Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2-Mercaptoquinazolinone as the Cap Moiety.

Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid-based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC50 values of 3.4-37.8 µM. Compound 8 with a 2-mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF-7 cells. For the HDAC6 target selectivity study, compound 8 displayed an IC50 value of 2.3 µM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (-7.92 kcal/mol) of compound 8 toward HDAC6. In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of HDAC11.

Identifying temporal sensory drivers of liking of biscuit supplemented with brewer's spent grain for young consumers.

Brewer's spent grain (BSG), a by-product of the brewing industry, has great potential as food additive. BSG is particularly rich in protein and fibre content which makes it an ideal nutritional fortifier for biscuits. However, adding BSG to biscuits can lead to changes in sensory perception and consumer acceptance. This study explored the temporal sensory profiles and drivers/inhibitors of liking in BSG-fortified biscuits. Six biscuit formulations were obtained from a design with factors oat flake particle size (three levels: 0.5 mm, small commercial flakes, large commercial flakes) and baking powder (two levels: with, without). Consumers (n = 104) tasted the samples, described their dynamic sensory perception using the Temporal Check-All-That-Apply (TCATA) method, and rated their liking on a 7-point categorical scale. The Clustering around Latent Variables (CLV) approach was used to group consumers into two clusters based on their preferences. The temporal sensory profiles and drivers/inhibitors of liking were investigated within each cluster. Foamy and Easy-to-swallow were sensory drivers of liking for both groups of consumers. However, inhibitors of liking were different in the two clusters: Dense and Hard-to-swallow for one cluster and Chewy, Hard-to-swallow and Hard for the other cluster. These findings give evidence that manipulating oat particle size and presence/absence of baking powder changes BSG-fortified biscuits' sensory profiles and consumer preferences. A complementary analysis of the area-under-curve of the TCATA data and inspection of individual temporal curves showed the dynamics of perception and showed how oat particle size and presence/absence of baking powder affected consumer perception and acceptance of BSG-fortified biscuits. The methods proposed in this paper can be further applied to understand how enriching products with ingredients that would otherwise go to waste affects acceptance in different consumer segments.

Desmodinosides A-E: New Flavonoid C-glycosides from Desmodium heterocarpon var. stigosum with hepatoprotective and antifungal activity.

Five new flavonoid C-glycosides named desmodinosides A-E (1-5) and one known compound, apigenin 6-C-ß-d-xylopyranosyl-2''-O-ß-D-glucopyranoside (6) have been isolated from the methanol extract of the aerial parts of Desmodium heterocarpon var. stigosum. These compounds were determined by 1D and 2D-NMR and HR-MS spectroscopies. The methanol extract of this plant, in particular, demonstrated hepatoprotection and antifungal inhibition. This extract has a remarkable hepatoprotection and activity-dose response with an EC50 of 43.07 µg/mL. The hepatoprotective effect on human liver hepatoma cells (HepG2) of the isolated flavonoid C-glycosides 1-6 was observed. Desmodinosides A-C (1-3) were found to exhibit moderate hepatoprotective activity on HepG2 cells. Of these, compound 2 showed the best hepatoprotective activity with an EC50 value of 74.12 µg/mL. While compounds 1 and 3 displayed EC50 values of 271.21 and 211.99 µg/mL, respectively. Quercetin, a positive control, also caused an EC50 value of 36.42 µg/mL. In addition to having hepatoprotective effect, the methanol extract had an inhibitory effect on the growth of oomycete; it inhibited Phytophthora infestans with IC50 of 13.3 µg/mL and IC90 of 78.7 µg/mL. The oomycete inhibition was directly attributed to compounds 5 and 6, which significantly inhibited P. infestans with IC50 values of 27.4 and 24.7 µg/mL, respectively. Both 5 and 6 and methanol extract were active against P. infestanse in a dose-dependent manner. Our study demonstrated for the first time the new flavonoid C-glycosides from D. heterocarpon var. stigosum and their novel pharmacological properties. The study findings also suggest the plant extract and its metabolites could be used as a new botanical source of bioactive compounds.

Changes in drug use are associated with health-related quality of life improvements among methadone maintenance patients with HIV/AIDS.

PURPOSE: This longitudinal study assessed the changes in drug use patterns and health-related quality of life (HRQL) among HIV-positive drug users in the first methadone maintenance treatment (MMT) cohort in Vietnam. METHODS: A secondary analysis was conducted on 370 HIV-positive drug users (age: mean ± SD: 29.5 ± 5.9 years; 95.7% men). Modified WHOQOL-BREF, self-report, and opioid confirmatory urine tests were used to assess HRQL and drug use behaviours at baseline, 3, 6, and 9 months. Generalized estimating equations (GEE) models were constructed to adjust for intra-individual correlations. RESULTS: MMT response rate after 9 months was 89.9%. Rates of positive heroin urine tests rapidly decreased at the first trimester (18.1%) and then stabilized during the next 2 trimesters (11.8 and 14.4%). Among patients with continued drug use, frequency of use decreased from 3.4 to 0.7 time/day. Improvements in HRQL were large over the course of the study and highest in the psychological domain. Adjusting for propensity score in GEE models, ongoing heroin use during MMT resulted in large decrements in all HRQL domains. CONCLUSIONS: MMT improved the outcomes of treatment for drug users in ways that might facilitate success of antiretroviral therapy. Integrating MMT to HIV care and treatment services could be beneficial in injection-driven HIV epidemics in resource-scare settings.

Moisturizing effectiveness of immediate compared with delayed moisturization.

INTRODUCTION: Moisturizers play an essential role in maintaining the integrity of the skin barrier by increasing stratum corneum hydration (SCH) and reducing transepidermal water loss (TEWL). According to dermatology and allergy guidelines, moisturizers should be applied on the skin within 3 min after bathing or showering. However, there is very little evidence supporting this recommendation. This study aimed to investigate the effectiveness of immediate and delayed moisturizing after bathing/washing on the improvement of SCH and TEWL. METHODS: This was a crossover study of 60 healthy Vietnamese volunteers aged 18-25 years. In each subject, SCH and TEWL levels were measured at three areas: non-moisturized, immediate moisturizing after washing, and delayed moisturizing at 30 min after washing. RESULTS: In non-moisturized skin, SCH and TEWL levels were significantly different from the baseline at 60 min after washing, while significantly decreased TEWL levels were observed immediately after moisturizing. In addition, moisturized skin had significantly higher SCH and lower TEWL levels compared with non-moisturized areas at every time point (p < 0.05). Interestingly, the percentage changes of SCH and TEWL levels from baseline did not differ between immediately and delayed moisturized areas. CONCLUSIONS: Tested moisturizer helped increase SCH and decrease TEWL; however, there was no difference in moisturizing effectiveness between immediate and delayed moisturizing in healthy skin. The recommendation of immediate application of moisturizers after bathing/washing should be reconsidered, and more studies are needed to establish a stronger recommendation.

Fast and Low-GPU-memory abdomen CT organ segmentation: The FLARE challenge.

Automatic segmentation of abdominal organs in CT scans plays an important role in clinical practice. However, most existing benchmarks and datasets only focus on segmentation accuracy, while the model efficiency and its accuracy on the testing cases from different medical centers have not been evaluated. To comprehensively benchmark abdominal organ segmentation methods, we organized the first Fast and Low GPU memory Abdominal oRgan sEgmentation (FLARE) challenge, where the segmentation methods were encouraged to achieve high accuracy on the testing cases from different medical centers, fast inference speed, and low GPU memory consumption, simultaneously. The winning method surpassed the existing state-of-the-art method, achieving a 19× faster inference speed and reducing the GPU memory consumption by 60% with comparable accuracy. We provide a summary of the top methods, make their code and Docker containers publicly available, and give practical suggestions on building accurate and efficient abdominal organ segmentation models. The FLARE challenge remains open for future submissions through a live platform for benchmarking further methodology developments at https://flare.grand-challenge.org/.

SO-PLS as an alternative approach for handling multi-dimensionality in modelling different aspects of consumer expectations.

In the development of sensory and consumer science, data are often collected in several blocks responding to different aspects of consumer experience. Sometimes the task of organizing the data and explaining their relation is non-trivial, especially when considering structural (casual) relationship between data sets. In this sense, PLS path modelling (PLS-PM) has been found as a good tool to model such relations, but this approach faces some issues regarding the assumption of uni-dimensionality of consumers' data blocks. Sequential Orthogonalised PLS path modelling (SO-PLS-PM) has been proposed as an alternative approach to handle the multi-dimensionality and to explain the relations between the original data blocks without any preprocessing of the data. This study aims at comparing the efficacy of SO-PLS-PM and PLS-PM (together with splitting blocks into uni-dimensional sub-blocks) for handling multi-dimensionality. Data sets from two satiety perception studies (yoghurt, biscuit) have been used as illustrations. The main novelty of this paper lies in underlining and solving a major, but little studied problem, related to the assumption of one-dimensional blocks in PLS-PM. The findings from the comparisons indicated that the two approaches (PLS-PM and SO-PLS-PM) highlighted the same main trends for the less complex samples (yoghurt samples): liking was the essential driver of satiation perception and portion size selection; while satiation mainly predicted satiety perception. For the more complex data set - from a sensory perspective - (biscuit samples), the relations between data blocks in PLS-PM model was difficult to interpret, whereas they were well explained by SO-PLS-PM. This underlines the ability of SO-PLS-PM to model multi-dimensional data sets without requiring any preprocessing steps.

Potential Impact of Oat Ingredient Type on Oral Fragmentation of Biscuits and Oro-Digestibility of Starch-An In Vitro Approach.

The aim of the present study was to determine how variation in the biscuit matrix affects both the degree of in vitro fragmentation and the starch hydrolysis that occurs during the oral phase of digestion. Using three different oat ingredient types (oat flour, small flakes, and big flakes) and baking powder (or none), six biscuits with different matrices were obtained. The instrumental texture (force and sound measurements) of the biscuits was analyzed. The samples were then subjected to in vitro fragmentation. The particle size distribution and in vitro oral starch hydrolysis over time of the fragmented samples were evaluated. The results showed that the samples presented different fragmentation patterns, mainly depending on the oat ingredient type, which could be related to their differences in texture. The biscuits made with oat flour were harder, had a more compact matrix and showed more irregular fragmentation and a higher percentage area of small particles than those made with big oat flakes, which were more fragile and crumbly. The highest degree of starch hydrolysis corresponded to the biscuits made with flour. Conclusions: Differences in the mechanical properties of the biscuit matrix, in this case due to differences in the oat ingredient, play a role in the in vitro fragmentation pattern of biscuits and in the oral phase of starch hydrolysis.

Expenditure Analysis of HIV Testing and Counseling Services Using the Cascade Framework in Vietnam.

OBJECTIVES: Currently, HIV testing and counseling (HTC) services in Vietnam are primarily funded by international sources. However, international funders are now planning to withdraw their support and the Government of Vietnam (GVN) is seeking to identify domestic funding and generate client fees to continue services. A clear understanding of the cost to sustain current HTC services is becoming increasingly important to facilitate planning that can lead to making HTC and other HIV services more affordable and sustainable in Vietnam. The objectives of this analysis were to provide a snapshot of current program costs to achieve key program outcomes including 1) testing and identifying PLHIV unaware of their HIV status and 2) successfully enrolling HIV (+) clients in care. METHODS: We reviewed expenditure data reported by 34 HTC sites in nine Vietnamese provinces over a one-year period from October 2012 to September 2013. Data on program outcomes were extracted from the HTC database of 42,390 client records. Analysis was carried out from the service providers' perspective. RESULTS: The mean expenditure for a single client provided HTC services (testing, receiving results and referral for care/treatment) was US $7.6. The unit expenditure per PLHIV identified through these services varied widely from US $22.8 to $741.5 (median: $131.8). Excluding repeat tests, the range for expenditure to newly diagnose a PLHIV was even wider (from US $30.8 to $1483.0). The mean expenditure for one successfully referred HIV client to care services was US $466.6. Personnel costs contributed most to the total cost. CONCLUSIONS: Our analysis found a wide range of expenditures by site for achieving the same outcomes. Re-designing systems to provide services at the lowest feasible cost is essential to making HIV services more affordable and treatment for prevention programs feasible in Vietnam. The analysis also found that understanding the determinants and reasons for variance in service costs by site is an important enhancement to the cascade of HIV services framework now adapted for and extensively used in Vietnam for planning and evaluation.

Implementation of web-based respondent-driven sampling among men who have sex with men in Vietnam.

OBJECTIVE: Lack of representative data about hidden groups, like men who have sex with men (MSM), hinders an evidence-based response to the HIV epidemics. Respondent-driven sampling (RDS) was developed to overcome sampling challenges in studies of populations like MSM for which sampling frames are absent. Internet-based RDS (webRDS) can potentially circumvent limitations of the original RDS method. We aimed to implement and evaluate webRDS among a hidden population. METHODS AND DESIGN: This cross-sectional study took place 18 February to 12 April, 2011 among MSM in Vietnam. Inclusion criteria were men, aged 18 and above, who had ever had sex with another man and were living in Vietnam. Participants were invited by an MSM friend, logged in, and answered a survey. Participants could recruit up to four MSM friends. We evaluated the system by its success in generating sustained recruitment and the degree to which the sample compositions stabilized with increasing sample size. RESULTS: Twenty starting participants generated 676 participants over 24 recruitment waves. Analyses did not show evidence of bias due to ineligible participation. Estimated mean age was 22 years and 82% came from the two large metropolitan areas. 32 out of 63 provinces were represented. The median number of sexual partners during the last six months was two. The sample composition stabilized well for 16 out of 17 variables. CONCLUSION: Results indicate that webRDS could be implemented at a low cost among Internet-using MSM in Vietnam. WebRDS may be a promising method for sampling of Internet-using MSM and other hidden groups.