Accurate Analysis of Tumor Margins Using a Fluorescent pH Low Insertion Peptide (pHLIP)

The recurrence of certain cancers remains quite high due to either incomplete surgical removal of the primary tumor or the presence of small metastases that are invisible to the surgeon. Near infrared (NIR) fluorescence imaging might improve surgical outcomes by providing sensitive, specific, and real-time visualization of normal and diseased tissues if agents can be found that discriminate between normal and diseased tissue and define tumor margins. We have developed a new approach for revealing tumor borders by using NIR fluorescently labeled pH Low Insertion Peptide (pHLIP) and have created a computational program for the quantitative assessment of tumor boundaries. The approach is tested in vivo by co-localization of GFP-tumors and NIR emission from the fluorescently labeled pHLIP, and it is found that boundaries are accurately reported and that sub-millimeter masses can be detected

Measuring socioeconomic status and environmental factors in the SAYCARE study in South America: Reliability of the methods

ABSTRACT: This paper aimed to test the reliability of two questionnaires in studies involving children and adolescents (aged 3-18 years) in seven South American cities. One assesses socioeconomic status (SES) and the other measures environmental factors. Methods: The SES questionnaire was composed of 14 questions, which included the presence of several consumer goods, domestic services, family income, parental education level, and current parental occupation status. The environmental questionnaire was composed of 15 questions to measure the social and infrastructure characteristics of the area of residence. Parents or guardians completed the questionnaires on behalf of their children. Adolescents answered the questions themselves for environmental factors, while those related to SES factors were answered by their parents or guardians. We analyzed the reliability of the questionnaires through kappa coefficient determination. Multilevel linear regression models were applied to calculate the correlation between the total household scores, the household income, and parents’ education level. Results: The environmental questionnaire showed good reproducibility in both age groups (k 5 0.132-0.612 in children and k 5 0.392-0.746 in adolescents). The SES questionnaire showed strong reliability in both age groups for all indicators (k 5 0.52-1.00 in children and k 5 0.296-0.964 in adolescents). Conclusions: Our multiple indicator questionnaires focused on environmental factors and SES in pediatric health surveys provided useful and easily applicable additional indicators to measure these important determinants of cardiovascular health

Pollen exposure is associated with risk of respiratory symptoms during the first year of life

BACKGROUND: Pollen exposure is associated with respiratory symptoms in children and adults. However, the association of pollen exposure with respiratory symptoms during infancy, a particularly vulnerable period, remains unclear. We examined whether pollen exposure is associated with respiratory symptoms in infants and whether maternal atopy, infant's sex or air pollution modifies this association. METHODS: We investigated 14,874 observations from 401 healthy infants of a prospective birth cohort. The association between pollen exposure and respiratory symptoms, assessed in weekly telephone interviews, was evaluated using generalized additive mixed models (GAMMs). Effect modification by maternal atopy, infant's sex, and air pollution (NO$_{2}$ , PM$_{2.5}$ ) was assessed with interaction terms. RESULTS: Per infant, 37 ± 2 (mean ± SD) respiratory symptom scores were assessed during the analysis period (January through September). Pollen exposure was associated with increased respiratory symptoms during the daytime (RR [95% CI] per 10% pollen/m$^{3}$ : combined 1.006 [1.002, 1.009]; tree 1.005 [1.002, 1.008]; grass 1.009 [1.000, 1.23]) and nighttime (combined 1.003 [0.999, 1.007]; tree 1.003 [0.999, 1.007]; grass 1.014 [1.004, 1.024]). While there was no effect modification by maternal atopy and infant's sex, a complex crossover interaction between combined pollen and PM$_{2.5}$ was found (p-value 0.003). CONCLUSION: Even as early as during the first year of life, pollen exposure was associated with an increased risk of respiratory symptoms, independent of maternal atopy and infant's sex. Because infancy is a particularly vulnerable period for lung development, the identified adverse effect of pollen exposure may be relevant for the evolvement of chronic childhood asthma

Self-report dieting and long-term changes in body mass index and waist circumference

Objective This prospective study explores whether dieting attempts and previous changes in weight predict changes in body mass index (BMI) and waist circumference (WC). Methods The study was based on the representative Finnish Health 2000 Survey and on its follow-up examination 11 years later. The sample included 2,785 participants, aged 30-69. BMI and WC were determined at health examinations. Information on dieting attempts and previous changes in weight was collected using a questionnaire including questions on whether participant had tried to lose weight (no/yes), gained weight (no/yes) or lost weight (no/yes) during the previous year. Results At baseline, 32.8% were dieters. Of these, 28.4% had lost weight during the previous year. Dieters had higher BMI and WC than non-dieters. During the follow-up, the measures increased more in dieters and in persons with previous weight loss. The mean BMI changes in non-dieters versus dieters were 0.74 (standard deviation [SD] 2.13) kg/m(2) and 1.06 (SD 2.77) kg/m(2) (P = 0.002), respectively. The corresponding numbers for those with no previous weight change versus those who had lost weight were 0.65 (SD 2.07) kg/m(2) and 1.52 (SD 2.61) kg/m(2). The increases in BMI and WC were most notable in dieters with initially normal weight. Conclusions The increases in BMI and WC were greater in dieters than in non-dieters, suggesting dieting attempts to be non-functional in the long term in the general population.Peer reviewe

A gene expression predictor of response to EGFR-targeted therapy stratifies progression-free survival to cetuximab in KRAS wild-type metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>The anti-EGFR monoclonal antibody cetuximab is used in metastatic colorectal cancer (CRC), and predicting responsive patients garners great interest, due to the high cost of therapy. Mutations in the KRAS gene occur in ~40% of CRC and are a negative predictor of response to cetuximab. However, many KRAS-wildtype patients do not benefit from cetuximab. We previously published a gene expression predictor of sensitivity to erlotinib, an EGFR inhibitor. The purpose of this study was to determine if this predictor could identify KRAS-wildtype CRC patients who will benefit from cetuximab therapy.</p> <p>Methods</p> <p>Microarray data from 80 metastatic CRC patients subsequently treated with cetuximab were extracted from the study by Khambata-Ford et al. The study included KRAS status, response, and PFS for each patient. The gene expression data were scaled and analyzed using our predictive model. An improved predictive model of response was identified by removing features in the 180-gene predictor that introduced noise.</p> <p>Results</p> <p>Forty-three of eighty patients were identified as harboring wildtype-KRAS. When the model was applied to these patients, the predicted-sensitive group had significantly longer PFS than the predicted-resistant group (median 88 days vs. 56 days; mean 117 days vs. 63 days, respectively, p = 0.008). Kaplan-Meier curves were also significantly improved in the predicted-sensitive group (p = 0.0059, HR = 0.4109. The model was simplified to 26 of the original 180 genes and this further improved stratification of PFS (median 147 days vs. 56.5 days in the predicted sensitive and resistant groups, respectively, p < 0.0001). However, the simplified model will require further external validation, as features were selected based on their correlation to PFS in this dataset.</p> <p>Conclusion</p> <p>Our model of sensitivity to EGFR inhibition stratified PFS following cetuximab in KRAS-wildtype CRC patients. This study represents the first true external validation of a molecular predictor of response to cetuximab in KRAS-WT metastatic CRC. Our model may hold clinical utility for identifying patients responsive to cetuximab and may therefore minimize toxicity and cost while maximizing benefit.</p

Signs of subclinical coronary atherosclerosis in relation to risk factor distribution in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR)

AIMS: Modern imaging technology allows us the visualization of coronary artery calcification (CAC), a marker of subclinical coronary atherosclerosis. The prevalence, quantity, and risk factors for CAC were compared between two studies with similar imaging protocols but different source populations: the Multi-Ethnic Study of Atherosclerosis (MESA) and the Heinz Nixdorf Recall Study (HNR). METHODS AND RESULTS: The measured CAC in 2220 MESA participants were compared with those in 3,126 HNR participants with the inclusion criteria such as age 45-75 years, Caucasian race, and free of baseline cardiovascular disease. Despite similar mean levels of CAC of 244.6 among participants in MESA and of 240.3 in HNR (P = 0.91), the prevalence of CAC &gt; 0 was lower in MESA (52.6%) compared with HNR (67.0%) with a prevalence rate ratio of CAC &gt; 0 of 0.78 [95% confidence interval (CI): 0.72-0.85] after adjustment for known risk factors. Consequently, among participants with CAC &gt; 0, the participants in MESA tended to have higher levels of CAC than those in HNR (ratio of CAC levels: 1.39; 95% CI: 1.19-1.63), since many HNR participants have small (near zero) CAC values. CONCLUSIONS: The CAC prevalence was lower in the United States (MESA) cohort than in the German (HNR) cohort, which may be explained by more favourable risk factor levels among the MESA participants. The predictors for increased levels of CAC were, however, similar in both cohorts with the exception that male gender, blood pressure, and body mass index were more strongly associated in the HNR cohort

Multimodal assessment of estrogen receptor mRNA profiles to quantify estrogen pathway activity in breast tumors

Background Molecular markers have transformed our understanding of the heterogeneity of breast cancer and have allowed the identification of genomic profiles of estrogen receptor (ER)-α signaling. However, our understanding of the transcriptional profiles of ER signaling remains inadequate. Therefore, we sought to identify the genomic indicators of ER pathway activity that could supplement traditional immunohistochemical (IHC) assessments of ER status to better understand ER signaling in the breast tumors of individual patients. Materials and Methods We reduced ESR1 (gene encoding the ER-α protein) mRNA levels using small interfering RNA in ER+ MCF7 breast cancer cells and assayed for transcriptional changes using Affymetrix HG U133 Plus 2.0 arrays. We also compared 1034 ER+ and ER− breast tumors from publicly available microarray data. The principal components of ER activity generated from these analyses and from other published estrogen signatures were compared with ESR1 expression, ER-α IHC, and patient survival. Results Genes differentially expressed in both analyses were associated with ER-α IHC and ESR1 mRNA expression. They were also significantly enriched for estrogen-driven molecular pathways associated with ESR1, cyclin D1 (CCND1), MYC (v-myc avian myelocytomatosis viral oncogene homolog), and NFKB (nuclear factor kappa B). Despite their differing constituent genes, the principal components generated from these new analyses and from previously published ER-associated gene lists were all associated with each other and with the survival of patients with breast cancer treated with endocrine therapies. Conclusion A biomarker of ER-α pathway activity, generated using ESR1-responsive mRNAs in MCF7 cells, when used alongside ER-α IHC and ESR1 mRNA expression, could provide a method for further stratification of patients and add insight into ER pathway activity in these patients

Melting and differentiation of early-formed asteroids: The perspective from high precision oxygen isotope studies

A number of distinct methodologies are available for determining the oxygen isotope composition of minerals and rocks, these include laser-assisted fluorination, secondary ion mass spectrometry (SIMS)and UV laser ablation. In this review we focus on laser-assisted fluorination, which currently achieves the highest levels of precision available for oxygen isotope analysis. In particular, we examine how results using this method have furthered our understanding of early-formed differentiated meteorites. Due to its rapid reaction times and low blank levels, laser-assisted fluorination has now largely superseded the conventional externally-heated Ni “bomb” technique for bulk analysis. Unlike UV laser ablation and SIMS analysis, laser-assisted fluorination is not capable of focused spot analysis. While laser fluorination is now a mature technology, further analytical improvements are possible via refinements to the construction of sample chambers, clean-up lines and the use of ultra-high resolution mass spectrometers. High-precision oxygen isotope analysis has proved to be a particularly powerful technique for investigating the formation and evolution of early-formed differentiated asteroids and has provided unique insights into the interrelationships between various groups of achondrites. A clear example of this is seenin samples that lie close to the terrestrial fractionation line (TFL). Based on the data from conventional oxygen isotope analysis, it was suggested that the main-group pallasites, the howardite eucrite diogenite suite (HEDs) and mesosiderites could all be derived from a single common parent body. However,high precision analysis demonstrates that main-group pallasites have a Δ17O composition that is fully resolvable from that of the HEDs and mesosiderites, indicating the involvement of at least two parent bodies. The range of Δ17O values exhibited by an achondrite group provides a useful means of assessing the extent to which their parent body underwent melting and isotopic homogenization. Oxygen isotope analysis can also highlight relationships between ungrouped achondrites and the more well-populated groups. A clear example of this is the proposed link between the evolved GRA 06128/9 meteorites and the brachinites. The evidence from oxygen isotopes, in conjunction with that from other techniques, indicates that we have samples from approximately 110 asteroidal parent bodies (∼60 irons, ∼35 achondrites and stony-iron, and ∼15 chondrites) in our global meteorite collection. However, compared to the likely size of the original protoplanetary asteroid population, this is an extremely low value. In addition, almost all of the differentiated samples (achondrites, stony-iron and irons) are derived from parent bodies that were highly disrupted early in their evolution. High-precision oxygen isotope analysis of achondrites provides some important insights into the origin of mass-independent variation in the early Solar System. In particular, the evidence from various primitive achondrite groups indicates that both the slope 1 (Y&R) and CCAM lines are of primordial significance. Δ17O differences between water ice and silicate-rich solids were probably the initial source of the slope 1 anomaly. These phases most likely acquired their isotopic composition as a result of UV photo-dissociation of CO that took place either in the early solar nebula or precursor giant molecular cloud. Such small-scale isotopic heterogeneities were propagated into larger-sized bodies, such as asteroids and planets, as a result of early Solar System processes, including dehydration, aqueous alteration,melting and collisional interactions