Swing Door Compressive Fracture Technique for Turbinoplasty: Retrospective Study Based on Computed Tomography and NOSE Scale.

BACKGROUND: Treatment of inferior turbinate hypertrophy is performed using different techniques in rhinoplasty. However, the reported results are not consistent. In this study, we aimed to evaluate the outcomes of Swing door compressive fracture (SDCF) technique for turbinoplasty using computed tomography (CT) and Nasal Obstruction Symptom Evaluation (NOSE) scale. METHODS: This study involved retrospective analysis of 24 patients who underwent inferior turbinoplasty using Swing door compressive fracture (SDCF) technique with or without septoplasty. The angle between the inferior turbinate and lateral nasal wall, total area, inferior turbinate area and the area medial to inferior turbinate were measured preoperatively and postoperatively using coronal section CT images for objective evaluation. Moreover, the NOSE scale was used for subjective evaluation. RESULTS: The angle between inferior turbinate and lateral nasal wall was decreased by 25.3% after the treatment (p <0.0001). Inevitably, postoperative total nasal airway area (area 1) did not face a statistically significant change (p = 0.6878). On the other hand, the area of inferior turbinate (area 2) decreased significantly compared to preoperative value (p = 0.0021), while the area 3, the area medial to inferior turbinate was widened 1.5 times postoperatively. The total preoperative NOSE score was moderate (39.58 ± 22.31%) and it was decreased to mild (5.83 ± 8.81%) after the treatment (p <0.0001). CONCLUSIONS: The Swing door compressive fracture (SDCF) technique for turbinoplasty is an effective and straightforward modality. However, the further study involving more patients and longer follow-up period is mandatory. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Multi-omic biomarker identification and validation for diagnosing warzone-related post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) impacts many veterans and active duty soldiers, but diagnosis can be problematic due to biases in self-disclosure of symptoms, stigma within military populations, and limitations identifying those at risk. Prior studies suggest that PTSD may be a systemic illness, affecting not just the brain, but the entire body. Therefore, disease signals likely span multiple biological domains, including genes, proteins, cells, tissues, and organism-level physiological changes. Identification of these signals could aid in diagnostics, treatment decision-making, and risk evaluation. In the search for PTSD diagnostic biomarkers, we ascertained over one million molecular, cellular, physiological, and clinical features from three cohorts of male veterans. In a discovery cohort of 83 warzone-related PTSD cases and 82 warzone-exposed controls, we identified a set of 343 candidate biomarkers. These candidate biomarkers were selected from an integrated approach using (1) data-driven methods, including Support Vector Machine with Recursive Feature Elimination and other standard or published methodologies, and (2) hypothesis-driven approaches, using previous genetic studies for polygenic risk, or other PTSD-related literature. After reassessment of ~30% of these participants, we refined this set of markers from 343 to 28, based on their performance and ability to track changes in phenotype over time. The final diagnostic panel of 28 features was validated in an independent cohort (26 cases, 26 controls) with good performance (AUC = 0.80, 81% accuracy, 85% sensitivity, and 77% specificity). The identification and validation of this diverse diagnostic panel represents a powerful and novel approach to improve accuracy and reduce bias in diagnosing combat-related PTSD.

Radiologic Analysis of Malar Arch Movement in Reduction Malarplasty Without Bony Resection.

BACKGROUND: Reduction malarplasty has been popular among Asians with a wide facial width. In general, malar setback after bony resection is regarded as the standard objective of reduction malarplasty. However, unnecessary bony resection may lead to various postoperative complications. Therefore, we suggest the use of reduction malarplasty without bony resection to achieve a similar narrowing effect of the facial width, based on radiographic analysis of malar arch movement. PATIENTS AND METHODS: This retrospective study analyzed 48 patients with a wide midface who underwent reduction malarplasty between September 2018 and December 2019. We included 40 cases of advancement repositioning malarplasty (AR) without bony resection and 8 cases of setback reduction malarplasty (SR) with bony resection. The three-dimensional position of the malar arch expressed by coordinates (x, y, and z) on three-dimensional computed tomography scans was used to compare the positional change between the surgical methods. The paired t-test, Wilcoxon text, and independent t-test were used in data analysis, and statistical analysis was performed using SPSS 23.0 software. RESULTS: Medial and superior movement of the freed malar arch segment was significantly different between AR and SR (P < 0.05). Although medialization and superiorization were not significantly different between AR and SR, there was a significant difference in anterior-posterior movement between AR and SR (P < 0.05). CONCLUSION: The radiologic analysis based on malar arch movement between AR and SR showed similar narrowing effects on medialization and superiorization of the malar arch regardless of bony resection. Therefore, the AR can be effectively applied in case of arch dominant type or malar asymmetry. In addition, further comprehensive study including analysis on movement of facial soft tissue following malar bony movement is expected based on this study in near future.

Measurement of Organ-Specific and Acute-Phase Blood Protein Levels in Early Lyme Disease.

Lyme disease results from infection of humans with the spirochete Borrelia burgdorferi. The first and most common clinical manifestation is the circular, inflamed skin lesion referred to as erythema migrans; later manifestations result from infections of other body sites. Laboratory diagnosis of Lyme disease can be challenging in patients with erythema migrans because of the time delay in the development of specific diagnostic antibodies against Borrelia. Reliable blood biomarkers for the early diagnosis of Lyme disease in patients with erythema migrans are needed. Here, we performed selected reaction monitoring, a targeted mass spectrometry-based approach, to measure selected proteins that (1) are known to be predominantly expressed in one organ (i.e., organ-specific blood proteins) and whose blood concentrations may change as a result of Lyme disease, or (2) are involved in acute immune responses. In a longitudinal cohort of 40 Lyme disease patients and 20 healthy controls, we identified 10 proteins with significantly altered serum levels in patients at the time of diagnosis, and we also developed a 10-protein panel identified through multivariate analysis. In an independent cohort of patients with erythema migrans, six of these proteins, APOA4, C9, CRP, CST6, PGLYRP2, and S100A9, were confirmed to show significantly altered serum levels in patients at time of presentation. Nine of the 10 proteins from the multivariate panel were also verified in the second cohort. These proteins, primarily innate immune response proteins or proteins specific to liver, skin, or white blood cells, may serve as candidate blood biomarkers requiring further validation to aid in the laboratory diagnosis of early Lyme disease.

In Vitro and in Vivo Biocompatibility and Degradability Evaluation of Modified Polydioxanone Plate.

BACKGROUND: Polydioxanone (PDS) has been widely used in the medical field over the past 30 years. In the 2000s, PDS plate began to be used for rhinoplasty and septoplasty. However, in Asia PDS plates are not widely used due to lack of awareness and high prices. The authors devised a method of producing a modified PDS (m-PDS; Rhinoblock Material & Design Co., Gyeonggi-do, Sothh Korea) at low cost, and compared the biocompatibilities and degradabilities of plates produced with m-PDS and commercial PDS plates (Ethicon, Somerville, NJ) in vivo and in vitro. METHODS: The melting point and decomposition rate of m-PDS were determined by differential scanning calorimetry and thermogravimetric analysis and its tensile strength was also measured. Implants (1 cm × 1 cm × 0.15 mm sized) were inserted subcutaneously into mice and harvested en bloc 2, 5, 10, 15, or 25 weeks later. Tissues were stained with hematoxylin and eosin or Masson's trichrome to evaluate inflammation, extracellular matrix deposition, and vascularization, and plate degradability was also assessed. RESULTS: No significant difference was observed between the thermal analysis and tensile test results of m-PDS and PDS plates. m-PDS started to degrade in vivo from around 10 weeks, and commercial PDS plates from around 15 weeks. After 25 weeks in vivo, both products were completely degraded and not observed in tissue slides. Histologic analysis of excised specimens showed m-PDS and PDS were similar in terms of inflammation, extracellular matrix deposition, and vascularization. CONCLUSION: In vivo and in vitro experiments detected no significant difference between the biocompatibilities and degradabilities of modified and commercial PDS plates. The results of this study suggest that the modified PDS can be used to produce versatile, low cost, absorbable graft materials for rhinoplasty and septoplasty.

Circulating RNAs as predictive markers for the progression of type 2 diabetes.

Type 2 Diabetes Mellitus (T2DM) is the most prevalent form of diabetes in the USA, thus, the identification of biomarkers that could be used to predict the progression from prediabetes to T2DM would be greatly beneficial. Recently, circulating RNA including microRNAs (miRNAs) present in various body fluids have emerged as potential biomarkers for various health conditions, including T2DM. Whereas studies that examine the changes of miRNA spectra between healthy controls and T2DM individuals have been reported, the goal of this study is to conduct a baseline comparison of prediabetic individuals who either progress to T2DM, or remain prediabetic. Using an advanced small RNA sequencing library construction method that improves the detection of miRNA species, we identified 57 miRNAs that showed significant concentration differences between progressors (progress from prediabetes to T2DM) and non-progressors. Among them, 26 have been previously reported to be associated with T2DM in either body fluids or tissue samples. Some of the miRNAs identified were also affected by obesity. Furthermore, we identified miRNA panels that are able to discriminate progressors from non-progressors. These results suggest that upon further validation these miRNAs may be useful to predict the risk of conversion to T2DM from prediabetes.

sRNAnalyzer-a flexible and customizable small RNA sequencing data analysis pipeline.

Although many tools have been developed to analyze small RNA sequencing (sRNA-Seq) data, it remains challenging to accurately analyze the small RNA population, mainly due to multiple sequence ID assignment caused by short read length. Additional issues in small RNA analysis include low consistency of microRNA (miRNA) measurement results across different platforms, miRNA mapping associated with miRNA sequence variation (isomiR) and RNA editing, and the origin of those unmapped reads after screening against all endogenous reference sequence databases. To address these issues, we built a comprehensive and customizable sRNA-Seq data analysis pipeline-sRNAnalyzer, which enables: (i) comprehensive miRNA profiling strategies to better handle isomiRs and summarization based on each nucleotide position to detect potential SNPs in miRNAs, (ii) different sequence mapping result assignment approaches to simulate results from microarray/qRT-PCR platforms and a local probabilistic model to assign mapping results to the most-likely IDs, (iii) comprehensive ribosomal RNA filtering for accurate mapping of exogenous RNAs and summarization based on taxonomy annotation. We evaluated our pipeline on both artificial samples (including synthetic miRNA and Escherichia coli cultures) and biological samples (human tissue and plasma). sRNAnalyzer is implemented in Perl and available at: http://srnanalyzer.systemsbiology.net/.

Extracellular vesicle RNAs reflect placenta dysfunction and are a biomarker source for preterm labour.

Preterm birth (PTB) can lead to lifelong complications and challenges. Identifying and monitoring molecular signals in easily accessible biological samples that can diagnose or predict the risk of preterm labour (PTL) in pregnant women will reduce or prevent PTBs. A number of studies identified putative biomarkers for PTL including protein, miRNA and hormones from various body fluids. However, biomarkers identified from these studies usually lack consistency and reproducibility. Extracellular vesicles (EVs) in circulation have gained significant interest in recent years as these vesicles may be involved in cell-cell communication. We have used an improved small RNA library construction protocol and a newly developed size exclusion chromatography (SEC)-based EV purification method to gain a comprehensive view of circulating RNA in plasma and its distribution by analysing RNAs in whole plasma and EV-associated and EV-depleted plasma. We identified a number of miRNAs in EVs that can be used as biomarkers for PTL, and these miRNAs may reflect the pathological changes of the placenta during the development of PTL. To our knowledge, this is the first study to report a comprehensive picture of circulating RNA, including RNA in whole plasma, EV and EV-depleted plasma, in PTL and reveal the usefulness of EV-associated RNAs in disease diagnosis.

Improved angular color uniformity and hydrothermal reliability of phosphor-converted white light-emitting diodes by using phosphor sedimentation.

We investigated the effect of phosphor deposition methods on the correlated color temperature (CCT), luminous flux and thermal characteristics of packaged white light-emitting diodes (WLEDs) for use in mobile display products. For both the samples, the CCT decreased with increasing viewing angle. Phosphor sedimentation samples displayed much better angular color uniformity than phosphor dispersion samples. The phosphor sedimentation sample had higher luminous flux and luminous efficacy at 20 mA than the phosphor dispersion sample. The phosphor sedimentation sample displayed much better high-temperature/humidity (85 °C/85%) reliability and lower package temperatures compared with the phosphor dispersion sample.

A Systematic Study of Dysregulated MicroRNA in Type 2 Diabetes Mellitus.

MicroRNAs (miRNAs) are small noncoding RNAs that modulate the cellular transcriptome at the post-transcriptional level. miRNA plays important roles in different disease manifestation, including type 2 diabetes mellitus (T2DM). Many studies have characterized the changes of miRNAs in T2DM, a complex systematic disease; however, few studies have integrated these findings and explored the functional effects of the dysregulated miRNAs identified. To investigate the involvement of miRNAs in T2DM, we obtained and analyzed all relevant studies published prior to 18 October 2016 from various literature databases. From 59 independent studies that met the inclusion criteria, we identified 158 dysregulated miRNAs in seven different major sample types. To understand the functional impact of these deregulated miRNAs, we performed targets prediction and pathway enrichment analysis. Results from our analysis suggested that the altered miRNAs are involved in the core processes associated with T2DM, such as carbohydrate and lipid metabolisms, insulin signaling pathway and the adipocytokine signaling pathway. This systematic survey of dysregulated miRNAs provides molecular insights on the effect of deregulated miRNAs in different tissues during the development of diabetes. Some of these miRNAs and their mRNA targets may have diagnostic and/or therapeutic utilities in T2DM.

Identification of Organ-Enriched Protein Biomarkers of Acute Liver Injury by Targeted Quantitative Proteomics of Blood in Acetaminophen- and Carbon-Tetrachloride-Treated Mouse Models and Acetaminophen Overdose Patients.

Organ-enriched blood proteins, those produced primarily in one organ and secreted or exported to the blood, potentially afford a powerful and specific approach to assessing diseases in their cognate organs. We demonstrate that quantification of organ-enriched proteins in the blood offers a new strategy to find biomarkers for diagnosis and assessment of drug-induced liver injury (and presumably the assessment of other liver diseases). We used selected reaction monitoring (SRM) mass spectrometry to quantify 81 liver-enriched proteins plus three aminotransferases (ALT1, AST1, and AST2) in plasma of C57BL/6J and NOD/ShiLtJ mice exposed to acetaminophen or carbon tetrachloride. Plasma concentrations of 49 liver-enriched proteins were perturbed significantly in response to liver injury induced by one or both toxins. We validated four of these toxin-responsive proteins (ALDOB, ASS1, BHMT, and GLUD1) by Western blotting. By both assays, these four proteins constitute liver injury markers superior to currently employed markers such as ALT and AST. A similar approach was also successful in human serum where we had analyzed 66 liver-enriched proteins in acetaminophen overdose patients. Of these, 23 proteins were elevated in patients; 15 of 23 overlapped with the concentration-increased proteins in the mouse study. A combination of 5 human proteins, AGXT, ALDOB, CRP, FBP1, and MMP9, provides the best diagnostic performance to distinguish acetaminophen overdose patients from controls (sensitivity: 0.85, specificity: 0.84, accuracy: 85%). These five blood proteins are candidates for detecting acetaminophen-induced liver injury using next-generation diagnostic devices (e.g, microfluidic ELISA assays).

A systematic study on dysregulated microRNAs in cervical cancer development.

MicroRNAs (miRNAs) are short regulatory RNAs that modulate the transcriptome and proteome at the post-transcriptional level. To obtain a better understanding on the role of miRNAs in the progression of cervical cancer, meta-analysis and gene set enrichment analysis were used to analyze published cervical cancer miRNA studies. From 85 published reports, which include 3,922 cases and 2,099 noncancerous control tissue samples, 63 differentially expressed miRNAs (DEmiRNAs) were identified in different stages of cervical cancer development (CIN 1-3 and CC). It was found that some of the dysregulated miRNAs were associated with specific stages of cervical cancer development. To illustrate the impact of miRNAs on the pathogenesis of cervical cancer, a miRNA-mRNA interaction network on selected pathways was built by integrating viral oncoproteins, dysregulated miRNAs and their predicted/validated targets. The results indicated that the deregulated miRNAs at the different stages of cervical cancer were functionally involved in several key cancer related pathways, such as cell cycle, p53 and Wnt signaling pathways. These dysregulated miRNAs could play an important role in cervical cancer development. Some of the stage-specific miRNAs can also be used as biomarkers for cancer classification and monitoring the progression of cancer development.

Circulating MicroRNAs and Life Expectancy Among Identical Twins.

Human life expectancy is influenced not only by longevity assurance mechanisms and disease susceptibility loci but also by the environment, gene-environment interactions, and chance. MicroRNAs (miRNAs) are a class of small noncoding RNAs closely related to genes. Circulating miRNAs have been shown as promising noninvasive biomarkers in the development of many pathophysiological conditions. However, the concentration of miRNA in the circulation may also be affected by environmental factors. We used a next-generation sequencing platform to assess the association of circulating miRNA with life expectancy, for which deaths are due to all causes independent of genes. In addition, we showed that miRNAs are present in 41-year archived plasma samples, which may be useful for both life expectancy and all-cause mortality risk assessment. Plasma miRNAs from nine identical male twins were profiled using next-generation sequencing. The average absolute difference in the minimum life expectancy was 9.68 years. Intraclass correlation coefficients were above 0.4 for 50% of miRNAs. Comparing deceased twins with their alive co-twin brothers, the concentrations were increased for 34 but decreased for 30 miRNAs. Identical twins discordant in life expectancy were dissimilar in the majority of miRNAs, suggesting that environmental factors are pivotal in miRNAs related to life expectancy.

Current State of Circulating MicroRNAs as Cancer Biomarkers.

BACKGROUND: Numerous studies have demonstrated the existence of stable regulatory RNAs, microRNAs (miRNAs), in the circulation and have shown that the spectrum of these extracellular miRNAs is affected by various pathologic conditions including cancers. CONTENT: Circulating miRNAs have been the focus of numerous cancer biomarker discovery efforts over the past few years; however, a considerable number of these studies have yielded inconsistent and irreproducible findings. Here, we have summarized and compared the results of studies covering 8 different cancer types to address key questions, including the possibility of using circulating miRNA to detect cancers and what factors may affect miRNA signatures. Although identifying circulating miRNA signatures to detect specific types of early stage cancers can be challenging, study results suggest that it may be possible to use miRNAs to detect cancers in general. SUMMARY: Circulating miRNA is a rich source for potential disease biomarkers; however, factors, both intrinsic and extrinsic, that may affect measurement of circulating miRNA have not been fully characterized. Better understanding of intra- and intercellular miRNA trafficking and the fundamental biology of cancer cell-derived lipid vesicles may facilitate the development of circulating miRNA-based biomarkers for cancer detection and classification.

Nasal Osteotomies Revisited in Asians: Surface Aesthetics, Anatomical and Technical Considerations.

Background Although osteotomy is commonly performed in rhinoplasty, it is difficult for less experienced surgeon to understand mechanism of the procedure. The primary goal of this study is to improve understanding of nasal osteotomy in Asians by considering the surface aesthetics and anatomy of the nose as well as their relationships with the surgical procedure. Methods Surface aesthetics, anatomic considerations, kinetics of medial and lateral osteotomy, fracture levels of osteotomy were discussed in detail by reviewing the previous publications and 18 years of our experience. Moreover, the technical details of osteotomy were explained and personal tips for performing successful osteotomy were described. Results Dorsal and lateral aesthetic lines, dorsal and basal widths are main characteristics related to the surface aesthetics of nose to perform the osteotomy. In addition, these features are different in Asian population due to the anatomic difference with Caucasians, which makes the procedure difficult and requires more attention to perform osteotomy. Conclusion Because osteotomy is one of the most traumatic and invasive part of the rhinoplasty, it is crucial for the rhinoplasty surgeon to understand the relationship between surface aesthetics and osteotomy techniques to produce consistent and reproducible results.

Complicated calcified alloplastic implants in the nasal dorsum: A clinical analysis.

BACKGROUND: In rhinoplasty, calcification around silicone implants is frequently observed in the tip dorsum (TD) area. Additionally, based on a review of various literature, it is presumed that calcification in silicone implants occurs due to both inflammatory chemical reactions and physical friction against the tissue. The calcification of nasal silicone implants not only results in the functional loss of the implants, but also leads to material deformation. However, there is a lack of research on calcification of nasal silicone implants in the current literature. AIM: To elucidate various clinical characteristics of calcification around nasal silicone implants, using histological and radiological analysis. METHODS: This study analyzed data from 16 patients of calcified nasal implants, who underwent revision rhinoplasty for various reasons after undergoing augmentation rhinoplasty with silicone implants. The collected data included information on implant duration, implant types, location of calcification, presence of inflammatory reactions, and computed tomography (CT) scans. RESULTS: The most common location of calcification, as visually analyzed, was in the TD area, accounting for 56%. Additionally, the analysis of CT scans revealed a trend of increasing Hounsfield Unit values for calcification with the duration of implantation, although this trend was not statistically significant (P = 0.139). CONCLUSION: Our study shows that reducing the frequency of calcification may be achievable by using softer silicone implants and by minimizing the damage to perioperative tissues.

Quantitative proteomics identifies a beta-catenin network as an element of the signaling response to Frizzled-8 protein-related antiproliferative factor.

Antiproliferative factor (APF), a Frizzled-8 protein-related sialoglycopeptide involved in the pathogenesis of interstitial cystitis, potently inhibits proliferation of normal urothelial cells as well as certain cancer cells. To elucidate the molecular mechanisms of the growth-inhibitory effect of APF, we performed stable isotope labeling by amino acids in cell culture analysis of T24 bladder cancer cells treated with and without APF. Among over 2000 proteins identified, 54 were significantly up-regulated and 48 were down-regulated by APF treatment. Bioinformatic analysis revealed that a protein network involved in cell adhesion was substantially altered by APF and that ß-catenin was a prominent node in this network. Functional assays demonstrated that APF down-regulated ß-catenin, at least in part, via proteasomal and lysosomal degradation. Moreover, silencing of ß-catenin mimicked the antiproliferative effect of APF whereas ectopic expression of nondegradable ß-catenin rescued growth inhibition in response to APF, confirming that ß-catenin is a key mediator of APF signaling. Notably, the key role of ß-catenin in APF signaling is not restricted to T24 cells, but was also observed in an hTERT-immortalized human bladder epithelial cell line, TRT-HU1. In addition, the network model suggested that ß-catenin is linked to cyclooxygenase-2 (COX-2), implying a potential connection between APF and inflammation. Functional assays verified that APF increased the production of prostaglandin E(2) and that down-modulation of ß-catenin elevated COX-2 expression, whereas forced expression of nondegradable ß-catenin inhibited APF-induced up-regulation of COX-2. Furthermore, we confirmed that ß-catenin was down-regulated whereas COX-2 was up-regulated in epithelial cells explanted from IC bladder biopsies compared with control tissues. In summary, our quantitative proteomics study describes the first provisional APF-regulated protein network, within which ß-catenin is a key node, and provides new insight that targeting the ß-catenin signaling pathway may be a rational approach toward treating interstitial cystitis.

Surgical anatomy for Asian rhinoplasty: Part III.

This article, which comprises the third part of a series on surgical anatomy for Asian rhinoplasty, addresses the lower one-third of the nose, including the alar cartilage and tip-supporting structures, known as distal mobile framework. As discussed in earlier parts of this series, diversity in surgical anatomy results in different surgical techniques in Asian rhinoplasty compared to rhinoplasty in Caucasian patients. Nasal tip structures are especially important due to their crucial importance for changing the nasal shape in Asians. This article, along with the previous ones, will provide both basic and advanced knowledge of practical surgical anatomy for Asian rhinoplasty.

Principal network analysis: identification of subnetworks representing major dynamics using gene expression data.

MOTIVATION: Systems biology attempts to describe complex systems behaviors in terms of dynamic operations of biological networks. However, there is lack of tools that can effectively decode complex network dynamics over multiple conditions. RESULTS: We present principal network analysis (PNA) that can automatically capture major dynamic activation patterns over multiple conditions and then generate protein and metabolic subnetworks for the captured patterns. We first demonstrated the utility of this method by applying it to a synthetic dataset. The results showed that PNA correctly captured the subnetworks representing dynamics in the data. We further applied PNA to two time-course gene expression profiles collected from (i) MCF7 cells after treatments of HRG at multiple doses and (ii) brain samples of four strains of mice infected with two prion strains. The resulting subnetworks and their interactions revealed network dynamics associated with HRG dose-dependent regulation of cell proliferation and differentiation and early PrPSc accumulation during prion infection. AVAILABILITY: The web-based software is available at: http://sbm.postech.ac.kr/pna.

Integration analysis of quantitative proteomics and transcriptomics data identifies potential targets of frizzled-8 protein-related antiproliferative factor in vivo.

UNLABELLED: What's known on the subject? and What does the study add? Interstitial cystitis (IC) is a prevalent and debilitating pelvic disorder generally accompanied by chronic pain combined with chronic urinating problems. Over one million Americans are affected, especially middle-aged women. However, its aetiology or mechanism remains unclear. No efficient drug has been provided to patients. Several urinary biomarker candidates have been identified for IC; among the most promising is antiproliferative factor (APF), whose biological activity is detectable in urine specimens from >94% of patients with both ulcerative and non-ulcerative IC. The present study identified several important mediators of the effect of APF on bladder cell physiology, suggesting several candidate drug targets against IC. In an attempt to identify potential proteins and genes regulated by APF in vivo, and to possibly expand the APF-regulated network identified by stable isotope labelling by amino acids in cell culture (SILAC), we performed an integration analysis of our own SILAC data and the microarray data of Gamper et al. (2009) BMC Genomics 10: 199. Notably, two of the proteins (i.e. MAPKSP1 and GSPT1) that are down-regulated by APF are involved in the activation of mTORC1, suggesting that the mammalian target of rapamycin (mTOR) pathway is potentially a critical pathway regulated by APF in vivo. Several components of the mTOR pathway are currently being studied as potential therapeutic targets in other diseases. Our analysis suggests that this pathway might also be relevant in the design of diagnostic tools and medications targeting IC. OBJECTIVE: • To enhance our understanding of the interstitial cystitis urine biomarker antiproliferative factor (APF), as well as interstitial cystitis biology more generally at the systems level, we reanalyzed recently published large-scale quantitative proteomics and in vivo transcriptomics data sets using an integration analysis tool that we have developed. MATERIALS AND METHODS: • To identify more differentially expressed genes with a lower false discovery rate from a previously published microarray data set, an integrative hypothesis-testing statistical approach was applied. • For validation experiments, expression and phosphorylation levels of select proteins were evaluated by western blotting. RESULTS: • Integration analysis of this transcriptomics data set with our own quantitative proteomics data set identified 10 genes that are potentially regulated by APF in vivo from 4140 differentially expressed genes identified with a false discovery rate of 1%. • Of these, five (i.e. JUP, MAPKSP1, GSPT1, PTGS2/COX-2 and XPOT) were found to be prominent after network modelling of the common genes identified in the proteomics and microarray studies. • This molecular signature reflects the biological processes of cell adhesion, cell proliferation and inflammation, which is consistent with the known physiological effects of APF. • Lastly, we found the mammalian target of rapamycin pathway was down-regulated in response to APF. CONCLUSION: • This unbiased integration analysis of in vitro quantitative proteomics data with in vivo quantitative transcriptomics data led to the identification of potential downstream mediators of the APF signal transduction pathway.