bluuebunny/crossref_metadata_2025 huggingface dataset:
Expected patterns of local ancestry in a hybrid zone
Authors: Smith Joel , Payseur Bret , Novembre John
Published: August 2018

1

The initial drivers of reproductive isolation between species are poorly characterized. In cases where partial reproductive isolation exists, genomic patterns of variation in hybrid zones may provide clues about the barriers to gene flow which arose first during the early stages of speciation. Purifying selection against incompatible substitutions that reduce hybrid fitness has the potential to distort local patterns of ancestry relative to background patterns across the genome. The magnitude and qualitative properties of this pattern are dependent on several factors including migration history and the relative fitnesses for different combinations of incompatible alleles. We present a model which may account for these factors and highlight the potential for its use in verifying the action of natural selection on candidate loci implicated in reducing hybrid fitness.
Preliminary prediction of the potential distribution and consequences of Haemaphysalis longicornis using a simple rule-based climate envelope model
Authors: Magori Krisztian
Published: August 2018

Haemaphysalis longicornis, the Asian longhorned (or bush) tick has been detected on a sheep in August 2017 in Hunterdon County, New Jersey. By October 26, 2018, this tick has been detected in 44 counties in 9 states along the Atlantic coast of the United States, with the first detection backdated to 2010. Here, I use a simple rule-based climate envelope model, based on a prior analysis in New Zealand, to provide a preliminary analysis of the potential range of this introduced tick species in North America. After validating this model against the counties where the tick has been already detected, I highlight the counties where this tick might cause considerable economic harm. I discuss the many limitations of this simple approach, and potential remedies for these limitations, and more sophisticated approaches. Finally, I conclude that substantial areas of the US, especially along the Gulf and Atlantic coast, are suitable for the establishment of this tick, putting millions of heads of livestock potentially at risk.
Reconstructing B cell receptor sequences from short-read single cell RNA-sequencir with BRAPeS
Authors: Afik Shaked , Raulet Gabriel , Yosef Nir
Published: August 2018

RNA-sequencing of single B cells provides simultaneous measurements of the cell state and its binding specificity. However, in order to uncover the latter further reconstruction of the B cell receptor (BCR) sequence is needed. We present BRAPeS, an algorithm for reconstructing BCRs from short-read paired-end single cell RNA-sequencing. BRAPeS is accurate and achieves a high success rate even at very short (25bp) read length, which can decrease the cost and increase the number of cells that can be analyzed compared to long reads. BRAPeS is publicly available in the following link:https://github.com/YosefLab/BRAPeS.
SNP-ChIP: A versatile and tag-free method to quantify changes in protein binding across the genome
Authors: Vale-Silva Luis A. , Markowitz Tovah E. , Hochwagen Andreas
Published: August 2018

Chromatin-immunoprecipitation followed by sequencing (ChIP-seq) is the method of choice for mapping genome-wide binding of chromatin-associated factors. However, broadly applicable methods for between-sample comparisons are lacking. Here, we introduce SNP-ChIP, a method that leverages small-scale intra-species polymorphisms, mainly SNPs, for quantitative spike-in normalization of ChIP-seq results. Sourcing spike-in material from the same species ensures antibody cross-reactivity and physiological coherence, thereby eliminating two central limitations of traditional spike-in approaches. We show that SNP-ChIP is robust to changes in sequencing depth and spike-in proportions, and reliably identifies changes in overall protein levels, irrespective of changes in binding distribution. Application of SNP-ChIP to test cases from budding yeast meiosis allowed discovery of novel regulators of the chromosomal protein Red1 and quantitative analysis of the DNA-damage associated histone modificationγ-H2AX. SNP-ChIP is fully compatible with the intra-species diversity of humans and most model organisms and thus offers a general method for normalizing ChIP-seq results.
Inactivation of medial frontal cortex changes risk preference
Authors: Chen Xiaomo , Stuphorn Veit
Published: August 2018

Humans and other animals need to make decisions under varying degrees of uncertainty. These decisions are strongly influenced by an individual’s risk preference, however the neuronal circuitry by which risk preference shapes choice is still unclear [1]. Supplementary eye field (SEF), an oculomotor area within primate medial frontal cortex, is thought to be an essential part of the neuronal circuit underlying oculomotor decision-making, including decisions under risk [2–5]. Consistent with this view, risk-related action value and monitoring signals have been observed in SEF [6–8]. However, such activity has also been observed in other frontal areas, including orbitofrontal [9–11], cingulate [12–14], and dorsal lateral frontal cortex [15]. It is thus unknown whether the activity in SEF causally contributes to risky decisions, or if it is merely a reflection of neural processes in other cortical regions. Here, we tested a causal role of SEF in risky oculomotor choices. We found that SEF inactivation strongly reduced the frequency of risky choices. This reduction was largely due to a reduced attraction to reward uncertainty and high reward gain, but not due to changes in the subjective estimation of reward probability or average expected reward. Moreover, SEF inactivation also led to increased sensitivity to differences between expected and actual reward during free choice. Nevertheless, it did not affect adjustments of decisions based on reward history.
Phosphatidylinositol 3,5-Bisphosphate Regulates Yeast Vacuole Fusion at the Transition betweentrans-SNARE Complex Formation and Hemifusion
Authors: Miner Gregory E. , Sullivan Katherine D. , Guo Annie , Jones Brandon C. , Starr Matthew L. , Fratti Rutilio A.
Published: August 2018

Phosphoinositides (PIs) regulate myriad cellular functions including membrane fusion, as exemplified by the yeast vacuole, which uses various PIs at different stages of fusion. In light of this, the effect of phos-phatidylinositol 3,5-bisphosphate [PI(3,5)P2] on vacuole fusion remains unknown. PI(3,5)P2is made by the PI3P 5-kinase Fab1/PIKfyve and has been characterized as a regulator of vacuole fission during hyperosmotic shock where it interacts with the TRP family Ca2+channel Yvc1. Here we demonstrate that exogenously added dioctanoyl (C8) PI(3,5)P2abolishes homotypic vacuole fusion. This effect was not linked to interactions with Yvc1, as fusion was equally affected usingyvc1Δvacuoles. Thus, the effects of C8-PI(3,5)P2on fusion versus fission operate through distinct mechanisms. Further testing showed that C8-PI(3,5)P2inhibited vacuole fusion after the formation oftrans-SNARE pairs. Although SNARE complex formation was unaffected we found that C8-PI(3,5)P2strongly inhibited hemifusion. Overproduction of endogenous PI(3,5)P2by thefab1T2250Ahyperactive kinase mutant also inhibited at the hemifusion stage, bolstering the model in which PI(3,5)P2inhibits fusion when present elevated levels. Taken together, this work identifies a novel function for PI(3,5)P2as a negative regulator of vacuolar fusion. Moreover, it suggests that this lipid acts as a molecular switch between fission and fusion.
Avian predation intensity as a driver of clinal variation in colour morph frequency
Authors: Matthews Genevieve , Goulet Celine T. , Delhey Kaspar , Atkins Zak S. , While Geoffrey M. , Gardner Michael G. , Chapple David G.
Published: August 2018

Phenotypic variation provides the framework for natural selection to work upon, enabling adaptive evolution. One of the most discernible manifestations of phenotypic variability is colour variation. When this variation is discrete, genetically based colour pattern morphs occur simultaneously within a population.

Why and how colour polymorphisms are maintained is an evolutionary puzzle. Several evolutionary drivers have been hypothesized as influencing clinal patterns of morph frequency, with spatial variation in climate and predation being considered especially important. Despite this, no study has examined both of their roles simultaneously. The aims of this study were to: (a) examine the covariation of physiology, environmental variables and colouration at a local scale; and (b) determine if these factors and their interplay explain broad clinal variation in morph frequency.

We used the lizard Liopholis whitii as a model system, as this species displays a discrete, heritable polymorphism for colour pattern (plain‐backed, patterned morphs) whose morph frequency varies latitudinally. We measured reflectance, field activity temperatures and microhabitat structure to test for differences in crypsis, thermal biology and microhabitat selection of patterned and plain‐backed morphs within a single population where colour morphs occur sympatrically. We then used data from the literature to perform a broad‐scale analysis to identify whether these factors also explained the latitudinal variation of morph frequency in this species.

At the local scale, plain‐backed morphs were found to be less cryptic than patterned morphs while no other differences were detected in terms of thermal biology, dorsal reflectance and microhabitat use. At a broader scale, predation was the most influential factor mediating morph frequency across latitudes. However, the observed pattern of morph frequency is opposite to what the modelling results suggest in that the incidence of the least cryptic morph is highest where predation pressure is most severe. Clinal variation in the level of background matching between morphs or the potential reproductive advantage by the plain‐backed morph may, instead, be driving the observed morph frequency.

Together, these results provide key insights into the evolution of local adaptation as well as the ecological forces involved in driving the dynamics of colour polymorphism.
Towards the development of general rules describing landscape heterogeneity–multifunctionality relationships
Authors: van der Plas Fons , Allan Eric , Fischer Markus , Alt Fabian , Arndt Hartmut , Binkenstein Julia , Blaser Stefan , Blüthgen Nico , Böhm Stefan , Hölzel Norbert , Klaus Valentin H. , Kleinebecker Till , Morris Kathryn , Oelmann Yvonne , Prati Daniel , Renner Swen C. , Rillig Matthias C. , Schaefer H. Martin , Schloter Michael , Schmitt Barbara , Schöning Ingo , Schrumpf Marion , Solly Emily F. , Sorkau Elisabeth , Steckel Juliane , Steffan‐Dewenter Ingolf , Stempfhuber Barbara , Tschapka Marco , Weiner Christiane N. , Weisser Wolfgang W. , Werner Michael , Westphal Catrin , Wilcke Wolfgang , Manning Peter
Published: August 2018

Rapid growth of the world's human population has increased pressure on landscapes to deliver high levels of multiple ecosystem services, including food and fibre production, carbon storage, biodiversity conservation, and recreation. However, we currently lack general principles describing how to achieve this landscape multifunctionality.

We combine theoretical simulations and empirical data on 14 ecosystem services measured across 150 grasslands in three German regions. In doing so, we investigate the circumstances under which spatial heterogeneity in a driver of ecosystem functioning (an “ecosystem‐driver,” e.g., the presence of keystone species, land‐use intensification, or habitat types) increases landscape‐level ecosystem multifunctionality.

Simulations based on theoretical data demonstrated that relationships between heterogeneity and landscape multifunctionality are highly variable and can range from nonsignificant to strongly positive. Despite this variability, we could identify criteria under which heterogeneity‐landscape multifunctionality relationships were most strongly positive: this happened when multiple ecosystem services responded contrastingly (both positively and negatively) to an ecosystem‐driver.

These findings were confirmed using empirical data, which showed that heterogeneity in land‐use intensity (LUI) promoted landscape multifunctionality in cases where functions with both positive (e.g., plant biomass) and negative (e.g., flower cover) responses to land use intensification were included. For example, the simultaneous provisioning of ecosystem functions related to forage production (generally profiting from land‐use intensification), biodiversity conservation and recreation (generally decreasing with land‐use intensification) was highest in landscapes consisting of sites varying in LUI.

Synthesis and applications. Our findings show that there are general principles governing landscape multifunctionality. A knowledge of these principles may support land management decisions. For example, knowledge of relationships between ecosystem services and their drivers, such as land use type, can help estimate the consequences of increasing or decreasing heterogeneity for landscape‐level ecosystem service supply, although interactions between landscape units (e.g., the movement of pollinators) must also be considered.
Winter cover crop legacy effects on litter decomposition act through litter quality and microbial community changes
Authors: Barel Janna M. , Kuyper Thomas W. , Paul Jos , de Boer Wietse , Cornelissen Johannes H. C. , De Deyn Gerlinde B.
Published: August 2018

In agriculture, winter cover crop (WCC) residues are incorporated into the soil to improve soil quality, as gradual litter decomposition can improve fertility. Decomposition rate is determined by litter quality, local soil abiotic and biotic properties. How these factors are interlinked and influenced by cropping history is, however, unclear.

We grewWCCmonocultures and mixtures in rotation with main cropsAvena sativa(oat) andCichorium endivia(endive) and tested how crop rotation influencesWCClitter quality, abiotic and biotic soil conditions, and litter decomposition rates. To disentangleWCClitter quality effects fromWCCsoil legacy effects on decomposition, we tested how rotation history influences decomposition of standard substrates and explored the underlying mechanisms.

In a common environment (e.g. winter fallow plots),WCCdecomposition rate constants (k) correlated negatively with litter C, lignin and, surprisingly, N content, due to strong positive correlations among these traits. Plots with a history of fast‐decomposingWCCs exhibited faster decomposition of their own litters as well as of the standard substrates filter paper and rooibos tea, as compared to winter fallow plots.

WCCtreatments differentially affected soil microbial biomass, as well as soil organic matter and mineral nitrogen content.WCC‐induced soil changes affected decomposition rates. Depending on the main crop rotation treatment, legacy effects were attributed to biomass input ofWCCs and their litter quality or changes in microbial biomass.

Synthesis and applications. These results demonstrate that decomposition in cropping systems is influenced directly through crop residues, as well as through crop‐induced changes in soil biotic properties. Rotation history influences decomposition, wherein productive winter cover crops (WCC) with low lignin content decompose fast and stimulate the turnover of both own and newly added residues via their knock‐on effect on the soil microbial community. Thus, WCC have promise for sustainable carbon‐ and nutrient‐cycling management through litter feedbacks.
Rising pregabalin use and misuse in Australia: trends in utilization and intentional poisonings
Authors: Cairns Rose , Schaffer Andrea L. , Ryan Nicole , Pearson Sallie‐Anne , Buckley Nicholas A.
Published: August 2018

Background and aims

Pregabalin is a gamma‐aminobutyric acid (GABA) analogue, used to treat neuropathic pain and epilepsy. Pregabalin was registered in Australia in 2005, and subsidized publically in 2013. We aimed to describe Australian patterns of pregabalin use and intentional poisoning, and identify people potentially at high risk of misuse.

Design and setting

Population‐based retrospective cohort study of dispensings in the 10% sample of Australian Pharmaceutical Benefits Scheme (July 2012–February 2017); intentional poisoning calls to New South Wales Poisons Information Centre (NSWPIC) (2004–2016); intentional poisonings in two Australian toxicology service databases; and poisoning fatalities in NSW coronial records (2005–2016).

Participants

A total of 122 572 people dispensed pregabalin, people with intentional pregabalin overdoses managed by NSWPIC and the toxicology services and pregabalin‐associated deaths referred to the NSW coroner.

Measurements

Trends in dispensing, poisoning, death; demographics and patient characteristics, proportion of users at high risk of misuse (latent class analysis, LCA) and characteristics of high‐risk users.

Findings

Pregabalin dispensing increased by 73 424 per year [95% confidence interval (CI) = 61726–85 121 P < 0.001] between 2013 and 2016. NSWPIC received 1158 reports of intentional pregabalin poisonings, with a 53.8% increase per year, 2005–2016 (95% CI = 44.0–64.2%, P < 0.001). We identified 88 pregabalin‐associated deaths, 57.8% yearly increase (95% CI = 30.0–91.6%, P < 0.001). Patients overdosing on pregabalin commonly co‐ingested opioids, benzodiazepines and illicit drugs, and had high rates of psychiatric and substance use comorbidities; 14.7% of pregabalin users were classed by the LCA as at high risk of misuse, and were more likely to be younger, male, co‐prescribed benzodiazepines or opioids, have more individual prescribers and higher pregabalin strengths dispensed.

Conclusions

There has been a dramatic increase in pregabalin use, poisonings and deaths in Australia since it became subsidized publicly in 2013. One in seven Australians dispensed pregabalin appears to be at high risk of misuse.
Patterns of use and optimal timing of antenatal corticosteroids in twin compared with singleton pregnancies
Authors: Rottenstreich Amihai , Levin Gabriel , Kleinstern Geffen , Haj Yahya Rani , Rottenstreich Misgav , Yagel Simcha , Elchalal Uriel
Published: August 2018

Introduction

Previous reports have shown that suboptimal antenatal corticosteroids administration occurs in most cases. However, as multifetal gestations were either excluded or constituted a small proportion of the participants in these studies, little is known about the patterns of use of antenatal corticosteroids in twin pregnancies.

Material and methods

We reviewed the records of women who received antenatal corticosteroids and delivered between 240/7 and 346/7 weeks of gestation during 2015‐2017 at 2 university hospitals. Optimal antenatal corticosteroids timing was defined as delivery ≥24 hours ≤7 days from the previous antenatal corticosteroids course.

Results

Of 424 pregnancies, 307 (72.4%) were singleton and 117 were (27.6%) twin. For twin compared with singleton pregnancies, gestational age at initial antenatal corticosteroids administration was lower (P = 0.02), the proportion of deliveries within the optimal window of the initial antenatal corticosteroids course was lower (19.7% vs 33.2%, P = 0.001), and the proportion of women eligible for a rescue antenatal corticosteroids course was higher (58.1% vs 32.9%, P < 0.0001). However, despite similar rates of rescue antenatal corticosteroids administration (P = 0.64), the overall rate of delivery within any optimal window (either initial or rescue course) was lower in twin than singleton pregnancies (26.5% vs 42.3%, P = 0.004), and the antenatal corticosteroids‐to‐delivery interval was longer (median 6.9 vs 4.2 days, P = 0.0009). In multivariate analysis, optimal antenatal corticosteroids administration was negatively associated with twin pregnancy (P = 0.04) and preterm labor (P = 0.05), and positively associated with the presence of gestational hypertensive disorders (P = 0.03).

Conclusions

Twin pregnancy is an independent risk factor for suboptimal antenatal corticosteroids administration. Directed efforts should be made to improve the utilization of antenatal corticosteroids in this vulnerable group of women.
Single‐ and multiple‐dose pharmacokinetics and safety of pimodivir, a novel, non‐nucleoside polymerase basic protein 2 subunit inhibitor of the influenza A virus polymerase complex, and interaction with oseltamivir: a Phase 1 open‐label study in healthy volunteers
Authors: Deleu Sofie , Kakuda Thomas N. , Spittaels Kurt , Vercauteren Jurgen J. , Hillewaert Vera , Lwin Amy , Leopold Lorant , Hoetelmans Richard M. W.
Published: August 2018

Aims

The aim of this study was to evaluate the drug–drug interaction between pimodivir, a novel, non‐nucleoside polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A virus polymerase complex, and oseltamivir, to assess the feasibility of this combination therapy. Furthermore, single‐ and multiple‐dose pharmacokinetics and safety of pimodivir in healthy volunteers were assessed.

Methods

In Part 1 of this open‐label Phase 1 study, healthy volunteers (n = 18) were randomized to one of six cross‐over treatment sequences, each comprising administration of oseltamivir 75 mg or pimodivir 600 mg or combination thereof twice daily on Days 1–4, followed by a single morning dose on Day 5. Between each treatment session, there was a minimum 5‐day washout period. In Part 2, healthy volunteers (n = 16) randomly received pimodivir 600 mg or placebo (3:1) twice daily on Days 1–9, followed by a single morning dose on Day 10. Pharmacokinetics of pimodivir, oseltamivir and oseltamivir carboxylate, and safety were assessed.

Results

In Part 1, co‐administration of pimodivir with oseltamivir increased the Cmax of pimodivir by 31% (90% CI: 0.92–1.85) with no change in Cmin or AUC12h. Pimodivir had no effect on oseltamivir or oseltamivir carboxylate pharmacokinetics. In Part 2, after single‐ and multiple‐dose administration of pimodivir, there was a 1.2‐ and 1.8‐fold increase in Cmax and AUC12h, respectively, between Day 1 and Day 10. The most frequently reported treatment‐emergent adverse event was diarrhoea (n = 7 each in Part 1 and 2).

Conclusion

Combination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug–drug interactions. No safety concerns were identified with pimodivir 600 mg twice daily alone or in combination with oseltamivir 75 mg twice daily.
Anticholinergic exposure and cognitive decline in older adults: effect of anticholinergic exposure definitions in a 3‐year analysis of the multidomain Alzheimer preventive trial (MAPT) study
Authors: Andre Laurine , Gallini Adeline , Montastruc François , Coley Nicola , Montastruc Jean‐Louis , Vellas Bruno , Andrieu Sandrine , Gardette Virginie ,   for the MAPT/DSA study group
Published: August 2018

Aim

The aim of the present study was to assess the association between anticholinergic (atropinic) burden and cognitive decline in older adults over the course of 3 years.

Methods

We used data from Multidomain Alzheimer Preventive Trial (MAPT) study participants aged ≥70 years and at risk of cognitive decline. Cognitive function was assessed with a composite score [Mini‐Mental State Examination (MMSE) orientation, Free and Cued Selective Reminding Test, Category Naming Test, Digit Symbol Substitution Test] at 12, 24 and 36 months. Participants declining by more than 0.236 points on the composite score (representing the lowest quintile of 1‐year cognitive change) during any 1‐year period were considered to have undergone cognitive decline. Anticholinergic exposure was defined by four methods for each of four anticholinergic scales (Anticholinergic Drug Scale, Anticholinergic Cognitive Burden, Anticholinergic Risk Scale, the Durán list). The association between cognitive decline and time‐varying anticholinergic exposure [primary analysis using the Durán list and maximal anticholinergic score (0, 1 or 3)] was assessed using Cox proportional hazards models. Other cognitive decline definitions were used in sensitivity analyses.

Results

At baseline, among 1396 patients included, 7.4–23.5% were exposed to anticholinergic agents, depending on the anticholinergic scale used. Sixty‐four per cent of participants experienced cognitive decline during follow‐up. Regardless of the anticholinergic scale/exposure measurement used, no significant association was observed with cognitive decline {primary analysis: compared with non‐anticholinergic agent users, hazard ratio [HR] = 1.14 [95% confidence interval (CI) = 0.95, 1.38] for anticholinergic score = 1; HR = 0.92 [95% CI = 0.65, 1.30] for score = 3}. Results were stable in sensitivity analyses.

Conclusion

We found no significant association between anticholinergic exposure and cognitive decline in older adults using anticholinergic scales and definitions of exposure.
Clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients
Authors: Li Xiaoye , Wang Zi , Wang Qibing , Xu Qing , Lv Qianzhou
Published: August 2018

Acute coronary syndrome (ACS) has become a vital disease with high mortality worldwide. A combined antiplatelet therapy (aspirin and a P2Y12 antagonist) is commonly used to prevent re‐infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel, a P2Y12 antagonist, plays an important role in the inhibition of platelet aggregation (IPA). However, it is a pro‐drug requiring biotransformation by cytochrome P450 (CYP450). The aim of this study is to unravel the effect of clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcomes in ACS patients. In our study, a total of 196 patients with metabolic gene polymorphism of clopidogrel were enrolled, and their antiplatelet effect as well as their cardiovascular events were collected. Approximately 2 mL of venous blood samples were used for genotype detection and another 4 mL were collected for platelet reactivity with thrombelastography. The primary clinical end‐point was defined as a combination of cardiovascular mortality and revascularization for targeted vascular lesion. Based on the results of IPA, the prevalence of high on‐treatment platelet reactivity (HPR) was 17.3% and the majority of patients (82.7%) obtained normal on‐treatment platelet reactivity (NPR). The HPR group had significantly higher body mass index (BMI) and lower arachidonic acid (AA) induced IPA (P < 0.05). Therapy including Glycoprotein (GP) IIb/IIIa antagonist increased IPA (P < 0.05). ADP‐induced IPA effect was lower with the presence of CYP2C19*2, *3 and paraoxonase (PON)1 Q192R loss‐of‐function (LOF) alleles, respectively (P < 0.05). Multivariate logistic regression analysis demonstrated that aspirin resistance (AA‐induced IPA < 50%) had a greater risk of the occurrence of major adverse cardiovascular events (MACE) (OR = 3.817; 95% CI: 1.672‐8.700; P = 0.002). CYP2C19*2 LOF alleles were associated with high risk of MACE in 1‐year post PCI operations (OR = 2.571; 95% CI: 1.143‐5.780; P = 0.030). For the ACS patients, the presence of CYP2C19*2 and PON1 Q192R LOF alleles were the major drivers of HPR.
An observational, multicentre study of cabazitaxel in patients with metastatic castration‐resistant prostate cancer previously treated with docetaxel (CAPRISTANA)
Authors: Carles Joan , Pichler Angelika , Korunkova Hana , Tomova Antoaneta , Ghosn Marwan , El Karak Fadi , Makdessi Joseph , Koroleva Irina , Barnes Gisoo , Bury Denise , Özatilgan Ayse , Hitier Simon , Katolicka Jana
Published: August 2018

Objectives

To obtain routine clinical practice data on cabazitaxel usage patterns for patients with metastatic castration‐resistant prostate cancer (mCRPC) and to describe physician‐assessed cabazitaxel effectiveness, health‐related quality of life (HRQoL) and safety.

Patients and Methods

CAPRISTANA was an international, observational cohort study examining cabazitaxel use for the treatment of patients with mCRPC. Effectiveness was assessed by overall survival (OS), progression‐free survival (PFS), time to treatment failure (TTF) and disease control rate. HRQoL was assessed using the Functional Assessment of Cancer Therapy‐Prostate questionnaire (FACT‐P) and the three‐level European Quality of Life questionnaire (EQ‐5D‐3L). Safety was assessed by adverse event (AE) reporting.

Results

A total of 189 patients were treated across 54 centres between April 2012 and June 2016. At baseline, 58.7% had ≥1 comorbidity, 93.7% had an Eastern Cooperative Oncology Group performance status ≤1, and 60.1% had a Gleason score at diagnosis of ≥8. Patients received a median of 6 cabazitaxel cycles; 84.7% received cabazitaxel as second‐line therapy. The median OS, PFS and TTF were 13.2, 5.6 and 4.4 months, respectively. Cabazitaxel led to disease control in 52.9% of patients. HRQoL was maintained (40.3%) or improved (32.2%) in 72.5% of patients based on total FACT‐P scores. Interestingly, 53.6% of patients reported pain improvement and a further 21.2% maintained pain control based on FACT‐P prostate cancer‐specific pain scores. The most common treatment‐related grade ≥3 AEs were neutropenia (7.9%) and anaemia (2.1%).

Conclusion

Patients in CAPRISTANA treated with cabazitaxel had similar disease outcomes and safety profiles compared with large phase III clinical trials. Most patients had maintained or improved HRQoL scores; >70% of patients had maintained or improved pain control.
Effect of positioning on ureteric stone retropulsion: ‘gravity works’
Authors: Patel Roshan M. , Walia Arman S. , Grohs Evan , Okhunov Zhamshid , Landman Jaime , Clayman Ralph V.
Published: August 2018

Objective

To evaluate the potential impact of alterations in ‘patient’ position on laser‐induced ureteric stone retropulsion in an in vitro model.

Materials and Methods

A ceramic (phantom) stone was placed in a water‐filled clear polymer tube and subjected to continuous laser energy until the stone had retropulsed a distance of 10 cm. The trial was stopped after 60 s if the stone had not reached 10 cm. The time and total energy needed to cause 10 cm of retropulsion were recorded at incline angles of 0°, 10°, 20°, and 40°; 10 trials at each angle were completed. The study was then repeated with pure calcium phosphate brushite stones.

Results

Retropulsion decreased with increasing incline angle of the saline‐filled clear polymer tube. At 0° of incline the phantom stone reached a distance of 10 cm after 7.4 s. At 10°, 20° and 40°, the phantom stone migrated a mean maximum distance of 3.1, 1.2 and 0.7 cm, respectively, and the trial was stopped after 60 s. For the calcium phosphate stone, at 0° and 10° of incline, the stone reached 10 cm after 6.9 and 42.8 s, respectively (P < 0.05). At 20° and 40°, the calcium phosphate stone moved a mean maximum distance of 2.4 and 1 cm, and the trial was stopped after 60 s.

Conclusion

Alterations in the angle of inclination reduced stone retropulsion during ureteroscopic lithotripsy in an in vitro model to <1 cm. Increasing the incline angle of a patient may effectively preclude retropulsion when performing laser lithotripsy of ureteric stones.
Inhibition of hyperpolarization‐activated cyclic nucleotide‐gated channels by β‐blocker carvedilol
Authors: Cao Ying , Chen Shujun , Liang Yemei , Wu Ting , Pang Jianxin , Liu Shuwen , Zhou Pingzheng
Published: August 2018

Background and Purpose

Carvedilol is a clinically effective β‐blocker broadly used for treating congestive heart failure (CHF), and several clinical trials have demonstrated that it shows a favourable effect compared with other β‐blockers in patients with CHF. The mechanism underlying this beneficial effect of carvedilol compared to other β‐blockers is not clearly understood. In addition to β‐blockers, inhibitors of hyperpolarization‐activated cyclic nucleotide (HCN)‐gated channels, which play a critical role in spontaneous rhythmic activity in the heart, have also been proposed to be suitable drugs for reducing heart rate and, therefore, beneficial for treating CHF. In the present study, we investigated the effect of carvedilol on HCN channels.

Experimental Approach

Whole‐cell patch‐clamp recordings were used to assess the effect of carvedilol on currents from wild‐type and mutant HCN1, HCN2 and HCN4 channels expressed in CHO cells.

Key Results

Carvedilol was the only β‐blocker tested that showed inhibitory effects on the major sinoatrial HCN channel isoform HCN4. Carvedilol inhibited HCN4 in a concentration‐dependent manner with an EC50 of 4.4 μM. In addition, carvedilol also inhibited HCN1 and HCN2 channels. Carvedilol blocked HCN channels by decelerating the rate of channel activation and increasing that of deactivation, and shifted the voltage‐dependence of activation leftwards. Our data also showed that carvedilol, unlike other inhibitors of this channel (ivabradine and ZD7288), is not an ‘open‐channel’ inhibitor of HCN4.

Conclusions and Implications

Carvedilol is a negative gating modulator of HCN channels. It represents a novel structure for future drug design of HCN channel inhibitors.
Therapeutic implications of how TNF links apolipoprotein E, phosphorylated tau, α‐synuclein, amyloid‐β and insulin resistance in neurodegenerative diseases
Authors: Clark I A , Vissel B
Published: August 2018

While cytokines such as TNF have long been recognized as essential to normal cerebral physiology, the implications of their chronic excessive production within the brain are now also increasingly appreciated. Syndromes as diverse as malaria and lead poisoning, as well as non‐infectious neurodegenerative diseases, illustrate this. These cytokines also orchestrate changes in tau, α‐synuclein, amyloid‐β levels and degree of insulin resistance in most neurodegenerative states. New data on the effects of salbutamol, an indirect anti‐TNF agent, on α‐synuclein and Parkinson's disease, APOE4 and tau add considerably to the rationale of the anti‐TNF approach to understanding, and treating, these diseases. Therapeutic advances being tested, and arguably useful for a number of the neurodegenerative diseases, include a reduction of excess cerebral TNF, whether directly, with a specific anti‐TNF biological agent such as etanercept via Batson's plexus, or indirectly via surgically implanting stem cells. Inhaled salbutamol also warrants investigating further across the neurodegenerative disease spectrum. It is now timely to integrate this range of new information across the neurodegenerative disease spectrum, rather than keep seeing it through the lens of individual disease states.
Stable isotope constraints on the fluid source of hydrothermal breccia pipes in the Tankwa Karoo depocentre, South Africa: Breakdown of authigenic minerals during sill intrusion
Authors: Harris Chris , Buthelezi Nonkululeko , Kahle Beth , Kahle Richard , Ramahala Kathlego , Smith George
Published: August 2018

The Karoo Basin covers much of South Africa and is an area of prospective shale gas exploration, with the Whitehill Formation the target shale unit. However, the sedimentary succession, including the Whitehill, has been intruded by a series of sills and dykes associated with the Karoo Large Igneous Province (~183 Ma), which are expected to have modified the thermal history of the basin dramatically. Here, we investigate a secondary effect of these intrusions: a series of hydrothermal vent complexes, or breccia pipes, focusing on using O, H, and C isotopes to constrain the origin and evolution of fluids produced during the intrusion of basaltic sills. A cluster of breccia pipes have been eroded down to the level of the Ecca Group at Luiperdskop on the western edge of the Karoo basin; a small isolated pipe of similar appearance crops out 13 km to the east. The Luiperdskop pipes are underlain by a Karoo dolerite sill that is assumed to provide the heat driving fluidization. The pipes consist of fine‐grained matrix and about 8% clasts, on average, of mostly sedimentary material; occasional large rafts of quartzite and dolerite are also present. The presence of clasts apparently from the Dwyka Group is consistent with the depth of formation of the pipes being at, or near, the base of the Karoo Supergroup, between 400 and 850 m below present surface. The presence of chlorite as the dominant hydrous mineral is consistent with an emplacement temperature between 300 and 350°C. The major and trace element, and O‐ and H‐isotope composition of the Tankwa breccias is homogenous, consistent with them being derived from the same source. The δ18O values (vsVSMOW) of the breccias are relatively uniform (7.1‰–8.7‰), and are similar to that of the country rock shale, and both are lower than expected for shale. The water content of the breccia is between 2.7 and 3.1 wt.% and the δD values range from −109‰ to −144‰. Calcite in vesicles has δ13C and δ18O (VSMOW) values of −4.2‰ and 24.0‰, respectively. The low δD value of the breccia rocks does not appear to be due to the presence of methane in the fluid. Instead, it is proposed that low δD and δ18O values are the result of the fluid being derived from the breakdown of clay minerals that formed and were deposited at a time of cold climate at ~290 Ma.
TRIM44 promotes human esophageal cancer progression via the AKT/mTOR pathway
Authors: Xiong Dian , Jin Chun , Ye Xudong , Qiu Baiquan , Jianjun Xu , Zhu Shuqiang , Xiang Long , Wu Haibo , Yongbing Wu
Published: August 2018

Aberrant expression of TRIM‐containing protein 44 (TRIM44) acts as a promoter in multiple cancers. Here, we investigated the biological functions and clinical significance of TRIM44 in human esophageal cancer (HEC). TRIM44 expression was significantly higher in HEC tissues than corresponding normal tissues at both the mRNA (2.42 ± 0.52 vs 0.99 ± 0.25) and protein (1.01 ± 0.27 vs 0.30 ± 0.13) levels. Patients with high TRIM44 expression showed poor differentiation (P = 1.39 × 10−5), advanced TNM stage (P = 3.87 × 10−4) and, most importantly, significantly poorer prognosis (P = 2.80 × 10−5). TRIM44 played a crucial role in epithelial mesenchymal transition (EMT). A significant correlation was observed between TRIM44 and Ki67 expression. We demonstrated that TRIM44 markedly enhanced HEC cell proliferation, migration, and invasion. Additionally, TRIM44 was involved in the AKT/mTOR signaling pathway and its downstream targets, such as STAT3 phosphorylation. Thus, elevated TRIM44 expression promotes HEC development by EMT via the AKT/mTOR pathway, and TRIM44 may be a novel prognostic indicator for HEC patients after curative resection.
Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer
Authors: Sato Hiroki , Yamamoto Hiromasa , Sakaguchi Masakiyo , Shien Kazuhiko , Tomida Shuta , Shien Tadahiko , Ikeda Hirokuni , Hatono Minami , Torigoe Hidejiro , Namba Kei , Yoshioka Takahiro , Kurihara Eisuke , Ogoshi Yusuke , Takahashi Yuta , Soh Junichi , Toyooka Shinichi
Published: August 2018

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.
Quantitative assessment of changes in anterior segment morphology after argon laser peripheral iridoplasty: findings from the EARL study group
Authors: Lim Dawn K , Chan Hwei W , Zheng Ce , Aquino Maria C , Wong Wan Ling , Ritch Robert , Chew Paul TK
Published: August 2018

Importance

Argon laser peripheral iridoplasty (ALPI) could be effective in widening residual angle closure following laser peripheral iridotomy (LPI).

Background

We investigated changes in angle parameters following ALPI and its safety profile in this study.

Design

Retrospective, observational case series.

Participants

The records from a single centre, of 36 patients (60 eyes) who underwent ALPI, for residual angle closure following LPI, were reviewed.

Methods

We analysed anterior chamber parameters in anterior segment optical coherence tomography (ASOCT) images using customized software pre‐ and post‐ALPI. Paired t‐test was used to compare changes.

Main Outcome Measures

ASOCT parameters analysed included angle opening distance (AOD 500 and 750), trabecular iris surface area (TISA 500 and 750), anterior chamber width (ACW), anterior chamber volume (ACV), angle recess area (ARA), anterior chamber area (ACA), anterior chamber depth (ACD) and lens vault (LV).

Results

There was a mean increase in AOD 500 (0.05 vs. 0.16 mm, P < 0.001), AOD 750 (0.15 vs. 0.27 mm, P < 0.001), TISA 500 (0.010 vs. 0.038 mm2, P < 0.001), TISA 750 (0.039 vs. 0.102 mm2, P < 0.001), ACV (89.76 vs. 102.25 mm3, P = 0.01), ARA 500 (0.015 vs. 0.033 mm2, P < 0.001) and ARA 750 (0.044 vs. 0.088 mm2, P < 0.001). There was no significant change in ACW, ACD, ACA and LV. Mean intraocular pressure (IOP) decreased post‐ALPI (17.2 vs. 15.7 mmHg, P = 0.002). The mean follow‐up duration was 2.1 years (range 0.5–5 years).

Conclusions and Relevance

ALPI results in changes to the angle morphology and lowered IOP in eyes with residual angle closure. Our findings suggest a possible role for ALPI in eyes with residual angle closure following peripheral iridotomy.
Once‐daily, prolonged‐release tacrolimus vs twice‐daily, immediate‐release tacrolimus in de novo living‐donor liver transplantation: A Phase 4, randomized, open‐label, comparative, single‐center study
Authors: Shin Min‐Ho , Song Gi‐Won , Lee Sung‐Gyu , Hwang Shin , Kim Ki‐Hun , Ahn Chul‐Soo , Moon Deok‐Bog , Ha Tae‐Yong , Jung Dong‐Hwan , Park Gil‐Chun , Yun Young‐In , Kim Wan‐Jun , Kang Woo‐Hyoung , Kim Seok‐Hwan , Jiang Hongsi , Lee Sungmin , Tak Eun‐Young
Published: August 2018

Randomized, open‐label, comparative, single‐center, Phase 4, 24‐week study comparing pharmacokinetics (PK), safety, and efficacy of once‐daily, prolonged‐release tacrolimus (PR‐T) with twice‐daily, immediate‐release tacrolimus (IR‐T) in adult de novo living‐donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR‐T or IR‐T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration‐time curve over 24 hour (AUC0‐24). Predefined similarity interval for confidence intervals of ratios: 80%‐125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C24), patient/graft survival, biopsy‐confirmed acute rejection (BCAR), treatment‐emergent adverse events (TEAEs). One‐hundred patients were included (PR‐T, n = 50; IR‐T, n = 50). Compared with IR‐T, 40% and 66% higher mean PR‐T daily doses resulted in similar AUC0‐24 between formulations on Day 6 (PR‐T:IR‐T ratio of means 96.8%), and numerically higher AUC0‐24 with PR‐T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC0‐24 and C24, and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR‐T vs IR‐T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR‐T was efficacious; no new safety signals were detected.
The risk of graft loss 5 years after kidney transplantation is increased if cold ischemia time exceeds 14 hours
Authors: Hansson Josefin , Mjörnstedt Lars , Lindnér Per
Published: August 2018

Background

The state of the evidence is unclear regarding the impact of cold ischemia time (CIT) on the outcome of kidney transplantation. The aim of this study was to investigate the effect of CIT on the short‐ and long‐term function of kidneys transplanted at the Sahlgrenska University Hospital in 2007‐2009 from donors after brain death (DBDs).

Methods

This study was designed as a retrospective analysis of data from local and national transplantation registers. The study endpoints were as follows: delayed graft function (DGF), primary nonfunction (PNF), biopsy‐proven acute rejection (BPAR), serum creatinine (S‐creatinine) level at discharge, days of hospitalization after transplantation, and graft survival at 5 years post‐transplantation. Adjusted regression analyses were used to determine causal relationships with CIT. A further aim was to estimate a threshold for CIT by analyzing event rates and coordinates of the receiver‐operated characteristic (ROC) curve.

Results

There was a causal relationship between CIT as a continuous variable and the following endpoints: graft survival at 5 years post‐transplantation, though this was not significant (hazard ratio (HR) 1.07, P = 0.057), DGF (odds ratio (OR) 1.09, P = 0.03) and S‐creatinine (P = 0.003). In our material, the risk for impaired outcome was higher with longer CIT. We were therefore able to estimate a threshold value for CIT, set to 14 hours for both graft survival at 5 years post‐transplantation and DGF. This was proved with significance by analyzing both event rates and the coordinates of the ROC curve. The risk of graft loss increased, with HR 2.3 (P = 0.023), when comparing a CIT cutoff of ≥14 hours with CIT < 14 hours. Delayed graft function increased, with an OR of 2.6 (P = 0.001).

Conclusion

Our study confirms that, in this patient material, longer CIT was associated with increased risk for both impaired graft survival and incidence of DGF. We estimated a threshold for CIT of 14 hours.