3 research outputs found
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Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors
Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor-mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting
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The Lancet NCDI Poverty Commission: bridging a gap in universal health coverage for the poorest billion
For the poorest of our world, non-communicable diseases
and injuries (NCDIs) account for more than a third of their
burden of disease; this burden includes almost
800000 deaths annually among those aged younger than
40 years, more than HIV, tuberculosis, and maternal
deaths combined.
• Despite already living in abject poverty, between
19 million and 50 million of the poorest billion spend a
catastrophic amount of money each year in direct
out-of-pocket costs on health care as a result of NCDIs.
• Progressive implementation of affordable, cost-effective,
and equitable NCDI interventions between 2020 and 2030
could save the lives of more than 4·6 million of the world’s
poorest, including 1·3 million who would otherwise die
before the age of 40 years.
• To avoid needless death and suffering, and to reduce the
risk of catastrophic health spending, essential NCDI
services must be financed through pooled, public
resources, either from increased domestic funding or
external funds.
• National governments should set and adjust priorities
based on the best available local data on NCDIs and the
specific needs of the worst off.
• International development assistance for health should
be augmented and targeted to ensure that the poorest
families affected by NCDIs are included in progress
towards universal health care