Treatments for advanced prostate cancer (CaP) typically involve androgen deprivation therapy. However, most patients eventually develop castration-resistant CaP (CRPC) for which highly effective ...therapies are limited. We explored the efficacy of a novel agent, HE3235, in inhibiting growth of CRPC in preclinical models. Castrated male mice were implanted subcutaneously with LuCaP35V CaP xenografts in the presence and absence of 5′-androstenediol (AED) and treated with HE3235. To investigate the effect of HE3235 on CaP tumor in the bone, castrated mice were injected intratibially with C4-2B CaP cells and treated with HE3235. Serum prostate-specific antigen (PSA) levels, tumor volume, immunohistochemistry, gene expression, and levels of intratumoral androgens were analyzed. HE3235 significantly prolonged the tumor doubling time of LuCaP35V, decreased androgen receptor expression, and lowered levels of intratumoral testosterone by ∼89% and dihydrotestosterone by ∼63% in both the presence and the absence of AED. HE3235 inhibited tumor growth in the bone environment. Weights of tumored tibiae of HE3235-treated animals were lower than those of control (P = .031), and normalized PSA levels were also significantly decreased at the end of study by HE3235 treatment (P = .0076). HE3235 inhibits the growth of subcutaneous CRPC as well as CRPC in the bone environment. Our data show that HE3235 exhibits a wide range of effects, including alteration of androgen receptor signaling and reductions in levels of intratumoral androgens. Our results support ongoing clinical investigations into the effectiveness of HE3235 in the setting of CRPC and warrants further studies into the mechanisms behind the effects of HE3235.
The SuperCDMS proposal for dark matter detection Akerib, D.S.; Attisha, M.J.; Bailey, C.N. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
04/2006, Letnik:
559, Številka:
2
Journal Article
Recenzirano
Presently the CDMS-II collaboration's Weakly Interacting Massive Particle (WIMP) search at the Soudan Underground Laboratory sets the most stringent exclusion limits of any WIMP cold dark matter ...direct-detection experiment. To extend our reach further, to WIMP-nucleon cross-sections in the range
10
-
46
-
10
-
44
cm
2
, we propose SuperCDMS, which would take advantage of a very deep site. One promising site is the recently approved SNOLab facility in Canada. In this paper we will present our overall program and focus on phase A of SuperCDMS.
Knowledge of the complete genomic DNA sequence of an organism allows a systematic approach to defining its genetic components. The genomic sequence provides access to the complete structures of all ...genes, including those without known function, their control elements, and, by inference, the proteins they encode, as well as all other biologically important sequences. Furthermore, the sequence is a rich and permanent source of information for the design of further biological studies of the organism and for the study of evolution through cross-species sequence comparison. The power of this approach has been amply demonstrated by the determination of the sequences of a number of microbial and model organisms. The next step is to obtain the complete sequence of the entire human genome. Here we report the sequence of the euchromatic part of human chromosome 22. The sequence obtained consists of 12 contiguous segments spanning 33.4 megabases, contains at least 545 genes and 134 pseudogenes, and provides the first view of the complex chromosomal landscapes that will be found in the rest of the genome.
Background & Aims: Free radicals are involved in the pathogenesis of acute pancreatitis, during which pancreatitis-associated protein (PAP)-I is overexpressed. We explored whether PAP-I expression ...could be induced by oxidative stress and whether it could affect apoptosis.
Methods: AR4-2J cells were exposed to H
2O
2 or menadione, and PAP-I messenger RNA (mRNA) expression was analyzed by Northern blotting.
Results: Maximal expression was observed with 0.1 mmol/L H
2O
2 or with 0.05 mmol/L menadione. Induction was detectable after 12 hours, reached a climax at 18 hours, and then decreased. Pretreatment of the cells with pyrrolidine dithiocarbamate completely abolished PAP-I mRNA induction, suggesting involvement of NFκB in the signaling pathway. These findings were confirmed in transient transfection assays using a plasmid containing the PAP-I promoter linked to the chloramphenicol acetyltransferase reporter gene. Then the relationship between PAP-I induction and protection against cell damage during oxidative stress was considered. Constitutive PAP-I expression in AR4-2J cells after transfection with PAP-I complementary DNA conferred significant resistance to apoptosis induced by low doses of H
2O
2 but not to necrosis induced by high doses of H
2O
2.
Conclusions: These results suggest that during oxidative stress, PAP-I might be part of a mechanism of pancreatic cell protection against apoptosis.
GASTROENTEROLOGY 1998;114:808-816
In a series of laboratory Y-maze experiments, we investigated the directional response of juveniles of the muricid snail Concholepas concholepas, a rocky-shore keystone predator characteristic of the ...southeastern Pacific coast, in displaying prey detection and predator escape behaviour after 5 mo rearing under contrasting levels of pCO₂: 390 (present-day), 700 and 1000 μatm CO₂ (as expected in near-future scenarios of ocean acidification OA). Regardless of the experimental condition, juveniles significantly chose the Y-maze arm containing prey. In general terms, the directions of the displacement paths of the snails in the Y-maze were straight from the starting point to the final position, where the prey items were offered. Moreover, juveniles reared at present-day concentrations and 700 μatm CO₂ significantly avoided displacement in the Y-maze arm receiving predator odours. This predator-avoidance behaviour was disrupted in juveniles reared at 1000 μatm CO₂. In most cases, displacements recorded under such conditions were sinuous, and the trial individuals did not significantly choose the predator-free arm. In contrast, displacement paths recorded for snails reared at present-day concentrations and at 700 μatm CO₂ were straight from the initial to the final position, with displacements mostly ending near the prey and in the arm free of cues associated with predation. The loss of responses to a natural predator under high pCO₂ levels in the early ontogeny of C. concholepas may result in ecologically deleterious decisions by this keystone species. We conclude that the negative effects of OA on the chemosensory behaviour of keystone species could have negative consequences for community dynamics.
We present the results of a LIGO search for gravitational waves (GWs) associated with GRB 051103, a short-duration hard-spectrum gamma-ray burst (GRB) whose electromagnetically determined sky ...position is coincident with the spiral galaxy M81, which is 3.6 Mpc from Earth. Possible progenitors for short-hard GRBs include compact object mergers and soft gamma repeater (SGR) giant flares. A merger progenitor would produce a characteristic GW signal that should be detectable at the distance of M81, while GW emission from an SGR is not expected to be detectable at that distance. We found no evidence of a GW signal associated with GRB 051103. Assuming weakly beamed gamma-ray emission with a jet semi-angle of 30 deg we exclude a binary neutron star merger in M81 as the progenitor with a confidence of 98%. Neutron star-black hole mergers are excluded with > 99% confidence. If the event occurred in M81 our findings support the the hypothesis that GRB 051103 was due to an SGR giant flare, making it the most distant extragalactic magnetar observed to date.
Penile erection is dependent on the nitric oxide (NO)/cGMP-dependent protein kinase I (PKGI) pathway. One important target
of PKGI in smooth muscle is the large-conductance, calcium-activated ...potassium (BK) channel, which upon activation hyperpolarizes
the smooth muscle cell membrane, causing relaxation. Relaxation of arterial and corpus cavernosum smooth muscle (CCSM) is
necessary to increase blood flow into the corpora cavernosa that leads to penile tumescence. We investigated the functional
role of BK channels in the corpus cavernosum utilizing a knock-out mouse lacking the Slo gene ( Slo â/â ) responsible for the pore-forming subunit of the BK channel. Whole-cell currents were recorded from isolated CCSM cells of
Slo +/+ and Slo â/â mice. Iberiotoxin-sensitive voltage- and Ca 2+ -activated K + currents, the latter activated by local transient calcium releases (calcium sparks), were present in Slo +/+ CCSM cells, but absent in Slo â/â cells. CCSM strips from Slo â/â mice demonstrated a four-fold increase in phasic contractions, in the presence of phenylephrine. Nerve-evoked relaxations
of precontracted strips were reduced by 50%, both in strips from Slo â/â mice and by blocking BK channels with iberiotoxin in the Slo +/+ strips. Consistent with the in vitro results, in vivo intracavernous pressure exhibited pronounced oscillations in Slo â/â mice, but not in Slo +/+ mice. Furthermore, intracavernous pressure increases to nerve stimulation, in vivo , were reduced by 22% in Slo â/â mice. These results indicate that the BK channel has an important role in erectile function, and loss of the BK channel leads
to erectile dysfunction.
Phytohormones such as cytokinins, abscisic acid (ABA) and auxins play a vital role in plant development and regulatory processes. Their role within the plant is a focus for much research, with ...studies using recent advances in mass spectrometry performance allowing the quantification of low levels of phytohormones extracted from plant tissues. Despite these advances, external factors influencing the production of phytohormones are less well studied. Here, a new approach is presented for the extraction of a range of phytohormones from plant growth media (soil and hydroponic solution), their identification using high mass accuracy mass spectrometry and subsequent quantification using multiple reaction monitoring (MRM). The ability to detect phytohormones in matrices other than plant tissue presents the opportunity to study further the influence of factors such as below ground organisms and soil bacteria on phytohormone production.
This novel approach was therefore applied to the plant growth media from a series of experiments comparing plant growth in the presence and absence of earthworms. A small but significant increase in ABA concentration was observed in the presence of earthworms, increasing even further when plants were also present. This finding suggests that earthworms could stimulate plant ABA production. This experiment and its outcomes demonstrate the value of studying phytohormones outside plant tissue, and the potential value of further research in this area.
•Mass spectrometry has been used to detect a range of phytohormones in soil and hydroponic solution.•Methods allow quantification of phytohormones at concentrations in the range of pg/g of dry soil.•Concentrations of ABA in hydroponic solution increased when both earthworms and plants were present.•These findings offer potential applications in investigating further plant – soil interaction mechanisms.
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