Hypermethylation of ACADVL is involved in the high-intensity interval training-associated reduction of cardiac fibrosis in heart failure patients.

BACKGROUND: Emerging evidence suggests that DNA methylation can be affected by physical activities and is associated with cardiac fibrosis. This translational research examined the implications of DNA methylation associated with the high-intensity interval training (HIIT) effects on cardiac fibrosis in patients with heart failure (HF). METHODS: Twelve HF patients were included and received cardiovascular magnetic resonance imaging with late gadolinium enhancement for cardiac fibrosis severity and a cardiopulmonary exercise test for peak oxygen consumption ([Formula: see text]O2peak). Afterwards, they underwent 36 sessions of HIIT at alternating 80% and 40% of [Formula: see text]O2peak for 30 min per session in 3-4 months. Human serum from 11 participants, as a means to link cell biology to clinical presentations, was used to investigate the exercise effects on cardiac fibrosis. Primary human cardiac fibroblasts (HCFs) were incubated in patient serum, and analyses of cell behaviour, proteomics (n = 6) and DNA methylation profiling (n = 3) were performed. All measurements were conducted after completing HIIT. RESULTS: A significant increase (p = 0.009) in [Formula: see text]O2peak (pre- vs. post-HIIT = 19.0 ± 1.1 O2 ml/kg/min vs. 21.8 ± 1.1 O2 ml/kg/min) was observed after HIIT. The exercise strategy resulted in a significant decrease in left ventricle (LV) volume by 15% to 40% (p < 0.05) and a significant increase in LV ejection fraction by approximately 30% (p = 0.010). LV myocardial fibrosis significantly decreased from 30.9 ± 1.2% to 27.2 ± 0.8% (p = 0.013) and from 33.4 ± 1.6% to 30.1 ± 1.6% (p = 0.021) in the middle and apical LV myocardium after HIIT, respectively. The mean single-cell migration speed was significantly (p = 0.044) greater for HCFs treated with patient serum before (2.15 ± 0.17 µm/min) than after (1.11 ± 0.12 µm/min) HIIT. Forty-three of 1222 identified proteins were significantly involved in HIIT-induced altered HCF activities. There was significant (p = 0.044) hypermethylation of the acyl-CoA dehydrogenase very long chain (ACADVL) gene with a 4.474-fold increase after HIIT, which could activate downstream caspase-mediated actin disassembly and the cell death pathway. CONCLUSIONS: Human investigation has shown that HIIT is associated with reduced cardiac fibrosis in HF patients. Hypermethylation of ACADVL after HIIT may contribute to impeding HCF activities. This exercise-associated epigenetic reprogramming may contribute to reduce cardiac fibrosis and promote cardiorespiratory fitness in HF patients. TRIAL REGISTRATION: NCT04038723. Registered 31 July 2019, https://clinicaltrials.gov/ct2/show/NCT04038723 .

A Positive Regulatory Feedback Loop between EKLF/KLF1 and TAL1/SCL Sustaining the Erythropoiesis.

The erythroid Krüppel-like factor EKLF/KLF1 is a hematopoietic transcription factor binding to the CACCC DNA motif and participating in the regulation of erythroid differentiation. With combined use of microarray-based gene expression profiling and the promoter-based ChIP-chip assay of E14.5 fetal liver cells from wild type (WT) and EKLF-knockout (Eklf-/-) mouse embryos, we identified the pathways and direct target genes activated or repressed by EKLF. This genome-wide study together with the molecular/cellular analysis of the mouse erythroleukemic cells (MEL) indicate that among the downstream direct target genes of EKLF is Tal1/Scl. Tal1/Scl encodes another DNA-binding hematopoietic transcription factor TAL1/SCL, known to be an Eklf activator and essential for definitive erythroid differentiation. Further identification of the authentic Tal gene promoter in combination with the in vivo genomic footprinting approach and DNA reporter assay demonstrate that EKLF activates the Tal gene through binding to a specific CACCC motif located in its promoter. These data establish the existence of a previously unknow positive regulatory feedback loop between two DNA-binding hematopoietic transcription factors, which sustains mammalian erythropoiesis.

Meta-analytic framework for liquid association.

MOTIVATION: Although coexpression analysis via pair-wise expression correlation is popularly used to elucidate gene-gene interactions at the whole-genome scale, many complicated multi-gene regulations require more advanced detection methods. Liquid association (LA) is a powerful tool to detect the dynamic correlation of two gene variables depending on the expression level of a third variable (LA scouting gene). LA detection from single transcriptomic study, however, is often unstable and not generalizable due to cohort bias, biological variation and limited sample size. With the rapid development of microarray and NGS technology, LA analysis combining multiple gene expression studies can provide more accurate and stable results. RESULTS: In this article, we proposed two meta-analytic approaches for LA analysis (MetaLA and MetaMLA) to combine multiple transcriptomic studies. To compensate demanding computing, we also proposed a two-step fast screening algorithm for more efficient genome-wide screening: bootstrap filtering and sign filtering. We applied the methods to five Saccharomyces cerevisiae datasets related to environmental changes. The fast screening algorithm reduced 98% of running time. When compared with single study analysis, MetaLA and MetaMLA provided stronger detection signal and more consistent and stable results. The top triplets are highly enriched in fundamental biological processes related to environmental changes. Our method can help biologists understand underlying regulatory mechanisms under different environmental exposure or disease states. AVAILABILITY AND IMPLEMENTATION: A MetaLA R package, data and code for this article are available at http://tsenglab.biostat.pitt.edu/software.htm. CONTACT: ctseng@pitt.edu. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The human C-type lectin 18 is a potential biomarker in patients with chronic hepatitis B virus infection.

BACKGROUND: Hepatitis B virus (HBV) infection is a common disease worldwide and is known to cause liver disease. C-type lectin 18 (CLEC18) is a novel secretory lectin highly expressed in human hepatocytes. Because the liver is the major target of HBV infection, we investigated whether the expression of CLEC18 can be used as a biomarker for HBV infection. METHODS: The expression level of CLEC18 in human liver chimeric mice with/without HBV infection was measured by quantitative real time polymerase chain reaction (qPCR) assay. Baseline plasma CLEC18 levels in 271 treatment-naive patients with chronic hepatitis B (CHB) undergoing nucleos(t)ide analogue (NUC) therapy and 35 healthy donors were measured by enzyme-linked immunosorbent assay, and the relationships to other clinical data were analyzed. RESULTS: The expression of CLEC18 was down-regulated in the human liver chimeric mice after HBV infection. Plasma CLEC18 levels were lower in the patients with CHB compared to the healthy donors and positively correlated with HBV DNA and HBsAg levels (P <  0.05). Multivariate Cox proportional hazard regression analysis identified a baseline plasma CLEC18 level of 320-2000 pg/mL to be an independent predictor of HBeAg loss (hazard ratio (HR): 2.077, P = 0.0318), seroconversion (HR: 2.041, P = 0.0445) and virological response (HR: 1.850, P = 0.0184) in 101 HBeAg-positive patients with CHB undergoing NUC therapy. CONCLUSIONS: Plasma CLEC18 levels were correlated with the stage of HBV infection and could predict HBeAg loss and seroconversion in the patients with CHB undergoing NUC therapy.

Serum Glutamine Levels as a Potential Diagnostic Biomarker in Sepsis following Surgery for Peritonitis.

Few diagnostic biomarkers for sepsis after emergency peritonitis surgery are available to clinicians, and, thus, it is important to develop new biomarkers for patients undergoing this procedure. We investigated whether serum glutamine and selenium levels could be diagnostic biomarkers of sepsis in individuals recovering from emergency peritonitis surgery. From February 2012 to March 2013, patients who had peritonitis diagnosed at the emergency department and underwent emergency surgery were screened for eligibility. Serum glutamine and selenium levels were obtained at pre-operative, post-operative and recovery time points. The average level of pre-operation serum glutamine was significantly different from that on the recovery day (0.317 ± 0.168 vs. 0.532 ± 0.155 mM, P < 0.001); moreover, serum glutamine levels were unaffected by surgery. Selenium levels were significantly lower on the day of surgery than they were at recovery (106.6 ± 36.39 vs. 130.68 ± 56.98 ng/mL, P = 0.013); no significant difference was found between pre-operation and recovery selenium levels. Unlike selenium, glutamine could be a sepsis biomarker for individuals with peritonitis. We recommend including glutamine as a biomarker for sepsis severity assessment in addition to the commonly used clinical indicators.

Risk of Mortality Among Patients Treated With Antipsychotic Medications: A Nationwide Population-Based Study in Taiwan.

In this nationwide population-based study, we examined whether haloperidol exposure is associated with a higher risk of mortality than are other antipsychotic medications. Patients who newly received monotherapy with chlorpromazine (n = 2133), haloperidol (n = 4454), quetiapine (n = 1513), and risperidone (n = 1046) between January 1, 2001, and December 31, 2011, were selected from a random sample of the 1 million enrollees of the Taiwan National Health Insurance Research Database. The association between antipsychotic prescription and mortality was estimated through Cox proportional hazard regression. To examine the mortality rates of antipsychotics at different exposure durations, we compared the differences among short-term (≤30 days), midterm (31-90 days), and long-term (>90 days) antipsychotic use. The mortality rates during the follow-up among the chlorpromazine, haloperidol, quetiapine, and risperidone groups were 17.4%, 45.5%, 26.8%, and 25.9%, respectively. The mortality risk among patients receiving haloperidol was the highest within 30 days of the prescription, after which the risk reduced rapidly. Compared with the patients receiving chlorpromazine, the mortality risk was higher in short-term (adjusted hazard ratio, 2.11; 95% confidence interval, 1.87-2.39) and midterm haloperidol users (1.86; 1.54-2.25) than in long-term users (0.99; 0.61-1.61). In conclusion, haloperidol use is associated with higher mortality risk than other antipsychotic medications. The mortality risk varies according to the duration of drug exposure. Underlying characteristics and medical conditions may influence the estimation of the mortality risk. Clinicians should pay attention to the mortality risk when prescribing antipsychotic medications, particularly for the elderly and critically ill patients.

Impact of negative media publicity on attention-deficit/hyperactivity disorder medication in Taiwan.

PURPOSE: This study explores trends in attention-deficit/hyperactivity disorder (ADHD) medications in Taiwan from 2000 to 2011 and whether negative media coverage of Ritalin in January 2010 impacted ADHD prescriptions throughout the country. METHOD: Patients throughout Taiwan who had been newly diagnosed with ADHD (n = 145,269) between January 2000 and December 2011 were selected from Taiwan's National Health Insurance database as subjects for this study. We analyzed monthly and yearly data on person-days of treatment with immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulation of methylphenidate (OROS-MPH), and atomoxetine (ATX) using linear models of curve estimation and the time series expert modeler. RESULTS: Of our sample, 57.8%, 28.9%, and 4.3% had been prescribed one or more doses of IR-MPH, OROS-MPH, or ATX, respectively. The annual person-days of IR-MPH use increased regularly from 2000 to 2009, dropped abruptly in 2010, and then increased again the next year. Furthermore, the person-days of OROS-MPH prescriptions did not reach their expected goal in 2010; however, the person-days of ATX prescriptions have increased constantly since entering the market in 2007. Compared with patients newly diagnosed with ADHD in 2009, those newly diagnosed in 2010 were less likely to be treated with medication. CONCLUSION: These findings suggest that negative publicity affected the writing of stimulant prescriptions for ADHD patients throughout Taiwan. Media reporting has a vital role in influencing children with ADHD, their parents, and their willingness to accept pharmacotherapy as treatment.

Shisa3 is associated with prolonged survival through promoting ß-catenin degradation in lung cancer.

RATIONALE: Despite advances in treatment and prognosis of non-small cell lung cancer (NSCLC), patient outcomes are still unsatisfactory. OBJECTIVES: To reduce the morbidity and mortality of patients with NSCLC, a more comprehensive understanding of mechanisms involved in cancer progression is urgently needed. METHODS: By comparison of gene expression profiles in the cell line pair with differential invasion ability, CL1-0 and CL1-5, we found that Shisa3 was highly expressed in the low invasive cells. The effect of Shisa3 on invasion, migration, proliferation, apoptosis, epithelial-mesenchymal transition, and anchorage-independent growth activities in vitro and on tumor growth and metastasis in mice models were examined. The underlying mechanism of Shisa3 was explored by microarray and pathway analysis. Finally, the correlation of Shisa3 expression and clinical outcome was also calculated. MEASUREMENTS AND MAIN RESULTS: We identified Shisa3 as a novel tumor suppressor, which induces ß-catenin degradation resulting in suppression of tumorigenesis and invasion in vitro. Shisa3 decreased the tumor growth in mice with subcutaneous implantation and reduced the number of metastatic nodules in mice with tail vein injection and orthotopic implantation. Shisa3 performs the tumor suppression activity through WNT signaling predicted by microarray analysis. Our data found that Shisa3 accelerates ß-catenin degradation and was positively associated with overall survival and progression-free survival of NSCLC. CONCLUSIONS: Our results reveal that Shisa3 acts as a tumor suppressor by acceleration of ß-catenin degradation and provide new insight for cancer prognosis and therapy.

Human protein-protein interaction prediction by a novel sequence-based co-evolution method: co-evolutionary divergence.

MOTIVATION: Protein-protein interaction (PPI) plays an important role in understanding gene functions, and many computational PPI prediction methods have been proposed in recent years. Despite the extensive efforts, PPI prediction still has much room to improve. Sequence-based co-evolution methods include the substitution rate method and the mirror tree method, which compare sequence substitution rates and topological similarity of phylogenetic trees, respectively. Although they have been used to predict PPI in species with small genomes like Escherichia coli, such methods have not been tested in large scale proteome like Homo sapiens. RESULT: In this study, we propose a novel sequence-based co-evolution method, co-evolutionary divergence (CD), for human PPI prediction. Built on the basic assumption that protein pairs with similar substitution rates are likely to interact with each other, the CD method converts the evolutionary information from 14 species of vertebrates into likelihood ratios and combined them together to infer PPI. We showed that the CD method outperformed the mirror tree method in three independent human PPI datasets by a large margin. With the arrival of more species genome information generated by next generation sequencing, the performance of the CD method can be further improved. AVAILABILITY: Source code and support are available at http://mib.stat.sinica.edu.tw/LAP/tmp/CD.rar.

Focal amplification of HOXD-harboring chromosome region is implicated in multiple-walled carbon nanotubes-induced carcinogenicity.

Multiple-walled carbon nanotubes (MWCNTs) may cause carcinogenesis. We found that long-term exposure to MWCNTs can induce irreversible oncogenic transformation of human bronchial epithelial cells and tumorigenicity in vivo. A genome-wide array-comparative genomic hybridization (aCGH) analysis revealed global chromosomal aberration in MWCNTs-treated clones, predominantly at chromosome 2q31-32, where the potential oncogenes HOXD9 and HOXD13 are located. Functional assays confirmed that this variation can modulate oncogenic signaling and plays a part in MWCNTs-induced tumorigenesis, suggesting that MWCNTs are carcinogens that act by altering genomic stability and oncogenic copy numbers.

Genome-wide analysis of three-way interplay among gene expression, cancer cell invasion and anti-cancer compound sensitivity.

BACKGROUND: Chemosensitivity and tumor metastasis are two primary issues in cancer management. Cancer cells often exhibit a wide range of sensitivity to anti-cancer compounds. To gain insight on the genetic mechanism of drug sensitivity, one powerful approach is to employ the panel of 60 human cancer cell lines developed by the National Cancer Institute (NCI). Cancer cells also show a broad range of invasion ability. However, a genome-wide portrait on the contributing molecular factors to invasion heterogeneity is lacking. METHODS: Our lab performed an invasion assay on the NCI-60 panel. We identified invasion-associated (IA) genes by correlating our invasion profiling data with the Affymetrix gene expression data on NCI-60. We then employed the recently released chemosensitivity data of 99 anti-cancer drugs of known mechanism to investigate the gene-drug correlation, focusing on the IA genes. Afterwards, we collected data from four independent drug-testing experiments to validate our findings on compound response prediction. Finally, we obtained published clinical and molecular data from two recent adjuvant chemotherapy cohorts, one on lung cancer and one on breast cancer, to test the performance of our gene signature for patient outcome prediction. RESULTS: First, we found 633 IA genes from the invasion-gene expression correlation study. Then, for each of the 99 drugs, we obtained a subset of IA genes whose expression levels correlated with drug-sensitivity profiles. We identified a set of eight genes (EGFR, ITGA3, MYLK, RAI14, AHNAK, GLS, IL32 and NNMT) showing significant gene-drug correlation with paclitaxel, docetaxel, erlotinib, everolimus and dasatinib. This eight-gene signature (derived from NCI-60) for chemosensitivity prediction was validated by a total of 107 independent drug tests on 78 tumor cell lines, most of which were outside of the NCI-60 panel. The eight-gene signature predicted relapse-free survival for the lung and breast cancer patients (log-rank P = 0.0263; 0.00021). Multivariate Cox regression yielded a hazard ratio of our signature of 5.33 (95% CI = 1.76 to 16.1) and 1.81 (95% CI = 1.19 to 2.76) respectively. The eight-gene signature features the cancer hallmark epidermal growth factor receptor (EGFR) and genes involved in cell adhesion, migration, invasion, tumor growth and progression. CONCLUSIONS: Our study sheds light on the intricate three-way interplay among gene expression, invasion and compound-sensitivity. We report the finding of a unique signature that predicts chemotherapy survival for both lung and breast cancer. Augmenting the NCI-60 model with in vitro characterization of important phenotype-like invasion potential is a cost-effective approach to power the genomic chemosensitivity analysis.

Feature selection translates drug response predictors from cell lines to patients.

Targeted therapies and chemotherapies are prevalent in cancer treatment. Identification of predictive markers to stratify cancer patients who will respond to these therapies remains challenging because patient drug response data are limited. As large amounts of drug response data have been generated by cell lines, methods to efficiently translate cell-line-trained predictors to human tumors will be useful in clinical practice. Here, we propose versatile feature selection procedures that can be combined with any classifier. For demonstration, we combined the feature selection procedures with a (linear) logit model and a (non-linear) K-nearest neighbor and trained these on cell lines to result in LogitDA and KNNDA, respectively. We show that LogitDA/KNNDA significantly outperforms existing methods, e.g., a logistic model and a deep learning method trained by thousands of genes, in prediction AUC (0.70-1.00 for seven of the ten drugs tested) and is interpretable. This may be due to the fact that sample sizes are often limited in the area of drug response prediction. We further derive a novel adjustment on the prediction cutoff for LogitDA to yield a prediction accuracy of 0.70-0.93 for seven drugs, including erlotinib and cetuximab, whose pathways relevant to anti-cancer therapies are also uncovered. These results indicate that our methods can efficiently translate cell-line-trained predictors into tumors.

Whole exome sequencing and MicroRNA profiling of lung adenocarcinoma identified risk prediction features for tumors at stage I and its substages.

OBJECTIVES: About 20% of stage I lung adenocarcinoma (LUAD) patients suffer a relapse after surgical resection. While finer substages have been defined and refined in the AJCC staging system, clinical investigations on the tumor molecular landscape are lacking. MATERIALS AND METHODS: We performed whole exome sequencing, DNA copy number and microRNA profiling on paired tumor-normal samples from a cohort of 113 treatment-naïve stage I Taiwanese LUAD patients. We searched for molecular features associated with relapse-free survival (RFS) of stage I or its substages and validated the findings with an independent Caucasian LUAD cohort. RESULTS: We found sixteen nonsynonymous mutations harbored at EGFR, KRAS, TP53, CTNNB1 and six other genes associated with poor RFS in a dose-dependent manner via variant allele fraction (VAF). An index, maxVAF, was constructed to quantify the overall mutation load from genes other than EGFR. High maxVAF scores discriminated a small group of high-risk LUAD at stage I (median RFS: 4.5 versus 69.5 months; HR = 10.5, 95% CI = 4.22-26.12, P < 0.001). At the substage level, higher risk was found for patients with high maxVAF or high miR-31; IA (median RFS: 32.1 versus 122.8 months, P = 0.005) and IB (median RFS: 7.1 versus 26.2, P = 0.049). MicroRNAs, miR-182, miR-183 and miR-196a were found correlated with EGFR mutation and poor RFS in stage IB patients. CONCLUSION: Distinctive features of somatic gene mutation and microRNA expression of stage I LUAD are characterized to complement the survival prognosis by substaging. The findings open up more options for precision management of stage I LUAD patients.

Genetic Disruption of KLF1 K74 SUMOylation in Hematopoietic System Promotes Healthy Longevity in Mice.

The quest for rejuvenation and prolonged lifespan through transfusion of young blood has been studied for decades with the hope of unlocking the mystery of the key substance(s) that exists in the circulating blood of juvenile organisms. However, a pivotal mediator has yet been identified. Here, atypical findings are presented that are observed in a knockin mouse model carrying a lysine to arginine substitution at residue 74 of Krüppel-like factor 1 (KLF1/EKLF), the SUMOylation-deficient Klf1K74R/K74R mouse, that displayed significant improvement in geriatric disorders and lifespan extension. Klf1K74R/K74R mice exhibit a marked delay in age-related physical performance decline and disease progression as evidenced by physiological and pathological examinations. Furthermore, the KLF1(K74R) knockin affects a subset of lymphoid lineage cells; the abundance of tumor infiltrating effector CD8+ T cells and NKT cells is increased resulting in antitumor immune enhancement in response to tumor cell administration. Significantly, infusion of hematopoietic stem cells (HSCs) from Klf1K74R/K74R mice extends the lifespan of the wild-type mice. The Klf1K74R/K74R mice appear to be an ideal animal model system for further understanding of the molecular/cellular basis of aging and development of new strategies for antiaging and prevention/treatment of age-related diseases thus extending the healthspan as well as lifespan.

Tissue-specific gene expression templates for accurate molecular characterization of the normal physiological states of multiple human tissues with implication in development and cancer studies.

BACKGROUND: To elucidate the molecular complications in many complex diseases, we argue for the priority to construct a model representing the normal physiological state of a cell/tissue. RESULTS: By analyzing three independent microarray datasets on normal human tissues, we established a quantitative molecular model GET, which consists of 24 tissue-specific Gene Expression Templates constructed from a set of 56 genes, for predicting 24 distinct tissue types under disease-free condition. 99.2% correctness was reached when a large-scale validation was performed on 61 new datasets to test the tissue-prediction power of GET. Network analysis based on molecular interactions suggests a potential role of these 56 genes in tissue differentiation and carcinogenesis.Applying GET to transcriptomic datasets produced from tissue development studies the results correlated well with developmental stages. Cancerous tissues and cell lines yielded significantly lower correlation with GET than the normal tissues. GET distinguished melanoma from normal skin tissue or benign skin tumor with 96% sensitivity and 89% specificity. CONCLUSIONS: These results strongly suggest that a normal tissue or cell may uphold its normal functioning and morphology by maintaining specific chemical stoichiometry among genes. The state of stoichiometry can be depicted by a compact set of representative genes such as the 56 genes obtained here. A significant deviation from normal stoichiometry may result in malfunction or abnormal growth of the cells.

Patterns of co-expression for protein complexes by size in Saccharomyces cerevisiae.

Many successful functional studies by gene expression profiling in the literature have led to the perception that profile similarity is likely to imply functional association. But how true is the converse of the above statement? Do functionally associated genes tend to be co-regulated at the transcription level? In this paper, we focus on a set of well-validated yeast protein complexes provided by Munich Information Center for Protein Sequences (MIPS). Using four well-known large-scale microarray expression data sets, we computed the correlations between genes from the same complex. We then analyzed the relationship between the distribution of correlations and the complex size (the number of genes in a protein complex). We found that except for a few large protein complexes, such as mitochondrial ribosomal and cytoplasmic ribosomal proteins, the correlations are on the average not much higher than that from a pair of randomly selected genes. The global impact of large complexes on the expression of other genes in the genome is also studied. Our result also showed that the expression of over 85% of the genes are affected by six large complexes: the cytoplasmic ribosomal complex, mitochondrial ribosomal complex, proteasome complex, F0/F1 ATP synthase (complex V) (size 18), rRNA splicing (size 24) and H+- transporting ATPase, vacular (size 15).

Genome-wide expression links the electron transfer pathway of Shewanella oneidensis to chemotaxis.

BACKGROUND: By coupling the oxidation of organic substrates to a broad range of terminal electron acceptors (such as nitrate, metals and radionuclides), Shewanella oneidensis MR-1 has the ability to produce current in microbial fuel cells (MFCs). omcA, mtrA, omcB (also known as mtrC), mtrB, and gspF are some known genes of S. oneidensis MR-1 that participate in the process of electron transfer. How does the cell coordinate the expression of these genes? To shed light on this problem, we obtain the gene expression datasets of MR-1 that are recently public-accessible in Gene Expression Omnibus. We utilize the novel statistical method, liquid association (LA), to investigate the complex pattern of gene regulation. RESULTS: Through a web of information obtained by our data analysis, a network of transcriptional regulatory relationship between chemotaxis and electron transfer pathways is revealed, highlighting the important roles of the chemotaxis gene cheA-1, the magnesium transporter gene mgtE-1, and a triheme c-type cytochrome gene SO4572. CONCLUSION: We found previously unknown relationship between chemotaxis and electron transfer using LA system. The study has the potential of helping researchers to overcome the intrinsic metabolic limitation of the microorganisms for improving power density output of an MFC.

Comorbidity of Narcolepsy and Psychotic Disorders: A Nationwide Population-Based Study in Taiwan.

BACKGROUND: Narcolepsy is a chronic sleep disorder that is likely to have neuropsychiatric comorbidities. Psychotic disorders are characterized by delusion, hallucination, and reality impairments. This study investigates the relationship between narcolepsy and psychotic disorders. DESIGN AND METHODS: This study involves patients who were diagnosed with narcolepsy between January 2002 and December 2011 (n = 258) and age- and gender-matched controls (n = 2580) from Taiwan's National Health Insurance database. Both the patients and the controls were monitored from January 1, 2002 to December 31, 2011 to identify any occurrence of a psychotic disorder. Drugs that have been approved for treating narcolepsy: immediate-release methylphenidate (IR-MPH), osmotic controlled-release formulations of methylphenidate (OROS-MPH), and modafinil, were analyzed. A multivariate logistic regression model was used to evaluate the potential comorbidity of narcolepsy with psychotic disorders. RESULTS: During the study period, 8.1% of the narcoleptic patients exhibited comorbidity with a psychotic disorder, whereas only 1.5% of the control subjects (1.5%) had psychotic disorders (aOR, 4.07; 95% CI, 2.21-7.47). Of the narcolepsy patients, 41.5, 5.4, and 13.2% were treated with MPH-IR, MPH-OROS, and modafinil, accordingly. Pharmacotherapy for narcolepsy did not significantly affect the risk of exhibiting a psychotic disorder. CONCLUSIONS: This nationwide study revealed that narcolepsy and psychotic disorders commonly co-occur. Pharmacotherapy for narcolepsy was not associated with the risk of psychotic disorders. Our findings serve as a reminder that clinicians must consider the comorbidity of narcolepsy and psychosis.

Landscape of Mitochondria Genome and Clinical Outcomes in Stage 1 Lung Adenocarcinoma.

Risk factors including genetic effects are still being investigated in lung adenocarcinoma (LUAD). Mitochondria play an important role in controlling imperative cellular parameters, and anomalies in mitochondrial function might be crucial for cancer development. The mitochondrial genomic aberrations found in lung adenocarcinoma and their associations with cancer development and progression are not yet clearly characterized. Here, we identified a spectrum of mitochondrial genome mutations in early-stage lung adenocarcinoma and explored their association with prognosis and clinical outcomes. Next-generation sequencing was used to reveal the mitochondrial genomes of tumor and conditionally normal adjacent tissues from 61 Stage 1 LUADs. Mitochondrial somatic mutations and clinical outcomes including relapse-free survival (RFS) were analyzed. Patients with somatic mutations in the D-loop region had longer RFS (adjusted hazard ratio, adjHR = 0.18, p = 0.027), whereas somatic mutations in mitochondrial Complex IV and Complex V genes were associated with shorter RFS (adjHR = 3.69, p = 0.012, and adjHR = 6.63, p = 0.002, respectively). The risk scores derived from mitochondrial somatic mutations were predictive of RFS (adjHR = 9.10, 95%CI: 2.93-28.32, p < 0.001). Our findings demonstrated the vulnerability of the mitochondrial genome to mutations and the potential prediction ability of somatic mutations. This research may contribute to improving molecular guidance for patient treatment in precision medicine.

Association of Bone Metastasis With Early-Stage Breast Cancer in Women With and Without Precancer Osteoporosis According to Osteoporosis Therapy Status.

Importance: Deaths from cancer are attributed more to secondary than primary tumors, but the pathogenesis of organ-specific cancer metastasis has not been determined. Objective: To investigate whether precancer osteoporosis and osteoporosis therapy are associated with alteration of bone metastasis patterns. Design, Setting, and Participants: This nationwide retrospective cohort study was performed from January 1, 2002, to December 31, 2013, using 2 cohorts from the Taiwan National Health Insurance Research Database: a random sample of 1 million beneficiaries from the Longitudinal Health Insurance Database who were enrolled in 2005 (LHID2005) and a specific data set of all the patients with osteoporosis. Patients diagnosed with breast cancer and precancer osteoporosis from January 1, 2002, to December 31, 2011, were included in the study, and their records were examined through December 31, 2013. From LHID2005, we selected 9104 women with early-stage breast cancer, of whom 705 had precancer osteoporosis. We identified 29 183 patients from the cohort of patients with breast cancer and osteoporosis, 14 020 of whom had precancer osteoporosis. Data analysis was performed from December 31, 2016, to August 31, 2018. Exposures: Precancer osteoporosis and osteoporosis therapy. Main Outcomes and Measures: The risk of bone metastasis in patients with and without precancer osteoporosis and patients receiving and not receiving osteoporosis therapy as well as time to bone metastasis development. Results: Among 9104 patients with breast cancer from the Longitudinal Health Insurance Database (mean [SD] age, 46.7 [14.0] years), precancer osteoporosis was not associated with a difference in risk of bone metastasis (adjusted hazard ratio [aHR], 0.87; 95% CI, 0.58-1.30; P = .49). Among 14 020 patients with precancer osteoporosis from the other cohort (mean [SD] age, 58.9 [11.6] years), osteoporosis therapy had no association with the risk of bone metastasis (bisphosphonates: aHR, 1.47; 95% CI, 1.00-2.17; P = .05; nonbisphosphonate drugs: aHR, 1.00; 95% CI, 0.72-1.39; P > .99). Compared with those without precancer osteoporosis (median time to bone metastasis development, 2.87 years; interquartile range [IQR], 1.34-4.86 years), among those with precancer osteoporosis, the median time to develop bone metastasis was shorter in those who did not receive treatment (1.74 years; IQR, 0.58-3.60 years; P < .001), whereas this time was the same for those who received treatment (bisphosphonates: 2.34 years; IQR, 1.23-3.13 years; nonbisphosphonate drugs: 2.08 years; IQR, 0.92-4.95 years). Conclusions and Relevance: Precancer osteoporosis was not associated with risk of bone metastasis, but untreated osteoporosis was associated with accelerated progression of bone metastasis when it occurred. Organ microenvironments interact with disseminated cancer mostly after the specific organ has been predetermined to be the designated location. Because recurrences and metastases are major obstacles to cancer treatments, determining which organs may be at risk for metastases may be crucial to treating the disease.