Physical Ageing of the Contact Line on Colloidal Particles at Liquid Interfaces

Young's law predicts that a colloidal sphere in equilibrium with a liquid interface will straddle the two fluids, its height above the interface defined by an equilibrium contact angle. This equilibrium analysis has been used to explain why colloids often bind to liquid interfaces, an effect first observed a century ago by Ramsden and Pickering and later exploited in a wide range of material processes, including emulsification, water purification, mineral recovery, encapsulation, and the making of nanostructured materials. But little is known about the dynamics of binding. Here we show that the adsorption of polystyrene microspheres to a water-oil interface is characterized by a sudden breach and an unexpectedly slow relaxation. Particles do not reach equilibrium even after 100 seconds, and the relaxation appears logarithmic in time, suggesting that complete equilibration may take months. Surprisingly, viscous dissipation appears to play little role. Instead, the observed dynamics, which bear strong resemblance to aging in glassy systems, agree well with a model describing activated hopping of the contact line over nanoscale surface heterogeneities. These results may provide clues to longstanding questions on colloidal interactions at an interface.Engineering and Applied SciencesPhysic

Ixazomib, daratumumab and low-dose dexamethasone in intermediate-fit patients with newly diagnosed multiple myeloma:an open-label phase 2 trial

Background: The outcome of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients is heterogeneous, partly depending on frailty level. The aim of this study was to prospectively investigate the efficacy and safety of Ixazomib-Daratumumab-low-dose dexamethasone (Ixa-Dara-dex) in NDMM intermediate-fit patients. Methods: In this phase II multicenter HOVON-143 study, IMWG Frailty index based intermediate-fit patients, were treated with 9 induction cycles of Ixa-Dara-dex, followed by maintenance with ID for a maximum of 2 years. The primary endpoint was overall response rate on induction treatment. Patients were included from October 2017 until May 2019. Trial Registration Number: NTR6297. Findings: Sixty-five patients were included. Induction therapy resulted in an overall response rate of 71%. Early mortality was 1.5%. At a median follow-up of 41.0 months, median progression-free survival (PFS) was 18.2 months and 3-year overall survival 83%. Discontinuation of therapy occurred in 77% of patients, 49% due to progression, 9% due to toxicity, 8% due to incompliance, 3% due to sudden death and 8% due to other reasons. Dose modifications of ixazomib were required frequently (37% and 53% of patients during induction and maintenance, respectively), mainly due to, often low grade, polyneuropathy. During maintenance 23% of patients received daratumumab alone. Global quality of life (QoL) improved significantly and was clinically relevant, which persisted during maintenance treatment. Interpretation: Ixazomib-Daratumumab-low-dose dexamethasone as first line treatment in intermediate-fit NDMM patients is safe and improves global QoL. However, efficacy was limited, partly explained by ixazomib-induced toxicity, hampering long term tolerability of this 3-drug regimen. This highlights the need for more efficacious and tolerable regimens improving the outcome in vulnerable intermediate-fit patients. Funding: Janssen Pharmaceuticals, Takeda Pharmaceutical Company Limited.</p

Chemical Probes that Competitively and Selectively Inhibit Stat3 Activation

Signal transducer and activator of transcription (Stat) 3 is an oncogene constitutively activated in many cancer systems where it contributes to carcinogenesis. To develop chemical probes that selectively target Stat3, we virtually screened 920,000 small drug-like compounds by docking each into the peptide-binding pocket of the Stat3 SH2 domain, which consists of three sites—the pY-residue binding site, the +3 residue-binding site and a hydrophobic binding site, which served as a selectivity filter. Three compounds satisfied criteria of interaction analysis, competitively inhibited recombinant Stat3 binding to its immobilized pY-peptide ligand and inhibited IL-6-mediated tyrosine phosphorylation of Stat3. These compounds were used in a similarity screen of 2.47 million compounds, which identified 3 more compounds with similar activities. Examination of the 6 active compounds for the ability to inhibit IFN-γ-mediated Stat1 phosphorylation revealed that 5 of 6 were selective for Stat3. Molecular modeling of the SH2 domains of Stat3 and Stat1 bound to compound revealed that compound interaction with the hydrophobic binding site was the basis for selectivity. All 5 selective compounds inhibited nuclear-to-cytoplasmic translocation of Stat3, while 3 of 5 compounds induced apoptosis preferentially of breast cancer cell lines with constitutive Stat3 activation. Thus, virtual ligand screening of compound libraries that targeted the Stat3 pY-peptide binding pocket identified for the first time 3 lead compounds that competitively inhibited Stat3 binding to its pY-peptide ligand; these compounds were selective for Stat3 vs. Stat1 and induced apoptosis preferentially of breast cancer cells lines with constitutively activated Stat3

Relaxation Dynamics of Colloidal Particles at Liquid Interfaces

We study the dynamics of colloidal particles as they approach and breach a water-oil interface. We use a fast 3D imaging technique, digital holographic microscopy, to track particles with 2 nm precision and sub-millisecond time resolution. We find that polystyrene particles dispersed in water or water-glycerol mixtures relax logarithmically with time after breaching the interface and do not reach equilibrium on experimental timescales. By contrast, decane-dispersed PMMA particles show fast dynamics and reach a steady-state height within milliseconds. We attribute the difference to the surface properties of the particles. We also probe the dependence of the relaxation rate on surface charge by studying carboxyl-functionalized particles under varying acid concentrations. We conclude that the slow relaxation may be due to contact-line pinning on topographical defects rather than surface charges.Engineering and Applied Science

Effect of Ramping-Up Rate on Film Thickness for Spin-On Processing

Spin-on processing is used in many industries to deposit very thin coatings on flat substrates, including silicon wafers, flat-panel displays, and precision optical components. A liquid precursor solution is first dispensed onto the surface of the substrate; this fluid then spreads out very evenly over the surface due to large rotational forces caused by spinning of the substrate. When looking for an optimum coating procedure process engineers can adjust many variables including the peak spin speed, the ramping rate to reach that speed, the spinning time, as well as allowing for dynamic solution dispense before ramping up, though most protocols focus on the peak spin speed as the primary controlling variable. Engineers often construct spin-speed versus thickness correlations that enable predictable adjustment of spin-speed to achieve a desired thickness. Yet, rather little attention has been paid to the importance of the acceleration rate used to reach the desired peak speed. We show here that ramping rate is also important in helping establish the final coating thickness. We present a numerical model of the fluid flow on a spinning wafer when the spin-speed is ramping linearly up to a desired peak speed and then held constant. It is shown that the coating may “set” into its final thickness before the spin-speed reaches its peak value. In these cases then the peak spin-speed parameter is no longer the primary variable that defines the final coating thickness. This also impacts the interpretation of critical exponents found when fitting spin-speed vs. thickness data. We perform parallel experimental measurements for different ramping-up times and confirm the results from the numerical model. Both experimental and theoretical results support use of the simplified model put forth by Meyerhofer over 25 years ago (J. Appl. Phys. 49 (1978) 3993-3997).This is the Author's accepted manuscript of an article published in Journal of Materials Science: Materials in Electronics. The final publication is available at Springer via http://dx.doi.org/10.1007/s10854-005-4973-6Peer reviewe

A systematic review of cost-effectiveness analyses of novel agents in the treatment of multiple myeloma

Background: Novel therapies for multiple myeloma (MM) promise to improve outcomes but are also associated with substantial increasing costs. Evidence regarding cost-effectiveness of novel treatments is necessary, but a comprehensive up-to-date overview of the cost-effectiveness evidence of novel treatments is currently lacking. Methods: We searched Embase, Medline via Ovid, Web of Science and EconLIT ProQuest to identify all cost-effectiveness evaluations of novel pharmacological treatment of MM reporting cost per quality-adjusted life year (QALY) and cost per life year (LY) gained since 2005. Quality and completeness of reporting was assessed using the Consolidated Health Economic Evaluation Reporting Standards. Results: We identified 13 economic evaluations, comprising 32 comparisons. Our results show that novel agents generate additional LYs (range: 0.311–3.85) and QALYs (range: 0.1–2.85) compared to backbone regimens and 0.02 to 1.10 LYs and 0.01 to 0.91 QALYs for comparisons between regimens containing two novel agents. Lifetime healthcare costs ranged from USD 60,413 to 1,434,937 per patient. The cost-effectiveness ratios per QALY gained ranged from dominating to USD 1,369,062 for novel agents compared with backbone therapies and from dominating to USD 618,018 for comparisons between novel agents. Conclusions: Cost-effectiveness ratios of novel agents were generally above current willingness-to-pay thresholds. To ensure access, cost-effectiveness should be improved or cost-effectiveness ratios above current thresholds should be accepted