bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics and exposure‐response of osimertinib in patients with non‐small cell lung cancer
Authors: Brown Kathryn , Comisar Craig , Witjes Han , Maringwa John , de Greef Rik , Vishwanathan Karthick , Cantarini Mireille , Cox Eugène 
Published: December 2016

AimsTo develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure–response relationships for selected efficacy and safety parameters.MethodsPK, safety and efficacy data were collected from two non‐small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once‐daily dosing of 20–240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF).ResultsA popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once‐daily dose at steady state.ConclusionsPopPK and exposure–response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed.
Direct Estimation for Adaptive Treatment Length Policies: Methods and Application to Evaluating the Effect of Delayed PEG Insertion
Authors: Lu Xin , Johnson Brent A. 
Published: December 2016

Summary
Dysphagia is a primary cause of death among patients diagnosed with amyotrophic lateral sclerosis (ALS), and percutaneous endoscopic gastrostomy (PEG) is a procedure to insert a tube into the stomach to assist or replace oral feeding. It is believed that PEG is beneficial and, generally, earlier insertion is preferable to later. However, gathering clinical evidence to support these beliefs on the use and timing of PEG is challenging because controlled clinical trials are not feasible and clinical endpoints are confounded with PEG in observational data. Moreover, the confounders are time-varying and time to PEG insertion may be only partially observed. We show how one can view this problem as an adaptive treatment length policy and propose a new estimator via g-computation. We show that our estimator is consistent and asymptotically normal for the causal estimand and explore its finite sample properties in simulation studies. Finally, using more than 10 years of data from Emory ALS clinic registry, we found no evidence to suggest that earlier PEG reduced 4-year mortality; thus, our results do not support the hypothesis and belief that initiating palliative care earlier extends life, on average. At the same, we cannot be certain that all important confounding variables are collected and observed to ensure our modeling assumptions are correct, so more work is needed to address these important end-of-life questions for ALS patients.
Inflammasomes as therapeutic targets for Alzheimer's disease
Authors: White Claire S. , Lawrence Catherine B. , Brough David , Rivers‐Auty Jack 
Published: December 2016

AbstractAlzheimer's disease is the most common form of progressive dementia, typified initially by short term memory deficits which develop into a dramatic global cognitive decline. The classical hall marks of Alzheimer's disease include the accumulation of amyloid oligomers and fibrils, and the intracellular formation of neurofibrillary tangles of hyperphosphorylated tau. It is now clear that inflammation also plays a central role in the pathogenesis of the disease through a number of neurotoxic mechanisms. Microglia are the key immune regulators of the CNS which detect amyloidopathy through cell surface and cytosolic pattern recognition receptors (PRRs) and respond by initiating inflammation through the secretion of cytokines such as interleukin‐1β (IL‐1β). Inflammasomes, which regulate IL‐1β release, are formed following activation of cytosolic PRRs, and using genetic and pharmacological approaches, NLRP3 and NLRP1 inflammasomes have been found to be integral in pathogenic neuroinflammation in animal models of Alzheimer's disease. Therefore, the inflammasomes are very promising novel pharmacological targets which merit further research in the continued endeavor for efficacious therapeutics for Alzheimer's disease.
Anti‐CD22 and anti‐CD79b antibody‐drug conjugates preferentially target proliferating B cells
Authors: Fuh Franklin K , Looney Caroline , Li Dongwei , Poon Kirsten A , Dere Randall C , Danilenko Dimitry M , McBride Jacqueline , Reed Chae , Chung Shan , Zheng Bing , Mathews William Rodney , Polson Andrew , Prabhu Saileta , Williams Marna 
Published: December 2016

Background and PurposeCD22 and CD79b are cell‐surface receptors expressed on B‐cell‐derived malignancies such as non‐Hodgkin's lymphoma (NHL). An anti‐mitotic agent, monomethyl auristatin E, was conjugated to anti‐CD22 and anti‐CD79b antibodies to develop target‐specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody‐drug conjugates (ADCs) were investigated in cynomolgus monkeys.Experimental ApproachAnimals were administered anti‐CD22 or anti‐CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody‐dependent cellular cytotoxicity (ADCC) and complement‐dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro.Key ResultsDepletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti‐human CD22 and anti‐human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity.Conclusions and ImplicationsThe findings support the proposed MOA: initial depletion of total B cells by antibody‐mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti‐mitotic action. Delivering potent anti‐mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk–benefit profiles over traditional chemotherapeutics.
Sunk costs and the measurement of commercial property depreciation
Authors: Diewert W. Erwin , Fox Kevin J. 
Published: December 2016

AbstractDevelopments in property markets greatly influence economic growth, monetary policy, productivity measurement, inflation measurement and hence welfare payments to the disadvantaged. Property price bubbles often lead to financial crises; those experienced during the 20th century were often triggered by commercial property price movements. Yet property poses significant challenges for national accountants in producing key economic variables used in informing policy assessment and formulation. To address these challenges, this paper formalizes a framework for measuring prices and quantities of capital inputs for a commercial property. In particular, it addresses problems associated with obtaining separate estimates for the land and structure components of a property, a decomposition of property value that is important for the national accounts, productivity measurement and taxation. A key contribution is to address the problem of estimating structure depreciation taking into account the fixity of the structure. We find that structure depreciation is determined primarily by the cash flows that the property generates rather than physical deterioration of the building. Finally, we provide a framework for the determination of the optimal length of life for a structure.
Has Canadian house price growth been excessive?
Authors: Head Allen , Lloyd‐Ellis Huw 
Published: December 2016

AbstractThe dramatic rise in the ratio of Canada's average house price to average rent has led to speculation that there is a bubble in the Canadian housing market. Others have argued, however, that the currently high level of house prices may be rationalized by the low cost of financing, given the decline in interest rates over the last two decades. In this article, we assess these arguments through the lens of a simple asset pricing model applied to city‐level data. We quantify the extent to which excess growth in Canadian house prices depends on the nature of the current regime governing real interest rates, expectations of rent growth in different cities and variations in property taxes.
Growth, expectations and tariffs
Authors: Honkapohja Seppo , Turunen‐Red Arja H. , Woodland Alan D. 
Published: December 2016

AbstractWe present a growth model of international trade in which expectations about profitability and growth influence innovation and investment. Adaptive learning dynamics determine transition paths for countries with differing structural parameters. Countries limiting trade by tariffs on imports of capital goods can experience gains in growth and perceived utility for a finite time, whereas the rest of the world is adversely affected. Asymmetric gains persist longer when structural advantages of the country applying tariffs are larger. Substantial differences in levels of innovation, output and utility can appear within our asymmetric country setting.
Cross‐border mergers and acquisitions in services: The role of policy and industrial structure
Authors: Barattieri Alessandro , Borchert Ingo , Mattoo Aaditya 
Published: December 2016

AbstractThis paper explores the role of policy and economic structure in determining international mergers and acquisitions (M&A) in services sectors. The analysis is based on bilateral sectoral M&A flow data and detailed information on policy barriers from a new database. Restrictive investment policies are found to reduce the probability of M&A inflows, controlling for bilateral frictions such as geography. This negative effect, however, is mitigated in countries with relatively large shares of manufacturing and (to a lesser extent) services in GDP. The same result holds for the number of M&A deals concluded. Findings are robust to accounting for the potential endogeneity of policy restrictiveness. The evidence suggests that the impact of policy is state‐dependent and related to the composition of GDP in the target economy.
The Clean Development Mechanism in a world carbon market
Authors: Bréchet Thierry , Ménière Yann , Picard Pierre M. 
Published: December 2016

AbstractThis paper discusses the role of the Clean Development Mechanism (CDM) in the market for carbon quotas and countries' commitments to reduce their carbon emission levels. We show that the CDM contributes to an efficient funding of clean technology investments in least developed countries. However, the CDM is not neutral on the global level of carbon emissions as it entices countries to raise their emission caps. The CDM may also make inappropriate the inclusion of any country that takes no emission abatement commitment. It can even make inefficient a country's decision to commit to an emission target. The implications of the presence of non‐additional projects are also analyzed.
Implementing partial tax harmonization in an asymmetric tax competition game with repeated interaction
Authors: Itaya Jun‐ichi , Okamura Makoto , Yamaguchi Chikara 
Published: December 2016

AbstractThis paper investigates the conditions under which partial harmonization for capital taxation is sustained in a repeated interactions model of tax competition when there are three countries with heterogenous capital endowments. We show that regardless of the structure of the coalition (i.e., full or partial tax coordination), whether partial tax harmonization is sustainable or not crucially depends on the extent to which the capital endowment of the medium‐sized country is similar to that of the large or small country. The most noteworthy finding is that the closer the capital endowment of the median country is to the average one, the less likely the tax harmonization including the median country is to prevail and the more likely the partial tax harmonization excluding the median country is to prevail. We also show that partial tax harmonization makes the member countries of the tax union better off and non‐member countries worse off, which stands in sharpe contrast with previous studies, such as Konrad and Schjelderup (1999) and Bucovetsky (2009).
Product sophistication and spillovers from foreign direct investment
Authors: Eck Katharina , Huber Stephan 
Published: December 2016

AbstractForeign direct investment (FDI) in developing countries is often associated with higher economic growth due to knowledge and technology spillovers to local firms. One way that FDI speeds up growth is by facilitating the manufacturing of more sophisticated products by local firms. So far, there is a lack of firm‐level evidence how the presence of multinational firms affects the product sophistication of firms in a developing country. The aim of this paper is to fill this gap. We compile an extensive firm–product‐level data set of Indian manufacturing firms, which we complement with information on product sophistication and spillovers from FDI. We then explore different channels through which spillovers from multinationals to local Indian firms foster the manufacturing of sophisticated products. We find evidence that spillovers through supplier linkages strongly increase the manufacturing of sophisticated products in India.
Changing income inequality: A distributional paradigm for Canada
Authors: Beach Charles M. 
Published: December 2016

AbstractThis paper examines the major changes in income inequality in Canada since the 1970s and collects them as a distributional paradigm for Canada. It focuses on labour market changes in terms of shares of workers and earnings shares for lower earners, middle‐class workers and higher earners in a flexible general framework. Polarization of full‐time workers, loss of middle‐class earnings share and increase in a higher earnings gap are highlighted. Changing returns to human capital, role of demographics and cohort effects and declining labour share are examined. The paper also reviews evidence of changing economic mobility and estimating the role of inequality of opportunity.
Targeting MUC1 and JNK by RNA interference and inhibitor inhibit the development of hepatocellular carcinoma
Authors: Wang Juan , Ni Wei‐hua , Hu Ke‐bang , Zhai Xiao‐yu , Xie Fei , Jie Jing , Zhang Nan‐nan , Jiang Li‐na , Yuan Hong‐yan , Tai Gui‐xiang 
Published: December 2016

Mucin 1 (MUC1), as an oncogene, is overexpressed in hepatocellular carcinoma (HCC) cells and promotes the progression and tumorigenesis of HCC through JNK/TGF‐β signaling pathway. In the present study, RNA interference (RNAi) and JNK inhibitor SP600125, which target MUC1 and/or JNK, were used to treat HCC cells in vitro, and the results showed that both silencing the expression of MUC1 and blocking the activity of JNK inhibited the proliferation of HCC cells. In addition, MUC1‐stable‐knockdown and SP600125 significantly inhibited the growth of tumors in the subcutaneous transplant tumor models that established in BALB/c nude mice rather than MUC1 or JNK siRNAs transiently transfection. Furthermore, the results from immunohistochemical staining assays showed that the inhibitory effects of MUC1 gene silencing and SP600125 on the proliferation of HCC cells in vivo were through the JNK/TGF‐β signaling pathway. These results indicate that MUC1 and JNK are attractive targets for HCC therapy and may provide new therapeutic strategies for the treatment of HCC.
MET4 expression predicts poor prognosis of gastric cancers with Helicobacter pylori infection
Authors: Sakamoto Naoko , Tsujimoto Hironori , Takahata Risa , Cao Brian , Zhao Ping , Ito Nozomi , Shimazaki Hideyuki , Ichikura Takashi , Hase Kazuo , Vande Woude George F. , Shinomiya Nariyoshi 
Published: December 2016

The role of HGF/SF‐MET signaling is important in cancer progression, but its relation with Helicobacter pylori‐positive gastric cancers remains to be elucidated. In total, 201 patients with primary gastric carcinoma who underwent curative or debulking resection without preoperative chemotherapy were studied. MET4 and anti‐HGF/SF mAbs were used for immunohistochemical analysis. Survival of gastric cancer patients was estimated by Kaplan–Meier method and compared with log‐rank. Cox proportional hazards models were fit to determine the independent association of MET‐staining status with outcome. The effect of live H. pylori bacteria on cell signaling and biological behaviors was evaluated using gastric cancer cell lines. MET4‐positive gastric cancers showed poorer prognosis than MET4‐negative cases (overall survival, P = 0.02; relapse‐free survival, P = 0.06). Positive staining for MET4 was also a statistically significant factor to predict poor prognosis in H. pylori‐positive cases (overall survival, P < 0.01; relapse‐free survival, P = 0.01) but not in H. pylori‐negative cases. Gastric cancers positively stained with both HGF/SF and MET4 showed a tendency of the worst prognosis. Stimulation of MET‐positive gastric cancer cells with live H. pylori bacteria directly upregulated MET phosphorylation and activated MET downstream signals such as p44/42MAPK and Akt, conferring cell proliferation and anti‐apoptotic activity. In conclusion, positive staining for MET4 was useful for predicting poor prognosis of gastric cancers with H. pylori infection. Helicobacter pylori stimulated MET‐positive gastric cancers and activated downstream signaling, thereby promoting cancer proliferation and anti‐apoptotic activity. These results support the importance of H. pylori elimination from gastric epithelial surface in clinical therapy.
Longitudinal monitoring of gene expression in ultra-low-volume blood samples self-collected at home
Authors: Speake C , Whalen E , Gersuk V H , Chaussabel D , Odegard J M , Greenbaum C J 
Published: December 2016

SummaryBlood transcriptional profiles could serve as biomarkers of clinical changes in subjects at-risk for or diagnosed with diabetes. However, transcriptional variation over time is poorly understood due to the impracticality of frequent longitudinal phlebotomy in large patient cohorts. We have developed a novel transcriptome assessment method that could be applied to fingerstick blood samples self-collected by study volunteers. Fifteen μL of blood from a fingerstick yielded sufficient RNA to analyse &gt; 176 transcripts by high-throughput quantitative polymerase chain reaction (PCR). We enrolled 13 subjects with type 1 diabetes and 14 controls to perform weekly collections at home for a period of 6 months. Subjects returned an average of 24 of 26 total weekly samples, and transcript data were obtained successfully for &gt; 99% of samples returned. A high degree of correlation between fingerstick data and data from a standard 3 mL venipuncture sample was observed. Increases in interferon-stimulated gene expression were associated with self-reported respiratory infections, indicating that real-world transcriptional changes can be detected using this assay. In summary, we show that longitudinal monitoring of gene expression is feasible using ultra-low-volume blood samples self-collected by study participants at home, and can be used to monitor changes in gene expression frequently over extended periods.
Pathogens and antibiotic sensitivities in endophthalmitis
Authors: Slean Geraldine R , Shorstein Neal H , Liu Liyan , Paschal John F , Winthrop Kevin L , Herrinton Lisa J 
Published: December 2016

AbstractBackgroundAntibiotic prophylaxis in cataract surgery is intended to minimize endophthalmitis. We describe pathogenic organisms, antibiotic sensitivities and antibiotic prophylaxis in culture‐proven endophthalmitis cases.DesignRetrospective consecutive case series and community‐based setting were used.ParticipantsTwo hundred fifteen cases of endophthalmitis after cataract surgery performed during 2007–2012 in Kaiser Permanente, California.Methods and Main Outcome MeasuresDescriptive analysis of isolated organisms and antibiotic sensitivities in relation to antibiotic prophylaxis in culture‐proven endophthalmitis cases.ResultsThe majority of culture‐confirmed organisms (n = 83) were Gram positive (96%), most notably coagulase‐negative Staphylococci (n = 34, 52%), of which all that underwent testing were sensitive to vancomycin (n = 32). Among 19 cases that had received only topical antibiotic prophylaxis, seven (37%) were resistant to the antibiotic given: 50% of cases (5 of 10 isolates) that had received ofloxacin were resistant to this antibiotic, 40% (2 of 5 isolates) that had received gatifloxacin were resistant. In contrast, 100% of cases (n = 4) that had received aminoglycosides were susceptible. Few culture‐confirmed cases occurred in patients who received intracameral antibiotic (n = 4).ConclusionsIn cases where fluoroquinolones were administered as antibiotic prophylaxis, isolates demonstrated a degree of bacterial resistance. The majority of endophthalmitis cases isolated occured following topical antibiotic prophylaxis only and were attributed to Gram‐positive organisms, while few occurred in association with intracameral antibiotic.