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The purpose of this study was to examine pazopanib/topotecan combination activity vs. pazopanib monotherapy on anaplastic thyroid cancer (ATC) cells. Proliferation analyses were performed on ATC cell lines administered for 72 h with pazopanib and topotecan alone and to their simultaneous combination. Pazopanib and topotecan produced a strong synergism on ATC cells, calculated by the combination index, increasing the intracellular concentrations of topotecan lactone measured by high-performance liquid chromatography. Furthermore, a significantly decrease of the gene expression of ATP-binding cassette transporter G2 (ABCG-2), vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α), and colony stimulating factor-1 (CSF-1) was presented in combination-treated ATC cells by real time PCR tests. In summary, the simultaneous association of pazopanib and topotecan established a highly synergistic ATC antiproliferative effect, suggesting a new possibility to translate this schedule into clinical trials.

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Non-steroidal anti-inflammatory drugs (NSAIDs) can damage the small intestine, mainly through an involvement of enteric bacteria. This study examined the pathophysiology of NSAID-associated intestinal lesions in a rat model of diclofenac-enteropathy and evaluated the effect of rifaximin on small bowel damage. Enteropathy was induced in 40-week old male rats by intragastric diclofenac (4 mg/kg BID, 14 days). Rifaximin (delayed release formulation) was administered (50 mg/kg BID) 1 h before the NSAID. At the end of treatments, parameters dealing with ileal damage, inflammation, barrier integrity, microbiota composition, and TLR-NF-κB-inflammasome pathway were evaluated. In addition, the modulating effect of rifaximin on NLRP3 inflammasome was tested in an in vitro cell system. Diclofenac induced intestinal damage and inflammation, triggering an increase in tissue concentrations of tumor necrosis factor and interleukin-1β, higher expression of TLR-2 and TLR-4, MyD88, NF-κB and activation of caspase-1. In addition, the NSAID decreased ileal occludin expression and provoked a shift of bacterial phyla toward an increase in Proteobacteria and Bacteroidetes abundance. All these changes were counterbalanced by rifaximin co-administration. This drug was also capable of increasing the proportion of Lactobacilli, a genus depleted by the NSAID. In LPS-primed THP-1 cells stimulated by nigericin (a model to study the NLRP3 inflammasome), rifaximin reduced IL-1β production in a concentration-dependent fashion, this effect being associated with inhibition of the up-stream caspase-1 activation. In conclusion, diclofenac induced ileal mucosal lesions, driving inflammatory pathways and microbiota changes. In conclusion, rifaximin prevents diclofenac-induced enteropathy through both anti-bacterial and anti-inflammatory activities.

Purpose: Luteolin exerts beneficial effects against obesity-associated comorbidities, although its influence on vascular dysfunction remains undetermined. We examined the effects of luteolin on endothelial dysfunction in a mouse model of diet-induced obesity.Methods: Standard diet (SD) or high-fat diet (HFD)-fed mice were treated daily with luteolin intragastrically. After 8 weeks, body and epididymal fat weight, as well as blood cholesterol, glucose, and triglycerides were evaluated. Endothelium-dependent relaxations of resistance mesenteric vessels was assessed by a concentration-response curve to acetylcholine, repeated upon Nw-nitro-L-arginine methylester (L-NAME) or ascorbic acid infusion to investigate the influence of nitric oxide (NO) availability and reactive oxygen species (ROS) on endothelial function, respectively. Intravascular ROS production and TNF levels were measured by dihydroethidium dye and ELISA, respectively. Endothelial NO synthase (eNOS) and superoxide dismutase 1 (SOD1), as well as microRNA-214-3p expression were examined by Western blot and RT-PCR assays, respectively.Results: HFD animals displayed elevated body weight, epididymal fat weight and metabolic indexes. Endothelium-dependent relaxation was resistant to L-NAME and enhanced by ascorbic acid, which restored also the inhibitory effect of L-NAME, suggesting a ROS-dependent reduction of NO availability in HFD vessels. Moreover, media-lumen ratio, intravascular superoxide anion and TNF levels were increased, while vascular eNOS, SOD1, and microRNA-214-3p expression were decreased. In HFD mice, luteolin counteracted the increase in body and epididymal fat weight, and metabolic alterations. Luteolin restored vascular endothelial NO availability, normalized the media-lumen ratio, decreased ROS and TNF levels, and normalized eNOS, SOD1 and microRNA-214-3p expression.Conclusion: Luteolin prevents systemic metabolic alterations and vascular dysfunction associated with obesity, likely through antioxidant and anti-inflammatory mechanisms.

Apigenin can exert beneficial actions in the prevention of obesity. However, its putative action on obesity-associated bowel motor dysfunctions is unknown. This study examined the effects of apigenin on colonic inflammatory and motor abnormalities in a mouse model of diet-induced obesity.Male C57BL/6J mice were fed with standard diet (SD) or high-fat diet (HFD). SD or HFD mice were treated with apigenin (10 mg/Kg/day). After 8 weeks, body and epididymal fat weight, as well as cholesterol, triglycerides and glucose levels were evaluated. Malondialdehyde (MDA), IL-1β and IL-6 levels, and let-7f expression were also examined. Colonic infiltration by eosinophils, as well as substance P (SP) and inducible nitric oxide synthase (iNOS) expressions were evaluated. Motor responses elicited under blockade of NOS and tachykininergic contractions were recorded in vitro from colonic longitudinal muscle preparations.When compared to SD mice, HFD animals displayed increased body weight, epididymal fat weight and metabolic indexes. HFD mice showed increments in colonic MDA, IL-1β and IL-6 levels, as well as a decrease in let-7f expression in both colonic and epididymal tissues. HFD mice displayed an increase in colonic eosinophil infiltration. Immunohistochemistry revealed an increase in SP and iNOS expression in myenteric ganglia of HFD mice. In preparations from HFD mice, electrically evoked contractions upon NOS blockade or mediated by tachykininergic stimulation were enhanced. In HFD mice, Apigenin counteracted the increase in body and epididymal fat weight, as well as the alterations of metabolic indexes. Apigenin reduced also MDA, IL-1β and IL-6 colonic levels as well as eosinophil infiltration, SP and iNOS expression, along with a normalization of electrically evoked tachykininergic and nitrergic contractions. In addition, apigenin normalized let-7f expression in epididymal fat tissues, but not in colonic specimens.Apigenin prevents systemic metabolic alterations, counteracts enteric inflammation and normalizes colonic dysmotility associated with obesity.

Objectives: Systemic sclerosis (SSc) is a connective tissue disorder presenting fibrosis of the skin and internal organs, for which no effective treatments are currently available. Increasing evidence indicates that the P2X7 receptor (P2X7R), a nucleotide-gated ionotropic channel primarily involved in the inflammatory response, may also have a key role in the development of tissue fibrosis in different body districts. This study was aimed at investigating P2X7R expression and function in promoting a fibrogenic phenotype in dermal fibroblasts from SSc patients, also analyzing putative underlying mechanistic pathways.Methods: Fibroblasts were isolated by skin biopsy from 9 SSc patients and 8 healthy controls. P2X7R expression, and function (cytosolic free Ca2+ fluxes, α-smooth muscle actin [α-SMA] expression, cell migration, and collagen release) were studied. Moreover, the role of cytokine (interleukin-1β, interleukin-6) and connective tissue growth factor (CTGF) production, and extracellular signal-regulated kinases (ERK) activation in mediating P2X7R-dependent pro-fibrotic effects in SSc fibroblasts was evaluated.Results: P2X7R expression and Ca2+ permeability induced by the selective P2X7R agonist 2′-3′-O-(4-benzoylbenzoyl)ATP (BzATP) were markedly higher in SSc than control fibroblasts. Moreover, increased αSMA expression, cell migration, CTGF, and collagen release were observed in lipopolysaccharides-primed SSc fibroblasts after BzATP stimulation. While P2X7-induced cytokine changes did not affect collagen production, it was completely abrogated by inhibition of the ERK pathway.Conclusion: In SSc fibroblasts, P2X7R is overexpressed and its stimulation induces Ca2+-signaling activation and a fibrogenic phenotype characterized by increased migration and collagen production. These data point to the P2X7R as a potential, novel therapeutic target for controlling exaggerated collagen deposition and tissue fibrosis in patients with SSc.

In their review, Ablon, Levy, and Smith-Hansen (2011) showed that the Psychotherapy Process Q-set (PQS; Jones, 2000) has been applied to a large range of studies with different methods and aims, from Randomized Control Trials (RCT) to naturalistic studies and single-case designs. Focusing on our colleagues’ work, we will highlight the contribution of the PQS to research in psychotherapy, not only in process-outcome studies, but also into the therapeutic action debates, the specific vs common factors discussion, and the insight vs relation dialect. According to our studies, PQS has played the most relevant and innovative role in psychoanalysis. Ablon et al. (2011) showed how Jones left the clinical inheritance of his empirical method. One of PQS’s strengths deals with the Q-sort methodology (Stephenson, 1953; Block, 1961) that enables both an empirical study of human subjectivity (McKnown & Thomas, 1988) and the application of rigorous data analysis for single-case designs, such as the P-technique and time series analysis. PQS, as colleagues have shown, is useful in single-case designs that, despite their limitations in the generalization of the findings (Kazdin, 2002), capture the richness and complexity of the clinical dialogue and describe the uniqueness of the patient and therapist dyad and interaction structures.

Questo contributo si propone di fornire una breve rassegna delle principali linee di ricerca seguite negli ultimi anni dal gruppo coordinato da Vittorio Lingiardi. Tra queste, ci soffermeremo in particolare su: a) valutazione e diagnosi della personalità con SWAP-200 e PDM (Psychodynamic Diagnostic Manual); b) sviluppo e validazione di strumenti clinician-report per operazionalizare l'uso del PDM; c) valutazione dei meccanismi di difesa e degli stili difensivi mediante DMRS e sua versione Q sort; d) studio del processo e della relazione terapeutica (alleanza terapeutica, rotture e riparazioni dell'alleanza controtransfert); in particolare, in quest'area di ricerca, ci siamo impegnati nello sviluppo e validazione di nuovi strumenti per la valutazione dei processi di rottura e riparazione dell'alleanza (Collaborative Interaction Scale) e della qualità dell'attaccamento tra paziente e terapeuta (Patient-Therapist Attachment Q Sort); d) sviluppo della ricerca clinica e applicativa sui temi dell'identità di genere, dell'orientamento sessuale e dell'omofobia sociale e interiorizzata.

Eugenol is a natural alkenylbenzene compound used in a variety of consumer products. There is limited evidence for the carcinogenicity of eugenol to experimental animals. However, in vitro tests for the genotoxic potential of eugenol have on occasion reported a positive result. In contrast, the structurally related alkenylbenzene methyleugenol is consistently reported as genotoxic and carcinogenic in vitro and in vivo. Metabolism of eugenol and methyleugenol has been documented but comparative kinetics have never been conducted in multiple species. Thus, we decided to investigate the bioactivation and detoxification kinetics of eugenol and methyleugenol in human, rat, and mouse to further assess their differential toxicity. The formation of a 1′-hydroxy proximate carcinogen, and a cytotoxic quinone methide, two key toxic metabolites for alkenylbenzenes, were quantified in hepatic and pulmonary microsomes and S9 fractions. Kinetic constants appKm, appVmax, and CLint were measured for these reactions. We report that methyleugenol generates a significant amount of the 1′-hydroxy proximate carcinogen while eugenol glucuronidation prevents the formation of both 1′-hydroxyeugenol and the quinone methide. Comparative kinetics highlighted key metabolic differences between human, mouse, and rat, providing a mechanistic insight into the bioactivation and detoxification of alkenylbenzenes in each species. [ABSTRACT FROM AUTHOR]

Eugenol is a natural alkenylbenzene compound used in a variety of consumer products. There is limited evidence for the carcinogenicity of eugenol to experimental animals. However, in vitro tests for the genotoxic potential of eugenol have on occasion reported a positive result. In contrast, the structurally related alkenylbenzene methyleugenol is consistently reported as genotoxic and carcinogenic in vitro and in vivo. Metabolism of eugenol and methyleugenol has been documented but comparative kinetics have never been conducted in multiple species. Thus, we decided to investigate the bioactivation and detoxification kinetics of eugenol and methyleugenol in human, rat, and mouse to further assess their differential toxicity. The formation of a 1'-hydroxy proximate carcinogen, and a cytotoxic quinone methide, two key toxic metabolites for alkenylbenzenes, were quantified in hepatic and pulmonary microsomes and S9 fractions. Kinetic constants (app)Km, (app)Vmax, and CLint were measured for these reactions. We report that methyleugenol generates a significant amount of the 1'-hydroxy proximate carcinogen while eugenol glucuronidation prevents the formation of both 1'-hydroxyeugenol and the quinone methide. Comparative kinetics highlighted key metabolic differences between human, mouse, and rat, providing a mechanistic insight into the bioactivation and detoxification of alkenylbenzenes in each species.