Natural killer (NK) cells provide a powerful weapon mediating immune defense against viral infections, tumor growth, and metastatic spread. NK cells demonstrate great potential for cancer ...immunotherapy; they can rapidly and directly kill cancer cells in the absence of MHC‐dependent antigen presentation and can initiate a robust immune response in the tumor microenvironment (TME). Nevertheless, current NK cell‐based immunotherapies have several drawbacks, such as the requirement for ex vivo expansion of modified NK cells, and low transduction efficiency. Furthermore, to date, no clinical trial has demonstrated a significant benefit for NK‐based therapies in patients with advanced solid tumors, mainly due to the suppressive TME. To overcome current obstacles in NK cell‐based immunotherapies, we describe here a non‐viral lipid nanoparticle‐based delivery system that encapsulates small interfering RNAs (siRNAs) to gene silence the key intrinsic inhibitory NK cell molecules, SHP‐1, Cbl‐b, and c‐Cbl. The nanoparticles (NPs) target NK cells in vivo, silence inhibitory checkpoint signaling molecules, and unleash NK cell activity to eliminate tumors. Thus, the novel NP‐based system developed here may serve as a powerful tool for future NK cell‐based therapeutic approaches.
Synopsis
Natural Killer (NK) cells serve as a first line of immune defense against tumor growth and viral infections. This study demonstrates a nanobiology‐based drug delivery system to enhance NK cytotoxicity by suppressing intracellular inhibitory checkpoints in the tumor microenvironment (TME).
NK cytotoxicity was enhanced by nano‐carriers encapsulating siRNAs that target the negative regulatory genes SHP‐1 and Cbls.
Tumor growth was suppressed by these molecularly modified NK cells in‐vivo.
Natural Killer (NK) cells serve as a first line of immune defense against tumor growth and viral infections. This study demonstrates a nanobiology‐based drug delivery system to enhance NK cytotoxicity by suppressing intracellular inhibitory checkpoints in the tumor microenvironment (TME).
Natural killer (NK) cells play a crucial role in immunity, killing virally infected and cancerous cells. The balance of signals initiated upon engagement of activating and inhibitory NK receptors ...with cognate ligands determines killing or tolerance. Nevertheless, the molecular mechanisms regulating rapid NK cell discrimination between healthy and malignant cells in a heterogeneous tissue environment are incompletely understood. The SHP-1 tyrosine phosphatase is the central negative NK cell regulator that dephosphorylates key activating signaling proteins. Though the mechanism by which SHP-1 mediates NK cell inhibition has been partially elucidated, the pathways by which SHP-1 is itself regulated remain unclear. Here, we show that phosphorylation of SHP-1 in NK cells on the S591 residue by PKC-θ promotes the inhibited SHP-1 'folded' state. Silencing PKC-θ maintains SHP-1 in the active conformation, reduces NK cell activation and cytotoxicity, and promotes tumor progression in vivo. This study reveals a molecular pathway that sustains the NK cell activation threshold through suppression of SHP-1 activity.
Purpose - The purpose of this paper is to provide an understanding of the WEB 2.0 phenomenon and its implications on knowledge management; thus, in order to learn whether using WEB 2.0 concepts and ...tools can yield better assimilation of knowledge management in organizations.Design methodology approach - A range of recently published articles regarding WEB 2.0, Enterprise 2.0 and KM 2.0 are examined and critiqued (2005-2007). These are analyzed and compared to knowledge management principles and attributes as known and learned from works defining the sharing of knowledge in organizations (1995-2005). The sources are divided into three basic elements: The Internet (WEB 2.0), the organizational implementation (Enterprise 2.0) and the organizational implementation of knowledge sharing (KM2.0).Findings - WEB 2.0 is very close in its principles and attributes to knowledge management. WEB 2.0 should affect knowledge management in organizations; yet, it cannot be copied, as differences between the two will not enable organizations to benefit from such. In the first stage, tools can be adopted, and in further stages, deeper aspects such as active users' participation will be followed.Practical implications - Organizations are encouraged to start using WIKI's and in some cases also blogs. Knowledge Managers should examine if younger employees can serve as knowledge catalysts. WEB 2.0 concepts should be tested as to organization's maturity, to decide if they can be adopted as part of the organizational knowledge sharing.Originality value - This paper analyzes an important issue whether better assimilation of knowledge management can exist triggered by the WEB 2.0 phenomenon. It is unique in its broad analysis of the three related terms - WEB 2.0, Enterprise 2.0 and KM2.0.
Understanding the crosstalk between natural killer (NK) cells and the tumor microenvironment (TME) has enhanced the potential of exploiting the interplay between activation and inhibition of NK cells ...for immunotherapy. This interaction is crucial for understanding how tumor cells escape NK cell immune surveillance. NK cell dysfunction is regulated by two molecular mechanisms, downregulated activating receptor ligand expression on the tumor cells, and upregulated inhibitory signals delivered to NK cells. Recent studies demonstrated the role of mechanotransduction in modulating NK cell responses in the TME. The immunological synapse represents a functional interface between the NK cell and its target, regulated by Actin Retrograde Flow (ARF), which drives the adhesion molecules and receptors toward the central zone of the immunological synapse (IS). Here, we further characterize the role of ARF in controlling the immune response of NK cells, using CRISPR/cas9-mediated Wiskott–Aldrich Syndrome protein (WASp) gene silencing of NK cells. We demonstrate that WASp regulates ARF velocity, affecting the conformation and function of the key NK inhibitory regulator, SH2-domain containing protein tyrosine phosphatase-1 (SHP-1), and consequently, the NK cell response. Our results demonstrate the potential of modulating the biophysical and intracellular regulation of NK activation as a promising approach for improving immunotherapy.
Purpose - Knowledge retention is becoming a main challenge in many countries, as knowledge becomes a main asset of organizations. The research questions the challenge of how can organizations ...minimize the loss of important knowledge while experiencing high levels of retiree? The research aims to suggest a framework for knowledge retention initiatives in organizations.Design methodology approach - The research methodology is multi-case research. The unit of analysis is organization (eight organizations analyzed, overall more than 30 retiree knowledge retention mini projects). Data linkage to the propositions and method of interpretation - explanation building technique.Findings - This research suggests that successful knowledge retention can be achieved in three primary stages: defining scope; documenting (planning and implementation); and integrating knowledge back into the organization. Special care must be dedicated throughout the process to: retaining best practices and unexpected situations; structuring the process of knowledge retention; structuring retained documentation.Research limitations implications - Academic implications are two-fold. First, it suggests that assessment projects, which estimate knowledge loss risk, and described in most academic researches, should be eliminated in knowledge retention models; second, research should continue, developing more models regarding detailed planning and implementation stages, as initiated in Hofer-Alfeis DeLong and here. Further research should be conducted in order to discover how effective the suggested methods are in retrospect (after years, and not only after months).Practical implications - Business implications do exist. The case studies described, using the proposed framework, show that knowledge retention is not only important, but also applicable. Structuring the process and results, as described above, may provide organizations with guidelines how to conduct such projects.Originality value - Its value is in changing the suggested known frameworks for knowledge retention, enabling more effective and efficient knowledge retention, and therefore less knowledge loss in organizations.
Purpose
– This paper is aimed at both researchers and organizations. For researchers, it seeks to provide a means for better analyzing the phenomenon of social media implementation in organizations ...as a knowledge management (KM) enabler. For organizations, it seeks to suggest a step-by-step architecture for practically implementing social media and benefiting from it in terms of KM.
Design/methodology/approach
– The research is an empirical study. A hypothesis was set; empirical evidence was collected (from 34 organizations). The data were analyzed both quantitatively and qualitatively, thereby forming the basis for the proposed architecture.
Findings
– Implementing social media in organizations is more than a yes/no question; findings show various levels of implementation in organizations: some implementing at all levels, while others implement only tools, functional components, or even only visibility.
Research limitations/implications
– Two main themes should be further tested: whether the suggested architecture actually yields faster/eased KM implementation compared to other techniques; and whether it can serve needs beyond the original scope (KM, Israel) as tested in this study (i.e. also for other regions and other needs – service, marketing and sales, etc.).
Practical implications
– Organizations can use the suggested four levels architecture as a guideline for implementing social media as part of their KM efforts.
Originality/value
– This paper is original and innovative. Previous studies describe the implementation of social media in terms of yes/no; this research explores the issue as a graded one, where organizations can and do implement social media step-by-step. The paper's value is twofold: it can serve as a foundational study for future researches, which can base their analysis on the suggested architecture of four levels of implementation. It also serves as applied research that will help organizations searching for social media implementation KM enablers.
Natural killer (NK) cells are critical to the innate immune system, as they recognize antigens without prior sensitization, and contribute to the control and clearance of viral infections and cancer. ...However, a significant proportion of NK cells in mice and humans do not express classical inhibitory receptors during their education process and are rendered naturally “anergic”, i.e., exhibiting reduced effector functions. The molecular events leading to NK cell anergy as well as their relation to those underlying NK cell exhaustion that arises from overstimulation in chronic conditions, remain unknown. Here, we characterize the “anergic” phenotype and demonstrate functional, transcriptional, and phenotypic similarities to the “exhausted” state in tumor-infiltrating NK cells. Furthermore, we identify zinc finger transcription factor Egr2 and diacylglycerol kinase DGKα as common negative regulators controlling NK cell dysfunction. Finally, experiments in a 3D organotypic spheroid culture model and an in vivo tumor model suggest that a nanoparticle-based delivery platform can reprogram these dysfunctional natural killer cell populations in their native microenvironment. This approach may become clinically relevant for the development of novel anti-tumor immunotherapeutic strategies.
Synopsis
The mechanisms underlying naturally occurring “anergic” and overstimulation-induced “exhausted” states of natural killer (NK) cells remain unclear. This study identifies common functional and phenotypic characteristics of these two dysfunctional states, and identifies common regulators that can be targeted to reprogram dysfunctional NK cells.
The transcription factor Egr2 and diacylglycerol kinase DGKα regulate both dysfunctional states of NK cells.
Egr2 silencing rescues anergic NK cell cytotoxicity via the EGR2-DGKα-MAPK-pERK axis, potentially modulating SHP-1 activity and calcium levels.
Naturally occurring anergic NK cells have functional, transcriptional, and phenotypic similarities to exhausted NK cells within the tumor microenvironment.
A nanoparticle-based method can reprogram dysfunctional NK cells in their native milieu and increase their anti-tumor activity.
Common intrinsic regulators of dysfunctional “anergic” and “exhausted” NK cells can be targeted to restore cytotoxicity.
Public health experts emphasize the need for quick, point-of-care SARS-CoV-2 detection as an effective strategy for controlling virus spread. To this end, many “antigen” detection devices were ...developed and commercialized. These devices are mostly based on detecting SARS-CoV-2’s nucleocapsid protein. Recently, alerts issued by both the FDA and the CDC raised concerns regarding the devices’ tendency to exhibit false positive results. In this work, we developed a novel alternative spike-based antigen assay, comprising four high-affinity, specific monoclonal antibodies, directed against different epitopes on the spike’s S1 subunit. The assay’s performance was evaluated for COVID-19 detection from nasopharyngeal swabs, compared to an in-house nucleocapsid-based assay, composed of novel antibodies directed against the nucleocapsid. Detection of COVID-19 was carried out in a cohort of 284 qRT-PCR positive and negative nasopharyngeal swab samples. The time resolved fluorescence (TRF) ELISA spike assay displayed very high specificity (99%) accompanied with a somewhat lower sensitivity (66% for Ct < 25), compared to the nucleocapsid ELISA assay which was more sensitive (85% for Ct < 25) while less specific (87% specificity). Despite being outperformed by qRT-PCR, we suggest that there is room for such tests in the clinical setting, as cheap and rapid pre-screening tools. Our results further suggest that when applying antigen detection, one must consider its intended application (sensitivity vs specificity), taking into consideration that the nucleocapsid might not be the optimal target. In this regard, we propose that a combination of both antigens might contribute to the validity of the results.
Graphical abstract
Schematic representation of sample collection and analysis. The figure was created using
BioRender.com
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