Development History and Concept of an Oral Anticancer Agent S-1 (TS-1®): Its Clinical Usefulness and Future Vistas

Dushinsky et al. left a great gift to human beings with the discovery of 5-fluorouracil (5-FU). Approximately 50 years have elapsed from that discovery to the development of S-1 (TS-1®). The concept of developing an anticancer agent that simultaneously possesses both efficacy-enhancing and adverse reaction-reducing effects could be achieved only with a three-component combination drug. S-1 is an oral anticancer agent containing two biochemical modulators for 5-FU and tegafur (FT), a metabolically activated prodrug of 5-FU. The first modulator, 5-chloro-2,4-dihydroxypyridine (CDHP), enhances the pharmacological actions of 5-FU by potently inhibiting its degradation. The second modulator, potassium oxonate (Oxo), localizing in mucosal cells of the gastrointestinal (GI) tract after oral administration, reduces the incidence of GI toxicities by suppressing the activation of 5-FU in the GI tract. Thus, S-1 combines FT, CDHP and Oxo at a molar ratio of 1:0.4:1. In 1999–2007, S-1 was approved for the treatment of the following seven cancers: gastric, head and neck, colorectal, non-small cell lung, breast, pancreatic and biliary tract cancers. ‘S-1 and low-dose cisplatin therapy’ without provoking Grade 3 non-hematologic toxicities was proposed to enhance its clinical usefulness. Furthermore, ‘alternate-day S-1 regimen’ may improve the dosing schedule for 5-FU by utilizing its strongly time-dependent mode of action; the former is characterized by the low incidences of myelotoxicity and non-hematologic toxicities (e.g. ≤Grade 1 anorexia, fatigue, stomatitis, nausea, vomiting and taste alteration). These two approaches are considered to allow long-lasting therapy with S-1

Borna disease virus (BDV) circulating immunocomplex positivity in addicted patients in the Czech Republic: a prospective cohort analysis

<p>Abstract</p> <p>Background</p> <p>Borna disease virus (BDV) is an RNA virus belonging to the family Bornaviridae. Borna disease virus is a neurotropic virus that causes changes in mood, behaviour and cognition. BDV causes persistent infection of the central nervous system. Immune changes lead to activation of infection. Alcohol and drug dependence are associated with immune impairment.</p> <p>Methods</p> <p>We examined the seropositivity of BDV circulating immunocomplexes (CIC) in patients with alcohol and drug dependence and healthy individuals (blood donors). We examined 41 addicted patients for the presence of BDV CIC in the serum by ELISA at the beginning of detoxification, and after eight weeks of abstinence. This is the first such study performed in patients with alcohol and drug dependence.</p> <p>Results</p> <p>BDV CIC positivity was detected in 36.59% of addicted patients on day 0 and in 42.86% on day 56. The control group was 37.3% positive. However, we did not detect higher BDV CIC positivity in addicted patients in comparison with blood donors (p = 0.179). The significantly higher level of BDV CIC was associated with lower levels of GGT (gamma glutamyl transferase) (p = 0.027) and approached statistical significance with the lower age of addicted patients (p = 0.064). We did not find any association between BDV CIC positivity and other anamnestic and demographic characteristics.</p> <p>Conclusions</p> <p>In our study addicted patients did not have significantly higher levels of BDV CIC than the control group. The highest levels of BDV CIC were detected in patients with lower levels of GGT and a lower age.</p> <p>Trial registration</p> <p>This study was approved by the ethical committee of the University Hospital Medical Faculty of Charles University in Pilsen, Czech Republic (registration number 303/2001).</p

PlaneFinder: a methodology to find the best plane for a set of atoms involved in the metal coordination in protein structures

Metal ions play a considerable role in protein structure and function. The roles of most metals and their importance are determined by the arrangements of the interacting atoms in the three-dimensional protein structure. This information is essential in predicting the geometry of the atoms involved in metal coordination. The deviation of the other atoms from the best plane is another crucial factor. The proposed web server, PlaneFinder, provides a fast and efficient method to calculate the best-fit plane for a set of atoms involved in the metal coordination. It provides in addition other possible planes by considering the maximum number of interacting atoms as well as user-selected atoms. The deviations of the selected atoms and other atoms from the best-fit plane are also displayed. PlaneFinder is freely available and can be accessed at http://bioserverl.physics. iisc.ac.in/plane/

25-Hydroxyvitamin D concentration, vitamin D intake and joint symptoms in postmenopausal women

Low 25-hydroxyvitamin D (25(OH) D) concentrations have been associated with radiologic worsening of osteoarthritis in some reports. However, the results are mixed and few studies have evaluated associations between 25(OH) D concentrations and both total vitamin D intake and clinical joint symptoms. Cross-sectional analyses of information from a subset of 1993 postmenopausal women obtained at baseline entry in the Women's Health Initiative Calcium plus Vitamin D clinical trial. 25(OH) D concentration, total vitamin D intake (diet plus supplements), presence and severity of joint pain and joint swelling. The 25(OH) D levels were commonly low with 53% having deficient (<50 nmol/L) and only 17% having sufficient (>72 nmol/L) levels. Joint pain (reported by 74%) and joint swelling (reported by 34%) were also commonly reported. 25(OH) D concentrations were modestly correlated with total vitamin D intake ( R = 0.29, p < 0.0001); however, considerable variability in 25(OH) D concentrations for a given vitamin D intake was seen. In adjusted linear regression models, lower serum 25(OH) D concentrations were associated with higher average joint pain score ( P = 0.01 for trend) with differences most apparent in the lowest 25(OH) D levels sextile. Relatively low 25(OH) D levels and a high frequency of joint symptoms were common in this population of postmenopausal women. Total vitamin D intake was only modestly associated with 25(OH) D. Low serum 25(OH) D concentrations were associated with higher joint pain scores. These findings can inform the design of future intervention trials

THE UMD-JHU 2011 SPEAKER RECOGNITION SYSTEM

In recent years, there have been significant advances in the field of speaker recognition that has resulted in very robust recognition systems. The primary focus of many recent developments have shifted to the problem of recognizing speakers in adverse conditions, e.g in the presence of noise/reverberation. In this paper, we present the UMD-JHU speaker recognition system applied on the NIST 2010 SRE task. The novel aspects of our systems are: 1) Improved performance on trials involving different vocal effort via the use of linearscale features; 2) Expected improved recognition performance in the presence of reverberation and noise via the use of frequency domain perceptual linear predictor and cortical features; 3) A new discriminative kernel partial least squares (KPLS) framework that complements state-of-the-art back-end systems JFA and PLDA to aid in better overall recognition; and 4) Acceleration of JFA, PLDA and KPLS back-ends via distributed computing. The individual components of the system and the fused system are compared against a baseline JFA system and results reported by SRI and MIT-LL on SRE2010