An Overview of Next-Generation Androgen Receptor-Targeted Therapeutics in Development for the Treatment of Prostate Cancer

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.     

Influence of Montmorillonite Clay Content on Thermal,Mechanical, Water Absorption and Biodegradability Properties of Treated Kenaf Fiber/ PLA-Hybrid Biocomposites

Silicon - Nowadays, the starring attentions of the polylactic acid based composites are improved due to environmental awareness and diminution of petroleum oil. The bio-plastics were restricted to...     

Influence of Ball Burnishing Process on Equal Channel Angular Pressed Mg-Zn-Si Alloy on the Evolution of Microstructure and Corrosion Properties

Silicon - In the present study, Mg-4Zn-1Si alloy was subjected to equal channel angular pressing (ECAP) up to 4 passes at 300 °C, followed by ball burnishing using 0.3 mm...     

Cumin Prevents 17β-Estradiol-Associated Breast Cancer in ACI Rats

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.     

Study of Magnetic and Electrical Properties of Poly(o-phenylenediamine)/Manganese Substituted ZnFe2O4 Nanocomposites

Journal of Inorganic and Organometallic Polymers and Materials - Different concentrations of ZnFe2O4 and manganese substituted ZnFe2O4 nanoparticles (10%, 20% and 30%) dispersed...     

Observations on the role of oxide scales in high-temperature erosion-corrosion of alloys

The results are presented of exposure to a controlled high-temperature erosive gas stream of a series of alloys, which were selected to represent the range of microstructures and mechanical properties available in commercial high-temperature alloys. Analysis of the kinetic and morphological data suggested that the high-temperature oxidation behavior of a given alloy plays a very important role in determining its erosion-corrosion behavior under the conditions studied. In terms of relative behavior, alloys which are weak but ductile at temperature, and which form tenacious oxide scales, exhibited the highest resistance to high-temperature erosion-corrosion. Simple models were developed to describe the expected interaction between high-temperature oxidation and erosion.     

Corrosion of Fe-10Al-Cr alloys by coal char

Corrosion of iron-base alloys at 982°C (1800°F) by coal char is observed and the phase morphologies are discussed. No sulfidation was observed at 50 hr exposure. After 100 hr internal aluminum-rich sulfides were observed along with thick outer scales of iron oxide. The species causing the hightemperature-induced corrosion are probably sulfides and sulfates, present in most coal chars. Possible mechanisms for the corrosion are also discussed.Department of Materials Science and Mineral Engineering.     

The heterogeneous nucleation of microcellular foams assisted by the survival of microvoids in polymers containing low glass transition particles. Part I: Mathematical modeling and numerical simulation

The existing models based on classical nucleation theory are not able to explain satisfactorily the nucleation phenomenon of microcellular foams in thermoplastics. Here, we extend the analysis of Kweeder (24), who developed a new model that considers the presence of microvoids, resulting from the thermal processing history of the polymer, as potential nucleation sites. The nucleation model “concentrates” on the stresses and thus void formations in the rubber particles. Since these are pre-existing microvoids, bubble nucleation depends on the survival of these voids to grow rather than the formation of a new phase as modeled by classical nucleation theory. The population of viable microvoids with a sufficiently large radius to survive and overcome surface and elastic forces has been modeled to yield the cell density. A log-normal distribution, which relates to the rubber particle size, has been used to model the distribution of microvoids in the polymer composite material. The model depends on various process parameters such as saturation pressure, foaming temperature, concentration of nucleating agents, solubility of the blowing agent in the polymer, and the modulus. High impact polystyrene (HIPS) was added to polystyrene to obtain polymers with different concentrations of rubber gel particles, the nucleating agent, and used here for this study.     

Structure of polyurethane elastomers. X-ray diffraction and conformational analysis of MDI-propandiol and MDI-ethylene glycol hard segments

X-ray diffraction and conformational analysis have been used to investigate the structure of polyurethane hard segments prepared from diphenylmethane 4,4′-diisocyanate (MDI) with propandiol (PDO) and ethylene glycol (EDO) as chain extenders. The results are compared with those obtained previously for MDI-butandiol (BDO) hard segments. In the latter system, the poly(MDI-BDO) chains are fully extended with an all-trans conformation for the O(CH₂)₄O unit, and a monomer repeat of 18.95 Å. The unit cell is triclinic with a tilted base plane such that adjacent chains are staggered along the fibre axis. In contrast both poly(MDI-PDO) and poly(MDI-EDO) adopt unstaggered structures, i.e. the chains are in register and the unit cell base planes are perpendicular to the chain axis. The monomer repeats of 16.2 Å for poly(MDI-PDO) and 15.0 Å for poly(MDI-EDO) are shorter than the predicted repeats for fully-extended chains, indicating that these polymers have contracted conformations containing some gauche CH₂ groups. Conformational analysis shows that the 16.2 Å repeat for poly(MDI-PDO) can be achieved with the O(CH₂)₃O unit in the trans-gauche⁺-gauche⁺-trans or gauche⁺-trans-trans-gauche⁺ conformations. Similarly the 15.0 Å repeat for poly(MDI-EDO) is predicted for the gauche⁺-trans-gauche^? conformation for the O(CH₂)₂O unit. These conformations are of higher energy than the all-trans fully-extended chains. This may explain the higher crystalline perfection of the poly(MDI-BDO) hard segments, for which crystallization in the all-trans form will probably provide a greater driving force for phase separation.     

Conformational analysis of poly(MDI-butandiol) hard segment in polyurethane elastomers

As part of our study of the structure of the hard segments of polyurethane elastomers, we have used conformational analysis to predict the conformation of the polyurethane chain formed from diphenylmethane 4,4′-diisocyanate (MDI), with butandiol as the chain extender. X-ray diffraction indicates the chain conformation is highly extended in the solid state, with a monomer repeat of 18.95 Å. The chain conformation can be predicted from the interaction between the large contiguous groups. Semiempirical and CNDO/2 molecular orbital calculations have been used to investigate the phenyl-phenyl, phenyl-urethane, and urethane-butandiol interactions. Minimum energy for the diphenyl-methane section occurs for a CCH₂C bridge angle of θ = 110°. However, the more likely conformation in the polymer is probably that at the subsidiary minimum at θ = 118°, in which the phenyl rings are mutually perpendicular, which is comparable to the conformation seen for model compounds. For the phenyl-urethane interactions the energy minimum is at $\text{ч = ±90°}$, with the combination $\text{(ч}{}_1\text{, ч}{}_2\text{) = (?90°, +90°)}$ leading to the necessary extended conformation. Calculations for the butandiol segment favour an all-trans conformation which is coplanar with the urethane groups. The predicted conformation of the polymer chain has a fibre repeat which matches the observed value, and this cannot be attained if the butandiol unit contains any gauche bonds. Model compounds show large variations for the phenyl-urethane conformation from the predicted minimum at $\text{ч = ±90°}$, indicating the importance of intermolecular stacking forces in determining the polymer conformation. However, provided the adjacent butandiol and urethane groups are coplanar, the fibre repeat is relatively insensitive to variations of ч.