bluuebunny/crossref_metadata_2025 huggingface dataset:
NRF2 activates a partial Epithelial-Mesenchymal Transition and is maximally present in a hybrid Epithelial/Mesenchymal phenotype
Authors: Bocci Federico , Tripathi Satyendra C , Vilchez Mercedes Samuel A , George Jason T , Casabar Julian P , Wong Pak Kin , Hanash Samir M , Levine Herbert , Onuchic José N , Jolly Mohit Kumar
Published: August 2018

The Epithelial-Mesenchymal Transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype - a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of Circulating Tumour Cells (CTCs) - the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Here, using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilised a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.
Enhanced Sampling of Protein Conformational Transitions via Dynamically Optimized Collective Variables
Authors: Brotzakis Z. Faidon , Parrinello Michele
Published: August 2018

Protein conformational transitions often involve many slow degrees of freedom. Their knowledge would give distinctive advantages since it provides chemical and mechanistic insight and accelerates the convergence of enhanced sampling techniques that rely on collective variables. In this study, we implemented a recently developed variational approach to conformational dynamics metadynamics to the conformational transition of the moderate size protein, L99A T4 Lysozyme. In order to find the slow modes of the system we combined data coming from NMR experiments as well as short MD simulations. A Metadynamics simulation based on these information reveals the presence of two intermediate states, at an affordable computational cost.
Genotype patterns in growing solid tumors
Authors: Nanda Mridu , Durrett Rick , Harvard U , Duke U
Published: August 2018

Over the past decade, the theory of tumor evolution has largely focused on the selective sweeps model. According to this theory, tumors evolve by a succession of clonal expansions that are initiated by driver mutations. In a 2015 analysis of colon cancer data, Sottoriva et al [34] proposed an alternative theory of tumor evolution, the so-called Big Bang model, in which one or more driver mutations are acquired by the founder gland, and the evolutionary dynamics within the expanding population are predominantly neutral. In this paper we will describe a simple mathematical model that reproduces qualitative features of the observed paatterns of genetic variability and makes quantitative predictions.
The claustrum is required for reward acquisition under high cognitive demand
Authors: White Michael G. , Mu Chaoqi , Zeng Hongkui , Mathur Brian N.
Published: August 2018

The claustrum is proposed to mediate a variety of functions ranging from sensory binding to top-down cognitive control of action, but direct functional assessments of this telencephalic nucleus are lacking. Here we employ the guanine nucleotide-binding subunit beta-4 cre driver line in mice to selectively monitor and manipulate claustrum projection neurons. Using fiber photometry, we find elevated claustrum activity prior to an expected cue during correct performance on a cognitively demanding five-choice response assay relative to a less-demanding one-choice version of the task. Claustrum activity during reward acquisition is also enhanced when cognitive demand is higher. Furthermore, we use optogenetic inhibition of claustrum prior to the expected cue to demonstrate that claustrum is critical for accurate performance on the five-choice, but not the one-choice, task. These results suggest the claustrum supports a cognitive control function necessary for reward acquisition under cognitively demanding conditions.
Large Fatty Acid-derived Aβ42 oligomers Form Ring-like Assemblies
Authors: Xi Wenhui , Dean Dexter N. , Stockmal Kelli A. , Morgan Sarah E. , Hansmann Ulrich H.E. , Rangachari Vijayaraghavan
Published: August 2018

As the primary toxic species in the etiology of Alzheimer disease (AD) are low molecular weight oligomers of Aβ, it is crucial to understand the structure of Aβ oligomers for gaining molecular insights into AD pathology. We have earlier demonstrated that in the presence of fatty acids Aβ42 peptides assemble as 12-24mer oligomers. These Large Fatty Acid-derived Oligomers (LFAOs) exist predominantly as 12mers at low, and as 24mers at high concentrations. The 12mers are more neurotoxic than the 24mers and undergo self-replication, while the latter propagate to morphologically distinct fibrils with succinct pathological consequences. In order to glean into their functional differences and similarities, we have determined their structures in greater detail by combining molecular dynamic simulations with biophysical measurements. We conjecture that the LFAO are made of Aβ units in an S-shaped conformation, with the 12mers forming a double-layered hexamer ring (6 × 2) while the structure of 24mers is a double-layered dodecamer ring (12 × 2). A closer inspection of the (6 × 2) and (12 × 2) structures reveals a concentration and pH dependent molecular reorganization in the assembly of 12 to 24mers, that seems to be the underlying mechanism for the observed biophysical and cellular properties of LFAOs.
Actively restoring resilience in selectively logged tropical forests
Authors: Cerullo Gianluca R. , Edwards David P.
Published: August 2018

Huge tracts of tropical forest are selectively logged. Meanwhile, emerging global agendas are providing unprecedented incentives for large‐scale restoration within human‐impacted tropical forest landscapes. Whilst logged forests have high conservation value, their adoption within these agendas remains controversial.

We review the value of restoring logged tropical forests for boosting economic and environmental resilience. Targeted interventions can recover depleted timber stocks, increase saleable carbon stores, and deliver employment and non‐timber forest products (NTFPs) to local communities. Restoration has mixed outcomes for biodiversity but if it improves relogging practices and protects forests from conversion to agricultural plantations may have major positive impacts.

We also examine socio‐economic and political pathways for upscaling logged forest restoration and their incorporation into sustainable forestry, given political and commercial malaise on post‐logging interventions. Spurring these transitions will require strong institutions, executed by policies that enable long‐term concession licences and community land tenure, that leverage commercial involvement and payments for ecosystem services, and that optimise existing interventions.

Research frontiers include: (a) validating the economic and technical feasibility of different interventions; (b) understanding how these interventions impact on synergies and trade‐offs between ecosystem services, NTFPs, and biodiversity; and (c) identifying when to restore a logged forest. This requires establishing long‐term experimental trials that jointly track environmental and socioeconomic outcomes.

Synthesis and applications. Post‐logging interventions can deliver various timber, carbon, socioeconomic and potentially biodiversity benefits but are underemployed and undervalued pantropically. Opportunities exist to optimise interventions by tailoring incentives, policies, and management to ecological and social circumstances. Governments, conservation bodies and the private sector must underscore restoration of production forests as a major future objective, including via greater adoption in global initiatives, including forest and landscape restoration under the Bonn Challenge and the Reducing Emissions from Deforestation and Forest Degradation (REDD+) agenda.
Distinct responses of niche and fitness differences to water availability underlie variable coexistence outcomes in semi‐arid annual plant communities
Authors: Wainwright Claire E. , HilleRisLambers Janneke , Lai Hao R. , Loy Xingwen , Mayfield Margaret M.
Published: August 2018

Climate change is predicted to have profound consequences for multispecies coexistence, and thus, patterns of biological diversity. These consequences will be mediated by direct and indirect impacts of environmental change on species’ vital rates and interactions. While the impacts of environmental change on individual species has received much attention to date, the consequences for coexistence mediated by changes in the strength and direction of multispecies interactions are not as well understood.

To investigate how coexistence dynamics may be sensitive to environmental change, we conducted a field experiment in a diverse semi‐arid annual plant system. We imposed a water manipulation treatment in two sites that vary in aridity and associated rainfall. Focusing on four common annual plant species in these sites, we quantified the fecundity (seed production) of individuals in response to a gradient of intra‐ and interspecific competitor densities and aridity. We then used these fecundities to parameterize an annual plant population model and examine the influence of aridity and species identity on resultant coexistence dynamics (as a function of stabilizing niche differences and fitness inequalities).

While the responses of some vital rates and competitive impacts to watering varied somewhat predictably across sites, coexistence metrics encapsulating changes in these vital rates and interaction strengths did not. Fitness inequalities among our focal species were driven largely by differences in sensitivity to competition, which were almost always much greater than the magnitude of stabilizing niche differences. These findings were surprising given observational evidence suggesting that these species do coexist at local scales in these natural communities.

Synthesis. Our study is one of the first to explicitly consider the influence of environmental variation on the individual components of coexistence outcomes. We show that environmental change has the ability to influence coexistence not only through direct pathways (i.e., vital rates), but also indirect pathways (i.e., species interactions). Despite the consistency of many of the responses of these individual components to environmental variation, their combined influence on predictions of both current and future coexistence remains unclear.
Upregulation of C/EBPβ and TSC2 by an HDAC inhibitor CG200745 protects heart from DOCA‐induced hypertrophy
Authors: Lee Eunjo , Lee Hae‐Ahm , Kim Mina , Do Ga young , Cho Hyun‐Min , Kim Gun Jik , Jung Hanna , Song Jung Hup , Cho Joong Myung , Kim Inkyeom
Published: August 2018

Histone deacetylases (HDACs) are a vast family divided into four major classes: class I (1, 2, 3, and 8), class II (4, 5, 6, 7, 9 and 10), class III (sirtuin family) and class IV (HDAC11). HDAC inhibition attenuates cardiac hypertrophy through suppression of the mechanistic target of rapamycin complex1 (mTORC1) signaling. HDAC inhibitors upregulate the expression of tuberous sclerosis complex 2 (TSC2), an mTORC1 inhibitor. However, the molecular mechanism underlying HDAC inhibitor‐mediated upregulation of TSC2 is unclear. We hypothesized that an HDAC inhibitor, CG200745 (CG), ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling by upregulating of the CCAAT/enhancer‐binding protein‐β (C/EBP‐β)/TSC2 pathway. To establish a cardiac hypertrophy model, deoxycorticosterone acetate (DOCA, 40 mg/kg/wk) was subcutaneously injected for 4 weeks into Sprague‐Dawley rats. All rats were unilaterally nephrectomized and had free access to drinking water containing 1% NaCl with or without CG of different concentrations. The expression level of TSC2 and C/EBP‐β was measured by quantitative real‐time PCR (qRT‐PCR) and western blot analysis. Acetylation of C/EBP‐β was analyzed by immunoprecipitation. The recruitment of C/EBP‐β and polymerase II (Pol II) on TSC2 promoter region was analyzed by chromatin immunoprecipitation (ChIP). CG treatment increased the expression of TSC2. In addition, CG treated rats showed an increased in the expression and acetylation of C/EBP‐β, owing to the increase in the recruitment of C/EBP‐β and Pol II at Tsc2 gene promoter. Thus, CG ameliorates cardiac hypertrophy through the inhibition of mTORC1 signaling via upregulation of the C/EBP‐β/TSC2 pathway in DOCA‐induced hypertensive rats.
The Two Kingdoms: The Norwegian Seamen's Church in London 1865–1905
Authors: Redvaldsen David
Published: August 2018

The Norwegian church in London began its life as a mission to Scandinavian seamen in 1868, after an evangelical society for this group had been founded in Bergen in 1864. Throughout the period covered, the former was involved in extensive cooperation with the other Nordic missions in the British capital. Yet it was always a congregation rather than just a mission and, as time went by, it became more self‐consciously Norwegian too. Evidence presented here suggests the mission was a place of worship for its domiciled compatriots before 1872, when the church building was completed. In common with many foreign Protestant churches in London, the Norwegian congregation experienced some conflict. There were restrictions on it owing to Norway having entered a forced union with Sweden in 1814. The Swedish church saw itself as catering for both nationalities and would not brook competition from what was officially a service for Scandinavian seamen. The clergy were not natural supporters of Norwegian nationalism. But as their country became more self‐assertive within the union from 1880, they began demanding enhanced rights for their church. It was only when Norway had unilaterally declared its independence in 1905 that the clergy became full‐blown adherents of this.
Adolescent parenthood associated with adverse socio‐economic outcomes at age 30 years in women and men of the Pelotas, Brazil: 1982 Birth Cohort Study
Authors: Gigante DP , de França GVA , De Lucia Rolfe E , Lima NP , dos Santos Motta JV , Gonçalves H , Horta BL , Barros FC , Ong KK
Published: August 2018

Objective

To investigate the potential long‐term effects of adolescent parenthood on completed education and income.

Design

Population‐based birth cohort study.

Setting

All live births in 1982, whose mothers lived in the urban area of Pelotas, southern Brazil.

Sample

A total of 3701 participants: 1914 women and 1787 men at age 30 years.

Methods

Questionnaires were completed by the mothers in the early phases of this study, and by the cohort members in adolescence and adulthood. Linear regression models and G‐computation were used in the analyses.

Main outcome measures

Educational attainment and income at age 30 years.

Results

In women, adolescent parenthood was associated with lower attained education compared with women without adolescent maternity: by −2.8 years [95% confidence interval (CI) −3.2 to −2.3] if their first birth was at age 16–19, and by −4.4 years (−5.5 to −3.3) at age 11–15. These effects were greater among women who had three or more children. Women with adolescent parenthood also had 49 or 33% lower income at age 30 if their first child was born when aged 16–19 or 11–15, respectively. In men, the adverse effect of adolescent parenthood on education appeared to be mediated by a higher number of children and there was no effect of adolescent paternity on income at age 30 years.

Conclusion

These findings suggest lasting socio‐economic disadvantages of adolescent parenthood, with larger effects being apparent in women than in men.

Tweetable abstract

Adolescent parenthood has an adverse effect on educational attainment later in life, and on household income among women.
MRI measurement of residual cervical length after radical trachelectomy for cervical cancer and the risk of adverse pregnancy outcomes: a blinded imaging analysis
Authors: Alvarez RM , Biliatis I , Rockall A , Papadakou E , Sohaib SA , deSouza NM , Butler J , Nobbenhuis M , Barton DJP , Shepherd JH , Ind TEJ
Published: August 2018

Objective

To determine the association between the residual cervix measured on postoperative MRI after radical vaginal trachelectomy (RVT) and adverse obstetrical outcomes.

Design

Observational study.

Setting

Referral Cancer centre.

Population

Women who conceived after RVT for cervical cancer at the Royal Marsden Hospital, London, between 1995 and 2015.

Methods

Postoperative MRI scans were analysed by three researchers. The agreement between researchers was assessed by Pearson's correlation coefficient and Bland–Altman plot. Patients were divided into two groups (<10 and ≥10 mm residual cervix) for the analysis of adverse obstetrical outcomes.

Main outcome measures

Late miscarriage, premature delivery, premature rupture of membranes (PROM) and chorioamnionitis.

Results

Thirty‐one MRI scans were available; 29 of these women had a pregnancy that progressed beyond the first trimester. There was a strong reproducibility of the measurement of residual cervix (P < 0.001). Nineteen women (65.5%) had <10 mm residual cervix and 10 (34.5%) had ≥10 mm. Among women with <10 mm residual cervix, seven (36.8%) experienced PROM and ten (66.7%) had a preterm birth; No women with ≥10 mm residual cervix had PROM and two (22.2%) had a preterm birth (P = 0.028 and P = 0.035, respectively). Overall, there were nine (16.7%) first‐trimester miscarriages, six (11.1%) late fetal losses, 12 (31.6%) preterm births and 36 (66.7%) live births. After a mean follow up of 78.1 months, 36 women were disease‐free and one woman had died.

Conclusions

MRI measurements of the residual cervix are reproducible between observers. The incidence of PROM and premature delivery is higher when the residual cervix after RVT is <10 mm.

Tweetable abstract

The risk of prematurity after RVT can be predicted from measurements of residual cervical length on postoperative MRI scan.
Varying 10‐year off‐treatment responses to nucleos(t)ide analogues in patients with chronic hepatitis B according to their pretreatment hepatitis B e antigen status
Authors: Liu Feng , Liu Zhi Rong , Li Tao , Liu You De , Zhang Meng , Xue Yan , Zhang Li Xin , Ye Qian , Fan Xiao Ping , Wang Lei
Published: August 2018

OBJECTIVE

To evaluate the long‐term durability and efficacy of nucleos(t)ide analogues (NAs) and to determine the related factors for virological relapse in chronic hepatitis B (CHB) patients.

METHODS

CHB patients who fulfilled the criteria for discontinuing NAs therapy in accordance with the published guidelines were included in the study from December 2001. Virological relapse was defined as serum hepatitis virus B (HBV) DNA >104 copies/mL twice at least 2 weeks apart.

RESULTS

A total of 223 CHB patients were enrolled at the time their NAs therapy was discontinued. The 10‐year cumulative relapse rate (CRR) in hepatitis B e antigen (HBeAg)‐positive patients was statistically lower than that in HBeAg‐negative patients (30.9% vs 62.3%, P < 0.001). In the HBeAg‐positive group, Cox regression analysis showed that age at cessation (hazard ratio [HR] 1.067, P < 0.001), consolidation therapy (HR 0.958, P = 0.021), and time to HBeAg seroconversion (HR 0.943, P = 0.019) were predictors for relapse. In the HBeAg‐negative group, age at cessation (HR 1.040, P = 0.004) and time to HBV DNA negativity (HR 1.246, P = 0.010) were potential predictors for virological relapse.

CONCLUSIONS

The off‐treatment responses to NAs differ in CHB patients with different pretreatment HBeAg status. NA withdrawal is generally safe and feasible in young patients with CHB. Long consolidation periods should be preferred in HBeAg‐positive patients to achieve better durability. Benefits of cessation of NAs do not last long in HBeAg‐negative CHB patients.
Population attributable fractions of the main type 2 diabetes mellitus risk factors in women: Findings from the French E3N cohort
Authors: Rajaobelina Kalina , Dow Courtney , Romana Mancini Francesca , Dartois Laureen , Boutron‐Ruault Marie‐Christine , Balkau Beverley , Bonnet Fabrice , Fagherazzi Guy
Published: August 2018

Background

Although many type 2 diabetes mellitus (T2DM) risk factors have been identified, little is known regarding their contributions to the diabetes burden at the population level.

Methods

The study included 72 655 French women from the Etude Epidemiologique de Femmes de la Mutuelle Générale de l'Education Nationale (E3N) prospective cohort followed between 1993 and 2011. Cox multivariable models including the main T2DM risk factors (metabolic, dietary, clinical, socioeconomic and hormonal) and a healthy lifestyle index combining five characteristics (smoking, body mass index [BMI], alcohol consumption, fruit and vegetable consumption, and physical activity) were used to estimate hazard ratios and population attributable fractions (PAFs) for T2DM.

Results

In multivariate models, factors with the strongest effect on T2DM risk were, in decreasing order, BMI ≥ 30 kg/m2 (PAF = 43%; 95% confidence interval [CI] 37–47), high adherence to a Western dietary pattern (PAF = 30%; 95% CI 20–40), hypertension (PAF = 26%; 95% CI 20–32), an acidogenic diet (PAF = 24%; 95% CI 16–32), a family history of diabetes (PAF = 20%; 95% CI 17–22), and, with a negative correlation, moderate alcohol consumption (PAF–19%; 95% CI –34, −4). The PAF for an unhealthy lifestyle was 57% (95% CI 50–63).

Conclusions

We have been able to sort out and quantify the effect of various dietary and biological T2DM risk factors simultaneously in a single population, and to highlight the importance of a healthy lifestyle for primary prevention: more than half the T2DM cases could have been prevented through a healthier lifestyle.
Shifts in Alcohol‐Related Diagnoses After the Introduction of International Classification of Diseases, Tenth Revision, Clinical Modification Coding in U.S. Hospitals: Implications for Epidemiologic Research
Authors: Heslin Kevin C. , Barrett Marguerite L.
Published: August 2018

Background

In October 2015, the United States transitioned healthcare diagnosis codes from the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD‐9‐CM), to the Tenth Revision (ICD‐10‐CM). Trend analyses of alcohol‐related stays could show discontinuities solely from the change in classification systems. This study examined the impact of the ICD‐10‐CM coding system on estimates of hospital stays involving alcohol‐related diagnoses.

Methods

This analysis used 2014 to 2017 administrative data from the Agency for Healthcare Research and Quality Healthcare Cost and Utilization Project State Inpatient Databases for 17 states. Quarterly ICD‐9‐CM data from second quarter 2014 through third quarter 2015 were concatenated with ICD‐10‐CM data from fourth quarter 2015 through first quarter 2017. Quarterly counts of alcohol‐related stays were examined overall and then by 6 diagnostic subgroups: withdrawal, abuse, dependence, alcohol‐induced mental disorders (AIMD), nonpsychiatric alcohol‐induced disease, and intoxication or toxic effects. Within each group, we calculated the difference in the average number of stays between ICD‐9‐CM and ICD‐10‐CM coding periods.

Results

On average, the number of stays involving any alcohol‐related diagnosis in the 6 quarters before and after the ICD‐10‐CM transition was stable. However, substantial shifts in stays occurred for alcohol abuse, AIMD, and intoxication or toxic effects. For example, the average quarterly number of stays involving AIMD was 170.7% higher in the ICD‐10‐CM period than in the ICD‐9‐CM period. This increase was driven in large part by 1 ICD‐10‐CM code, Alcohol use, unspecified with unspecified alcohol‐induced disorder.

Conclusions

Researchers conducting trend analyses of inpatient stays involving alcohol‐related diagnoses should consider how ongoing modifications in the ICD‐10‐CM code system and coding guidelines might affect their work. An advisable approach for trend analyses across the ICD‐10‐CM transition is to aggregate diagnosis codes into broader, clinically meaningful groups—including a single global group that encompasses all alcohol‐related stays—and then to select diagnostic groupings that minimize discontinuities between the 2 coding systems while providing useful information on this important indicator of population health.
Investor reaction to accounting misstatements under IFRS: Australian evidence
Authors: Goodwin John , Atilgan Yigit , Simsir Serif Aziz , Ahmed Kamran
Published: August 2018

We examine the investor reaction to misstatement news for Australian listed firms from 2006 to 2013. We find 4.1 percent of firm‐years have a misstatement and 79 percent of misstatements are disclosed initially only in the periodic filings (stealth misstatements). We find no investor reaction for the average misstatement, reactions of between −2.3 percent and −2.8 percent (−1.5 and −1.7 percent) for misstatements that reduce prior‐period earnings or equity (affect revenue) and reactions of between −1.3 and −2.7 percent for non‐stealth misstatements. Investor reactions are more negative for non‐stealth misstatements that reduce prior‐period earnings or equity than for stealth misstatements.
Legibility of floor plans and wayfinding satisfaction of residents in Care and Attention homes in Hong Kong
Authors: Tao Yiqi , Gou Zhonghua , Lau Stephen Siu‐Yu , Lu Yi , Fu Jiayan
Published: August 2018

Objective

Focusing on Hong Kong Care and Attention homes which provide residential care, meals, personal care and limited nursing care for older people, this study aimed to understand the impact of floor plans’ legibility (layout and complexity) on residents’ wayfinding satisfaction and self‐reported health status.

Methods

A questionnaire survey was conducted in nine Care and Attention homes. Space syntax, a well‐established method, was used to evaluate the legibility of their floor plans via calculating the integration value.

Results

Familiarity with Care and Attention homes did not influence the residents’ satisfaction with wayfinding. The integration value had a significant impact on residents’ satisfaction with wayfinding. No relationship was observed between integration value and self‐reported health status.

Conclusion

Increasing complexity in floor plans appears to negatively affect residents’ wayfinding satisfaction. These data suggest that circulation patterns should be improved for better wayfinding.
Upregulation and release of soluble fms‐like tyrosine kinase receptor 1 mediated by complement activation in human syncytiotrophoblast cells
Authors: Banadakoppa Manu , Balakrishnan Meena , Yallampalli Chandra
Published: August 2018

Problem

Antiangiogenic molecule soluble fms‐like tyrosine kinase receptor 1 (sFLT1) released from trophoblast cells is associated with pregnancy‐specific hypertensive disorder pre‐eclampsia. Cause of elevated sFLT1 in pre‐eclampsia patients is not well understood. Despite evidence of excess systemic and placental complement activation in pre‐eclampsia patients, its role in pathophysiology is not clear. If the complement activation plays a role in upregulation and secretion of sFLT1 is not known.

Method of study

Human trophoblast cells were isolated from term placentas and allowed to syncytialize. Complement was activated in vitro at sublethal levels on syncytiotrophoblast cells. Effect of complement activation on expression and release of sFLT1 was assessed by comparing its levels in these cells with and without complement activation.

Results

Sublethal level of complement activation on syncytialized human trophoblast cells induced upregulation of sFLT1 mRNA and protein. Complement also induced secretion of sFLT1 in a manner depending on degree of activation. Anaphylatoxins C3a induced upregulation but not the release of sFLT1. Release of terminal membrane attack complex (MAC) was associated with sFLT1 secretion.

Conclusion

Complement activation plays a major role in both the expression and secretion of sFLT1 from syncytial trophoblast cells. The terminal MAC complex is involved in its secretion. Increased levels of sFLT1 in pre‐eclampsia patients may be due to complement‐induced upregulation and secretion.
Multivariate Poisson hidden Markov models with a case study of modelling seismicity
Authors: Orfanogiannaki K. , Karlis D.
Published: August 2018

While the literature on multivariate models for continuous data flourishes, there is a lack of models for multivariate counts. We aim to contribute to this framework by extending the well known class of univariate hidden Markov models to the multidimensional case, by introducing multivariate Poisson hidden Markov models. Each state of the extended model is associated with a different multivariate discrete distribution. We consider different distributions with Poisson marginals, starting from the multivariate Poisson distribution and then extending to copula based distributions to allow flexible dependence structures. An EM type algorithm is developed for maximum likelihood estimation. A real data application is presented to illustrate the usefulness of the proposed models. In particular, we apply the models to the occurrence of strong earthquakes (surface wave magnitude ≥5), in three seismogenic subregions in the broad region of the North Aegean Sea for the time period from 1 January 1981 to 31 December 2008. Earthquakes occurring in one subregion may trigger events in adjacent ones and hence the observed time series of events are cross‐correlated. It is evident from the results that the three subregions interact with each other at times differing by up to a few months. This migration of seismic activity is captured by the model as a transition to a state of higher seismicity.
Stillbirth and preterm birth and associated factors in one of the largest cities in central Vietnam
Authors: Giang Hoang Thi Nam , Bechtold‐Dalla Pozza Susanne , Tran Hoang Thi , Ulrich Sarah
Published: August 2018

Aim

Little is known about the rate of stillbirths, preterm births and associated risk factors in resource‐limited settings like Vietnam. This study reports those rates for Da Nang, which is one of the largest cities in central Vietnam.

Methods

Data on 20 762 births including stillbirths and preterm births and associated risk factors were prospectively collected from health facilities from April 2015 to March 2016.

Results

The data represented 85% of the total births in Da Nang during the study period, and a stillbirth rate of 9.7 per 1000 live births was recorded. The preterm rate for live births was just under 5%. Independent factors associated with an increased risk of stillbirth and preterm births were mothers aged 35 plus, working as farmers, living in the provinces and a history of abortion. Mothers under 20 years with previous preterm births faced a higher risk of another preterm birth.

Conclusion

The stillbirth and premature birth rates in Da Nang were higher than rates in high‐income countries. Developing registration programmes in Vietnam will provide improved data that will enable researchers and policymakers to identify strategies to reduce the number of stillbirths and premature births.
Effects of self‐regulatory skill usage on weight management behaviours: Mediating effects of induced self‐efficacy changes in non‐obese through morbidly obese women
Authors: Annesi James J.
Published: August 2018

Objectives

Self‐regulation is thought to play a role in overcoming barriers to weight management behaviour changes. This research assessed the extent that relationship is manifested through associated changes in self‐efficacy, and effects based on degree of obesity.

Design

Data sets from three previous studies of the present research group were utilized. After assessment of change scores using repeated‐measures ANOVA, mediation and moderation analyses assessed effects of changes in self‐regulatory skill usage on changes in physical activity and fruit/vegetable intake through self‐efficacy changes. Moderating effects of BMI were then assessed.

Methods

Women with body compositions ranging from non‐obese (BMI < 30 kg/m2) to those with morbid obesity (BMI ≥ 40 kg/m2) were administered similar cognitive‐behavioural treatments, and assessed on theory‐based psychosocial and behavioural measures over 6 months.

Results

From baseline to Month 6, changes in self‐regulation for physical activity and eating, physical activity behaviours, fruit/vegetable intake, and self‐efficacy for controlled eating were significant in non‐obese women (n = 48) and women with Class 1 (n = 43), Class 2 (n = 70), and Class 3 (n = 48) obesity. Positive effects were smaller in exercise self‐efficacy. For each of the BMI‐based groups, changes in self‐efficacy significantly mediated the prediction of physical activity and fruit/vegetable intake by changes in self‐regulation. In aggregated data, BMI significantly moderated the prediction of change in physical activity (higher BMI associated with a stronger association), but not fruit/vegetable intake, within those models.

Conclusion

Increasing self‐regulatory skills to overcome lifestyle barriers was found to be important for fostering improved weight loss behaviours, especially in the treatment of higher degrees of obesity in women.

Statement of contribution

What is already known on this subject?

Self‐efficacy is a malleable factor that predicts behaviour change within multiple theories.

Learned self‐regulatory skills may effectively deal with lifestyle barriers associated with improvements in weight management behaviours.

Increased physical activity and fruit/vegetable consumption predicts success with weight loss.

What does this study add?

Much of self‐regulation's effect on physical activity and eating behaviours is through its impact on self‐efficacy.

Weight management treatments should emphasize self‐regulatory skills development over simply health education.

Effects of interrelations of self‐regulation and self‐efficacy are more effective as female weight increases.
Switch from abiraterone plus prednisone to abiraterone plus dexamethasone at asymptomatic PSA progression in patients with metastatic castration‐resistant prostate cancer
Authors: Fenioux Charlotte , Louvet Christophe , Charton Emilie , Rozet Francois , Ropert Stanislas , Prapotnich Dominique , Barret Eric , Sanchez‐Salas Rafael , Mombet Annick , Cathala Nathalie , Joulia Marie‐Liesse , Molitor Jean‐Luc , Henriques Julie , Bonnetain Franck , Cathelineau Xavier , Bennamoun Mostefa
Published: August 2018

Objective

To evaluate the effects of switching from prednisone (P) to dexamethasone (D) at asymptomatic prostate‐specific antigen (PSA) progression in patients with metastatic castration‐resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA).

Materials and Methods

Among 93 patients treated with AA between January 2013 and April 2016 in our institution, 48 consecutive asymptomatic patients with mCRPC, who experienced biochemical progression on treatment with AA+P 10 mg/day, were included. A corticosteroid switch to AA+D 0.5 mg/day at PSA increase was administered until radiological and/or clinical progression. The primary endpoint was progression‐free‐survival (PFS). A prognostic score based on independent prognostic factors was defined.

Results

The median time to PSA progression on AA+P was 8.94 months. The median PFS on AA+D and AA+corticosteroids (P then D) was 10.35 and 20.07 months, respectively. A total of 56.25% of patients showed a decrease or stabilization in PSA levels after the switch. In univariate analysis, three markers of switch efficiency were significantly associated with a longer PFS: long hormone‐sensitivity duration (≥5 years; median PFS 16.62 vs 4.17 months, hazard ratio [HR] 0.30, 90% confidence interval [CI] 0.16–0.56); low PSA level at the time of switch (<50 ng/mL; median PFS 15.21 vs 3.86 months, HR 0.33, 90% CI 0.18–0.60); and short time to PSA progression on AA+P (<6 months; median PFS 28.02 vs 6.65 months, HR 0.41 (90% CI 0.21–0.81). In multivariate analysis, hormone sensitivity duration and PSA level were independent prognostic factors.

Conclusion

A steroid switch from P to D appears to be a safe and non‐expensive way of obtaining long‐term responses to AA in selected patients with mCRPC. A longer PFS has been observed in patients with previous long hormone sensitivity duration, and/or low PSA level and/or short time to PSA progression on AA+P.
P2X7 as a scavenger receptor for innate phagocytosis in the brain
Authors: Gu Ben J , Wiley James S
Published: August 2018

The P2X7 receptor has been widely studied for its ATP‐induced pro‐inflammatory effect, but in the absence of a ligand, P2X7 has a second function as a scavenger receptor, which is active in the development of the human brain. The scavenger activity of P2X7 is only evident in the absence of serum but is fully active in cerebrospinal fluid. P2X7 on the cell surface is present as a membrane complex, and an attachment to non‐muscle myosin of the cytoskeleton is required for particle engulfment. Selective antagonists of P2X7 pro‐inflammatory function have little effect on phagocytosis, but inheritance of a variant haplotype spanning the P2RX7 and P2RX4 genes has been associated with loss of P2X7‐mediated phagocytosis. Recent studies in mice suggest that the innate phagocytosis mediated by P2X7 receptors declines with ageing. Thus, defective P2X7‐mediated phagocytosis may contribute to age‐related neuro‐degenerative diseases including Alzheimer's disease, age‐related macular degeneration and primary progressive multiple sclerosis.
Targeting the FOXM1‐regulated long noncoding RNA TUG1 in osteosarcoma
Authors: Li Yang , Zhang Tao , Zhang Yanhui , Zhao Xingkai , Wang Wenbo
Published: August 2018

Long noncoding RNAs (lncRNAs) play an important role in the proliferation and metastasis of osteosarcoma. Identification of the pathogenesis of osteosarcoma and development of new therapeutic strategies against osteosarcoma are urgently needed. In this study, we evaluated the expression of TUG1 (Taurine Upregulated Gene 1) in osteosarcoma tissues and selected it as our target for further analyses. In vitro, we found that TUG1 was upregulated by FOXM1 (Forkhead Box M1) in osteosarcoma cells. TUG1 accelerated osteosarcoma proliferation, migration, and invasion by competitively sponging miR‐219a‐5p, leading to upregulation of Phosphatidylinositol‐4, 5‐Bisphosphate 3‐Kinase Catalytic Subunit Alpha and activation of the protein kinase B (AKT) signaling pathway. In addition, the AKT pathway activation promoted TUG1 expression by upregulating the expression of FOXM1, forming a positive feedback loop in osteosarcoma. Furthermore, we designed and synthesized therapeutic locked nucleic acids targeting TUG1. The proliferation of osteosarcoma was significantly repressed. Hence, TUG1 may be a potential biomarker and therapeutic target for osteosarcoma.
Fatty pancreas: A possible risk factor for pancreatic cancer in animals and humans
Authors: Takahashi Mami , Hori Mika , Ishigamori Rikako , Mutoh Michihiro , Imai Toshio , Nakagama Hitoshi
Published: August 2018

Obesity, type 2 diabetes mellitus (T2DM) and aging are associated with pancreatic cancer risk, but the mechanisms of pancreatic cancer development caused by these factors are not clearly understood. Syrian golden hamsters are susceptible to N‐nitrosobis(2‐oxopropyl)amine (BOP)‐induced pancreatic carcinogenesis. Aging, BOP treatment and/or a high‐fat diet cause severe and scattered fatty infiltration (FI) of the pancreas with abnormal adipokine production and promote pancreatic ductal adenocarcinoma (PDAC) development. The KK‐Ay mouse, a T2DM model, also develops severe and scattered FI of the pancreas. Treatment with BOP induced significantly higher cell proliferation in the pancreatic ducts of KK‐Ay mice, but not in those of ICR and C57BL/6J mice, both of which are characterized by an absence of scattered FI. Thus, we hypothesized that severely scattered FI may be involved in the susceptibility to PDAC development. Indeed, severe pancreatic FI, or fatty pancreas, is observed in humans and is associated with age, body mass index (BMI) and DM, which are risk factors for pancreatic cancer. We analyzed the degree of FI in the non‐cancerous parts of PDAC and non‐PDAC patients who had undergone pancreatoduodenectomy by histopathology and demonstrated that the degree of pancreatic FI in PDAC cases is significantly higher than that in non‐PDAC controls. Moreover, the association with PDAC is positive, even after adjusting for BMI and the prevalence of DM. Accumulating evidence suggests that pancreatic FI is involved in PDAC development in animals and humans, and further investigations to clarify the genetic and environmental factors that cause pancreatic FI are warranted.
Human immunodeficiency virus Tat‐TIP30 interaction promotes metastasis by enhancing the nuclear translocation of Snail in lung cancer cell lines
Authors: Liu Yu‐Peng , Chen Chao‐Hsiung , Yen Chia‐Hung , Tung Chun‐Wei , Chen Chao‐Ju , Chen Yi‐Ming A. , Huang Ming‐Shyan
Published: August 2018

Lung cancer patients with human immunodeficiency virus (HIV) have a poorer prognosis than do patients without HIV infection. HIV1 Tat is a secreted viral protein that penetrates the plasma membrane and interacts with a number of proteins in non‐HIV‐infected cells. The loss of function of Tat‐interacting protein 30 (TIP30) has been linked to metastasis in non‐small cell lung cancer (NSCLC). However, it is unknown how the interaction of HIV1 Tat with TIP30 regulates the metastasis of NSCLC cells. In this study, the overexpression of TIP30 decreased tumor growth factor‐β‐induced epithelial‐to‐mesenchymal transition (EMT) and invasion of NSCLC cells, whereas the knockdown of TIP30 promoted EMT, invasion and stemness. Exposure to recombinant HIV1 Tat proteins promoted EMT and invasion. A mechanistic study showed that the interaction of HIV1 Tat with TIP30 blocked the binding of TIP30 to importin‐β, which is required for the nuclear translocation of Snail. Indeed, the loss of TIP30 promoted the nuclear translocation of Snail. In vivo studies demonstrated that the overexpression of TIP30 inhibited the metastasis of NSCLC cells. In contrast, the coexpression of HIV1 Tat and TIP30 diminished the inhibitory effect of TIP30 on metastasis. Immunohistochemistry confirmed that TIP30 overexpression reduced the nuclear localization of Snail, whereas the coexpression of HIV1 Tat and TIP30 increased nuclear Snail in metastatic tumors. In conclusion, the binding of HIV1 Tat to TIP30 enhanced EMT and metastasis by regulating the nuclear translocation of Snail. Targeting Tat‐interacting proteins may be a potential therapeutic strategy to prevent metastasis in NSCLC patients with HIV infection.
Identification of gibberellin‐regulated protein as a new allergen in orange allergy
Authors: Inomata  Naoko , Miyakawa Mami , Ikeda Nobuyuki , Oda Kayoko , Aihara Michiko
Published: August 2018

Background

To date, three orange allergens have been reported. However, it is still unclear whether gibberellin‐regulated proteins (GRPs), identified as new allergens in other fruit allergies, are also involved in orange allergy.

Objective

To investigate the allergenicity of orange GRP and to determine the clinical characteristics of patients with orange allergy who are sensitized to orange GRP.

Methods

We enrolled 14 patients (four men, 10 women, mean age: 29.6 years) who were diagnosed with orange allergy based on relevant clinical history, positive skin test, and/or positive challenge test. Orange GRP (molecular weight: 6941.6 Da) was purified by ion‐exchange column chromatography. To test for orange GRP‐specific IgE, we performed ELISA, basophil activation tests, and skin prick tests. Cross‐reactivity of orange GRP with native peach allergen nPru p 7 and Japanese apricot nPru m 7 was analysed by ELISA inhibition assays. IgE specific for orange, grapefruit, and peach allergens rPru p 1, rPru p 3, and rPru p 4 was measured using ImmunoCAP.

Results

Twelve of the 14 patients (85.7%) were positive for orange GRP allergy in at least one test: 71.4% (10/14) were positive by ELISA, 50% (3/6) were positive in the basophil activation test, and 100% (4/4) were positive in the skin prick test. ELISA inhibition assays revealed cross‐reactivity of orange GRP with both nPru p 7 and nPru m 7. The patients showed variable positivity for specific IgE against orange, grapefruit, rPru p 1, rPru p 3, and rPru p 4 (57.1%, 71.4%, 7.1%, 0%, and 21.4%, respectively). The most frequent symptoms of orange GRP allergy were facial swelling and oropharyngeal symptoms.

Conclusions and Clinical Relevance

Orange GRP may be involved in orange allergy and may be a cross‐reactive allergen between citrus fruits and the Rosaceae family of fruits.
Pathogen infections and primary biliary cholangitis
Authors: Tanaka A , Leung P S C , Gershwin M E
Published: August 2018

Primary biliary cholangitis (PBC) is a multi-factorial disease caused by the interaction of both genetic predisposition and environmental triggers. Bacterial infection has been investigated most intensively, both epidemiologically and experimentally, as a prime environmental aetiology in PBC. The association of recurrent history of urinary tract infection (UTI) with PBC has been frequently confirmed by several large-scale, case–control studies, despite variation in geographic area or case-finding methods. Escherichia coli is a predominant pathogen in most cases with UTI. Animal studies and molecular mimicry analysis between the human and E. coli E2 subunit of the 2-oxo-acid dehydrogenase complexes demonstrated that E. coli infection is a key factor in breaking immunological tolerance against the mitochondria, resulting in the production of anti-mitochondrial autoantibodies (AMA), the disease-specific autoantibodies of PBC. Novosphingobium aromaticivorans, a ubiquitous xenobiotic-metabolizing bacterium, is another candidate which may be involved in the aetiology of PBC. Meanwhile, improved environmental hygiene and increased prevalence of PBC, especially in males, may argue against the aetiological role of bacterial infection in PBC. Multiple mechanisms can result in the loss of tolerance to mitochondrial autoantigens in PBC; nonetheless, bacterial infection is probably one of the dominant pathways, especially in female patients. Notably, there is a rising prevalence of male patients with PBC. With increasing exposure to environmental xenobiotics in both genders, studies directed towards identifying the environmental culprit with systematically designed case–control studies are much needed to further determine the environmental factors and role of bacterial infections in PBC.