Experience With Bexarotene to Treat Cutaneous T-Cell Lymphomas: A Study of the Spanish Working Group of Cutaneous Lymphomas

Background and objectives: Bexarotene has been approved to treat advanced stage cutaneous T -cell lymphomas (CTCL) since 1999. However, very few data have been published on its long-term safety and efficacy profile. The aim of this study is to determine the tolerability to bexarotene and outcomes by collecting the 2nd largest case series to date on its long-term use vs CTCL. Material and method: This was a multicenter retrospective review of 216 patients with mycosis fungoides (174), or S & eacute;zary syndrome (42) on a 10 -year course of bexarotene alone or in combination with other therapies at 19 tertiary referral teaching hospitals. Results: A total of 133 men (62%) and 83 women (38%) were included, with a mean age of 63.5 year (27 - 95). A total of 45% were on bexarotene monotherapy for the entire study period, 22% started on bexarotene but eventually received an additional therapy, 13% were on another treatment but eventually received bexarotene while the remaining 20% received a combination therapy since the beginning. The median course of treatment was 20.78 months (1 - 114); and the overall response rate, 70.3%. Complete and partial response rates were achieved in 26% and 45% of the patients, respectively. Treatment was well tolerated, being the most common toxicities hypertriglyceridemia (79%), hypercholesterolemia (71%), and hypothyroidism (52%). No treatment -related grade 5 adverse events were reported. Conclusions: Our study confirms bexarotene is a safe and effective therapy for the long-term treatment of CTCL. (c) 2024 AEDV. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY -NC -ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Intraoperative oxygen tension and redox homeostasis in Pseudomyxoma peritonei: A short case series

IntroductionPseudomyxoma peritonei (PMP) is a rare malignant disease characterized by a massive multifocal accumulation of mucin within the peritoneal cavity. The current treatment option is based on complete cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy. However, the recurrence is frequent with subsequent progression and death. To date, most of the studies published in PMP are related to histological and genomic analyses. Thus, the need for further studies unveiling the underlying PMP molecular mechanisms is urgent. In this regard, hypoxia and oxidative stress have been extensively related to tumoral pathologies, although their contribution to PMP has not been elucidated.MethodsIn this manuscript, we have evaluated, for the first time, the intratumoral real-time oxygen microtension (pO2mt) in the tumor (soft and hard mucin) and surrounding healthy tissue from five PMP patients during surgery. In addition, we measured hypoxia (Hypoxia Inducible Factor-1a; HIF-1α) and oxidative stress (catalase; CAT) markers in soft and hard mucin from the same five PMP patient samples and in five control samples.ResultsThe results showed low intratumoral oxygen levels, which were associated with increased HIF-1α protein levels, suggesting the presence of a hypoxic environment in these tumors. We also found a significant reduction in CAT activity levels in soft and hard mucin compared with healthy tissue samples.DiscussionIn conclusion, our study provides the first evidence of low intratumoral oxygen levels in PMP patients associated with hypoxia and oxidative stress markers. However, further investigation is required to understand the potential role of oxidative stress in PMP in order to find new therapeutic strategies

Differential Scanning Fluorometry Signatures as Indicators of Enzyme Inhibitor Mode of Action: Case Study of Glutathione S-Transferase

Differential scanning fluorometry (DSF), also referred to as fluorescence thermal shift, is emerging as a convenient method to evaluate the stabilizing effect of small molecules on proteins of interest. However, its use in the mechanism of action studies has received far less attention. Herein, the ability of DSF to report on inhibitor mode of action was evaluated using glutathione S-transferase (GST) as a model enzyme that utilizes two distinct substrates and is known to be subject to a range of inhibition modes. Detailed investigation of the propensity of small molecule inhibitors to protect GST from thermal denaturation revealed that compounds with different inhibition modes displayed distinct thermal shift signatures when tested in the presence or absence of the enzyme's native co-substrate glutathione (GSH). Glutathione-competitive inhibitors produced dose-dependent thermal shift trendlines that converged at high compound concentrations. Inhibitors acting via the formation of glutathione conjugates induced a very pronounced stabilizing effect toward the protein only when GSH was present. Lastly, compounds known to act as noncompetitive inhibitors exhibited parallel concentration-dependent trends. Similar effects were observed with human GST isozymes A1-1 and M1-1. The results illustrate the potential of DSF as a tool to differentiate diverse classes of inhibitors based on simple analysis of co-substrate dependency of protein stabilization

Electrostatic Effects in the Folding of the SH3 Domain of the c-Src Tyrosine Kinase: pH-Dependence in 3D-Domain Swapping and Amyloid Formation

The SH3 domain of the c-Src tyrosine kinase (c-Src-SH3) aggregates to form intertwined dimers and amyloid fibrils at mild acid pHs. In this work, we show that a single mutation of residue Gln128 of this SH3 domain has a significant effect on: (i) its thermal stability; and (ii) its propensity to form amyloid fibrils. The Gln128Glu mutant forms amyloid fibrils at neutral pH but not at mild acid pH, while Gln128Lys and Gln128Arg mutants do not form these aggregates under any of the conditions assayed. We have also solved the crystallographic structures of the wild-type (WT) and Gln128Glu, Gln128Lys and Gln128Arg mutants from crystals obtained at different pHs. At pH 5.0, crystals belong to the hexagonal space group P6522 and the asymmetric unit is formed by one chain of the protomer of the c-Src-SH3 domain in an open conformation. At pH 7.0, crystals belong to the orthorhombic space group P212121, with two molecules at the asymmetric unit showing the characteristic fold of the SH3 domain. Analysis of these crystallographic structures shows that the residue at position 128 is connected to Glu106 at the diverging β-turn through a cluster of water molecules. Changes in this hydrogen-bond network lead to the displacement of the c-Src-SH3 distal loop, resulting also in conformational changes of Leu100 that might be related to the binding of proline rich motifs. Our findings show that electrostatic interactions and solvation of residues close to the folding nucleation site of the c-Src-SH3 domain might play an important role during the folding reaction and the amyloid fibril formation.This research was funded by the Spanish Ministry of Science and Innovation and Ministry of Economy and Competitiveness and FEDER (EU): BIO2009-13261-C02-01/02 (ACA); BIO2012-39922-C02-01/02 (ACA); CTQ2013-4493 (JLN) and CSD2008-00005 (JLN); Andalusian Regional Government (Spain) and FEDER (EU): P09-CVI-5063 (ACA); and Valentian Regional Government (Spain) and FEDER (EU): Prometeo 2013/018 (JLN). Data collection was supported by European Synchrotron Radiation Facility (ESRF), Grenoble, France: BAG proposals MX-1406 (ACA) and MX-1541 (ACA); and ALBA (Barcelona, Spain) proposals 2012010072 (ACA) and 2012100378 (ACA)

Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor

[EN] A series of tetrahydroisoquinolines functionalized with carbamates is reported here as highly selective ligands on the dopamine D2 receptor. These compounds were selected by means of a molecular modeling study. The studies were carried out in three stages: first an exploratory study was carried out using combined docking techniques and molecular dynamics simulations. According to these results, the bioassays were performed; these experimental studies corroborated the results obtained by molecular modeling. In the last stage of our study, a QTAIM analysis was performed in order to determine the main molecular interactions that stabilize the different ligand-receptor complexes. Our results show that the adequate use of combined simple techniques is a very useful tool to predict the potential affinity of new ligands at dopamine D1 and D2 receptors. In turn the QTAIM studies show that they are very useful to evaluate in detail the molecular interactions that stabilize the different ligand-receptor complexes; such information is crucial for the design of new ligands.This work was supported by Universidad Nacional de San Luis (UNSL) and CONICET grants 2-1214 and PIP444, respectively. E.L.A, L.J.G, S.A.A and R.D.E are staff members of the National Scientific and Technical Research Council - Argentina ( CONICET, Argentina).Parravicini, O.; Bogado, ML.; Rojas, S.; Angelina, EL.; Andujar, SA.; Gutierrez, LJ.; Cabedo Escrig, N.... (2017). Tetrahydroisoquinolines functionalized with carbamates as selective ligands of D2 dopamine receptor. Journal of Molecular Modeling. 23(9):1-14. https://doi.org/10.1007/s00894-017-3441-6S114239Beaulieu JM, Gainetdinov RR (2011) The physiology, signaling, and pharmacology of dopamine receptors. 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Not AvailableThe current study evaluated the key characters of aroma composition in diversified red wines (Cinsaut, Grenache, Cabernet Franc, Petit Verdot, Cabernet Sauvignon, Nielluccio, Tempranillo, Syrah, Merlot and Caladoc). Out of hundreds of volatile compounds 64 compounds were considered for study. Different groups consisting of fatty acids, volatile alcohols, aldehydes, esters, volatile phenols and terpenes were analysed using gas chromatography mass spectrometry coupled with thermal desorption (TD–GC–MS). Among all these diversified classes, alcohols were found as the most dominant group followed by esters and acids whereas aldehydes, phenols and terpenes were found to be minor compounds. Among the varieties, Nielluccio wine recorded highest concentration of total volatile compounds (191.53 mg/L) while, it was least in Caladoc wines (15.45 mg/L). The principal component analysis clearly differentiated Grenache wines based on their relationships between scores and their aroma composition followed by Nielluccio and Cinsuat wines. Out of sixty four compounds, only six aromatic compounds viz. butanediol, isoamyl actate, c-Terpene, butanol, acetic acid and furfural have satisfying aroma descriptors with floral and fruity nuances and contribute to differentiate the Grenache wines from other varieties which have similar scores in PC1 analysis. The cluster analysis also suggested that the wines in the same group (Cinsaut, Tempranillo and Syrah), (Cabernet Franc, Cabernet Sauvignon, Caladoc and Merlot) and (Nielluccio and Petit Verdot) had similar aroma characterization. Grenache wines were well differentiated from the sub group formed by other red varieties.Not Availabl

Volatile composition and sensory profile of wines obtained from partially defoliated vines: the case of Nero di Troia wine

The effects of defoliation treatments performed in the bunch-zone on volatile composition and sensory attributes of the corresponding wines were evaluated. Nero di Troia grapes were subjected to four different treatments: no leaf removal (N); leaf removal in the fruit-zone along the east side (at complete veraison) (E); leaf removal in the fruit-zone along the east and west side (at complete veraison) (E/W); almost complete leaf removal along the west side (at complete veraison) and at pre-harvest also along the east side (F). For each defoliation thesis, half of the wine was treated with oak chips in order to verify whether the treatments with oak chips can mask the effects of defoliation. Defoliation partially affected the volatile profiles. Data concerning the volatile profiles show that the highest concentrations of total acids were detected in N and E wines, while those of the total ethyl esters were detected in F wines, and the lowest terpenes concentrations were found in E wines. The oak-treated wines show the highest contents of 1-heptanol, 1-octanol, many ethyl esters, and total hydrocarbons. They were the only in which the whisky lactone was detected. From a sensory point of view, the wines from almost completely defoliated grapes exhibited the lowest scores of gustatory-olfactory intensity, persistence, and quality. The wines that were not treated with chips exhibited sensory profiles characterized by floral and fruity notes, while those treated with oak chips showed sensory profiles characterized by spicy and fruity notes