Fluoride-doped amorphous calcium phosphate nanoparticles as a promising biomimetic material for dental remineralization

Demineralization of dental hard tissue is a widespread problem and the main responsible for dental caries and dentin hypersensitivity. The most promising strategies to induce the precipitation of new mineral phase are the application of materials releasing gradually Ca2+ and PO43- ions or mimicking the mineral phase of the host tissue. However, the design of formulations covering both processes is so far a challenge in preventive dentistry. In this work, we have synthesized innovative biomimetic amorphous calcium phosphate (ACP), which has been, for the first time, doped with fluoride ions (FACP) to obtain materials with enhanced anti-caries and remineralizing properties. Significantly, the doping with fluoride (F) did not vary the physico-chemical features of ACP but resulted in a faster conversion to the crystalline apatite phase in water, as observed by in-situ time-dependent Raman experiments. The efficacy of the as synthesized ACP and FACP samples to occlude dentinal tubules and induce enamel remineralization has been tested in vitro in human molar teeth. The samples showed good ability to partially occlude the tubules of acid-etched dentin and to restore demineralized enamel into its native structure. Results demonstrate that ACP and FACP are promising biomimetic materials in preventive dentistry to hinder demineralization of dental hard tissues

Randomized phase III study (ADMYRE) of plitidepsin in combination with dexamethasone vs. dexamethasone alone in patients with relapsed/refractory multiple myeloma

The randomized phase III ADMYRE trial evaluated plitidepsin plus dexamethasone (DXM) versus DXM alone in patients with relapsed/refractory multiple myeloma after at least three but not more than six prior regimens, including at least bortezomib and lenalidomide or thalidomide. Patients were randomly assigned (2:1) to receive plitidepsin 5 mg/m2 on D1 and D15 plus DXM 40 mg on D1, D8, D15, and D22 (arm A, n = 171) or DXM 40 mg on D1, D8, D15, and D22 (arm B, n = 84) q4wk. The primary endpoint was progression-free survival (PFS). Median PFS without disease progression (PD) confirmation (IRC assessment) was 2.6 months (arm A) and 1.7 months (arm B) (HR = 0.650; p = 0.0054). Median PFS with PD confirmation (investigator’s assessment) was 3.8 months (arm A) and 1.9 months (arm B) (HR = 0.611; p = 0.0040). Median overall survival (OS, intention-to-treat analysis) was 11.6 months (arm A) and 8.9 months (arm B) (HR = 0.797; p = 0.1261). OS improvement favoring arm A was found when discounting a crossover effect (37 patients crossed over from arm B to arm A) (two-stage method; HR = 0.622; p = 0.0015). The most common grade 3/4 treatment-related adverse events (% of patients arm A/arm B) were fatigue (10.8%/1.2%), myalgia (5.4%/0%), and nausea (3.6%/1.2%), being usually transient and reversible. The safety profile does not overlap with the toxicity observed with other agents used in multiple myeloma. In conclusion, efficacy data, the reassuring safety profile, and the novel mechanism of action of plitidepsin suggest that this combination can be an alternative option in patients with relapsed/refractory multiple myeloma after at least three prior therapy lines

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Characteristic Ratios of Atactic Poly(vinylethylene) and Poly(ethylethylene)

The characteristic ratios of atactic poly(vinylethylene) and poly(ethylethylene) have been determined by combining intrinsic viscosity and weight-average molecular weight measurements on a series of near-monodisperse samples. The poly(vinylethylenes) were prepared by the anionic polymerization of 1,3-butadiene while the poly(ethylethylene) samples were the product of the hydrogenation of the poly(vinylethylene) materials. The characteristic ratio for poly(ethylethylene) of 5.3, although not in accord with available experimental values, is in excellent agreement with the predictions of Flory, Mark, and Abe. © 1983, American Chemical Society. All rights reserved

Characteristic Ratios of Atactic Poly(vinylethylene) and Poly(ethylethylene)

The characteristic ratios of atactic poly(vinylethylene) and poly(ethylethylene) have been determined by combining intrinsic viscosity and weight-average molecular weight measurements on a series of near-monodisperse samples. The poly(vinylethylenes) were prepared by the anionic polymerization of 1,3-butadiene while the poly(ethylethylene) samples were the product of the hydrogenation of the poly(vinylethylene) materials. The characteristic ratio for poly(ethylethylene) of 5.3, although not in accord with available experimental values, is in excellent agreement with the predictions of Flory, Mark, and Abe. © 1983, American Chemical Society. All rights reserved

Chronic myeloid leukemia: the basis of treatment for tomorrow.

Recent years have seen dramatic advances in deciphering the molecular pathogenesis of chronic myeloid leukemia (CML). This has resulted in the rapid development of many BCR-ABL1-specific tyrosine kinase inhibitors (TKI) which have improved 10-year survival to more than 80%. In this paper we focus on some future directions for CML biology and therapy