In vivo effects of interleukin-17 on haematopoietic cells and cytokine release in normal mice

In order to gain more insight into mechanisms operating on the haematopoietic activity of the T-cell-derived cytokine, interleukin-17 (IL-17) and target cells that first respond to its action in vivo, the influence of a single intravenous injection of recombinant mouse IL-17 on bone marrow progenitors, further morphologically recognizable cells and peripheral blood cells was assessed in normal mice up to 72 h after treatment. Simultaneously, the release of IL-6, IL-10, IGF-I, IFN-gamma and NO by bone marrow cells was determined. Results showed that, in bone marrow, IL-17 did not affect granulocyte-macrophage (CFU-GM) progenitors, but induced a persistant increase in the number of morphologically recognizable proliferative granulocytes (PG) up to 48 h after treatment. The number of immature erythroid (BFU-E) progenitors was increased at 48 h, while the number of mature erythroid (CFU-E) progenitors was decreased up to 48 h. In peripheral blood, white blood cells were increased 6 h after treatment, mainly because of the increase in the number of lymphocytes. IL-17 also increased IL-6 release and NO production 6 h after administration. Additional in vitro assessment on bone marrow highly enriched Lin(-) progenitor cells, demonstrated a slightly enhancing effect of IL-17 on CFU-GM and no influence on BFU-E, suggesting the importance of bone marrow accessory cells and secondary induced cytokines for IL-17 mediated effects on progenitor cells. Taken together, these results demonstrate that in vivo IL-17 affects both granulocytic and erythroid lineages, with more mature haematopoietic progenitors responding first to its action. The opposite effects exerted on PG and CFU-E found at the same time indicate that IL-17, as a component of a regulatory network, is able to intervene in mechanisms that shift haematopoiesis from the erythroid to the granulocytic lineage

Symmetry of Magnetically Ordered Quasicrystals

The notion of magnetic symmetry is reexamined in light of the recent observation of long range magnetic order in icosahedral quasicrystals [Charrier et al., Phys. Rev. Lett. 78, 4637 (1997)]. The relation between the symmetry of a magnetically-ordered (periodic or quasiperiodic) crystal, given in terms of a ``spin space group,'' and its neutron diffraction diagram is established. In doing so, an outline of a symmetry classification scheme for magnetically ordered quasiperiodic crystals is provided. Predictions are given for the expected diffraction patterns of magnetically ordered icosahedral crystals, provided their symmetry is well described by icosahedral spin space groups.Comment: 5 pages. Accepted for publication in Phys. Rev. Letter

Diffusion in liquid mixtures

The understanding of transport and mixing in fluids in the presence and in the absence of external fields and reactions represents a challenging topic of strategic relevance for space exploration. Indeed, mixing and transport of components in a fluid are especially important during long-term space missions where fuels, food and other materials, needed for the sustainability of long space travels, must be processed under microgravity conditions. So far, the processes of transport and mixing have been investigated mainly at the macroscopic and microscopic scale. Their investigation at the mesoscopic scale is becoming increasingly important for the understanding of mass transfer in confined systems, such as porous media, biological systems and microfluidic systems. Microgravity conditions will provide the opportunity to analyze the effect of external fields and reactions on optimizing mixing and transport in the absence of the convective flows induced by buoyancy on Earth. This would be of great practical applicative relevance to handle complex fluids under microgravity conditions for the processing of materials in space

Diffractive point sets with entropy

After a brief historical survey, the paper introduces the notion of entropic model sets (cut and project sets), and, more generally, the notion of diffractive point sets with entropy. Such sets may be thought of as generalizations of lattice gases. We show that taking the site occupation of a model set stochastically results, with probabilistic certainty, in well-defined diffractive properties augmented by a constant diffuse background. We discuss both the case of independent, but identically distributed (i.i.d.) random variables and that of independent, but different (i.e., site dependent) random variables. Several examples are shown.Comment: 25 pages; dedicated to Hans-Ude Nissen on the occasion of his 65th birthday; final version, some minor addition

973MO KEYNOTE-189 5-year update: First-line pembrolizumab (pembro) + pemetrexed (pem) and platinum vs placebo (pbo) + pem and platinum for metastatic nonsquamous NSCLC

Background: Pembro + pem-platinum significantly improved survival vs pbo + pem-platinum in patients (pts) with previously untreated, metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations, regardless of PD-L1 TPS, in the phase III KEYNOTE-189 study (NCT02578680). We report updated results with ∼5 y of follow-up. Methods: Pts were randomized 2:1 to receive pembro 200 mg or pbo Q3W for up to 35 cycles (2y). All pts also received pem and investigator’s choice of carboplatin/cisplatin for 4 cycles, followed by maintenance pem until PD/unacceptable toxicity. Crossover from the pbo + pem-platinum group to pembro monotherapy was permitted after PD. Primary endpoints were OS and PFS. Results: Among 616 pts randomized (pembro + pem-platinum, n = 410; pbo + pem-platinum, n = 206), median time from randomization to data cutoff (Mar 8, 2022) was 64.6 (range, 60.1–72.4) mo. 116/202 (57.4%) treated pts crossed over from pbo + pem-platinum to anti–PD-(L)1 therapy during/outside the study. Median (95% CI) OS was 22.0 (19.5‒24.5) mo vs 10.6 (8.7‒13.6) mo with pembro + pem-platinum vs pbo + pem-platinum (HR, 0.60; 95% CI, 0.50‒0.72) and 5-y OS rates were 19.4% vs 11.3%, respectively. Median (95% CI) PFS was 9.0 (8.1‒10.4) mo vs 4.9 (4.7‒5.5) mo (HR, 0.50; 95% CI, 0.42‒0.60). Additional efficacy results are in the table. Among pts with ≥1 dose of assigned treatment, grade 3‒5 AEs occurred in 295/405 (72.8%) vs 136/202 (67.3%) of pts. Among 57 pts who completed 35 cycles of pembro, ORR was 86.0% (CR, n = 8; PR, n = 41); 3-y OS rate after completion of 35 cycles of pembro was 71.9%. Conclusions: First-line pembro + pem-platinum continued to show OS and PFS benefits with manageable toxicity vs pbo + pem-platinum, irrespective of PD-L1 expression. Pts who completed 35 cycles of pembro experienced durable responses. These data further support pembro + pem-platinum as a standard of care for metastatic nonsquamous NSCLC without sensitizing EGFR/ALK alterations

Methodological considerations in the analysis of fecal glucocorticoid metabolites in tufted capuchins (Cebus apella)

Analysis of fecal glucocorticoid (GC) metabolites has recently become the standard method to monitor adrenocortical activity in primates noninvasively. However, given variation in the production, metabolism, and excretion of GCs across species and even between sexes, there are no standard methods that are universally applicable. In particular, it is important to validate assays intended to measure GC production, test extraction and storage procedures, and consider the time course of GC metabolite excretion relative to the production and circulation of the native hormones. This study examines these four methodological aspects of fecal GC metabolite analysis in tufted capuchins (Cebus apella). Specifically, we conducted an adrenocorticotrophic hormone (ACTH) challenge on one male and one female capuchin to test the validity of four GC enzyme immunoassays (EIAs) and document the time course characterizing GC me- tabolite excretion in this species. In addition, we compare a common field-friendly technique for extracting fecal GC metabolites to an established laboratory extraction methodology and test for effects of storing “field extracts” for up to 1 yr. Results suggest that a corticosterone EIA is most sensitive to changes in GC production, provides reliable measures when extracted according to the field method, and measures GC metabolites which remain highly stable after even 12 mo of storage. Further, the time course of GC metabolite excretion is shorter than that described yet for any primate taxa. These results provide guidelines for studies of GCs in tufted capuchins, and underscore the importance of validating methods for fecal hormone analysis for each species of interest

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Interleukin 17 inhibits myogenic and promotes osteogenic differentiation of C2C12 myoblasts by activating ERK1,2

The present study evaluated the role of interleukin (IL) 17 in multilineage commitment of C2C12 myoblastic cells and investigated associated signaling pathways. The results concerning the effects on cell function showed that IL-17 inhibits the migration of C2C12 cells, while not affecting their proliferation. The data regarding the influence on differentiation demonstrated that IL-17 inhibits myogenic differentiation of C2C12 cells by down-regulating the myogenin mRNA level, myosin heavy chain expression and myotube formation, but promotes their osteogenic differentiation by up-regulating the Runt-related transcription factor 2 mRNA level, cyclooxygenase-2 expression and alkaline phosphatase activity. IL-17 exerted these effects by activating ERK1,2 mitogen activated protein kinase signaling pathway, which in turn regulated the expression of relevant genes and proteins to inhibit myogenic differentiation and induce osteogenic differentiation. Additional analysis showed that the induction of osteogenic differentiation by IL-17 is independent of BMP signaling. The results obtained demonstrate the potential of IL-17 not only to inhibit the myogenic differentiation of C2C12 myoblasts but also to convert their differentiation pathway into that of osteoblast lineage providing new insight into the capacities of IL-17 to modulate the differentiation commitment