The protein biomarkers described in this study have all been

The protein biomarkers described in this study have all been associated with lung cancer, and characterized previously for cancer diagnostic potential. The elevated CRP preceded lung cancer diagnosis by several years (Chaturvedi et al., 2010), and were associated with increasing lung cancer risk (Xu et al., 2013). Elevation of serum prolactin could be served as diagnostic biomarkers for lung cancer (Bigbee et al., 2012; Nolen et al., 2011). Sera HGF were significantly elevated in lung cancer patients (Tanaka et al., 2011), and a high level of blood HGF exhibited a poor prognosis of metastatic disease in primary lung cancer patients (Hosoda et al., 2012). NY-ESO-1 autoantibody frequencies in lung cancer have been reported to range from 4 to 23% (Chapman et al., 2008; Tureci et al., 2006; Stockert et al., 1998). More importantly, NY-ESO-1 autoantibody was detected in patients with small primary tumors and more frequently before distant MLN 8237 occurred, suggesting that NY-ESO-1 antibody is an early event (Tureci et al., 2006).
Although the biomarker panel we described here could not detect every lung cancer patient, it offers a high specificity in detecting healthy controls as well as the patients with benign lung diseases. After the appropriate confirmatory clinical trials, one could envision that the most immediate scenario in which this panel could be used is to improve interpretation of CT images in the setting of a suspicious pulmonary nodule. In this context, a diagnostic biomarker panel must perform at a maximal level of specificity in order to reduce the number of false positive results rendered by CT. Actually, of the 80 prospective patients, the 4-biomarker predictor produced 82.6% sensitivity and 98.2% specificity as determined by post-surgery histologic results or 2years clinical follow-up. Therefore, as a supplementary diagnostic approach to CT scan, such a strategy could significantly reduce the number of futile invasive procedures. Upon further validation and optimization, these serum biomarkers could provide an effective means to further assess the malignant patients designated as having a high risk for lung cancer by LDCT scanning.


Authors Contributions

The study was supported by grants from the Major Science and Technology Innovation Project of Hangzhou (20112312A01), the National Natural Science Foundation (81172072), the Science Foundation for Distinguished Young Scholars of Zhejiang (R2101405), the International Science and Technology Cooperation Project of Zhejiang (2012C24008), and the Collaborative Innovation Projects of Science and Technology Department of Zhejiang (2014F50014), China. The funders had no role in study design, data collection, data analysis, interpretation and writing of the report.

Conflict of Interest

Cigarette smoking is the leading modifiable risk for cancer and multiple major chronic illnesses. Growing evidence identifies that genetic variation in the α5 nicotinic cholinergic receptor subunit (CHRNA5) gene plays a key role in both heavy smoking and nicotine dependence (Bierut et al., 2007; Bierut et al., 2008a). Multiple large meta-analyses demonstrated the association with smoking quantity, defined by number of cigarettes smoked per day (CPD) (Liu et al., 2010; Saccone et al., 2010; TAG, 2010; Thorgeirsson et al., 2010), with the most robust signal for two highly correlated genetic variants, rs16969968 and rs1051730 in subjects of European ancestry (TAG, 2010). The coding variant, rs16969968, results in an amino acid change in the α5 nicotinic cholinergic receptor subunit, and subsequently alters nicotinic receptor conductance in vitro (Bierut et al., 2008b; Kuryatov et al., 2011). Genetic variation in CHRNA5 increases risk for smoking-related disorders such as lung cancer and chronic obstructive pulmonary disease (COPD) (Amos et al., 2008; Pillai et al., 2009; Thorgeirsson et al., 2008). Research suggests that the association between CHRNA5 and lung cancer may be mediated by COPD (Young et al., 2011; Brennan et al., 2011; Wang et al., 2010). Further, CHRNA5 has been reported to predict smoking cessation in both cessation trials (Baker et al., 2009; Bergen et al., 2013; Chen et al., 2012; Munafo et al., 2011; Sarginson et al., 2011) and general population studies (TAG, 2010; Chen et al., 2012; Chen et al., 2015a). The CHRNA5 variant rs16969968 was recently shown to be a marker of delayed smoking cessation in a meta-analysis (Chen et al., 2015a). Smokers with the high-risk genotype had delayed age of smoking cessation compared with those with the low-risk genotype (age 56 versus age 52). Similarly, those with the high-risk genotype had a 4-year earlier age of lung cancer diagnosis compared to those with the low-risk genotypes (age 61 vs. age 65).

MLN 8237 br Conclusions br Acknowledgments This study was


This study was supported by Key Projects in the National Science & Technology Pillar Program during the Twelfth Five-Year Plan Period (2012 BAI13 B00) and Fundamental Research Funds for Jilin University (201103082). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the article.

Neurologic diseases ranging from epilepsy to movement disorders continue to evade effective medical management for many patients. When conventional pharmacotherapeutic approaches have been exhausted for such disorders, surgery becomes a potential modality of choice. For example, patients with temporal lobe epilepsy that is refractory to various combinations of anti-epileptic drugs become candidates for surgical resection of part or all of the temporal lobe. This type of surgery can be highly invasive and require the removal of substantial amounts of cortical tissue. Complications can include bleeding, infection, blood clots, stroke, seizures, swelling of the MLN 8237 and nerve damage (McClelland et al. 2011). Moreover, persistent functional deficits in memory, language comprehension and visual processing may occur (Helmstaedter et al. 2004). Importantly, this type of surgery is quite effective in improving epilepsy in upward of 70% of patients (Wiebe et al. 2001). Alternatives to major invasive procedures include minimally invasive laser ablation (Willie et al. 2014) and non-invasive radiosurgery (Quigg and Barbaro 2008). Finally, non-invasive, high-intensity focused ultrasound is under development as another non-invasive surgical tool for epilepsy and other disorders (Elias et al. 2013; Martin et al. 2009; Monteith et al. 2013). One limitation of magnetic resonance (MR)–guided focused ultrasound (MRgFUS) is that its ablation effect requires the deposition of a significant amount of energy in the brain tissue. This critical amount of energy deposition can be achieved only when the gain of the focused beam is high enough to overcome the dissipation effect of the skull. The resulting treatment envelope includes tissues located a greater distance from the skull (e.g., thalamus), MLN 8237 whereas structures located nearer to bone (e.g., hippocampus) are more challenging to treat (Aubry et al. 2003; Hynynen and Sun 1999; Lu et al. 2006; Marquet et al. 2009; Pinton et al. 2012).
It therefore remains critical to identify alternative approaches that lessen the complications of major invasive surgery, do not require the ablation of large areas of the brain and minimize injury to functional circuitries, but still provide effective outcomes. This is true not only for the aforementioned example of temporal lobe epilepsy, but for a variety of neurologic disorders involving circuitry dysfunction. Seeking to develop a means of selectively disrupting impaired neuronal circuitry in a non-invasive and targeted manner, in the present study we took advantage of certain key features of FUS and a centrally acting neurotoxin. First, FUS at adequately low intensities does not produce thermal lesions (Choi et al. 2007; Hynynen et al. 2001; McDannold et al. 2005). Second, when combined with systemic (intravenous) injection of microbubbles, low-intensity FUS is capable of transiently disrupting the blood–brain barrier (BBB) without producing sustained injury to the BBB or brain (Hynynen et al. 2001). A major benefit of introducing microbubbles into the circulation is that the intensity of ultrasound beam needed to disrupt the BBB is reduced significantly, which minimizes both thermal effects and persistent disturbance of the tissue (Konofagou et al. 2012). Third, magnetic resonance imaging can be used to guide and selectively target the site of sonification (Cline et al. 1992). Thus, MRgFUS allows planned and spatially restricted modification of BBB permeability. Finally, the neurotoxin quinolinic acid (QA) poorly penetrates the intact BBB. The neurotoxic effects of QA are dependent primarily on direct access to neural N-methyl-D-aspartate receptors. Consequently, systemic administration of QA is relatively innocuous (Foster et al. 1984). Even when very high dosages are administered over a sustained period, only moderate central nervous system changes are observed (Beskid et al. 1997). Exploiting these characteristics, the current proof-of-concept study examined the concept that a systemically administered neurotoxin can be delivered to a specific and restricted area of the brain to destroy target neurons and disrupt central nervous system circuitry.

MLN 8237 The Tuscany Archipelago test case is chosen because

The Tuscany Archipelago test case is chosen because two CTD surveys were carried out to validate the forecasting skill of the structured and unstructured model components of SURF. Two synoptic cruises were organised in the days 17th and 21st of May 2014 with the contemporary acquisition of physical and bio-chemical data from two different vessels. These cruises were part of the activities of the Serious Game exercise organised in the eastern Ligurian Sea in the framework of the MEDESS-4MS project, co-funded by the Med Programme. The hydrological grid had a horizontal MLN 8237 of 3unm with CTD 45 stations also inside an oil slick located in an area of about 70ukm2 north of the Elba island (Fig. 2, red rectangle). This area is characterised by a high level risk for oil spills but no previous in-depth environmental studies are present. Aim of the Serious Game exercise was to acquire data to characterise the area for the first time and validate a circulation numerical model and an oil spill numerical model realised in the framework of the MEDESS-4MS project and part of its oil-spill management online system. Physical and bio-chemical data were collected using a CTD Seabird SBE19 equipped with sensors of pressure, temperature, conductivity, dissolved oxygen, turbidity, Chl α and CDOM fluorescence. In situ data collection activities were performed on board of the vessels made available by the Italian Coast Guard and used as Ships MLN 8237 of Opportunity. The two surveys collected hydrological data each in about 24uh, thus realising a synoptic estimate of the thermocline properties of the area. CTD data collection has a grid spacing of approximately 5a6ukm, therefore experimental data are diastole able to resolve the Rossby radius, which corresponds to about 10ukm in the Mediterranean sea.

Mass balances of the recovery of ammonia

Mass balances of the recovery of ammonia from digested swine effluent in two farms using gas-permeable membrane module with and without aeration treatmenta.TreatmentsTimeTime to maximum recoveryInitial NH4+ in manureRemaining NH4+ in manureNH4+ removed from manurebNH4+ potentially volatilized in aircNH4+ recovered in acidic solutionNH4–N removal efficiencydNH4–N recovery efficiencyeMaximum NH4+ recovery rateAverage NH4+ recovery ratef(days)(mg N)(%)(mg NH4–N day−1)Farm 1 aerated543133 (151)96 (29)3037582979 (2)97981621596Farm 1 non aerated25253157 (132)71 (19)30861502936 (40)9895424117Farm 2 aerated552332 (28)34 (8)2298942204 (44)9996768441Farm 2 non aerated28242062 (56)155 (72)19074651442 (83)927653852a1.5 L manure in MLN 8237 2 L vessel, using 250 mL 1 N H2SO4 of acidic solution in the concentrator tank (recirculation rate of 4 mL min−1) and membrane tubing length = 0.6 m (area = 194 cm2). Aeration rate = 180 mL min−1 (0.12 L-air L-manure−1 min−1). Data are cytoskeleton average and std. dev. of duplicate reactors.bNH4+ removed from manure = initial NH4+ in manure − remaining NH4+ in manure.cNH4+ potentially volatilized in the air = initial NH4+ in manure − remaining NH4+ in manure − NH4+ recovered in the acidic solution.dNH4+ removal efficiency = (NH4+ removed from manure/initial NH4+ in manure) × 100.eNH4+ recovery efficiency = (NH4+ recovered in the acidic solution/NH4+ removed from manure) × 100.fAverage NH4+ recovery rate = mass NH4–N recovered in the acidic solution/days in experiment.Full-size tableTable optionsView in workspaceDownload as CSV

Lesser availability of longer duration RCTs for this study was

Lesser availability of longer duration RCTs for this study was an important limitation which might be overcome to some extent in coming years when the results of some ongoing trials will be available. Higher levels of statistical heterogeneity observed in many comparisons may also be considered as a limitation. Sensitivity analyses could reduce heterogeneity significantly at least in one comparison in which I2 declined from 85% to 0% when a single trial was excluded (see para 6 of Section 3). To which extent it MLN 8237 was attributable to clinical and methodological heterogeneity could not be elucidated. However, the age of the participant population deviated 10 years from the mean (54) and mean duration of disease since diagnosis was 5.15 with a standard deviation of 4.13 and range of 1.7–7.0 years. Furthermore BMI deviated about 5 from a mean of 30, though relatively smaller deviations were noted for major clinical indicators. In multi-center and multi-national trials ethnicity may also contribute to overall heterogeneity.

Table Fig xA Scatter plots

Table 2.
Fig. 3. Scatter plots demonstrating the percentage of change in tumor apparent MLN 8237 coefficient (ADC) value during chemoradiotherapy (ΔADCduring) and after completion of chemoradiotherapy prior to surgery (ΔADCpost) for esophageal cancer in pathologic complete responders (pathCR) versus pathologic non-complete responders (no pathCR) (a and c), and in good responders (GR) versus poor responders (no GR) (b and d). Horizontal continuous and dotted lines represent group means and optimal cut-off levels, respectively.Figure optionsDownload full-size imageDownload high-quality image (259 K)Download as PowerPoint slide
Results of ROC analyses on the value of ADC measurements in the prediction of pathologic response are substrate feeders outlined in Supplementary Table 2. ROC analysis for ΔADCduring resulted in an AUC of 0.90 for discriminating pathCR from no pathCR. An optimal cut-off value of 29% yielded a sensitivity of 100%, specificity of 75%, accuracy of 95%, PPV of 94%, and NPV of 100% for predicting residual cancer (e.g., no pathCR). For discriminating good responders from poor responders, ΔADCduring showed an AUC of 0.92 with an optimal cut-off value of 21% resulting in a sensitivity of 82%, specificity of 100%, accuracy of 89%, PPV of 100%, and NPV of 80%. ROC analyses for initial ADC, and ΔADCpost, showed inferior AUC values in comparison with ΔADCduring.