No abstract

Cyclic GMP-AMP synthase (cGAS) is an endogenous DNA sensor that synthesizes cyclic guanosine monophosphate–adenosine monophosphate (2′3′-cGAMP) from ATP and GTP. 2′3′-cGAMP activates the stimulator of interferon genes (STING) pathway, resulting in the production of interferons and pro-inflammatory cytokines. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) is the phosphodiesterase that negatively regulates the STING pathway by hydrolyzing 2′3′-cGAMP. It has been established that the cGAS–STING pathway plays a major role in inhibiting tumor growth by upregulating T cell response. Herein, we demonstrate that AVA-NP-695, a selective and highly potent ENPP1 inhibitor, apart from the immunomodulatory effect also modulates cancer metastasis by negatively regulating epithelial–mesenchymal transition (EMT). We established that the combined addition of 2′3′-cGAMP and AVA-NP-695 significantly abrogated the transforming growth factor beta (TGF-ꞵ)-induced EMT in MDA-MB-231 cells. Finally, results from the in vivo study showed superior tumor growth inhibition and impact on tumor metastasis of AVA-NP-695 compared to Olaparib and PD-1 in a syngeneic 4T1 breast cancer mouse model. The translation of efficacy from in vitro to in vivo 4T1 tumor model provides a strong rationale for the therapeutic potential of AVA-NP-695 against triple-negative breast cancer (TNBC) as an immunomodulatory and anti-metastatic agent.

The life cycle assessment of the battery will help one to identify the energy and cost associated with the product from the cradle to gate processes. The ecological footprint of a company can reduce the power of a brand when consumers avoid unsustainable practices. The performance of the product can be compared with its competitors. The potential areas of improvement can be identified, which in turn helps to improve the performance of the product. The energy associated with the product during processing, manufacturing, usage and transportation stages has been identified in this paper. The energy pay back for the battery has been calculated, which can be used to compare batteries among each other. On finding the energy payback of the battery, a framework has been developed which can be used in future to compare different batteries. And the impact assessment helped to interpret the important areas of improvement and the sector producing maximum impact. And some methods which can be implemented to decrease the impact and burdens produced during the product development stages are discussed.