Effect of Mitomycin - C and Triamcinolone on Preventing Urethral Strictures

Urethral stricture is a common disease with high recurrence rate. Several manipulations were defined to prevent the recurrence but the results were disappointing. This study aimed to evaluate the efficacy of triamcinolone and mitomycin-C on urethral stricture formation and their effect on inhibition of urethral fibrosis. A total of 24 New Zealand rabbits were divided into 3 groups. Urethras of rabbits were traumatized with pediatric resectoscope. Resection area was irrigated with 10mL saline, swapped with a cotton wool soaked with 0.5mg/mL MMC and injected by 40mg triamcinolone in groups 1, 2 and 3 respectively. Retrograde urethrogram was performed at 28th day of procedure and the urethra was removed for histopathologic evaluation. There were significant differences in urethral diameters and in lumen reduction rate between the control and study groups (p< 0.001). Compared to control group, all treatment groups showed mild fibrosis, less collagen bundle irregularity, and lower numbers of fibroblasts (p= 0.003). The Tunnel assay showed that the number of apoptotic cells in the submucosal connective tissue was quantitatively higher in control groups (p= 0.034). In the view of efficacy and safety, MMC and triamcinolone have the potential to replace the use of stents, clean intermittent catheterization, or long term catheters following internal urethrotomy. There were no statistically significant differences between two agents in terms of preventing urethral stricture formation in the present study. Mitomycin C and triamcinolone decreased the recurrence rates of urethral stricture

Prognostic and therapeutic relevance of FLIP and procaspase-8 overexpression in non-small cell lung cancer

Non-small cell lung carcinoma remains by far the leading cause of cancer-related deaths worldwide. Overexpression of FLIP, which blocks the extrinsic apoptotic pathway by inhibiting caspase-8 activation, has been identified in various cancers. We investigated FLIP and procaspase-8 expression in NSCLC and the effect of HDAC inhibitors on FLIP expression, activation of caspase-8 and drug resistance in NSCLC and normal lung cell line models. Immunohistochemical analysis of cytoplasmic and nuclear FLIP and procaspase-8 protein expression was carried out using a novel digital pathology approach. Both FLIP and procaspase-8 were found to be significantly overexpressed in tumours, and importantly, high cytoplasmic expression of FLIP significantly correlated with shorter overall survival. Treatment with HDAC inhibitors targeting HDAC1-3 downregulated FLIP expression predominantly via post-transcriptional mechanisms, and this resulted in death receptor- and caspase-8-dependent apoptosis in NSCLC cells, but not normal lung cells. In addition, HDAC inhibitors synergized with TRAIL and cisplatin in NSCLC cells in a FLIP- and caspase-8-dependent manner. Thus, FLIP and procaspase-8 are overexpressed in NSCLC, and high cytoplasmic FLIP expression is indicative of poor prognosis. Targeting high FLIP expression using HDAC1-3 selective inhibitors such as entinostat to exploit high procaspase-8 expression in NSCLC has promising therapeutic potential, particularly when used in combination with TRAIL receptor-targeted agents

Histone deacetylase (HDAC) inhibitors in recent clinical trials for cancer therapy

Heritable changes in gene expression that are not based upon alterations in the DNA sequence are defined as epigenetics. The most common mechanisms of epigenetic regulation are the methylation of CpG islands within the DNA and the modification of amino acids in the N-terminal histone tails. In the last years, it became evident that the onset of cancer and its progression may not occur only due to genetic mutations but also because of changes in the patterns of epigenetic modifications. In contrast to genetic mutations, which are almost impossible to reverse, epigenetic changes are potentially reversible. This implies that they are amenable to pharmacological interventions. Therefore, a lot of work in recent years has focussed on the development of small molecule enzyme inhibitors like DNA-methyltransferase inhibitors or inhibitors of histone-modifying enzymes. These may reverse misregulated epigenetic states and be implemented in the treatment of cancer or other diseases, e.g., neurological disorders. Today, several epigenetic drugs are already approved by the FDA and the EMEA for cancer treatment and around ten histone deacetylase (HDAC) inhibitors are in clinical development. This review will give an update on recent clinical trials of the HDAC inhibitors used systemically that were reported in 2009 and 2010 and will present an overview of different biomarkers to monitor the biological effects

The Catalysis of Nuclear Reactions by mu Mesons

In the course of a recent experiment involving the stopping of negative K mesons in a 10-inch liquid hydrogen bubble chamber, an interesting new reaction was observed to take place. The chamber is traversed by many more negative {mu} mesons than K mesons, so that in the last 75,000 photographs, approximately 2500 {mu}{sup -} decays at rest have been observed. In the same pictures, several hundred {pi}{sup -} mesons have been observed to disappear at rest, presumably by one of the ''Panofsky reactions''. For tracks longer than 10 cm, it is possible to distinguish a stopping {mu} meson from a stopping {pi} meson by comparing its curved path (in a field of 11,000 gauss) with that of a calculated template. In addition to the normal {pi}{sup -} and {mu}{sup -} stoppings, we have observed 15 cases in which what appears (from curvature measurement) to be a {mu}{sup -} meson comes to rest in the hydrogen, and then gives rise to a secondary negative particle of 1.7 cm range, which in turn decays by emitting an electron. (A 4.1-Mev {mu} meson from {pi} - {mu} decay has a range of 1.0 cm.) The energy spectrum of the electrons from these 15 secondary particles looks remarkably like that of the {mu} meson. There are four electrons in the energy range 50 to 55 Mev, and none higher; the other electrons have energies varying from 50 Mev to 13 Mev. The most convincing proof that the primary particle actually comes to rest, and does not--for example--have a large resonant cross section for scattering at a residual range of 1.7 cm, is the following: In five of the 15 special events, there is a large gap between the last bubble of the primary track and the first bubble of the secondary track. This gap is a real effect, and not merely a statistical fluctuation in the spacing of the bubbles, since in some cases the tracks form a letter X, and in another case the secondary track is parallel to the primary, but displaced transversely by about 1 mm at the end of the primary. These real gaps appear also (although perhaps less frequently) between some otherwise normal-looking {mu}{sup -} endings and the subsequent decay electron; they are thought to be the distance traveled by the small neutral mesic atom

At-line determining spore germination of Penicillium chrysogenum bioprocesses in complex media

Spore inoculum quality in filamentous bioprocesses is a critical parameter associated with viable spore concentration (1) and spore germination (2). It influences pellet morphology and, consequently, process performance. The state-of-the-art method to measure viable spore concentration is tedious, associated with significant inherent bias, and not applicable in real-time. Therefore, it is not usable as process analytical technology (PAT). Spore germination has so far been monitored using image analysis, which is hampered by complex medium background often observed in filamentous bioprocesses. The method presented here is based on the combination of viability staining and large-particle flow cytometry which enables measurements in real-time and hence aims to be applicable as a PAT tool. It is compatible with the complex media background and allows the quantification of metabolically active spores and the monitoring of spore germination. A distinction of germinated spores and not germinated spores was based on logistic regression, using multiparameteric data from flow cytometry. In a first step, a significant correlation between colony-forming unit (CFU) counts and viable spore concentration (1) in an industrially relevant model bioprocess was found. Spore germination (2) was followed over the initial process phase with close temporal resolution. The validation of the method showed an error below 5 %. Differences in spore germination for various spore inocula ages and spore inoculum concentrations were monitored. The real-time applicability of the method suggests the implementation as a PAT tool in filamentous bioprocesses.