Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

Gas hold-up, mixing time and gas-liquid volumetric mass transfer coefficient of various multiple-impeller configurations: Rushton turbine, pitched blade and techmix impeller and their combinations

Gas hold-up, mixing intensity of dispersion characterised by exchange flows between adjacent impellers and a volumetric mass transfer coefficient are presented for 18 impeller configurations in triple-impeller vessel of inner diameter . Rushton Turbines, six Pitched Blade impellers pumping down and hydrofoil impellers Techmix 335 (Techmix co., Czech republic) pumping up or down and their combinations were used. aqueous solution was used as a liquid phase, which represents non-coalescent batches. Gas hold-ups and volumetric mass transfer coefficients are presented for individual configurations as functions of specific power dissipated and superficial gas velocity. The regression of the mass transfer coefficients shows large standard deviation (30%). The power number included to the regression to express the impeller configuration effect did not improve the standard deviation significantly (23%). The impeller configurations with low power number (less than unity) provide higher dispersion mixing intensities, while the impeller configurations with high power number provide better mass transfer performance.     

Poly(p-tert-butoxycarbonyloxystyrene): a convenient precursor to p-hydroxystyrene resins

An efficient synthetic route to pure, high molecular weight poly(p-hydroxystyrene) is reported. The route involves synthesis of a new monomer, p-tert-butoxycarbonyloxystyrene, polymerization by radical initiation or by cationic initiation in liquid SO₂, followed by thermolysis or acidolysis of the tert-butoxycarbonyl protecting group. Porous, crosslinked resin beads containing the nucleophilic, phenol pendant group have been prepared in a similar fashion from the precursor terpolymer of p-tert-butoxycarbonyloxystyrene, styrene and divinylbenzene. The utility of this resin for solid-phase synthesis has been demonstrated.     

A study of sulfur bridges in filled natural rubber vulcanizates by pyrolysis gas chromatography with flame-photometric detection

Natural rubber vulcanizates of two formulations, with sulfur/N-cyclohexyl-2-benzothiazolesulfenamide (CBS) and tetramethylthiuram disulfide (TMTD), respectively, were analyzed by pyrolysis gas chromatography. A sulfur-selective flame-photometric detector was utilized. The main pyrolysis products were identified as CS₂ and some thiophenes. The yields of the pyrolysis products from the two types of rubber were very different. The yields also varied with the curing time of the rubbers.     

Sufficient conditions for stability and stabilization of networked control systems with uncertainties and nonlinearities

In this paper, we consider the problem of robust stability and stabilization for networked control systems (NCS) with uncertain/nonlinear dynamics AUTHOR: Please check that authors and their affiliations are correct. in which the network‐induced delays are time‐varying and bounded. Based on some recent achievements, a relatively simple Lyapunov–Krasovskii functional is proposed to derive sufficient conditions both for analysis and synthesis of NCS in the form of LMIs depending on the delay bounds. The effectiveness of the proposed method is illustrated by several benchmark examples available in the literature. Copyright © 2014 John Wiley & Sons, Ltd.     

Minimising total tardiness in the m-machine flowshop problem: A review and evaluation of heuristics and metaheuristics

In this work, a review and comprehensive evaluation of heuristics and metaheuristics for the m-machine flowshop scheduling problem with the objective of minimising total tardiness is presented. Published reviews about this objective usually deal with a single machine or parallel machines and no recent methods are compared. Moreover, the existing reviews do not use the same benchmark of instances and the results are difficult to reproduce and generalise. We have implemented a total of 40 different heuristics and metaheuristics and we have analysed their performance under the same benchmark of instances in order to make a global and fair comparison. In this comparison, we study from the classical priority rules to the most recent tabu search, simulated annealing and genetic algorithms. In the evaluations we use the experimental design approach and careful statistical analyses to validate the effectiveness of the different methods tested. The results allow us to clearly identify the state-of-the-art methods.     

Distance-based local linear regression for functional predictors

The problem of nonparametrically predicting a scalar response variable from a functional predictor is considered. A sample of pairs (functional predictor and response) is observed. When predicting the response for a new functional predictor value, a semi-metric is used to compute the distances between the new and the previously observed functional predictors. Then each pair in the original sample is weighted according to a decreasing function of these distances. A Weighted (Linear) Distance-Based Regression is fitted, where the weights are as above and the distances are given by a possibly different semi-metric. This approach can be extended to nonparametric predictions from other kinds of explanatory variables (e.g., data of mixed type) in a natural way.