Poly(p-xylylene) derivatives, widely known as Parylenes, have been considerably adopted by the scientific community for several applications, ranging from simple passive coatings to active device components. Here, we explore the thermal, structural, and electrical properties of Parylene C, and further present a variety of electronic devices featuring this polymer: transistors, capacitors, and digital microfluidic (DMF) devices. We evaluate transistors produced with Parylene C as a dielectric, substrate, and encapsulation layer, either semitransparent or fully transparent. Such transistors exhibit steep transfer curves and subthreshold slopes of 0.26 V/dec, negligible gate leak currents, and fair mobilities. Furthermore, we characterize MIM (metal–insulator–metal) structures with Parylene C as a dielectric and demonstrate the functionality of the polymer deposited in single and double layers under temperature and AC signal stimuli, mimicking the DMF stimuli. Applying temperature generally leads to a decrease in the capacitance of the dielectric layer, whereas applying an AC signal leads to an increase in said capacitance for double-layered Parylene C only. By applying the two stimuli, the capacitance seems to suffer from a balanced influence of both the separated stimuli. Lastly, we demonstrate that DMF devices with double-layered Parylene C allow for faster droplet motion and enable long nucleic acid amplification reactions.

The success of personalized medicine depends on the discovery of biomarkers that allow oncologists to identify patients that will benefit from a particular targeted drug. Molecular tests are mostly performed using tumor samples, which may not be representative of the tumor’s temporal and spatial heterogeneity. Liquid biopsies, and particularly the analysis of circulating tumor DNA, are emerging as an interesting means for diagnosis, prognosis, and predictive biomarker discovery. In this study, the amplification refractory mutation system (ARMS) coupled with high-resolution melting analysis (HRMA) was developed for detecting two of the most relevant KRAS mutations in codon 12. After optimization with commercial cancer cell lines, KRAS mutation screening was validated in tumor and plasma samples collected from patients with pancreatic ductal adenocarcinoma (PDAC), and the results were compared to those obtained by Sanger sequencing (SS) and droplet digital polymerase chain reaction (ddPCR). The developed ARMS-HRMA methodology stands out for its simplicity and reduced time to result when compared to both SS and ddPCR but showing high sensitivity and specificity for the detection of mutations in tumor and plasma samples. In fact, ARMS-HRMA scored 3 more mutations compared to SS (tumor samples T6, T7, and T12) and one more compared to ddPCR (tumor sample T7) in DNA extracted from tumors. For ctDNA from plasma samples, insufficient genetic material prevented the screening of all samples. Still, ARMS-HRMA allowed for scoring more mutations in comparison to SS and 1 more mutation in comparison to ddPCR (plasma sample P7). We propose that ARMS-HRMA might be used as a sensitive, specific, and simple method for the screening of low-level mutations in liquid biopsies, suitable for improving diagnosis and prognosis schemes. Graphical Abstract: [Figure not available: see fulltext.]

The vast ocean holds many unexplored organisms with unique adaptive features that enable them to thrive in their environment. The secretion of fluorescent proteins is one of them, with reports on the presence of such compounds in marine annelids being scarce. The intertidal Eulalia sp. is an example. The worm secretes copious amounts of mucus, that when purified and concentrated extracts, yield strong fluorescence under UV light. Emission has two main maxima, at 400 nm and at 500 nm, with the latter responsible for the blue–greenish fluorescence. Combining proteomics and transcriptomics techniques, we identified ubiquitin, peroxiredoxin, and 14-3-3 protein as key elements in the mucus. Fluorescence was found to be mainly modulated by redox status and pH, being consistently upheld in extracts prepared in Tris-HCl buffer with reducing agent at pH 7 and excited at 330 nm. One of the proteins associated with the fluorescent signal was localized in secretory cells in the pharynx. The results indicate that the secretion of fluorescent proteinaceous complexes can be an important defense against UV for this dweller. Additionally, the internalization of fluorescent complexes by ovarian cancer cells and modulation of fluorescence of redox status bears important considerations for biotechnological application of mucus components as markers.

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, and is highly resistant to conventional radiotherapy and chemotherapy. Therefore, the development of multidrug resistance and tumor recurrence are frequent. Given the poor survival with the current treatments, new therapeutic strategies are urgently needed. Radiotherapy (RT) is a common cancer treatment modality for GBM. However, there is still a need to improve RT efficiency, while reducing the severe side effects. Radiosensitizers can enhance the killing effect on tumor cells with less side effects on healthy tissues. Herein, we present our pioneering study on the highly stable and amphiphilic metallacarboranes, ferrabis(dicarbollides) ([o-FESAN]− and [8,8′-I2-o-FESAN]−), as potential radiosensitizers for GBM radiotherapy. We propose radiation methodologies that utilize secondary radiation emissions from iodine and iron, using ferrabis(dicarbollides) as iodine/iron donors, aiming to achieve a greater therapeutic effect than that of a conventional radiotherapy. As a proof-of-concept, we show that using 2D and 3D models of U87 cells, the cellular viability and survival were reduced using this treatment approach. We also tested for the first time the proton boron fusion reaction (PBFR) with ferrabis(dicarbollides), taking advantage of their high boron (11B) content. The results from the cellular damage response obtained suggest that proton boron fusion radiation therapy, when combined with boron-rich compounds, is a promising modality to fight against resistant tumors. Although these results are encouraging, more developments are needed to further explore ferrabis(dicarbollides) as radiosensitizers towards a positive impact on the therapeutic strategies for GBM.

Ruthenium(II) arene complexes exhibit promising chemotherapeutic properties. In this study, the effect of the counter anion in Ru(II) complexes was evaluated by analyzing the biological effect of two Ru(II) p-cymene derivatives with the 1,10-phenanthroline-5,6-dione ligand of general-formula [(η6-arene)Ru(L)Cl][X] X = CF3SO3 (JHOR10) and PF6 (JHOR11). The biological activity of JHOR10 and JHOR11 was examined in the ovarian carcinoma cell line A2780, colorectal carcinoma cell line HCT116, doxorubicin-resistant HCT116 (HCT116-Dox) and in normal human dermal fibroblasts. Both complexes JHOR10 and JHOR11 displayed an antiproliferative effect on A2780 and HCT116 cell lines, and low cytotoxicity in fibroblasts. Interestingly, JHOR11 also showed antiproliferative activity in the HCT116-Dox cancer cell line, while JHOR10 was inactive. Studies in A2780 cells showed that JHOR11 induced the production of reactive oxygen species (ROS) that trigger autophagy and cellular senescence, but no apoptosis induction. Further analysis showed that JHOR11 presented no tumorigenicity, with no effect in the cellular mobility, as evaluated by thye wound scratch assay, and no anti- or pro-angiogenic effect, as evaluated by the ex-ovo chorioallantoic membrane (CAM) assay. Importantly, JHOR11 presented no toxicity in chicken and zebrafish embryos and reduced in vivo the proliferation of HCT116 injected into zebrafish embryos. These results show that these are suitable complexes for clinical applications with improved tumor cell cytotoxicity and low toxicity, and that counter-anion alteration might be a viable clinical strategy for improving chemotherapy outcomes in multidrug-resistant (MDR) tumors.

Eight new amorphous organic salts of folic acid (FA) were prepared by mechanochemistry. FA can prevent cardiovascular and neurological diseases. Mechanochemistry overcomes serious FA solubility issues avoiding the use of toxic solvents. Due to low FA solubility, therapeutic effects in supplements and drugs are not achieved. Current strategies to improve FA solubility include its derivatization by using complex synthetic procedures. Herein, a simple and green procedure, avoiding structural modifications, was designed using mechanochemistry. Biocompatible amine-derivative coformers were strategically combined with FA to obtain salts with good physicochemical properties. New 1 : 1 and 1 : 2 amorphous FA salts offer 10 to 10,000 times better aqueous solubility and 10 to 100 times better octanol-water partition coefficient values (Koctanol/water) than FA alone. Koctanol/water is considered as a surrogate of cell permeability. No toxic effects in normal human primary dermal fibroblasts were detected for the prepared FA salts. Our findings suggest that 1 : 2 FA salts of choline hydroxide and derivatives could be good candidates for future pharmaceutical/nutraceutical applications.

The antiproliferative activity of [Mn(CO)3(N^N)Br] (N^N = phendione 1, bipy 3) and of the two newly synthesized Mn complexes [Mn(CO)3(acridine)(phendione)]OTf (2) and [Mn(CO)3(di-triazole)Br] (4) has been evaluated by MTS against three tumor cell lines A2780 (ovarian carcinoma), HCT116 (colorectal carcinoma), HCT116doxR (colorectal carcinoma resistant to doxorubicin), and in human dermal fibroblasts. The antiproliferative assay showed a dose-dependent effect higher in complex 1 and 2 with a selectivity toward ovarian carcinoma cell line 21 times higher than in human fibroblasts. Exposure of A2780 cells to IC50 concentrations of complex 1 and 2 led to an increase of reactive oxygen species that led to the activation of cell death mechanisms, namely via intrinsic apoptosis for 2 and autophagy and extrinsic apoptosis for 1. Both complexes do not target DNA or interfere with cell cycle progression but are able to potentiate cell migration and neovascularization (for 2) an indicative that their application might be directed for initial tumor stages to avoid tumor invasion and metastization and opening a new avenue for complex 2 application in regenerative medicine. Interestingly, both complexes do not show toxicity in both in vivo models (CAM and zebrafish). Graphical abstract: [Figure not available: see fulltext.]

To investigate the effect of different halogen substituents and leaving groups and the flexibility of ligands on the anticancer activity of copper complexes, sixteen copper(ii) complexes with eight different tridentate Schiff-base ligands containing pyridine and 3,5-halogen-substituted phenol moieties were synthesized and characterized by spectroscopic methods. Four of these complexes were also characterized by X-ray crystallography. The cytotoxicity of the complexes was determined in three different tumor cell lines (i.e.the A2780 ovarian, HCT116 colorectal and MCF7 breast cancer cell line) and in a normal primary fibroblast cell line. Complexes were demonstrated to induce a higher loss of cell viability in the ovarian carcinoma cell line (A2780) with respect to the other two tumor cell lines, and therefore the biological mechanisms underlying this loss of viability were further investigated. Complexes with ligandL1(containing a 2-pycolylamine-type motif) were more cytotoxic than complexes withL2(containing a 2-(2-pyridyl)ethylamine-type motif). The loss of cell viability in A2780 tumor cells was observed in the orderCu(Cl2-L1)NO3>Cu(Cl2-L1)Cl>Cu(Br2-L1)Cl>Cu(BrCl-L1)Cl. All complexes were able to induce reactive oxygen species (ROS) that could be related to the loss of cell viability. ComplexesCu(BrCl-L1)ClandCu(Cl2-L1)NO3were able to promote A2780 cell apoptosis and autophagy and for complexCu(BrCl-L1)Clthe increase in apoptosis was due to the intrinsic pathway.Cu(Cl2-L1)ClandCu(Br2-L1)Clcomplexes lead to cellular detachment allowing to correlate with the results of loss of cell viability. Despite the ability of theCu(BrCl-L1)Clcomplex to induce programmed cell death in A2780 cells, its therapeutic window turned out to be low making theCu(Cl2-L1)NO3complex the most promising candidate for additional biological applications.

Cancer is one of the worst health issues worldwide, representing the second leading cause of death. Current chemotherapeutic drugs face some challenges like the acquired resistance of the tumoral cells and low specificity leading to unwanted side effects. There is an urgent need to develop new compounds that may target resistant cells. The synthesis and characterization of two Cu(i) complexes of general formula [Cu(PP)(LL)][BF4], where PP is a phosphane ligand (triphenylphosphine or 1,2-bis(diphenylphosphano) ethane) and LL = is a heteroaromatic bidentate ligand (4,4′-dimethyl-2,2′-bipyridine and 6,3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine). The new compounds were fully characterized by spectroscopic techniques (NMR, FTIR and UV-vis.), elemental analysis (C, H, N and S) and two structures were determined by single X-ray diffraction studies. The antiproliferative potential of the new Cu(i) complexes were studied in tumor (breast adenocarcinoma, ovarian carcinoma and in colorectal carcinoma sensitive and resistant to doxorubicin) and normal (fibroblasts) cell lines. Complexes1-4did not show any antiproliferative potential. Amongst the complexes5-8, complex8shows high cytotoxic potential against colorectal cancer sensitive and resistant to doxorubicin and low cytotoxicity towards healthy cells. We show that complexes5-8can cleave pDNA and, in particular, thein vitropDNA cleavage is due to an oxidative mechanism. This oxidative mechanism corroborates the induction of reactive oxygen species (ROS), that triggers HCT116 cell deathviaapoptosis, as proved by the increased expression of BAX protein relative to BCL-2 protein and the depolarization of mitochondrial membrane potential, andviaautophagy. Additionally, complex8can block the cell cycle in the G1 phase, also exhibiting a cytostatic potential. Proteomic analysis confirmed the apoptotic, autophagic and cytostatic potential of complex8, as well as its ability to produce ROS and cause DNA damage. The interference of the complex in folding and protein synthesis and its ability to cause post-translational modifications was also verified. Finally, it was observed that the complex causes a reduction in cellular metabolism. The results herein demonstrated the potential of Cu(i) complexes in targeting doxorubicin sensitive and resistant cells which is positive and must be further explored usingin vivoanimal models.

Preterm birth is a major clinical and public health challenge, with a prevalence of 11% worldwide. It is the leading cause of death in children younger than five years old and represents 70% of neonatal deaths and 75% of neonatal morbidity. Despite the clinical and public health significance, this condition's aetiology is still unclear, and most of the cases are spontaneous. There are several known preterm birth risk factors, including inflammatory diseases and the genetic background, although the underlying molecular mechanisms are far from understood. The present review highlights the research advances on the association between inflammatory-related genes and the increased risk for preterm delivery. The most associated genetic variants are the TNFα rs1800629, the IL1α rs17561, and the IL1RN rs2234663. Moreover, many of the genes discussed in this review are also implicated in pathologies involving inflammatory or autoimmune systems, such as periodontal disease, bowel inflammatory disease, and autoimmune rheumatic diseases. This review presents evidence suggesting a common genetic background to preterm birth, autoimmune and inflammatory diseases susceptibility. This article is protected by copyright. All rights reserved.