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Pathobiology and Chemoprevention of Bladder Cancer
Takuji Tanaka,Katsuhito Miyazawa,Tetsuya Tsukamoto,Toshiya Kuno,Koji Suzuki
Journal of Oncology , 2011, DOI: 10.1155/2011/528353
Abstract: Our understanding of the pathogenesis of bladder cancer has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies, prevention, or strategies to manage patients who are suspected to have or who have been diagnosed with bladder cancer is the ultimate goal. In particular, the chemoprevention of bladder cancer development is important, since urothelial cancer frequently recurs, even if the primary cancer is completely removed. The numerous alterations of both oncogenes and tumor suppressor genes that have been implicated in bladder carcinogenesis represent novel targets for therapy and prevention. In addition, knowledge about these genetic alterations will help provide a better understanding of the biological significance of preneoplastic lesions of bladder cancer. Animal models for investigating bladder cancer development and prevention can also be developed based on these alterations. This paper summarizes the results of recent preclinical and clinical chemoprevention studies and discusses screening for bladder cancer. 1. Introduction There has recently been an increasing incidence of and significant mortality rates attributed to bladder cancer. Fortunately, our understanding of the pathobiology of this malignancy has improved considerably over the past decade. Translating these novel pathobiological discoveries into therapies or strategies to manage patients who are suspected to have or who have been previously diagnosed with bladder cancer is the ultimate goal. Of the three main histological variants of epithelial malignancies arising from the urothelium of the urinary bladder, transitional cell carcinoma (TCC, Figure 1) is the most prevalent in Japan, North America, and other developed countries, while squamous cell carcinoma (Figure 2) and adenocarcinoma (Figure 2) are diagnosed less frequently. Figure 1: Natural history of bladder cancer (transitional cell carcinoma). Tis, transitional cell carcinoma in situ; and TCC, transitional cell carcinoma. Figure 2: Three main histological types of bladder cancer and their urinary cytology. TCC, transitional cell carcinoma; SCC, squamous cell carcinoma; and ADC, adenocarcinoma. In this paper, the reported alterations of both oncogenes and tumor suppressor genes in bladder cancer will be outlined and described in the context of possible novel therapies targeting these alterations. Several investigators have hypothesized that certain chromosomal abnormalities and mutations play definite roles in bladder cancer development, while other alterations correlate
Csn3 Gene Is Regulated by All-Trans Retinoic Acid during Neural Differentiation in Mouse P19 Cells
Rie Komori, Takanobu Kobayashi, Hikaru Matsuo, Katsuhito Kino, Hiroshi Miyazawa
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061938
Abstract: κ-Casein (CSN3) is known to play an essential role in controlling the stability of the milk micelles. We found that the expression of Csn3 was induced by all-trans retinoic acid (ATRA) during neural differentiation in P19 embryonal carcinoma cells from our study using DNA microarray. In this paper, we describe the detailed time course of Csn3 expression and the induction mechanism of Csn3 transcription activation in this process. The Csn3 expression was induced rapidly and transiently within 24 h of ATRA treatment. Retinoic acid receptor (RAR)-specific agonists were used in expression analysis to identify the RAR subtype involved upregulation of Csn3; a RARα-specific agonist mimicked the effects of ATRA on induction of Csn3 expression. Therefore, RARα may be the RAR subtype mediating the effects of ATRA on the induction of Csn3 gene transcription in this differentiation-promoting process of P19 cells. We found that the promoter region of Csn3 contained a typical consensus retinoic acid response element (RARE), and this RARE was necessary for ATRA-dependent transcriptional regulation. We confirmed that RARα bound to this RARE sequence in P19 cells. These findings indicated that the Csn3 expression is upregulated via ATRA-bound RARα and binding of this receptor to the RARE in the Csn3 promoter region. This will certainly serve as a first step forward unraveling the mysteries of induction of Csn3 in the process of neural differentiation.
Calculation of the Stabilization Energies of Oxidatively Damaged Guanine Base Pairs with Guanine
Masayo Suzuki,Katsuhito Kino,Masayuki Morikawa,Takanobu Kobayashi,Rie Komori,Hiroshi Miyazawa
Molecules , 2012, DOI: 10.3390/molecules17066705
Abstract: DNA is constantly exposed to endogenous and exogenous oxidative stresses. Damaged DNA can cause mutations, which may increase the risk of developing cancer and other diseases. G:C-C:G transversions are caused by various oxidative stresses. 2,2,4-Triamino-5(2H)-oxazolone (Oz), guanidinohydantoin (Gh)/iminoallantoin (Ia) and spiro-imino-dihydantoin (Sp) are known products of oxidative guanine damage. These damaged bases can base pair with guanine and cause G:C-C:G transversions. In this study, the stabilization energies of these bases paired with guanine were calculated in vacuo and in water. The calculated stabilization energies of the Ia:G base pairs were similar to that of the native C:G base pair, and both bases pairs have three hydrogen bonds. By contrast, the calculated stabilization energies of Gh:G, which form two hydrogen bonds, were lower than the Ia:G base pairs, suggesting that the stabilization energy depends on the number of hydrogen bonds. In addition, the Sp:G base pairs were less stable than the Ia:G base pairs. Furthermore, calculations showed that the Oz:G base pairs were less stable than the Ia:G, Gh:G and Sp:G base pairs, even though experimental results showed that incorporation of guanine opposite Oz is more efficient than that opposite Gh/Ia and Sp.
Effects of Stability of Base Pairs Containing an Oxazolone on DNA Elongation
Masayo Suzuki,Kazuya Ohtsuki,Katsuhito Kino,Teruhiko Kobayashi,Masayuki Morikawa,Takanobu Kobayashi,Hiroshi Miyazawa
Journal of Nucleic Acids , 2014, DOI: 10.1155/2014/178350
Abstract: The nucleoside 2,2,4-triamino-5(2H)-oxazolone (Oz) can result from oxidative damage to guanine residues in DNA. Despite differences among the three polymerases (Pol β, KF exo?, and Pol η) regarding nucleotide incorporation patterns opposite Oz, all three polymerases can incorporate guanine opposite Oz. Based on ab initio calculations, we proposed a structure for a stable Oz:G base pair. Here, to assess the stability of each Oz-containing base pair (Oz:G, Oz:A, Oz:C, and Oz:T) upon DNA replication, we determined the efficiency of Pol β-, KF exo?-, or Pol η-catalyzed primer extension beyond each base pair. With each polymerase, extension beyond Oz:G was more efficient than that beyond Oz:A, Oz:C, or Oz:T. Moreover, thermal denaturation studies revealed that the value for the duplex containing Oz:G was significantly higher than those obtained for duplexes containing Oz:A, Oz:C, or Oz:T. Therefore, the results from ab initio calculations along with those from DNA replication assays and thermal denaturation experiments supported the conclusion that Oz:G is the most stable of the Oz-containing base pairs. 1. Introduction DNA is constantly damaged by various oxidative stresses. Oxidized DNA causes mutations that can lead to aging, carcinogenesis, and other diseases. Guanine has the lowest oxidation potential among the four bases; therefore, it is much more sensitive than A, T, or C to oxidative stresses. G:C to T:A and G:C to C:G transversions are preferentially caused by several oxidative stresses and are observed in vivo; for example, G:C-T:A and G:C-C:G transversions caused by passive smoking were detected in codons 12 and 13 of the K-ras gene [1]. 8-Oxo-7,8-dihydro-guanine (8-oxoG) is a typical form of oxidative guanine damage (Scheme 1), and 8-oxoG arises under various oxidative conditions. 8-oxoG can pair with adenine but not guanine; therefore, 8-oxoG can generate G:C-T:A transversions [2]. G:C-C:G transversions are assumed to be caused by other forms of oxidative guanine damage. Scheme 1: Products of oxidation of guanine and 8-oxoG. 2,5-Diamino-4H-imidazol-4-one (Iz) can be formed from guanine or 8-oxoG under various oxidative conditions (Scheme 1) [3, 4]. Iz and guanine can potentially form base pairing structures that can in turn cause G:C-C:G transversions [5]. However, Iz is slowly hydrolyzed to 2,2,4-triamino-5(2H)-oxazolone (Oz); this reaction has a half-life of 147?min under physiological conditions (Scheme 1) [3]. In samples of liver DNA, two to six molecules of Oz are detected per 107 guanine bases [6], and the biological impact of Oz should
The Effects of Chlormadinone Acetate on Lower Urinary Tract Symptoms and Erectile Functions of Patients with Benign Prostatic Hyperplasia: A Prospective Multicenter Clinical Study
Kiyohide Fujimoto,Yoshihiko Hirao,Yasuo Ohashi,Yasuhiro Shibata,Kohzo Fuji,Hidenori Tsuji,Katsuhito Miyazawa,Mikinobu Ohtani,Ryoji Furuya,Eitetsu Boku
Advances in Urology , 2013, DOI: 10.1155/2013/584678
Abstract: Purpose. To evaluate the effects of chlormadinone acetate (CMA), progesterone-derived antiandrogen, on lower urinary tract symptoms (LUTS) and erectile functions of benign prostatic hyperplasia (BPH). Methods. A multicenter, single-cohort prospective study was conducted. A total of 114 patients received CMA for 16 weeks. The endpoints were changes in International Prostate Symptom Scores (IPSS), IPSS-QOL, International Index of Erectile Function-5, prostate volume, and residual urine volume. Results. Significant improvements were observed in IPSS from week 8 to week 48 (32 weeks after treatment). IPSS-QOL improvements were also significant from week 8 to week 48. increased to a maximum at Week 16 and remained elevated throughout the study. Moreover, a decrease of 25% in prostate volume was observed at Week 16. IPSS, QOL, and Qmax changes during the study were not different between the previously treated and untreated patients. IPSS storage subscore changes differed between the age groups. Few severe adverse reactions were observed, except for erectile dysfunction. Conclusions. CMA rapidly and significantly reduced prostate volume and improved voiding and storage symptoms and QOL. Our results suggest that CMA is safe and beneficial, especially for elderly patients with LUTS associated with BPH. 1. Introduction Cases of glandular hyperplasia and those of mixture type with stromal hyperplasia constitute approximately 90% of benign prostatic hyperplasia (BPH) cases; therefore, antiandrogens are very likely effective in most patients with BPH reducing prostate volume, relieving mechanical obstructions at the prostatic urethra, and improving urinary flow. Meanwhile, 5-alpha reductase inhibitors (5-ARIs), which inhibit the conversion of testosterone to dihydrotestosterone, have been approved for treating BPH. Because adverse effects on sexual function are less frequently encountered with 5-ARI treatment than with antiandrogen treatment, the 2012 Guidelines of the European Association of Urology recommend 5-ARIs, including dutasteride, as a first-line treatment for BPH in patients with large prostate volumes of 40?mL or more. Conversely, for patients with small prostate volumes of less than 40?mL, anticholinergic treatment with an α1-blocker is first recommended [1]. The Medical Therapy of Prostatic Symptoms (MTOPS) study also concluded that patients with baseline prostate volumes of 31?mL or more showed a high rate of clinical progression of BPH such as exacerbation of lower urinary tract symptoms (LUTS), urinary retention, or requiring surgical treatments
Stochastic Process Optimization Technique  [PDF]
Hiroaki Yoshida, Katsuhito Yamaguchi, Yoshio Ishikawa
Applied Mathematics (AM) , 2014, DOI: 10.4236/am.2014.519293
Abstract: The conventional optimization methods were generally based on a deterministic approach, since their purpose is to find out an accurate solution. However, when the solution space is extremely narrowed as a result of setting many inequality constraints, an ingenious scheme based on experience may be needed. Similarly, parameters must be adjusted with solution search algorithms when nonlinearity of the problem is strong, because the risk of falling into local solution is high. Thus, we here propose a new method in which the optimization problem is replaced with stochastic process based on path integral techniques used in quantum mechanics and an approximate value of optimal solution is calculated as an expected value instead of accurate value. It was checked through some optimization problems that this method using stochastic process is effective. We call this new optimization method “stochastic process optimization technique (SPOT)”. It is expected that this method will enable efficient optimization by avoiding the above difficulties. In this report, a new optimization method based on a stochastic process is formulated, and several calculation examples are shown to prove its effectiveness as a method to obtain approximate solution for optimization problems.
Properties and Thermal Stress Analysis of Blended Cement Self-Compacting Concrete  [PDF]
Benson Kipkemboi, Benson Kipkemboi, Shingo Miyazawa, Shingo Miyazawa
Open Journal of Civil Engineering (OJCE) , 2018, DOI: 10.4236/ojce.2018.82009
Abstract: Self-Compacting concrete is a concrete that is able to flow and consolidate under its own weight, completely fill the formwork even in the presence of dense reinforcement, whilst maintaining homogeneity and without the need for any additional compaction. Self-Compacting concrete is achieved by using high proportions of powder content and super?plasticizers. Due to this, pronounced thermal cracking is anticipated. Thermal cracking in concrete structures is of great concern. The objective of this research is to carry out experiments and investigate fresh and hardened properties of SCC developed using a blend of ordinary Portland cement and ground granulated blast furnace slag (GGBFS), to evaluate the applicability of Japan Concrete Institute (JCI) model?equations and?to find out any similarities and differences between Self-?Compacting concrete and normal vibrated concrete—Portland blast furnace slag concrete class B. Thermal stress analysis of the proposed Self-Compacting concrete and normal vibrated concretes were investigated by simulation using 3D FEM analysis. To carry out these objectives, concrete properties such as autogenous shrinkage, adiabatic temperature rise, drying shrinkage, modulus of elasticity, splitting tensile strength and compressive strength were determined through experiments. From experimental results, it was observed that except for the fresh properties, the hardened properties of Self-Compacting exhibit similar characteristics to those of normal vibrated concrete at almost similar water to binder ratios. It was also established that Self-Compacting concrete at W/B of 32% with a 50% replacement of ground granulated blast furnace slag has better thermal cracking resistance than SCC with 30% GGBFS replacement. It is also found that provided the relevant constants are derived from experimental data, JCI model equations can be applied successfully to evaluate hardened properties of Self-Compacting concrete.
Selective Constraints on Amino Acids Estimated by a Mechanistic Codon Substitution Model with Multiple Nucleotide Changes
Sanzo Miyazawa
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017244
Abstract: Empirical substitution matrices represent the average tendencies of substitutions over various protein families by sacrificing gene-level resolution. We develop a codon-based model, in which mutational tendencies of codon, a genetic code, and the strength of selective constraints against amino acid replacements can be tailored to a given gene. First, selective constraints averaged over proteins are estimated by maximizing the likelihood of each 1-PAM matrix of empirical amino acid (JTT, WAG, and LG) and codon (KHG) substitution matrices. Then, selective constraints specific to given proteins are approximated as a linear function of those estimated from the empirical substitution matrices.
Advantages of a Mechanistic Codon Substitution Model for Evolutionary Analysis of Protein-Coding Sequences
Sanzo Miyazawa
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028892
Abstract: Background A mechanistic codon substitution model, in which each codon substitution rate is proportional to the product of a codon mutation rate and the average fixation probability depending on the type of amino acid replacement, has advantages over nucleotide, amino acid, and empirical codon substitution models in evolutionary analysis of protein-coding sequences. It can approximate a wide range of codon substitution processes. If no selection pressure on amino acids is taken into account, it will become equivalent to a nucleotide substitution model. If mutation rates are assumed not to depend on the codon type, then it will become essentially equivalent to an amino acid substitution model. Mutation at the nucleotide level and selection at the amino acid level can be separately evaluated. Results The present scheme for single nucleotide mutations is equivalent to the general time-reversible model, but multiple nucleotide changes in infinitesimal time are allowed. Selective constraints on the respective types of amino acid replacements are tailored to each gene in a linear function of a given estimate of selective constraints. Their good estimates are those calculated by maximizing the respective likelihoods of empirical amino acid or codon substitution frequency matrices. Akaike and Bayesian information criteria indicate that the present model performs far better than the other substitution models for all five phylogenetic trees of highly-divergent to highly-homologous sequences of chloroplast, mitochondrial, and nuclear genes. It is also shown that multiple nucleotide changes in infinitesimal time are significant in long branches, although they may be caused by compensatory substitutions or other mechanisms. The variation of selective constraint over sites fits the datasets significantly better than variable mutation rates, except for 10 slow-evolving nuclear genes of 10 mammals. An critical finding for phylogenetic analysis is that assuming variable mutation rates over sites lead to the overestimation of branch lengths.
Prediction of Contact Residue Pairs Based on Co-Substitution between Sites in Protein Structures
Sanzo Miyazawa
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0054252
Abstract: Residue-residue interactions that fold a protein into a unique three-dimensional structure and make it play a specific function impose structural and functional constraints in varying degrees on each residue site. Selective constraints on residue sites are recorded in amino acid orders in homologous sequences and also in the evolutionary trace of amino acid substitutions. A challenge is to extract direct dependences between residue sites by removing phylogenetic correlations and indirect dependences through other residues within a protein or even through other molecules. Rapid growth of protein families with unknown folds requires an accurate de novo prediction method for protein structure. Recent attempts of disentangling direct from indirect dependences of amino acid types between residue positions in multiple sequence alignments have revealed that inferred residue-residue proximities can be sufficient information to predict a protein fold without the use of known three-dimensional structures. Here, we propose an alternative method of inferring coevolving site pairs from concurrent and compensatory substitutions between sites in each branch of a phylogenetic tree. Substitution probability and physico-chemical changes (volume, charge, hydrogen-bonding capability, and others) accompanied by substitutions at each site in each branch of a phylogenetic tree are estimated with the likelihood of each substitution, and their direct correlations between sites are used to detect concurrent and compensatory substitutions. In order to extract direct dependences between sites, partial correlation coefficients of the characteristic changes along branches between sites, in which linear multiple dependences on feature vectors at other sites are removed, are calculated and used to rank coevolving site pairs. Accuracy of contact prediction based on the present coevolution score is comparable to that achieved by a maximum entropy model of protein sequences for 15 protein families taken from the Pfam release 26.0. Besides, this excellent accuracy indicates that compensatory substitutions are significant in protein evolution.
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