SOX4 is a potential prognostic factor in human cancers: a systematic review and meta-analysis.

OBJECTIVE: The aim of the this study was to analyze the status of sex-determining region Y-related high-mobility group box 4 (SOX4) expression in varied human cancers and its correlation with overall survival in patients with human cancers. METHODS: To observe initially the expression status of SOX4 in twenty kinds of human cancers at protein database (The Human Protein Atlas). We systematically and carefully searched the studies from electronic databases and seriously identified according to eligibility criteria. The correlation between SOX4 expression and overall survival in human cancers was evaluated through Review Manager. RESULTS: We found that SOX4 expression was significantly positive in most types of human cancer tissues, and the positive rate of SOX4 expression was about 78 % in overall cancer tissues. Furthermore, a total of 10 studies which included 1348 cancer patients were included in the final analysis. Meta-analysis showed that SOX4 overexpression was correlated with a poor overall survival and the pooled hazard ratio (HR), and corresponding 95 % confidence interval (CI) was 1.67 (95 % CI 1.01-2.78). From subgroup analyses, we present evidence that SOX4 overexpression was an unfavorable prognostic factor for colorectal cancer patients' recurrence-free survival and gastric cancer patients' overall survival, and the pooled HRs (95 % CI) were 1.73 (95 % CI 1.04-2.88) and 3.74 (95 % CI 1.04-13.45), respectively. CONCLUSIONS: In summary, SOX4 is a potential prognostic biomarker in human cancers.

Characterization of biochemical properties of a selenium-independent glutathione peroxidase of Cryptosporidium parvum.

Glutathione peroxidase (GPx; EC 1.11.1.9) is an important antioxidant enzyme that catalyses the reduction of organic and inorganic hydroperoxides to water in oxygen-consuming organisms, using glutathione as an electron donor. Here, we report the characterization of a GPx of Cryptosporidium parvum (CpGPx). CpGPx contained a standard UGU codon for cysteine instead of a UGA opal codon for seleno-cysteine (SeCys) at the active site, and no SeCys insertion sequence (SECIS) motif was identified within the 3'-untranslated region (UTR) of CpGPx, which suggested its selenium-independent nature. In silico and biochemical analyses indicated that CpGPx is a cytosolic protein with a monomeric structure. Recombinant CpGPx was active over a wide pH range and was stable under physiological conditions. It showed a substrate preference against organic hydroperoxides, such as cumene hydroperoxide and t-butyl hydroperoxide, but it also showed activity against inorganic hydroperoxide, hydrogen peroxide. Recombinant CpGPx was not inhibited by potassium cyanide or by sodium azide. The enzyme effectively protected DNA and protein from oxidative damage induced by hydrogen peroxide, and was functionally expressed in various developmental stages of C. parvum. These results collectively suggest the essential role of CpGPx for the parasite's antioxidant defence system.

Cryptostatin, a chagasin-family cysteine protease inhibitor of Cryptosporidium parvum.

Cysteine proteases of pathogenic protozoan parasites play pivotal roles in the life cycle of parasites, but strict regulation of their activities is also essential for maintenance of parasite physiology and interaction with hosts. In this study, we identified and characterized cryptostatin, a novel inhibitor of cysteine protease (ICP) of Cryptosporidium parvum. Cryptostatin showed low sequence identity to other chagasin-family ICPs, but 3 motifs (NPTTG, GXGG, and RPW/F motifs), which are evolutionarily conserved in chagasin-family ICPs, were found in the sequence. The overall structure of cryptostatin consisted of 8 ß-strands that progressed in parallel and closely resembled the immunoglobulin fold. Recombinant cryptostatin inhibited various cysteine proteases, including papain, human cathepsin B, human cathepsin L, and cryptopain-1, with K i's in the picomolar range. Cryptostatin was active over a wide pH range and was highly stable under physiological conditions. The protein was thermostable and retained its inhibitory activity even after incubation at 95°C. Cryptostatin formed tight complexes with cysteine proteases, so the complexes remained intact in the presence of sodium dodecyl sulfate and ß-mercaptoethanol, but they were disassembled by boiling. An immunogold electron microscopy analysis demonstrated diffused localization of cryptostatin within oocystes and meronts, but not within trophozoites, which suggests a possible role for cryptostatin in host cell invasion by C. parvum.

Molecular cloning and characterization of a M17 leucine aminopeptidase of Cryptosporidium parvum.

Leucine aminopeptidases (LAPs) are a group of metalloexopeptidases that catalyse the sequential removal of amino acids from the N-termini of polypeptides or proteins. They play an important role in regulating the balance between catabolism and anabolism in living cells. LAPs of apicomplexa parasitic protozoa have been intensively investigated due to their crucial roles in parasite biology as well as their potentials as drug targets. In this study, we identified an M17 leucine aminopeptidase of Cryptosporidium parvum (CpLAP) and characterized the biochemical properties of the recombinant protein. Multiple sequence alignment of the deduced amino acid sequence of CpLAP with those of other organisms revealed that typical amino acid residues essential for metal binding and active-site formation in M17 LAPs were well conserved in CpLAP. Recombinant CpLAP shared similar biochemical properties such as optimal pH, stability at neutral pHs, and metal-binding characteristics with other characterized LAPs. The enzyme showed a marked preference for Leu and its activity was effectively inhibited by bestatin. These results collectively suggest that CpLAP is a typical member of the M17 LAP family and may play an important role in free amino acid regulation in the parasite.

Synthesis and magnetic and transport properties of Sr6V9S22O2: "AM2S5" phases revisited.

The compound Sr6V9S22O2 was prepared from SrS, sulfur, vanadium metal, and V2O5 at 950 degrees C in an evacuated quartz tube. The compound is rhombohedral, R3, with a = 8.7538(6) A, c = 34.934(3) A, and Z = 3, and shows strong preferred orientation in its XRD profiles (00l) due to the layered nature of the structure. The compound contains charged CdI2 type VS2 layers of formula [V7S14]4- separated by [Sr6(VOS3)2(S2)]4+ layers. The latter has VOS3(3-) tetrahedra and S2(2-) disulfide units linked by Sr2+ ions. Magnetic susceptibility and four-probe resistivity studies show essentially temperature-independent paramagnetism above 80 K and small gap semiconductor behavior, respectively. The compound has a positive Hall coefficient at room temperature. The relationship among Sr6V9S22O2, "SrV2S5" (J. Solid State Chem. 1996, 126, 189), and other AM2S5 phases is discussed.

On TIER method for assessment of individual bioequivalence.

The bioavailability and bioequivalence between drug products has become an important subject in drug development. The average bioavailability of the test (T) and the reference (R) products is currently specified in the FDA guidelines to be used for assessing the bioequivalence of the drug products. However, it has been recognized that the safety for the substitution of a reference drug product with a test drug product in patients, whose concentration may have been titrated to a steady efficacious and safe level, could be a concern. Therefore, it is suggested that individual bioequivalence within each subject be assessed to assure the safety of the drug switchability. This paper examines the statistical properties of TIER procedure that Anderson and Hauck proposed to assess individual bioequivalence. It is shown that Anderson and Hauck's procedure could be improved by imposing some distribution assumption such as lognormal distribution for assessment of individual bioequivalence. This paper also compares the relative performance of the individual bioequivalence based on TIER procedure and the average bioequivalence based on two one-sided tests procedure suggested by Schuirmann. The relationship between equivalence limits for the improved TIER procedure and average bioequivalence is also examined.

On stability designs in drug shelf-life estimation.

In this paper, various stability designs, including matrixing and bracketing designs for determining drug shelf-life, are considered. We propose a criterion for design selection based on the precision of drug shelf-life estimates. For a fixed sample size, it is recommended that the design with the best precision for estimating the shelf-life should be used. For a fixed desired precision, the design with the smallest sample size is the best choice of design. An example is presented to illustrate the proposed method.