Outcome Evaluation of a Transnational Postgraduate Capacity-Building Program Using the Objective Structured Clinical Examination.

Previous studies have applied interview-oriented self-reported or peer-centered evaluation methods, rather than an objective and quantitative method, to evaluate outcome of a postgraduate capacity-building program and have mainly focused on the cognitive level. To investigate the feasibility of the objective structured clinical examination (OSCE) in an international setting and report the results of the outcome evaluation for the behavioral aspect. A case-control study. Ninety examinees divided into 2 case-control groups: 17 program-experienced doctors and 17 control doctors in the first group, and 28 mentees of the program-experienced doctors and 28 control doctors in the second group. A six-station OSCE was implemented. The OSCE scores were measured to evaluate (1) the direct educational effect regarding learning in the first group and (2) the indirect educational effects regarding transfer in the second group. Written questionnaire and interview data were collected for qualitative analysis. The quantitative results of the overall or subcomponent OSCE scores indicated no significant differences in the comparisons of the first and second case-control groups. The qualitative data indicated that the program improved participants' medical knowledge, skills, and self-confidence, however, it also revealed limited learning environment provided by the program. This transnational study has demonstrated the process for introducing and successfully completing the testing of an OSCE in Laos. Discrepancy in the goals of the OSCE and the education program limited the usefulness of OSCE as an assessment tool, leading to the lack of significant differences in its results.

Contribution Ratio of Metatarsal Osteotomy and First Tarsometatarsal Joint Reduction in Moderate to Severe Hallux Valgus Correction.

Hallux valgus is a common foot and ankle disease, for which numerous surgical procedures were introduced. So, understanding the mechanism of deformity reduction is important to select the proper method. Intermetatarsal angle (IMA) determines the severity of hallux valgus, which is influenced by the translated metatarsal head and the reduction of the first tarsometatarsal joint. We hypothesized that both of the mechanisms simultaneously contribute to the correction of IMA. Hallux valgus (70 feet) operated with a Scarf osteotomy with the Akin procedure were reviewed. Hallux valgus angle (HVA), IMA (mechanical and anatomical), hallux valgus interphalangeal angle (HVIP), distal metatarsal articular angle (DMAA), and sesamoid position were checked. The ratio of contributions to the IMA changes were calculated and compared. When the individual contributions by metatarsal head translation and first tarsometatarsal joint reduction were compared, metatarsal head translation contributed by 82%, whereas first tarsometatarsal joint reduction contributed by 18%. Both were responsible for mechanical IMA correction. However, IMA change by metatarsal head translation was a major correction mechanism compared to anatomical IMA change by first tarsometatarsal joint reduction.

2A-linked bi-, tri-, and quad-cistrons for the stepwise biosynthesis of ß-carotene, zeaxanthin, and ketocarotenoids in rice endosperm.

Foot-and-mouth disease virus (FMDV) 2A constructs have been successfully used for the production of "Golden Rice", a ß-carotene producing rice strain. However, to allay public fears and opposition to plants carrying a mammalian pathogenic viral sequence, 2A-like synthetic sequences from Thosea asigna virus and Infectious myonecrosis virus were used to coordinate the coexpression of carotenoid biosynthetic genes. Here, up to four carotenogenic genes encoding PSY, CRTI, BCH and BKT were concatenated and produced ß-carotene, zeaxanthin, and ketocarotenoids (astaxanthin and adonixanthin) in transgenic rice seeds displaying color variation due to the difference in carotenoid content and composition.

Oral proteasome inhibitor with strong preclinical efficacy in myeloma models.

BACKGROUND: The proteasome is a validated anti-cancer target and various small-molecule inhibitors are currently in clinical development or on the market. However, adverse events and resistance associated with those proteasome inhibitors indicate the need for a new generation of drugs. Therefore, we focused on developing an oral proteasome inhibitor with improved efficacy and safety profiles. METHOD: The in vitro inhibition of the 20S proteasome catalytic activities was determined in human multiple myeloma (MM) cellular lysates with fluorogenic peptide substrates specific for each catalytic subunit. Cell cytotoxicity was assessed with the ATP bioluminescence assay using human cell samples from tumor cell lines, MM patients or normal healthy donors. In mice bearing human MM xenografts, a single dose of LC53-0110 was administered orally, and concentration-time profiles of LC53-0110 and the 20S proteasome catalytic activities in plasma, blood, and tumor were determined. The efficacy of repeat-dose compound with regard to tumor growth inhibition in vivo was also evaluated in the same MM xenograft models. RESULTS: LC53-0110 is far more specific for the chymotrypsin-like proteolytic (ß5) site of the 20S proteasome as compared to bortezomib, carfilzomib, or ixazomib. LC53-0110 treatment showed accumulation of ubiquitinated proteins, inhibited cell viability with a low nM range potency in various tumor cell lines, and showed potent activity on CD138(+) cells isolated from MM patients who are resistant/refractory to current FDA-approved drug treatment. When a single dose was administered orally to tumor-bearing mice, LC53-0110 showed both greater maximum and sustained tumor proteasome inhibition as compared with ixazomib in MM xenograft models. The robust pharmacodynamic responses in tumor correlated with tumor growth regression. In addition, LC53-0151, an analog of LC53-0110, in combination with pomalidomide, a third-generation immunomodulatory drug, showed synergistic inhibition of tumor growth both in vitro and in the xenograft mouse model. CONCLUSIONS: In view of the in vitro, in vivo, and ex vivo profiles, further investigation of additional LC compounds in preclinical studies is warranted for the nomination of a clinical development candidate.

Improvement of neutralizing activity of human scFv antibodies against hepatitis B virus binding using CDR3 V(H) mutant library.

CDR3 of the heavy-chain variable region of immunoglobulin is a region in which somatic mutation occurs heavily after secondary antibody response, resulting in an affinity maturation of antibodies in vivo. The aim of this study was to improve the affinity of a human single-chain variable fragment (scFv) specific for pre-S1 of hepatitis B virus (HBV) by introducing random mutagenesis in CDR3 variable region of heavy chain (V(H)) of the parental scFv clone 1E4. By using a BIAcore for panning and screening, we have selected three clones (A9, B2, and B9) with lower highest affinity (K(D)) than 1E4. Affinities of selected clones ranged from 1.7 x 10(7) mol/L to 6.3 x 10(8) mol/L, which were increased by factors of 1.4 to 4.0, respectively, compared to the parental clone. Binding inhibition assay using flow cytometry and polymerase chain reaction revealed that B2 (6.4 x 10(8) mol/L) had a higher neutralizing activity against pre-S1 or HBV virion binding to liver cell line. This anti-pre-S1 scFv can be considered as a potential therapeutic tool for a passive immunotherapy for HBV infection.

TGF-beta1 inhibits Fas-mediated apoptosis by regulating surface Fas and cFLIPL expression in human leukaemia/lymphoma cells.

Transforming growth factor-beta1 (TGF-beta1) is a pleiotrophic cytokine that mediates differentiation, growth, and apoptosis. As a potent immunosuppressive agent, TGF-beta1 induces apoptosis in primary lymphocytes. However, it has been recognized that TGF-beta1 plays certain roles in development or progression of hematopoietic tumours via inhibition of Fas-mediated apoptotic cell death. Several studies have highlighted the mechanisms of TGF-beta1-induced Fas resistance and its contribution to aggressive tumour behavior. In this study, we have focused on the mechanisms by which TGF-beta1 protected leukaemia/lymphoma cells from Fas-mediated apoptosis. The presented study provides that TGF-beta1 inhibited Fas-mediated apoptosis of leukaemia/lymphoma cells in two distinct pathways. First, TGF-beta1 reduced expression of surface Fas receptors by blockade of trafficking cytoplasmic Fas to the surface, which allowed the leukaemia cells to resist Fas-mediated cell death. However, total Fas levels including both surface and cytoplasmic Fas were not altered, indicating that forced degradation of Fas or transcriptional regulation was not involved. Second, TGF-beta1 up-regulated Fas signaling pathway inhibitor cFLIPL to block the pro-caspase-8 cleavage and thus promoted survival of leukaemia/lymphoma cells. Our findings may partly explain why higher concentration of serum TGF-beta1 in cancer patient was related with poor prognosis.