Time-dependent Relationship Research Articles

Sex-specific effects of in utero and adult tobacco smoke exposure.

Tobacco smoke has harmful effects on a multiorgan level. Exposure to smoke, whether in utero or environmental, significantly increases susceptibility. This susceptibility has been identified to be divergent between males and females. However, there remains a distinct lack of thorough research into the relationship between sex and exposure to tobacco. Females tend to generate a more significant response than males during adulthood exposure. The intrauterine environment is meticulously controlled, and exposure to tobacco presents a significant factor that contributes to poor health outcomes and susceptibility later in life. Analysis of these effects in relation to the sex of the offspring is yet to be holistically reviewed and summarized. In this review, we will delineate the time-dependent relationship between tobacco smoke exposure and sex-specific disease susceptibility. We further outline possible biological mechanisms that may contribute to the identified pattern.

An Accurate Inverse Model for the Detection of Leaks in Sealed Landfills

Leaks from landfills to underlying soil layers are one of the main problems that endanger the sustainability of waste disposal in landfills. Indeed, the possible failing of in-situ equipment can give rise to serious pollution consequences or costly inspection work in the landfill body. In this paper, we develop the time dependent mathematical relationship between the concentration of water at the surface of the landfill and the flux at the bottom of the landfill. This makes it possible to detect a leak using non-expensive measurements made at the surface of the landfill. The resulting model is obtained by analytically solving Richard’s equation with a piecewise linear boundary condition at the bottom. The unknown coefficients of the piecewise linear functions, which can be estimated using the measurements at the surface, provide the necessary information for detecting leaks. The algorithm has been numerically tested using simulated data of rain precipitation. The method proposed could be conveniently used to complement the usual monitoring techniques due to the limited costs of its implementation.

Effects of H2O2 on growth, metabolic activity and membrane integrity in three strains of Microcystis aeruginosa.

The application of hydrogen peroxide (H2O2) as a management tool to control Microcystis blooms has become increasingly popular due to its short lifetime and targeted action. H2O2 increases intracellular reactive oxygen species resulting in oxidative stress and subsequently cell death. H2O2 is naturally produced in freshwater bodies as a result of photocatalytic reactions between dissolved organic carbon and sunlight. Previously, some studies have suggested that this environmental source of H2O2 selectively targets for toxigenic cyanobacteria strains in the genus Microcystis. Also, past studies only focused on the morphological and biochemical changes of H2O2-induced cell death in Microcystis with little information available on the effects of different H2O2 concentrations on growth, esterase activity and membrane integrity. Therefore, this study investigated the effects of non-lethal (40-4000nM) concentrations on percentage cell death; with a focus on sub-lethal (50μM) and lethal (275μM; 500μM) doses of H2O2 on growth, cells showing esterase activity and membrane integrity. The non-lethal dose experiment was part of a preliminary study. Results showed a dose- and time-dependent relationship in all three Microcystis strains post H2O2 treatment. H2O2 resulted in a significant increase in intracellular reactive oxygen species, decreased chlorophyll a content, decreased growth rate and esterase activity. Interestingly, at sub-lethal (50μM H2O2 treatment), percentage of dead cells in microcystin-producing strains was significantly higher (p < 0.05) than that in non-microcystin-producing strains at 72h. These findings further cement our understanding of the influence of H2O2 on different strains of Microcystis and its impact on membrane integrity and metabolic physiology: important to future toxic bloom control programmes.

Accumulation and toxicity of multi-walled carbon nanotubes in Xenopus tropicalis tadpoles

Multi-walled carbon nanotubes (MWCNTs), a common nanomaterial widely used and discharged in environment, might exert toxic effects on aquatic animals. In this paper, filter-feeding tadpole of Xenopus tropicalis was selected as bioindicator to study the exposure effects of MWCNTs suspensions of 0.5, 1, 2, 4 and 8 mg/L for 72 h. The results showed that the tadpoles could remain high survival rate of over 96.7% after 24 h’s exposure to MWCNTs, but then decrease considerably, showing a significant time-dependent relationship. The LC50 was 2.53 mg/L for tadpoles exposed to MWCNTs for 72 h, when MWCNTs accumulated in their gills and digestive tracts. Moreover, the enrichment degree of MWCNTs in tadpole was related to exposure density than time. When MWCNTs suspension concentration was not over 1 mg/L, the heart rates increased significantly and then decreased continuously. The survivors from the toxicity test were transferred to fresh filtered water for recovery, but MWCNTs accumulated in the tadpoles’ body didn’t decrease obviously after 4 days. Although the maximum tadpoles survival rate of 80% was recorded in the exposure group of 0.5 mg/L MWCNTs, only 43.3% of the survivors could recover. Therefore, the final survival rate was negative related to the exposure densities of MWCNTs but positive related to the accumulating degree in tadpoles’ body. The results demonstrated that MWCNTs exposure posed potential health risks to filter-feeding organisms by intake and accumulation in organs, which could provide useful information for the reasonable evaluation and scientific management of nanomaterials.

Risk of colorectal cancer in patients with alcoholism: A nationwide, population-based nested case-control study

Colorectal cancer (CRC) is regarded as a multifactorial disease and shares many risk factors with alcoholism. However, the association between alcoholism and CRC remains controversial. In this study, we aimed to evaluate the association between alcoholism and risk of CRC. We performed a large-scale, population-based nested case-control study using the Longitudinal Health Insurance Database 2013, derived from Taiwan's National Health Insurance Research Database, and collected data from 2000 to 2013. There were 49,095 diagnosed cases of CRC defined according to the International Classification of Diseases, Ninth Revision, Clinical Modification. Each case was matched with three controls by sex, age, index date of CRC, and annual medical visits; a total of 147,285 controls were identified. Multiple risk factors of CRC in alcoholism cases were investigated using unconditional multiple logistic regression analysis. Among 49,095 cases of CRC, alcoholism was associated with a significantly higher risk of CRC (adjusted odds ratio (OR), 1.631; 95% CI, 1.565-1.699) in multivariate logistic regression, after adjusting other CRC risk factors, and in stratified analysis with multivariate logistic regression. In addition, there was a time-dependent relationship between alcoholism duration and CRC risk in >1 year, > 2 years, >5 years, and > 11 years groups (adjusted ORs, 1.875, 2.050, 2.662 and 2.670; 95% CI, 1.788-1.967, 1.948-2.158, 2.498-2.835, and 2.511-2.989 respectively). An association between alcoholism and risk of CRC was found in this study. Furthermore, patients with longer alcoholism history showed higher likelihood of developing CRC, which indicates a time-dependent relationship between alcoholism exposure and CRC. Further research on colorectal tumorigenesis is needed.

SUN-689 Treatment of Hepatitis C Has Time-Dependent Relationship with Type 2 Diabetes Progress

IntroductionHepatitis C virus (HCV) is not only related to hepatic impairment but also associated with metabolic complications, such as glucose intolerance and lipid dis-regulation. In addition, HCV can affect pancreatic Beta-cells function. There are multiple controversial reports regarding the relationship between antiviral treatment and diabetes mellitus (DM) development. We performed continuous observation of a long-term nursing home facility DM patient treated with HCV.Case Presentation52 y/o white male nursing home patient history of hepatitis C and type 2 diabetes mellitus was treated with ledipasvir/sofosbuvir (90 mg - 400 mg) for 12 weeks. Prior to HCV treatment patient DM control was treated with oral medications (metformin and glipizide) with fast glucose level fluctuating 143±44 mg/dl; 2 hours postprandial level 205±57mg/dl; HbA1c 7.0%. There was no significant change of finger sticks during the 12 weeks of HCV treatment fast glucose 121 ±27 mg/dl and 2 hours postprandial level 176±62 mg/dl.DM management remained the same treatment plan. In the first three months after HCV treatment course patient DM was progressively getting worse with fast glucose level 221±56mg/dl; 2 hours postprandial levels 300±71 mg/dl. HbA1c 8.7% (3 months after HCV treatment). Oral DM medications were doubled dosages and maximum dosage of pioglitazone was added on. In addition, insulin sliding scale and long acting insulin accumulated daily dosage around 120 units. Starting from four months after HCV treatment patient DM was gradually improving evidenced by fast glucose levels 92±10mg/dl and 2 hours postprandial levels 117±30 mg/dl; HbA1c 5.6% with the same management strategies. Seven months after HCV treatment patient DM was stable with fast glucose levels 91±8 mg/dl and 2 hours postprandial levels 115±29 mg/dl; HbA1c 4.8% and insulin sliding scale and glipizide were discontinued. Long acting insulin dosage was decreased to 74 units daily. Eighteen months after HCV treatment patient fast glucose levels and 2 hours postprandial levels were in normal range and HbA1c 5.6%.DiscussionBased on our observation there are four phases of DM development related to the HCV treatment: phase I silence stage (during 3 month HCV treatment) DM is stable; phase II deterioration stage (First 3 month after HCV treatment) DM is progressively getting worse; phase III recovery stage (4 to 6 month after HCV treatment) DM is gradually improving; phase IV stabilization stage (6 month after HCV treatment) DM is stabilized and improved.ConclusionAnti-viral treatment of HCV has possible intrinsic time-dependent relationship with DM development.

The Time-Dependent Lead-Lag Relationship Between WTI and Brent Crude Oil Spot Markets

Based on daily returns, we comprehensively characterize the lead-lag relationship between Brent and WTI crude oil spot markets from 1987 to 2017 with the non-parametric symmetric thermal optimal path (TOPS) method. The empirical results indicate that WTI spot price leads Brent spot price slightly, which provides support to the price leadership of WTI over Brent. However, the lead-lag relationship is volatile and sensitive to extreme events like geopolitical conflict and policy shift. Due to the concerns about future oil supply triggered by the two Gulf wars, both WTI and Brent experienced extreme uncertainty and co-moved closely during wartime. Notably, the TOPS method captures the structural break in the WTI-Brent price spread in 2011 which is influenced by the U.S. oil export ban and transportation bottleneck. After the lift of the ban, the two benchmark prices have reconnected. The lead-lag signals basically coincide with major influential changes in the oil markets, which suggests that the TOPS method provides a viable approach to reflecting the impact of extreme events on the crude oil prices motion.

Rapid formation of antheraxanthin and zeaxanthin in seconds in microalgae and its relation to non-photochemical quenching.

The violaxanthin (V)-antheraxanthin (A)-zeaxanthin (Z) (VAZ) cycle was deemed a non-second-scale process of photoprotection in higher plants and microalgae, but the validity of this view has not been confirmed. To test this view, we explored responses of the VAZ cycle and the relationship between the VAZ cycle and non-photochemical quenching (NPQ) under highlight at second and minute scales in Heterosigma akashiwo and Platymonas sp. Both A and Z were generated in H. akashiwo during 15s of light exposure, whereas only A rapidly accumulated within 15s of exposure in Platymonas sp. The above results, together with a time-dependent sigmoidal relationship between the VAZ cycle (de-epoxidation state, A/Chl a, and Z/Chl a) and NPQ, proved that the VAZ cycle was a second-scale process related to NPQ. In addition, we found that not all NPQ was dependent on the VAZ cycle and suggested that NPQ model should be carefully modified due to the species-specific proportions of de-epoxidation-dependent NPQ.

Antioxidant responses in cyanobacterium Microcystis aeruginosa caused by two commonly used UV filters, benzophenone-1 and benzophenone-3, at environmentally relevant concentrations

Benzophenone-type ultraviolet filters (BPs) have recently been recognized as emerging organic contaminants. In the present study, the cyanobacterium Microcystis aeruginosa was exposed to environmentally relevant levels (0.01-1000 μg L-1) of benzophenone-1 (BP-1) and benzophenone-3 (BP-3) for seven days. A battery of tested endpoints associated with photosynthetic pigments and oxidative stress was employed for a better understanding of the mode of action. The tested cyanobacterium could uptake the two BPs (27.4-54.9%) from culture media. The two BPs were able to inhibit the production of chlorophyll a (chl-a) and promote the accumulation of carotenoids, leading to unaffected chl-a autofluorescence. Slightly increased malondialdehyde (MDA) contents suggested that BP-1 and BP-3 caused moderate oxidative stress. BP-1 stimulated the activities of superoxide dismutase (SOD), glutathione reductase (GR) and glutathione S-transferase (GST) in M. aeruginosa while BP-3 increased the activities of SOD, GST, and glutathione (GSH), showing a concentration- and time-dependent relationship. The activities of other biomarkers, such as catalase (CAT) and glutathione peroxidase (GPx) fluctuated depending on exposure time and concentration. The overall results suggested that the two BPs can trigger moderate oxidative stress in M. aeruginosa and the tested cyanobacterium was capable of alleviating stress by different mechanisms.

The buyer–seller relationship: a literature synthesis on dynamic perspectives

PurposeContemporary scholars contend that the buyer–seller relationship is dynamic in nature, so it grows, matures and declines over time. However, most studies that adopt the dynamic perspective debates its conceptualization and how dynamic effects are captured. This scholarly discourse has led to multiple dynamic perspectives and resulted in fragmented and scattered literature on the subject. This study aims to synthesize the large body of research on dynamic perspectives in a systematic way.Design/methodology/approachThis paper follows a systematic review approach to extract and review 192 research articles from four electronic databases: Web of Science, EBSCOhost Business, ScienceDirect and Emerald. Based on the inclusion criteria that the articles examine time-dependent relationship development in light of a generalizable dynamic perspective, 61 articles were selected for the final examination and reporting.FindingsThis review reveals that most research on the buyer–seller dynamic relationship follows at least one of four perspectives: the relationship lifecycle, relationship age, relationship velocity and the asymmetric–dynamic perspective. Each perspective offers a distinct conceptualization of relationship development and has certain advantages that enable researchers to capture information about relationships’ growth trajectory in a unique manner.Practical implicationsFirms need a set of diverse strategies for their customers, depending on the state of the relationships’ development, as strategies that pay off at initial levels may fail at later stages. This study helps managers select an appropriate dynamic perspective that best aligns with their customers’ stage of relationship development so they can devise customized relationship-management strategies.Originality/valueTo the best of the authors’ knowledge, this article is the first attempt to organize the discourse of a large body of research on dynamic perspectives, and therefore it helps academicians and practitioners to choose the dynamic perspective that best suits their objectives and research settings. This review documents key research areas that have been overlooked and highlights opportunities for future research.

Chondrotoxicity of Local Anesthetics: Liposomal Bupivacaine Is Less Chondrotoxic than Standard Bupivacaine.

Objective The purpose of this study is to determine whether (1) liposomal bupivacaine is chondrotoxic; (2) the chondrotoxicity of liposomal bupivacaine differs from standard bupivacaine; and (3) chondrotoxic effects are time dependent. Materials and Methods We obtained 72 10 mm articular cartilage plugs from 12 fresh bovine distal femoral knee joints and exposed them to either saline, 0.5% bupivacaine, or liposomal bupivacaine for either 30 or 90 minutes. Twenty-four hours after treatment, chondrocyte viability was measured with the use of a fluorescent live/dead assay. An ANOVA test of variance was performed followed by a Holm–Sidak test to make pairwise comparisons across conditions. Student's t-test was used to compare means. Results Percent viability of cells exposed to liposomal bupivacaine for 30 minutes was less versus saline control (53.9% ± 21.5% vs. 73.7 ± 18.4%, p=0.035), and this remained significant at 90 minutes (49.1% ± 20.3% vs. 67.2% ± 25.6%, p < 0.001). Liposomal bupivacaine had less chondrotoxic effects when compared with bupivacaine after 90 minutes, with greater viability (49.1% ± 20.3% vs. 21.4% ± 14.0%, p=0.003). Chondrotoxicity was found to be time dependent within the bupivacaine group (percent viability at 30 min: 45.5 ± 18.2%, 90 min: 21.4 ± 14.0%, p=0.001); however, liposomal bupivacaine did not demonstrate a significant time-dependent chondrotoxic relationship (p=0.583). Conclusions Bupivacaine and liposomal bupivacaine are both toxic to chondrocytes. Liposomal bupivacaine is less chondrotoxic than standard bupivacaine and does not demonstrate a time-dependent toxicity.

Dendritic Spines in the Spinal Cord: Live Action Pain.

Dendritic spines are microscopic protrusions on neurons that house the postsynaptic machinery necessary for neurotransmission between neurons. As such, dendritic spine structure is intimately linked with synaptic function. In pathology, dendritic spine behavior and its contribution to disease are not firmly understood. It is well known that dendritic spines are highly dynamic in vivo. In our recent publication, we used an intravital imaging approach, which permitted us to repeatedly visualize the same neurons located in lamina II, a nociceptive processing region of the spinal cord. Using this imaging platform, we analyzed the intravital dynamics of dendritic spine structure before and after nerve injury–induced pain. This effort revealed a time-dependent relationship between the progressive increase in pain outcome, and a switch in the steady-state fluctuations of dendritic spine structure. Collectively, our in vivo study demonstrates how injury that leads to abnormal pain may also contribute to synapse-associated structural remodeling in nociceptive regions of the spinal cord dorsal horn. By combining our live-imaging approach with measures of neuronal activity, such as with the use of calcium or other voltage-sensitive dyes, we expect to gain a more complete picture of the relationship between dendritic spine structure and nociceptive physiology.

Antibacterial mechanism of the synergistic combination between streptomycin and alcohol extracts from the Chimonanthus salicifolius S. Y. Hu. leaves.

Chimonanthus salicifolius S. Y. Hu. Is a unique traditional medicinal plant in ancient China, and it can eliminate turbid pathogens with aromatics, clear heat, detoxify, prevent colds and influenza, Xinhua Compendium of Materia Medica records that. In previous study, we investigated the regulation of ethanol extracts (EEs) from C. salicifolius S. Y. Hu. leaves on three common antibiotics (chloramphenicol, streptomycin, imipenem) by the checkerboard method. The combination exhibited the best synergy among all combinations, which were composed of streptomycin and 50% EE (SE) from the C. salicifolius S. Y. Hu. leaves. The aim of this study was to investigate the antibacterial mechanism of the SE against Escherichia coli (E. coli, G-) and Staphylococcus aureus (S. aureus, G+). The antibacterial mechanism of the SE was explored by the time-kill test, the phosphorus metabolism, cell membrane integrity assays, the SDS-PAGE, the SEM and TEM observation. The time-kill test illustrated that the SE was bacteriostatic with a time-dependent relationship, not sterilization. The phosphorus metabolism indicated that the SE lowered phosphorus consumption. The cell membrane integrity assays demonstrated that the cell membrane was damaged, with the nucleic acid flowing out. The SDS-PAGE analysis found that the SE inhibited the synthesis of the total protein. The SEM and TEM results revealed that the surface and internal ultrastructure of bacteria were damaged. The surface of the bacteria was shriveled and deformed, and the internal structure of the cells was also mutilated. The SE damaged the cell membrane, with the cytoplasm flowing out, disturbed the synthesis of total protein and phosphorus metabolism, and ultimately killed the bacteria.

Systematic use of the serum C-reactive protein concentration and computed tomography for the detection of intestinal anastomotic leaks.

This study aimed to characterize the time-dependent relationship between serum C-reactive protein (CRP) and anastomotic integrity in the early post-operative period and to develop a systematic use of CRP and computed tomography. Patients aged 18 years or over who had the formation of a left-sided colonic or a colorectal anastomosis, in Royal Sussex County Hospital, were included. The post-operative day (POD) CRP cut-off values were calculated according to receiver operating characteristic analysis to evaluate the sensitivities and specificities of the proposed cut-off parameters. A total of 125 left-sided colonic and colorectal anastomoses were recruited and analysed. When comparing to POD1 CRP cut-off, the calculated CRP ratio cut-off values of all the rest of PODs (2-5) were highly significant in the laparoscopic group and the overall group (P < 0.001). This statistically significant ratio was also demonstrated in the open group at POD2 (P < 0.0001). CRP and CRP ratios cut-off values were sensitive to detect an anastomotic leak in the early post-operative period. The cut-off values could facilitate the development of systematic use of CRP and computed tomography.

A crank-kinematics-based engine cylinder pressure reconstruction model

A new inverse model is proposed for reconstructing steady-state and transient engine cylinder pressure using measured crank kinematics. An adaptive nonlinear time-dependent relationship is assumed between windowed-subsections of cylinder pressure and measured crank kinematics in a time-domain format (rather than in crank-angle domain). This relationship comprises a linear sum of four separate nonlinear functions of crank jerk, acceleration, velocity and crank angle. Each of these four nonlinear functions is obtained at each time instant by fitting separate m-term Chebyshev polynomial expansions, where the total 4 m instantaneous expansion coefficients are found using a standard (overdetermined) linear least-square solution method. A convergence check on the calibration accuracy shows that this initially improves as more Chebyshev polynomial terms are used, but with further increase, the overdetermined system becomes singular. Optimal accuracy Chebyshev expansions are found to be of degree m = 4, using 90 or more cycles of engine data to fit the model. To confirm the model accuracy in predictive mode, a defined measure is used, namely the ‘ calibration peak pressure error’. This measure allows effective a priori exclusion of occasionally unacceptable predictions. The method is tested using varying speed data taken from a three-cylinder direct-injection spark ignition engine fitted with cylinder pressure sensors and a high-resolution shaft encoder. Using appropriately filtered crank kinematics (plus the ‘calibration peak pressure error’), the model produces fast and accurate predictions for previously unseen data. Peak pressure predictions are consistently within 6.5% of target, whereas locations of peak pressure are consistently within ±2.7 °CA. The computational efficiency makes it very suitable for real-time implementation.

Dynamic correlations between oil prices and the stock prices of clean energy and technology firms: The role of reserve currency (US dollar)

There is increased interest in the dynamic relationships between the stock prices of clean energy and technology firms and oil prices in the literature. Existing works suggest a time-dependent link between them, but there is a gap of knowledge regarding the drivers of this time-dependent relationship. To contribute to this literature, we first identify dynamic conditional correlations (DCCs) between the prices of clean energy and technology stocks and oil prices to investigate the nature of these dynamic correlations. Our findings suggest the existence of significant asymmetric effects in the DCCs. Using the autoregressive distributed lag (ARDL) model, we then investigate the impact of reserve currency (US dollar) value changes on the DCCs while also controlling for business cycles, monetary conditions, and financial stress. Our results highlight the dominant role of US dollar appreciations in driving the DCCs. This role intensifies when asymmetric impacts are taken into account. The implications of this study are important for clean energy investments and for optimal risk management strategies in the energy and financial markets.

Binding capacity and diffusivity of concrete subjected to freeze-thaw and chloride attack: A numerical study

Existing concrete structures in cool coastal areas are prone to be attacked by both chloride penetration and freeze-thaw cycles (FTCs). This study establishes a multi-phase and multi-component ionic transport model for concrete serving in cold-climate coast or ocean engineering, aiming at further exploring chloride transport mechanism under freeze-thaw cycles in a quantitative manner. Unlike the most of existing work, herein the time-varying porosity is described and involved in both the binding isotherm and diffusion coefficient to consider the pore evolution induced by FTCs. By solving the modified mass conservation equations, the time-dependent relationship between the bound and free chlorides as well as the spatial-temporal distributions of multi-species is obtained by using this model, and its reliability is validated against third-party experimental data. Parametric analysis is carefully performed on a series of significant influencing factors (i.e., water-to-cement ratios, hydroxyl concentrations, external chloride concentrations and internal temperature variations), which affect chloride binding remarkably during freeze-thaw actions. Bayesian sense is applied to combine the common regularity of numerical models and individual information of experimental by updating the penetration depth, which can calculate a more reasonable penetration depth.

Liraglutide in a real-world setting: Joint modeling of metabolic response, prediction of efficacy, and cardiovascular risk

Introduction and objectivesThe worldwide prevalence of type 2 diabetes mellitus increases in parallel to that of obesity. Liraglutide (LRG), a glucagon-like peptide-1 receptor agonist, can reduce body weight. This study assessed the metabolic efficacy of LRG in real-world clinical practice. MethodsAn observational, retrospective cohort study including patients treated with LRG for at least one year (187 patients). Anthropometric and metabolic variables, a composite endpoint, factors predicting response to LRG, and cardiovascular risk over time were assessed. A linear mixed-effects model with a bivariate structure was constructed to investigate the time-dependent relationship between weight and HbA1c values. ResultsHbA1c levels and weight significantly decreased in the first 12 weeks, and the decrease persisted at 12 and 24 months in all subgroups studied. Mean weight and HbA1c decreases after 24 months were 8.5kg and 1.7% respectively. HbA1c values <7% were achieved by 42% of patients at 12 months and by 40% at 24 months. Treatment with LRG allowed for reduction in insulin dose. No serious adverse events were noted. Cardiovascular risk decreased from high to moderate-low. ConclusionsUnder standard clinical practice conditions, LRG achieved a better metabolic response than seen in clinical trials. Efficacy at 12 weeks of treatment is a good predictor of response. LRG allows for delaying or reducing insulin dose by improving both weight and glucose control. Cardiovascular risk improved.

A potential therapeutic neutralization monoclonal antibody specifically against multi-coxsackievirus A16 strains challenge

ABSTRACT Coxsackievirus A16 (CA16) has caused worldwide epidemics of hand, foot and mouth disease (HFMD), particularly in infants and pre-school children. Currently, there are no vaccines or antiviral drugs available for CA16-associated disease. In this study, a CA16-specific monoclonal antibody (MAb) NA11F12 was derived with an epidemic CA16 strain (GenBank no. JX127258). NA11F12 was found to have high cross-neutralization activity against different CA16 subgenotypes but not EV71 using RD cells. The neutralizing titers of NA11F12 ranged from 1:1024 to 1:12288 against A, B1, B2 and C subgenotypes of CA16 and was less than 8 against EV71 strain. In the neonatal mouse model, a single treatment of NA11F12 showed effective protection with a dose- and time-dependent relationship against lethal challenge by CA16 strain (GenBank no. JX481738). At day 1 post-infection, administering more than 0.1 μg/g of NA11F12 could protect 100% newborn mice from mobility and mortality challenged by CA16. With dose of 10 μg/g of NA11F12, a single administration fully protected mice against CA16-associated disease within 4 days post-infection. And there were 80% and 60% mice protected by administering NA11F12 at day 5 post-infection and day 6 post-infection when the control mice had shown clinical symptoms for 1- and 2-day, respectively. Immunohistochemical and histological analysis confirmed that NA11F12 significantly prohibited CA16 VP1 expression in various tissues and prevented CA16-induced necrosis. In conclusion, a CA16-specific MAb NA11F12 with high cross-neutralization activity was identified, which could effectively protect lethal CA16 challenge in mice. It could be a potential therapeutic MAb against CA16 in the future.

Abstract ES5-2: Clinical and molecular profiles to identify who is at risk?

Abstract The persistent risk of recurrence from ER-positive primary breast cancer has been known for many years. It was recently described in detail and in relation to baseline clinicopathologic factors in a meta-analysis by the EBCTCG. This involved nearly 63,000 patients that had been prescribed 5 years of endocrine therapy and had reached the end of that time recurrence-free (Pan et al, NEJM, 2017, 377, 1836). Among other things this revealed that even among patients with T1N0 disease 13% had a distant recurrence between years 5 and 20. Our group have previously created a Clinical Treatment Score (CTS) from nodal status, tumor size, grade, age and type of adjuvant endocrine treatment and validated this for estimating risk of distant recurrence from the time of diagnosis. Drawing on a training dataset of 4,735 patients from the ATAC trial and a validation set of 6,711 patients from the BIG1-98 trial we created the CTS5, a prognostic score of risk from year 5, that features the same factors as CTS other than type of endocrine treatment (Dowsett et al, JCO, 2018, 36, 1941). Of note, only 4/304 patients with one to three positive nodes that were categorized as low risk in the validation set had a distant recurrence between years 5 and 10. The CTS5 calculator can be accessed online at www.cts5-calculator.com. There are several commercially available molecular profiles that estimate the risk of recurrence over years 0-10 after diagnosis in endocrine-treated primary breast cancer. In the TransATAC study some of these, including the EPClin and PAM50-ROR, show similar prognostic information over years 5-10 (after 5 years of endocrine therapy) as they do over years 0-5 (during endocrine therapy). In contrast, while the Oncotype Recurrence Score (RS) showed similar prognostic information to EPClin and PAM50-ROR in years 0-5 its performance in years 5-10 was substantially worse. Examination of the time-dependent prognostic relationship of each of the individual genes and modules in the RS showed that those patients with higher ER signaling had good prognosis before year 5 but poorer after year 5, suggesting that the cessation of endocrine therapy may lead to this poorer post-5 year outcome (Dowsett et al Clin Cancer Res, 2015, 21, 2763). A broad-based assessment of gene expression in the TransATAC sample set found that there was limited potential to identify a prognostic profile that performed substantially better after 5 years (Buus et al, Breast Cancer Res, 2018, 20, 103). One test, the 7-gene Breast Cancer Index, has reported on a relatively small sample set that it can predict the benefit or not from extended adjuvant endocrine therapy. Further validation studies of this are warranted as well as other tests that provide the same predictive information. Citation Format: Dowsett M. Clinical and molecular profiles to identify who is at risk? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr ES5-2.