S100A9 induces differentiation of acute myeloid leukemia cells through TLR4.

S100A8 and S100A9 are calcium-binding proteins predominantly expressed by neutrophils and monocytes and play key roles in both normal and pathological inflammation. Recently, both proteins were found to promote tumor progression through the establishment of premetastatic niches and inhibit antitumor immune responses. Although S100A8 and S100A9 have been studied in solid cancers, their functions in hematological malignancies remain poorly understood. However, S100A8 and S100A9 are highly expressed in acute myeloid leukemia (AML), and S100A8 expression has been linked to poor prognosis in AML. We identified a small subpopulation of cells expressing S100A8 and S100A9 in AML mouse models and primary human AML samples. In vitro and in vivo analyses revealed that S100A9 induces AML cell differentiation, whereas S100A8 prevents differentiation induced by S100A9 activity and maintains AML immature phenotype. Treatment with recombinant S100A9 proteins increased AML cell maturation, induced growth arrest, and prolonged survival in an AML mouse model. Interestingly, anti-S100A8 antibody treatment had effects similar to those of S100A9 therapy in vivo, suggesting that high ratios of S100A9 over S100A8 are required to induce differentiation. Our in vitro studies on the mechanisms/pathways involved in leukemic cell differentiation revealed that binding of S100A9 to Toll-like receptor 4 (TLR4) promotes activation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, and Jun N-terminal kinase signaling pathways, leading to myelomonocytic and monocytic AML cell differentiation. These findings indicate that S100A8 and S100A9 are regulators of myeloid differentiation in leukemia and have therapeutic potential in myelomonocytic and monocytic AMLs.

Development and Validation of IBSA Photographic Scale for the Assessment of Neck Laxity.

OBJECTIVE: To describe the development and validation of the 5-grade photographic IBSA Neck Laxity Scale. METHODS: The scale was developed from 2 real images, which led to the creation of 5 morphed images, representing different degrees of severity of laxity of the neck. For validation, a set of 50 images (25 real and 25 morphed) was created and sent for evaluation to 6 trained raters (physicians) in 2 rounds, 1 month apart. Raters had to assess each image according to the 5-image scale. Inter-rater and intra-rater reliability in both rounds was evaluated. RESULTS: As to intra-rater reliability, single rater kappa scores between 0.69 and 0.87, and a global kappa score of 0.78 were observed. Inter-rater agreement was measured by means of the intra-class correlation coefficient and scores higher than 0.85 were reported, indicating excellent reliability. CONCLUSION: IBSA Neck Laxity Scale is a validated and reliable scale.

Development and Validation of IBSA Photographic Scale for the Assessment of Inner Upper Arm Laxity.

OBJECTIVE: To describe the development and validation of the 5-grade photographic IBSA inner upper arm scale. METHODS: From 2 real-life pictures, a scale made up of 5 morphed images showing increasing severity of inner upper arm laxity was created. For validation, a set of 50 images (half of which real and the other morphed) was developed and sent to 5 trained physicians in two rounds 30 days apart. Raters' task was to make a selection of each image according to the given scale. Inter-rater and intra-rater reliability were evaluated in both rounds. RESULTS: As to intra-rater reliability, single-rater kappa scores between 0.74 and 1.00 and a global kappa score of 0.846 were observed, while inter-rater agreement was calculated with intra-class correlation coefficient reporting scores higher than 0.91, which indicate excellent reliability. CONCLUSION: IBSA inner upper arm laxity scale proved to be a validated and reliable tool.