Description: Owing to drug synergy effects, drug combinations have become a new trend in combating complex diseases like cancer, HIV and cardiovascular diseases. However, conventional synergy quantification methods often depend on experimental dose–response data which are quite resource-demanding. In addition, these methods are unable to interpret the explicit synergy mechanism. In this review, we give representative examples of how systems biology modeling offers strategies toward better understanding of drug synergy, including the protein-protein interaction (PPI) network-based methods, pathway dynamic simulations, synergy network motif recognitions, integrative drug feature calculations, and “omic”-supported analyses. Although partially successful in drug synergy exploration and interpretation, more efforts should be put on a holistic understanding of drug-disease interactions, considering integrative pharmacology and toxicology factors. With a comprehensive and deep insight into the mechanism of drug synergy, systems biology opens a novel avenue for rational design of effective drug combinations.

Description: Background: Sensory consequences of our own actions are perceived differently from the sensory stimuli that are generated externally. The present event-related potential (ERP) study examined the neural responses to self-triggered stimulation relative to externally-triggered stimulation as a function of delays between the motor act and the stimulus onset. While sustaining a vowel phonation, subjects clicked a mouse and heard pitch-shift stimuli (PSS) in voice auditory feedback at delays of either 0 ms (predictable) or 500-1000 ms (unpredictable). The motor effect resulting from the mouse click was corrected in the data analyses. For the externally-triggered condition, PSS were delivered by a computer with a delay of 500-1000 ms after the vocal onset. Results: As compared to unpredictable externally-triggered PSS, P2 responses to predictable self-triggered PSS were significantly suppressed, whereas an enhancement effect for P2 responses was observed when the timing of self-triggered PSS was unpredictable. Conclusions: These findings demonstrate the effect of the temporal predictability of stimulus delivery with respect to the motor act on the neural responses to self-triggered stimulation. Responses to self-triggered stimulation were suppressed or enhanced compared with the externally-triggered stimulation when the timing of stimulus delivery was predictable or unpredictable. Enhancement effect of unpredictable self-triggered stimulation in the present study supports the idea that sensory suppression of self-produced action may be primarily caused by an accurate prediction of stimulus timing, rather than a movement-related non-specific suppression.

Description: Background: SOX genes play an important role in a number of developmental processes. Potential roles of SOXs have been demonstrated in various neoplastic tissues as tumor suppressors or promoters depending on tumor status and types. The aim of this study was to investigate the involvement of SOXs in the progression and prognosis of human prostate cancer (PCa). Methods: The gene expression changes of SOXs in human PCa tissues compared with non-cancerous prostate tissues was detected using gene expression microarray, and confirmed by real-time quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) analysis and immunohositochemistry. The roles of these genes in castration resistance were investigated in LNCaP xenograft model of PCa. Results: The microarray analysis identified three genes (SOX7, SOX9 and SOX10) of SOX family that were significantly dis-regulated in common among four PCa specimens. Consistent with the results of the microarray, differential mRNA and protein levels of three selected genes were found in PCa tissues by QRT-PCR analysis and immunohistochemistry. Additionally, we found that the immunohistochemical staining scores of SOX7 in PCa tissues with higher serum PSA level (P = 0.02) and metastasis (P = 0.03) were significantly lower than those with lower serum PSA level and without metastasis; the increased SOX9 protein expression was frequently found in PCa tissues with higher Gleason score (P = 0.02) and higher clinical stage (P 〈 0.0001); the down-regulation of SOX10 tend to be found in PCa tissues with higher serum PSA levels (P = 0.03) and advanced pathological stage (P = 0.01). Moreover, both univariate and multivariate analyses showed that the down-regulation of SOX7 and the upregulation of SOX9 were independent predictors of shorter biochemical recurrence-free survival. Furthermore, we discovered that SOX7 was significantly down-regulated and SOX9 was significantly up-regulated during the progression to castration resistance. Conclusions: Our data offer the convince evidence that the dis-regulation of SOX7, SOX9 and SOX10 may be associated with the aggressive progression of PCa. SOX7 and SOX9 may be potential markers for prognosis in PCa patients. Interestingly, the down-regulation of SOX7 and the up-regulation of SOX9 may be important mechanisms for castration-resistant progression of PCa.

Description: Background: Diffusion-weighted (DW) imaging has shown potential to differentiate between malignant and benign breast lesions. However, different b values have been used with varied sensitivity and specificity. This study aims to prospectively evaluate the influence of b value on the detection and assessment of breast lesions. Methods: Institutional review board approval and informed patient consent were obtained. Between February 2010 and September 2010, sixty women suspected of having breast cancer by clinical examination and mammography underwent bilateral breast MRI and DW imaging (with maximum b values of 600, 800, and 1000s/mm2). Conspicuity grades of lesions at different b values on DW images were performed. Signal intensity and apparent diffusion coefficient (ADC) values were recorded and compared among different b values by the signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR) and receiver operating characteristic (ROC) curve. Results: Fifty-seven lesions from 52 recruited patients including 39/57 (68%) malignant and 18/57 (32%) benign were confirmed with pathology. DCE MRI accurately detected 53 lesions with the sensitivity of 93.0% and specificity of 66.7%, and DW imaging accurately detected 51 lesions with the sensitivity of 89.5% and specificity of 100%. There were no significant differences in conspicuity grades compared among the three b values (P=0.072), although the SNR and CNR of breast lesions decreased significantly with higher b values. Mean ADCs of malignant lesions (b=600s/mm2, 1.07+/-0.26 x10-3 mm2/s; b=800s/mm2, 0.96+/-0.22 x10-3 mm2/s; b=1000s/mm2, 0.92+/-0.26 x10-3 mm2/s) were significantly lower than those of benign lesions (b=600s/mm2, 1.55+/-0.40 x10-3 mm2/s; b=800s/mm2, 1.43+/-0.38 x10-3 mm2/s; b=1000s/mm2, 1.49+/-0.38 x10-3 mm2/s) with all P values

Description: Background: Zona pellucida domain-containing proteins (ZP proteins) have been identified as the principle constituents of the egg coat (EC) of diverse metazoan taxa, including jawed vertebrates, urochordates and molluscs that span hundreds of millions of years of evolutionary divergence. Although ZP proteins generally contain the zona pellucida (ZP) structural modules to fulfill sperm recognition and EC polymerization functions during fertilization, the primary sequences of the ZP proteins from the above-mentioned animal classes are drastically different, which makes it difficult to assess the evolutionary relationships of ZP proteins. To understand the origin of vertebrate ZP proteins, we characterized the egg coat components of Branchiostoma belcheri, an invertebrate species that belongs to the chordate subphylum Cephalochordata. Results: Five ZP proteins (BbZP1-5) were identified by mass spectrometry analyses using the egg coat extracts from both unfertilized and fertilized eggs. In addition to the C-terminal ZP module in each of the BbZPs, the majority contain a low-density lipoprotein receptor domain and a von Willebrand factor type A (vWFA) domain, but none possess an EGF-like domain that is frequently observed in the ZP proteins of urochordates. Fluorescence in situ hybridization and immuno-histochemical analyses of B. belcheri ovaries showed that the five BbZPs are synthesized predominantly in developing eggs and deposited around the extracellular space of the egg, which indicates that they are bona fide egg coat ZP proteins. BbZP1, BbZP3 and BbZP4 are significantly more abundant than BbZP2 and BbZP5 in terms of gene expression levels and the amount of mature proteins present on the egg coats. The major ZP proteins showed high polymorphism because multiple variants are present with different molecular weights. Sequence comparison and phylogenetic analysis between the ZP proteins from cephalochordates, urochordates and vertebrates showed that BbZP1-5 form a monophyletic group and share no significant sequence similarities with the ZP proteins of urochordates and the ZP3 subtype of jawed vertebrates. By contrast, small regions of homology were identifiable between the BbZP and ZP proteins of the non-jawed vertebrate, the sea lamprey Petromyzon marinus. The lamprey ZP proteins were highly similar to the ZP1 and ZP2 subtypes of the jawed vertebrates, which suggests that the ZP proteins of basal chordates most likely shared a recent common ancestor with vertebrate ZP1/2 subtypes and lamprey ZP proteins. Conclusions: The results document the spectra of zona pellucida domain-containing proteins of the egg coat of basal chordates. Particularly, the study provides solid evidence for an invertebrate origin of vertebrate ZP proteins and indicates that there are diverse domain architectures in ZP proteins of various metazoan groups.

Description: Background: The role of postoperative adjuvant treatment for sinonasal malignant melanoma remains unclear. This study evaluates the impact of three different surgical and postoperative adjuvant treatment modalities: surgery alone(open and endoscopic approaches), surgery plus radiotherapy and surgery, radiotherapy plus chemotherapy on survival of patients with primary sinonasal malignant melanoma (SMM). Methods: The data of 69 patients who underwent primary surgical treatments at Eye & ENT hospital of Fudan University between January 1st, 2000 and December 31st, 2010 were retrospectively reviewed. Survival comparison of different surgical and postoperative adjuvant treatment modalities (surgery alone, surgery plus radiotherapy and surgery, radiotherapy plus chemotherapy), as well as survival comparison between open and endoscopic surgical approaches were performed. Curves depicting survival were performed using Kaplan-Meier method. Statistical analysis was performed using log-rank test software SPSS19 and p 〈 .05 is considered as statistically significant. Results: The median overall survival time was found to be 18 months for surgery alone (27 cases), 32 months for surgery plus radiotherapy (24 cases), 42 months for surgery, radiotherapy plus chemotherapy (18 cases). The 3 and 5 year survival rates for groups mentioned above were 14.8% and 5.6%, 45.1% and 31.6%, 55% and 32.1%, respectively. Statistical significances were found not only between surgery alone and surgery plus radiotherapy treatment group(P = 0.012), but also surgery alone and surgery, radiotherapy plus chemotherapy group (P = 0.002). There was no statistically significant survival difference found between the two different surgical approaches (41 cases for open approach and 28 cases for endoscopic approach) . Conclusions: Sinonasal malignant melanoma is a disease with a poor prognosis. Patients who underwent surgery plus radiotherapy or surgery, radiotherapy plus chemotherapy had better survival outcomes than those underwent surgery alone. Endoscopic approach provided similar survival outcome as an open approach.

Description: Background: Community health service center (CHSC) in China is always regarded as a good facility of primary care, which plays an important role in chronic non-communicable disease management. This study aimed to investigate the blood pressure (BP) control rate in a real life CHSC-based management program and its determinants. Methods: The study enrolled 3191 patients (mean age of 70 +/- 10 years, 43% males) in a hypertension management program provided by the Yulin CHSC (Chengdu, China), which had been running for 9 years. Uncontrolled BP was defined as the systolic BP of 〉=140 mmHg and/or the diastolic BP of 〉=90 mmHg, and its associated factors were analyzed by using logistic regression. Results: The duration of stay in the program was 33 +/- 25 months. When compared with the BP at entry, the recent BP was significantly lowered (147 +/- 17 vs. 133 +/- 8 mmHg; 83 +/- 11 vs. 75 +/- 6 mmHg) and the BP control rate was dramatically increased (32 vs. 85%) (all p 〈 0.001). The age of 〉70 years [1.40 (odds ratio), 1.15-1.71 (95% confidence interval)], female gender (0.76, 0.63-0.93), longer stay of 〉33 months (0.77, 0.63-0.94), doctor in charge (0.97, 0.95-0.99), and the use of calcium channel blocker (1.35, 1.09-1.67) were significantly related to uncontrolled BP at the recent follow up (all p 〈 0.05). Conclusions: This CHSC-run hypertension program provides an ideal platform of multi-intervention management, which is effective in achieving higher BP control rate in community patient population. However, the BP control status could be affected by age, gender and adherence of the patients, as well as practice behavior of the doctors.

Description: Background: Maize is a major economic crop worldwide, with substantial crop loss attributed to flooding. During a stress response, programmed cell death (PCD) can be an effective way for plants better adapt. To identify flooding stress related PCD proteins in maize leaves, proteomic analysis was performed using two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) and mass spectrometry. Results: Comparative proteomics was combined with physiological and biochemical analysis of maize leaves under flooding stress. Fv/Fm, qP, qN and relative water content (RWC) were found to be altered in response to flooding stress, with an increase in H2O2 content noted in vivo. Furthermore, DNA ladder detection indicated that PCD had occurred under flooding treatment. The maize leaf proteome was analyzed via 2D-DIGE gel, with a total of 32 differentially expressed spots isolated, 31 spots were successfully identified via MALDI-TOF/TOF MS which represent 28 proteins. The identified proteins were related to energy metabolism and photosynthesis, PCD, phytohormones and polyamines. To better characterize the role of translationally controlled tumor protein (TCTP) in PCD during a stress response, mRNA expression was examined in different plants by stress-induced PCD. These included heat stress induced rice protoplasts, Tobacco Mosaic Virus infected tobacco leaves and dark induced rice and Arabidopsis thaliana leaves, all of which showed active PCD, and TCTP expression was increased in different degrees. Moreover, S-adenosylmethionine synthase 2 (SAMS2) and S-adenosylmethionine decarboxylase (SAMDC) mRNA expression were also increased, but ACC synthase (ACS) and ACC oxidase (ACO) mRNA expression were not found in maize leaves following flooding. Lastly, ethylene and polyamine concentrations were increased in response to flooding treatment in maize leaves. Conclusions: Following flooding stress, the photosynthetic systems were damaged, resulting in a disruption in energy metabolism, with the noted photosynthetic decline also possibly attributed to ROS production. The observed PCD could be regulated by TCTP with a possible role for H2O2 in TCTP induction under flooding stress. Additionally, increased SAMS2 expression was closely associated with an increased polyamine synthesis during flooding treatment.

Description: Background: Nonurgent use of hospital emergency departments (ED) is a controversial topic. It is thought to increase healthcare costs and reduce quality, but is also considered a symptom of unequal access to health care. In this article, we investigate whether convenience (as proxied by travel distances to the hospital ED and to the closest federally qualified health center) is associated with nonurgent ED use, and whether evidence of health disparities exist in the way vulnerable populations use the hospital ED for medical care in South Carolina. Methods: Our data includes 6,592,501 ED visits in South Carolina between 2005 and 2010 from the South Carolina Budget Control Board and Office of Research and Statistics. All ED visits by South Carolina residents with unmasked variables and nonmissing urgency measures, or approximately 76 % of all ED visits, are used in the analysis. We perform multivariable linear regressions to estimate correlations between (1) travel distances and observable sociodemographic characteristics and (2) measures of nonurgent ED use or frequent nonurgent ED use, as defined by the New York University ED Algorithm. Results: Patients with commercial private insurance, self-pay patients, and patients with other payment sources have lower measures of nonurgent ED use the further away the ED facility is from the patients’ home address. Vulnerable populations, particularly African American and Medicaid patients, have higher measures of nonurgent ED scores, and are more frequent users of the ED for both nonurgent and urgent reasons in South Carolina. At the same time, African Americans visit the hospital ED for medical conditions with higher primary care-preventable scores. Conclusions: Contrary to popular belief, convenient access (in terms of travel distances) to hospital ED is correlated with less-urgent ED use among privately insured patients and self-pay patients in South Carolina, but not publicly insured patients. Unequal access to primary care appears to exist, as suggested by African American patients’ use of the hospital ED for primary care-treatable conditions while experiencing more frequent and more severe primary care-preventable conditions.

Description: Defects in distal oesophageal peristalsis was thought to be an indication of incomplete bolus transit (BT). However, the role of transition zone (TZ) defects in the BT in gastroesophageal reflux disease (GORD)...