Estrogen receptor-Beta activated apoptosis in benign hyperplasia and cancer of the prostate is androgen independent and TNF-alpha mediated

Prostate cancer (PCa) and benign prostatic hyperplasia (BPH) are androgen-dependent diseases commonly treated by inhibiting androgen action. However, androgen ablation or castration fail to target androgen-independent cells implicated in disease etiology and recurrence. Mechanistically different to castration, this study shows beneficial proapoptotic actions of estrogen receptor–β (ERβ) in BPH and PCa. ERβ agonist induces apoptosis in prostatic stromal, luminal and castrate-resistant basal epithelial cells of estrogen-deficient aromatase knock-out mice. This occurs via extrinsic (caspase-8) pathways, without reducing serum hormones, and perturbs the regenerative capacity of the epithelium. TNFα knock-out mice fail to respond to ERβ agonist, demonstrating the requirement for TNFα signaling. In human tissues, ERβ agonist induces apoptosis in stroma and epithelium of xenografted BPH specimens, including in the CD133+ enriched putative stem/progenitor cells isolated from BPH-1 cells in vitro. In PCa, ERβ causes apoptosis in Gleason Grade 7 xenografted tissues and androgen-independent cells lines (PC3 and DU145) via caspase-8. These data provide evidence of the beneficial effects of ERβ agonist on epithelium and stroma of BPH, as well as androgen-independent tumor cells implicated in recurrent disease. Our data are indicative of the therapeutic potential of ERβ agonist for treatment of PCa and/or BPH with or without androgen withdrawal.

Varenicline, an alpha-4 beta-2 nicotinic acetylcholine receptor partial agonist, selectively decreases ethanol consumption and seeking

Abstract Alcohol dependence is a disease that impacts millions of individuals worldwide. There has been some progress with pharmacotherapy for alcohol-dependent individuals; however, there remains a critical need for the development of novel and additional therapeutic approaches. Alcohol and nicotine are commonly abused together, and there is evidence that neuronal nicotinic acetylcholine receptors (nAChRs) play a role in both alcohol and nicotine dependence. Varenicline, a partial agonist at the alpha4beta2 nAChRs, reduces nicotine intake and was recently approved as a smoking cessation aid. We have investigated the role of varenicline in the modulation of ethanol consumption and seeking using three different animal models of drinking. We show that acute administration of varenicline, in doses reported to reduce nicotine reward, selectively reduced ethanol but not sucrose seeking using an operant self-administration drinking paradigm and also decreased voluntary ethanol but not water consumption in animals chronically exposed to ethanol for 2 months before varenicline treatment. Furthermore, chronic varenicline administration decreased ethanol consumption, which did not result in a rebound increase in ethanol intake when the varenicline was no longer administered. The data suggest that the alpha4beta2 nAChRs may play a role in ethanol-seeking behaviors in animals chronically exposed to ethanol. The selectivity of varenicline in decreasing ethanol consumption combined with its reported safety profile and mild side effects in humans suggest that varenicline may prove to be a treatment for alcohol dependence.

Mutations in exon 3 of the beta-catenin gene are rare in melanoma cell lines

Mutations in exon 3 of the CTNNB1 gene encoding beta-catenin have been reported in colorectal cancer cell lines and tumours. Although one study reported mutations or deletions affecting beta-catenin in 20% of melanoma cell lines, subsequent reports detected a much lower frequency of aberrations in uncultured melanomas. To determine whether this difference in mutation frequency reflected an in vitro culturing artefact, exon 3 of CTNNB1 was screened in a panel of 62 melanoma cell lines. In addition, reverse transcription-polymerase chain reaction (RT-PCR) was performed to detect intragenic deletions affecting exon 3. One out of 62 (1.6%) cell lines was found to carry a mutation, indicating that aberration of the Wnt-1/wingless pathway through activation of beta-catenin is a rare event, even in melanoma cell lines.

Investigation of phenol degradation : True reaction kinetics on fixed film titanium dioxide photocatalyst

This study of photocatalytic oxidation of phenol over titanium dioxide films presents a method for the evaluation of true reaction kinetics. A flat plate reactor was designed for the specific purpose of investigating the influence of various reaction parameters, specifically photocatalytic film thickness, solution flow rate (1–8 l min−1), phenol concentration (20, 40 and 80 ppm), and irradiation intensity (70.6, 57.9, 37.1and 20.4 W m−2), in order to further understand their impact on the reaction kinetics. Special attention was given to the mass transfer phenomena and the influence of film thickness. The kinetics of phenol degradation were investigated with different irradiation levels and initial pollutant concentration. Photocatalytic degradation experiments were performed to evaluate the influence of mass transfer on the reaction and, in addition, the benzoic acid method was applied for the evaluation of mass transfer coefficient. For this study the reactor was modelled as a batch-recycle reactor. A system of equations that accounts for irradiation, mass transfer and reaction rate was developed to describe the photocatalytic process, to fit the experimental data and to obtain kinetic parameters. The rate of phenol photocatalytic oxidation was described by a Langmuir–Hinshelwood type law that included competitive adsorption and degradation of phenol and its by-products. The by-products were modelled through their additive effect on the solution total organic carbon.

Biomaterials in orthopedic bone plates : a review

This paper aims to review biomaterials used in manufacturing bone plates including advances in recent years and prospect in the future. It has found among all biomaterials, currently titanium and stainless steel alloys are the most common in production of bone plates. Other biomaterials such as Mg alloys, Ta alloys, SMAs, carbon fiber composites and bioceramics are potentially suitable for bone plates because of their advantages in biocompatibility, bioactivity and biodegradability. However, today either they are not used in bone plates or have limited applications in only some flexible small-size implants. This problem is mainly related to their poor mechanical properties. Additionally, production processes play an effective role. Therefore, in the future, further studies should be conducted to solve these problems and make them feasible for heavy-duty bone plates.

The microRNA expression signature on modified titanium implant surfaces influences genetic mechanisms leading to osteogenic differentiation

Topographically and chemically modified titanium implants are recognized to have improved osteogenic properties; however, the molecular regulation of this process remains unknown. This study aimed to determine the microRNA profile and the potential regulation of osteogenic differentiation following early exposure of osteoprogenitor cells to sand-blasted, large-grit acid-etched (SLA) and hydrophilic SLA (modSLA) surfaces. Firstly, the osteogenic characteristics of the primary osteoprogenitor cells were confirmed using ALP activity and Alizarin Red S staining. The effect of smooth (SMO), SLA and modSLA surfaces on the TGF-β/BMP (BMP2, BMP6, ACVR1) and non-canonical WNT/Ca2+ (WNT5A, FZD6) pathways, as well as the integrins ITGB1 and ITGA2, was determined. It was revealed that the modified titanium surfaces could induce the activation of TGF-β/BMP and non-canonical WNT/Ca2+ signaling genes. The expression pattern of microRNAs (miRNAs) related to cell differentiation was evaluated. Statistical analysis of the differentially regulated miRNAs indicated that 35 and 32 miRNAs were down-regulated on the modSLA and SLA surfaces respectively, when compared with the smooth surface (SMO). Thirty-one miRNAs that were down-regulated were common to both modSLA and SLA. There were 10 miRNAs up-regulated on modSLA and nine on SLA surfaces, amongst which eight were the same as observed on modSLA. TargetScan predictions for the down-regulated miRNAs revealed genes of the TGF-β/BMP and non-canonical Ca2+ pathways as targets. This study demonstrated that modified titanium implant surfaces induce differential regulation of miRNAs, which potentially regulate the TGF-β/BMP and WNT/Ca2+ pathways during osteogenic differentiation on modified titanium implant surfaces.

Orthopedic bone plates : evolution in structure implementation technique and biomaterial

With many important developments over the last century, nowadays orthopedic bone plate now excels over other types of internal fixators in bone fracture fixation. The developments involve the design, material and implementation techniques of the plates. This paper aims to review the evolution in implementation technique and biomaterial of the orthopedic bone plates. Plates were initially used to fix the underlying bones firmly. Accordingly, Compression plate (CP), Dynamic compression plate (DCP), Limited contact dynamic compression plate (LC-DCP) and Point contact fixator (PC-Fix) were developed. Later, the implementation approach was changed to locking, and the Less Invasive Stabilization System (LISS) plate was introduced as a result. Finally, a combination of both of these approaches has been used by introducing the Locking Compression Plate (LCP). Currently, precontoured LCPs are mainly used for bone fracture fixation. In parallel with structure and implementation techniques, numerous advances have occurred in biomaterials of the plates. Titanium and stainless steel alloys are now the most common biomaterials in production of orthopedic bone plates. However, regarding the biocompatibility, bioactivity and biodegradability characteristics of Mg alloys, Ta alloys, SMAs, carbon fiber composites and bioceramics, these materials are considered as potentially suitable for plates. However, due to poor mechanical properties, they have very limited applications. Therefore, further studies are required in future to solve these problems and make them feasible for heavy-duty bone plates.

Studies of bone cell adhesion and proliferation on ion implanted titanium discs

Argon ions were implanted on titanium discs to study its effect on bone cell adhesion and proli feration. Polished titanium discs were prepared and implanted with argon ions with different doses. Afterwards the samples were sterilized using UV light, inocu lated with human bone cells and incubated. Once fixed and rinsed, image analysis has been used to quantify the number of cells attached to the titanium discs. Cell proliferation tests were also conducted after a period of 120 hours. Cell adhesion was seen to be higher with ion im planted surface. SEM analysis has shown that the cells attached spread more on ion implanted surface. The numbers of cells attached were seen to be higher on implanted surfaces; they tend to occupy wider areas with healthier cells.

The asthmatic athlete, inhaled beta agonists, and performance

INTRODUCTION: The large increase in the number of athletes who apply to use inhaled beta agonists (IBAs) at the Olympic Games is a concern to the medical community. This review will examine the use of IBAs in the asthmatic athlete, the variability that exists between countries and sport, and outline a plan to justify the use of these medications. DATA SOURCES: Much of this article is a result of an International Olympic Committee (IOC) Medical Commission-sponsored meeting that took place in May 2001. Records of the use of IBAs at previous Olympics were reviewed. MEDLINE Searches (PubMed interface) were performed using key words to locate published work relating to asthma, elite athletes, performance, treatment, and ergogenic aids. MAIN RESULTS: Since 1984 there have been significant increases in the use of IBAs at the Olympic Games as well as marked geographical differences in the percentage of athletes requesting the use of IBAs. There are large differences in the incidence of IBA use between sports with a trend towards increased use in endurance sports. There are no ergogenic effects of any IOC-approved IBA given in a therapeutic dose. CONCLUSIONS: In many cases, the prescription of IBAs to this population has been made on empirical grounds. Beginning with the 2002 Winter Games, athletes will be required to submit to the IOC Medical Commission clinical and laboratory evidence that justifies the use of this medication. The eucapnic voluntary hyperpnea test will be used to assess individuals who have not satisfied an independent medical panel of the need to use an IBA.

Interstellar titanium-oxides in interplanetary dust

Interstellar gas abundances (Clayton et al., 1986) suggest that titanium may be bound up in dust and indeed, excess titanium in carbonaceous chondrites is attributed to mixing of interstellar and Solar System materials (Morton, 1974). Fine-grained chondritic interplanetary dust particles (lOPs) of cometary origin are relatively pristine early Solar System materials (Mackinnon and Rietmeijer, 1987; Rietmeijer, 1987) and show chemical and mineralogical signatures related to a pre-solar or nebular origin. For example, large OtH ratios suggest a presolar or interstellar dust component in some chondritic lOPs(Mackinnon and Rietmeijer, 1987). Ti/Si ratios (normalized to bulk CI) in lOPs and carbonaceous chondrite matrices exceed solar abundances but are similar to dust from comet Halley (Jessberger et al., 1987). The Ti-distribution in chondritic lOPs shows major, small-scale « 0.1 urn) variations (Flynn et al., 1978) consistent with heterogeneously distributed Ti-bearingphases. Analytical electron microscope (AEM) studies, in fact, have identified platey grains of Ti-metal, Ti407 and Ti s09 in two different lOPs (Mackinnon and Rietmeijer, 1987). The occurrence of Ti407 was related in situ low-temperature aqueous alteration and therefore implied the presence of BaTi03 (Rietmeijer and Mackinnon, 1984). Yet, the presence ofTis09 in an lOp which shows no evidence of aqueous alteration (Rietmeijer.and McKay, 1986) requires a different interpretation. The distribution of Ti-oxides in chondritic lOPs were investigated with ultra-microtomed thin sections of fluffy chondri tic lOP U2011*B (lSC allocation U2011C2) using a lEOL 2000FX AEM operating at an accelerating voltage of 200kV and with an attached Tracor Northern TN5500 energy dispersive spectrometer.

Grain size distributions of Magneli phases and metallic titanium in chondritic porous interplanetary dust particles

A mineralogical survey of chondritic interplanetary dust particles (IDPs)showed that these micrometeorites differ significantly in form and texture from components of carbonaceous chondrites and contain some mineral assemblages which do not occur in any meteorite class1. Models of chondritic IDP mineral evolution generally ignore the typical (ultra-) fine grain size of consituent minerals which range between 0.002-0.1µm in size2. The chondritic porous (CP) subset of chondritic IDPs is probably debris from short period comets although evidence for a cometary origin is still circumstantial3. If CP IDPs represent dust from regions of the Solar System in which comet accretion occurred, it can be argued that pervasive mineralogical evolution of IDP dust has been arrested due to cryogenic storage in comet nuclei. Thus, preservation in CP IDPs of "unusual meteorite minerals", such as oxides of tin, bismuth and titanium4, should not be dismissed casually. These minerals may contain specific information about processes that occurred in regions of the solar nebula, and early Solar System, which spawned the IDP parent bodies such as comets and C, P and D asteroids6. It is not fully appreciated that the apparent disparity between the mineralogy of CP IDPs and carbonaceous chondrite matrix may also be caused by the choice of electron-beam techniques with different analytical resolution. For example, Mg-Si-Fe distributions of Cl matrix obtained by "defocussed beam" microprobe analyses are displaced towards lower Fe-values when using analytical electron microscope (AEM)data which resolve individual mineral grains of various layer silicates and magnetite in the same matrix6,7. In general, "unusual meteorite minerals" in chondritic IDPs, such as metallic titanium, Tin01-n(Magneli phases) and anatase8 add to the mineral data base of fine-grained Solar System materials and provide constraints on processes that occurred in the early Solar System.