Nesfatin-1 Stimulates CCL2-dependent Monocyte Migration And M1 Macrophage Polarization: Implications For Rheumatoid Arthritis Therapy.

Rheumatoid arthritis (RA) is a prototypic inflammatory disease, characterized by the infiltration of proinflammatory cytokines into the joint synovium and the migration of mononuclear cells into inflammatory sites. The adipokine nesfatin-1 is linked to inflammatory events in various diseases, although its role in RA pathology is uncertain. Analysis of the Gene Expression Omnibus GSE55235 dataset revealed high levels of expression of the adipokine nesfatin-1 in human RA synovial tissue. Similarly, our human synovial tissue samples exhibited increasing levels of nesfatin-1 expression and Ccl2 mRNA expression. Nesfatin-1-induced stimulation of CCL2 expression and monocyte migration involved the MEK/ERK, p38, and NF-κB signaling pathways. Notably, nesfatin-1-induced increases in CCL2 expression favored M1 macrophage polarization, which increased the expression of proinflammatory cytokines IL-1ß, IL-6, and TNF-α. Finally, nesfatin-1 shRNA ameliorated the severity of inflammatory disease and reduced levels of M1 macrophage expression in CIA mice. Our studies confirm that nesfatin-1 appears to be worth targeting in RA treatment.

Transdermal nanolipoplex simultaneously inhibits subcutaneous melanoma growth and suppresses systemically metastatic melanoma by activating host immunity.

Benefit for clinical melanoma treatments, the transdermal neoadjuvant therapy could reduce surgery region and increase immunotherapy efficacy. Using lipoplex (Lipo-PEG-PEI-complex, LPPC) encapsulated doxorubicin (DOX) and carrying CpG oligodeoxynucleotide; the transdermally administered nano-liposomal drug complex (LPPC-DOX-CpG) would have high cytotoxicity and immunostimulatory activity to suppress systemic metastasis of melanoma. LPPC-DOX-CpG dramatically suppressed subcutaneous melanoma growth by inducing tumor cell apoptosis and recruiting immune cells into the tumor area. Animal studies further showed that the colonization and growth of spontaneously metastatic melanoma cells in the liver and lung were suppressed by transdermal LPPC-DOX-CpG. Furthermore, NGS analysis revealed IFN-γ and NF-κB pathways were triggered to recruit and activate the antigen-presenting-cells and effecter cells, which could activate the anti-tumor responses as the major mechanism responsible for the therapeutic effect of LPPC-DOX-CpG. Finally, we have successfully proved transdermal LPPC-DOX-CpG as a promising penetrative carrier to activate systemic anti-tumor immunity against subcutaneous and metastatic tumor.

Genetic co-expression networks contribute to creating predictive model and exploring novel biomarkers for the prognosis of breast cancer.

Genetic co-expression network (GCN) analysis augments the understanding of breast cancer (BC). We aimed to propose GCN-based modeling for BC relapse-free survival (RFS) prediction and to discover novel biomarkers. We used GCN and Cox proportional hazard regression to create various prediction models using mRNA microarray of 920 tumors and conduct external validation using independent data of 1056 tumors. GCNs of 34 identified candidate genes were plotted in various sizes. Compared to the reference model, the genetic predictors selected from bigger GCNs composed better prediction models. The prediction accuracy and AUC of 3 ~ 15-year RFS are 71.0-81.4% and 74.6-78% respectively (rfm, ACC 63.2-65.5%, AUC 61.9-74.9%). The hazard ratios of risk scores of developing relapse ranged from 1.89 ~ 3.32 (p < 10-8) over all models under the control of the node status. External validation showed the consistent finding. We found top 12 co-expressed genes are relative new or novel biomarkers that have not been explored in BC prognosis or other cancers until this decade. GCN-based modeling creates better prediction models and facilitates novel genes exploration on BC prognosis.

Usability of Wearable Devices With a Novel Cardiac Force Index for Estimating the Dynamic Cardiac Function: Observational Study.

BACKGROUND: Long-distance running can be a form of stress to the heart. Technological improvements combined with the public's gradual turn toward mobile health (mHealth), self-health, and exercise effectiveness have resulted in the widespread use of wearable exercise products. The monitoring of dynamic cardiac function changes during running and running performance should be further studied. OBJECTIVE: We investigated the relationship between dynamic cardiac function changes and finish time for 3000-meter runs. Using a wearable device based on a novel cardiac force index (CFI), we explored potential correlations among 3000-meter runners with stronger and weaker cardiac functions during running. METHODS: This study used the American product BioHarness 3.0 (Zephyr Technology Corporation), which can measure basic physiological parameters including heart rate, respiratory rate, temperature, maximum oxygen consumption, and activity. We investigated the correlations among new physiological parameters, including CFI = weight * activity / heart rate, cardiac force ratio (CFR) = CFI of running / CFI of walking, and finish times for 3000-meter runs. RESULTS: The results showed that waist circumference, smoking, and CFI were the significant factors for qualifying in the 3000-meter run. The prediction model was as follows: ln (3000 meters running performance pass probability / fail results probability) = -2.702 - 0.096 × [waist circumference] - 1.827 × [smoke] + 0.020 × [ACi7]. If smoking and the ACi7 were controlled, contestants with a larger waist circumference tended to fail the qualification based on the formula above. If waist circumference and ACi7 were controlled, smokers tended to fail more often than nonsmokers. Finally, we investigated a new calculation method for monitoring cardiac status during exercise that uses the CFI of walking for the runner as a reference to obtain the ratio between the cardiac force of exercise and that of walking (CFR) to provide a standard for determining if the heart is capable of exercise. A relationship is documented between the CFR and the performance of 3000-meter runs in a healthy 22-year-old person. During the running period, data are obtained while participant slowly runs 3000 meters, and the relationship between the CFR and time is plotted. The runner's CFR varies with changes in activity. Since the runner's acceleration increases, the CFR quickly increases to an explosive peak, indicating the runner's explosive power. At this period, the CFI revealed a 3-fold increase (CFR=3) in a strong heart. After a time lapse, the CFR is approximately 2.5 during an endurance period until finishing the 3000-meter run. Similar correlation is found in a runner with a weak heart, with the CFR at the beginning period being 4 and approximately 2.5 thereafter. CONCLUSIONS: In conclusion, the study results suggested that measuring the real-time CFR changes could be used in a prediction model for 3000-meter running performance.

Evaluation of the pain intensity differences among hospitalized cancer patients based on a nursing information system.

Evaluating the absolute difference in pain intensity and the percentage difference in pain intensity could facilitate an understanding of pain reduction among cancer patients during repeated hospitalizations. Examinations of the absolute differences in pain intensity and the percentage differences in pain intensity according to the worst pain intensity and last evaluated pain intensity before discharge are lacking. The aim of this study was to evaluate the absolute and percentage difference in pain intensities among cancer patients with moderate or severe pain from their 1st to 18th hospitalizations from 2011-2013. A population-based retrospective cohort study was conducted. Pain intensity was assessed using scales and was recorded in a nursing information system. The absolute and percentage difference in pain intensities were examined via the one-sample Kolmogorov-Smirnov test, and group differences in moderate or severe pain were evaluated with the Mann-Whitney U test. For moderate pain patients, the mean absolute difference in pain intensity was 1.52, and the percentage difference in pain intensity was 29.0%; both these values were significant. More significant changes in the absolute and percentage difference in pain intensities were associated with severe pain patients. Both the average absolute difference in pain intensity (3.09) and the percentage difference in pain intensity (38.5%) in patients with severe pain were significantly higher than the average absolute difference in pain intensity (1.52) and the percentage difference in pain intensity (29.0%) in patients with moderate pain. Cancer patients with moderate and severe pain experienced pain reductions of approximately 30% and 40%, respectively. Early pain management intervention in patients with severe pain is necessary to achieve an obvious analgesic effect, and the formula of the percentage difference in pain intensity should be incorporated into the nursing information system to alert clinicians for early detection of the effectiveness of cancer pain management.

Association between health behaviors and mood disorders among the elderly: a community-based cohort study.

BACKGROUND: According to a WHO report, nearly 15% of adults aged 60 and over suffer from a mental disorder, constituting 6.6% of the total disability for this age group. Taipei City faces rapid transformation towards an aging society, with the proportion of elderly in the total population rising from 12% in 2008 to 16% in 2016. The aim of this study is to identify the prevalence of mental disorders among the elderly in Taipei City and to elucidate risk factors contributing to mental disorders. METHODS: The elderly health examination database was obtained from the Department of Health, Taipei City government, from 2005 to 2012. A total of 86,061 people underwent publicly funded health examinations, with 348,067 visits. Each year, there are around 43,000 elderly persons in Taipei City using this service. We used a mental health questionnaire including five questions to estimated relative risks among potential risk factors with the generalized estimating equations (GEE) model to measure the mental health status of the elderly. Mood disorders were measured with the Brief Symptom Rating Scale (BSRS-5) questionnaire. Age, education level, gender, marital status, living alone, drinking milk, eating vegetables and fruits, long-term medication, smoking status, frequency of alcohol consumption, frequency of physical activity, BMI, and number of chronic diseases were included as covariates. RESULTS: The results show that being male (odds ratio (OR) 0.57; 95% CI = 0.56, 0.59), higher education (OR 0.88; 95% CI = 0.82, 0.95), no long-term medication (OR 0.57; 95% CI = 0.56, 0.58), and exercising three or more times per week (OR 0.94; 95% CI = 0.91, 0.98) were all positively correlated with better emotional status. However, being divorced (OR = 1.22, 95% CI = 1.09, 1.36), not drinking milk (OR = 1.12, 95% CI = 1.09, 1.14), not eating enough vegetables and fruits every day (OR = 1.78, 95% CI = 1.73, 1.83), daily smoking (OR = 1.15, 95% CI = 1.01, 1.32), and having more chronic diseases (OR = 1.02, 95% CI = 1.01, 1.03) were all correlated with poor mental status among the elderly. CONCLUSIONS: The findings of this research can both estimate the prevalence of mood disorders at the community level, and identify risk factors of mood disorders at the personal level.

Glioblastoma cells labeled by robust Raman tags for enhancing imaging contrast.

Complete removal of a glioblastoma multiforme (GBM), a highly malignant brain tumor, is challenging due to its infiltrative characteristics. Therefore, utilizing imaging agents such as fluorophores to increase the contrast between GBM and normal cells can help neurosurgeons to locate residual cancer cells during image guided surgery. In this work, Raman tag based labeling and imaging for GBM cells in vitro is described and evaluated. The cell membrane of a GBM adsorbs a substantial amount of functionalized Raman tags through overexpression of the epidermal growth factor receptor (EGFR) and "broadcasts" stronger pre-defined Raman signals than normal cells. The average ratio between Raman signals from a GBM cell and autofluorescence from a normal cell can be up to 15. In addition, the intensity of these images is stable under laser illuminations without suffering from the severe photo-bleaching that usually occurs in fluorescent imaging. Our results show that labeling and imaging GBM cells via robust Raman tags is a viable alternative method to distinguish them from normal cells. This Raman tag based method can be used solely or integrated into an existing fluorescence system to improve the identification of infiltrative glial tumor cells around the boundary, which will further reduce GBM recurrence. In addition, it can also be applied/extended to other types of cancer to improve the effectiveness of image guided surgery.

Albuminuria and neck circumference are determinate factors of successful accurate estimation of glomerular filtration rate in high cardiovascular risk patients.

BACKGROUND: Estimated glomerular filtration rate (eGFR) is used for diagnosis of chronic kidney disease (CKD). The eGFR models based on serum creatinine or cystatin C are used more in clinical practice. Albuminuria and neck circumference are associated with CKD and may have correlations with eGFR. AIM: We explored the correlations and modelling formulates among various indicators such as serum creatinine, cystatin C, albuminuria, and neck circumference for eGFR. DESIGN: Cross-sectional study. METHODS: We reviewed the records of patients with high cardiovascular risk from 2010 to 2011 in Taiwan. 24-hour urine creatinine clearance was used as the standard. We utilized a decision tree to select for variables and adopted a stepwise regression method to generate five models. Model 1 was based on only serum creatinine and was adjusted for age and gender. Model 2 added serum cystatin C, models 3 and 4 added albuminuria and neck circumference, respectively. Model 5 simultaneously added both albuminuria and neck circumference. RESULTS: Total 177 patients were recruited in this study. In model 1, the bias was 2.01 and its precision was 14.04. In model 2, the bias was reduced to 1.86 with a precision of 13.48. The bias of model 3 was 1.49 with a precision of 12.89, and the bias for model 4 was 1.74 with a precision of 12.97. In model 5, the bias could be lower to 1.40 with a precision of 12.53. CONCLUSIONS: In this study, the predicting ability of eGFR was improved after the addition of serum cystatin C compared to serum creatinine alone. The bias was more significantly reduced by the calculation of albuminuria. Furthermore, the model generated by combined albuminuria and neck circumference could provide the best eGFR predictions among these five eGFR models. Neck circumference can be investigated potentially in the further studies.

Using a New Measurement to Evaluate Pain Relief Among Cancer Inpatients with Clinically Significant Pain Based on a Nursing Information System: A Three-Year Hospital-Based Study.

OBJECTIVE: Developing a new measurement index is the first step in evaluating pain relief outcomes. Although the percentage difference in pain intensity (%PID) is the most popular indicator, this indicator does not take into account the goal of pain relief. Therefore, the aims of this study were to develop a pain relief index (PRI) for outcome evaluation and to examine the index using demographic characteristics of cancer inpatients with clinically significant pain. DESIGN: Retrospective cohort study. SETTING: A national hospital. SUBJECTS: All cancer inpatients. METHODS: Pain intensity was assessed using a numerical rating scale, a faces pain scale or the Face, Legs, Activity, Cry, Consolability (FLACC) Behavioral Tool. Using a nursing information system, a pain score database containing data from 2011 through 2013 was analyzed. RESULTS: Cancer patients representing 93,812 hospitalizations were considered in this study. We focused on cancer patients for whom the worst pain intensity (WPI) was ≥ 4 points. PRI values of -62.02% to -72.55% were observed in the WPI ≥ 7 and 4 ≤ WPI ≤ 6 groups. Significant (P < 0.05) effects on PRI values were observed among patients who were > 65 years old, those who were admitted to the medicine or gynecology and those who had a hospital stay > 30 days. CONCLUSION: This hospital-based study demonstrated that the PRI is an effective and valid measure for evaluating outcome data using an electronic nursing information system. We will further define the meaningful range of percentage difference in PRI from various perspectives.

Gene expression profile of peripheral blood in colorectal cancer.

AIM: Optimal molecular markers for detecting colorectal cancer (CRC) in a blood-based assay were evaluated. METHODS: A matched (by variables of age and sex) case-control design (111 CRC and 227 non-cancer samples) was applied. Total RNAs isolated from the 338 blood samples were reverse-transcribed, and the relative transcript levels of candidate genes were analyzed. The training set was made of 162 random samples of the total 338 samples. A logistic regression analysis was performed, and odds ratios for each gene were determined between CRC and non-cancer. The samples (n = 176) in the testing set were used to validate the logistic model, and an inferred performance (generality) was verified. By pooling 12 public microarray datasets(GSE 4107, 4183, 8671, 9348, 10961, 13067, 13294, 13471, 14333, 15960, 17538, and 18105), which included 519 cases of adenocarcinoma and 88 controls of normal mucosa, we were able to verify the selected genes from logistic models and estimate their external generality. RESULTS: The logistic regression analysis resulted in the selection of five significant genes (P < 0.05; MDM2, DUSP6, CPEB4, MMD, and EIF2S3), with odds ratios of 2.978, 6.029, 3.776, 0.538 and 0.138, respectively. The five-gene model performed stably for the discrimination of CRC cases from controls in the training set, with accuracies ranging from 73.9% to 87.0%, a sensitivity of 95% and a specificity of 95%. In addition, a good performance in the test set was obtained using the discrimination model, providing 83.5% accuracy, 66.0% sensitivity, 92.0% specificity, a positive predictive value of 89.2% and a negative predictive value of 73.0%. Multivariate logistic regressions analyzed 12 pooled public microarray data sets as an external validation. Models that provided similar expected and observed event rates in subgroups were termed well calibrated. A model in which MDM2, DUSP6, CPEB4, MMD, and EIF2S3 were selected showed the result in logistic regression analysis (H-L P = 0.460, R2= 0.853, AUC = 0.978, accuracy = 0.949, specificity = 0.818 and sensitivity = 0.971). CONCLUSION: A novel gene expression profile was associated with CRC and can potentially be applied to blood-based detection assays.

Validation of the Chinese version of the hypomania checklist (HCL-32) as an instrument for detecting hypo(mania) in patients with mood disorders.

BACKGROUND: Bipolar disorder (BP) has been consistently under-recognized and erroneously diagnosed as major depression. The resulting inappropriate or delayed treatment is associated with elevated risk of (hypo)mania or cycling. The recognition of (hypo)manic episodes is essential for the correct diagnosis of BP. The Hypomania CheckList (HCL-32) is developed to increase the detection of suspected or manifest but mistreated BP cases. We aimed to determine the accuracy and validity of the Chinese version of the HCL-32 in an adult psychiatric setting. We also compared the results with prior studies carried out in a comparable sample. METHODS: Patients suffering from mood disorders completed the HCL-32 before being interviewed with the Schedule for Affective Disorder and Schizophrenia-Lifetime (SADS-L) to make DSM-IV diagnosis. The 4-day duration criterion for hypomania was replaced by a 2-day cut-off for BPII. The internal consistency and discriminatory capacity of the HCL-32 were analyzed. RESULTS: Results indicated high internal consistency of the Chinese version of the HCL-32. The dual factor structure was confirmed. A score of 14 or more on the HCL-32 total scale distinguished between BP and MDD yielding a sensitivity of 82% and a specificity of 67%. This scale also distinguished between BPI and BPII with a sensitivity of 64% and a specificity of 73% for the cut-off score of 21. LIMITATIONS: The sample size of MDD patients needs to be increased. CONCLUSIONS: The Chinese HCL-32 is a useful screening tool for BP in a psychiatric setting. Its performance is also comparable to that reported in previous studies.