The neuropeptide receptor calcitonin receptor-like (CALCRL) is a potential therapeutic target in acute myeloid leukemia.

Calcitonin receptor-like (CALCRL) is a G-protein-coupled neuropeptide receptor involved in the regulation of blood pressure, angiogenesis, cell proliferation, and apoptosis, and is currently emerging as a novel target for the treatment of migraine. This study characterizes the role of CALCRL in acute myeloid leukemia (AML). We analyzed CALCRL expression in collectively more than 1500 well-characterized AML patients from five international cohorts (AMLCG, HOVON, TCGA, Leucegene, and UKM) and evaluated associations with survival. In the AMLCG analytic cohort, increasing transcript levels of CALCRL were associated with decreasing complete remission rates (71.5%, 53.7%, 49.6% for low, intermediate, high CALCRL expression), 5-year overall (43.1%, 26.2%, 7.1%), and event-free survival (29.9%, 15.8%, 4.7%) (all P < 0.001). CALCRL levels remained associated with all endpoints on multivariable regression analyses. The prognostic impact was confirmed in all validation sets. Genes highly expressed in CALCRLhigh AML were significantly enriched in leukemic stem cell signatures and CALCRL levels were positively linked to the engraftment capacity of primary patient samples in immunocompromised mice. CRISPR-Cas9-mediated knockout of CALCRL significantly impaired colony formation in human myeloid leukemia cell lines. Overall, our study demonstrates that CALCRL predicts outcome beyond existing risk factors and is a potential therapeutic target in AML.

Effect of primary particle morphology on the structure of gels formed in intense turbulent shear.

We study the effect of primary particle morphology on intense shear-induced gelation without adding electrolytes. The primary particles are composed of a rubbery core grafted with a polystyrene shell. Depending on the shell-to-core mass ratio, the core can be partially covered by the shell, leading to strawberry-like morphology. It is found that at a fixed core mass the fractal dimension of the clusters constructing the gel decreases (i.e., more open cluster structure) as the shell mass increases, until reaching a plateau. The SEM pictures of the gels reveal that the structure variations are due to the occurrence of partial coalescence among particles, which decreases as the shell mass increases. In the region where the fractal dimension reaches a plateau, the coalescence is negligible. The conversion of the primary particles to gels is incomplete and increases as the extent of coalescence decreases. This is related to the fact that the smaller the extent of coalescence, the larger the cluster size. Thus, because of its cubic dependence on the cluster size, the aggregation rate increases as the extent of coalescence decreases, leading to increased conversion. It is therefore evident that the key parameter controlling the gel structure and the particle conversion is the core surface coverage by the shell. To further verify this conclusion, we have carried out the shear-induced gelation of another set of particles with varying core mass. It is found that the only parameter that can well correlate the values of the fractal dimension and particle conversion from the two sets of particles is the core surface coverage.

Bis(diphenylphosphino)acetonitrile: synthesis, ligand properties and application in catalytic carbon-carbon coupling.

Treatment of acetonitrile (1 equiv.) with n-butyllithium (0.95 equiv.) followed by chlorodiphenylphosphine (0.95 equiv.) under optimised reaction conditions gave a ca. 60% yield of bis(diphenylphosphino)acetonitrile (dppmCN, 1). The bidentate ligand was employed in the synthesis of the four-membered chelate metal complexes (dppmCN)MCl(2) [M = Pd (6a), Pt (6b)] and (dppmCN)RuCp*(Cl) (7). A very active catalyst for bromobenzene/phenylboronic acid Suzuki-Miyaura coupling was in situ generated by treatment of Pd(OAc)(2) with bis(diphenylphosphino)acetonitrile [TOF (1 h) >600000].

Stereoelectronic influence of the type of bifunctional ansa-monocyclopentadienyldimethylsilylamido ligand on the molecular structures displayed by zirconium dichloride and 1,4-diphenylbutadiene complexes.

A series of organozirconium dichloride and 1,4-diphenylbutadiene complexes featuring a dianionic bifunctional ligand with a cyclopentadienyl-type functionality and an appended amido N donor have been prepared and structurally characterized. [(C(5)H(4))SiMe(2)(N-t-Bu)]ZrCl(2), 1, [(C(9)H(6))SiMe(2)(N-t-Bu)]ZrCl(2), 2, and [(C(5)Me(4))SiMe(2)(N-i-Pr)]ZrCl(2), 3, were prepared in two steps, with ligand chelation accomplished by an amine elimination reaction followed by treatment of the diamido Zr intermediate with an excess of SiMe(3)Cl. X-ray structural analyses reveal that in the solid state 2 is monomeric, whereas 1 and 3 are centrosymmetric dimers linked by a pair of bridging chlorides. The level of asymmetry displayed by the central Zr(2)(micro-Cl)(2) moiety is indicated by the variation in the pair of independent bridging Zr-Cl bond distances, which are 2.618(1) and 2.657(1) A in 1 and 2.542(1) and 2.745(1) A in 3, respectively. The metathetical reactions of [Mg(C(4)H(4)Ph(2))(THF)(3)](n)() with 1, 2, 3, and [(C(5)Me(4))SiMe(2)(N-t-Bu)]ZrCl(2) proceed to afford the corresponding 1,4-diphenylbutadiene derivatives 4, 5, 6, and 7, respectively. Solution NMR data show that 6 is obtained exclusively as the supine isomer, whereas compounds 4, 5, and 7 exist as >20:1, 6:1, and 2:1 mixtures of the supine and prone isomers at ambient temperature. The molecular structures of the supine forms of 4, 5, 6, and 7 are appreciably folded (70-80 degrees ) along the line of intersection between the plane containing the Zr and the two terminal butadiene carbons and the plane of the cis-butadiene fragment. An increase in the folding is accompanied by a decrease in the difference between the average Zr-C(terminal) and Zr-C(internal) bond distances and leads to a more pronounced long-short-long C-C bond sequence within the coordinated butadiene.