Prognostic value of CT-derived fractional flow reserve and fat attenuation index in patients with suspected coronary artery disease: a sex-disaggregated analyses.

BACKGROUND: There are sex differences in many risk factors associated with coronary artery disease (CAD). CT-derived fractional flow reserve (CT-FFR) and fat attenuation index (FAI) have been shown to independently predict cardiovascular events. We aimed to examine the impact of sex on the prognostic value of CT-FFR and FAI in suspected CAD patients, and to examine the incremental prognostic value of FAI over CT-FFR in both sex. METHODS: A total of 1334 consecutive suspected CAD subjects who underwent coronary computed tomographic angiography (CCTA) were retrospectively collected. We divided the patients into males and females and calculated CT-FFR and FAI data from CCTA images. Kaplan-Meier analysis was used to assess the risk of major adverse cardiovascular events (MACE) stratified by CT-FFR and FAI in both sex. Cox regression models were used to assess the incremental prognostic value of FAI by adding the variable to a model that included CT-FFR and clinical variables. RESULTS: During a median follow-up of 2.08 years, 212 patients had MACE. CT-FFR ≤ 0.80 was significantly associated with MACE in both sex. FAI value of left anterior descending artery (FAI[LAD]) and FAI value of left circumflex (FAI[LCX]) ≥ 70.1 were significantly associated with MACE in females. FAI[LCX] added incremental prognostic value over clinical and CT-FFR variables in females, with hazard ratio (HR) 3.230 (1.982-5.265, P = 0.000), Harrel's C 0.669 (P < 0.001), net reclassification improvement (NRI) 0.161 (0.073-0.260, P < 0.001), and integrated discrimination index (IDI) 0.036 (0.008-0.090, P = 0.010). FAI[LAD] did not enhance risk prediction in females (Harrel's C 0.643, P = 0.054; NRI 0.041, P = 0.189; IDI 0.005, P = 0.259). The decision curve analysis demonstrated that the model including FAI[LCX] resulted in the highest net benefit. CONCLUSIONS: In suspected CAD patients, the prognostic value of CT-FFR is not significantly biased by sex. The prognostic value of FAI[LAD] and FAI[LCX] were significantly associated with MACE in females, but not males. FAI[LCX], not FAI[LAD], added incremental prognostic value over CT-FFR and might enhance CT-FFR risk stratification in females.

Lysine-372-dependent SUMOylation inhibits the enzymatic activity of glutamine synthases.

Glutamine synthetase (GS) is a crucial enzyme involved in de novo synthesis of glutamine and participates in several biological processes, including nitrogen metabolism, nucleotide synthesis, and amino acid synthesis. Post-translational modification makes GS more adaptable to the needs of cells, and acetylation modification of GS at double sites has attracted considerable attention. Despite very intensive research, how SUMOylation affects GS activity at a molecular level remains unclear. Here, we report that previously undiscovered GS SUMOylation which is deficient mutant K372R of GS exhibits more bluntness under glutamine starvation. Mechanistically, glutamine deprivation triggers the GS SUMOylation, and this SUMOylation impaired the protein stability of GS, within a concomitant decrease in enzymatic activity. In addition, we identified SAE1, Ubc9, and PIAS1 as the assembly enzymes of GS SUMOylation respectively. Furthermore, Senp1/2 functions as a SUMO-specific protease to reverse the SUMOylation of GS. This study provides the first evidence that SUMOylation serves as a regulatory mechanism for determining the GS enzymatic activity, contributing to understanding the GS regulation roles in various cellular and pathophysiological processes.

Gene Expression and Pathway Analysis in Rat Brain and Liver After Exposure to Royal Demolition Explosive (Hexahydro-1,3,5-Trinitro-1,3,5-Triazine).

The nitramine explosive, hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) is associated with acute and chronic toxicity in mammals and targets both the central nervous system and liver. After a single oral dose of RDX in male rats, the systemic distribution of RDX and the toxicodynamic response was measured using clinical chemistry and Affymetrix Rat Genome® 230 2.0 gene expression arrays, respectively. Nominal doses of 0, 9 and 36 mg/kg pure RDX were administered to animals followed by liver, cerebral cortex, and hippocampus gene expression analysis at 0, 3.5, 24, and 48 hours. RDX quickly entered the liver and brain, increasing up to 24 hours. For the 36 mg/kg dose, RDX was still measurable in liver and brain at 48 hours, but was non-detectible for the 9 mg/kg dose. At 3.5 hours, the time within which most convulsions reportedly occur after RDX ingestion, the hippocampus displayed the highest response for both gene expression and pathways, while the cortex was relatively non-responsive. The top 2 impacted pathways, primarily involved in neurotransmission, were the GABAergic and glutamatergic pathways. High numbers of genes also responded to RDX in the liver with P450 metabolism pathways significantly involved. Compared to the liver, the hippocampus displayed more consistent biological effects across dose and time with neurotransmission pathways predominating. Overall, based on gene expression data, RDX responses were high in both the hippocampus and liver, but were minimal in the cerebral cortex. These results identify the hippocampus as an important target for RDX based on gene expression.

Left atrial appendage filling defects restricted to the early phase of cardiac computed tomography is significantly associated with ischemic stroke.

PURPOSE: To investigate the relationship between filling defects in the left atrial appendage restricted to the early phase of cardiac computed tomography (CCT), and ischemic stroke in patients with atrial fibrillation (AF). MATERIALS AND METHODS: A total of 152 patients with non-valvular AF were retrospectively enrolled and divided into two groups according to the stroke history, as confirmed by brain computed tomography (CT) or magnetic resonance imaging (MRI), as the non-stroke group (n = 89) and stroke group (n = 63), respectively. The numbers of patients with filling defects in the early phase of CCT images without thrombi were recorded. Morphological parameters of the LAA were measured for all participants. All patients with early-phase filling defects (n = 44) were assigned to two groups according to ischemic stroke history: the filling defects with stroke group (n = 28) and the filling defects without stroke group (n = 16). The clinical characteristics and LAA morphological parameters were compared. RESULTS: Univariate analysis showed that compared with the non-stroke group，LAA volume index and age were higher in the stroke group, and the ratio of early phase filling defect in LAA, hypertension and diabetes were also higher, in the meanwhile the LVEF and BMI were lower (P < 0.05).After adjusting confounding factors by the multivariate logistic regression analysis, filling defect was significantly related with stroke [odds ratio (OR): 4.339, 95% confidence interval (CI): 1.951-9.653, P = 0.000]. LAA morphological parameters were not significantly different between the filling defects with stroke group and the group without stroke. CONCLUSION: AF patients with LAA non-thrombotic filling defects in the early-phase of CCT had an increased risk of ischemic stroke compared to those without filling defects. This finding may help to optimize stroke risk stratification in patients with AF.

Metabolic tumor volume derived from 18F-FDG PET/CT as a prognostic parameter for non-small cell lung cancer (NSCLC) patients.

To determine whether the prognostic stratification of non-small cell lung cancer (NSCLC) patients could be made by fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)-derived parameters such as maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). A total of 106 patients who were initially diagnosed with NSCLC with clinical stage III or stage IV at our hospital from January 2015 to January 2018 were included. The metabolic and volumetric parameters of 18F-FDG PET/CT were systematically collected, and their optimal cut-off values were determined on the basis of the receiver operating characteristic (ROC) curves. Kaplan-Meier methods and log-rank test were used to evaluate the relationships between 18F-FDG PET/CT-derived parameters and overall survival (OS) of NSCLC patients. The univariate and multivariate Cox analysis were conducted to identify the independent predictors of OS. The optimal cut-off value of SUVmax was 8.94 and area under the curve (AUC) for identifying patients with mortality risk was 0.618 (95% confidence interval [CI]: 0.490-0.745), with a sensitivity of 78.6% and specificity of 53.3%. The optimal cut-off value of MTV40 was 12.44 and the AUC value was 0.785 (95%CI: 0.676-0.893), with a sensitivity of 85.7% and specificity of 71.7%. Furthermore, the ROC curves identified 71.95 as the optimal cut-off value of TLG40, and the AUC value, sensitivity and specificity were 0.782 (95%CI: 0.681-0.883), 78.6% and 70.4%, respectively. The Kaplan-Meier curves showed that SUVmax (HR for SUVmax >8.94: 3.501, 95%CI: 1.133-10.817, P=0.029), MTV40 (HR: 6.926 for MTV40 >12.44, 95%CI: 2.244-21.378, P=0.001) and TLG40 (HR: 4.314 for TLG40 >71.95, 95%CI: 1.503-12.381, P=0.007) were significantly associated with poor OS of NSCLC patients. However, only MTV40 (HR: 4.235, 95%CI: 1.324-13.526, P=0.015) was shown to have an independent role in the multivariate Cox analysis. Metabolic tumor volume had a superiority in predicting the prognosis of NSCLC patients compared with other metabolic and volumetric parameters, suggesting that it might be a valuable prognostic marker.

Use of Clinical Data Interchange Standards Consortium (CDISC) Standards for Real-world Data: Expert Perspectives From a Qualitative Delphi Survey.

BACKGROUND: Real-world data (RWD) and real-world evidence (RWE) are playing increasingly important roles in clinical research and health care decision-making. To leverage RWD and generate reliable RWE, data should be well defined and structured in a way that is semantically interoperable and consistent across stakeholders. The adoption of data standards is one of the cornerstones supporting high-quality evidence for the development of clinical medicine and therapeutics. Clinical Data Interchange Standards Consortium (CDISC) data standards are mature, globally recognized, and heavily used by the pharmaceutical industry for regulatory submissions. The CDISC RWD Connect Initiative aims to better understand the barriers to implementing CDISC standards for RWD and to identify the tools and guidance needed to more easily implement them. OBJECTIVE: The aim of this study is to understand the barriers to implementing CDISC standards for RWD and to identify the tools and guidance that may be needed to implement CDISC standards more easily for this purpose. METHODS: We conducted a qualitative Delphi survey involving an expert advisory board with multiple key stakeholders, with 3 rounds of input and review. RESULTS: Overall, 66 experts participated in round 1, 56 in round 2, and 49 in round 3 of the Delphi survey. Their inputs were collected and analyzed, culminating in group statements. It was widely agreed that the standardization of RWD is highly necessary, and the primary focus should be on its ability to improve data sharing and the quality of RWE. The priorities for RWD standardization included electronic health records, such as data shared using Health Level 7 Fast Health care Interoperability Resources (FHIR), and the data stemming from observational studies. With different standardization efforts already underway in these areas, a gap analysis should be performed to identify the areas where synergies and efficiencies are possible and then collaborate with stakeholders to create or extend existing mappings between CDISC and other standards, controlled terminologies, and models to represent data originating across different sources. CONCLUSIONS: There are many ongoing data standardization efforts around human health data-related activities, each with different definitions, levels of granularity, and purpose. Among these, CDISC has been successful in standardizing clinical trial-based data for regulation worldwide. However, the complexity of the CDISC standards and the fact that they were developed for different purposes, combined with the lack of awareness and incentives to use a new standard and insufficient training and implementation support, are significant barriers to setting up the use of CDISC standards for RWD. The collection and dissemination of use cases, development of tools and support systems for the RWD community, and collaboration with other standards development organizations are potential steps forward. Using CDISC will help link clinical trial data and RWD and promote innovation in health data science.

Assessing reproducibility of inherited variants detected with short-read whole genome sequencing.

BACKGROUND: Reproducible detection of inherited variants with whole genome sequencing (WGS) is vital for the implementation of precision medicine and is a complicated process in which each step affects variant call quality. Systematically assessing reproducibility of inherited variants with WGS and impact of each step in the process is needed for understanding and improving quality of inherited variants from WGS. RESULTS: To dissect the impact of factors involved in detection of inherited variants with WGS, we sequence triplicates of eight DNA samples representing two populations on three short-read sequencing platforms using three library kits in six labs and call variants with 56 combinations of aligners and callers. We find that bioinformatics pipelines (callers and aligners) have a larger impact on variant reproducibility than WGS platform or library preparation. Single-nucleotide variants (SNVs), particularly outside difficult-to-map regions, are more reproducible than small insertions and deletions (indels), which are least reproducible when > 5 bp. Increasing sequencing coverage improves indel reproducibility but has limited impact on SNVs above 30×. CONCLUSIONS: Our findings highlight sources of variability in variant detection and the need for improvement of bioinformatics pipelines in the era of precision medicine with WGS.

Cross-oncopanel study reveals high sensitivity and accuracy with overall analytical performance depending on genomic regions.

BACKGROUND: Targeted sequencing using oncopanels requires comprehensive assessments of accuracy and detection sensitivity to ensure analytical validity. By employing reference materials characterized by the U.S. Food and Drug Administration-led SEquence Quality Control project phase2 (SEQC2) effort, we perform a cross-platform multi-lab evaluation of eight Pan-Cancer panels to assess best practices for oncopanel sequencing. RESULTS: All panels demonstrate high sensitivity across targeted high-confidence coding regions and variant types for the variants previously verified to have variant allele frequency (VAF) in the 5-20% range. Sensitivity is reduced by utilizing VAF thresholds due to inherent variability in VAF measurements. Enforcing a VAF threshold for reporting has a positive impact on reducing false positive calls. Importantly, the false positive rate is found to be significantly higher outside the high-confidence coding regions, resulting in lower reproducibility. Thus, region restriction and VAF thresholds lead to low relative technical variability in estimating promising biomarkers and tumor mutational burden. CONCLUSION: This comprehensive study provides actionable guidelines for oncopanel sequencing and clear evidence that supports a simplified approach to assess the analytical performance of oncopanels. It will facilitate the rapid implementation, validation, and quality control of oncopanels in clinical use.

A verified genomic reference sample for assessing performance of cancer panels detecting small variants of low allele frequency.

BACKGROUND: Oncopanel genomic testing, which identifies important somatic variants, is increasingly common in medical practice and especially in clinical trials. Currently, there is a paucity of reliable genomic reference samples having a suitably large number of pre-identified variants for properly assessing oncopanel assay analytical quality and performance. The FDA-led Sequencing and Quality Control Phase 2 (SEQC2) consortium analyze ten diverse cancer cell lines individually and their pool, termed Sample A, to develop a reference sample with suitably large numbers of coding positions with known (variant) positives and negatives for properly evaluating oncopanel analytical performance. RESULTS: In reference Sample A, we identify more than 40,000 variants down to 1% allele frequency with more than 25,000 variants having less than 20% allele frequency with 1653 variants in COSMIC-related genes. This is 5-100× more than existing commercially available samples. We also identify an unprecedented number of negative positions in coding regions, allowing statistical rigor in assessing limit-of-detection, sensitivity, and precision. Over 300 loci are randomly selected and independently verified via droplet digital PCR with 100% concordance. Agilent normal reference Sample B can be admixed with Sample A to create new samples with a similar number of known variants at much lower allele frequency than what exists in Sample A natively, including known variants having allele frequency of 0.02%, a range suitable for assessing liquid biopsy panels. CONCLUSION: These new reference samples and their admixtures provide superior capability for performing oncopanel quality control, analytical accuracy, and validation for small to large oncopanels and liquid biopsy assays.

Effects of Adding Zero Valent Iron on the Anaerobic Digestion of Cow Manure and Lignocellulose.

Previous studies showed that adding zero valent iron (ZVI) can increase the methane production and degradation rate of organic waste by improving the performance of anaerobic digester. However, our study firstly found that ZVI (37 µm, 10 g/L) inhibited the anaerobic digestion (AD) of cow manure and lignocellulose. ZVI significantly increased the methanogenic rate of cow manure in the first 6 days, but decreased the accumulative methane yield and volatile fatty acids yield by 10.3 and 12%, respectively. The effect of ZVI on AD of liquid biomass separated from cow manure was positive, but the effect on solid biomass was negative. These results indicated that ZVI enhanced the AD of easily biodegradable organics but inhibited the biodegradation of refractory organics (lignocellulose). By analyzing the varying effects of ZVI in diverse anaerobic systems, it was found that the effects were influenced by the characteristics of substrate and inoculum-substrate ratio. This study suggested that only proper ZVI addition can improve the AD process depending on the feeding materials.

A comprehensive rat transcriptome built from large scale RNA-seq-based annotation.

The rat is an important model organism in biomedical research for studying human disease mechanisms and treatments, but its annotated transcriptome is far from complete. We constructed a Rat Transcriptome Re-annotation named RTR using RNA-seq data from 320 samples in 11 different organs generated by the SEQC consortium. Totally, there are 52 807 genes and 114 152 transcripts in RTR. Transcribed regions and exons in RTR account for ∼42% and ∼6.5% of the genome, respectively. Of all 73 074 newly annotated transcripts in RTR, 34 213 were annotated as high confident coding transcripts and 24 728 as high confident long noncoding transcripts. Different tissues rather than different stages have a significant influence on the expression patterns of transcripts. We also found that 11 715 genes and 15 852 transcripts were expressed in all 11 tissues and that 849 house-keeping genes expressed different isoforms among tissues. This comprehensive transcriptome is freely available at http://www.unimd.org/rtr/. Our new rat transcriptome provides essential reference for genetics and gene expression studies in rat disease and toxicity models.

Insights into the effects of caffeic acid and amylose on in vitro digestibility of maize starch-caffeic acid complex.

Starch digestibility can be decreased by phenolic acids. The physicochemical and digestive properties of high-amylose maize starch, normal maize starch (NMS) and waxy maize starch (WMS) complexed with caffeic acid (CA) were investigated to determine the effects of CA and amylose on starch digestibility. CA inhibited the activity of α-glucosidase and α-amylase in a dose-dependent manner. The inhibitory effect of CA on α-glucosidase was reversible and anti-competitive, while that on α-amylase was irreversible. With the increase of the amylose content in starches, the complexing index of starch-CA decreased, while the relative crystallinity increased. The crystallinity of all three starches decreased after incorporating CA, and the hydroxyl peak in the 1H-NMR spectrum of the WMS-CA complex increased significantly. The resistant starch content of the WMS-CA and NMS-CA complexes increased significantly compared with the control. The inhibitory effect of CA on amylolytic enzymes played a major role and the change of starch structure exhibited a minor role in the digestibility of the maize starch-CA complexes.

Gene expression in mouse muscle over time after nickel pellet implantation.

The transition metal nickel is used in a wide variety of alloys and medical devices. Nickel can cause a range of toxicities from allergy in humans to tumors when implanted in animals. Several microarray studies have examined nickel toxicity, but so far none have comprehensively profiled expression over an extended period. In this work, male mice were implanted with a single nickel pellet in the muscle of the right leg with the left leg used as a control. At 3 week intervals up to 12 months, nickel concentrations in bioflulids and microarrays of surrounding tissue were used to track gene expression patterns. Pellet biocorrosion resulted in varying levels of systemic nickel over time, with peaks of 600 µg L-1 in serum, while global gene expression was cyclical in nature with immune related genes topping the list of overexpressed genes. IPA and KEGG pathway analyses was used to attribute overall biological function to changes in gene expression levels, supported by GO enrichment analysis. IPA pathways identified sirtuin, mitochondria, and oxidative phosphorylation as top pathways, based predominantly on downregulated genes, whereas immune processes were associated with upregulated genes. Top KEGG pathways identified were lysosome, osteoclast differentiation, and phasgosome. Both pathway approaches identified common immune responses, as well as hypoxia, toll like receptor, and matrix metalloproteinases. Overall, pathway analysis identified a negative impact on energy metabolism, and a positive impact on immune function, in particular the acute phase response. Inside the cell the impacts were on mitochondria and lysosome. New pathways and genes responsive to nickel were identified from the large dataset in this study which represents the first long-term analysis of the effects of chronic nickel exposure on global gene expression.

Enhanced lipid production by Yarrowia lipolytica cultured with synthetic and waste-derived high-content volatile fatty acids under alkaline conditions.

BACKGROUND: Volatile fatty acids (VFAs) can be effective and promising alternate carbon sources for microbial lipid production by a few oleaginous yeasts. However, the severe inhibitory effect of high-content (> 10 g/L) VFAs on these yeasts has impeded the production of high lipid yields and their large-scale application. Slightly acidic conditions have been commonly adopted because they have been considered favorable to oleaginous yeast cultivation. However, the acidic pH environment further aggravates this inhibition because VFAs appear largely in an undissociated form under this condition. Alkaline conditions likely alleviate the severe inhibition of high-content VFAs by significantly increasing the dissociation degree of VFAs. This hypothesis should be verified through a systematic research. RESULTS: The combined effects of high acetic acid concentrations and alkaline conditions on VFA utilization, cell growth, and lipid accumulation of Yarrowia lipolytica were systematically investigated through batch cultures of Y. lipolytica by using high concentrations (30-110 g/L) of acetic acid as a carbon source at an initial pH ranging from 6 to 10. An initial pH of 8 was determined as optimal. The highest biomass and lipid production (37.14 and 10.11 g/L) were obtained with 70 g/L acetic acid, whereas cultures with > 70 g/L acetic acid had decreased biomass and lipid yield due to excessive anion accumulation. Feasibilities on high-content propionic acid, butyric acid, and mixed VFAs were compared and evaluated. Results indicated that Y X/S and Y L/S of cultures on butyric acid (0.570, 0.144) were comparable with those on acetic acid (0.578, 0.160) under alkaline conditions. The performance on propionic acid was much inferior to that on other acids. Mixed VFAs were more beneficial to fast adaptation and lipid production than single types of VFA. Furthermore, cultures on food waste (FW) and fruit and vegetable waste (FVW) fermentate were carried out and lipid production was effectively improved under this alkaline condition. The highest biomass and lipid production on FW fermentate reached 14.65 g/L (Y X/S: 0.414) and 3.20 g/L (Y L/S: 0.091) with a lipid content of 21.86%, respectively. By comparison, the highest biomass and lipid production on FVW fermentate were 11.84 g/L (Y X/S: 0.534) and 3.08 g/L (Y L/S: 0.139), respectively, with a lipid content of 26.02%. CONCLUSIONS: This study assumed and verified that alkaline conditions (optimal pH 8) could effectively alleviate the lethal effect of high-content VFA on Y. lipolytica and significantly improve biomass and lipid production. These results could provide a new cultivation strategy to achieve simple utilizations of high-content VFAs and increase lipid production. Feasibilities on FW and FVW-derived VFAs were evaluated, and meaningful information was provided for practical applications.

The long-term outcome of trabeculotomy: comparison with filtering surgery in Japan.

BACKGROUND: To investigate the long-term outcome of trabeculotomy and to compare it with that of trabeculectomy. METHODS: We retrospectively reviewed the medical records of patients who had undergone standalone trabeculotomy. Inclusion criteria included a follow-up period of at least 6 years, availability of reliable static visual field results, etc. Age- and preoperative intraocular pressure -matched trabeculectomy cases served as controls. A Kaplan-Meier analysis was employed as a measure of surgical success. Additional clinical factors were also analyzed. RESULTS: Twenty-five eyes of 25 trabeculotomy patients and 20 eyes of 20 trabeculectomy patients with a mean postoperative follow-up period of 8.0 years were selected. The Kaplan-Meier analysis estimated that the success probability defined as intraocular pressure < 16 mmHg was 44.0 ± 9.9% and 75.0 ± 9.7% at 6 years for trabeculotomy and trabeculectomy, respectively. The final mean deviation significantly progressed in trabeculotomy cases in Central 30-2 programs of the Humphrey Field Analyzer (P = 0.025). Patient characteristics and postoperative clinical data were analyzed by Mann-Whitney's U test and Wilcoxon signed-rank test. CONCLUSIONS: While trabeculotomy was inferior to trabeculectomy in terms of intraocular pressure control and visual field stability in our series, surgical indications should always be determined on an individual basis, pending further research.

Postoperative outcome of three different procedures for childhood glaucoma.

PURPOSE: To investigate the long-term postoperative outcome of three surgical procedures for childhood glaucoma. PATIENTS AND METHODS: In this retrospective study, the patients were divided into a goniotomy group, a trabeculotomy group, and a filtering surgery group, based on the initial surgical procedure. Failure was defined as an IOP ≥21 mmHg with medication at two consecutive visits. A Kaplan-Meier analysis was applied to calculate the probability of success. Additional metrics included IOP, number of additional operations, eye drop scores, and visual acuity. RESULTS: We studied 40 eyes of 25 patients, 21 eyes of 15 patients, and 12 eyes of 7 patients in the goniotomy, trabeculotomy, and filtering surgery groups, respectively. The 10- and 20-year probability of success was 65.2% and 65.2%, 42.2% and NA (no data for 20 years), and 91.7% and 80.2% for the goniotomy, trabeculotomy, and filtering surgery groups, respectively. CONCLUSION: All three procedures maintained an IOP of less than 21 mmHg for up to 10 years in 65.2%, 42.2%, and 91.7% of childhood glaucoma cases.

Insights into the crystallinity and in vitro digestibility of chestnut starch during thermal processing.

The crystallinity is of importance for in vitro digestibility of starch. Six chestnut cultivars were selected to study the relationship between the crystallinity and in vitro digestibility of chestnut starch during thermal processing. After heat treatment, the total starch and amylose content remained unchanged or decreased, but the amount of damaged starch increased significantly (P < 0.05). Thermal processing enhanced the short-range ordered structure of starch and reduced its relative crystallinity. Thermal processing also decreased the resistant starch (RS) content, but a high RS content (57.2-67.9% of total starch) still remained in cooked chestnut starch. The relative crystallinity was negatively correlated with the estimated glycemic index (eGI) (r = -0.6416), and positively correlated with RS content (r = 0.6189). Accordingly, by altering the relative crystallinity and damage degree of chestnut starch, thermal processing changed the overall starch fractions and eGI, which can affect the overall in vitro digestibility.

Computational drug repositioning for rare diseases in the era of precision medicine.

There are tremendous unmet needs in drug development for rare diseases. Computational drug repositioning is a promising approach and has been successfully applied to the development of treatments for diseases. However, how to utilize this knowledge and effectively conduct and implement computational drug repositioning approaches for rare disease therapies is still an open issue. Here, we focus on the means of utilizing accumulated genomic data for accelerating and facilitating drug repositioning for rare diseases. First, we summarize the current genome landscape of rare diseases. Second, we propose several promising bioinformatics approaches and pipelines for computational drug repositioning for rare diseases. Finally, we discuss recent regulatory incentives and other enablers in rare disease drug development and outline the remaining challenges.

Proteomic profiling reveals candidate markers for arsenic-induced skin keratosis.

Proteomics technology is an attractive biomarker candidate discovery tool that can be applied to study large sets of biological molecules. To identify novel biomarkers and molecular targets in arsenic-induced skin lesions, we have determined the protein profile of arsenic-affected human epidermal stratum corneum by shotgun proteomics. Samples of palm and foot sole from healthy subjects were analyzed, demonstrating similar protein patterns in palm and sole. Samples were collected from the palms of subjects with arsenic keratosis (lesional and adjacent non-lesional samples) and arsenic-exposed subjects without lesions (normal). Samples from non-exposed healthy individuals served as controls. We found that three proteins in arsenic-exposed lesional epidermis were consistently distinguishably expressed from the unaffected epidermis. One of these proteins, the cadherin-like transmembrane glycoprotein, desmoglein 1 (DSG1) was suppressed. Down-regulation of DSG1 may lead to reduced cell-cell adhesion, resulting in abnormal epidermal differentiation. The expression of keratin 6c (KRT6C) and fatty acid binding protein 5 (FABP5) were significantly increased. FABP5 is an intracellular lipid chaperone that plays an essential role in fatty acid metabolism in human skin. This raises a possibility that overexpression of FABP5 may affect the proliferation or differentiation of keratinocytes by altering lipid metabolism. KRT6C is a constituent of the cytoskeleton that maintains epidermal integrity and cohesion. Abnormal expression of KRT6C may affect its structural role in the epidermis. Our findings suggest an important approach for future studies of arsenic-mediated toxicity and skin cancer, where certain proteins may represent useful biomarkers of early diagnoses in high-risk populations and hopefully new treatment targets. Further studies are required to understand the biological role of these markers in skin pathogenesis from arsenic exposure.