Altered Distribution and Expression of Syndecan-1 and -4 as an Additional Hallmark in Psoriasis

Syndecans act as independent co-receptors to exert biological activities and their altered function is associated with many pathophysiological conditions. Here, syndecan-1 and -4 were examined in lesional skin of patients with psoriasis. Immunohistochemical staining confirmed altered syndecan-1 distribution and revealed absence of syndecan-4 expression in the epidermis. Fibronectin (FN)—known to influence inflammation and keratinocyte hyperproliferation via α5β1 integrin in psoriasis—was also decreased. Syndecan-1 and -4 expression was analyzed in freshly isolated lesional psoriatic human keratinocytes (PHK) characterized based on their proliferation and differentiation properties. mRNA levels of syndecan-1 were similar between healthy and PHK, while syndecan-4 was significantly decreased. Cell growth and release of the pro-inflammatory Tumor Necrosis Factor-alpha (TNFα) were selectively and significantly induced in PHKs plated on FN. Results from co-culture of healthy keratinocytes and psoriatic fibroblasts led to the speculation that at least one factor released by fibroblasts down-regulate syndecan-1 expression in PHK plated on FN. To assay if biological treatments for psoriasis target keratinocyte proliferation, gelatin-based patches enriched with inteleukin (IL)-17α or TNFα blockers were prepared and tested using a full-thickness healthy epidermal model (Phenion^®). Immunohistochemistry analysis showed that both blockers impacted the localisation of syndecan-1 within the refined epidermis. These results provide evidence that syndecans expression are modified in psoriasis, suggesting that they may represent markers of interest in this pathology.     

Enapotamab Vedotin,an AXL-Specific Antibody-Drug Conjugate,Demonstrates Antitumor Efficacy in Patient-Derived Xenograft Models of Soft Tissue Sarcoma

Doxorubicin (doxo) remains the standard of care for patients with advanced soft tissue sarcoma (STS), even though response rates to doxo are only around 14% to 18%. We evaluated enapotamab vedotin (EnaV), an AXL-specific antibody-drug conjugate (ADC), in a panel of STS patient-derived xenografts (PDX). Eight models representing multiple STS subtypes were selected from our STS PDX platform (n = 45) by AXL immunostaining on archived passages. Models were expanded by unilateral transplantation of tumor tissue into the left flank of 20 NMRI nu/nu mice. Once tumors were established, mice were randomized into an EnaV treatment group, or a group treated with isotype control ADC. Treatment efficacy was assessed by tumor volume evaluation, survival analysis, and histological evaluation of tumors, and associated with AXL expression. EnaV demonstrated significant tumor growth delay, regression, and/or prolonged survival compared to isotype control ADC in 5/8 STS PDX models investigated. Experimental passages of responding models were all found positive for AXL at varying levels, but no linear relationship could be identified between the level of expression and level of response to EnaV. One model was found negative for AXL on experimental passage and did not respond to EnaV. This study provides a preclinical rationale for the evaluation of AXL-targeting ADCs in the treatment of AXL-expressing sarcomas.     

Preparations for Y2K: Revisiting the Behavioral Component of the Third-Person Effect

Although the behavioral component was an integral part of the original formulation of the third-person effect hypothesis, little research has examined the impact of biased media effect perceptions on behaviors that assume others have already been affected. The present study examines how third-person perceptions (the belief that other people are particularly vulnerable to media messages) contributed to intentions to prepare for problems stemming from Y2K, also known as the "millennium bug." Analyses using data from 2 regional probability samples taken in late 1999 show that perceptions about the potential effects of news messages influenced public anxiety about the Y2K situation and beliefs that other people would overprepare for the new year. These 2 variables, in turn, predicted intentions to stockpile supplies of food, water, gasoline, and cash. The article discusses the implications of these findings for understanding the relationship between perceptions of media effects and an extended range of behaviors.     

Direct and Differential Effects of the Internet on Political and Civic Engagement

Given the significant rise in the number of Americans who turn to the Internet for political information, we examine the effects of these behaviors on political and civic engagement in an evolving media landscape. Specifically, we test hypotheses derived from competing models—the instrumental approach, which posits direct effects of Internet use and a psychological approach, which predicts contingent effects. Analyses of the 2004 American National Election Studies ( N = 1,212) reveal a pattern of direct effects of Internet use on basic information acquisition and use but contingent effects for concrete acts of civic or political engagement. These results provide an important window on the political impacts of contemporary Internet use and suggest that future reassessments of the Internet's role in public life should continue to probe for direct as well as differential effects.     

Large face to face tetraphenylporphyrin/fullerene nanoaggregates. A DFT study

Large face to face tetraphenylporphyrin/fullerene nanoaggregates containing up six C60 units and six tetraphenylporphyrin (H2TPP) or tetraphenylporphyrinato-zinc (TPP-Zn) moieties have been studied using dispersion corrected PBE/def2-SVP level of theory. It has been found that most important contribution to the binding energy between fragments comes from dispersion interactions. The binding energies for Zn containing nanoaggregates are slightly higher than those for metal free ones what is not related to the difference in dispersion contributions to the binding energy but comes from DFT term. Center to center distances for large nanoaggregates are shorter than those for the complexes H2TPP/C₆₀ and TPP-Zn/C₆₀ and this effect is more obvious for metal free nanoaggregates. According to the calculations, the band gap of nanoaggregates barely depends on its size being close to 2 eV. The nature of electronic excitations in Zn containing nanoaggregates has strong charge transfer (CT) contribution and does not depend on nanoaggregate size, while for metal free nanoaggregate most of low energy excitations are not CT by nature. Ionization potentials and electron affinities of nanoaggregates depend strongly on their size. Polaron cations are uniformly delocalized over donor H2TPP or TPP-Zn units, while polaron anions are delocalized over acceptor C₆₀ units. The reorganization energies calculated for hole and electron transport decreased linearly with 1/n where n is the number of repeating units in nanoaggregate.     

Ultrastructural alterations during embryonic rats' lung development caused by ozone

Ozone (O3) is an oxidizing agent that acts on phospholipids, proteins and sugars of cellular membranes producing free radicals, which cause oxidative damages. The O3 exposure has been used as a model to study oxidative stress, in which the respiratory airways represent the entrance to the organism. In this study, ultrastructural alterations were identified at the bronchiolar level during the intra-uterine lung development, using an O3 exposure model in pregnant rats during 18, 20 and 21 days of gestation. Twelve pregnant Wistar rats, six controls and six exposed to 1 ppm O3 inhalation during 12 h per day, were used. The rats were sacrificed at gestational days 18, 20 and 21; the fetuses were obtained and their lungs dissected. The ultrastructural analysis evidenced swollen mitochondria, cytoplasmic vacuolization of the epithelial cells and structural disorder caused by the oxidative stress. At gestation day 20, flake-off epithelial cells and laminar bodies in the bronchiolar lumen were observed. In the 21-gestation-day group, the mitochondria were edematous and their cristae were disrupted by the damage caused in mitochondrial membranes.