Discovery of N-(1-(2-hydroxyethyl)quinolin-2-one)-N'-(1-phenyl-1H-pyrazol-5-yl)methyl) urea as Mode-Selective TRPV1 antagonist.

To discover mode-selective TRPV1 antagonists as thermoneutral drug candidates, the previous potent antagonist benzopyridone 2 was optimized based on the pharmacophore A- and C-regions. The structure activity relationship was investigated systematically by modifying the A-region by incorporating a polar side chain on the pyridone and then by changing the C-region with a variety of substituted pyridine and pyrazole moieties. The 3-t-butyl and 3-(1-methylcyclopropyl) pyrazole C-region analogs provided high potency as well as mode-selectivity. Among them, 51 and 54 displayed potent and capsaicin-selective antagonism with IC50 = 2.85 and 3.27 nM to capsaicin activation and 28.5 and 31.5 % inhibition at 3 µM concentration toward proton activation, respectively. The molecular modeling study of 51 with our homology model indicated that the hydroxyethyl side chain in the A-region interacted with Arg557 and Glu570, the urea B-region engaged in hydrogen bonding with Tyr511 and Thr550, respectively, and the pyrazole C-region made two hydrophobic interactions with the receptor. Optimization of antagonist 2, which has full antagonism for activators of all modes, lead to mode-selective antagonists 51 and 54. These observations will provide insight into the future development of clinical TRPV1 antagonists without target-based side effects.

Discovery of N-(1,4-Benzoxazin-3-one) urea analogs as Mode-Selective TRPV1 antagonists.

A series of 1,4-benzoxazin-3-one analogs were investigated to discover mode-selective TRPV1 antagonists, since such antagonists are predicted to minimize target-based adverse effects. Using the high-affinity antagonist 2 as the lead structure, the structure activity relationship was studied by modifying the A-region through incorporation of a polar side chain on the benzoxazine and then by changing the C-region with a variety of substituted pyridine, pyrazole and thiazole moieties. The t-butyl pyrazole and thiazole C-region analogs provided high potency as well as mode-selectivity. Among them, antagonist 36 displayed potent and capsaicin-selective antagonism with IC50 = 2.31 nM for blocking capsaicin activation and only 47.5 % inhibition at 3 µM concentration toward proton activation, indicating that more than a 1000-fold higher concentration of 36 was required to inhibit proton activation than was required to inhibit capsaicin activation. The molecular modeling study of 36 with our homology model indicated that two π-π interactions with the Tyr511 and Phe591 residues by the A- and C-region and hydrogen bonding with the Thr550 residue by the B-region were critical for maintaining balanced and stable binding. Systemic optimization of antagonist 2, which has high-affinity but full antagonism for activators of all modes, led to the mode-selective antagonist 36 which represents a promising step in the development of clinical TRPV1 antagonists minimizing side effects such as hyperthermia and impaired heat sensation.

Inhalable Nitric Oxide Delivery Systems for Pulmonary Arterial Hypertension Treatment.

Pulmonary arterial hypertension (PAH) is a severe medical condition characterized by elevated blood pressure in the pulmonary arteries. Nitric oxide (NO) is a gaseous signaling molecule with potent vasodilator effects; however, inhaled NO is limited in clinical practice because of the need for tracheal intubation and the toxicity of high NO concentrations. In this study, inhalable NO-releasing microspheres (NO inhalers) are fabricated to deliver nanomolar NO through a nebulizer. Two NO inhalers with distinct porous structures are prepared depending on the molecular weights of NO donors. It is confirmed that pore formation can be controlled by regulating the migration of water molecules from the external aqueous phase to the internal aqueous phase. Notably, open porous NO inhalers (OPNIs) can deliver NO deep into the lungs through a nebulizer. Furthermore, OPNIs exhibit vasodilatory and anti-inflammatory effects via sustained NO release. In conclusion, the findings suggest that OPNIs with highly porous structures have the potential to serve as tools for PAH treatment.

Transcriptome-based variant calling and aberrant mRNA discovery enhance diagnostic efficiency for neuromuscular diseases.

BACKGROUND: Whole-exome sequencing-based diagnosis of rare diseases typically yields 40%-50% of success rate. Precise diagnosis of the patients with neuromuscular disorders (NMDs) has been hampered by locus heterogeneity or phenotypic heterogeneity. We evaluated the utility of transcriptome sequencing as an independent approach in diagnosing NMDs. METHODS: The RNA sequencing (RNA-Seq) of muscle tissues from 117 Korean patients with suspected Mendelian NMD was performed to evaluate the ability to detect pathogenic variants. Aberrant splicing and CNVs were inspected to identify additional causal genetic factors for NMD. Aberrant splicing events in Dystrophin (DMD) were investigated by using antisense oligonucleotides (ASOs). A non-negative matrix factorisation analysis of the transcriptome data followed by cell type deconvolution was performed to cluster samples by expression-based signatures and identify cluster-specific gene ontologies. RESULTS: Our pipeline called 38.1% of pathogenic variants exclusively from the muscle transcriptomes, demonstrating a higher diagnostic rate than that achieved via exome analysis (34.9%). The discovery of variants causing aberrant splicing allowed the application of ASOs to the patient-derived cells, providing a therapeutic approach tailored to individual patients. RNA-Seq data further enabled sample clustering by distinct gene expression profiles that corresponded to clinical parameters, conferring additional advantages over exome sequencing. CONCLUSION: The RNA-Seq-based diagnosis of NMDs achieves an increased diagnostic rate and provided pathogenic status information, which is not easily accessible through exome analysis.

The lung microbiota in Korean patients with non-tuberculous mycobacterial pulmonary disease.

BACKGROUND: The microbiota of the lower respiratory tract in patients with non-tuberculous mycobacterial pulmonary disease (NTM-PD) has not been fully evaluated. We explored the role of the lung microbiota in NTM-PD by analyzing protected specimen brushing (PSB) and bronchial washing samples from patients with NTM-PD obtained using a flexible bronchoscope. RESULTS: Bronchial washing and PSB samples from the NTM-PD group tended to have fewer OTUs and lower Chao1 richness values compared with those from the control group. In both bronchial washing and PSB samples, beta diversity was significantly lower in the NTM-PD group than in the control group (P = 2.25E-6 and P = 4.13E-4, respectively). Principal component analysis showed that the PSBs and bronchial washings exhibited similar patterns within each group but differed between the two groups. The volcano plots indicated differences in several phyla and genera between the two groups. CONCLUSIONS: The lower respiratory tract of patients with NTM-PD has a unique microbiota distribution that is low in richness/diversity.

Fast Healthcare Interoperability Resources (FHIR)-Based Quality Information Exchange for Clinical Next-Generation Sequencing Genomic Testing: Implementation Study.

BACKGROUND: Next-generation sequencing (NGS) technology has been rapidly adopted in clinical practice, with the scope extended to early diagnosis, disease classification, and treatment planning. As the number of requests for NGS genomic testing increases, substantial efforts have been made to deliver the testing results clearly and unambiguously. For the legitimacy of clinical NGS genomic testing, quality information from the process of producing genomic data should be included within the results. However, most reports provide insufficient quality information to confirm the reliability of genomic testing owing to the complexity of the NGS process. OBJECTIVE: The goal of this study was to develop a Fast Healthcare Interoperability Resources (FHIR)-based web app, NGS Quality Reporting (NGS-QR), to report and manage the quality of the information obtained from clinical NGS genomic tests. METHODS: We defined data elements for the exchange of quality information from clinical NGS genomic tests, and profiled a FHIR genomic resource to enable information exchange in a standardized format. We then developed the FHIR-based web app and FHIR server to exchange quality information, along with statistical analysis tools implemented with the R Shiny server. RESULTS: Approximately 1000 experimental data entries collected from the targeted sequencing pipeline CancerSCAN designed by Samsung Medical Center were used to validate implementation of the NGS-QR app using real-world data. The user can share the quality information of NGS genomic testing and verify the quality status of individual samples in the overall distribution. CONCLUSIONS: This study successfully demonstrated how quality information of clinical NGS genomic testing can be exchanged in a standardized format. As the demand for NGS genomic testing in clinical settings increases and genomic data accumulate, quality information can be used as reference material to improve the quality of testing. This app could also motivate laboratories to perform diagnostic tests to provide high-quality genomic data.

KEDDY: a knowledge-based statistical gene set test method to detect differential functional protein-protein interactions.

MOTIVATION: Identifying differential patterns between conditions is a popular approach to understanding the discrepancy between different biological contexts. Although many statistical tests were proposed for identifying gene sets with differential patterns based on different definitions of differentiality, few methods were suggested to identify gene sets with differential functional protein networks due to computational complexity. RESULTS: We propose a method of Knowledge-based Evaluation of Dependency DifferentialitY (KEDDY), which is a statistical test for differential functional protein networks of a set of genes between two conditions with utilizing known functional protein-protein interaction information. Unlike other approaches focused on differential expressions of individual genes or differentiality of individual interactions, KEDDY compares two conditions by evaluating the probability distributions of functional protein networks based on known functional protein-protein interactions. The method has been evaluated and compared with previous methods through simulation studies, where KEDDY achieves significantly improved performance in accuracy and speed than the previous method that does not use prior knowledge and better performance in identifying gene sets with differential interactions than other methods evaluating changes in gene expressions. Applications to cancer data sets show that KEDDY identifies alternative cancer subtype-related differential gene sets compared to other differential expression-based methods, and the results also provide detailed gene regulatory information that drives the differentiality of the gene sets. AVAILABILITY AND IMPLEMENTATION: The Java implementation of KEDDY is freely available to non-commercial users at https://sites.google.com/site/sjunggsm/keddy. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The association of socioeconomic and clinical characteristics with health-related quality of life in patients with psoriasis: a cross-sectional study.

BACKGROUND: This study aimed to determine the socioeconomic and clinical characteristics affecting health-related quality of life (HRQoL) in patients with psoriasis. METHODS: A cross-sectional study was conducted between March and June 2015 using data obtained via an Internet-based survey completed by a psoriasis patient group in Korea. The survey included items regarding demographic, socioeconomic, and clinical characteristics and HRQoL. Patients' HRQoL impairment was classified as severe if their Dermatology Life Quality Index Scores were ≥ 11. Factors influencing HRQoL impairment were identified using multivariate logistic regression analysis. RESULTS: Of the 299 respondents, 161 (53.8%) exhibited severe HRQoL impairment. The Dermatology Life Quality Index scores were significantly associated with gender, annual income, neck psoriasis, psoriasis-related resignation from work, and use of oral and herbal medications. The severity of HRQoL impairment in women was twice that observed in men (odds ratio [OR] = 2.00, 95% confidence interval (CI): 1.05-3.80). Patients with psoriasis on the neck exhibited significantly greater HRQoL impairment than those with psoriasis on other areas of their bodies (OR = 2.30, 95% CI: 1.20-4.43). With respect to the socioeconomic status, patients who earned > 40 million KRW (approximately 34,000 USD; high-income group) showed less HRQoL impairment compared with those who had lower incomes (OR = 0.47, 95% CI: 0.28-0.80). Patients with severe HRQoL impairment used oral (OR = 2.04, 95% CI: 1.20-3.44) and herbal (OR = 1.86, 95% CI: 1.04-3.34) medications more often relative to patients with less severe HRQoL impairment. CONCLUSIONS: HRQoL in patients with psoriasis was significantly associated with their demographic and socioeconomic characteristics and employment status. The presence of psoriasis on exposed areas of the body was significantly associated with patients' HRQoL and employment status. Further research is required to evaluate the impact of psoriasis on patients' productivity.

Quadrant-Based Minimum Bounding Rectangle-Tree Indexing Method for Similarity Queries over Big Spatial Data in HBase.

With the rapid development of mobile devices and sensors, effective searching methods for big spatial data have recently received a significant amount of attention. Owing to their large size, many applications typically store recently generated spatial data in NoSQL databases such as HBase. As the index of HBase only supports a one-dimensional row keys, the spatial data is commonly enumerated using linearization techniques. However, the linearization techniques cannot completely guarantee the spatial proximity of data. Therefore, several studies have attempted to reduce false positives in spatial query processing by implementing a multi-dimensional indexing layer. In this paper, we propose a hierarchical indexing structure called a quadrant-based minimum bounding rectangle (QbMBR) tree for effective spatial query processing in HBase. In our method, spatial objects are grouped more precisely by using QbMBR and are indexed based on QbMBR. The QbMBR tree not only provides more selective query processing, but also reduces the storage space required for indexing. Based on the QbMBR tree index, two query-processing algorithms for range query and kNN query are also proposed in this paper. The algorithms significantly reduce query execution times by prefetching the necessary index nodes into memory while traversing the QbMBR tree. Experimental analysis demonstrates that our method significantly outperforms existing methods.

EDDY: a novel statistical gene set test method to detect differential genetic dependencies.

Identifying differential features between conditions is a popular approach to understanding molecular features and their mechanisms underlying a biological process of particular interest. Although many tests for identifying differential expression of gene or gene sets have been proposed, there was limited success in developing methods for differential interactions of genes between conditions because of its computational complexity. We present a method for Evaluation of Dependency DifferentialitY (EDDY), which is a statistical test for differential dependencies of a set of genes between two conditions. Unlike previous methods focused on differential expression of individual genes or correlation changes of individual gene-gene interactions, EDDY compares two conditions by evaluating the probability distributions of dependency networks from genes. The method has been evaluated and compared with other methods through simulation studies, and application to glioblastoma multiforme data resulted in informative cancer and glioblastoma multiforme subtype-related findings. The comparison with Gene Set Enrichment Analysis, a differential expression-based method, revealed that EDDY identifies the gene sets that are complementary to those identified by Gene Set Enrichment Analysis. EDDY also showed much lower false positives than Gene Set Co-expression Analysis, a method based on correlation changes of individual gene-gene interactions, thus providing more informative results. The Java implementation of the algorithm is freely available to noncommercial users. Download from: http://biocomputing.tgen.org/software/EDDY.

In-silico interaction-resolution pathway activity quantification and application to identifying cancer subtypes.

BACKGROUND: Identifying subtypes of complex diseases such as cancer is the very first step toward developing highly customized therapeutics on such diseases, as their origins significantly vary even with similar physiological characteristics. There have been many studies to recognize subtypes of various cancer based on genomic signatures, and most of them rely on approaches based on the signatures or features developed from individual genes. However, the idea of network-driven activities of biological functions has gained a lot of interests, as more evidence is found that biological systems can show highly diverse activity patterns because genes can interact differentially across specific molecular contexts. METHODS: In this study, we proposed an in-silico method to quantify pathway activities with a resolution of genetic interactions for individual samples, and developed a method to compute the discrepancy between samples based on the quantified pathway activities. RESULTS: By using the proposed discrepancy measure between sample pathway activities in clustering melanoma gene expression data, we identified two potential subtypes of melanoma with distinguished pathway activities, where the two groups of patients showed significantly different survival patterns. We also investigated selected pathways with distinguished activity patterns between the two groups, and the result suggests hypotheses on the mechanisms driving the two potential subtypes. CONCLUSIONS: By using the proposed approach of modeling pathway activities with a resolution of genetic interactions, potential novel subtypes of disease were proposed with accompanying hypotheses on subtype-specific genetic interaction information.

Fatal Graft-Versus-Host Disease Following Adult-To-Adult Living Donor Liver Transplantation From an HLA Nonhomozygous Donor.

The use of a human leukocyte antigen (HLA) homozygous donor to a haploidentical recipient is a well-documented cause of transfusion-associated graft-versus-host disease (GVHD). Several authors have reported that use of a graft from an HLA-homozygous donor with 1-way donor-recipient HLA matching led to an extremely high risk of developing GVHD in LDLT. We have experienced a fatal case of acute GVHD following adult-to-adult LDLT from a donor who was heterozygous at a single HLA locus. A 53-year-old female underwent LDLT for chronic hepatitis B and recurrent hepatocellular carcinoma. The donor was her 23-year-old son. The HLA phenotype of the donor was not homozygous (A24, -; B54, -; DR4, 9) and revealed one-way donor-dominant HLA matching at two loci with the recipient (A2, 24; B48, 54; DR4, 12). On the fortieth postoperative day, the patient showed erythematous skin lesions. Skin biopsy revealed typical findings of GVHD. Donor-derived chimerism was demonstrated by performing fluorescent in situ hybridization (FISH) using the recipient's skin tissue. As the clinical course deteriorated, etanercept was started in addition to broad-spectrum antibiotics but there was no improvement. As multi-organ failure progressed, the patient succumbed to death on the 54th postoperative day, which was 2 weeks after onset of GVHD. The prevention of GVHD is more important since the results of treatment have been disappointing. We have experienced a fatal case of acute GVHD following adult-to-adult LDLT from a HLA non-homozygous donor. HLA heterozygosity at a single locus does not preclude the possibility of developing GVHD following adult-to-adult LDLT.

Uncovering the biology of multiple myeloma among African Americans: a comprehensive genomics approach.

Epidemiological data have suggested that African American (AA) persons are twice as likely to be diagnosed with multiple myeloma (MM) compared with European American (EA) persons. Here, we have analyzed a set of cytogenetic and genomic data derived from AA and EA MM patients. We have compared the frequency of IgH translocations in a series of data from 115 AA patients from 3 studies and 353 EA patients from the Eastern Cooperative Oncology Group (ECOG) studies E4A03 and E9487. We have also interrogated tumors from 45 AA and 196 EA MM patients for somatic copy number abnormalities associated with poor outcome. In addition, 35 AA and 178 EA patients were investigated for a transcriptional profile associated with high-risk disease. Overall, based on this cohort, genetic profiles were similar except for a significantly lower frequency of IgH translocations (40% vs 52%; P = .032) in AA patients. Frequency differences of somatic copy number aberrations were not significant after correction for multiple testing. There was also no significant difference in the frequency of high-risk disease based on gene expression profiling. Our study represents the first comprehensive comparisons of the frequency and distribution of molecular alterations in MM tumors between AA and EA patients. ECOG E4A03 is registered with ClinicalTrials.gov, number NCT00098475. ECOG E9487 is a companion validation set to the ECOG study E9486 and is registered with the National Institutes of Health, National Cancer Institute, Clinical Trials (PDQ), number EST-9486.

Transenteral bowel preparation for colonoscopy is more comfortable than the traditional method with no inferiority in efficacy.

BACKGROUND: Transenteral (TE) administration of a bowel cleanser prior to colonoscopy avoids the discomfort associated with drinking a large volume of unpalatable cleanser. AIM: To explore patient comfort, preference for future colonoscopy, the efficacy and adverse events associated with TE bowel preparation. METHODS: Bowel preparation is traditionally practised using polyethylene glycol (PEG) + ascorbic acid (ASC), which was the treatment used in the control group (peroral group; PO group). In the study group (TE group), PEG + ASC were administered directly to the third portion of the duodenum through a scope immediately after completing upper gastrointestinal endoscopy. RESULTS: A higher proportion of subjects in the TE group graded their degree of comfort as very or rather comfortable (28.4 % in the PO group, 65.1 % in the TE group; p = 0.000) and had greater preference for future colonoscopy (69.6 % in the PO group, 82.5 % in the TE group; p = 0.030), compared with the PO group. The TE group had non-inferiority in efficacy compared with the PO group (non-inferiority margin -15 %; lower limit of 95 % confidence interval for difference between success rates -6.4 %, when using the Aronchick Scale, and -7.1 % when using the Ottawa Scale). Nausea or vomiting were more prevalent during preparation in the PO group (46.1 vs. 17.5 %; p = 0.000), and dizziness was more common in the TE group (0 vs. 12.6 %; p = 0.000). CONCLUSIONS: TE preparation was found to be more comfortable than the traditional peroral method and not inferior in efficacy. The adverse events rate was acceptable.

Infliximab partially alleviates the bite force reduction in a mouse model of temporomandibular joint pain.

Temporomandibular joint (TMJ) disorder is clinically important because of its prevalence, chronicity, and therapy-refractoriness of the pain. In this study, we investigated the effect of infliximab in a mouse model of TMJ pain using a specially-engineered transducer for evaluating the changes in bite force (BF). The mice were randomly divided into three groups (7 mice per group): the control group, the complete Freund's adjuvant (CFA) group, and the infliximab group. BF was measured at day 0 (baseline BF). After measuring the baseline BF, CFA or incomplete Freund's adjuvant was injected into both TMJs and then the changes in BF were measured at days 1, 3, 5, 7, 9, and 13 after the TMJ injection. For measuring the BF, we used a custom-built BF transducer. Control, CFA, and infliximab groups showed similar baseline BF at day 0. From day 1, a significant reduction in BF was observed in the CFA group, and this reduction in BF was statistically significant compared to that in the control group (P < 0.05). This reduction in BF was maintained until day 7, and BF started to recover gradually from day 9. In the infliximab group also, the reduction in BF was observed on day 1, and this reduction was maintained until day 7. However, the degree of reduction in BF was less remarkable compared to that in the CFA group. The reduction in BF caused by injection of CFA into the TMJ could be partially alleviated by the injection of anti-tumor necrosis factor alpha, infliximab.

Efficacy and safety of selegiline transdermal system (STS) for the atypical subtype of major depressive disorder: pooled analysis of 5 short-term, placebo-controlled trials.

OBJECTIVE: The objective of the present study is to investigate the efficacy and safety of the selegiline transdermal system (STS) in major depressive disorder (MDD) with atypical features. METHODS: This was a post-hoc analysis of 5 short-term trials. The atypical subtype was defined as the presence of at least 1 item with a score of 2 or greater from items 22-26 on the 28-item Hamilton Depression Rating Scale (HAMD-28), and a maximum score of 1 point for items 6 (insomnia late), 12 (somatic symptoms, gastrointestinal), and 16 (loss of weight) to exclude vegetative features of melancholic depression. The mean changes of HAMD-28 total score from baseline to the endpoint (response rate defined as ≥50% reduction in HAMD-28 scores and remission rate defined as ≤10 HAMD-28 total score at the treatment endpoint) were compared between atypical and nonatypical groups. RESULTS: In this analysis, 352 subjects (STS = 168 vs placebo = 184) met the definition of atypical subtype at baseline. STS (n = 641) significantly decreased HAMD-28 total score compared with placebo (n = 648) from beginning to end of treatment (-10.7 ± 9.3 vs -9.4 ± 9.3; p = 0.014). STS showed comparable efficacy in patients with the atypical subtype compared with the nonatypical subtype for placebo-subtracted mean change in HAMD-28 total score (-2.11 ± 1.01 vs. -1.0 ± 0.60; p = 0.34), odds ratio (OR) for response (1.41 vs 1.23, p = 0.62), and OR for remission (1.77 vs 1.18, p = 0.22). CONCLUSION: STS appears to be comparably efficacious and tolerable in atypical and nonatypical subtypes of MDD. Adequately powered, controlled, clinical trials are necessary to confirm our findings.

Robotic versus laparoscopic liver resection: a comparative study from a single center.

PURPOSE: The significant advantages of robotic surgery have expanded the scope of surgical procedures that can be performed through minimally invasive techniques. The aim of this study was to compare the perioperative outcomes between robotic and laparoscopic liver surgeries at a single center. METHODS: From July 2007 to October 2011, a total of 206 patients underwent laparoscopic or robotic liver surgery at the Asan Medical Center, Seoul, Korea. We compared the surgical outcomes between robotic liver surgery and laparoscopic liver surgery during the same period. Only patients who underwent left hemihepatectomy or left lateral sectionectomy were included in this study. RESULTS: The robotic group consisted of 13 patients who underwent robotic liver resection including 10 left lateral sectionectomies and three left hemihepatectomies. The laparoscopic group consisted of 17 patients who underwent laparoscopic liver resection during the same period including six left lateral sectionectomies and 11 left hemihepatectomies. The groups were similar with regard to age, gender, tumor type, and tumor size. There were no significant differences in perioperative outcome such as operative time, intraoperative blood loss, postoperative liver function tests, complication rate, and hospital stay between robotic liver resection and laparoscopic liver resection. However, the medical cost was higher in the robotic group. CONCLUSIONS: Robotic liver resection is a safe and feasible option for liver resection in experienced hands. The authors suggest that since the robotic surgical system provides sophisticated advantages, the retrenchment of medical cost for the robotic system in addition to refining its liver transection tool may substantially increase its application in clinical practice in the near future.

Effectiveness and Tolerability of Combination Pharmacotherapy With Stimulant and Non-Stimulant in Children With Attention Deficit Hyperactivity Disorder.

Objectives: This study aimed to investigate the effectiveness and safety of combining psychostimulants and nonstimulants for patients under treatment for attention deficit hyperactivity disorder (ADHD). Methods: The study included 96 patients aged 6-12 years who were diagnosed with ADHD, among whom 34 received combination pharmacotherapy, 32 received methylphenidate monotherapy, and 30 received atomoxetine monotherapy. Statistical analysis was conducted to compare treatment and adverse effects among groups and to analyze changes before and after combination pharmacotherapy. The difference between combination pharmacotherapy and monotherapy was investigated. Logistic regression analysis was used to identify the predictors of combination pharmacotherapy. Results: No significant differences were observed between the groups in terms of age or pretreatment scores. The most common adverse effect experienced by 32% of patients in the combination pharmacotherapy group was decreased appetite. Clinical global impression- severity score decreased significantly after combination pharmacotherapy. All three groups showed significant clinical global impression- severity score improvements over time, with no significant differences among them. The predictive factors for combination pharmacotherapy included the Child Behavior Checklist total score internalizing subscale. Conclusion: Combination pharmacotherapy with methylphenidate and atomoxetine is a relatively effective and safe option for patients with ADHD who do not respond to monotherapy.

Learning contextual gene set interaction networks of cancer with condition specificity.

BACKGROUND: Identifying similarities and differences in the molecular constitutions of various types of cancer is one of the key challenges in cancer research. The appearances of a cancer depend on complex molecular interactions, including gene regulatory networks and gene-environment interactions. This complexity makes it challenging to decipher the molecular origin of the cancer. In recent years, many studies reported methods to uncover heterogeneous depictions of complex cancers, which are often categorized into different subtypes. The challenge is to identify diverse molecular contexts within a cancer, to relate them to different subtypes, and to learn underlying molecular interactions specific to molecular contexts so that we can recommend context-specific treatment to patients. RESULTS: In this study, we describe a novel method to discern molecular interactions specific to certain molecular contexts. Unlike conventional approaches to build modular networks of individual genes, our focus is to identify cancer-generic and subtype-specific interactions between contextual gene sets, of which each gene set share coherent transcriptional patterns across a subset of samples, termed contextual gene set. We then apply a novel formulation for quantitating the effect of the samples from each subtype on the calculated strength of interactions observed. Two cancer data sets were analyzed to support the validity of condition-specificity of identified interactions. When compared to an existing approach, the proposed method was much more sensitive in identifying condition-specific interactions even in heterogeneous data set. The results also revealed that network components specific to different types of cancer are related to different biological functions than cancer-generic network components. We found not only the results that are consistent with previous studies, but also new hypotheses on the biological mechanisms specific to certain cancer types that warrant further investigations. CONCLUSIONS: The analysis on the contextual gene sets and characterization of networks of interaction composed of these sets discovered distinct functional differences underlying various types of cancer. The results show that our method successfully reveals many subtype-specific regions in the identified maps of biological contexts, which well represent biological functions that can be connected to specific subtypes.

Impact of childhood adversity on the course and suicidality of depressive disorders: the CRESCEND study.

OBJECTIVE: The impact of childhood adversity persists across the life course. This study aimed to investigate the associations of childhood adversity with the course, suicidality, and treatment outcomes of depressive disorders. METHOD: A total of 919 people with depressive disorders were recruited. Childhood adversities (≤12 years old) were ascertained using a checklist, in sexual abuse, physical abuse by parents, and separation of parents. Various assessment scales were administered at baseline and over 12 weeks of antidepressants treatment. RESULTS: All three forms of childhood adversity were associated with an increased likelihood of experiencing more current stressful events. Scores on the Beck Depression Inventory and Hamilton Anxiety Rating Scale were significantly higher in participants with a history of sexual abuse. Scores on the Beck Depression Inventory, Hamilton Depression Rating Scale, and Perceived Stress Scale were significantly higher, and scores on the WHO Quality of life instrument were significantly lower in participants with a history of physical abuse by parents. They were more likely to receive augmentation and combination treatment after the initial antidepressant treatment, whereas overall response rates to treatment did not differ. Scores on the Beck Scale for suicide ideation were significantly higher after treatment and/or at baseline in patients with sexual or physical abuse. Physical illness was more prevalent in individuals with physical abuse by parents or separation of parents. CONCLUSIONS: Depressive patients with a history of childhood adversities had more severe and chronic forms of depression with high suicidality. More intensive treatment with particular clinical attention is indicated for this special population.