High Target Research Articles

Abstract 2179: Gene expression models for predicting doxorubicin response in canine osteosarcoma

Abstract Purpose: The use of gene expression models for predicting individual response to cancer therapy is a promising area of research for improving outcome. Osteosarcoma is the most common primary bone cancer in dogs, with an average 1 year survival after treatment. The co-expression extrapolation (COXEN) method has been established as a gene expression method for accurately predicting drug sensitivity in human cancer. Our purpose is to explore the ability of COXEN for the intra- or interspecies extrapolation of cancer cell line data for prediction of chemosensitivity in canine osteosarcoma patients. Methods: Gene expression and drug sensitivity data to doxorubicin (DOX) for the human NCI60 cell line panel were publicly available. Corresponding data was obtained and generated for the canine ACC29 cell line panel and canine osteosarcoma tumors via cell viability assays, hospital record search, and microarray gene expression analysis. Differentially expressed genes (DEGs) were identified in reference sets by Significance Analysis of Microarrays or t-test analysis between sensitive and resistant samples to DOX. Probe matching between species was done based on highest target sequence homology or by collapsing probes to gene level by selecting probes with maximum variance between samples. Hierarchical clustering was done using the CIMminer program. DEGs are filtered for genes sharing strong co-expression between reference and co-expression datasets, followed by prediction model building using the Misclassification Penalized Posterior (MiPP) algorithm. Results: The NCI60 and ACC29 panels are similarly sensitive to DOX with log GI50 molar ranges of -8.3 to -5.7 and -8.2 to -5.9, respectively. Samples from ACC29 and COS16 clustered according to DOX sensitivity 67 and 100% correctly when DEGs from NCI60 were used. NCI60-trained models using DEGs co-expressed with the ACC29 were 83% accurate in predicting sensitivity to DOX in ACC29 (p = 0.019, binomial). NCI60-trained models using DEGs co-expressed with COS49 were 67% accurate in predicting response to DOX in COS49 (p = 0.049, binomial, p = 0.045, Log Rank test). Models with NCI60 DEGs but co-expressed and built on COS16 were 73% accurate in COS33 (p = 0.026, binomial, p = 0.001, Log Rank test). ACC29-trained models using DEGs co-expressed with COS49 were 73% accurate in COS49 (p = 0.008, binomial). Models with ACC29 or ACCosteo DEGs but co-expressed and built on COS16 were each 70% accurate in COS33 (p = 0.047, binomial, p = 0.071 and 0.071, Log Rank test). Conclusions: Both human and canine COXEN models were able to accurately predict response of canine osteosarcoma patients to DOX. The best performing model involved identifying DEGs from human cell lines, co-expressing and building the model with dog tumors, suggesting that genomic strategies in canine oncology could benefit from the wealth of available human genomic data, and could provide validation for personalized medicine in human cancer. Citation Format: Jared S. Fowles, Kristen C. Brown, Ann M. Hess, Dawn L. Duval, Daniel L. Gustafson. Gene expression models for predicting doxorubicin response in canine osteosarcoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2179. doi:10.1158/1538-7445.AM2015-2179

Aptamer for imaging and therapeutic targeting of brain tumor glioblastoma.

Aptamers are short single-stranded nucleic acids (RNA or ssDNA), identified by an in vitro selection process, denominated SELEX, from a partially random oligonucleotide library. They bind to a molecular target, a protein or other complex macromolecular structures of interest with high affinity and specificity, comparable to those of antibodies. Recently, aptamer selection protocols were developed for targeting living cells, including tumors. Chemical modifications of the aptamers and modalities of their detection and delivery systems are already available with high selectivity and targeting ability for the desired cancer cell type, making them promising for diagnosis and therapy. Glioblastoma multiformae represents the most malignant and fatal stage of glioma, and is also the most frequent brain tumor. Glioblastoma-specific aptamers were developed by either targeting the whole cell surface or known glioma biomarkers. These aptamers may gain importance for imaging, tumor cell isolation from biopsies and drug delivery. In biomedical imaging techniques, aptamers coupled with radionuclide or fluorescent labels, bioconjugates and nanoparticles offer an advanced, noninvasive manner for defining the glioblastoma tissue border. Though single modality aptamer imaging probes have some limitations, these are overcome by the use of multimodal probes. Due to selectivity and chemical characteristics, aptamers can be coupled to functionalized nanoparticles and loaded with a drug, appeared promising for in vivo targeting of glioblastoma. Finally, aptamers are effective mediators for gene silencing when coupled to small interfering RNA and a viral vector, thus providing a novel tool with enhanced targeting capability in drug delivery, designed for tailored treatment of glioblastoma patients.

Validation of moving target doses using ArcCHECK Planned Dose Perturbation Algorithm

 The aim of the study is to use Planned Dose Perturbation (PDP™) measurement-guided reconstruction method to estimate dynamic 4D dose and evaluate both 3D dose and DVH changes caused by target motion resulting from respiration. Five patients of Ca lung were selected for the study. Target and Organ at risks were (OARs) delineated on 4DCT data set of each patient. Dose of moving target vs. stationary target were simulated and compared for OARs and target by analyzing 3D dose and DVH(Dose Volume Histogram).There was almost 3.5% higher target maximum doses measured with moving target after applying the target motion trajectory data as compared to the stationary target whereas OARs doses were comparable. The results, clinically signifies the importance of motion management in lung tumors.

ENGINEERING STUDENTS’ SELF-EFFICACY RELATED TO PHYSICS LEARNING

Various studies have demonstrated that students who have high levels of academic high levels of academic self-efficacy are better at overcoming obstacles, have higher targets and are more confident. So, the aim of this research was to determine the self-efficacy levels of engineering students regarding physics, and to analyse the effect of their alma mater, class levels, the type of engineering programme in which they are being educated and academic success variables on their self-efficacy regarding physics. In the present research “Physics self-efficacy scale” including two factors which were developed by the authors was used to collect the data. Considering one of the independent variables, such as their alma mater, it can be seen that students who graduated from private high schools had a higher level of self-efficacy. In addition, compared to other students, those in their first year had a higher level of self-efficacy, which led to greater academic success. Key words: engineering students, learning, self-efficacy, physics education, physics learning.

Site-specific ground motion simulation and seismic response analysis for microzonation of Nanded City, India

We study strong ground motion characteristics and ground response analysis of different sites in Nanded City, India. Synthetic strong ground motion records are obtained for two scenario earthquakes of magnitude M 5.2 and M 6.8 in southern Peninsular India using the finite fault model. Shear-wave velocity averaged over top 30 m of the soil is obtained from multichannel analysis of surface wave survey at 60 sites at depths of 20–50 m below the ground surface. The sites in different parts of the city are characterized by peak ground acceleration (PGA) at the surface and bedrock level, 5 % damped response spectra at the ground surface and the amplification factor defined as the ratio of ground motion at the surface to that at the bedrock. The area east to the lineament is characterized by low V S30 values (<200 m/s), probably associated with Godavari River basin sediments with alluvial deposits, composed of brown clay with intercalated bands of sand and gravel. A relatively high PGA value at the surface of about 0.24 g for the M 5.2 target event and hence high ground motion amplification indicative of major damage are observed at sites E-NE to the lineament in the area that are associated with the top soil column consisting of unconsolidated river basin sediments with very low V S30 values (<200 m/s). The amplification factor for the city ranges from 3 to 8 for the highest target event of magnitude M 6.8. There is a strong lateral variation in PGA values at the surface for the part of the city lying to the east of the lineament and parallel to its trend, where a relatively high amplification factor of 6–8 is found at a dominant frequency of 1.5–2.5 Hz, which can be considered as a significant zone of amplification and hence areas with high seismic hazard. The site-specific response spectra show that the peak of spectral acceleration for different sites occurs around 3 Hz. There is a large spatial variation of spectral acceleration at any given frequency for the city. For example, site nos. 9 and 50 are characterized by a peak in spectral acceleration of 0.55 and 0.9 g, respectively, at 3 Hz frequency.

PD-0181: Image-guided adaptive brachytherapy for cervix cancer: higher target dose by increasing planning aim

PD-0181: Image-guided adaptive brachytherapy for cervix cancer: higher target dose by increasing planning aim

Auto-induction expression of human consensus interferon-alpha in Escherichia coli.

BackgroundIsopropyl-β-D-1-thiolgalactopyranoside (IPTG)-inducible expression of recombinant proteins in E. coli is commonly used and effective. Nevertheless, unintended induction was encountered as a problem when using these bacterial expression systems, generating cultures that give reduced or variable protein yields. Auto-induction allows for production of much higher target protein yield and cell mass than conventional procedures using induction with IPTG without monitoring cell growth then adding IPTG at the appropriate cell density. This method involves special media recipes that promote growth to high density and automatically induce expression of target protein from T7 promoter. Consensus interferon is a synthetic artificially engineered interferon having an amino acid sequence that is a rough average of the sequences of all natural human alpha interferon subtypes and has greater potency than other interferons even the pegylated versions. The purpose of this study was high-level expression of human consensus interferon-alpha (cIFN-α) in E. coli using an auto-induction protocol. The cIFN-α gene was cloned into pET101/D-TOPO expression vector under the T7 promoter transcriptional regulation. Expression was optimized with respect to temperature and length of incubation in shake flask cultures. The antiviral potency and anticancer activity of cIFN-α were evaluated in comparison to IFN-α2a.ResultsThe expressed cIFN-α protein in auto-induction T7 system was found mostly in soluble fraction of the cell lysate (about 70% of yield in total cell lysate) after lowering incubation temperature to 25°C or 30°C. Protein expression was maximal after 24 h incubation at 25°C or 30°C. After purification via single-step chromatography using DEAE-Sepharose, the yield was 270 mg/L in shake flask E. coli cultures which is much higher than IPTG-inducible T7 expression system and other systems according to available data. The synthesized cIFN-α was biologically active as confirmed by its anticancer and antiviral effects and was significantly more potent than IFN-α2a.ConclusionsThe auto-induction process was reliable and convenient for production of cIFN-α protein in E. coli, and can be adapted for large-scale therapeutic protein production.

Increased Systemic and Plaque Inflammation in ABCA1 Mutation Carriers With Attenuation by Statins

We previously demonstrated that subjects with functional ATP-binding cassette (ABC) A1 mutations have increased atherosclerosis, which has been attributed to the role of ABCA1 in reverse cholesterol transport. More recently, a proinflammatory effect of Abca1 deficiency was shown in mice, potentially contributing to atherogenesis. In this study, we investigated whether ABCA1 deficiency was associated with proinflammatory changes in humans. Thirty-one heterozygous, 5 homozygous ABCA1 mutation carriers, and 21 matched controls were studied. (18)Fluorodeoxyglucose positron emission tomography with computed tomographic scanning was performed in a subset of carriers and controls to assess arterial wall inflammation (target:background ratio). Heterozygous ABCA1 mutation carriers had a 20% higher target:background ratio than in controls (target:background ratio; P=0.008). In carriers using statins (n=7), target:background ratio was 21% reduced than in nonstatin users (n=7; P=0.03). We then measured plasma cytokine levels. Tumor necrosis factor α, monocyte chemoattractant protein-1, and interleukin-6 levels were increased in heterozygous and homozygous ABCA1 mutation carriers. We isolated monocytes from carriers and controls and measured inflammatory gene expression. Only TNFα mRNA was increased in monocytes from heterozygous ABCA1 mutation carriers. Additional studies in THP-1 macrophages showed that both ABCA1 deficiency and lipoprotein-deficient plasma from ABCA1 mutation carriers increased inflammatory gene expression. Our data suggest a proinflammatory state in ABCA1 mutation carriers as reflected by an increased positron emission tomography-MRI signal in nonstatin using subjects, and increased circulating cytokines. The increased inflammation in ABCA1 mutation carriers seems to be attenuated by statins.

Maximum detection range limitation of pulse laser radar with Geiger-mode avalanche photodiode array

When designing and evaluating the performance of laser radar system, maximum detection range achievable is an essential parameter. The purpose of this paper is to propose a theoretical model of maximum detection range for simulating the Geiger-mode laser radar’s ranging performance. Based on the laser radar equation and the requirement of the minimum acceptable detection probability, and assuming the primary electrons triggered by the echo photons obey Poisson statistics, the maximum range theoretical model is established. By using the system design parameters, the influence of five main factors, namely emitted pulse energy, noise, echo position, atmospheric attenuation coefficient, and target reflectivity on the maximum detection range are investigated. The results show that stronger emitted pulse energy, lower noise level, more front echo position in the range gate, higher atmospheric attenuation coefficient, and higher target reflectivity can result in greater maximum detection range. It is also shown that it’s important to select the minimum acceptable detection probability, which is equivalent to the system signal-to-noise ratio for producing greater maximum detection range and lower false-alarm probability.

Facile preparation of hyaluronic acid and transferrin co-modified Fe3O4 nanoparticles with inherent biocompatibility for dual-targeting magnetic resonance imaging of tumors in vivo.

Clinical diagnosis of malignant tumors using nanoprobes needs severe improvements in the aspects of sensitivity and biocompatibility. Integrating a dual-targeting strategy with the selection of human-inherent elements and molecules as raw materials shows great potential in the development of a biosafe and sensitive nanoplatform. To carry out the proposed design, we constructed a biocompatible, dual-targeting MR imaging nanoprobe, based on Fe3O4 nanoparticles (NPs) co-modified with inherently innoxious hyaluronic acid (HA) and transferrin (Tf). HA was used as both a template and a targeting molecule to form Fe3O4@HA NPs through a one-step co-precipitation method, which were then further modified with Tf to obtain the dual-targeting Fe3O4@HA@Tf NPs at room temperature. The excellent biocompatibility of the nanoprobe was demonstrated via toxicity assays in vitro and in vivo. The desirable dual-targeting ability towards tumor cells was confirmed by a cellular uptake test (Hela cells, overexpressing both CD44 and transferrin receptors), and the developed nanoprobe was successfully applied in tumor-targeted MR imaging in vivo. In summation, we developed a dual-targeting Fe3O4 nanoprobe, following a facile procedure at room temperature. The nanoprobe showed a high targeting ability towards tumor cells and excellent biocompatibility, which showed its great potential to be applied in the clinical diagnosis of tumors.

Challenges of optimizing glycaemic control in children with Type 1 diabetes: a qualitative study of parents' experiences and views.

To explore the difficulties parents encounter in trying to achieve clinically recommended blood glucose levels and how they could be better supported to optimize their child's glycaemic control. In-depth interviews were conducted with 54 parents of children with Type 1 diabetes (≤12years). Data were analysed thematically. Parents described being reluctant and finding it difficult to keep their child's blood glucose levels consistently within clinically recommended ranges. As well as worrying about their child's ability to detect/report hypoglycaemia, parents highlighted a multitude of factors that had an impact on their child's blood glucose levels and over which they could exercise little control. These included: leaving their child with other caregivers who could not be trusted to detect hypoglycaemia; difficulties remotely monitoring and regulating their child's food consumption and activity; and physical and social changes accompanying childhood development. Most parents used two sets of blood glucose targets, with clinically recommended targets employed when their child was in their immediate care and higher targets when in the care of others. Parents described health professionals as lacking understanding of the difficulties they encountered keeping blood glucose within target ranges and needing more empathetic, tailored and realistic advice. It is not parents' fear of hypoglycaemia in isolation that leads to decisions to raise their child's blood glucose but, rather, parental fear in conjunction with other factors and considerations. Hence, to improve diabetes management in children, these factors may need to be addressed; for instance, by training others in diabetes management and using new technologies. Changes to consultations are also recommended.

Determinants and Shareholder Wealth Effects of the Sales Method in M&amp;A

We analyze the sales method for a sample of 575 acquisitions announced between 1998 and 2012 and find that targets choose auctions to maximize the target takeover premium through greater competition and to relax their financial constraints. Auctions, compared to negotiated deals, are associated with significantly higher target announcement returns, especially for relatively small targets. Bidder returns are positively related to auctions for bidders acquiring relatively small targets, not for the full sample. Taking into account size differences, we find that auctions, decrease target gains and increase bidder gains expressed in dollars.

Methods to enhance the guaranteed tensile strength of GFRP rebar to 900 MPa with general fiber volume fraction

The corrosion of reinforcement (rebar) in concrete members is one of the governing factors deteriorating the load carrying capacity of concrete members. Fiber reinforced polymer (FRP) has been the subject of much interest from researchers and engineers due to its enhanced durability and non-corrosive characteristics. Corrosion problems in reinforced concrete (RC) members can be resolved through the use of FRP rebar as its reinforcement. In order to expand usage of FRP rebar, rebar with various shapes and sizes has been developed and manufactured for RC structures. However, currently, a limited number of FRP rebar selections are available on the market. The obstacles preventing the wider application of FRP rebar are the relatively high price of FRP rebar compared to steel rebar and insufficient design guidelines for various FRP rebars sold in the market. Since there is a wide variety of unstandardized FRP rebar sold in the market, the application of these rebars in concrete structural design must be carefully conducted by modifying related coefficients and safety factors to assure the safety of the designed structures. Therefore, the enhancement of the performance of FRP rebar by means of efficient manufacturing methods would reduce its cost and increase its usage. Sufficient tensile and bonding strengths are necessary properties of rebar. However, depending on the material and shape of FRP rebar, these properties vary significantly. This study focuses on the tensile performance of rebar realized through enhancements in its constituent materials and manufacturing processes. Constituent materials and manufacturing processes were thoroughly researched and evaluated to maximize the tensile performance. A total of six factors affecting the tensile and bonding capacities of FRP rebar were modified in the study. For the new FRP rebar, a higher target with a guaranteed tensile strength of 900MPa and a 78% fiber volume fraction by weight, manufactured using E-glass fiber TEX 4400, was chosen. The verification study results showed that the new glass FRP (GFRP) rebar showed better material properties than other types of GFRP rebar currently available on the market.

Rough Fuzzy Set Based Strength Calculation Method for Transmission Tower

In this paper,the basic idea is to use fuzzy conversion principle,through membership degree theory to qualitative evaluation into quantitative evaluation,and consider all relevant factors, from the lowest level of each factor level comprehensive evaluation, followed up until the highest target layer, thus subject to many factors thing or object to make a relatively objective, accurate, realistic assessment. Then solve practical problems with fuzzy nature. It has the result of clear, systematic and strong features can solve vague, difficult to quantify the problem, suitable for solving a variety of non-deterministic problem.

Effects of long-term blood pressure lowering and dual antiplatelet treatment on cognitive function in patients with recent lacunar stroke: a secondary analysis from the SPS3 randomised trial

The primary outcome results for the SPS3 trial suggested that a lower systolic target blood pressure (<130 mm Hg) might be beneficial for reducing the risk of recurrent stroke compared with a higher target (130-149 mm Hg), but that the addition of clopidogrel to aspirin was not beneficial compared with aspirin plus placebo. In this prespecified secondary outcome analysis of the SPS3 trial, we aimed to assess whether blood pressure reduction and dual antiplatelet treatment affect changes in cognitive function over time in patients with cerebral small vessel disease. In the SPS3 trial, patients with recent (within 6 months) symptomatic lacunar infarcts from 81 centres in North America, Latin America, and Spain were randomly assigned, in a two-by-two factorial design, to target levels of systolic blood pressure (1:1; 130-149 mm Hg vs <130 mm Hg; open-label) and to a once-daily antiplatelet treatment (1:1; aspirin 325 mg plus clopidogrel 75 mg vs aspirin 325 mg plus placebo; double-blind). For this analysis, the main cognitive outcome was change in Cognitive Abilities Screening Instrument (CASI) during follow-up. Patients were tested annually for up to 5 years, during which time the mean difference in systolic blood pressure was 11 mm Hg (SD 16) between the two targets (138 mm Hg vs 127 mm Hg at 1 year). We used linear mixed models to compare changes in CASI Z scores over time. The SPS3 trial is registered with ClinicalTrials.gov, number NCT00059306. The study took place between March 23, 2003, and April 30, 2012. 2916 of 3020 SPS3 participants (mean age 63 years [SD 11]) with CASI scores at study entry were included in the analysis, with a median follow-up of 3·0 years (IQR 1·0-4·9). Mean changes in CASI Z scores from study entry to assessment at years 1 (n=2472), 2 (n=1968), 3 (n=1521), 4 (n=1135), and 5 (n=803) were 0·12 (SD 0·83), 0·15 (0·84), 0·16 (0·95), 0·19 (0·99), and 0·14 (1·09), respectively. Changes in CASI Z scores over time did not differ between assigned antiplatelet groups (p=0·858) or between assigned blood pressure target groups (p=0·520). There was no interaction between assigned antiplatelet groups and assigned blood pressure target groups and change over time (p=0·196). Cognitive function is not affected by short-term dual antiplatelet treatment or blood pressure reduction in fairly young patients with recent lacunar stroke. Future studies of cognitive function after stroke should be of longer duration or focus on patients with higher rates of cognitive decline. US National Institute of Neurological Disorders and Stroke.

PO-0441 Oxygen Reduction Initiative That Decreased Incidence And Severity Of Retinopathy Of Prematurity Results In Favourable Neuropsychological Outcomes At Age Three

Background and aims High oxygen exposure has adverse long-term medical consequences in premature infants. We hypothesised that a quality improvement initiative decreasing oxygen saturation limits in NICU-admitted infants would affect neuropsychological outcomes at age 3. Methods We studied 83 NICU-admitted participants born at 23–27 weeks; n = 37 (b.2009–2010) with targeted supplemental oxygen rates of 83–93% until 32 weeks, 85–95% until 35 weeks, and >95% after 35 weeks (O 2 Reduced); 8% laser eye surgery; 65% ROP compared with n = 46 (b.2007–2008) with higher target rates (89–100%; O 2 Higher); 28% laser eye surgery; 83% ROP. Group mortality rates ( 2 (n = 83, df=1)= 0.16, p = 0.900. ANCOVAs and regressions were conducted for 19 neuropsychological outcomes. Results O 2 Reduced performed significantly better than O 2 Higher in visual attention, controlling GA (p = 0.042; d= .47); O 2 Reduced was significantly correlated with visual attention (r = 0.288, p 5); ROP was not (r=-0.183, p > 0.05). 18/19 outcome scores favoured O 2 Reduced, low-to-moderate effect sizes ( d range:12–0.47). GA was positively related to all outcomes. A meaningful interaction effect between GA and O 2 Reduced for auditory attention and manual dexterity explained 3%-4% unique variance, respectively. Interaction showed O 2 Reduced’s effect on attention was greatest at 23–24 weeks, and at 27 weeks for manual dexterity. Conclusions Systematic reduction of saturation parameters that decreased retinopathy and laser surgery rates in infancy resulted in favourable three-year-old outcomes suggesting cognitive as well as medical advantages for O 2 Reduced. Moderate effect sizes demonstrated important associations between reduced oxygen saturation rates and 18/19 sensitive performance-based measures. Lowered targeted oxygen saturation rate had favourable yet differential effects across GA in extremely premature survivors.

Abstract 153: High neuropilin-1 expression on monocytes is positively associated with trastuzumab-mediated antibody-dependent cellular cytotoxicity of the HER2-overexpressing breast cancer cell line

Abstract Purpose Neuropilin-1 (Nrp1) was initially characterized as a guide for migrating cells and axons in developing nervous systems and is essential for the precise formation of neurons and vasculature. However, it was recently reported to also play an important role in the immune system. This study aimed to investigate the role of Nrp1 on monocytes in trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) targeting the HER2-positive human breast cancer cell line SKBR3. In addition, we evaluated the gene expression profile of monocytes expressing high and low levels of Nrp1. Methods Peripheral blood mononuclear cells from healthy volunteers were prepared using BD Vacutainer CPT Cell Preparation Tubes. The cells were stained with fluorescein isothiocyanate-conjugated anti-CD14 and allophycocyanin-conjugated anti-Nrp1 antibodies, and Nrp1high and Nrp1low monocyte subsets were sorted using FACSAria. These cells were used as effector cells in a conventional ADCC assay with SKBR3 as target cells and trastuzumab as the antibody. Target cell cytotoxicity was measured using the LDH cytotoxic test kit. The effector cell to target cell ratios of 20:1 and 10:1 were used. Gene expression analysis was performed by Affymetrix GeneChip microarrays. All study protocols were approved by the Ethics Committee for Clinical Research, Kyoto University Hospital, Kyoto, Japan (authorization number G424). Results The LDH cytotoxic test revealed significantly higher target cancer cell cytotoxicity in sorted Nrp1high monocytes than in Nrp1low monocytes (75% vs. 45%, p&amp;lt;0.01). Trastuzumab-mediated ADCC was significantly suppressed by Nrp1 neutralization antibodies in a dose-dependent manner (Control arm 14.3%, Treatment arm 6%; p&amp;lt;0.01). Gene expression analysis revealed that 308 genes were up-regulated in the Nrp1high population, including monocyte-specific chemokine receptor and hematopoietic transcriptional factor. Conclusion These results suggest that determination of Nrp1 expression can be used to classify monocytes as populations with and without cellular cytotoxic activity. Analysis of Nrp1 expression levels in monocytes can therefore be used to identify HER2-positive breast cancer patients for whom trastuzumab therapy will be less effective. Citation Format: Kosuke Kawaguchi, Eiji Suzuki, Masao Kawashima, Masakazu Toi. High neuropilin-1 expression on monocytes is positively associated with trastuzumab-mediated antibody-dependent cellular cytotoxicity of the HER2-overexpressing breast cancer cell line. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 153. doi:10.1158/1538-7445.AM2014-153

Synthesis of core-shell graphitic carbon@silica nanospheres with dual-ordered mesopores for cancer-targeted photothermochemotherapy.

Tumor site-directed multifunctional therapeutic platforms such as photothermochemotherapy that respond to tumor-focused physical and biological stimuli are highly demanded for effective cancer therapy. Herein, targeting peptide-conjugated core–shell graphitic carbon@silica nanospheres with dual-ordered mesopores (MMPS) were successfully fabricated and developed as antitumoral doxorubicin (DOX) delivery system (MMPSD) for synergistic targeted photothermal chemotherapy of breast cancer. The hydrophilic mesoporous silica shell guarantees good water dispersity of MMPSD. The hydrophobic graphitic mesoporous carbon core provides excellent hydrophobic drug loading, immediate contact between the drug and photothermal hotspots, and high NIR photothermal conversion efficiency. SP13 peptide facilitates MMPSD for targeted and enhanced delivery of DOX within HER2-positive SK-BR-3 breast cancer cells, while PEGylation ensures biocompatibility. Thus, the MMPSD system exhibited efficient drug loading capacity, high targeting ability, sensitive NIR/pH-responsive DOX release, sustained release, and excellent combined antitumor activity.

What Should the Systolic Blood Pressure Treatment Goal Be in Patients Aged 60 Years and Older with Hypertension?

While there is consensus that high blood pressure in older adults should be treated, there is significant variability among prominent therapeutic guidelines. This review will present seminal anti-hypertension trials establishing efficacy of BP-lowering therapy. Subanalyses focused on efficacy of antihypertensive therapy as part of management strategies for diverse CV diseases will also be provided. On the basis of these analyses, recommended guidelines will then be assessed. Guidelines from the recently published Eighth Joint National Committee (JNC 8) will be compared to the 2011 American College of Cardiology Foundation/American Heart Association, 2013 American Diabetes Society, 2012 International Society of Nephrology, and 2013 European Society of Hypertension/European Society of Cardiology guidelines for management of hypertension. Whereas most guidelines recommend treating systolic blood pressure in older adults to <140 mmHg, the JNC 8 recommendations are notably higher, targeting SBP of <150 mmHg for patients who do not have diabetes or CKD. To many experts, including this author, the higher target threshold seems imprudent, as increased risk for CV events likely outweighs any benefits.

High versus Low Blood-Pressure Target in Patients with Septic Shock

BackgroundThe Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown.MethodsIn a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28.ResultsAt 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality.ConclusionsTargeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.)