bluuebunny/crossref_metadata_2025 huggingface dataset:
Sorafenib dose escalation in treatment‐naïve patients with metastatic renal cell carcinoma: a non‐randomised, open‐label, Phase 2b study
Authors: Gore Martin E. , Jones Robert J. , Ravaud Alain , Kuczyk Markus , Demkow Tomasz , Bearz Alessandra , Shapiro JoAnn , Strauss Uwe Phillip , Porta Camillo
Published: December 2016

Objective

To assess the efficacy and safety of sorafenib dose escalation in metastatic renal cell carcinoma (mRCC).

Patients and Methods

Intra‐patient dose escalation may enhance the clinical benefit of targeted anticancer agents in metastatic disease. In this non‐randomised, open‐label, Phase 2b study, treatment‐naïve patients with mRCC were initially treated with the standard oral sorafenib dose [400 mg twice daily (BID)]. Two dose escalations were planned, each 200 mg BID after 28 days at the prior level. Dose reductions, interruptions, or delayed escalations were used to manage adverse events (AEs). The primary endpoint was objective response rate (ORR) in the modified intent‐to‐treat (mITT) population, which comprised patients with ≥6 months of treatment including ≥4 months of therapy at their highest tolerated dose. Secondary endpoints included progression‐free survival (PFS) and safety.

Results

In all, 83 patients received sorafenib. The dose received for the longest duration was 400, 600, and 800 mg BID in 48.2%, 15.7%, and 24.1% of patients, respectively. The ORR was 44.4% [n = 8/18; 95% confidence interval (CI) 21.5–69.2] and 17.9% (n = 12/67; 95% CI 9.6–29.2) in the mITT and ITT populations, respectively. The median (95% CI) PFS was 7.4 (6.0–11.7) months (ITT). The most common AEs of any grade were hand–foot skin reaction (66.3%) and diarrhoea (63.9%).

Conclusion

Sorafenib demonstrated clinical benefit in treatment‐naïve patients with mRCC. However, relatively few patients could sustain doses of >400 mg BID. There was evidence that, where tolerated, escalation from the standard sorafenib dose may have enhanced clinical benefit. However, this study does not support dose escalation for most patients with treatment‐naïve mRCC. Alternative protocols for sorafenib dose escalation could be explored.
Development, validation and clinical application of Pelvic Lymphadenectomy Assessment and Completion Evaluation: intraoperative assessment of lymph node dissection after robot‐assisted radical cystectomy for bladder cancer
Authors: Hussein Ahmed A. , Hinata Nobuyuki , Dibaj Shiva , May Paul R. , Kozlowski Justen D. , Abol‐Enein Hassan , Abaza Ronney , Eun Daniel , Khan Mohamed S. , Mohler James L. , Agarwal Piyush , Pohar Kamal , Sarle Richard , Boris Ronald , Mane Sridhar S. , Hutson Alan , Guru Khurshid A.
Published: December 2016

Objectives

To develop a scoring tool, Pelvic Lymphadenectomy Appropriateness and Completion Evaluation (PLACE), to assess the intraoperative completeness and appropriateness of pelvic lymph node dissection (PLND) following robot‐assisted radical cystectomy (RARC).

Patients, Subjects and Methods

A panel of 11 open and robotic surgeons developed the content and structure of PLACE. The PLND template was divided into three zones. In all, 21 de‐identified videos of bilateral robot‐assisted PLNDs were assessed by the 11 experts using PLACE to determine inter‐rater reliability. Lymph node (LN) clearance was defined as the proportion of cleared LNs from all PLACE zones. We investigated the correlation between LN clearance and LN count. Then, we compared the LN count of 18 prospective PLNDs using PLACE with our retrospective series performed using the extended template (No PLACE).

Results

A significant reliability was achieved for all PLACE zones among the 11 raters for the 21 bilateral PLND videos. The median (interquartile range) for LN clearance was 468 (431–545). There was a significant positive correlation between LN clearance and LN count (R2 = 0.70, P < 0.01). The PLACE group yielded similar LN counts when compared to the No PLACE group.

Conclusions

Pelvic Lymphadenectomy Appropriateness and Completion Evaluation is a structured intraoperative scoring system that can be used intraoperatively to measure and quantify PLND for quality control and to facilitate training during RARC.
Co‐occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma
Authors: Pagès Mélanie , Beccaria Kevin , Boddaert Nathalie , Saffroy Raphaël , Besnard Aurore , Castel David , Fina Frédéric , Barets Doriane , Barret Emilie , Lacroix Ludovic , Bielle Franck , Andreiuolo Felipe , Tauziède‐Espariat Arnault , Figarella‐Branger Dominique , Puget Stéphanie , Grill Jacques , Chrétien Fabrice , Varlet Pascale
Published: December 2016

Ganglioglioma (GG) is a grade I tumor characterized by alterations in the MAPK pathway, including BRAF V600E mutation. Recently, diffuse midline glioma with an H3 K27M mutation was added to the WHO 2016 classification as a new grade IV entity. As co‐occurrence of H3 K27M and BRAF V600E mutations has been reported in midline tumors and anaplastic GG, we searched for BRAF V600E and H3 K27M mutations in a series of 54 paediatric midline grade I GG (midline GG) to determine the frequency of double mutations and its relevance for prognosis. Twenty‐seven patients (50%) possessed the BRAF V600E mutation. The frequency of the co‐occurrence of H3F3A/BRAF mutations at diagnosis was 9.3%. No H3 K27M mutation was detected in the absence of the BRAF V600E mutation. Double‐immunostaining revealed that BRAF V600E and H3 K27M mutant proteins were present in both the glial and neuronal components. Immunopositivity for the BRAF V600E mutant protein correlated with BRAF mutation status as detected by massARRAY or digital droplet PCR. The median follow‐up of patients with double mutation was 4 years. One patient died of progressive disease 8 years after diagnosis, whereas the four other patients were all alive with stable disease at the last clinical follow‐up (at 9 months, 1 year and 7 years) without adjuvant therapy. We demonstrate in this first series of midline GGs that the H3 K27M mutation can occur in association with the BRAF V600E mutation in grade I glioneuronal tumors. Despite the presence of H3 K27M mutations, these cases should not be graded and treated as grade IV tumors because they have a better spontaneous outcome than classic diffuse midline H3 K27M‐mutant glioma. These data suggest that H3 K27M cannot be considered a specific hallmark of grade IV diffuse gliomas and highlight the importance of integrated histomolecular diagnosis in paediatric brain tumors.
Mitochondrial activity in the frontal cortex area 8 and angular gyrus in Parkinson's disease and Parkinson's disease with dementia
Authors: Garcia‐Esparcia Paula , Koneti Anusha , Rodríguez‐Oroz M. Cruz , Gago Belen , del Rio José Antonio , Ferrer Isidro
Published: December 2016

Altered mitochondrial function is characteristic in the substantia nigra in Parkinson's disease (PD). Information about mitochondria in other brain regions such as the cerebral cortex is conflicting mainly because most studies have not contemplated the possibility of variable involvement depending on the region, stage of disease progression and clinical symptoms such as the presence or absence of dementia. RT‐qPCR of 18 nuclear mRNAs encoding subunits of mitochondrial complexes and 12 mRNAs encoding energy metabolism‐related enzymes; western blotting of mitochondrial proteins; and analysis of enzymatic activities of complexes I, II, II, IV and V of the respiratory chain were assessed in frontal cortex area 8 and the angular gyrus of middle‐aged individuals (MA), and those with incidental PD (iPD), long‐lasting PD with parkinsonism without dementia (PD) and long‐lasting PD with dementia (PDD). Up‐regulation of several genes was found in frontal cortex area 8 in PD when compared with MA and in the angular gyrus in iPD when compared with MA. Marked down‐regulation of genes encoding mitochondrial subunits and energy metabolism‐related enzymes occurs in frontal cortex but only of genes coding for energy metabolism‐related enzymes in the angular gyrus in PDD. Significant decrease in the protein expression levels of several mitochondrial subunits encoded by these genes occurs in frontal cortex area 8 and angular gyrus in PDD. Moreover, expression of MT‐ND1 which is encoded by mitochondrial DNA is also reduced in PDD. Reduced enzymatic activity of complex III in frontal cortex area 8 and angular gyrus is observed in PD, but dramatic reduction in the activity of complexes I, II, II and IV in both regions characterizes PDD. Dementia in the context of PD is linked to region‐specific deregulation of genomic genes encoding subunits of mitochondrial complexes and to marked reduction in the activity of mitochondrial complexes I, II, III and IV.
Activation of MMP‐9 by membrane type‐1 MMP/MMP‐2 axis stimulates tumor metastasis
Authors: Li Zichen , Takino Takahisa , Endo Yoshio , Sato Hiroshi
Published: December 2016

An artificial receptor for proMMP‐9 was created by fusing tissue inhibitor of MMP‐1 (TIMP‐1) with type II transmembrane mosaic serine protease (MSP‐T1). Expression of MSP‐T1 in 293T cells induced binding of proMMP‐9, which was processed by MMP‐2 activated by membrane type 1 MMP (MT1‐MMP). HT1080 cells transfected with the MSP‐T1 gene produced activated MMP‐9 in collagen gel, and addition of proMMP‐2 to the culture augmented it, which resulted in intensive collagen digestion. These cells metastasized into chick embryonic liver more than control cells. Treatment of HT1080 cells with concanavalin A in the presence of exogenous proMMP‐2 induced activation of not only proMMP‐2 but also proMMP‐9. Knockdown of MT1‐MMP or TIMP‐2 expression with siRNA suppressed activation of both proMMP‐2 and proMMP‐9. Transfection of TIMP‐1 siRNA suppressed cell binding and activation of proMMP‐9, but not proMMP‐2 activation. Knockdown of a disintegrin and metalloproteinase 10 (ADAM10) expression reduced cell binding and processing of proMMP‐9. These results suggest that proMMP‐9, which binds to a receptor complex containing TIMP‐1 and ADAM10, is activated by the MT1‐MMP/MMP‐2 axis, and MMP‐9 thus activated stimulates cellular proteolysis and metastasis.
Mutations in CRLF1 cause familial achalasia
Authors: Busch A. , Žarković M. , Lowe C. , Jankofsky M. , Ganschow R. , Buers I. , Kurth I. , Reutter H. , Rutsch F. , Hübner C.A.
Published: December 2016

We here report a family from Libya with three siblings suffering from early onset achalasia born to healthy parents. We analyzed roughly 5000 disease‐associated genes by a next‐generation sequencing (NGS) approach. In the analyzed sibling we identified two heterozygous variants in CRLF1 (cytokine receptor‐like factor 1). Mutations in CRLF1 have been associated with autosomal recessive Crisponi or cold‐induced sweating syndrome type 1 (CS/CISS1), which among other symptoms also manifests with early onset feeding difficulties. Segregation analysis revealed compound heterozygosity for all affected siblings, while the unaffected mother carried the c.713dupC (p.Pro239Alafs*91) and the unaffected father carried the c.178T>A (p.Cys60Ser) variant. The c.713dupC variant has already been reported in affected CS/CISS1 patients, the pathogenicity of the c.178T>A variant was unclear. As reported previously for pathogenic CRLF1 variants, cytokine receptor‐like factor 1 protein secretion from cells transfected with the c.178T>A variant was severely impaired. From these results we conclude that one should consider a CRLF1‐related disorder in early onset achalasia even if other CS/CISS1 related symptoms are missing.
Development of endometrioid adenocarcinoma despite Levonorgestrel‐releasing intrauterine system: a case report with discussion and review of the RCOG/BSGE Guideline on the Management of Endometrial Hyperplasia
Authors: van der Meer A. C. L. , Hanna L. S.
Published: December 2016

Obesity is a significant risk factor for the development of endometrial hyperplasia and cancer. More conservative prevention and management strategies are attractive due to the increased surgical risk and complication rates associated with obesity. The Levonorgestrel‐releasing intrauterine system (LNG‐IUS, Mirena) has been shown to reduce the risk of developing endometrial cancer. The recent joint Green Top Guideline on the Management of Endometrial Hyperplasia published by the Royal College of Obstetricians and Gynaecologists (RCOG) with the British Society for Gynaecological Endoscopy (BSGE) recommends the LNG‐IUS for the medical management of endometrial hyperplasia without atypia. This case study reports on the development of endometrioid adenocarcinoma despite the presence of an LNG‐IUS following a negative hysteroscopy in a 56‐year‐old woman with morbid obesity. This report highlights the need for patients and clinicians to remain vigilant to the early warning signs of developing endometrial cancer, especially in those at an increased risk secondary to obesity.
Consistency of effects of tropical‐forest disturbance on species composition and richness relative to use of indicator taxa
Authors: Stork N.E. , Srivastava D.S. , Eggleton P. , Hodda M. , Lawson G. , Leakey R.R.B. , Watt A.D.
Published: December 2016

Lawton et al. (1998) found, in a highly cited study, that the species richness of 8 taxa each responds differently to anthropogenic disturbance in Cameroon forests. Recent developments in conservation science suggest that net number of species is an insensitive measure of change and that understanding which species are affected by disturbance is more important. It is also recognized that all disturbance types are not equal in their effect on species and that grouping species according to function rather than taxonomy is more informative of responses of biodiversity to change. In a reanalysis of most of the original Cameroon data set (canopy and ground ants, termites, canopy beetles, nematodes, and butterflies), we focused on changes in species and functional composition rather than richness and used a more inclusive measure of forest disturbance based on 4 component drivers of change: years since disturbance, tree cover, soil compaction, and degree of tree removal. Effects of disturbance on compositional change were largely concordant between taxa. Contrary to Lawton et al.’s findings, species richness for most groups did not decline with disturbance level, providing support for the view that trends in species richness at local scales do not reflect the resilience of ecosystems to disturbance. Disturbance affected species composition more strongly than species richness for butterflies, canopy beetles, and litter ants. For these groups, disturbance caused species replacements rather than just species loss. Only termites showed effects of disturbance on species richness but not composition, indicating species loss without replacement. Although disturbance generally caused changes in composition, the strength of this relationship depended on the disturbance driver. Butterflies, litter ants, and nematodes were correlated with amount of tree cover, canopy beetles were most strongly correlated with time since disturbance, and termites were most strongly correlated with degree of soil disturbance. There were moderately divergent responses to disturbance between functional feeding groups. Disturbance was most strongly correlated with compositional differences of herbivores within beetles and nematodes and humus feeders within termites. Our results suggest that consideration of the impact of different forms of disturbance on species and functional composition, rather than on net numbers of species, is important when assessing the impacts of disturbance on biodiversity.
Vector‐based modelling of colour difference: a pilot study of theDE2000 colour difference model
Authors: Oulton David P. , Westland Stephen
Published: December 2016

A novel approach to colour difference modelling is presented whereby for any givenCMC(1:1) orCIE DE2000 ∆E, ∆C, ∆H, and ∆Lcolour difference, the equivalentCIEXYZ,L*a*b*, andL*C*hcoordinate changes are derived by optimising the inputRGBstimuli from which they are all calculated. Single‐dimensionLorCorHdifference loci expressed inDE2000 difference units are thus generated, and the additive equivalence of tristimulus values is likewise projected forward onto each locus and also onto a set ofCIE DE2000 three‐unit ellipse boundaries. Using the datasets thus generated, it is then shown firstly that the derived ellipses have well‐defined semi‐axes, which explain the detailed orientation of the MacAdam ellipses inx,y,Yspace. UnitCIE DE2000 difference is confirmed as a successful quantifying constant of visual difference over a wide range of chroma, hue, and lightness differences. As a constant,CIE DE2000 unit difference is shown to have a significantly variable value at high and low chroma: evidence is established for systematic changes in both chroma and hue difference sensitivity. A hitherto unresolved non‐linearity is revealed in theC*dimension ofL*C*hspace that is not replicated in theCIE DE2000 model. The derived difference loci appear to specify physically reproducible experimental stimuli that could be used in the estimation of visual difference magnitude. Overall, the data derived by the new approach and presented in this paper increase the probability that a true vector model of the visual difference response may eventually be derived.
What do Parents and Children talk about at a Natural History Museum?
Authors: To Cheryl , Tenenbaum Harriet R. , Wormald Daniel
Published: December 2016

This study investigated the ways in which families constructed an understanding of evolution exhibits at a natural history museum. We examined museum visitors’ use of exhibit text and the types of evolution‐related talk in parent‐child conversations while visiting the chimp/human and the artiodactyl exhibits. Participants were 52 families with children aged 2‐ to 11‐years who agreed to be digitally recorded. Analyses of parent‐child conversations indicated that families who read exhibit text were more likely to stay longer at the exhibits and to encounter the intended content of the exhibits than families who did not read the text. On‐topic conversations tended to focus on labelling and describing the exhibit content rather than talking about evolutionary concepts. Physical descriptions of exhibit displays allowed children to make inferences about novel entities (i.e., those in the exhibits) based on prior knowledge.
Developing a Research Agenda Aimed at Understanding the Teaching and Learning of Science at a Natural History Museum
Authors: Hammerness Karen , MacPherson Anna , Gupta Preeti
Published: December 2016

Over the past two decades, cultural institutions such as museums are beginning to develop their capacity for engaging in long‐term research on teaching and learning (Rennie et al. 2003; see also Crowley 2014). In this article, we describe one museum's efforts to develop an educational research agenda in relationship to these broader efforts. We explain how we got started; share steps taken; describe the agenda itself; and give examples of some of our current research studies. We end with insights into some of the challenges we've faced in developing this work and how we've addressed them and our next steps.
Investigating the Development of the “Mobile Museum” from the Perspective of Service
Authors: HUang Chia‐Hui , Lin Fang‐Suey
Published: December 2016

During economic development, modern museums face competition from various leisure activities and entertainment sites, and to achieve sustainable development, museums should reflect on providing high‐quality service to satisfy visitors’ expectations. Based on service design‐related theories, this research team conducted a case study to explore the planning, implementation, and meaning of Mobile Museums. It investigated design development from the perspective of public service design and summarized the policy, design, and service satisfaction results for Mobile Museums. Finally, the similarities in service processes are discussed between Mobile Museums and the general service industry. According to this study, attracting more visitors is the biggest issue facing museums today, as are the ways in which museums must actively provide service and become recognized to compete with others. This study identifies the onstage and backstage support of museums as well as their cultural features and non‐profit services.
Frontal theta activation associated with error detection in toddlers: influence of familial socioeconomic status
Authors: Conejero Ángela , Guerra Sonia , Abundis‐Gutiérrez Alicia , Rueda M. Rosario
Published: December 2016

Error detection is one of the functions of the executive attention network, a brain system involved in executive control that includes the anterior cingulate cortex and other prefrontal regions. Despite the key role of this function in a wide range of life outcomes, very limited research has examined the early development of the network and whether its functional efficacy is related to environmental factors. Electrophysiological studies with adults have shown oscillatory activity in theta (4–7 Hz) range arising from medial frontal cortex that follows the detection of self‐committed or observed errors. In the current study, we designed a novel experimental procedure that involved a familiarization phase with simple three‐pieces puzzles followed by an experimental phase in which toddlers observed the puzzles being formed either correctly or incorrectly. Observation of incorrect configurations produced increased potentials in midline channels and greater power theta activity for both toddlers (n = 56) and adults (n = 14). In addition, socioeconomic status of the family in general, and parental education in particular, contributed to individual differences in the amplitude of the error‐related signal and associated theta power in toddlers, indicating that children raised in lower SES families show poorer activation of the executive attention network. These data demonstrate the influence of environmental factors at the earliest stages of development of the executive attention network. Importantly, the results show that error‐detection EEG signals can be used as neural markers of the initial development of executive attention, which can be of great help for the early detection of risk for developmental disorders involving deficits in this function.
Attaching meaning to the number words: contributions of the object tracking and approximate number systems
Authors: vanMarle Kristy , Chu Felicia W. , Mou Yi , Seok Jin H. , Rouder Jeffrey , Geary David C.
Published: December 2016

Children's understanding of the quantities represented by number words (i.e., cardinality) is a surprisingly protracted but foundational step in their learning of formal mathematics. The development of cardinal knowledge is related to one or two core, inherent systems – the approximate number system (ANS) and the object tracking system (OTS) – but whether these systems act alone, in concert, or antagonistically is debated. Longitudinal assessments of 198 preschool children on OTS, ANS, and cardinality tasks enabled testing of two single‐mechanism (ANS‐only and OTS‐only) and two dual‐mechanism models, controlling for intelligence, executive functions, preliteracy skills, and demographic factors. Measures of both OTS and ANS predicted cardinal knowledge in concert early in the school year, inconsistent with single‐mechanism models. The ANS but not the OTS predicted cardinal knowledge later in the school year as well the acquisition of the cardinal principle, a critical shift in cardinal understanding. The results support a Merge model, whereby both systems initially contribute to children's early mapping of number words to cardinal value, but the role of the OTS diminishes over time while that of the ANS continues to support cardinal knowledge as children come to understand the counting principles.
Investigating the strategic antecedents of agility in humanitarian logistics
Authors: L'Hermitte Cécile , Brooks Benjamin , Bowles Marcus , Tatham Peter H.
Published: December 2016

This study investigates the strategic antecedents of operational agility in humanitarian logistics. It began by identifying the particular actions to be taken at the strategic level of a humanitarian organisation to support field‐level agility. Next, quantitative data (n=59) were collected on four strategic‐level capabilities (being purposeful, action‐focused, collaborative, and learning‐oriented) and on operational agility (field responsiveness and flexibility). Using a quantitative analysis, the study tested the relationship between organisational capacity building and operational agility and found that the four strategic‐level capabilities are fundamental building blocks of agility. Collectively they account for 52 per cent of the ability of humanitarian logisticians to deal with ongoing changes and disruptions in the field. This study emphasises the need for researchers and practitioners to embrace a broader perspective of agility in humanitarian logistics. In addition, it highlights the inherently strategic nature of agility, the development of which involves focusing simultaneously on multiple drivers.
Vulnerability assessments as a political creation: tsunami management in Portugal
Authors: Pronk Maartje , Maat Harro , Crane Todd A.
Published: December 2016

Vulnerability assessments are a cornerstone of contemporary disaster research. This paper shows how research procedures and the presentation of results of vulnerability assessments are politically filtered. Using data from a study of tsunami risk assessment in Portugal, the paper demonstrates that approaches, measurement instruments, and research procedures for evaluating vulnerability are influenced by institutional preferences, lines of communication, or lack thereof, between stakeholder groups, and available technical expertise. The institutional setting and the pattern of stakeholder interactions form a filter, resulting in a particular conceptualisation of vulnerability, affecting its operationalisation via existing methods and technologies and its institutional embedding. The Portuguese case reveals a conceptualisation that is aligned with perceptions prevalent in national government bureaucracies and the exclusion of local stakeholders owing to selected methodologies and assessment procedures. The decisions taken by actors involved in these areas affect how vulnerability is assessed, and ultimately which vulnerability reduction policies will be recommended in the appraisal.
Once‐weekly dulaglutide 1.5 mg restores insulin secretion in response to intravenous glucose infusion
Authors: de la Peña Amparo , Loghin Corina , Cui Xuewei , Zhang Xin , Kapitza Christoph , Kelly Ronan P.
Published: December 2016

Aims

To evaluate the effects of dulaglutide 1.5 mg on first‐ and second‐phase insulin secretion in response to an intravenous (i.v.) glucose bolus challenge, in subjects with type 2 diabetes mellitus (T2DM; primary objective) and in healthy subjects.

Materials and methods

In this randomized, double‐blind, placebo‐controlled, 2‐period crossover study, subjects received a single subcutaneous injection of dulaglutide 1.5 mg or placebo on day 1 of each period. On day 3, subjects underwent a 6‐hour insulin infusion, followed by an i.v. glucose bolus and a glucagon challenge during hyperglycaemia. Areas under the concentration–time curve and maximum concentrations for first‐ (AUC0
‐10 and Cmax0‐10) and second‐phase secretion (AUC10‐180 and Cmax10‐180) were calculated for insulin and C‐peptide. The glucose disappearance constant (Kg) and homeostasis model assessment of β‐cell function (HOMA‐β) were assessed.

Results

In 20 subjects with T2DM, dulaglutide increased mean insulin AUC0‐10 by 7.92‐fold and Cmax0‐10 by 5.40‐fold vs placebo, and mean AUC10‐180 and Cmax10‐180 by 2.44‐ and 3.78‐ fold, respectively. In 10 healthy subjects, dulaglutide increased the mean insulin AUC0‐10 by 3.09‐fold and Cmax0‐10 by 2.96‐fold vs placebo, and mean AUC10‐180 and Cmax10‐180 by 2.04‐ and 4.15‐fold, respectively. The corresponding C‐peptide values also increased. Mean Kg and HOMA‐β were higher after dulaglutide compared with placebo.

Conclusions

In subjects with T2DM, a single dulaglutide 1.5‐mg dose restored the first‐phase insulin secretion in response to an i.v. glucose bolus, increased the second‐phase insulin response and enhanced β‐cell function.
Comparison of exposure response relationship of atrasentan between North American and Asian populations
Authors: Heerspink Hiddo J. L. , Makino Hirofumi , Andress Dennis , Brennan John J. , Correa‐Rotter Ricardo , Coll Blai , Davis Justin W. , Idler Ken , Kohan Donald E. , Liu Mohan , Perkovic Vlado , Remuzzi Giuseppe , Tobe Sheldon W. , Toto Robert , Parving Hans‐Henrik , de Zeeuw Dick
Published: December 2016

Aims

The selective endothelin (ET) A receptor antagonist atrasentan has been shown to lower albuminuria in North American and Asian patients with type 2 diabetes and nephropathy. As drug responses to many drugs may differ between North American and Asian populations, we assessed the influence of geographical region on the albuminuria and fluid retention response to atrasentan.

Materials and methods

Two 12‐week double‐blind randomised controlled trials were performed with atrasentan 0.75 or 1.25 mg/d vs placebo in patients with type 2 diabetes and nephropathy. The efficacy endpoint was the percentage change in albuminuria. Bodyweight change, a proxy of fluid retention, was used as a safety endpoint. Pharmacodynamics were determined in Asians (N = 77) and North Americans (N = 134). Atrasentan plasma concentration was measured in 161 atrasentan‐treated patients.

Results

Mean albuminuria reduction in Asian, compared to North American, patients was, respectively, −34.4% vs −26.3% for 0.75 mg/d (
P
 = .44) and −48.0% vs −28.9% for 1.25 mg/d (
P
 = .035). Bodyweight gain did not differ between North American and Asian populations. Atrasentan plasma concentrations were higher in Asians compared to North Americans and correlated with albuminuria response (7.2% albuminuria reduction per doubling atrasentan concentration;
P
 = .024). Body surface area (β = −1.09 per m2;
P
 < .001) and bilirubin, as a marker of hepatic organic anion transporter activity, (β = 0.69 per mg/dL increment;
P
 = .010) were independent determinants of atrasentan plasma concentration; correction by body surface area and bilirubin left no significant difference in plasma concentration between Asian and North American populations.

Conclusion

The higher exposure and albuminuria reduction of atrasentan in Asian patients is not associated with more fluid retention, suggesting that Asian patients are less sensitive to atrasentan‐induced sodium retention.
Efficacy and safety of dapagliflozin over 1 year as add‐on to insulin therapy in Japanese patients with type 2 diabetes: the DAISY (Dapagliflozin Added to patients under InSulin therapY) trial
Authors: Araki Eiichi , Onishi Yukiko , Asano Michiko , Kim Hyosung , Yajima Toshitaka
Published: December 2016

Aims

To evaluate the efficacy and safety of dapagliflozin as add‐on to insulin in Japanese patients with type 2 diabetes.

Materials and methods

Insulin‐treated Japanese patients were randomized to 5 mg dapagliflozin or placebo during a 16‐week double‐blind treatment period. Both groups then received dapagliflozin 5 or 10 mg (the dose was increased at or after week 24 if glycated haemoglobin [HbA1c] at the previous visit was >7.5%) during a 36‐week open‐label extension period. The exploratory efficacy endpoint was to assess the maintenance efficacy of 5/10 mg dapagliflozin + insulin over 52 weeks of treatment. Safety was assessed in terms of adverse events, laboratory variables and vital signs.

Results

The changes in HbA1c from baseline to weeks 16 and 52 were −0.62% and −0.74%, respectively, in the dapagliflozin group, vs −0.08% and −0.83%, respectively, in the placebo–dapagliflozin group. Body weight decreased at both time points in the dapagliflozin group and after switching to open‐label dapagliflozin in the placebo–dapagliflozin group. The total insulin dose decreased slightly after starting dapagliflozin. Adverse events occurred in 82.9% and 71.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively. Hypoglycaemia occurred in 35.0% and 41.7% of patients in the dapagliflozin and placebo–dapagliflozin groups, respectively, but the incidence was not increased by use of dapagliflozin in either trial period. Genital/urinary tract infections, renal impairment/failure, volume depletion, fracture and hepatic disorders occurred in ≤5% of patients.

Conclusion

This trial showed that administration of dapagliflozin as an add‐on to insulin therapy was effective, was well tolerated and had insulin‐sparing effects in Japanese patients with type 2 diabetes.
Understanding and overcoming metformin gastrointestinal intolerance
Authors: Bonnet Fabrice , Scheen André
Published: December 2016

Metformin is the most widely prescribed drug for patients with type 2 diabetes mellitus and the first‐line pharmacological option as supported by multiple international guidelines, yet a rather large proportion of patients cannot tolerate metformin in adequate amounts because of its associated gastrointestinal (GI) adverse events (AEs). GI AEs typically encountered with metformin therapy include diarrhoea, nausea, flatulence, indigestion, vomiting and abdominal discomfort, with diarrhoea and nausea being the most common. Although starting at a low dose and titrating slowly may help prevent some GI AEs associated with metformin, some patients are unable to tolerate metformin at all and it may also be difficult to convince patients to start metformin again after a bout of GI AEs. Despite this clinical importance, the underlying mechanisms of the GI intolerance associated with metformin are poorly known. In the present review, we discuss: the epidemiology of metformin‐associated GI intolerance and its underlying mechanisms; genotype variability and associated factors affecting metformin GI intolerance, such as comorbidities, co‐medications and bariatric surgery; clinical consequences and therapeutic strategies to overcome metformin GI intolerance. These strategies include appropriate titration of immediate‐release metformin, use of extended‐release metformin, the promise of delayed‐release metformin and gut microbiome modulators, as well as alternative pharmacological therapies when metformin cannot be tolerated at all. Given the available data, all efforts should be made to maintain metformin before considering a shift to another drug therapy.
Similar pharmacokinetics and pharmacodynamics of rapid‐acting insulin lispro products SAR342434 and US‐ and EU‐approved Humalog in subjects with type 1 diabetes
Authors: Kapitza Christoph , Nowotny Irene , Lehmann Anne , Bergmann Karin , Rotthaeuser Baerbel , Nosek Leszek , Becker Reinhard H. A.
Published: December 2016

Aim

To compare the pharmacokinetics (PK) and pharmacodynamics (PD) of 3 rapid‐acting insulin lispro products: SAR342434 solution, United States (US)‐approved Humalog and European Union (EU)‐approved Humalog.

Methods

In a single‐centre, randomized, double‐blind, 3‐treatment, 3‐period, 6‐sequence, crossover, euglycaemic clamp study (NCT02273258), adult male subjects with type 1 diabetes were randomized to receive 0.3 U/kg of SAR342434 solution, US‐approved and EU‐approved Humalog under fasted conditions. PK and PD (glucose infusion rate [GIR]) were assessed up to 12 hours.

Results

Of the 30 subjects randomized, 28 completed all 3 treatment periods. Mean concentration and GIR vs time profiles were similar for all 3 products. Exposure (INS‐Cmax, INS‐AUClast and INS‐AUC) and activity (GIRmax and GIR‐AUC0‐12h) of SAR342434, US‐approved and EU‐approved Humalog were similar in all comparisons (point estimates of treatment ratios, 0.95‐1.03 for PK parameters and 1.00‐1.07 for PD parameters), with 90% confidence intervals for the ratios of geometric least squares means within the pre‐specified bioequivalence limit (0.80‐1.25) and no significant differences in time‐related parameters. Within‐subject variability of exposure and activity was low across the 3 clamps, indicating high day‐to‐day reproducibility in clamp performance, irrespective of the individual product. Adverse events were similar for all 3 products. No safety concerns were noted in vital signs or in laboratory and electrocardiogram data.

Conclusions

The results of this study demonstrate similarity in insulin lispro exposure profiles and PD activity of SAR342434 solution to both US‐ and EU‐approved Humalog, and between both US‐ and EU‐approved Humalog, supporting the use of SAR342434 solution for injection as a follow‐on product.
Quantitative and longitudinal imaging of intramuscular transplanted islets of Langerhans with SPECT using [123I]IBZM
Authors: Willekens Stefanie M. A. , van der Kroon Inge , Bos Desirée , Joosten Lieke , Frielink Cathelijne , Boerman Otto C. , Brom Maarten , Gotthardt Martin
Published: December 2016

A non‐invasive imaging method to monitor islet grafts could provide novel and improved insight into the fate of transplanted islets and, potentially, monitor the effect of therapeutic interventions. Therefore, such an imaging method could help improve long‐term transplantation outcome. Here, we investigated the use of [
123I]IBZM for insulin positive graft volume quantification and longitudinal graft monitoring. SPECT images were acquired 6 weeks after islet transplantation in the calf muscle of rats. For longitudinal graft analysis, rats were monitored by SPECT for 10 weeks. After animals were euthanized, graft containing muscles were dissected for ex vivo analysis and insulin‐positive graft volume determination. Six weeks after transplantation, a clear signal was observed in all grafts by SPECT imaging. Moreover, the intensity of the SPECT signal correlated linearly with insulin‐positive graft volume, as determined histologically. Longitudinal graft follow‐up showed a clear SPECT signal of the transplant from 3 until 10 weeks after transplantation. In this study, we demonstrate for the first time the successful application of a radiotracer, [
123I]IBZM, for non‐invasive, in vivo graft volume quantification and longitudinal graft monitoring.
Susceptibility of Macrosiphum euphorbiae to the parasitoid Aphidius ervi: larval development depends on host aphid genotype
Authors: Clarke Hannah Victoria , Cullen Daniel , Hubbard Stephen Francis , Karley Alison Jane
Published: December 2016

The potato aphid, Macrosiphum euphorbiae Thomas (Hemiptera: Aphididae: Macrosiphini), is a common polyphagous aphid in Europe and North America. However, the factors influencing potato aphid dynamics and susceptibility to natural enemies are largely undescribed, particularly in relation to facultative endosymbiotic bacteria, which can provide protection against parasitism and disease in some aphid species. This study investigated whether potato aphid susceptibility to one of its principal natural enemies, the parasitoid Aphidius ervi Haliday (Hymenoptera: Braconidae: Aphidiinae), varied in relation to aphid genotype and/or endosymbiont presence. Parasitism and aphid fitness assays were conducted on clonal lineages of aphids, harbouring their natural endosymbiont infections, collected over 3 years from separate geographic locations. Parasitized aphids were dissected to quantify parasitoid oviposition, larval development, and mummification. Amongst the 19 clonal lines of M. euphorbiae tested, seven aphid genotypes were identified, and 11 lines harboured one or both of the facultative endosymbionts Hamiltonella defensa Moran et al. and Regiella insecticola Moran et al.; H. defensa infections were associated exclusively with two of the seven M. euphorbiae genotypes. Parasitism resistance was detected in clonal lines belonging to a single aphid genotype and resulted from failure of parasitoid eggs to develop into larvae rather than failure of the parasitoid to oviposit. Contrary with studies of several other aphid species, there was little evidence that H. defensa provided strong protection to M. euphorbiae from parasitism by A. ervi. Furthermore, there were no clear fitness costs to the aphid associated with parasitism resistance or with H. defensa infection. The two M. euphorbiae genotypes in which H. defensa occurred, which included the resistant genotype, exhibited faster development, higher survival, and greater fecundity than the other five aphid genotypes. These findings suggest that biological control of M. euphorbiae using A. ervi alone could exacerbate pest problems by selecting for the fittest parasitism‐resistant genotypes.
Rituximab in immune thrombocytopenia: gender, age, and response as predictors of long‐term response
Authors: Marangon Miriam , Vianelli Nicola , Palandri Francesca , Mazzucconi Maria Gabriella , Santoro Cristina , Barcellini Wilma , Fattizzo Bruno , Volpetti Stefano , Lucchini Elisa , Polverelli Nicola , Carpenedo Monica , Isola Miriam , Fanin Renato , Zaja Francesco
Published: December 2016

Objectives

To evaluate the efficacy of a salvage treatment with rituximab (RTX) in adults with primary immune thrombocytopenia (ITP), in terms of short‐term response and long‐term response (LTR, i.e., probability to achieve and maintain response) and to identify biological and clinical predictors of response.

Methods

We retrospectively evaluated the outcome of patients with primary ITP treated with standard dosage RTX (375 mg/m2 × 4) as salvage therapy in five Italian centers. One hundred and three patients, median age of 46 yr, were included. The median period of observation was 59 months.

Results

Response (R) and complete response (CR) were documented in 57 (55%) and 37 (36%) patients, respectively. Patients younger than 40 yr had a higher probability to achieve CR (P = 0.025). Younger women (age < 40 yr) had a significantly higher probability to achieve R and CR (P = 0.039 and P = 0.009, respectively). The estimated LTR rate was 36% and 31% after 48 and 72 months, respectively; female sex (P = 0.033) and younger age (P = 0.021) were associated with better LTR. Younger women had the highest LTR rate (P = 0.006). Response duration was associated with the obtainment of CR after RTX (CR vs. partial response, P = 0.002).

Conclusions

The effect of RTX salvage treatment appears higher in younger women, with LTR rate possibly approaching that of splenectomy.
Intentionality, Constitution and Merleau‐Ponty's Concept of ‘The Flesh’
Authors: Apostolopoulos Dimitris
Published: December 2016

Since Husserl, the task of developing an account of intentionality and constitution has been central to the phenomenological enterprise. Some of Merleau‐Ponty's descriptions of ‘the flesh’ suggest that he gives up on this task, or, more strongly, that the flesh is in principle incompatible with intentionality or constitution. I show that these remarks, as in Merleau‐Ponty's earlier writings, refer to the classical, early Husserlian interpretations of these concepts, and argue that the concept of the flesh can plausibly be understood to advance a refined account of intentionality and constitution. Instead of a first‐personal, unidirectional act or embodied motor project, intentionality is a latent openness to things, where the roles of subject and object are reversible. Whereas the view of constitution as meaning‐bestowal is untenable, the flesh has a constitutive role, which is supported by a ‘constitutional passivity’ from the subject. On this reading, Merleau‐Ponty's later work aims to develop basic tenets of his earlier thought, albeit at a critical distance, an attempt he thought was continuous with the central problems that Husserl claimed a phenomenological philosophy must grapple with, even if Merleau‐Ponty's answers to these problems are not Husserl's.
Population‐specific genotype x genotype x environment interactions in bacterial disease of early life stages of Pacific oyster larvae
Authors: Wendling Carolin C. , Fabritzek Armin G. , Wegner K. Mathias
Published: December 2016

The consequences of emerging marine diseases on the evolutionary trajectories of affected host populations in the marine realm are largely unexplored. Evolution in response to natural selection depends on the genetic variation of the traits under selection and the interaction of these traits with the environment (GxE). However, in the case of diseases, pathogen genotypes add another dimension to this interaction. Therefore, the study of disease resistance needs to be extended to the interaction of host genotype, pathogen genotype and environment (GxGxE). In this study, we used a full‐sib breeding design crossing two genetically differentiated populations of the Pacific oyster Crassostrea gigas (Thunberg, 1793), to determine the influence of host genotype, pathogen genotype and temperature on disease resistance. Based on a controlled infection experiment on two early life stages, that is, D‐larvae and Pediveliger larvae at elevated and ambient water temperatures, we estimated disease resistance to allopatric and sympatric Vibrio sp. by measuring survival and growth within and between genetically differentiated oyster populations. In both populations, survival was higher upon infection with sympatric Vibrio sp., indicating that disease resistance has a genetic basis and is dependent on host genotype. In addition, we observed a significant GxGxE effect in D‐larvae, where contrary to expectations, disease resistance was higher at warm than at cold temperatures. Using thermal reaction norms, we could further show that disease resistance is an environment dependent trait with high plasticity, which indicates the potential for a fast acclimatization to changing environmental conditions. These population‐specific reaction norms disappeared in hybrid crosses between both populations which demonstrates that admixture between genetically differentiated populations can influence GxGxE interactions on larger scales.
Pioglitazone inhibits mitochondrial pyruvate metabolism and glucose production in hepatocytes
Authors: Shannon Christopher E. , Daniele Giuseppe , Galindo Cynthia , Abdul‐Ghani Muhammad A. , DeFronzo Ralph A. , Norton Luke
Published: December 2016

Pioglitazone is used globally for the treatment of type 2 diabetes mellitus (T2DM) and is one of the most effective therapies for improving glucose homeostasis and insulin resistance in T2DM patients. However, its mechanism of action in the tissues and pathways that regulate glucose metabolism are incompletely defined. Here we investigated the direct effects of pioglitazone on hepatocellular pyruvate metabolism and the dependency of these observations on the purported regulators of mitochondrial pyruvate transport, MPC1 and MPC2. In cultured H4IIE hepatocytes, pioglitazone inhibited [2‐14C]‐pyruvate oxidation and pyruvate‐driven oxygen consumption and, in mitochondria isolated from both hepatocytes and human skeletal muscle, pioglitazone selectively and dose‐dependently inhibited pyruvate‐driven ATP synthesis. Pioglitazone also suppressed hepatocellular glucose production (HGP), without influencing the mRNA expression of key HGP regulatory genes. Targeted siRNA silencing of MPC1 and 2 caused a modest inhibition of pyruvate oxidation and pyruvate‐driven ATP synthesis, but did not alter pyruvate‐driven HGP and, importantly, it did not influence the actions of pioglitazone on either pathway. In summary, these findings outline a novel mode of action of pioglitazone relevant to the pathogenesis of T2DM and suggest that targeting pyruvate metabolism may lead to the development of effective new T2DM therapies.