Explore the vast range of titles available.

Cancer is emerging as a major public health challenge globally. Recently, IARC (International Association of Research on Cancer) published global cancer burden using GLOBOCAN 2020 estimates for 36 cancers in 185 countries of the world. As per the estimates of the World Health Organization (WHO) in 2019, cancer is the first or second leading cause of death in 112 of 183 countries. The major takeaways of the GLOBOCAN 2020 report relevant to the surgical oncology community include the rising global burden of cancer, global disparity in cancer incidence and mortality in different geographic regions, and the impact of the human development index (HDI) on cancer incidence and projected global cancer burden by 2040. In this article, we discuss the implications of the GLOBOCAN report on future global cancer control strategies and the role of surgical oncologists in the fight against cancer.

INTRODUCTION Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS‐AD). Our findings identified widespread dysregulation of the endolysosomal network (ELN) in DS and DS‐AD brains, driven by increased APP gene dose, hyperactivation of RAB5, and elevated levels of guanine nucleotide exchange factors (GEFs) for RABs 7 and 11. METHODS We investigated whether increasing APP gene dose and RAB5 hyperactivation contributed to neuropathogenesis and whether a clinically feasible intervention could reverse ELN changes. The Dp16 DS‐AD mouse model was treated with a mouse App‐specific antisense oligonucleotide (App‐ASO) and Rab5‐specific ASOs targeting Rab5a and Rab5b. RESULTS App‐ASO treatment normalized full‐length APP (fl‐APP) and its products, RAB5 activity, and downstream RABs 7 and 11 pathways. Rab5‐ASOs reduced RAB5 levels and restored endosomal Rab activity. Both ASO treatments mitigated DS‐AD‐linked pathologies. DISCUSSION These findings highlight ELN dysregulation in DS and the therapeutic potential of ASO‐based strategies targeting APP or Rab5 to counteract DS‐AD features. Highlights App‐ASO treatment reduced the levels of APP and its products and normalized endosomal Rab activity and GEF levels in Dp16 mice. Administration of Rab5‐ASOs reduced RAB5 levels and normalized endosomal Rab activity and GEF levels in Dp16 mice. Both ASO treatments were well tolerated and mitigated APP‐linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, and synaptic protein loss. App‐ASO or Rab5‐ASOs reversed established pathological phenotypes in Dp16 mice.

Mucopolysaccharidosis type IIIC is a neurodegenerative lysosomal storage disorder (LSD) characterized by the accumulation of undegraded heparan sulfate (HS) due to the lack of an enzyme responsible for its degradation: acetyl-CoA:α-glucosaminide N-acetyltransferase (HGSNAT). Classical treatments are ineffective. Here, we attempt a new approach in genetic medicine, genetic substrate reduction therapy (gSRT), to counteract this neurological disorder. Briefly, we used synthetic oligonucleotides, particularly gapmer antisense oligonucleotides (ASOs), to target the synthesis of the accumulated compounds at the molecular level, downregulating a specific gene involved in the first step of HS biosynthesis, XYLT1. Our goal was to reduce HS production and, consequently, its accumulation. Initially, five gapmer ASOs were designed and their potential to decrease XYLT1 mRNA levels were tested in patient-derived fibroblasts. Subsequent analyses focused on the two best performing molecules alone. The results showed a high inhibition of the XYLT1 gene mRNA (around 90%), a decrease in xylosyltransferase I (XT-I) protein levels and a reduction in HS storage 6 and 10 days after transfection (up to 21% and 32%, respectively). Overall, our results are highly promising and may represent the initial step towards the development of a potential therapeutic option not only for MPS IIIC, but virtually for every other MPS III form. Ultimately, the same principle may also apply to other neuropathic MPS.