms rendering the inhibitory mechanism irreversible, i.e., preventing the efficacy loss upon dilution. However, all our HSPG-mimicking MEIs only showed reversible inhibition against HSPG-binding SARS-CoV-2. Here, we present a systematic investigation of a series of small molecules, all containing a core and multiple hydrophobic arms terminated with HSPG-mimicking moieties. We identify the ones that have irreversible inhibition against all viruses including SARS-CoV-2 and discuss their design principles. We show efficacy in vivo against SARS-CoV-2 in a Syrian hamster model through both intranasal instillation and aerosol inhalation in a therapeutic setting (12 h postinfection). We also show the utility of the presented design rules in producing SA-mimicking MEIs with irreversible inhibition against SA-binding influenza viruses

Flavor changing single top quark production channels at e^+e^- colliders in the effective Lagrangian description

We perform a global analysis of the sensitivity of LEP2 and e^+e^- colliders with a c.m. energy in the range 500 - 2000 GeV to new flavor-changing single top quark production in the effective Lagrangian approach. The processes considered are sensitive to new flavor-changing effective vertices such as Ztc, htc, four-Fermi tcee contact terms as well as a right-handed Wtb coupling. We show that e^+ e^- colliders are most sensitive to the physics responsible for the contact tcee vertices. For example, it is found that the recent data from the 189 GeV LEP2 run can be used to rule out any new flavor physics that can generate these four-Fermi operators up to energy scales of \Lambda > 0.7 - 1.4 TeV, depending on the type of the four-Fermi interaction. We also show that a corresponding limit of \Lambda > 1.3 - 2.5 and \Lambda > 17 - 27 TeV can be reached at the future 200 GeV LEP2 run and a 1000 GeV e^+e^- collider, respectively. We note that these limits are much stronger than the typical limits which can be placed on flavor diagonal four-Fermi couplings. Similar results hold for \mu^+\mu^- colliders and for tu(bar) associated production. Finally we briefly comment on the necessity of measuring all flavor-changing effective vertices as they can be produced by different types of heavy physics.Comment: 34 pages, plain latex, 7 figures embadded in the text using epsfig. Added new references and discussions regarding their relevance to the paper. Added more comments on the comparison between flavor-changing and flavor-diagonal contact terms and on the importance of measuring the Ztc verte

Apoptosis in human liver carcinoma caused by gold nanoparticles in combination with carvedilol is mediated via modulation of MAPK/Akt/mTOR pathway and EGFR/FAAD proteins

Imaging- and therapeutic targets in neoplastic and musculoskeletal inflammatory diseas