Simultaneous, But Not Consecutive, Combination With Folinate Salts Potentiates 5-fluorouracil Antitumor Activity In Vitro and In Vivo

The combination of folinate salts to 5-fluoruracil (5-FU)-based schedules is an established clinical routine in the landscape of the colorectal cancer treatment. The aim of this study was to investigate the pharmacological differences between the sequential administration of folinate salts (1 h before, as in clinical routine) followed by 5-FU and the simultaneous administration of both drugs. Proliferation and apoptotic assays were performed on human colon cancer cells exposed to 5-FU, calcium (CaLV) or disodium (NaLV) levofolinate or their simultaneous and sequential combination for 24 and 72h. TYMS and SLC19A1 gene expression was performed with real time PCR. In vivo experiments were performed in xenografted nude mice, treated with 5-FU escalating doses and CaLV or NaLV alone or in simultaneous and sequential combination. The simultaneous combination of folinate salts and 5-FU was synergistic (NaLV) or additive (CaLV) in a 24h treatment in both cell lines. In contrast, the sequential combination of both folinate salts and 5-FU was antagonistic at 24 and 72h. The simultaneous combination of 5-FU and NaLV or CaLV inhibited TYMS gene expression at 24h, whereas the sequential combination reduced SLC19A1 gene expression. In vivo experiments confirmed the enhanced antitumor activity of the 5-FU+NaLV simultaneous combination with a good toxicity profile, whereas the sequential combination with CaLV failed to potentiate 5-FU activity. In conclusion, only the simultaneous, but not the consecutive, in vitro and in vivo combination of 5-FU and both folinate salt formulations potentiated the antiproliferative effects of the drugs

Photodynamic therapy for the eradication of biofilms formed by catheter associated Pseudomonas aeruginosa strains

Pseudomonas aeruginosa has emerged as a major opportunistic pathogen causing catheter-associated urinary tract infections (CA-UTIs) associated with high mortality and morbidity. In this study 18 P. aeruginosa isolates from urine of catheterized patients were evaluated for in vitro biofilm formation.All the tested strains showed the ability to form biofilm more thicker than those formed by a cohort of 29 blood culture strains belonging to the same species. Photodynamic antimicrobial chemotherapy (PACT) is a novel antimicrobial treatment that exploits a photosensitizer (PS) and visible light to induce lethal oxidative damages in bacterial cells and could be used as local antimicrobial approach in CA-UTIs. Here we tested the susceptibility of planktonic and sessile cultures of P. aeruginosa strains, the model strain PAO1 and CA-UTI isolates, to photodynamic inactivation with a di cationic porphyrinic photosensitizer, the 5, 15-di (N-benzyl-4-pyridynium)-porphyrin di chloride.Although Pseudomonas aeruginosa is regarded as a difficult target for antimicrobial chemotherapy, satisfactory bactericidal activities on both planktonic and biofilm cultures were observed

Towards the Development of a Z-Scheme FeOx/g-C3N4 Thin Film and Perspectives for Ciprofloxacin Visible Light-Driven Photocatalytic Degradation

Thermally synthesized graphitic carbon nitride (g-C3N4) over pulsed laser deposition (PLD) produced urchin-like iron oxide (FeOx) thin films were fabricated via in situ and ex situ processes. Materials characterisation revealed the formation of the graphitic allotrope of C3N4 and a bandgap Eg for the combined FeOx/g-C3N4 of 1.87 and 1.95 eV for each of the different fabrication strategies. The in situ method permitted to develop a novel petal-like morphology, whereas for the ex situ method, a morphological mixture between FeOx bulk and g-C3N4 was observed. Given the improved optical and morphological properties of the in situ film, it was employed as a proof of concept for the direct photocatalysis and photo-Fenton removal of ciprofloxacin antibiotic (CIP) under visible light irradiation. Improved photocatalytic activity (rate constant k = 8.28 × 10−4 min−1) was observed, with further enhancement under photo-Fenton conditions (k = 2.6 × 10−3 min−1), in comparison with FeOx + H2O2 (k = 1.6 × 10−3 min−1) and H2O2 only (k = 1.3 × 10−4 min−1). These effects demonstrate the in situ methodology as a viable route to obtain working heterojunctions for solar photocatalysis in thin-film materials, rather than the more common powder materials

Extraction of antibacterial active compounds from dry leaves of African plants of the Combretaceae family

The dry leaves of two African plants of the Combretaceae family, furnished by the botanist of the St. Jean de Dieu hospital of Tangueita (Benin, central Africa),were extracted with a sequence of 5 solvents with increasing polarity (from cyclohexane to water).The raw materials, obtained from these extractions following solvent evaporations, were tested for antibiotic activity against gram negative and gram positive bacterial strains. According to the results of a modified Kirby-Bauer test, no promising effect was obtained against Gram negative bacteria while interesting dose-effect activities were observed against Gram positive strains. In particular, from G. senegalensis active compounds were found in the low polarity extract (dichloromethane) which, at a concentration of 800 μg/disk (13 mm diameter disk), resulted in a grow inhibition crown of 4.7 mm and 2.6 mm on Enterococcus faecalis and Staphylococcus aureus MSSA, respectively. An higher amount of the aqueous extract (4760 μg/disk) also produced a good result as 5.7 mm and 5.0 mm crowns were observed. The extracts from C. micranthum showed an inhibiting effect in the more polar extracts (i.e. from ethanol and water) which gave 1 mm of grow inhibition crown on both strains at a concentration of 1000 μg/disk. The most promising extract from each plant was partially purified and then tested on some clinical relevant bacterial strains: S. aureus MRSA, Clostridium difficile, Streptococcus pyogenes, Streptococcus pneumoniae, Corynebacterium striatum, Neisseria gonorrhoeae, Haemophylus influenzae, Escherichia coli, obtaining a good killing effects on the Gram positive bacteria of the panel

Acompañar desde la gestión, mediante proyectos de intervención pedagógica que colaboran a la mejora institucional

Desde la cátedra de Trabajo Final, la propuesta para el abordaje de nuestro trabajo es un proyecto de intervención educativa, situado en un establecimiento educativo del nivel medio, de gestión privada, de una congregación católica de hermanas religiosas; actualmente sin presencia de representantes religiosos en el colegio. Cuenta con los tres niveles de enseñanza: jardín, primario y secundario. Ubicado en el departamento Punilla. El tema elegido es acompañar las trayectorias escolares de nuestros estudiantes, mediante distintas estrategias que validen el mejoramiento de los aprendizajes y posibiliten una mejora institucional, haciendo foco en la repitencia, permanencia y promoción de los aprendizajes, ya que contábamos con algunas estadísticas de dos equipos de gestión, de la misma institución (sumamente diferenciados), que nos permitieron observar a priori, que el cambio de equipo de gestión directiva había posibilitado un incipiente cambio en el aumento de la matrícula, permanencia y repitencia de los alumnos del nivel medio. El avance del análisis estadístico de la información, nos ha permitido demostrar que al hacer foco en las trayectorias pedagógicas de los alumnos y en el acompañamiento pedagógico de los docentes, los indicadores de permanencia aumentaban y los de repitencia bajaban, así como también los de deserción. Esta realidad nos hizo reflexionar en el marco teórico de diferentes cátedras cursadas desde la licenciatura como ser: investigación educativa, innovaciones educativas, calidad y mejora institucional, mediación y resolución de conflictos y otras que fueron fortaleciendo y enriqueciendo nuestro trabajo, su composición y el posicionamiento de nuestro equipo de trabajo para esta cátedra que será el corolario de nuestra carrera de grado.Fil: Domínguez, María Gabriela. Universidad Católica de Córdoba. Facultad de Educación; Argentina.Fil: Orlandi, Paola de las Mercedes. Universidad Católica de Córdoba. Facultad de Educación; Argentina.Fil: Perafán, Noelía Paola. Universidad Católica de Córdoba. Facultad de Educación; Argentina.Fil: Rodríguez, María Alejandra. Universidad Católica de Córdoba. Facultad de Educación; Argentina

Markerless Analysis of Articulatory Movements in Patients With Parkinson's Disease

Objectives: A large percentage of patients with Parkinson's disease have hypokinetic dysarthria, exhibiting reduced peak velocities of jaw and lips during speech. This limitation implies a reduction of speech intelligibility for such patients. This work aims at testing a cost-effective markerless approach for assessing kinematic parameters of hypokinetic dysarthria. Study design: Kinematic parameters of the lips are calculated during a syllable repetition task from 14 Parkinsonian patients and 14 age-matched control subjects. Methods: Combining color and depth frames provided by a depth sensor (Microsoft Kinect), we computed the three-dimensional coordinates of main facial points. The peak velocities and accelerations of the lower lip during a syllable repetition task are considered to compare the two groups. Results: Results show that Parkinsonian patients exhibit reduced peak velocities of the lower lip, both during the opening and the closing phase of the mouth. In addition, peak values of acceleration are reduced in Parkinsonian patients, although with significant differences only in the opening phase with respect to healthy control subjects. Conclusions: The novel contribution of this work is the implementation of an entirely markerless technique capable to detect signs of hypokinetic dysarthria for the analysis of articulatory movements during speech. Although a large number of Parkinsonian patients have hypokinetic dysarthria, only a small percentage of them undergoes speech therapy to increase their articulatory movements. The system proposed here could be easily implemented in a home environment, thus, increasing the percentage of patients who can perform speech rehabilitation at home

Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer in vitro and in vivo

Lenvatinib is an oral, multitargeted tyrosine kinase inhibitor (TKI) of VEGFR1-VEGFR3, FGFR1-FGFR4, PDGFRα, RET and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) signaling networks involved in tumor angiogenesis. We have evaluated the antitumor activity of lenvatinib in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C (undifferentiated thyroid cancer) and in an ATC-cell line (AF). The AF cell line was obtained from the primary ATC cultures and was the one that grew over 50 passages. The effect of lenvatinib (1 and 100 nM; and 1, 10, 25 and 50 μM) was investigated in primary ATC, 8305C and AF cells as well as in AF cells in CD nu/nu mice. Lenvatinib significantly reduced ATC cell proliferation (P<0.01, ANOVA) and increased the percentage of apoptotic ATC cells (P<0.001, ANOVA). Furthermore, lenvatinib inhibited migration (P<0.01) and invasion (P<0.001) in ATC. In addition, lenvatinib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in the ATC cells. Lenvatinib also significantly inhibited 8305C and AF cell proliferation, increasing apoptosis. AF cells were subcutaneously injected into CD nu/nu mice and tumor masses were observed 20 days later. Tumor growth was significantly inhibited by lenvatinib (25 mg/kg/day), as well as the expression of VEGF-A and microvessel density in the AF tumor tissues. In conclusion, the antitumor and antiangiogenic activities of lenvatinib may be promising for the treatment of anaplastic thyroid cancer, and may consist a basis for future clinical therapeutic applications

Vandetanib has antineoplastic activity in anaplastic thyroid cancer, in vitro and in vivo

The antitumor activity of vandetanib [a multiple signal transduction inhibitor including the RET tyrosine kinase, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) receptor (VEGFR), ERK and with antiangiogenic activity], in primary anaplastic thyroid cancer (ATC) cells, in the human cell line 8305C [undifferentiated thyroid cancer (TC)] and in an ATC-cell line (AF), was investigated in the present study. Vandetanib (1 and 100 nM; 1, 10, 25 and 50 μM) was tested by WST-1, apoptosis, migration and invasion assays: in primary ATC cells, in the 8305C continuous cell line, and in AF cells; and in 8305C cells in CD nu/nu mice. Vandetanib significantly reduced ATC cell proliferation (P<0.01, ANOVA), induced apoptosis dose-dependently (P<0.001, ANOVA), and inhibited migration (P<0.01) and invasion (P<0.001). Furthermore, vandetanib inhibited EGFR, AKT and ERK1/2 phosphorylation and downregulated cyclin D1 in ATC cells. In 8305C and AF cells, vandetanib significantly inhibited the proliferation, inducing also apoptosis. 8305C cells were injected subcutaneously in CD nu/nu mice and tumor masses became detectable after 30 days. Vandetanib (25 mg/kg/day) significantly inhibited tumor growth and VEGF-A expression and microvessel density in 8305C tumor tissues. In conclusion, the antitumor and antiangiogenic activity of vandetanib is very auspicious in ATC, opening the way to a future clinical evaluation

Discovery of a Potent Dual Inhibitor of Aromatase and Aldosterone Synthase.

Estrogen deficiency derived from inhibition of estrogen biosynthesis is a typical condition of postmenopausal women and breast cancer (BCs) patients undergoing antihormone therapy. The ensuing increase in aldosterone levels is considered to be the major cause for cardiovascular diseases (CVDs) affecting these patients. Since estrogen biosynthesis is regulated by aromatase (CYP19A1), and aldosterone biosynthesis is modulated by aldosterone synthase (CYP11B2), a dual inhibitor would allow the treatment of BC while reducing the cardiovascular risks typical of these patients. Moreover, this strategy would help overcome some of the disadvantages often observed in single-target or combination therapies. Following an in-depth analysis of a library of synthesized benzylimidazole derivatives, compound was found to be a potent and selective dual inhibitor of aromatase and aldosterone synthase, with IC values of 2.3 and 29 nM, respectively. Remarkably, the compound showed high selectivity with respect to 11β-hydroxylase (CYP11B1), as well as CYP3A4 and CYP1A2. When tested in cells, showed potent antiproliferative activity against BC cell lines, particularly against the ER+ MCF-7 cells (IC of 0.26 ± 0.03 μM at 72 h), and a remarkable pro-apoptotic effect. In addition, the compound significantly inhibited mTOR phosphorylation at its IC concentration, thereby negatively modulating the PI3K/Akt/mTOR axis, which represents an escape for the dependency from ER signaling in BC cells. The compound was further investigated for cytotoxicity on normal cells and potential cardiotoxicity against ERG and Nav1.5 ion channels, demonstrating a safe biological profile. Overall, these assays demonstrated that the compound is potent and safe, thus constituting an excellent candidate for further evaluation. [Abstract copyright: © 2023 The Authors. Published by American Chemical Society.

Valproic Acid, a Histone Deacetylase Inhibitor, in Combination with Paclitaxel for Anaplastic Thyroid Cancer: Results of a Multicenter Randomized Controlled Phase II/III Trial

Anaplastic thyroid cancer (ATC) has a median survival less than 5 months and, to date, no effective therapy exists. Taxanes have recently been stated as the main drug treatment for ATC, and the histone deacetylase inhibitor valproic acid efficiently potentiates the effects of paclitaxel in vitro. Based on these data, this trial assessed the efficacy and safety of the combination of paclitaxel and valproic acid for the treatment of ATC. This was a randomized, controlled phase II/III trial, performed on 25 ATC patients across 5 centers in northwest Italy. The experimental arm received the combination of paclitaxel (80 mg/m2/weekly) and valproic acid (1,000 mg/day); the control arm received paclitaxel alone. Overall survival and disease progression, evaluated in terms of progression-free survival, were the primary outcomes. The secondary outcome was the pharmacokinetics of paclitaxel. The coadministration of valproic acid did not influence the pharmacokinetics of paclitaxel. Neither median survival nor median time to progression was statistically different in the two arms. Median survival of operated-on patients was significantly better than that of patients who were not operated on. The present trial demonstrates that the addition of valproic acid to paclitaxel has no effect on overall survival and disease progression of ATC patients. This trial is registered with EudraCT 2008-005221-11