Biocide effect against SARS-CoV-2 and ESKAPE pathogens of a noncytotoxic silver-copper nanofilm.

Nanometric materials with biocidal properties effective against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) and pathogenic bacteria could be used to modify surfaces, reducing the risk of touching transmission. In this work, we showed that a nanometric layer of bimetallic AgCu can be effectively deposited on polypropylene (PP) fibers. The virucidal properties of the AgCu nanofilm were evaluated by comparing the viral loads remaining on uncoated and coated PP after contact times between 2 and 24 h. Quantification of virion numbers for different initial concentrations indicated a reduction of more than 95% after 2 h of contact. The bactericidal action of the AgCu nanofilm was also confirmed by inoculating uncoated and coated PP with a pool of pathogenic bacteria associated with pneumonia (ESKAPE). Meanwhile, no cytotoxicity was observed for human fibroblasts and keratinocyte cells, indicating that the nanofilm could be in contact with human skin without threat. The deposition of the AgCu nanofilm on the nonwoven component of reusable cloth masks might help to prevent virus and bacterial infection while reducing the pollution burden related to the disposable masks. The possible mechanism of biocide contact action was studied by quantum chemistry calculations that show that the addition of Ag and/or Cu makes the polymeric fiber a better electron acceptor. This can promote the oxidation of the phospholipids present at both the virus and bacterial membranes. The rupture at the membrane exposes and damages the genetic material of the virus. More studies are needed to determine the mechanism of action, but the results reported here indicate that Cu and Ag ions are good allies, which can help protect us from the virus that has caused this disturbing pandemic.

Targeting vasculogenic mimicry by phytochemicals: A potential opportunity for cancer therapy.

Vasculogenic mimicry (VM) is regarded as a process where very aggressive cancer cells generate vascular-like patterns without the presence of endothelial cells. It is considered as the main mark of malignant cancer and has pivotal role in cancer metastasis and progression in various types of cancers. On the other hand, resistance to the antiangiogenesis therapies leads to the cancer recurrence. Therefore, development of novel chemotherapies and their combinations is urgently needed for abolition of VM structures and also for better tumor therapy. Hence, identifying compounds that target VM structures might be superior therapeutic factors for cancers treatment and controlling the recurrence and metastasis. In recent times, naturally occurring compounds, especially phytochemicals have obtained great attention due to their safe properties. Phytochemicals are also capable of targeting VM structure and also their main signaling pathways. Consequently, in this review article, we illustrated key signaling pathways in VM, and the phytochemicals that affect these structures including curcumin, genistein, lycorine, luteolin, columbamine, triptolide, Paris polyphylla, dehydroeffusol, jatrorrhizine hydrochloride, grape seed proanthocyanidins, resveratrol, isoxanthohumol, dehydrocurvularine, galiellalactone, oxacyclododecindione, brucine, honokiol, ginsenoside Rg3, and norcantharidin. The recognition of these phytochemicals and their safety profile may lead to new therapeutic agents' development for VM elimination in different types of tumors.

Targeting PDGF-mediated recruitment of pericytes blocks vascular mimicry and tumor growth.

Aggressive tumor cells can adopt an endothelial cell-like phenotype and contribute to the formation of a tumor vasculature, independent of tumor angiogenesis. This adoptive mechanism is referred to as vascular mimicry and it is associated with poor survival in cancer patients. To what extent tumor cells capable of vascular mimicry phenocopy the angiogenic cascade is still poorly explored. Here, we identify pericytes as important players in vascular mimicry. We found that pericytes are recruited by vascular mimicry-positive tumor cells in order to facilitate sprouting and to provide structural support of the vascular-like networks. The pericyte recruitment is mediated through platelet-derived growth factor (PDGF)-B. Consequently, preventing PDGF-B signaling by blocking the PDGF receptors with either the small tyrosine kinase inhibitor imatinib or blocking antibodies inhibits vascular mimicry and tumor growth. Collectively, the current study identifies an important role for pericytes in the formation of vascular-like structures by tumor cells. Moreover, the mechanism that controls the pericyte recruitment provides therapeutic opportunities for patients with aggressive vascular mimicry-positive cancer types. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

CDK4/6 inhibition triggers anti-tumour immunity.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are fundamental drivers of the cell cycle and are required for the initiation and progression of various malignancies. Pharmacological inhibitors of CDK4/6 have shown significant activity against several solid tumours. Their primary mechanism of action is thought to be the inhibition of phosphorylation of the retinoblastoma tumour suppressor, inducing G1 cell cycle arrest in tumour cells. Here we use mouse models of breast carcinoma and other solid tumours to show that selective CDK4/6 inhibitors not only induce tumour cell cycle arrest, but also promote anti-tumour immunity. We confirm this phenomenon through transcriptomic analysis of serial biopsies from a clinical trial of CDK4/6 inhibitor treatment for breast cancer. The enhanced anti-tumour immune response has two underpinnings. First, CDK4/6 inhibitors activate tumour cell expression of endogenous retroviral elements, thus increasing intracellular levels of double-stranded RNA. This in turn stimulates production of type III interferons and hence enhances tumour antigen presentation. Second, CDK4/6 inhibitors markedly suppress the proliferation of regulatory T cells. Mechanistically, the effects of CDK4/6 inhibitors both on tumour cells and on regulatory T cells are associated with reduced activity of the E2F target, DNA methyltransferase 1. Ultimately, these events promote cytotoxic T-cell-mediated clearance of tumour cells, which is further enhanced by the addition of immune checkpoint blockade. Our findings indicate that CDK4/6 inhibitors increase tumour immunogenicity and provide a rationale for new combination regimens comprising CDK4/6 inhibitors and immunotherapies as anti-cancer treatment.

The Impact of Detoxification Costs and Predation Risk on Foraging: Implications for Mimicry Dynamics.

Prey often evolve defences to deter predators, such as noxious chemicals including toxins. Toxic species often advertise their defence to potential predators by distinctive sensory signals. Predators learn to associate toxicity with the signals of these so-called aposematic prey, and may avoid them in future. In turn, this selects for mildly toxic prey to mimic the appearance of more toxic prey. Empirical evidence shows that mimicry could be either beneficial ('Mullerian') or detrimental ('quasi-Batesian') to the highly toxic prey, but the factors determining which are unknown. Here, we use state-dependent models to explore how tri-trophic interactions could influence the evolution of prey defences. We consider how predation risk affects predators' optimal foraging strategies on aposematic prey, and explore the resultant impact this has on mimicry dynamics between unequally defended species. In addition, we also investigate how the potential energetic cost of metabolising a toxin can alter the benefits to eating toxic prey and thus impact on predators' foraging decisions. Our model predicts that both how predators perceive their own predation risk, and the cost of detoxification, can have significant, sometimes counterintuitive, effects on the foraging decisions of predators. For example, in some conditions predators should: (i) avoid prey they know to be undefended, (ii) eat more mildly toxic prey as detoxification costs increase, (iii) increase their intake of highly toxic prey as the abundance of undefended prey increases. These effects mean that the relationship between a mimic and its model can qualitatively depend on the density of alternative prey and the cost of metabolising toxins. In addition, these effects are mediated by the predators' own predation risk, which demonstrates that, higher trophic levels than previously considered can have fundamental impacts on interactions among aposematic prey species.