Structures of ß-klotho reveal a 'zip code'-like mechanism for endocrine FGF signalling.

Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss. Endocrine FGFs signal through FGFRs in a manner that requires klothos, which are cell-surface proteins that possess tandem glycosidase domains. Here we describe the crystal structures of free and ligand-bound ß-klotho extracellular regions that reveal the molecular mechanism that underlies the specificity of FGF21 towards ß-klotho and demonstrate how the FGFR is activated in a klotho-dependent manner. ß-Klotho serves as a primary 'zip code'-like receptor that acts as a targeting signal for FGF21, and FGFR functions as a catalytic subunit that mediates intracellular signalling. Our structures also show how the sugar-cutting enzyme glycosidase has evolved to become a specific receptor for hormones that regulate metabolic processes, including the lowering of blood sugar levels. Finally, we describe an agonistic variant of FGF21 with enhanced biological activity and present structural insights into the potential development of therapeutic agents for diseases linked to endocrine FGFs.

Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition.

Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants.

Suppression of EGFR endocytosis by dynamin depletion reveals that EGFR signaling occurs primarily at the plasma membrane.

The role of endocytosis in the control of EGF receptor (EGFR) activation and cell signaling was explored by using mouse fibroblasts in which dynamin was conditionally depleted. Dynamin is a GTPase shown to play an important role in the control clathrin mediated endocytosis of EGFR and other cell surface receptors. In this report, we demonstrate that EGF binding activity and the display of high and low affinity EGFRs on the cell surface are not affected by dynamin depletion. By contrast, dynamin depletion leads to a strong inhibition of EGFR endocytosis, robust enhancement of EGFR autophosphorylation and ubiquitination, and slower kinetics of EGFR degradation. Surprisingly, MAPK stimulation induced by either low or high EGF concentrations is not affected by dynamin depletion. While a similar initial Akt response is detected in control or dynamin depleted fibroblasts, a somewhat more sustained Akt stimulation is detected in the dynamin depleted cells. These experiments demonstrate that dynamin-mediated endocytosis leads to attenuation of EGFR activation and degradation and that stimulation of the MAPK response and Akt activation are primarily mediated by activated EGFR located in the plasma membrane.

A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .

Anaemia among children living in land reform colonization projects in the Northeast region of Brazil: a population-based cross-sectional study / Anemia en niños que viven en proyectos de colonización de reforma agraria en el nordeste de Brasil: un estudio transversal basado en la población

This study evaluated the prevalence of anaemia and its social determinants among Brazilian children from rural settlements of the land reform colonization projects of Teresina city, in Northeast, Brazil. This is a population-based cross-sectional study involving 131 children younger than 5 years. Anaemia was diagnosed by haemoglobin measurements using an automated haematology analyser. The prevalence of anaemia was 29%. Multiple Poisson regression showed that anemia prevalence decreased by 39% for each year of the child's age (aPR= 0.61; 95% CI= 0.50 - 0.74), 14% for each year of maternal education (aPR= 0.86; 95% CI= 0.79 - 0.94) and 6% for each year of maternal age (aPR= 0.94; 95% CI= 0.89 - 1.00). In addition, children living in clay or in unfinished masonry houses had a higher prevalence of anemia than those living in finished masonry houses (aPR= 2.73; 95% CI= 1.50 - 4.97). Anaemia is a moderate public health problem in rural land reform settlements in Teresina and is probably a health issue in other land reform colonization projects in Brazil and worldwide. Strategies that promote the economic and social development of this population need to be implemented, as well as strengthening the implementation of the National Iron Supplementation Program (Programa Nacional de Suplementação de Ferro).

Este estudio evaluó la prevalencia de la anemia y sus determinantes sociales en niños brasileños de los asentamientos rurales de los proyectos de colonización de la reforma agraria de la ciudad de Teresina, nordeste de Brasil. Este es un estudio transversal basado en la población de 131 niños menores de 5 años. La anemia fue diagnosticada mediante mediciones de hemoglobina usando un analizador de hematología automatizado. La prevalencia de anemia fue del 29%. En un modelo múltiple, la prevalencia de anemia disminuyó 39% por cada año de edad infantil (aPR = 0.61; IC 95% = 0.50 - 0.74), 14% por cada año de educación materna (aPR = 0.86; IC 95% = 0.79 - 0.94) y 6% por cada año de edad materna (aPR = 0,94; IC del 95% = 0,89 a 1,00). Además, los niños residentes en casas de de adobe o mampostería sin terminar presentaron una mayor prevalencia que los que viven en casas de mampostería terminada (aPR = 2.73; IC 95% = 1.50 - 4.97). La anemia es un problema de salud pública moderado en los asentamientos de reforma agraria en Teresina y es probablemente un problema de salud en otros proyectos de colonización de la reforma agraria en Brasil y en todo el mundo. Se deben implementar estrategias que promuevan el desarrollo económico y social de esta población, así como fortalecer la implementación del Programa Nacional de Suplementación de Hierro (Programa Nacional de Suplementação de Ferro).