Gonadal suppression alters axillary steroid secretions in men, but does that affect olfactory social signaling?

Background and objective: Luteinizing hormone-releasing hormone agonists (LHRHa) suppress gonadal hormone production and are commonly used to treat prostate cancer (PC) in men and conditions ranging from uterine fibroids to estrogen-sensitive cancers in women. They are also used to delay sexual development in children considering gender reassignment or experiencing premature puberty. As chemically castrating agents, LHRHa may affect cutaneous steroid secretions, which, in turn, could alter body odor and influence the psycho-sexual dynamics between individuals. The objectives of the present study were to determine (1) if LHRHa indeed alter cutaneous skin secretions, and (2) whether this leads to perceivable changes in body odor. Material and methods: Axillary skin secretions were collected on new cotton T-shirts worn by men undergoing androgen deprivation therapy with an LHRHa to treat PC (n = 10), both before starting the LHRHa and 3 months later. Healthy heterosexual university students (50 males, 50 females) were recruited to smell and rate the shirts for their masculinity, attractiveness, and intensity of odor. Liquid chromatography-mass spectrometry (LC-MS) was also used to analyze steroids extracted from the shirt samples. Results: LC-MS showed a statistically significant decline in the concentration of the androgenic metabolites, androsterone and 5α-androstane-3,17-dione. This confirms that LHRHa drugs that suppress gonadal hormone production markedly reduce cutaneous secretion of androgenic metabolic intermediates in adult males. However, no differences in odor were detected in the ratings of the shirts by male, female, nor male and female raters combined for any of the three variables assessed. Possible reasons why the human sniffers failed to perceive a change in odor are explored. Conclusion: Our data document that LHRHa alter steroid skin secretions in older men, but whether such changes alter the olfactory signals that might influence psychosocial interactions remains unresolved

Sex steroid profiles and pair-maintenance behavior of captive wild-caught zebra finches (Taeniopygia guttata)

Here, we studied the life-long monogamous zebra finch, to examine the relationship between circulating sex steroid profiles and pair-maintenance behavior in pairs of wild-caught zebra finches (paired in the laboratory for >1 month). We used liquid chromatography–tandem mass spectrometry to examine a total of eight androgens and progestins [pregnenolone, progesterone, dehydroepiandrosterone (DHEA), androstenediol, pregnan-3,17-diol-20-one, androsterone, androstanediol, and testosterone]. In the plasma, only pregnenolone, progesterone, DHEA, and testosterone were above the limit of quantification. Sex steroid profiles were similar between males and females, with only circulating progesterone levels significantly different between the sexes (female > male). Circulating pregnenolone levels were high in both sexes, suggesting that pregnenolone might serve as a circulating prohormone for local steroid synthesis in zebra finches. Furthermore, circulating testosterone levels were extremely low in both sexes. Additionally, we found no correlations between circulating steroid levels and pair-maintenance behavior. Taken together, our data raise several interesting questions about the neuroendocrinology of zebra finches.10 page(s

Androgen receptor (AR) antagonism triggers acute succinate‐mediated adaptive responses to reactivate AR signaling

Abstract Treatment‐induced adaptive pathways converge to support androgen receptor (AR) reactivation and emergence of castration‐resistant prostate cancer (PCa) after AR pathway inhibition (ARPI). We set out to explore poorly defined acute adaptive responses that orchestrate shifts in energy metabolism after ARPI and identified rapid changes in succinate dehydrogenase (SDH), a TCA cycle enzyme with well‐known tumor suppressor activity. We show that AR directly regulates transcription of its catalytic subunits (SDHA, SDHB) via androgen response elements (AREs). ARPI acutely suppresses SDH activity, leading to accumulation of the oncometabolite, succinate. Succinate triggers calcium ions release from intracellular stores, which in turn phospho‐activates the AR‐cochaperone, Hsp27 via p‐CaMKK2/p‐AMPK/p‐p38 axis to enhance AR protein stabilization and activity. Activation of this pathway was seen in tissue microarray analysis on prostatectomy tissues and patient‐derived xenografts. This adaptive response is blocked by co‐targeting AR with Hsp27 under both in vitro and in vivo studies, sensitizing PCa cells to ARPI treatments

Internalization and trafficking of CSPG-bound recombinant VAR2CSA lectins in cancer cells

Proteoglycans are proteins that are modified with glycosaminoglycan chains. Chondroitin sulfate proteoglycans (CSPGs) are currently being exploited as targets for drug-delivery in various cancer indications, however basic knowledge on how CSPGs are internalized in tumor cells is lacking. In this study we took advantage of a recombinant CSPG-binding lectin VAR2CSA (rVAR2) to track internalization and cell fate of CSPGs in tumor cells. We found that rVAR2 is internalized into cancer cells via multiple internalization mechanisms after initial docking on cell surface CSPGs. Regardless of the internalization pathway used, CSPG-bound rVAR2 was trafficked to the early endosomes in an energy-dependent manner but not further transported to the lysosomal compartment. Instead, internalized CSPG-bound rVAR2 proteins were secreted with exosomes to the extracellular environment in a strictly chondroitin sulfate-dependent manner. In summary, our work describes the cell fate of rVAR2 proteins in tumor cells after initial binding to CSPGs, which can be further used to inform development of rVAR2-drug conjugates and other therapeutics targeting CSPGs

Language and Totalitarianism

The diploma thesis Language and totalitarianism deals with the relation between these two phenomena. On the basis of key thinkers dealing with totalitarianism it formulates its own definition of totalitarianism. It presents the communication theory of Karl Wolfgang Deutsch, on which basis it points to the close relation between communication and political systems, concretely between language and totalitarianism. Language is analysed mainly on the thoughts of Ferdinand de Saussure and Ludwig Wittgenstein. Totalitarian language is explained using mainly Orwell's totalitarian language newspeak in 1984. A practical analysis of a sample of Rudé právo form the era of the communist regime in Czechoslovakia in the years 1948-1989 shows its manifestations in real use. At the end of the thesis political correctness is introduced as an example of totalitarian tendencies in liberal democracies

Primers for real time gene expression analysis.

<p>Primers for real time gene expression analysis.</p

The effect of DMSO on the (A) IL-6, (B) PGE₂ and (C) 15 cytokine/chemokine secreted in a whole human blood assay in response to <i>E. coli</i> or (D) HSV stimulation.

<p>* denotes significant difference (P < 0.05) from non-DMSO treated, <i>E. coli</i> challenged or HSV-stimulated blood.</p

Plasma DMSO levels in mice following different routes of administration.

<p>Plasma DMSO levels in mice following different routes of administration.</p