Effect of nomegestrol acetate on estrone-sulfatase and 17beta-hydroxysteroid dehydrogenase activities in human breast cancer cells

It is well recognized that estradiol (E2) is one of the most important hormones supporting the growth and evolution of breast cancer. Consequently, to block this hormone before it enters the cancer cell or in the cell itself, has been one of the main targets in recent years. In the present study we explored the effect of the progestin, nomegestrol acetate, on the estrone sulfatase and 17beta-hydroxysteroid dehydrogenase (17beta-HSD) activities of MCF-7 and T-47D human breast cancer cells. Using physiological doses of estrone sulfate (E1S: 5 x 10(-9)M), nomegestrol acetate blocked very significantly the conversion of E1S to E2. In the MCF-7 cells, using concentrations of 5 x 10(-6)M and 5 x 10(-5) M of nomegestrol acetate, the decrease of E1S to E2 was, respectively, -43% and -77%. The values were, respectively, -60% and -71% for the T-47D cells. Using E1S at 2 x 10(-6) M and nomegestrol acetate at 10(-5) M, a direct inhibitory effect on the enzyme of -36% and -18% was obtained with the cell homogenate of the MCF-7 and T-47D cells, respectively. In another series of studies, it was observed that after 24 h incubation of a physiological concentration of estrone (E1: 5 x 10(-9)M) this estrogen is converted in a great proportion to E2. Nomegestrol acetate inhibits this transformation by -35% and -85% at 5 x 10(-7)M and 5 x 10(-5)M, respectively in T-47D cells; whereas in the MCF-7 cells the inhibitory effect is only significant, -48%, at 5 x 10(-5)M concentration of nomegestrol acetate. It is concluded that nomegestrol acetate in the hormone-dependent MCF-7 and T-47D breast cancer cells significantly inhibits the estrone sulfatase and 17beta-HSD activities which converts E1S to the biologically active estrogen estradiol. This inhibition provoked by this progestin on the enzymes involved in the biosynthesis of E2 can open new clinical possibilities in breast cancer therapy.     

Leucocyte activity in chronic venous insufficiency

We present the clinical and laboratory findings in an institutionalised adult patient originally referred for autism. A high risk of colorectal cancer was predicted when an interstitial deletion of the long arm of chromosome 5, del(5)(q15q22.3), was detected in her lymphocytes and deletion of the MCC and APC genes confirmed by molecular analysis. Adenomatous polyposis coli and carcinoma of the rectum were subsequently diagnosed in the patient. She was profoundly mentally retarded, autistic, and had minor dysmorphic features consistent with those of previous patients with similar deletions. The deletion arose as a result of recombination within the small insertion loop formed at meiosis by the direct insertion (dir ins(5)(q22.3q14.2q15)) found in the patient's mother. This family further confirms the cytogenetic mapping of both MCC and APC genes to 5q22 and comparison with other recent cases suggests that both genes and their closely linked markers lie within the 5q22.1 subband.     

Intramuscular electrical stimulation of facial muscles in humans and chimpanzees: Duchenne revisited and extended.

[Correction Notice: An erratum for this article was reported in Vol 7(2) of Emotion (see record 2007-06782-006). The address provided for the on-line supplemental materials was incorrect. The correct address at which the supplemental materials can be viewed is the following: http://dx.doi.org/10.1037/1528-3542.6.3.367.supp] The pioneering work of Duchenne (1862/1990) was replicated in humans using intramuscular electrical stimulation and extended to another species (Pan troglodytes: chimpanzees) to facilitate comparative facial expression research. Intramuscular electrical stimulation, in contrast to the original surface stimulation, offers the opportunity to activate individual muscles as opposed to groups of muscles. In humans, stimulation resulted in appearance changes in line with Facial Action Coding System (FACS) action units (AUs), and chimpanzee facial musculature displayed functional similarity to human facial musculature. The present results provide objective identification of the muscle substrate of human and chimpanzee facial expressions- data that will be useful in providing a common language to compare the units of human and chimpanzee facial expression. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of ethanol on the expression and secretion of bile salt-dependent lipase by pancreatic AR4-2J cells

Recordings were made in the peroneal nerve of healthy volunteer subjects from C-mechano-heat (CMH) nociceptors (n=25) with their receptive fields in the skin on the dorsum of the foot. The investigation focused on afferent single C-fiber activity induced by short (200 ms) high-intensity argon-laser light pulses projected to localized spots of the skin. Cutaneous heat stimulation with the argon laser, 2-3 times the activation threshold, induced inter-burst spike frequencies in the nerve, reaching 50 Hz, while mechanical stimulation 10-20 times threshold only evoked frequencies reaching 10 Hz. The decrease in conduction velocity of action potentials in the C-fiber afferents following mechanical and heat stimulation was closely related to the degree of activation. Following a laser pulse of 200 ms, a spike pattern with highly reproducible inter-spike intervals was evoked with a fast saturation. On the contrary, a high variability in the number of action potentials evoked by both heat and mechanical stimuli was found, depending on the location of stimuli within the receptive field. A relation between the conduction velocity and the peak firing within the spike train following laser stimulation was detected. Heat and mechanical stimulation activated single C-fibers in matching spots within the same skin areas, in line with the assumption that the two modalities in the CMH-fibers share matching morphological cutaneous substrates. No correlation was found in thresholds or excitability to mechanical and heat stimulation, respectively. This suggests that subsets of receptors exist within nerve endings of the cutaneous receptive fields, with the ability to generate action potentials independent of heat and mechanical stimuli. Unexpectedly, no signs of sensitization or other inflammatory responses were observed after repeated laser pulses; on the contrary, a rapidly developing fatigue was observed when single spots were repeatedly stimulated. However, no fatigue was observed if neighboring spots were stimulated, indicating a localized generator of the fatigue. In each subject, a good correlation was observed between the reported pain sensation and the activity evoked in the afferent C-fibers by the laser. However, the magnitude of the reported pain sensation to comparable degrees of C-fiber activation showed a high variability between different subjects. A fairly good subjective estimate of the afferent-fiber activation was observed when skin spots from 3- down to 1-mm diameter were stimulated. In a few individuals, no painful sensation was reported when the stimulated spots were reduced to 1-mm diameter, despite the occurrence of multiple spikes in single C-fiber afferents, amplifying the importance of spatial summation in the perception of pain.     

Houssay and biomedical research

The possible algogenic effects of elevated serum endothelin levels in cardiac syndrome X were investigated in a case-control study that examined somatic pain perception in the forearm during submaximal effort tourniquet and cold immersion tests. Pain threshold to both ischemic and cold stimulation of the forearm was demonstrated to be significantly lower in patients with syndrome X than in matched healthy controls, and a negative correlation between ischemic pain threshold and endothelin levels was demonstrated.     

Concentrations of estrone, estradiol, and estrone sulfate and evaluation of sulfatase and aromatase activities in pre- and postmenopausal breast cancer patients

This report concerns the evaluation of various estrogens, estrone (El), estradiol (E2), and estrone sulfate (E1S), as well as E1S-sulfatase and aromatase activities in pre- and postmenopausal women with breast cancer. The levels (in picomoles per g; mean +/- SEM) of the various estrogens in the breast tissue from premenopausal patients (n = 11) are: El, 1.4 +/- 0.5; E2, 1.2 +/- 0.6; and E1S, 1.2 +/- 0.3. In postmenopausal patients (n = 23), the values are, respectively, 1.0 +/- 0.4, 1.4 +/- 0.7, and 3.3 +/- 1.9. These concentrations of estrogens in the tumors of postmenopausal patients are significantly higher than those found in plasma. The activity of E1S-sulfatase in both pre- and postmenopausal patients was 50-200 times higher than that of aromatase. E1S-sulfatase and aromatase activities are significantly higher in post-menopausal than in cycling patients. It is concluded that despite the low levels of circulating estrogens in postmenopausal patients, the tissue concentrations of these steroids are several-fold higher than those in plasma, suggesting tumor accumulation of these estrogens. The physiopathology and clinical significance of these high levels of the various estrogens (E1, E2, and E1S) as well as sulfatase and aromatase activities in postmenopausal patients with breast cancer is yet to be explored.     

Cancer treatment by targeted drug delivery to tumor vasculature in a mouse model

In vivo selection of phage display libraries was used to isolate peptides that home specifically to tumor blood vessels. When coupled to the anticancer drug doxorubicin, two of these peptides-one containing an alphav integrin-binding Arg-Gly-Asp motif and the other an Asn-Gly-Arg motif-enhanced the efficacy of the drug against human breast cancer xenografts in nude mice and also reduced its toxicity. These results indicate that it may be possible to develop targeted chemotherapy strategies that are based on selective expression of receptors in tumor vasculature.     

Life-Cycle Analysis of Roofing Insulation Levels for Cold Storage Buildings

To reduce operating costs, cold storage buildings are being designed with increasing levels of thermal roof insulation. This paper examines the current state of the art in order to estimate average roof insulation requirements in modern cold storage buildings. This research includes both economic and environmental considerations. The added environmental impact of manufacturing thermal insulation is compared to the reduced environmental impact of the building’s cooling load. The cost of purchasing and installing additional roof insulation is also compared to the annual energy savings associated with the increase to establish the most economic insulating level given today’s cost of energy. This paper shows that, from an economic, as well as from an environmental performance perspective, there is a need to design more efficient, sustainable cold storage buildings now.     

Combinatorial vascular targeting in translational medicine

In the post-genomic era, the phage display technology surfaces as an alternative approach for large-scale study of tissue-specific protein interactions with direct clinical and therapeutic applications. The unbiased identification of molecular complexes expressed on the surface of cells and blood vessels of organs and tissues may eventually lead to a considerably improved understanding of cellular and vascular proteomics. The ultimate value of this technology consists in the conception of a new ligand-directed pharmacology, with broad implications for both treatment and molecular imaging of cancer patients. In this review, we describe the use and applications of phage display for efficient development of targeted drug discovery and design.