Establishment of patient-derived tumor organoids to functionally inform treatment decisions in metastatic colorectal cancer.

BACKGROUND: Metastatic colorectal cancer (mCRC) patients tend to have modest benefits from molecularly driven therapeutics. Patient-derived tumor organoids (PDTOs) represent an unmatched model to elucidate tumor resistance to therapy, due to their high capacity to resemble tumor characteristics. MATERIALS AND METHODS: We used viable tumor tissue from two cohorts of patients with mCRC, naïve or refractory to treatment, respectively, for generating PDTOs. The derived models were subjected to a 6-day drug screening assay (DSA) with a comprehensive pipeline of chemotherapy and targeted drugs against almost all the actionable mCRC molecular drivers. For the second cohort DSA data were matched with those from PDTO genotyping. RESULTS: A total of 40 PDTOs included in the two cohorts were derived from mCRC primary tumors or metastases. The first cohort included 31 PDTOs derived from patients treated in front line. For this cohort, DSA results were matched with patient responses. Moreover, RAS/BRAF mutational status was matched with DSA cetuximab response. Ten out of 12 (83.3%) RAS wild-type PDTOs responded to cetuximab, while all the mutant PDTOs, 8 out of 8 (100%), were resistant. For the second cohort (chemorefractory patients), we used part of tumor tissue for genotyping. Four out of nine DSA/genotyping data resulted applicable in the clinic. Two RAS-mutant mCRC patients have been treated with FOLFOX-bevacizumab and mitomycin-capecitabine in third line, respectively, based on DSA results, obtaining disease control. One patient was treated with nivolumab-second mitochondrial-derived activator of caspases mimetic (phase I trial) due to high tumor mutational burden at genotyping, experiencing stable disease. In one case, the presence of BRCA2 mutation correlated with DSA sensitivity to olaparib; however, the patient could not receive the therapy. CONCLUSIONS: Using CRC as a model, we have designed and validated a clinically applicable methodology to potentially inform clinical decisions with functional data. Undoubtedly, further larger analyses are needed to improve methodology success rates and propose suitable treatment strategies for mCRC patients.

Chitosan hollow fibers as effective biosorbent toward dye: preparation and modeling.

Chitosan hollow fibers were produced via a dry-wet spinning technique with good mechanical properties. The prepared membranes were tested for removal of reactive blue 19 as a model anionic dye. Response surface methodology was employed for the modeling of adsorption capacity of fibers. A second-order empirical relationship between adsorption capacity and independent variables (initial pH, contact time, initial dye concentration and amount of fibers) was obtained. Pareto analysis established that initial pH was the most effective parameter. The adsorption capacity value of reactive blue 19 on chitosan hollow fibers was 454.5 mg g(-1). The adsorption was well described by pseudo-second-order kinetics and Freundlich equation.

On the cause of controlling affinity to small molecules of imprinted polymeric membranes prepared by noncovalent approach: a computational and experimental investigation.

Imprinting technique applied to membrane preparation via phase inversion methods yields membranes with enhanced affinity toward target molecules. In the imprinted membranes prepared by noncovalent approach hydrogen bond and electrostatic interactions can play a crucial role in determining the performance of these membranes. In this work, quantum mechanical calculations and experiments were performed to understand the physical-chemical causes of the affinity increase in imprinted polymeric membranes to 4,4'-methylendianiline (MDA), dissolved in an organic solvent. An ad hoc synthesized copolymer of acrylonitrile and acrylic acid was used to prepare the membranes. The calculated binding energies show that the hydrogen bonds and electrostatic interactions among polymeric chains are comparable to the strength of the same interactions occurring between polymer and MDA. Using this result and correlated experimental data, this work concluded that one of the causes responsible for the increased affinity of the imprinted membranes is the augmented availability of free carboxylic groups in the nanocavities of the membranes. However, along with this reason, the membrane pore sizes must evermore be taken into account. The knowledge acquired in this study helps us to better understand the mechanisms of molecular recognition and hence to optimize the design of new imprinted membranes.