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The development of a tailored filament is reported composed of reduced graphene oxide (rGO) and carbon black (CB) in a polylactic acid (PLA) matrix and its use in the production of electrochemical sensors. The electrodes containing rGO showed superior performance when compared with  those prepared in the absence of this material. Physicochemical and electrochemical characterizations of the electrodes showed the successful incorporation of both rGO and CB and an improved conductivity in the presence of rGO (lower resistance to charge transfer). As a proof-of-concept, the developed electrodes were applied to the detection of the forensic analytes TNT and cocaine. The electrodes containing rGO presented a superior analytical performance for both TNT and cocaine detection, showing the lower limit of detection values (0.22 and 2.1 µmol L −1 , respectively) in comparison with pure CB-PLA electrodes (0.93 and 11.3 µmol L −1 , respectively). Besides, better-defined redox peaks were observed, especially for TNT, as well as increased sensitivity for both molecules. Graphical abstract

Graphene-based materials present unique properties for electrochemical applications, and laser-induced conversion of polyimide to graphene is an emerging route to obtain a high-quality material for sensing. Herein we present compact and low-cost equipment constructed from an open-source 3D printer at which a 3.5-W visible (449 nm) laser was adapted to fabricate laser-induced graphene (LIG) electrodes from commercial polyimide, which resulted in electron transfer kinetic ( k 0 ) of 5.6 × 10 −3  cm s −1 and reproducibility calculated by relative standard deviation (RSD < 5%) from cyclic voltammograms of [Fe(CN) 6 ] 3−/4− using 5 different electrodes. LIG electrodes enabled the simultaneous voltammetric determination of uric acid (+ 0.1 V vs. pseudo-reference) and nitrite (+ 0.4 V vs pseudo-reference), with limit of detection (LOD) values of 0.07 and 0.27 µmol L −1 , respectively. Amperometric measurements for the detection of H 2 O 2 (applying + 0.0 V vs. Ag|AgCl|KCl (sat.) ) after Prussian blue (PB) modification and ciprofloxacin (applying + 1.2 V vs. Ag|AgCl|KCl (sat.) ) were performed under flow conditions, which confirmed the high stability of LIG and LIG-PB surfaces. The LOD values were 1.0 and 0.2 µmol L −1 for H 2 O 2 and ciprofloxacin, respectively. The RSD values (< 12%) obtained for the analysis using three different electrodes attested the precision of LIG electrodes manufactured in two designs. No sample matrix effects on the determination of ciprofloxacin in milk samples were observed  (recoveries between 84 and 96%). The equipment can be built with less than $300 and each LIG electrode costs less than $0.01. Graphical abstract

Silver materials are known to present excellent properties, such as high electrical and thermal conductivity as well as chemical stability. Silver-based inks have drawn a lot of attention for being compatible with various substrates, which can be used in the production uniform and stable pseudo-reference electrodes with low curing temperatures. Furthermore, the interest in the use of disposable electrodes has been increasing due to the low cost and the possibility of their use in point-of-care and point-of-need situations. Thus, in this work, two new inks were developed using Ag as conductive material and colorless polymers (nail polish (NP) and shellac (SL)), and applied to different substrates (screen-printed electrodes, acetate sheets, and 3D-printed electrodes) to verify the performance of the proposed inks. Measurements attained with open circuit potential (OCP) attested to the stability of the potential of the pseudo-reference proposed for 1 h. Analytical curves for β-estradiol were also obtained using the devices prepared with the proposed inks as pseudo-references electrodes, which presented satisfactory results concerning the potential stability (RSD < 2.6%). These inks are simple to prepare and present great alternatives for the development of pseudo-reference electrodes useful in the construction of disposable electrochemical systems.

Drug combinations are increasingly studied in the field of anticancer agents. Mathematical models, such as Loewe, Bliss, and HSA, are used to interpret drug combinations, while informatics tools help cancer researchers identify the most effective combinations. However, the different algorithms each software uses lead to results that do not always correlate. This study compared the performance of Combenefit (Ver. 2.021) and SynergyFinder (Ver. 3.6) in analyzing drug synergy by studying combinations involving non-steroidal analgesics (celecoxib and indomethacin) and antitumor drugs (carboplatin, gemcitabine, and vinorelbine) on two canine mammary tumor cell lines. The drugs were characterized, their optimal concentration–response ranges were determined, and nine concentrations of each drug were used to make combination matrices. Viability data were analyzed under the HSA, Loewe, and Bliss models. Celecoxib-based combinations showed the most consistent synergistic effect among software and reference models. Combination heatmaps revealed that Combenefit gave stronger synergy signals, while SynergyFinder produced better concentration–response fitting. When the average values of the combination matrices were compared, some combinations shifted from synergistic to antagonistic due to differences in the curve fitting. We also used a simulated dataset to normalize each software’s synergy scores, finding that Combenefit tends to increase the distance between synergistic and antagonistic combinations. We conclude that concentration–response data fitting biases the direction of the combination (synergistic or antagonistic). In contrast, the scoring from each software increases the differences among synergistic or antagonistic combinations in Combenefit when compared to SynergyFinder. We strongly recommend using multiple reference models and reporting complete data analysis for synergy claiming in combination studies.

Background Non-small cell lung cancer (NSCLC) accounts for most lung cancer cases and poses major challenges due to late-stage diagnosis and limited options. A substantial subset of NSCLC harbors KRAS mutations, most commonly at codon 12. Although KRAS G12C inhibitors show clinical activity, their efficacy is frequently limited by acquired resistance. Polyamines (putrescine, spermidine, and spermine) regulate key cellular processes and are dysregulated during tumorigenesis. S-adenosylmethionine decarboxylase 1 (AMD1) inhibitors such as SAM486A reduce tumor cell proliferation and migration. Thus, we evaluated the combination of the KRAS G12C inhibitor adagrasib with SAM486A in KRAS G12C -mutant NSCLC, in vitro and in vivo. Methods In vitro assays included viability (MTT), clonogenic, BrdU incorporation, and Western blot analyses across four NSCLC cell lines. Drug–drug interactions were quantified using Combenefit software. In vivo efficacy was tested in C57BL/6 mice using an orthotopic model with LLC46 (KRAS G12C /NRAS KO ) cells and a metastatic model with LL2 (KRAS G12C /NRAS Q61H ) cells. Tumor growth was monitored by µCT or caliper measurements, and immunohistochemistry (PCNA) was used to assess proliferation. Results In vitro, adagrasib reduced AMD1 levels, and SAM486A synergistically enhanced its antiproliferative effects, particularly in KRAS G12C -mutant cell lines, with minimal effects on KRAS–wild-type cells. In an orthotopic mouse model using a KRAS G12C /NRAS KO NSCLC line, the combination provided minimal additional benefit over adagrasib monotherapy. In a metastatic model, however, the combination reduced tumor size and PCNA staining more than either monotherapy. Conclusions Our results suggest that targeting polyamine metabolism with SAM486A enhances the efficacy of KRAS G12C inhibitors and may mitigate resistance. This combination represents a promising therapeutic approach for KRAS G12C -mutant NSCLC and warrants further clinical investigation.

Background Lung cancer constitutes the leading cause of cancer mortality. High levels of endothelin-1 (ET-1), its cognate receptor ET A R and its activating enzyme, the endothelin-converting enzyme-1 (ECE-1), have been reported in several cancer types, including lung cancer. ECE-1 comprises four isoforms, which only differ in their cytoplasmic N-terminus. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE-1c, increasing its stability and leading to enhanced invasiveness in glioblastoma and colorectal cancer cells, which is believed to be mediated by the amino acid residue Lys-6, a conserved putative ubiquitination site neighboring the CK2-phosphorylated residues Ser-18 and Ser-20. Whether Lys-6 is linked to the acquisition of a cancer stem cell (CSC)-like phenotype and aggressiveness in human non–small cell lung cancer (NSCLC) cells has not been studied. Methods In order to establish the role of Lys-6 in the stability of ECE-1c and its involvement in lung cancer aggressiveness, we mutated this residue to a non-ubiquitinable arginine and constitutively expressed the wild-type (ECE-1c WT ) and mutant (ECE-1c K6R ) proteins in A549 and H1299 human NSCLC cells by lentiviral transduction. We determined the protein stability of these clones alone or in the presence of the CK2 inhibitor silmitasertib, compared to ECE-1c WT and mock-transduced cells. In addition, the concentration of secreted ET-1 in the growth media was determined by ELISA. Expression of stemness genes were determined by Western blot and RT-qPCR. Chemoresistance to cisplatin was studied by MTS viability assay. Migration and invasion were measured through transwell and Matrigel assays, respectively, and the side-population was determined using flow cytometry. Results ECE-1c K6R displayed higher stability in NSCLC cells compared to ECE-1c WT -expressing cells, but ET-1 secreted levels showed no difference up to 48 h. Most importantly, ECE-1c K6R promoted expression of the stemness genes c-Myc, Sox-2, Oct-4, CD44 and CD133, which enhance cellular self-renewal capability. Also, the ECE-1c K6R -expressing cells showed higher cisplatin chemoresistance, correlating with an augmented side-population abundance due to the increased expression of the ABCG2 efflux pump. Finally, the ECE-1c K6R -expressing cells showed enhanced invasiveness, which correlated with the regulated expression of known EMT markers. Conclusions Our findings suggest an important role of ECE-1c in lung cancer. ECE-1c is key in a non-canonical ET-1-independent mechanism which triggers a CSC-like phenotype, leading to enhanced lung cancer aggressiveness. Underlying this mechanism, ECE-1c is stabilized upon phosphorylation by CK2, which is upregulated in many cancers. Thus, phospho-ECE-1c may be considered as a novel prognostic biomarker of recurrence, as well as the CK2 inhibitor silmitasertib as a potential therapy for lung cancer patients.

Visceral leishmaniasis is a reemerging neglected tropical disease with limitations for its diagnosis, including low concentration of antibodies in the serum of asymptomatic patients and cross-reactions. In this context, this work proposes an electrochemical immunosensor for the diagnosis of visceral leishmaniasis in a more sensitive way that is capable of avoiding cross-reaction with Chagas disease (CD). Crude Leishmania infantum antigens tested in the enzyme-linked immunosorbent assay (ELISA) were methodologically standardized to best engage to the sensor. The antibodies anti-Trypanosoma cruzi and anti-Leishmania sp. Present in serum from patients with diverse types of CD or leishmaniasis were chosen. A screen-printed carbon electrode modified with gold nanoparticles was the best platform to guarantee effective adsorption of all antigens so that the epitope of specific recognition for leishmaniasis occurred efficiently and without cross-reaction with the evaluated CD. The current peaks reduced linearly after the recognition, and still were able to notice the discrimination between different kinds of diseases (digestive, cardiac, undetermined Chagas/acute and visceral chronic leishmaniasis). Comparative analyses with ELISA were performed with the same groups, and a low specificity (44%) was verified due to cross-reactions (high number of false positives) on ELISA tests, while the proposed immunosensor presented high selectivity and specificity (100%) without any false positives or false negatives for the serum samples from isolated patients with different types of CD and visceral leishmaniasis. Furthermore, the biosensor was stable for 5 days and presented a detection limit of 200 ng mL−1.

Indomethacin is a non-selective NSAID used against pain and inflammation. Although cyclooxygenase (COX) inhibition is considered indomethacin’s primary action mechanism, COX-independent ways are associated with beneficial effects in cancer. In colon cancer cells, the activation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) is related to the increase in spermidine/spermine-N1-acetyltransferase-1 (SSAT-1), a key enzyme for polyamine degradation, and related to cell cycle arrest. Indomethacin increases the SSAT-1 levels in lung cancer cells; however, the mechanism relying on the SSAT-1 increase is unclear. Thus, we asked for the influence of the PPAR-γ on the SSAT-1 expression in two lung cancer cell lines: H1299 and A549. We found that the inhibition of PPAR-γ with GW9662 did not revert the increase in SSAT-1 induced by indomethacin. Because the mRNA of SSAT-1 suffers a pre-translation retention step by nucleolin, a nucleolar protein, we explored the relationship between indomethacin and the upstream translation regulators of SSAT-1. We found that indomethacin decreases the nucleolin levels and the cyclin-dependent kinase 1 (CDK1) levels, which phosphorylates nucleolin in mitosis. Overexpression of nucleolin partially reverts the effect of indomethacin over cell viability and SSAT-1 levels. On the other hand, Casein Kinase, known for phosphorylating nucleolin during interphase, is not modified by indomethacin. SSAT-1 exerts its antiproliferative effect by acetylating polyamines, a process reverted by the polyamine oxidase (PAOX). Recently, methoctramine was described as the most specific inhibitor of PAOX. Thus, we asked if methoctramine could increase the effect of indomethacin. We found that, when combined, indomethacin and methoctramine have a synergistic effect against NSCLC cells in vitro. These results suggest that indomethacin increases the SSAT-1 levels by reducing the CDK1-nucleolin regulatory axis, and the PAOX inhibition with methoctramine could improve the antiproliferative effect of indomethacin.

We show that fused deposition modelling (FDM) 3D-printed electrodes can be used for quality control of fuel bioethanol. 3D-printing using carbon black/polylactic acid (CB-PLA) filaments resulted in conductive and biodegradable electrodes for biofuel analysis. As a proof-of-concept, copper determination in fuel bioethanol was performed, as such ions catalyse oxidation processes during storage and transport. Square-wave anodic-stripping voltammetry (SWASV) of copper was achieved after sample dilution in 0.1 mol L−1 HCl as supporting electrolyte (resulting in 30:70% v/v ethanol:water). The linear responses were in the range between 10 and 300 μg L−1 (R = 0.999), inter-day precision was lower than 8% (n = 10, for 20 μg L−1) and limits of detection (LOD) and quantification (LOQ) using 180 s as deposition time were 0.097 μg L−1 and 0.323 μg L−1, respectively. Recovery values between 95 and 103% for the analysis of bioethanol spiked with known amounts of copper were obtained. These results show great promise of the application of 3D-printed sensors for the quality control of biofuels.