To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.
We prospectively evaluated the ...efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples.
Complete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. NGS of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2+ tumors. The relationship between CCNE1 amplification and lack of response to HER2-targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; P=0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared with patients with low level ERBB2 amplification (P=0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications.
The present study showed that HER2+GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.
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•Preparation and optimization of MIPs for detection of noradrenaline.•Screen-printing MIPs onto different support surfaces (polyester, PVC and paper).•Thermal detection noradrenaline ...with HTM and TWTA.•Development paper-based MIP sensing platform, which is sustainable and flexible.
Molecularly Imprinted Polymers (MIPs) are synthesized for the neurotransmitter noradrenaline with the optimal composition and binding conditions being determined via optical batch rebinding experiments. Next, the obtained MIP polymer particles are mixed within screen-printed inks to produce mass-producible bulk modified MIPs screen-printed electrodes (MIP-SPEs). In this contribution, the supporting surface which the MIP-SPEs are screen-printed upon are explored to deviate from conventional polyester, to polyvinylchloride, tracing paper and household-printing paper. The performance of the MIP-SPEs are measured using the Heat-Transfer Method (HTM), a straightforward and low-cost detection technique based on thermal resistance. At first, the noise on the signal is minimized by adjusting the settings of the temperature feedback loop. Second, the response of the MIP-SPEs to noradrenaline is measured and compared for the different substrate materials. Sensors printed onto paper are considered in further experiments as their response to noradrenaline is the highest and advantageous material properties, including sustainability and flexibility of the material. Subsequently, dose-response curves are determined by simultaneously measuring HTM and Thermal Wave Transport Analysis (TWTA). The latter is a new thermal detection method that relies on the use of thermal waves and has the advantage of a short measurement time (2min). With these thermal methods, it is possible to specifically detect noradrenaline in aqueous solutions and quantify it at relevant concentrations. In summary, by combining synthetic receptors with thermal measurement techniques it is possible to develop a portable sensor platform that is capable of low-cost and straightforward detection of biomolecules. Through exploring novel SPE substrates, a system is designed that is flexible and holds potential for the use in commercial biomedical devices and complex sensor architectures.
The Coulomb phase, with its dipolar correlations and pinch-point–scattering patterns, is central to discussions of geometrically frustrated systems, from water ice to binary and mixed-valence alloys, ...as well as numerous examples of frustrated magnets. The emergent Coulomb phase of lattice-based systems has been associated with divergence-free fields and the absence of long-range order. Here, we go beyond this paradigm, demonstrating that a Coulomb phase can emerge naturally as a persistent fluctuating background in an otherwise ordered system. To explain this behavior, we introduce the concept of the fragmentation of the field of magnetic moments into two parts, one giving rise to a magnetic monopole crystal, the other a magnetic fluid with all the characteristics of an emergent Coulomb phase. Our theory is backed up by numerical simulations, and we discuss its importance with regard to the interpretation of a number of experimental results.
Resistance at the brain receptors for leptin and insulin has been associated with increased feeding, obesity and cognitive impairments. The causal agent for central resistance is unknown but could be ...derived from the blood. Here we postulate whether hypertriglyceridemia, the major dyslipidemia of the metabolic syndrome, could underlie central leptin and insulin resistance.
We used radioactively labeled triglycerides to measure blood-brain barrier (BBB) penetration, western blots to measure receptor activation, and feeding and cognitive tests to assess behavioral endpoints.
Human CSF was determined to contain triglycerides, a finding previously unclear. The radioactive triglyceride triolein readily crossed the BBB and centrally administered triolein and peripherally administered lipids induced in vivo leptin and/or insulin resistance at hypothalamic receptors. Central triolein blocked the satiety effect of centrally administered leptin. Decreasing serum triglycerides with gemfibrozil improved both learning and memory inversely proportionate to triglyceride levels.
Triglycerides cross the blood-brain barrier rapidly, are found in human cerebrospinal fluid, and induce central leptin and insulin receptor resistance, decreasing satiety and cognition.
Low-dimensional magnetic heterostructures are a key element of spintronics, where magnetic interactions between different materials often define the functionality of devices. Although some interlayer ...exchange coupling mechanisms are by now well established, the possibility of direct exchange coupling via proximity-induced magnetization through non-magnetic layers is typically ignored due to the presumed short range of such proximity effects. Here we show that magnetic order can be induced throughout a 40-nm-thick amorphous paramagnetic layer through proximity to ferromagnets, mediating both exchange-spring magnet behaviour and exchange bias. Furthermore, Monte Carlo simulations show that nearest-neighbour magnetic interactions fall short in describing the observed effects and long-range magnetic interactions are needed to capture the extent of the induced magnetization. The results highlight the importance of considering the range of interactions in low-dimensional heterostructures and how magnetic proximity effects can be used to obtain new functionality.
Groundwater provides a vital source of drinking water for rural communities in many parts of Africa, particularly in the dry season when there are few safe alternative sources. This paper summarises ...results from a study (n = 428) assessing dry season water quality, both microbiological and inorganic chemistry, in handpump equipped boreholes (HPBs) across the Ethiopia Highlands (n = 142), Malawi (n = 162) and Uganda (n = 124) using a stratified, randomised sampling design. This study seeks to examine general water quality by randomly sampling rural groundwater supplies across larger areas with different geology and climate. The majority, 72%, of HPBs surveyed provide good quality dry season drinking water as defined by WHO drinking water quality criteria. Within this overall picture, the most notable constraints were from thermotolerant coliforms (TTCs), which exceeded the WHO drinking water guideline of zero colony forming units (cfu/100 ml) in 21% of sites (range 0-626 cfu/100 ml). TTC contamination was found to have a significant and positive correlation with annual average rainfall (ρ = 0.2, p = 0.00003). Across all three countries, WHO health based chemical drinking water quality values were exceeded at 9% of sites and were found for manganese (4%), fluoride (2.6%) and nitrate (2.5%); arsenic concentrations were below the guideline value of 10 μg l−1 (range < 0.5-7 μg l−1). The high percentage of Mn exceedances (14% ± 5.2% >400 μg l−1) found in drinking water sources in Uganda challenges the decision by WHO not to formalise a health-based guideline for Mn. While the overall level of microbiological contamination from HPBs is low, results from this study strongly suggest that at a national and regional level, microbiological contamination rather than chemical contamination will provide a greater barrier to achieving targets set for improved drinking water quality under the UN-SDG 6. Efforts should be made to ensure that boreholes are properly sited and constructed effectively to reduce pathogen contamination.
The present study explores psychosocial needs among university employees and the extent to which these needs influence employee perceptions of how work positively or negatively affects their health. ...Structural equation modeling (SEM) analyses among Norwegian faculty members (N = 11,533) suggest that needs differ in importance to the two work-related health outcomes. Multi-group analyses suggest gender differences in the level of these needs and in their degree of relationship with positive/negative work-related health. Among women, the strongest predictors of positive and negative work-related health are work engagement and autonomy, respectively. Among men, the strongest predictors of positive and negative work-related health are meaning and social community, respectively. Although significant differences were found in the level of the psychosocial needs across different university groups (faculty, PhD students, administrative/technical staff), their predictive value for how work affects their health positively or negatively is basically equivalent across groups. Study findings raise two implications: (1) the mechanisms and characteristics of the work environment that promote versus detract from health in the university setting do not appear to be two sides of the same coin and suggest different sets of interventions for improving employee health, and (2) gender differences should be taken into account in designing interventions to improve health and well-being in universities.
This work presents a portable electrochemical system for the continuous monitoring of corrosion inhibitors in a wide range of matrices including ethanol, seawater and mineral oil following simple ...dilution of the samples. Proof-of-concept is demonstrated for the sensing of 2,5-dimercapto-1,3,5-thiadiazole (DMCT), an important corrosion inhibitor. Disposable screen-printed graphitic electrodes (SPGEs) associated with a portable batch-injection cell are proposed for the amperometric determination of DMCT following sample dilution with electrolyte (95% v/v ethanol + 5% v/v 0.1molL-1 H2SO4 solution). This electrolyte was compatible with all samples and the organic-resistant SPGE could be used continuously for more than 200 injections (100µL injected at 193µLs-1) free from effects of adsorption of DMCT, which have a great affinity for metallic surfaces, and dissolution of the other reported SPGE inks which has hampered prior research efforts. Fast (180h-1) and precise responses (RSD < 3% n = 10) with a detection limit of 0.3µmolL-1 was obtained. The accuracy of the proposed method was attested through recovery tests (93–106%) and the reasonable agreement of results of DMCT concentrations in samples analyzed by both proposed and spectrophotometric (comparative) methods.
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•Continuous sensing of a corrosion inhibitor on screen-printed graphitic electrodes.•Batch-injection analysis with organic-resistant electrodes for portable detection.•Ethanol, seawater and mineral oil samples analyzed after simple dilution.•High sample throughput (180h-1), RSD < 3% (n = 10) and low LOD (0.3µmolL-1).•Recovery tests (93–106%) and comparison with spectrophotometry attested accuracy.
Aliment Pharmacol Ther 2011; 33: 149–159
Summary
Background Effectiveness of medical therapies in chronic pancreatitis has been described in small studies of selected patients.
Aim To describe ...frequency and perceived effectiveness of non‐analgesic medical therapies in chronic pancreatitis patients evaluated at US referral centres.
Methods Using data on 516 chronic pancreatitis patients enrolled prospectively in the NAPS2 Study, we evaluated how often medical therapies pancreatic enzyme replacement therapy (PERT), vitamins/antioxidants (AO), octreotide, coeliac plexus block (CPB) were utilized and considered useful by physicians.
Results Oral PERT was commonly used (70%), more frequently in the presence of exocrine insufficiency (EI) (88% vs. 61%, P < 0.001) and pain (74% vs. 59%, P < 0.002). On multivariable analyses, predictors of PERT usage were EI (OR 5.14, 95% CI 2.87–9.18), constant (OR 3.42, 95% CI 1.93–6.04) or intermittent pain (OR 1.98, 95% CI 1.14–3.45). Efficacy of PERT was predicted only by EI (OR 2.16, 95% CI 1.36–3.42). AO were tried less often (14%) and were more effective in idiopathic and obstructive vs. alcoholic chronic pancreatitis (25% vs. 4%, P = 0.03). Other therapies were infrequently used (CPB – 5%, octreotide – 7%) with efficacy generally <50%.
Conclusions Pancreatic enzyme replacement therapy is commonly utilized, but is considered useful in only subsets of chronic pancreatitis patients. Other medical therapies are used infrequently and have limited efficacy.
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