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21.
Michael L. Mohler Arunima Sikdar Suriyan Ponnusamy Dong-Jin Hwang Yali He Duane D. Miller Ramesh Narayanan 《International journal of molecular sciences》2021,22(4)
Traditional endocrine therapy for prostate cancer (PCa) has been directed at suppression of the androgen receptor (AR) signaling axis since Huggins et al. discovered that diethylstilbestrol (DES; an estrogen) produced chemical castration and PCa tumor regression. Androgen deprivation therapy (ADT) still remains the first-line PCa therapy. Insufficiency of ADT over time leads to castration-resistant PCa (CRPC) in which the AR axis is still active, despite castrate levels of circulating androgens. Despite the approval and use of multiple generations of competitive AR antagonists (antiandrogens), antiandrogen resistance emerges rapidly in CRPC due to several mechanisms, mostly converging in the AR axis. Recent evidence from multiple groups have defined noncompetitive or noncanonical direct binding sites on AR that can be targeted to inhibit the AR axis. This review discusses new developments in the PCa treatment paradigm that includes the next-generation molecules to noncanonical sites, proteolysis targeting chimera (PROTAC), or noncanonical N-terminal domain (NTD)-binding of selective AR degraders (SARDs). A few lead compounds targeting each of these novel noncanonical sites or with SARD activity are discussed. Many of these ligands are still in preclinical development, and a few early clinical leads have emerged, but successful late-stage clinical data are still lacking. The breadth and diversity of targets provide hope that optimized noncanonical inhibitors and/or SARDs will be able to overcome antiandrogen-resistant CRPC. 相似文献
22.
Farrukh Aqil Jeyaprakash Jeyabalan Radha Munagala Iqbal Ahmad David J. Schultz Ramesh C. Gupta 《International journal of molecular sciences》2021,22(12)
Breast cancer (BC) is a leading cause of cancer deaths in women in less developed countries and the second leading cause of cancer death in women in the U.S. In this study, we report the inhibition of E2-mediated mammary tumorigenesis by Cuminum cyminum (cumin) administered via the diet as cumin powder, as well as dried ethanolic extract. Groups of female ACI rats were given either an AIN-93M diet or a diet supplemented with cumin powder (5% and 7.5%, w/w) or dried ethanolic cumin extract (1%, w/w), and then challenged with subcutaneous E2 silastic implants (1.2 cm; 9 mg). The first appearance of a palpable mammary tumor was significantly delayed by both the cumin powder and extract. At the end of the study, the tumor incidence was 96% in the control group, whereas only 55% and 45% animals had palpable tumors in the cumin powder and extract groups, respectively. Significant reductions in tumor volume (660 ± 122 vs. 138 ± 49 and 75 ± 46 mm3) and tumor multiplicity (4.21 ± 0.43 vs. 1.16 ± 0.26 and 0.9 ± 0.29 tumors/animal) were also observed by the cumin powder and cumin extract groups, respectively. The cumin powder diet intervention dose- and time-dependently offset E2-related pituitary growth, and reduced the levels of circulating prolactin and the levels of PCNA in the mammary tissues. Mechanistically, the cumin powder diet resulted in a significant reversal of E2-associated modulation in ERα, CYP1A1 and CYP1B1. Further, the cumin powder diet reversed the expression levels of miRNAs (miR-182, miR-375, miR-127 and miR-206) that were highly modulated by E2 treatment. We analyzed the composition of the extract by GC/MS and established cymene and cuminaldehyde as major components, and further detected no signs of gross or systemic toxicity. Thus, cumin bioactives can significantly delay and prevent E2-mediated mammary tumorigenesis in a safe and effective manner, and warrant continued efforts to develop these clinically translatable spice bioactives as chemopreventives and therapeutics against BC. 相似文献
23.
We consider the problem of monitoring the Euclidean plane using rotating sensors with detection sectors and beam sensors. We assume that intruders can appear anywhere at any time and move arbitrarily fast, and may have full knowledge of the sensor network. We require that such intruders be detected within a finite amount of time. We give an optimal network for this problem consisting of a combination of rotating sensors of angle 0 and beam sensors that uses the minimum number of both types of sensors. We show a trade-off between the density of beam sensors needed and the angle of the detection sector of the rotating sensors. Secondly, we give a family of sensor networks using only rotating sensors for the same problem, that demonstrate a trade-off between the detection time and the density of rotating sensors used. We show that the density of rotating sensors required in this case can be significantly reduced by increasing the angle of detection sectors. Finally, we show that our results on the infinite plane can be used to derive sensor networks that monitor some finite regions using a density of sensors that is asymptotically the same, or close to that of the infinite plane case. 相似文献
24.
T.S.N. Sankara Narayanan S. Jegannathan K. Ravichandran 《Progress in Organic Coatings》2006,55(4):355-362
The formation of phosphate coatings by cathodic electrochemical treatment using graphite and steel anodes and evaluation of their corrosion resistance is addressed in this paper. The type of anode used, graphite/steel, has an obvious influence on the composition of the coating, resulting in zinc–zinc phosphate composite coating with graphite anode and zinc–iron alloy–zinc phosphate–zinc–iron phosphate composite coating with steel anode. The corrosion resistance of the coating is found to be a function of the composition of the coating. The deposition of zinc/zinc–iron alloy along with the zinc phosphate/zinc and zinc–iron phosphate using graphite/steel anodes has caused a cathodic shift in the Ecorr compared to uncoated mild steel substrates. The icorr values of these coatings is very high. EIS studies reveal that zinc/zinc–iron alloy dissolution is the predominant reaction during the initial stages of immersion. Subsequently, the formation of zinc and iron corrosion products imparts resistance to the charge transfer process and increases the corrosion resistance with increase in immersion time. The corrosion products formed might consist of oxides and hydroxychlorides of zinc and iron. The study suggests that cathodic electrochemical treatment could be effectively utilized to impart the desirable characteristics of the coating by choosing appropriate anode materials, bath composition and operating conditions. 相似文献
25.
A differentiation between free carboxyl and various lactone groups in different types of oxycelluloses was carried out based on the variation in their reaction rate with KI/KIO3 solution. For oxycelluloses prepared under acidic conditions, a large proportion of carboxyl groups are present in free form. Each oxycellulose was also studied after cation freeing as well as after blocking the free carboxyl groups by treatment with sodium chloride. Cation freeing was found to cause considerable lactonization of carboxyl groups; sodium chloride treatment blocked them only partially. 相似文献
26.
Poly(l-lactic acid) with 4% d-lactic acid comonomer has been drawn in the amorphous state at 80, 90, 100, 110 and 120 °C at an extension rate of 4 s−1 while simultaneously recording WAXS and SAXS patterns at intervals of 0.12 s. At 80, 90 and 100 °C, crystallisation is very rapid (1-4 s−1) and follows a first order transformation process to give highly oriented crystals. SAXS patterns were barely detectable at these temperatures despite fractional crystallinity of ∼0.2. At 110 and 120 °C, crystallisation was very slow (∼0.01 s−1) and gave rise to crystals with a lower degree of orientation. After eventual crystallisation at 120 °C, a two-point SAXS pattern develops with narrow lateral spread, suggesting ‘shish kebab’ morphology. When the 80 °C drawn sample was annealed at 120 °C, a strong four point SAXS pattern develops. The change in drawing and crystallisation behaviour at higher draw temperature is attributed to the onset of chain retraction relaxation processes. The WAXS fibre pattern after annealing shows sampling on intermediate layer lines that is consistent with the α crystal form with a 103 helix. However, prior to annealing, sampling indicates a different, less defined helical configuration. 相似文献
27.
The dynamic response of a gas fluidised bed has been measured for a range of particle sizes of lead glass ballotini and a range of particle Reynolds numbers. A dispersion model has been formulated that includes the effects of gas and particle mixing, fluid-to-particle heat transfer and intraparticle thermal conductivity, and the dynamic thermal response in theory has been found by solving the partial differential equations in the Laplace transform domain. The coefficient of thermal dispersion, the particle-to-fluid heat transfer coefficient and the intraparticle thermal conductivity have been found for the experimental response by non-linear regression. The coefficient of axial dispersion was found to be large and the particle to fluid heat transfer coefficients agreed with an established correlation for fixed and fluidised beds. The intraparticle thermal conductivity agreed with literature values for lead glass, the estimates showed no trend with flowrate, and the standard deviation of the estimate was three times smaller than the deviation found from similar experiments in fixed beds. 相似文献
28.
Media access protocols in wireless networks require each contending node to wait for a backoff time, chosen randomly from a fixed range, before attempting to transmit on a shared channel. However, nodes acting in their own selfish interest may not follow the protocol. In this paper, a static version of the problem is modeled as a strategic game played by non-cooperating, rational players (the nodes). The objective is to design a game which exhibits a unique, a priori mixed-strategy Nash equilibrium. In the context of the media access problem, the equilibrium of the game would correspond to nodes choosing backoff times randomly from a given range of values, according to the given distribution. We consider natural variations of the problems concerning the number of actions available to the players and show that it is possible to design such a game when there are at least two players that each have the largest number of possible actions among all players. In contrast, we show that if there are exactly two players with different number of actions available to them, then it becomes impossible to design a strategic game with a unique such Nash equilibrium. 相似文献
29.
Human Perception of Audio-Visual Synthetic Character Emotion Expression in the Presence of Ambiguous and Conflicting Information 总被引:1,自引:0,他引:1
Computer simulated avatars and humanoid robots have an increasingly prominent place in today's world. Acceptance of these synthetic characters depends on their ability to properly and recognizably convey basic emotion states to a user population. This study presents an analysis of the interaction between emotional audio (human voice) and video (simple animation) cues. The emotional relevance of the channels is analyzed with respect to their effect on human perception and through the study of the extracted audio-visual features that contribute most prominently to human perception. As a result of the unequal level of expressivity across the two channels, the audio was shown to bias the perception of the evaluators. However, even in the presence of a strong audio bias, the video data were shown to affect human perception. The feature sets extracted from emotionally matched audio-visual displays contained both audio and video features while feature sets resulting from emotionally mismatched audio-visual displays contained only audio information. This result indicates that observers integrate natural audio cues and synthetic video cues only when the information expressed is in congruence. It is therefore important to properly design the presentation of audio-visual cues as incorrect design may cause observers to ignore the information conveyed in one of the channels. 相似文献
30.
C Frey K Narayanan K McMillan L Spack SS Gross BS Masters OW Griffith 《Canadian Metallurgical Quarterly》1994,269(42):26083-26091
Nitric-oxide synthase (NOS) catalyzes the oxidation of L-arginine to citrulline and nitric oxide (NO). The enzyme is inhibited by a variety of N omega-monosubstituted L-arginine analogs, and some of these compounds are useful in reversing pathologies associated with the overproduction of NO (e.g. the hypotension of septic shock). We report here that L-thiocitrulline (gamma-thioureido-L-norvaline) is a potent, stereospecific inhibitor of the constitutive brain and endothelial isoforms of NOS as well as the isoform induced in vascular smooth muscle cells by lipopolysaccharide and interferon-gamma. Steady state kinetic studies show L-thiocitrulline inhibition is competitive with L-arginine (Ki approximately 4-20% of KArgm), indicating that initial binding is as a substrate/product analog. In contrast to L-arginine and N omega-methyl-L-arginine, the prototypic NOS inhibitor, L-thiocitrulline binding elicits a "Type II" difference spectrum, indicating a high spin to low spin transition of the iron in the heme cofactor. This finding suggests that L-thiocitrulline is contributing the sixth ligand to heme iron, probably through the thioureido sulfur. Such interaction with heme iron neither stimulates nor inhibits the direct flavin-mediated cytochrome c reduction activity of the enzyme, but it does inhibit heme-dependent superoxide formation. In vivo, L-thiocitrulline is a potent pressor agent in both normal and endotoxemic rats, the latter finding suggesting utility in treating the hypotension of septic shock. 相似文献