Objective: This study compared the clinicopathological features and survival of metastatic prostate cancer (mPCa) after stratification by age and non-bone-related metastasis to identify prognostic factors. Methods: Patients with mPCa between 2010 and 2015 were identified from the Surveillance, Epidemiology and End Results database and analyzed. The overall survival (OS) rate was assessed using the Kaplan-Meier curve and log-rank test as well as multivariate Cox regression analysis. Results: Among the 10147 patients with mPCa, 5378 were classified as young (≤70 years), 3140 were classified as middle-aged (70-82 years), and 1629 were classified as elderly (> 82 years). The younger patients with a single site metastasis with non-regional lymph nodes (NRLN) had a better prognosis than those with bone metastasis [hazard ratio (HR), 0.59, 95% confidence interval (CI), 0.47-0.73, P < 0.001], whereas patients with liver metastasis had the worst OS rate (P = 0.001). Moreover, patients in the middle-aged group with NRLN or lung metastasis had a better prognosis than those with bone metastasis (P < 0.05). The OS rate of patient with bone + liver and bone + brain metastasis was poorer (P < 0.001) than those with bone + NRLN metastasis in the younger patients (P < 0.05). The elder patients with bone + lung metastasis had the worst OS (HR, 1.54; 95% CI, 1.25-1.90, P < 0.001), although the death risk of patients with bone + brain and bone + NRLN metastasis not significantly different (P > 0.05). However, the OS of the patients with bone + liver metastasis remained the worst (P < 0.001). Conclusions: Prostate cancer patients with lung metastasis or younger patients (≤70 years old) with bone + lung metastases had better OS than patients with other types of metastasis or old age.

Background: The predictive roles of secreted protein acidic and rich in cysteine (SPARC) in pancreatic ductal adenocarcinoma (PDAC) patients after curative resection have not been clarified. We investigated the correlations between the SPARC expression and the postoperative prognosis. Methods: We retrospectively analyzed the clinical data from consecutive patients who underwent curative resection for pancreatic cancer in our institution from 2005 to 2014. Stromal SPARC expression was analyzed by immunohistochemistry on tumor tissue microarrays (TMAs) from the patients. Results: A total of 179 patients were enrolled to this study. The median follow-up period of the present study was 62.1 months. Seventy patients had positive SPARC expression (39.1%). There were no significant differences between the positive SPARC-positive group and the SPARC-negative group. In the survival analysis, there was a significant difference between the SPARC-positive and SPARC-negative groups in the 5-year overall survival (OS) rates after surgery, which were 8.1% and 19.8%, respectively (p=0.0316). A univariate analysis showed that the SPARC expression, size of tumor, lymph node metastasis, and residual tumor were possible prognostic factors. A multivariate analysis showed that the SPARC expression (hazard ratio [HR]: 1.44, 95% confidence interval [CI]: 1.017-2.051), lymph node metastasis (HR: 2.019, 95% CI: 1.318-3.091), and residual tumor (HR: 1.648, 95% CI: 1.132-2.401) were independent prognostic factors. Conclusions: The stromal SPARC expression in resectable pancreatic cancer patients might be useful as a prognostic marker.

Background & aims: It remains controversial whether patients with advanced-stage hepatocellular carcinoma could be benefit from transarterial chemoembolization (TACE) treatment. The purpose of the present study is to identify predictors of survival following TACE in patients with advanced HCC. Methods: Overall, 303 patients with Barcelona Clinic Liver Cancer (BCLC) stage C HCC who were first treated with TACE from Sun Yat-sen University Cancer Centre between January 2009 and December 2013 were reviewed and enrolled in this study. We carried out Kaplan-Meier and Cox proportional hazard model analyses of prognostic factors. Results: The median survival of the whole cohort was 8.4 months. Multivariable Cox regression analyses confirmed that four risk factors, high serum levels of gamma-glutamyl transpeptidase (GGT), C-reactive protein (CRP), alkaline phosphatase (ALP) and presence of portal vein tumour thrombosis (PVTT), were independent prognostic factors for overall survival. The expected median survival among patients with 0-1 and 2-4 risk factors were 18.1 (95% CI: 15.5-20.7) and 6.8 (95% CI: 5.8-7.8) months, respectively. Objective tumor response among patients with 0-1 and 2-4 risk factors were 38.9% and 17.3%, respectively. Conclusion: We found four risk factors were associated with dismal overall survival for advanced HCC patients: serum GGT level, serum CRP, serum ALP and presence of PVTT. TACE may be recommended for patients with advanced HCC with 0-1 risk factors due to the favourable prognosis.

Switching aerobic respiration to anaerobic glycolysis of cancer cells plays an important role in development and progression of acquired resistance. Since vitamin C enabled the inhibition of glycolysis of cancer cells, and erlotinib-resistant sub-line of HCC827 (ER6 cells) switched its metabolic features to higher glycolysis for survival, we hypothesize that vitamin C is able to inhibit glycolysis of ER6 cells. In this study, we found that both reduced vitamin C and oxidized vitamin C (DHA) could selectively suppress the viability of ER6 cells. DHA was efficient in inhibiting glycolysis and leading to energy crisis, which could be one mechanism for overcoming drug resistance to erlotinib of ER6 cells. Our data suggest that applying DHA could be a novel treatment strategy for NSCLC with acquired resistance to targeted therapy.

Clinical variables contribute to the severity of Kashin-Beck disease (KBD). However, it is unclear if there is a correlation between gene expression and clinical variables. Peripheral blood samples were collected from 100 patients with KBD and 100 healthy controls from KBD-endemic areas to identify differentially expressed genes in KBD. Correlation analysis and multiple logistic regression analysis were performed using gene expression and clinical parameters. Immunohistochemistry (IHC) was used to detect the expression of related proteins in articular cartilage tissues. Thirty-nine differentially expressed genes were identified in patients with KBD. Nine differentially expressed genes were correlated with the metacarpal length/metacarpal breadth index. FZD1 was identified as having statistical significance in establishing the regression model of clinical parameters and gene expression. FZD1 expression levels were remarkably reduced in patients with KBD. Our results indicate that FZD1 could be involved in the pathological process of phalanges tuberositas and brachydactylia and may provide new insight into the pathogenesis of articular cartilage destruction observed in patients with KBD.

Biodegradable hydrogels have become promising materials for many biological applications in the past years. Recently, novel waterborne biodegradable polyurethane (WDPU) nanoparticles have been synthesized by a green water-based process, and serve as fundamental building blocks to form materials with great biocompatibility, biodegradability, and mechanical properties. However, the molecular structures and mechanisms of the WDPU nanoparticles and the relationship between the chemical compositions of the polymer segments and the material properties of the biodegradable hydrogels at macro-scale are still not well understood. In this study, we explore the fundamental mechanisms of WDPU nanoparticles through a full atomistic simulation approach to understand how the chemical compositions at the molecular level affect the molecular structures and material properties of WDPU nanoparticles. Specifically, we compare two WDPUs, i.e. PCL75LL25 and PCL75DL25, of the same hard segment composition and very similar soft segment composition [75% poly(e-caprolatone) and 25% polylactide], except the lactide in the former is L-form and in the latter is D,L-form. Our results show that the material properties of the biodegradable hydrogel can be designed by tuning the chemical compositions of the polymer segments. We find that the PCL75DL25 and PCL75LL25 have distinct molecular structures and physical crosslinks within the nanoparticles. The molecular structure of WDPU with PDLLA as soft segments is more extended, leading to more physical crosslinks between PCL segments. This study provide fundamental insights into the molecular structures and mechanisms of WDPU nanoparticles and help enabling the design of material properties of biocompatible hydrogel.

Species delineation based on bacterial genomes is an essential part of the research of prokaryotes. In silico genome-to-genome comparison methods are computationally demanding, but much less tedious and error prone than the wet-lab methods. In this paper, we present a novel method for the delineation of bacterial genomes based on genomic signal processing. The proposed method uses numerical representations of whole bacterial genomes, phase signal and cumulated phase signal, from which four parameters are derived for each genome. The parameters characterize a genome and their calculation is independent of the other genomes comprising a delineation dataset. The delineation itself is processed as a calculation of the parameters' average similarity. The method was statistically verified on 1826 bacterial genomes. A similarity threshold of 96% was set based on the receiver operating characteristic curve that featured sensitivity of 99.78% and specificity of 97.25%. Additionally, comparative analysis on another 33 bacterial genomes was conducted using standard delineation tools as these tools were not able to process the dataset of 1826 genomes using desktop computer. The proposed method achieved comparable or better delineation results in comparison with the standard tools. Besides the excellent delineation results, another great advantage of the method is its small computational demands, which enables the delineation of thousands of genomes on a desktop computer. The calculation of the parameters takes tens of minutes for thousands of genomes. Moreover, they can be calculated in advance by creating a database, meaning the delineation itself is then completed in a matter of seconds.

As knowledge of the genetics behind inflammatory bowel disease (IBD) has continually improved, there has been a demand for methods that can use this data in a clinically significant way. Genome-wide association analyses for IBD have identified 232 risk genetic loci for the disorder. While identification of these risk loci enriches our understanding of the underlying biology of the disorder, their identification does not serve a clinical purpose. A potential use of this genetic information is to look for potential IBD drugs that target these loci in a procedure known as drug repurposing. The demand for new drug treatments for IBD is high due to the side effects and high costs of current treatments. We hypothesize that IBD genetic variants obtained from GWAS and the candidate genes prioritized from the variants have a causal relationship with IBD drug targets. A computational drug repositioning study was done due to its efficiency and inexpensiveness compared to traditional in vitro or biochemical approaches. Our approach for drug repurposing was multi-layered; it not only focused on the interactions between drugs and risk IBD genes, but also the interactions between drugs and all of the biological pathways the risk genes are involved in. We prioritized IBD candidate genes using identified genetic variants and identified potential drug targets and drugs that can be potentially repositioned or developed for IBD using the identified candidate genes. Our analysis strategy can be applied to repurpose drugs for other complex diseases using their risk genes identified from genetic analysis.

Bone/cartilage interfacial tissue engineering needs to satisfy the differential properties and architectures of the osteochondral region. Therefore, biphasic or multiphasic scaffolds that aim to mimic the gradient hierarchy are widely used. Here, we find that two differently structured (topographically) three-dimensional scaffolds, namely, "dense" and "nanofibrous" surfaces, show differential stimulation in osteo- and chondro-responses of cells. While the nanofibrous scaffolds accelerate the osteogenesis of mesenchymal stem cells, the dense scaffolds are better in preserving the phenotypes of chondrocytes. Two types of porous scaffolds, generated by a salt-leaching method combined with a phase-separation process using the poly(lactic acid) composition, had a similar level of porosity (~90%) and pore size (~150 μm). The major difference in the surface nanostructure led to substantial changes in the surface area and water hydrophilicity (nanofibrous ≫ dense); as a result, the nanofibrous scaffolds increased the cell-to-matrix adhesion of mesenchymal stem cells significantly while decreasing the cell-to-cell contracts. Importantly, the chondrocytes, when cultured on nanofibrous scaffolds, were prone to lose their phenotype, including reduced chondrogenic expressions (SOX-9, collagen type II, and Aggrecan) and glycosaminoglycan content, which was ascribed to the enhanced cell-matrix adhesion with reduced cell-cell contacts. On the contrary, the osteogenesis of mesenchymal stem cells was significantly accelerated by the improved cell-to-matrix adhesion, as evidenced in the enhanced osteogenic expressions (RUNX2, bone sialoprotein, and osteopontin) and cellular mineralization. Based on these findings, we consider that the dense scaffold is preferentially used for the chondral-part, whereas the nanofibrous structure is suitable for osteo-part, to provide an optimal biphasic matrix environment for osteochondral tissue engineering.

Atopic dermatitis (AD) is a complex heterogeneous chronic inflammatory skin disease. Specific IgE antibodies against autoantigens have been observed in a subgroup of AD patients, however, little is known about IgG-auto-reactivity in AD. To investigate the presence of autoreactive IgG antibodies, we performed autoantibody profiling of IgG in patients with AD of different severities and in healthy controls (HC).

GR24 is a synthetic strigolactone analog, demonstrated to regulate the development of plants and arbuscular mycorrhizal fungi. GR24 possesses anti-cancer and anti-apoptotic properties, enhances insulin sensitivity and mitochondrial biogenesis in skeletal myotubes, inhibits adipogenesis, decreases inflammation in adipocytes and macrophages and downregulates the expression of hepatic gluconeogenic enzymes. Transcription factor Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) is a master regulator of antioxidant response, regulating a multitude of genes involved in cellular stress responses and anti-inflammatory pathways, thus maintaining cellular redox homeostasis. Nrf2 activation reduces the deleterious effects of mitochondrial toxins and has multiple roles in promoting mitochondrial function and dynamics. We studied the role of GR24 on gene expression in rat L6 skeletal muscle cells which were differentiated into myotubes. The myotubes were treated with GR24 and analyzed by microarray gene expression profiling. GR24 upregulated the cytoprotective transcription factor Nrf2 and its target genes, activating antioxidant defences, suggesting that GR24 may protect skeletal muscle from the toxic effects of oxidative stress.

Using a deep neural network, we demonstrate a digital staining technique, which we term PhaseStain, to transform the quantitative phase images (QPI) of label-free tissue sections into images that are equivalent to the brightfield microscopy images of the same samples that are histologically stained. Through pairs of image data (QPI and the corresponding brightfield images, acquired after staining), we train a generative adversarial network and demonstrate the effectiveness of this virtual-staining approach using sections of human skin, kidney, and liver tissue, matching the brightfield microscopy images of the same samples stained with Hematoxylin and Eosin, Jones' stain, and Masson's trichrome stain, respectively. This digital-staining framework may further strengthen various uses of label-free QPI techniques in pathology applications and biomedical research in general, by eliminating the need for histological staining, reducing sample preparation related costs and saving time. Our results provide a powerful example of some of the unique opportunities created by data-driven image transformations enabled by deep learning.

Apple latent spherical virus (ALSV) vector is a convenient alternative to genetic transformation in horticultural plants, especially in species recalcitrant to genetic transformation. ALSV, an RNA virus, can infect a wide variety of plant species including major horticultural plants without inducing symptoms. Here, methodologies were developed for infection of ALSV vectors to strawberry seedlings and plantlets cultured in vitro. A seed-propagated F1 hybrid strawberry cultivar 'Yotsuboshi' was aseptically grown on half-strength Murashige-Skoog medium for 1 month and true leaves were inoculated with an ALSV RNA preparation by particle bombardment. ALSV vector infection rates varied from 58 to 100% according to the insertion sequences, in 'Yotsuboshi' seedlings. Plantlets ('Dover') propagated in vitro could also be infected with ALSV vector at a similar infection rate. For virus-induced gene silencing (VIGS), we prepared an ALSV vector carrying a 201 nucleotide segment of the strawberry phytoene desaturase gene. 'Yotsuboshi' and 'Dover' plants infected by this vector generated completely white leaves at fifth or sixth true leaves and above. For virus-induced flowering (VIF), we used an ALSV vector expressing the Arabidopsis thaliana flowering locus T gene. Strawberry seedlings infected by this vector started to flower from about 2 months post inoculation and bore fruits with viable seeds. The ALSV vector was no longer detected in any of the seedlings from early-flowered strawberries. Thus, the ALSV vector may be beneficial for examination of gene functions by VIGS in strawberry, and VIF using ALSV vector constitutes an effective new plant breeding technique for the promotion of cross-breeding in strawberry.

Chrysanthemums are sensitive to waterlogging stress, and the development of screening methods for tolerant germplasms or genes and the breeding of tolerant new varieties are of great importance in chrysanthemum breeding. To understand the genetic basis of waterlogging tolerance (WT) in chrysanthemums, we performed a genome-wide association study (GWAS) using 92,811 single nucleotide polymorphisms (SNPs) in a panel of 88 chrysanthemum accessions, including 64 spray cut and 24 disbud chrysanthemums. The results showed that the average MFVW (membership function value of waterlogging) of the disbud type (0.65) was significantly higher than that of the spray type (0.55) at P < 0.05, and the MFVW of the Asian accessions (0.65) was significantly higher than that of the European accessions (0.48) at P < 0.01. The GWAS performed using the general linear model (GLM) and mixed linear model (MLM) identified 137 and 14 SNP loci related to WT, respectively, and 11 associations were commonly predicted. By calculating the phenotypic effect values for 11 common SNP loci, six highly favorable SNP alleles that explained 12.85-21.85% of the phenotypic variations were identified. Furthermore, the dosage-pyramiding effects of the favorable alleles and the significant linear correlations between the numbers of highly favorable alleles and phenotypic values were identified (r 2 = 0.45; P < 0.01). A major SNP locus (Marker6619-75) was converted into a derived cleaved amplified polymorphic sequence (dCAPS) marker that cosegregated with WT with an average efficiency of 78.9%. Finally, four putative candidate genes in the WT were identified via quantitative real-time PCR (qRT-PCR). The results presented in this study provide insights for further research on WT mechanisms and the application of molecular marker-assisted selection (MAS) in chrysanthemum WT breeding programs.

SCR/SP11 encodes the male determinant of recognition specificity of self-incompatibility (SI) in Brassica species and is sporophytically expressed in the anther tapetum. Based on dominance relationships in pollen and nucleotide sequence similarity, the S haplotypes in Brassica have been classified as class I or class II, with class-I S haplotypes being dominant over class-II S haplotypes. Here, we revealed that S-22 in B. rapa belonging to class I is recessive to class-II S-44 and class-I S-36 in pollen, whereas it is dominant over S-60, S-40, and S-29 based on pollination tests. SCR/SP11 of S-22 (SCR-22) was sequenced, revealing that the deduced amino-acid sequence of SCR-22 has the longest C-terminal domain among the SCR/SP11 sequences. The expression of SCR-22 was found to be suppressed in S-22/S-44 and S-22/S-36 heterozygotes. Normal transcription of SCR-44 was considered to be due to the transcription suppression of Smi sRNA of the S-22 haplotype and a very low methylation state of the SCR-44 promoter region in the tapetum of S-22/S-44 heterozygotes. In SCR-22, only the cytosine residue located at the -37 bp position of the promoter region was hypermethylated in the tapetum of S-22/S-44 heterozygotes, and few methylated cytosines were detected in the promoter and coding regions of SCR-22 in S-22/S-36 heterozygotes. SCR-22 was also expressed in microspores in S-22 homozygotes but not in S-22/S-44 and S-22/S-36 heterozygotes. These results suggest that a mechanism different from class-II SCR/SP11 suppression may operate for the suppression of recessive class-I SCR-22 in S heterozygotes.

Our previous studies indicated that tomato miR482b could negatively regulate the resistance of tomato to Phytophthora infestans and the expression of miR482b was decreased after inoculation with P. infestans. However, the mechanism by which the accumulation of miR482b is suppressed remains unclear. In this study, we wrote a program to identify 89 long noncoding RNA (lncRNA)-originated endogenous target mimics (eTMs) for 46 miRNAs from our RNA-Seq data. Three tomato lncRNAs, lncRNA23468, lncRNA01308 and lncRNA13262, contained conserved eTM sites for miR482b. When lncRNA23468 was overexpressed in tomato, miR482b expression was significantly decreased, and the expression of the target genes, NBS-LRRs, was significantly increased, resulting in enhanced resistance to P. infestans. Silencing lncRNA23468 in tomato led to the increased accumulation of miR482b and decreased accumulation of NBS-LRRs, as well as reduced resistance to P. infestans. In addition, the accumulation of both miR482b and NBS-LRRs was not significantly changed in tomato plants that overexpressed lncRNA23468 with a mutated eTM site. Based on the VIGS system, a target gene of miR482b, Solyc02g036270.2, was silenced. The disease symptoms of the VIGS-Solyc02g036270.2 tomato plants were in accordance with those of tomato plants in which lncRNA23468 was silenced after inoculation with P. infestans. More severe disease symptoms were found in the modified plants than in the control plants. Our results demonstrate that lncRNAs functioning as eTMs may modulate the effects of miRNAs in tomato and provide insight into how the lncRNA23468-miR482b-NBS-LRR module regulates tomato resistance to P. infestans.

Natalizumab is an effective treatment for relapsing multiple sclerosis. Return of disease activity upon natalizumab discontinuance creates the need for follow-up therapeutic strategies.

Sleep quality is an essential component of athlete's recovery. However, a better understanding of the parameters to adequately quantify sleep quality in team sport athletes is clearly warranted.

Although conventional genetic modification approaches for protein knockdown work very successfully due to the increasing use of CRISPR/Cas9, effective techniques for achieving protein depletion in adult animals, especially in large animals such as non-human primates, are lacking. Here, we report a chemical approach based on PROTACs technology that efficiently and quickly knocks down FKBP12 (12-kDa FK506-binding) protein globally in vivo. Both intraperitoneal and oral administration led to rapid, robust, and reversible FKBP12 degradation in mice. The efficiency and practicality of this method were successfully demonstrated in both large and small animals (mice, rats, Bama pigs, and rhesus monkeys). Furthermore, we showed this approach can also be applied to effectively knockdown other target proteins such as Bruton's tyrosine kinase (BTK). This chemical protein knockdown strategy provides a powerful research tool for gene function studies in animals, particularly in large animals, for which gene-targeted knockout strategies may remain unfeasible.

The integration of genomic and DNA methylation data has been demonstrated as a powerful strategy in understanding cancer mechanisms and identifying therapeutic targets. The TCGA consortium has mapped DNA methylation in thousands of cancer samples using Illumina Infinium Human Methylation 450 K BeadChip (Illumina 450 K array) that only covers about 1.5% of CpGs in the human genome. Therefore, increasing the coverage of the DNA methylome would significantly leverage the usage of the TCGA data. Here, we present a new model called EAGLING that can expand the Illumina 450 K array data 18 times to cover about 30% of the CpGs in the human genome. We applied it to analyze 13 cancers in TCGA. By integrating the expanded methylation, gene expression, and somatic mutation data, we identified the genes showing differential patterns in each of the 13 cancers. Many of the triple-evidenced genes identified in majority of the cancers are biomarkers or potential biomarkers. Pan-cancer analysis also revealed the pathways in which the triple-evidenced genes are enriched, which include well known ones as well as new ones, such as axonal guidance signaling pathway and pathways related to inflammatory processing or inflammation response. Triple-evidenced genes, particularly TNXB, RRM2, CELSR3, SLC16A3, FANCI, MMP9, MMP11, SIK1, and TRIM59 showed superior predictive power in both tumor diagnosis and prognosis. These results have demonstrated that the integrative analysis using the expanded methylation data is powerful in identifying critical genes/pathways that may serve as new therapeutic targets.