Novel Therapeutic Opportunities in Neoadjuvant Setting in Urothelial Cancers: A New Horizon Opened by Molecular Classification and Immune Checkpoint Inhibitors

Muscle invasive bladder cancer (MIBC) is a widespread malignancy with a worse prognosis often related to a late diagnosis. For early-stage MIBC pts, a multidisciplinary approach is mandatory to evaluate the timing of neoadjuvant chemotherapy (NAC) and surgery. The current standard therapy is platinum-based NAC (MVAC-methotrexate, vinblastine, doxorubicin, and cisplatin or Platinum–Gemcitabine regimens) followed by radical cystectomy (RC) with lymphadenectomy. However, preliminary data from Vesper trial highlighted that dose-dense NAC MVAC is endowed with a good pathological response but shows low tolerability. In the last few years, translational-based research approaches have identified several candidate biomarkers of NAC esponsiveness, such as ERCC2, ERBB2, or DNA damage response (DDR) gene alterations. Moreover, the recent consensus MIBC molecular classification identified six molecular subtypes, characterized by different sensitivity to chemo- or targeted or immunotherapy, that could open a novel procedure for patient selection and also for neoadjuvant therapies. The Italian PURE-01 phase II Trial extended data on efficacy and resistance to Immune Checkpoint Inhibitors (ICIs) in this setting. In this review, we summarize the most relevant literature data supporting NAC use in MIBC, focusing on novel therapeutic strategies such as immunotherapy, considering the better patient stratification and selection emerging from novel molecular classification.     

Fetal Undernutrition Modifies Vascular RAS Balance Enhancing Oxidative Damage and Contributing to Remodeling

Fetal stress is known to increase susceptibility to cardiometabolic diseases and hypertension in adult age in a process known as fetal programming. This study investigated the relationship between vascular RAS, oxidative damage and remodeling in fetal programming. Six-month old Sprague-Dawley offspring from mothers that were fed ad libitum (CONTROL) or with 50% intake during the second half of gestation (maternal undernutrition, MUN) were used. qPCR or immunohistochemistry were used to obtain the expression of receptors and enzymes. Plasma levels of carbonyls were measured by spectrophotometry. In mesenteric arteries from MUN rats we detected an upregulation of ACE, ACE2, AT₁ receptors and NADPH oxidase, and lower expression of AT₂, Mas and MrgD receptors compared to CONTROL. Systolic and diastolic blood pressure and plasma levels of carbonyls were higher in MUN than in CONTROL. Vascular morphology evidenced an increased media/lumen ratio and adventitia/lumen ratio, and more connective tissue in MUN compared to CONTROL. In conclusion, fetal undernutrition indices RAS alterations and oxidative damage which may contribute to the remodeling of mesenteric arteries, and increase the risk of adverse cardiovascular events and hypertension.     

Teriflunomide Preserves Neuronal Activity and Protects Mitochondria in Brain Slices Exposed to Oxidative Stress

Teriflunomide (TFN) limits relapses in relapsing–remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria.     

On the Acetylation of Phenanthrene and 9-chlorophenanthrene

Friedel-Crafts acetylation of phenanthrene ( 1a ) in sym-tetrachloroethane yields mixtures of 2-, 3- and 9-acetylphenanthrenes ( 2a, 3a, 4 ). The distribution of isomers is found to depend strongly upon the method of mixing the reagents. Acetylation of 9-chlorophenanthrene ( 1b ), performed by a variety of methods and solvents, led mainly to 3-acetyl-9-chlorophenanthrene ( 3b ) (≥85%). Previously unreported 2-acetyl-9-chlorophenanthrene ( 2b ) was found to form up to a maximum 11% in nitrobenzene.     

The Impact of [C16Pyr][Amp] on the Aggressiveness in Breast and Prostate Cancer Cell Lines

Breast (BrCa) and prostate (PCa) cancers are the most common malignancies in women and men, respectively. The available therapeutic options for these tumors are still not curative and have severe side effects. Therefore, there is an urgent need for more effective antineoplastic agents. Herein, BrCa, PCa, and benign cell lines were treated with two ionic liquids and two quinoxalines and functional experiments were performed—namely cell viability, apoptosis, cytotoxicity, and colony formation assays. At the molecular level, an array of gene expressions encompassing several molecular pathways were used to explore the impact of treatment on gene expression. Although both quinoxalines and the ionic liquid [C2OHMIM][Amp] did not show any effect on the BrCa and PCa cell lines, [C16Pyr][Amp] significantly decreased cell viability and colony formation ability, while it increased the apoptosis levels of all cell lines. Importantly, [C16Pyr][Amp] was found to be more selective for cancer cells and less toxic than cisplatin. At the molecular level, this ionic liquid was also associated with reduced expression levels of CPT2, LDHA, MCM2, and SKP2, in both BrCa and PCa cell lines. Hence, [C16Pyr][Amp] was shown to be a promising anticancer therapeutic agent for BrCa and PCa cell lines.     

New Formulation of a Methylseleno-Aspirin Analog with Anticancer Activity Towards Colon Cancer

Aspirin (ASA) has attracted wide interest of numerous scientists worldwide thanks to its chemopreventive and chemotherapeutic effects, particularly in colorectal cancer (CRC). Incorporation of selenium (Se) atom into ASA has greatly increased their anti-tumoral efficacy in CRC compared with the organic counterparts without the Se functionality, such as the promising antitumoral methylseleno-ASA analog (1a). Nevertheless, the efficacy of compound 1a in cancer cells is compromised due to its poor solubility and volatile nature. Thus, 1a has been formulated with native α-, β- and γ-cyclodextrin (CD), a modified β-CD (hydroxypropyl β-CD, HP-β-CD) and Pluronic F127, all of them non-toxic, biodegradable and FDA approved. Water solubility of 1a is enhanced with β- and HP- β-CDs and Pluronic F127. Compound 1a forms inclusion complexes with the CDs and was incorporated in the hydrophobic core of the F127 micelles. Herein, we evaluated the cytotoxic potential of 1a, alone or formulated with β- and HP- β-CDs or Pluronic F127, against CRC cells. Remarkably, 1a formulations demonstrated more sustained antitumoral activity toward CRC cells. Hence, β-CD, HP-β-CD and Pluronic F127 might be excellent vehicles to improve pharmacological properties of organoselenium compounds with solubility issues and volatile nature.     

Extrusion deactivation of rice bran enzymes by pH modification

Rice bran is considered in Mexico as “waste”, useful only for feeds. As considerable amounts of oil are available in rice bran, it might be worthwhile to stabilize it and extract the edible oil before using it for feedstuffs. Precisely these oils are responsible for rice bran rapid deterioration, particularly in climatic conditions such as those prevalent in Mexico's tropical areas (high humidity and high temperature). This paper deals with the study of the effect of pH during extrusion of fresh rice bran in order to inactivate lipid‐breaking enzymes. Hydrochloric acid or calcium hydroxide, Ca(OH)₂, were added at 0, 1, 5, 10% (dry basis), and moisture content of the bran samples was varied (20, 30, 40%, dry basis) in a 3² factorial design to corroborate its effect at acid and alkaline pH range. Free fatty acids (FFA) increase was the control variable. Extruded samples were stored at room temperature (between 20 and 28 °C) using a non‐extruded sample as control to assess the shelf life effects. Results indicate that in acid‐extruded samples, the increase in FFA concentration after 98 days was much less than in the unmodified‐pH or alkaline samples. The lowest FFA increase after 3 months of storage time was <10 mg FFA/g rice bran using extrusion with no water or chemicals added or using extrusion adding HCl, irrespective of the moisture content of rice bran.     

Vitamins A and E content in infant milk-based powdered formulae after opening the packet

Vitamins A and E were determined by HPLC in 20 starting, milk-based powdered infant formulae from local markets. We traced the evolution of these compounds, once the packets had been opened, during 0, 30 and 70 days of storage at room temperature (≈25 °C; min. 23 °C, max. 25.5 °C). Immediately after opening the packets, vitamin A ranged from 0.55 to 0.94 mg RE/100 g (93.3–183 μg RE/100 kcal) and vitamin E from 6.58 to 27.8 mg α-TE/100 g (1.36–5.39 mg α-TE/100 kcal). All the samples had higher vitamins A and E contents than those declared on the label, vitamin A mean adequacy values: 134% ± 17, min. 98%, max. 162%, and vitamin E 185% ± 47, min. 101%, max. 286%, including values at 0, 30 and 70 days of storage.     

Indentation Damage and Residual Stress Field in Alumina-Y2O3-Stabilized Zirconia Composites

Fracture features, residual stresses, and zirconia transformation are studied in indentation strength specimens of alumina-Y₂O₃-stabilized zirconia (3% mol of Y₂O₃, 3YTZP) ceramics in order to analyze the extension of the indentation damage in the bulk of the specimens. Two compositions, 5 vol% 3YTZP (A5) and 40 vol% 3YTZP (A40), have been prepared by stacking tape-casted tapes and sintering. After indentation with loads ranging from 50 to 300 N, samples were fractured in four-point bending and the fracture surfaces were characterized by scanning electron microscopy. Raman and piezospectroscopic techniques were used to determine the monoclinic zirconia fraction and the residual stresses through the fracture surfaces. In the A5 composition, the indentation damage morphology was clearly half-penny, whereas the A40 composition presented Palmqvist crack formation. Zirconia transformation was only observed in the plastically deformed zones underneath the imprints whereas there were significant residual compressive stresses outside the plastic zones due to the indentation damage. The intensity of this residual compressive field was dependent on the level of zirconia transformation due to indentation damage because zirconia transformation induced tensile stress fields superimposed on the compressive stresses.     

The effect of additives on the treatment of oil-in-water emulsions by vacuum evaporation

A simple batch vacuum evaporation process for the treatment of several oil-in-water (O/W) emulsions is reported. The experiments were carried out with waste emulsions from an industrial copper rolling process and with model emulsions prepared in the laboratory. No detailed information on the formulation of the industrial waste O/W emulsions was available. Several model emulsions were formulated using the same base oil (an 85–15% (w/w) mixture of a synthetic poly-α-olefin and a trimethylol propane trioleate ester, respectively) and one of the three following surfactants: Brij-76 (polyethylene glycol octadecyl ether, non-ionic), CTAB (hexadecyltrimethyl ammonium bromide, cationic), and Oleth-10 (glycolic acid ethoxylate oleyl ether, anionic). Experimental results show a strong influence of operating conditions, such as pressure or bath temperature, on the evaporation performance. As a general trend, the higher the values of these parameters, the higher the pollutant content in the obtained aqueous effluent. The presence of surfactants increase the evaporation rate, especially at low operating vacuum pressures, the solubility of oil molecules in water and the evaporation temperature of model O/W emulsions. Furthermore, COD reductions higher than 99.5% for the treated waste O/W emulsions were achieved.