Tumour microenvironment hinders nanoparticle transport deep into the tissue precluding thorough treatment of solid tumours and metastatic nodes. We introduce an anticancer drug delivery concept ...termed FlaRE (Flash Release in Endothelium), which represents alternative to the existing approaches based on enhanced permeability and retention effect. This approach relies on enhanced drug-loaded nanocarrier accumulation in vessels of the target tumour or metastasised organ, followed by a rapid release of encapsulated drug within tens of minutes. It leads to a gradient-driven permeation of the drug to the target tissue. This pharmaceutical delivery approach is predicted by theoretical modelling and validated experimentally using rationally designed MIL-101(Fe) metal-organic frameworks. Doxorubicin-loaded MIL-101 nanoparticles get swiftly trapped in the vasculature of the metastasised lungs, disassemble in the blood vessels within 15 minutes and release drug, which rapidly impregnates the organ. A significant improvement of the therapeutic outcome is demonstrated in animal models of early and late-stage B16-F1 melanoma metastases with 11-fold and 4.3-fold decrease of pulmonary melanoma nodes, respectively.
PPM1D/Wip1 is a negative regulator of the tumor suppressor p53 and is overexpressed in several human solid tumors. Recent reports associate gain-of-function mutations of PPM1D in immune cells with ...worse outcomes for several human cancers. Here we show that mice with genetic knockout of Ppm1d or with conditional knockout of Ppm1d in the hematopoietic system, in myeloid cells, or in neutrophils all display significantly reduced growth of syngeneic melanoma or lung carcinoma tumors. Ppm1d knockout neutrophils infiltrate tumors extensively. Chemical inhibition of Wip1 in human or mouse neutrophils increases anti-tumor phenotypes, p53-dependent expression of co-stimulatory ligands, and proliferation of co-cultured cytotoxic T cells. These results suggest that inhibition of Wip1 in neutrophils enhances immune anti-tumor responses.
Communication as the Origin of Consciousness Fedotov, Sergei A.; Baidyuk, Ekaterina V
Integrative psychological & behavioral science,
03/2023, Letnik:
57, Številka:
1
Journal Article
Recenzirano
Since the middle of the 20th century, more and more data have appeared on the limited role of consciousness in determining human behavior. In this opinion paper, we hypothesize that the basis of ...consciousness is precisely the communicative function, and discuss relations of consciousness to other cognitive processes such sensory detection, decision-making and emotions. Within the framework of the hypothesis, consciousness is considered as a highly specialized function of the brain, which ensures encoding of personal information as communication messages. On a subjective level, mental representation just means the state of information to be shared in a human group. Accordingly, consciousness affects only those components of human behavior that are associated with the transmission of messages. Sensory detection, decision-making, emotions and other processes are only projected into consciousness during the encoding of information of them. The communication hypothesis assumes that consciousness is an adaptation that increases the efficiency of a collective way of life, and the emergence of consciousness is inextricably linked with the development of language in human culture. In the future, our view of consciousness provides an opportunity for an objective analysis of subjective phenomena by means of a directed study of the formation of messages both at the level of brain processes and at the level of interactions between individuals.
In recent years, molecularly imprinted polymer nanoparticles (nanoMIPs) have proven to be an attractive alternative to antibodies in diagnostic and therapeutic applications. However, several key ...questions remain: how suitable are intracellular epitopes as targets for nanoMIP binding? And to what extent can protein function be modulated via targeting specific epitopes? To investigate this, three extracellular and three intracellular epitopes of epidermal growth factor receptor (EGFR) were used as templates for the synthesis of nanoMIPs which were then used to treat cancer cells with different expression levels of EGFR. It was observed that nanoMIPs imprinted with epitopes from the intracellular kinase domain and the extracellular ligand binding domain of EGFR caused cells to form large foci of EGFR sequestered away from the cell surface, caused a reduction in autophosphorylation, and demonstrated effects on cell viability. Collectively, this suggests that intracellular domain-targeting nanoMIPs can be a potential new tool for cancer therapy.
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