Although activating mutations of the anaplastic lymphoma kinase (ALK) membrane receptor occur in ∼10% of neuroblastoma (NB) tumors, the role of the wild-type (WT) receptor, which is aberrantly expressed in most non-mutated cases, is unclear. Both WT and mutant proteins undergo extracellular domain (ECD) cleavage. Here, we map the cleavage site to Asn654-Leu655 and demonstrate that cleavage inhibition of WT…
Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited. The authors used linked-read genome sequencing…
The trafficking of proteins such as aquaporin-2 (AQP2) in the exocytotic pathway requires an active actin cytoskeleton network, but the mechanism is incompletely understood. Here, we show that the actin-related protein (Arp) 2/3 complex, a key factor in actin filament branching and polymerization, is involved in the shuttling of aquaporin-2 (AQP2) between the trans Golgi network (TGN) and the plasma…
Drug-induced nephrotoxicity represents an important cause of acute kidney injury with associated patient morbidity and mortality and is often responsible for termination of drug development, after extensive resource allocation. We have developed a human kidney tubuloid system that phenocopies, in 3D culture, kidney proximal tubules, a primary injury site of most nephrotoxicants. Traditional end point assays are often performed on…
This week we profile a recent publication in Cell from Dr. Thorsten Mempel's lab at Massachusetts General Hospital and Harvard Medical School with first author Dr. Francesco Marangoni. Their general interest is to understand how the communication between cells of the innate and the adaptive arms of the immune system is organized in our body’s tissues. They primarily study how the interactions of antigen-presenting dendritic cells (DCs) and various types of T cells are orchestrated both in secondary lymphoid organs where adaptive immune responses are initiated as well as at sites of inflammation.
This week we profile a recent publication in the Journal of Pathology from Dr. Rosario Fernández Godino's lab at Harvard Medical School. Their focus is to understand the role of the complement system in the early pathogenesis of age-related macular degeneration (AMD). Understanding the molecular mechanisms underlying AMD is critical to design effective therapies.
Patients with bacterial sepsis or severe COVID-19 have increased numbers of suppressive myeloid cells in their blood. Reyes et al. now show that similar cells can be induced by treatment of healthy human bone marrow progenitor cells in culture with plasma from patients with bacterial sepsis or severe COVID-19. The differentiation of suppressive myeloid cells in this cell model depended on…
Patients with simple steatosis (SS) and nonalcoholic steatohepatitis can develop progressive liver fibrosis, which is associated with liver-related mortality. The mechanisms contributing to liver fibrosis development in SS, however, are poorly understood. SS is characterized by hepatocellular free fatty acid (FFA) accumulation without lobular inflammation seen in nonalcoholic steatohepatitis. Because the Hippo signaling transcriptional coactivator YAP1 (YAP) has previously been…
Stem cell derived insulin producing cells or islets have shown promise in reversing Type 1 Diabetes (T1D), yet successful transplantation currently necessitates long-term modulation with immunosuppressant drugs. An alternative approach to avoiding this immune response is to utilize an islet macroencapsulation device, where islets are incorporated into a selectively permeable membrane that can protect the transplanted cells from acute host…