Consensus for antifungal stewardship in China (2024 edition).

Background: Invasive fungal disease (IFD) has become a serious threat to human health in China and around the world, with high mortality and morbidity. Currently, the misdiagnosis rate of IFD is extremely high, compounded with the low quality of prescription antifungals and the high incidence of adverse events associated with IFD treatment, resulting in lengthy hospitalization, low clinical response, and high disease burden, which have become serious challenges in clinical practice. Antifungal stewardship (AFS) can not only significantly increase the early diagnosis rate of IFD, reduce inappropriate utilization of antifungal drugs, improve patient prognosis, but can also improve therapeutic safety and reduce healthcare expenses. Thus, it is urgent to identify key AFS metrics suitable for China's current situation. Methods: Based on metrics recommended by international AFS consensuses, combined with the current situation of China and the clinical experience of authoritative experts in various fields, several metrics were selected, and experts in the fields of respiratory diseases, hematology, intensive care units (ICUs), dermatology, infectious diseases, microbiology laboratory and pharmacy were invited to assess AFS metrics by the Delphi method. Consensus was considered to be reached with an agreement level of ≥80% for the metric. Results: Consensus was reached for 24 metrics, including right patient metrics (n=4), right time metrics (n=3), and right use metrics (n=17). Right use metrics were further subdivided into drug choice (n=8), drug dosage (n=4), drug de-escalation (n=1), drug duration (n=2), and drug consumption (n=2) metrics. Forty-six authoritative experts assessed and reviewed the above metrics, and a consensus was reached with a final agreement level of ≥80% for 22 metrics. Conclusions: This consensus is the first to propose a set of AFS metrics suitable for China, which helps to establish AFS standards in China and is also the first AFS consensus in Asia, and may improve the standard of clinical diagnosis and treatment of IFD, and guide hospitals to implement AFS, ultimately promoting the rational use of antifungal drugs and improving patient prognosis.

Function and mechanism of action of the TRPV1 channel in the development of triple-negative breast cancer.

Transient receptor potential channel subfamily vanilloid 1 (TRPV1) is a member of the transient receptor potential family of nonselective cationic transmembrane channel proteins that are involved in the regulation of calcium homeostasis. It is expressed in various tumor types and has been implicated in the regulation of cancer growth, metastasis, apoptosis, and cancer-related pain. TRPV1 is highly expressed in triple-negative breast cancer (TNBC), and both its agonists and antagonists may exert anti-cancer effects. In this review, we provide an overview of the effect of TRPV1 on TNBC development and its influence on immunotherapy in an attempt to facilitate the development of future treatment strategies.

Pharmacokinetics and safety of EVER206, a novel polymyxin antimicrobial, in healthy Chinese subjects.

EVER206 (also known as SPR206) is a novel polymyxin analog that has shown in vitro potency and in vivo efficacy against multidrug-resistant (MDR) Gram-negative pathogens. This randomized, double-blinded, placebo-controlled, Phase I study evaluated the safety, tolerability, and pharmacokinetics of EVER206 in healthy Chinese subjects. After single administration of 50-300 mg EVER206, the Cmax ranged from 3.94 to 25.82 mg/L, and the AUC0-inf ranged from 12.42 to 101.67 h·mg/L. The plasma exposure displayed a linear relationship with the dose administered. After administration of 75 and 100 mg of EVER206 every 8 hours (q8 hour), a steady state was achieved on Day 2. The accumulation ratios of Cmax and AUC from Day 1 to Day 7 were in the range of 1.12 to 1.3. The elimination half-lives ranged from 2.86 to 4.32 hours in the single-ascending-dose (SAD) study and 4.71 to 6.18 hours in the multiple-ascending-dose (MAD) study. The urinary excretion of unchanged EVER206 increased with the dose, with the mean cumulative fraction ranging from 23.70% to 47.10%. EVER206 was safe and well-tolerated in Chinese healthy subjects. No severe treatment emerging adverse events (TEAEs), serious adverse events, or TEAEs leading to discontinuation were reported. The results of the present study demonstrated a similar safety profile of EVER206 with data reported in an earlier study on SPR206-101. The exposure of EVER206 in Chinese healthy subjects was higher than that in Australian healthy subjects. These results could enable further clinical development of EVER206 in Chinese patients with severe MDR Gram-negative pathogen infections.CLINICAL TRIALSThis study was registered at the Chinese Clinical Trial Registry under identifier ChiCTR2200056692.

MUMA: a multi-omics meta-learning algorithm for data interpretation and classification.

Multi-omics data integration is a promising field combining various types of omics data, such as genomics, transcriptomics, and proteomics, to comprehensively understand the molecular mechanisms underlying life and disease. However, the inherent noise, heterogeneity, and high dimensionality of multi-omics data present challenges for existing methods to extract meaningful biological information without overfitting. This paper introduces a novel Multi-Omics Meta-learning Algorithm (MUMA) that employs self-adaptive sample weighting and interaction-based regularization for enhanced diagnostic performance and interpretability in multi-omics data analysis. Specifically, MUMA captures crucial biological processes across different omics layers by learning a flexible sample reweighting function adaptable to various noise scenarios. Additionally, MUMA incorporates an interaction-based regularization term, encouraging the model to learn from the relationships among different omics modalities. We evaluate MUMA using simulations and eighteen real datasets, demonstrating its superior performance compared to state-of-the-art methods in classifying biological samples (e.g., cancer subtypes) and selecting relevant biomarkers from noisy multi-omics data. As a powerful tool for multi-omics data integration, MUMA can assist researchers in achieving a deeper understanding of the biological systems involved. The source code for MUMA is available at https://github.com/bio-ai-source/MUMA.

Phosphorylated vimentin at Ser72 is associated with epithelial-mesenchymal transition in lupus nephritis.

OBJECTIVES: To measure the expression of vimentin and its phosphorylated forms in lupus nephritis (LN) and explore their potential role in LN development. METHODS: Lupus renal biopsies from LN patients and normal renal biopsies from kidney transplant donors were collected. The expression of vimentin and its phosphorylated forms (p-vimentin (Ser39, Ser56, Ser72, Ser83, and Tyr117)) were measured by Western blots and immunohistochemistry. To construct stable cell line that overexpress vimentin and its phosphorylated forms, an immortalized proximal tubule epithelial cell line (HK-2 cells) was utilized. The roles of vimentin and its phosphorylated forms on the migration of HK-2 cells were examined by transwell migration assay and wound healing analysis. RESULTS: We first observed a significant upregulation of vimentin protein in TGFß1-induced HK-2 cells. This finding was further confirmed in renal tissues obtained from LN patients and animal model. Interestingly, among the five phosphorylated forms of vimentin, only vimentin phosphorylated at Ser72 was upregulated in LN. Through the establishment of stable vimentin and its phosphorylated forms overexpression in HK-2 cells, we found that the overexpression of vimentin and its phosphorylated forms at Ser72 significantly enhances the cell migration. CONCLUSIONS: Vimentin phosphorylated on Ser72 is important for renal epithelial cell migration, which would enhance the progression of vimentin-induced epithelial-mesenchymal transition during LN development.

ALOX5AP is a new prognostic indicator in acute myeloid leukemia.

BACKGROUND: The overexpression of ALOX5AP has been observed in many types of cancer and has been identified as an oncogene. However, its role in acute myeloid leukemia (AML) has not been extensively studied. This study aimed to identify the expression and methylation patterns of ALOX5AP in bone marrow (BM) samples of AML patients, and further explore its clinical significance. METHODS: Eighty-two de novo AML patients and 20 healthy donors were included in the study. Meanwhile, seven public datasets from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) were included to confirm the alteration of ALOX5AP. Receiver operating characteristic (ROC) curve analysis was applied to determine the discriminative capacity of ALOX5AP expression to discriminate AML. The prognostic value of ALOX5AP was identified by the Kaplan-Meier method and log-rank test. It was further validated in four independent cohorts (n = 1186). Significantly different genes associated with ALOX5AP expression were subsequently compared by LinkedOmics, and Metascape database. RESULTS: The level of ALOX5AP expression was significantly increased in bone marrow cells of AML patients compared with healthy donors (P < 0.05). ROC curve analysis suggested that ALOX5AP expression might be a potential biomarker to discriminate AML from controls. ALOX5AP overexpression was associated with decreased overall survival (OS) in AML according to the TCGA data (P = 0.006), which was validated by other four independent cohorts. DNA methylation levels of ALOX5AP were significantly lower in AML patients compared to normal samples (P < 0.05), as confirmed in the Diseasemeth database and the independent cohort GSE63409. ALOX5AP level was positively associated with genes with proleukemic effects such as PAX2, HOX family, SOX11, H19, and microRNAs that act as oncogenes in leukemia, such as miR125b, miR-93, miR-494, miR-193b, while anti-leukemia-related genes and tumor suppressor microRNAs such as miR-582, miR-9 family and miR-205 were negatively correlated. CONCLUSION: ALOX5AP overexpression, associated with its hypomethylation, predicts poorer prognosis in AML.

Enhancement of ß-Lactam-Mediated Killing of Gram-Negative Bacteria by Lysine Hydrochloride.

Widespread bacterial resistance among Gram-negative bacteria is rapidly depleting our antimicrobial arsenal. Adjuvants that enhance the bactericidal activity of existing antibiotics provide a way to alleviate the resistance crisis, as new antimicrobials are becoming increasingly difficult to develop. The present work with Escherichia coli revealed that neutralized lysine (lysine hydrochloride) enhances the bactericidal activity of ß-lactams in addition to increasing bacteriostatic activity. When combined, lysine hydrochloride and ß-lactam increased expression of genes involved in the tricarboxylic acid (TCA) cycle and raised reactive oxygen species (ROS) levels; as expected, agents known to mitigate bactericidal effects of ROS reduced lethality from the combination treatment. Lysine hydrochloride had no enhancing effect on the lethal action of fluoroquinolones or aminoglycosides. Characterization of a tolerant mutant indicated involvement of the FtsH/HflkC membrane-embedded protease complex in lethality enhancement. The tolerant mutant, which carried a V86F substitution in FtsH, exhibited decreased lipopolysaccharide levels, reduced expression of TCA cycle genes, and reduced levels of ROS. Lethality enhancement by lysine hydrochloride was abolished by treating cultures with Ca2+ or Mg2+, cations known to stabilize the outer membrane. These data, plus damage observed by scanning electron microscopy, indicate that lysine stimulates ß-lactam lethality by disrupting the outer membrane. Lethality enhancement of ß-lactams by lysine hydrochloride was also observed with Acinetobacter baumannii and Pseudomonas aeruginosa, thereby suggesting that the phenomenon is common among Gram-negative bacteria. Arginine hydrochloride behaved in a similar way. Overall, the combination of lysine or arginine hydrochloride and ß-lactam offers a new way to increase ß-lactam lethality with Gram-negative pathogens. IMPORTANCE Antibiotic resistance among Gram-negative pathogens is a serious medical problem. The present work describes a new study in which a nontoxic nutrient increases the lethal action of clinically important ß-lactams. Elevated lethality is expected to reduce the emergence of resistant mutants. The effects were observed with significant pathogens (Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa), indicating widespread applicability. Examination of tolerant mutants and biochemical measurements revealed involvement of endogenous reactive oxygen species in response to outer membrane perturbation. These lysine hydrochloride-ß-lactam data support the hypothesis that lethal stressors can stimulate the accumulation of ROS. Genetic and biochemical work also revealed how an alteration in a membrane protease, FtsH, abolishes lysine stimulation of ß-lactam lethality. Overall, the work presents a method for antimicrobial enhancement that should be safe, easy to administer, and likely to apply to other nutrients, such as arginine.

Progress on mechanisms of antibiotic resistance in Clostridioides difficile.

Clostridioides difficile (CD) is one of the most common pathogens causing health-care-associated infectious diarrhea and is listed by the U.S. Centers for Disease Control and Prevention as an urgent antibiotic resistance (AR) threat. Many resistance genes can be transferred between different CD strains present in the clinical setting, community, and environment. The antimicrobial resistance (AMR) of CD continues to evolve with the emergence and acquisition of new drug resistance mechanisms. CD has developed diverse drug resistance mechanisms, such as drug alteration, modification of the target site, and extrusion of drugs via efflux pumps. Researches have provided comprehensive knowledge about resistance mechanisms of macrolides and quinolones in CD. However, the mechanisms of resistance for metronidazole, vancomycin, and other therapeutic antibiotics against Clostridioides difficile infection (CDI) are only beginning to be elucidated. Some previously unfound mechanisms, such as plasmid-mediated drug resistance in CD, may also play an important role. In this review, we summarize the research progress on drug resistance mechanisms of CD with antimicrobial drugs already used clinically, such as metronidazole, vancomycin, and fidaxomicin, thereby providing the references for the clinical treatment and prevention of CDI, as well as the development of new antibacterial drugs and detection kits for drug resistant bacteria.

Development of a risk prediction model for bloodstream infection in patients with fever of unknown origin.

BACKGROUND: Bloodstream infection (BSI) is a significant cause of mortality among patients with fever of unknown origin (FUO). Inappropriate empiric antimicrobial therapy increases difficulty in BSI diagnosis and treatment. Knowing the risk of BSI at early stage may help improve clinical outcomes and reduce antibiotic overuse. METHODS: We constructed a multivariate prediction model based on clinical features and serum inflammatory markers using a cohort of FUO patients over a 5-year period by Least Absolute Shrinkage and Selection Operator (LASSO) and logistic regression. RESULTS: Among 712 FUO patients, BSI was confirmed in 55 patients. Five independent predictors available within 24 h after admission for BSI were identified: presence of diabetes mellitus, chills, C-reactive protein level of 50-100 mg/L, procalcitonin > 0.3 ng/mL, neutrophil percentage > 75%. A predictive score incorporating these 5 variables has adequate concordance with an area under the curve of 0.85. The model showed low positive predictive value (22.6%), but excellent negative predictive value (97.4%) for predicting the risk of BSI. The risk of BSI reduced to 2.0% in FUO patients if score < 1.5. CONCLUSIONS: A simple tool based on 5 variables is useful for timely ruling out the individuals at low risk of BSI in FUO population.

Stereo vision-based Kinematic calibration method for the Stewart platforms.

Accuracy is the most important index for the industrial applications of the Stewart platform, which can be guaranteed by the kinematic calibration method to improve the motion orbit performance of this platform. In order to improve the effectiveness of the least squares algorithm and the identified accuracy of the platform's geometric parameter errors, an applicab-le dimensionless error model based on the structural characteristics of the Stewart platform is investigated. Moreover, a novel stereo vision-based measurement method is proposed, which can measure the 6-degree-of-freedom (DOF) pose of the moving platform. On this basis, an identification simulation is schemed to validate the efficiency of the dimensionless error model, and the kinematic calibration experiment is carried out on a prototype. The experimental results demonstrate that the position error is decreased to 0.261 mm with an improved accuracy of 89.720%, the orientation error is decreased to 0.051° with an improved accuracy of 90.351%.

Safety of oral nemonoxacin: A systematic review of clinical trials and postmarketing surveillance.

Background: Postmarketing safety analysis is an effective supplement for new drugs in clinical practice. Therefore, we aimed to systematically assess the safety of oral nemonoxacin malate, the first approved C-8-methoxy non-fluorinated quinolone, in clinical studies and via postmarketing safety surveillance. Methods: We electronically and manually searched and screened safety data (including premarketing and postmarketing data) of oral nemonoxacin from clinical registries. We standardized and summarized the reported adverse events according to the Medical Dictionary for Regulatory Activities System Organ Class and Preferred Terms. We summarized and reported the number and frequency (%) of the AEs and serious AEs in patients with community-acquired pneumonia and in specific patients. Results: Three Phase II/III comparator studies (n = 670, nemonoxacin), one Phase IV study (n = 461), two special population pharmacokinetic studies (n = 40), four observational studies (n = 1,852), and one 5-year postmarketing surveillance project (n = 257,420) were included in this study. The Phase II/III studies showed that the commonly reported drug-related AEs were similar for oral 500 mg nemonoxacin and levofloxacin treatments, which mainly included increased alanine aminotransferase levels (4.4% vs. 2.5%), neutropenia (2.5% vs. 4.4%), nausea (2.5% vs. 1.6%), and leukopenia (2.3% vs. 3.2%). No drug-related deaths were reported. Postmarketing safety surveillance revealed that known adverse drug reaction characteristics were generally unchanged. Pharmacokinetic data suggested that dose adjustment was not necessary in elderly patients, which was confirmed by a Phase IV study in an elderly population, in patients with renal impairment with CLcr ≥50 ml/min, and in those with mild-to-moderate hepatic impairment. Conclusion: Clinical trial data of approximately 1,450 patients and postmarketing data of >257,420 patients suggest that nemonoxacin is generally well tolerated and can be a suitable alternative to fluoroquinolones for patients with CAP.

A novel meta-analysis based on data augmentation and elastic data shared lasso regularization for gene expression.

BACKGROUND: Gene expression analysis can provide useful information for analyzing complex biological mechanisms. However, many reported findings are unrepeatable due to small sample sizes relative to a large number of genes and the low signal-to-noise ratios of most gene expression datasets. RESULTS: Meta-analysis of multi-data sets is an efficient method for tackling the above problem. To improve the performance of meta-analysis, we propose a novel meta-analysis framework. It consists of two parts: (1) a novel data augmentation strategy. Various cross-platform normalization methods exist, which can preserve original biological information of gene expression datasets from different angles and add different "perturbations" to the dataset. Using such perturbation, we provide a feasible means for gene expression data augmentation; (2) elastic data shared lasso (DSL-[Formula: see text]). The DSL-[Formula: see text] method spans the continuum between individual models for each dataset and one model for all datasets. It also overcomes the shortcomings of the data shared lasso method when dealing with highly correlated features. Comprehensive simulation experiment results show that the proposed method has high prediction and gene selection performance. We then apply the proposed method to non-small cell lung cancer (NSCLC) blood gene expression data in order to identify key tumor-related genes. The outcomes of our experiment indicate that the method could be used for identifying a set of robust disease-related gene signatures that may be used for NSCLC early diagnosis or prognosis or even targeting. CONCLUSION: We propose a novel and effective meta-analysis method for biological research, extrapolating and integrating information from multiple gene expression datasets.

Sparse principal component analysis based on genome network for correcting cell type heterogeneity in epigenome-wide association studies.

In epigenome-wide association studies (EWAS), the mixed methylation expression caused by the combination of different cell types may lead the researchers to find the false methylation site related to the phenotype of interest. To correct the EWAS false discovery, some non-reference models based on sparse principal component analysis (sparse PCA) have been proposed. These models assume that all methylation sites have the same priori probability in each PC load. However, it is known that there already has gene network structure corresponding to the methylation site. How to integrate this genome network knowledge into the sparse PCA models to enhance the performance of existing models is an open research problem. We introduce GN-ReFAEWAS, a non-reference analysis model which integrates the prior gene network structure into the PCA framework to control the false discovery in EWAS. We used one simulated data set, three real data sets, and three additional tests for experiments and compared with four existing models. Experimental results show that the GN-ReFAEWAS model is better than the existing model by 2-90% in the indicators of sensitivity, specificity, genomic control factor λ, and correlation coefficient factor cov with known cell phenotype ratio.

Clinical Pharmacology and Utility of Contezolid in Chinese Patients with Complicated Skin and Soft-Tissue Infections.

This study aimed to build a population pharmacokinetic (PopPK) model for contezolid tablet (MRX-I) in healthy subjects and adults with complicated skin and soft-tissue infections (cSSTIs) to further evaluate the efficacy and safety of contezolid and recommend the optimal dosing regimen based on pharmacokinetic/pharmacodynamic (PK/PD) analysis. PopPK analysis was performed using a nonlinear mixed-effects model (NONMEM) to examine the effects of age, body weight, sex, liver and renal functions, albumin, food, dosage strength, and subject type on the PK parameters of contezolid. PK/PD analysis was combined with the MIC of contezolid, clinical/microbiological efficacy, and nonclinical study data. Adverse events (AEs) and study drug-related AEs reported were summarized to examine the relationship between contezolid exposure level and safety measures. A two-compartment model was built. An exponential model was used to describe the interindividual variation. A proportional model was used to describe the intraindividual variation of PK parameters. Good clinical and microbiological efficacy are expected for the infections caused by S. aureus when contezolid is administered at 600 mg or 800 mg every 12 h (q12h). The area under the concentration-time curve from 0 to 24 h at steady state and maximum concentration of drug in serum at steady state of contezolid did not show significant association with the incidence of any AE. The dosing regimen of contezolid at 800 mg q12h administered postprandially for 7 to 14 days is expected to achieve satisfactory clinical and microbiological efficacy in cSSTIs, which is slightly better than that of 600 mg contezolid. This administration has been added to the prescribing information of contezolid tablets.

Metronidazole-resistant Clostridioides difficile: genomic and transcriptomic traits acquired under in-vitro metronidazole induction.

Decreased effectiveness of metronidazole for the treatment of Clostridioides difficile infection has been documented. One reason for this is that levels of metronidazole in the colon are generally low; therefore, a modest increase in the minimum inhibitory concentration of metronidazole for C. difficile may result in an insufficient therapeutic concentration. Due to the lack of efficient genetic manipulation tools for C. difficile strains, the resistance mechanism is largely unknown. In this study, a metronidazole-resistant strain (SH182IR) was acquired by in-vitro induction with metronidazole from a clinical metronidazole-heteroresistant strain (SH182), and the genomic and transcriptional changes were investigated through whole-genome sequencing and RNA-seq. The morphology of the two strains was studied by transmission electron microscopy, and the roles of drug efflux pumps in metronidazole resistance were determined by inhibition assay. Genomic analysis showed that the ferrous iron transporter feoB3 was truncated in SH182IR, indicating that feoB3 contributed to the metronidazole resistance of C. difficile. RNA-seq analysis showed that genes involved in peptidoglycan synthesis, efflux pumps and metronidazole reductive action were expressed differentially between the two strains. Further cell imaging confirmed that cell wall thickness was significantly greater in SH182IR. The efflux pump inhibitor test showed that addition of reserpine or cyanide 3-chlorophenylhydrazone reduced metronidazole resistance in SH182IR, thus proving the role of efflux pumps in metronidazole resistance. These results found an association between genomic variation and metronidazole resistance in C. difficile, and show that metronidazole resistance in C. difficile is multi-factorial, involving metronidazole metabolism, cell wall thickness and efflux pumps. These findings will help improve knowledge and understanding of metronidazole resistance of C. difficile.

A Phase III multicentre, randomized, double-blind trial to evaluate the efficacy and safety of oral contezolid versus linezolid in adults with complicated skin and soft tissue infections.

OBJECTIVES: Contezolid is a novel oxazolidinone antibacterial agent for managing infections caused by aerobic and anaerobic Gram-positive bacteria including methicillin-resistant strains. A Phase III, multicentre, randomized, double-blind, active-controlled trial evaluated the efficacy and safety of contezolid versus linezolid in adults with complicated skin and soft tissue infections (cSSTIs). METHODS: Adult patients with cSSTI were randomized in a ratio of 1:1 to receive contezolid 800 mg or linezolid 600 mg q12h for 7-14 days. Clinical cure rate and safety were assessed at the test of cure (TOC) visit in the full analysis set (FAS) and clinical evaluable (CE) population. Non-inferiority was defined as a lower limit of the 95% CI around the treatment difference of clinical cure rates greater than -10%. Chinadrugtrials.org.cn registration identifier: CTR20150855. RESULTS: Clinical cure rates at TOC indicated non-inferiority of contezolid 800 mg to linezolid 600 mg q12h for patients in the FAS with clinical evaluation, FAS, and CE populations: 92.8% (271/292) versus 93.4% (284/304) (difference -0.6%, 95% CI: -4.7% to 3.5%), 81.4% (271/333) versus 84.5% (284/336) (difference -3.1%, 95% CI: -8.8% to 2.6%) and 90.5% (267/295) versus 90.1% (282/313) (difference 0.4%, 95% CI: -4.3% to 5.1%). Contezolid and linezolid showed similar efficacy for the cSSTIs caused by methicillin-susceptible or methicillin-resistant Staphylococcus aureus. Contezolid demonstrated significant lower incidence of leucopenia (0.3% versus 3.4%) and thrombocytopenia (0% versus 2.3%) than linezolid. The frequency of treatment-emergent adverse events was comparable between the two groups. CONCLUSIONS: Contezolid 800 mg q12h is as effective as linezolid for treatment of cSSTIs in adults, but safer than linezolid in terms of haematological abnormalities.

Integrating molecular interactions and gene expression to identify biomarkers and network modules of chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) causes chronic obstructive conditions, chronic bronchitis, and emphysema, and is a major cause of death worldwide. Although several efforts for identifying biomarkers and pathways have been made, specific causal COPD mechanism remains unknown. OBJECTIVE: This study combined biological interaction data with gene expression data for a better understanding of the biological process and network module for COPD. METHODS: Using a sparse network-based method, we selected 49 genes from peripheral blood mononuclear cell expression data of 136 subjects, including 42 ex-smoking controls and 94 subjects with COPD. RESULTS: These 49 genes might influence biological processes and molecular functions related to COPD. For example, our result suggests that FoxO signaling may contribute to the atrophy of COPD peripheral muscle tissues via oxidative stress. CONCLUSIONS: Our approach enhances the existing understanding of COPD disease pathogenesis and predicts new genetic markers and pathways that may influence COPD pathogenesis.

Integrating molecular interactions and gene expression to identify biomarkers to predict response to tumor necrosis factor inhibitor therapies in rheumatoid arthritis patients.

BACKGROUND: Targeted therapy using anti-TNF (tumor necrosis factor) is the first option for patients with rheumatoid arthritis (RA). Anti-TNF therapy, however, does not lead to meaningful clinical improvement in many RA patients. To predict which patients will not benefit from anti-TNF therapy, clinical tests should be performed prior to treatment beginning. OBJECTIVE: Although various efforts have been made to identify biomarkers and pathways that may be helpful to predict the response to anti-TNF treatment, gaps remain in clinical use due to the low predictive power of the selected biomarkers. METHODS: In this paper, we used a network-based computational method to identify the select the predictive biomarkers to guide the treatment of RA patients. RESULTS: We select 69 genes from peripheral blood expression data from 46 subjects using a sparse network-based method. The result shows that the selected 69 genes might influence biological processes and molecular functions related to the treatment. CONCLUSIONS: Our approach advances the predictive power of anti-TNF therapy response and provides new genetic markers and pathways that may influence the treatment.