bluuebunny/crossref_metadata_2025 huggingface dataset:
Complete Hematologic and Molecular Response in Adult Patients With Relapsed/Refractory Philadelphia Chromosome–Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment With Blinatumomab: Results From a Phase II, Single-Arm, Multicenter Study
Authors: Martinelli Giovanni , Boissel Nicolas , Chevallier Patrice , Ottmann Oliver , Gökbuget Nicola , Topp Max S. , Fielding Adele K. , Rambaldi Alessandro , Ritchie Ellen K. , Papayannidis Cristina , Sterling Lulu Ren , Benjamin Jonathan , Stein Anthony
Published: March 2017

Purpose

Few therapeutic options are available for patients with Philadelphia chromosome–positive (Ph+) B-precursor acute lymphoblastic leukemia (ALL) who progress after failure of tyrosine kinase inhibitor (TKI) −based therapy. Here, we evaluated the efficacy and tolerability of blinatumomab in patients with relapsed or refractory Ph+ALL.

Patients and Methods

This open-label phase II study enrolled adults with Ph+ALL who had relapsed after or were refractory to at least one second-generation or later TKI or were intolerant to second-generation or later TKIs and intolerant or refractory to imatinib. Blinatumomab was administered in 28-day cycles by continuous intravenous infusion. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first two cycles. Major secondary end points included minimal residual disease response, rate of allogeneic hematopoietic stem-cell transplantation, relapse-free survival, overall survival, and adverse events (AEs).

Results

Of 45 patients, 16 (36%; 95% CI, 22% to 51%) achieved CR/CRh during the first two cycles, including four of 10 patients with the T315I mutation; 88% of CR/CRh responders achieved a complete minimal residual disease response. Seven responders (44%) proceeded to allogeneic hematopoietic stem-cell transplantation, including 55% (six of 11) of transplantation-naïve responders. Median relapse-free survival and overall survival were 6.7 and 7.1 months, respectively. The most frequent AEs were pyrexia (58%), febrile neutropenia (40%), and headache (31%). Three patients had cytokine release syndrome (all grade 1 or 2), and three patients had grade 3 neurologic events, one of which (aphasia) required temporary treatment interruption. There were no grade 4 or 5 neurologic events.

Conclusion

Single-agent blinatumomab showed antileukemia activity in high-risk patients with Ph+ALL who had relapsed or were refractory to TKIs. AEs were consistent with previous experience in Ph–ALL.
Quality of Survivorship in a Rare Disease: Clinicofunctional Outcome and Physical Activity in an Observational Cohort Study of 618 Long-Term Survivors of Ewing Sarcoma
Authors: Ranft Andreas , Seidel Corinna , Hoffmann Christiane , Paulussen Michael , Warby Ann-Christin , van den Berg Henk , Ladenstein Ruth , Rossig Claudia , Dirksen Uta , Rosenbaum Dieter , Juergens Herbert
Published: March 2017

Purpose

Significantly improved survival rates in patients with Ewing sarcoma have raised interest in accessing the quality of long-term survivorship. In this study, subjective and objective measurement tools, preclassified as physical or mental scores, were used to assess clinicofunctional outcome and physical activity after intensive bone tumor treatment.

Methods

Long-term outcome of 618 survivors from consecutive Ewing sarcoma trials was assessed by the Toronto Extremity Salvage Score, Short-Form Health Survey (SF-36), Brief Symptom Inventory (BSI), and Rosenberg Self-Esteem Scale questionnaires and by the accelerometric StepWatch 3 Activity Monitor. Prospective measurements were correlated retrospectively with standardized primary trial data. Results were compared with 316 nonrandom healthy peers by using effect sizes ( d). Median observation time was 12.9 years from primary diagnosis (range, 3.7 to 31.2 years).

Results

Absolute subjective scores were moderate to good for survivors. Compared with control subjects, unfavorable outcome was shown on physical Toronto Extremity Salvage Score, SF-36 Physical Component Summary, and BSI-Somatization scales (| d| ≥ 0.50; P < .01), in contrast to SF-36 Mental Component Summary, BSI-Anxiety, BSI-Depression, and Rosenberg Self-Esteem Scale mental scales (| d| ≤ 0.31). Survivors were less active than control subjects, as demonstrated by a step count difference of 1,742 steps per day ( d = −0.43; P < .01); however, on average, the recommended level for an active lifestyle was achieved (≥ 10,000 steps). Location of pelvic tumor was the major inferior disease-specific prognostic factor in physical scores ( P < .01), whereas nondisease-specific inferior factors in questionnaires were older age and female sex ( P < .01).

Conclusion

Survivors of Ewing sarcoma apparently returned to a normal life with minor limitations. Observed reductions in physical scores should be a focus in future research to optimize treatment strategies to reduce a negative impact on the quality of survivorship.
Defining predictors of early, intermediate, and late biochemical recurrence in men with clinically localized prostate cancer treated with minimally invasive radical prostatectomy.
Authors: Barreras Silvia Garcia , Nunes-Silva Igor , Sanchez-Salas Rafael , Secin Fernando P. , Srougi Victor , Baghdadi Mohammed , Barret Eric , Rozet Francois , Galiano Marc , Cathelineau Xavier
Published: March 2017

113

Background: Follow up after radical prostatectomy should be tailored to clinical and pathologic characteristics. To determine predictive factors for early, intermediate and late biochemical recurrence (BCR) after minimally invasive radical prostatectomy (MIRP: lap and robot) in patients with localized prostate cancer (PCa). Methods: Prospective clinical, pathologic, and outcome data were collected for 6195 patients with cT1-3N0M0 PCa treated with MIRP at our institution from 2000 to 2016. None of them received neoadjuvant therapy. BCR was defined as PSA level greater than 0.2 ng/ml. Time to BCR was divided in terciles to identify variables associated with early ( < 12 months), intermediate (12-36 months) and late BCR ( > 36 months). Comparisons among groups were performed using ANOVA or Chi square test. Logistic regression models were built to determine risk factors associated with BCR at each time interval. Results: We identified 1148 (19%) patients with BCR. Median time to BCR was 24 months. Statistically significant differences were found between the groups concerning PSA preoperative, D’Amico risk, type of surgery, pT stage, pathological Gleason, positive margins and extracapsular extension. Multivariable logistic regression analysis showed preoperative PSA, positive nodes, positive surgical margins and laparoscopic surgery were associated with early BCR. Laparoscopic surgery was the only risk factor associated with intermediate term BCR. Significant predictors of late BCR included Gleason ≥ 7, ≥ pT3, positive surgical margins, lymph node dissection performance and laparoscopic surgery. Conclusions: Patients with high risk features like Gleason ≥ 7, ≥ pT3 and or positive surgical margins may develop late recurrence and deserve long term follow up. Identify patients with higher PSA and lymph node invasion has an important predictive role due to the risk of BCR within the first year. The association between laparoscopic technique and late BCR deserves further evaluation.
Whole-exome sequencing of single circulating tumor cells is a useful tool for studying the intrapatient genetic heterogeneity in metastatic prostate cancer.
Authors: Faugeroux Vincent , Lefebvre Celine , Pailler Emma , Pierron Valerie , Billiot Fanny , Marcaillou Charles , Tourlet Sebastien , Vielh Philippe , Dogan Semih , Rameau Philippe , Ngocamus Maud , Massard Christophe , Soria Jean-Charles , Fizazi Karim , Tibbe Arjan , Julien Sylvia , Loriot Yohann , Farace Francoise
Published: March 2017

148

Background: Molecular characterization of metastatic castration resistant prostate cancer (mCRPC) is limited by tumor tissue availability. The analysis of circulating tumor cells (CTC) offers an attractive noninvasive surrogate option to analyze molecular alterations. We report whole exome sequencing (WES) of CTCs at the single cell level in mCRPC patients. Methods: Blood samples were drawn from 11 enzalutamide or abiraterone pre-treated mCRPC patients enrolled in the clinical program MOSCATO (NCT02613962). CTC enrichment, immunofluorescent detection and single cell isolation were performed using three methods (ISET filtration, CellSearch and the VyCap puncher system and RosetteSep enrichment) to obtain pools of 1-10 CTCs with distinct epithelial or mesenchymal phenotypes. After Whole Genome Amplification (WGA), WES was performed on the Illumina HiSeq 2000 platform. GATK Haplotype Caller enabled identification of germline polymorphisms from each patient in normal DNA, metastatic sample and CTCs in order to consider WGA induced bias. The detection of sSNV in tumor biopsies and CTCs was assessed with Mutect and IndelGenotyper respectively. Results: 189 WGA of CTC pools were performed. 34 pools of phenotypically different CTCs from 7 patients were selected and sequenced. Mean coverage of 51% was obtained at a sequencing depth of 10X. Allelic drop out was lower for CTC pools containing 5-10 cells. 17/34 (50%) CTC samples had shared sSNV with the paired tumor sample (range 0.35%-68%) Epithelial CTCs had more shared sSNV with metastatic biopsies than CTCs of other phenotypes but shared sSNV were also detected in large non epithelial CTC pointing out a high level of genetic heterogeneity between CTC. Overall, 89 deleterious protein-coding mutations were found only in pools of CTC, including mutations affecting oncogenic drivers such as MAPK1, HSP90AB1 or KDM5B. Conclusions: We present single cell WES of CTCs harboring distinct phenotypes. The detection of shared sSNV between CTC pools and corresponding biopsy could validate the use of CTCs as a liquid biopsy. The finding of sSNV specific to CTCs could offer additional data on tumor heterogeneity.
Survival outcomes for African-American (AA) vs matched Caucasian (CAU) patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) treated with sipuleucel-T (sip-T).
Authors: Quinn David I. , Freedland Stephen J. , Heath Elisabeth I. , Tutrone Ronald F. , McLeod David G. , Sheikh Nadeem Anwar , Chang Nancy N. , Sartor A. Oliver
Published: March 2017

192

Background: Prostate cancer risk and mortality is higher in AA vs CAU men. In an analysis of three phase 3 mCRPC trials, AA pts appear to derive greater survival benefit with sip-T, an autologous cellular immunotherapy for asymptomatic/minimally symptomatic mCRPC. AA pts on sip-T had a 30.7-month (mo) median overall survival (OS) benefit vs control (AUA 2012 P953), in contrast to a 4.1-mo OS benefit with sip-T vs control for all pts in IMPACT (NEJM 2010;363:411). As the prior analysis did not adjust for baseline differences between races, we matched AA to CAU pts on sip-T to better assess racial differences in sip-T benefit and cumulative antigen presenting cell (APC) activation, which correlates with OS (CII 2013;62:137). Methods: Data were from phase 3 mCRPC trials that randomized pts 2:1 to sip-T or control (D9901 [NCT00005947]; D9902A [NCT01133704]; IMPACT [NCT00065442]). Thirty-three AA sip-T pts were matched with 66 CAU sip-T pts based on predicted Halabi survival. Data were evaluated by the Kaplan-Meier method (event rates) and ANOVA (APC activation). Results: Median follow-up was 23.2 mos. AA pts on sip-T had a 20.6-mo longer median OS (45.3 mos; 95% CI 23.4–NE) vs CAU pts (24.7 mos; 95% CI 18.1–29.4) (HR = 0.49; 95% CI 0.26–0.91; p = 0.02). Median event-free survival (time to death or anticancer intervention [ACI]) was 10.7 mos for AA pts (95% CI 8.5–21.5) vs 8.7 mos for CAU pts (95% CI 6.6–11.5) (HR = 0.74; 95% CI 0.47–1.18; p = 0.20). Median time to next ACI was 23.5 mos in AA pts (95% CI 9.4–NE) vs 16.3 mos in CAU pts (95% CI 9.7–25.6) (HR = 0.78; 95% CI 0.42–1.43; p = 0.42). In AA pts, median APC activation was higher with sip-T infusion 1 vs CAU pts (7.0 vs 5.5, p = 0.004). Median cumulative APC activation over the three infusions was 27.7 (22.6–42.4, AA) vs 25.7 (21.5–33.9, CAU) (p = 0.083). Conclusions: Prior studies found sip-T provides OS benefit to both AA and CAU mCRPC pts. Herein, for men treated with sip-T, AA had longer survival, suggesting sip-T may provide greater OS benefit in AA. The basis for this may be biologic (greater APC activation). Further studies with larger sample sizes are needed to confirm if AA pts derive greater OS benefit from sip-T. Clinical trial information: NCT00005947; NCT01133704; NCT00065442.
The impact of TAS3681, a new type of androgen receptor antagonist, on aberrant AR signaling that drives tumor resistance to AR-targeted therapies by down-regulating full length and splice variant AR.
Authors: Kajiwara Daisuke , Minamiguchi Kazuhisa , Seki Masanao , Mizutani Hiroya , Yamamura Keisuke , Okajima Shigeo , Sasaki Eiji , Utsugi Teruhiro , Iwasawa Yoshikazu
Published: March 2017

197

Background: The treatment of castration-resistant prostate cancer (CRPC) has changed dramatically with the use of two new therapies, enzalutamide and abiraterone, directed at the androgen receptor (AR) signaling axis. However, eventually almost all patients relapse after these agents because of acquired resistance by a variety of mechanisms such as AR overexpression, the occurrence of AR mutations, or the induction of AR splice variants that confer ligand independent AR transactivation. TAS3681 is an oral pure AR antagonist with AR down-regulating activity. In this study, we investigated the effect of TAS3681 on several issues related to resistance to current AR-targeted therapy. Methods: VCaP cells transfected with wild-type AR-expressing vector, which overexpress AR, were treated with TAS3681 in the presence of androgen. Cells were harvested and luciferase activity was determined. For the analysis of F876L mutant AR, LNCaP cells stably expressing F876L AR protein were incubated with TAS3681 in the presence of androgen. The WST-8 assay was performed to measure cell viability. Prostate cancer cells expressing AR-v7 were treated with TAS3681, and full length (FL)-AR and AR-v7 protein levels were determined by Western blot. TAS3681 was orally dosed to confirm AR down-regulation in tumor and evaluate antitumor efficacy in AR-v7 positive CRPC tumor xenograft mouse model. Results: In prostate cancer (PCa) cells which overexpress AR, in contrast to enzalutamide, TAS3681 effectively suppressed AR transactivation and cell proliferation via AR down-regulation. TAS3681 effectively antagonized F876L mutant AR which confers resistance to cell growth inhibition by enzalutamide. Moreover, TAS3681 reduced both FL-AR and AR-v7 protein level in PCa cells in vitro and in vivo, and showed strong antitumor efficacy in AR-v7 positive xenografts. Conclusions: TAS3681 disrupts the aberrant AR signaling via a novel mechanism of action: pure AR antagonism plus down-regulation of full-length and splice variant AR. These findings suggest that TAS3681 has the potential to overcome resistance to current AR pathway target drugs.
A phase II study combining ipilimumab and degarelix with or without radical prostatectomy (RP) in men with newly diagnosed metastatic noncastration prostate cancer (mNCPC) or biochemically recurrent (BR) NCPC.
Authors: Autio Karen A. , Eastham James Andrew , Danila Daniel Costin , Slovin Susan F. , Morris Michael J. , Abida Wassim , Laudone Vincent Paul , Touijer Karim A. , Gopalan Anuradha , Wong Phillip , Curley Tracy , Dayan Erica Simone , Bellomo Lawrence P. , Scardino Peter T. , Scher Howard I.
Published: March 2017

203

Background: Androgen deprivation therapy (ADT) does not completely eliminate disease in mNCPC or BRPC. We explored a multimodality treatment (tx) approach combining ADT with ipilimumab (ipi) with the aim of achieving no evidence of disease or complete elimination of disease, given the potential for cure seen with immunotherapy. Methods: Cohort A (Coh A) enrolled men with ≤ 10 bone metastases treated with induction of degarelix (deg) and ipi prior to RP and subsequent ipi q3 weeks x 3 and 8 months (mos) total of deg. Cohort B (Coh B) opened later and enrolled men with BRNCPC after RP with a doubling time ≤ 12 mos, and received ipi q3 weeks x 4 and 8 mos of deg. The primary endpoint was an undetectable PSA (<0.05) at 12 and 20 mos with non-castrate testosterone. Results: 16 pts (7 Coh A; 9 Coh B) were treated. No Coh A pts experienced immune related toxicities (irAE) that delayed surgery. 4/7 (57%) Coh A pts came off study for irAE, 1 (14%) for insurance reasons, and 2 (29%) completed all protocol requirements. In Coh B 6/9 (67%) pts have completed tx and entered follow-up. Conclusions: A combined modality approach with ipi 10mg/kg, ADT, and RP in mNCPC was associated with limiting toxicities, however 3mg/kg was better tolerated and more feasible in a BRNCPC cohort. One pt in Coh A (14%) had an undetectable PSA with testosterone recovery while evaluation of efficacy for Coh B is ongoing. The role for RP and other immunotherapeutic approaches in NCPC remain viable interests to the field. Clinical trial information: NCT02020070. [Table: see text]
Premature clinical trial discontinuation in all and genitourinary (GU) cancers in the era of immune checkpoint inhibitors (ICI).
Authors: Khunger Monica , Rakshit Sagar , Tullio Katherine , Galsky Matt D. , Grivas Petros
Published: March 2017

394

Background: Clinical trial completion is critical for evaluating new therapies. Premature termination or withdrawal of clinical trials is common, impairs progress and results in waste of resources. We assessed features and reasons of early terminated and withdrawn cancer trials focusing on trials with ICI (anti-CTLA-4, anti-PD-1, anti-PD-L1). Methods: We reviewed all adult, intervention, cancer clinical trials registered in ClinicalTrials.gov from November 16, 2011 to April 16, 2015 to identify all early terminated and withdrawn trials. Reasons for termination were captured. Logistics regression model was used to identify factors associated with early termination or withdrawal. Discontinuation rate was compared between ICI and all trials (χ2); p < 0.05 was set as significant. Results: We identified 12875 clinical trials (35% industry-funded, 12% federal-funded; 772 in prostate and 386 in non-prostate GU cancers); 8.5% of all trials were prematurely terminated (5%) or withdrawn (3.5%); main reason for discontinuation was poor accrual (33%) followed by logistical reasons (26%). When comparing trials with ICI (n = 350) to all cancer trials, lower rate of termination or withdrawal was noted with ICI [5.4% vs 8.5%, p = 0.05]. Trials with ICI were less likely to discontinue due to poor accrual compared to all trials, but the difference was not significant (21% vs 33%, p = 0.4). Of the 1158 GU cancers trials, 75 (6.5%) were prematurely terminated and 56 (4.8%) withdrawn; reasons for discontinuation are shown in the table. Conclusions: Poor accrual represents the main cause of early termination of all cancer clinical trials. Premature termination/withdrawal rate appears lower in ICI trials which may be attributed to accrual differences. Clinical trial completion remains a high priority. [Table: see text]
Treatment utilization patterns for prostate cancer (PCa): An analysis from the National Cancer Database (NCDB).
Authors: Aragon-Ching Jeanny B. , Hussey Heather M. , Nguyen Hong , Chen Dechang , Henson Donald , Simmens Samuel J.
Published: March 2017

99

Background: We previously reported the effects of the PSA screening guidelines on the patterns of diagnosis and treatment for PCa based on analyses from the NCDB dataset (Aragon-Ching et al., ASCO GU 2016). Given increasing use and advocacy for active surveillance, we now report on the treatment utilization patterns for PCa by facility type and overall incidence of active treatment (surgery or radiation), no treatment, or active surveillance by PCa stage using the NCDB dataset. Methods: Using a de-identified dataset acquired from NCDB from 1998 to 2012, treatment status of all 337,568 men for which information was available was tabulated according to whether active treatment, no treatment, or active surveillance (i.e. watchful waiting) was performed. Patient characteristics, stage, and treatment status by facility type was determined. Results: There were 1,802,596 patients diagnosed with prostate cancer between 1998 and 2012 in the NCDB. Of the 337,568 men for which treatment status was available, 92% received treatment, nearly 4% were under active surveillance, and another 4% did not receive any form of treatment or active surveillance. Of patients diagnosed with TNM Stage I and II PCa, only 7.5% and 2.22%, respectively, were followed under active surveillance. Overall, active surveillance was most utilized (n = 7,524; 5.7% of men) in academic research programs compared to other treatment facilities. Of the 310,898 men who received any form of active treatment, 193,889 men (62.3%) received surgery and 108,925 men (35%) received radiation. Conclusions: Active surveillance as a treatment modality comprised only a minority of patients who underwent treatment for PCa from 1998–2012, even among men with early Stage I and II Pca. Interestingly, the majority of the men who did receive active surveillance as their treatment option were treated at academic research programs, perhaps alluding to increased recognition and adherence to the PSA screening and active surveillance guidelines compared to other treatment facility types. Datasets including PCa patients beyond 2012 will be explored to further evaluate these changes in treatment modalities.
Cross-linking mass spectrometry identifies new interfaces of Augmin required to localise the γ-Tubulin Ring Complex to the mitotic spindle
Authors: Chen Jack W. C. , Chen Zhuo A. , Rogala Kacper B. , Metz Jeremy , Deane Charlotte M. , Rappsilber Juri , Wakefield James G.
Published: March 2017

The hetero-octameric protein complex, Augmin, recruits γ-Tubulin Ring Complex (γ-TuRC) to pre-existing microtubules (MTs) to generate branched MTs during mitosis, facilitating robust spindle assembly. However, despite a recent partial reconstitution of the human Augmin complex in vitro, the molecular basis of this recruitment remains unclear. Here, we used immuno-affinity purification of in vivo Augmin from Drosophila and cross-linking/mass spectrometry to identify distance restraints between residues within the eight Augmin subunits in the absence of any other structural information. The results allowed us to predict potential interfaces between Augmin and γ-TuRC. We tested these predictions biochemically and in the Drosophila embryo, demonstrating that specific regions of the Augmin subunits, Dgt3, Dgt5 and Dgt6 all directly bind the γ-TuRC protein, Dgp71WD, and are required for the accumulation of γ-TuRC, but not Augmin, to the mitotic spindle. This study therefore substantially increases our understanding of the molecular mechanisms underpinning MT-dependent MT nucleation.
Humidity-mediated changes in an orb spider's glycoprotein adhesive impact prey retention time
Authors: Opell Brent D. , Buccella Katrina E. , Godwin Meaghan K. , Rivas Malik X. , Hendricks Mary L.
Published: March 2017

Properties of the viscous prey capture threads of araneoid orb spiders change in response to their environment. Relative humidity (RH) affects the performance of the thread's hygroscopic droplets by altering the viscoelasticity of each droplet's adhesive glycoprotein core. Studies that have characterized this performance used smooth glass and steel surfaces and uniform forces. In this study, we tested the hypothesis that these changes in performance translate into differences in prey retention times. We first characterized the glycoprotein contact surface areas and maximum extension lengths of Araneus marmoreus droplets at 20%, 37%, 55%, 72% and 90% RH and then modeled the relative work required to initiate pull-off of a 4 mm thread span, concluding that this species' droplets and threads performed optimally at 72% RH. Next, we evaluated the ability of three equally spaced capture thread strands to retain a house fly at 37%, 55% and 72% RH. Each fly's struggle was captured in a video and bouts of active escape behavior were summed. House flies were retained 11 s longer at 72% RH than at 37% and 55% RH. This difference is ecologically significant because the short time after an insect strikes a web and before a spider begins wrapping it is an insect's only opportunity to escape from the web. Moreover, these results validate the mechanism by which natural selection can tune the performance of an orb spider's capture threads to the humidity of its habitat.
Bringing a genomic perspective to the safety of drug treatment in oncology
Authors: Innocenti Federico
Published: March 2017

This article describes the clinical relevance of toxicity of therapies administered to patients with cancer, putting the patient, rather than disease, at the center of the evaluation of safety of anti-cancer therapy. Hence, the implications of adverse events are described from the patient perspective, focusing on the impact of patient safety on quality of life and efficacy of treatment. Issues revolving around other types of safety, such as financial toxicity, are also discussed. The role played by genetics in the assessment of a patient’s risk of adverse events is also discussed, both in relation to the potential of genomic research and in the context of current tools of fruition in clinical care.
Engaging high school students in neuroscience research -through an e-internship program
Authors: Crusio Wim E , Rubino Cynthia , Delprato Anna
Published: March 2017

In this article, we describe the design and implementation of an e-internship program that BioScience Project offers high school students over the summer. Project topics are in the areas of behavioral neuroscience and brain disorders. All research, teaching, and communication is done online using open access databases and webtools, a learning management system, and Google apps. Students conduct all aspects of a research project from formulating a question to collecting and analyzing the data, to presenting their results in the form of a scientific poster. Results from a pilot study involving fifteen students indicate that students are capable of successfully completing such a project, and benefit both intellectually and professionally from participating in the e-internship program.
Wash-in and wash-out of sevoflurane in a test-lung model: A comparison between Aisys and FLOW-i
Authors: Jakobsson Petter , Lindgren Madleine , Jakobsson Jan G.
Published: March 2017

Background:Modern anaesthesia workstations are reassuringly tight and are equipped with effective gas monitoring, thus providing good opportunities for low/minimal flow anaesthesia. A prerequisite for effective low flow anaesthesia is the possibility to rapidly increase and decrease gas concentrations in the circle system, thereby controlling the depth of anaesthesia. Methods:We studied the wash-in and wash-out of sevoflurane in the circle system with fixed fresh gas flow and vaporizer setting. We compared two modern anaesthesia work stations, the Aisys (GE, Madison, WI, USA) and FLOW-i (Maquet, Solna, Sweden) in a test lung model. Results: We found fresh-gas flow to have, as expected, a major influence on wash-in, as well as wash-out of sevoflurane. The wash-in time to reach a stable circle 1 MAC (2.1%) decreased from an average of 547 ± 83 seconds with a constant fresh gas flow of 300 ml/min and vaporizer setting of 8%, to a mean of 38 ± 6 seconds at a fresh gas flow of 4 L/min. There were only minor differences between the two works-stations tested; the Aisys was slightly faster at both 300 and 4 L/min flow. Time to further increase circle end-tidal concentration from 1-1.5 MAC showed likewise significant associations to fresh gas and decreased from 330 ± 24 seconds at 300 ml/L to less than a minute at constant 4 L/min (17 ± 11 seconds), without anaesthetic machine difference. Wash-out was also fresh gas flow dependent and plateaued at 7.5 L/min. Conclusions: Circle system wash-in and wash-out show clear fresh gas dependency and varies somewhat between the Aisys and Flow-i. The circle saturation, reaching 1 MAC end-tidal or increasing from 1-1.5 MAC can be achieved with both work-stations within 1.5 minutes at a constant fresh gas flow of 2 and 4 L/min. Wash-out plateaued at 7.5 L/min.
METALLURGICAL ASPECTS RELATED TO CONTACT FATIGUE PHENOMENA IN STEELS FOR BACK-UP ROLLS
Authors: Di Schino Andrea , Di Nunzio Paolo Emilio
Published: March 2017

The need of even longer rolling sessions is driving the improvement of back up rolls in terms of wear resistance. This is also aimed to reduce costs. In this paper the effect of steel chemical composition on contact fatigue phenomena, bringing to the macroscopic damage named spalling is reported. Results show that the removal by grinding operations of damaged portion of rolls surface should be not sufficient to restore the initial performances of material. Experimental tests showed that a portion of material below the damaged one keeps memory of the last fatigue cycle, and has to be removed.
Flight Network-Based Approach for Integrated Airline Recovery with Cruise Speed Control
Authors: Arıkan Uğur , Gürel Sinan , Aktürk M. Selim
Published: March 2017

Airline schedules are generally tight and fragile to disruptions. Disruptions can have severe effects on existing aircraft routings, crew pairings, and passenger itineraries that lead to high delay and recovery costs. A recovery approach should integrate the recovery decisions for all entities (aircraft, crew, passengers) in the system as recovery decisions about an entity directly affect the others’ schedules. Because of the size of airline flight networks and the requirement for quick recovery decisions, the integrated airline recovery problem is highly complex. In the past decade, an increasing effort has been made to integrate passenger and crew related recovery decisions with aircraft recovery decisions both in practice and in the literature. In this paper, we develop a new flight network based representation for the integrated airline recovery problem. Our approach is based on the flow of each aircraft, crew member, and passenger through the flight network of the airline. The proposed network structure allows common recovery decisions such as departure delays, aircraft/crew rerouting, passenger reaccommodation, ticket cancellations, and flight cancellations. Furthermore, we can implement aircraft cruise speed (flight time) decisions on the flight network. For the integrated airline recovery problem defined over this network, we propose a conic quadratic mixed integer programming formulation that can be solved in reasonable CPU times for practical size instances. Moreover, we place a special emphasis on passenger recovery. In addition to aggregation and approximation methods, our model allows explicit modeling of passengers and evaluating a more realistic measure of passenger delay costs. Finally, we propose methods based on the proposed network representation to control the problem size and to deal with large airline networks.
RFID Security Issues in IoT: A Comparative Study
Authors: Braganza Denver , Tulasi B.
Published: March 2017

The landscape of Internet of Things (IoT) has been evolving at an increasing rate over the recent years. With the ease of availability of mobile devices, there has been a tremendous leap in technology associated with it. Thus, the need for efficient intercommunication among these devices arises. To ensure that IoT is seamlessly integrated into the daily life of people using appropriate technology is essential. One of the important associated technologies with IoT is RFID. RFID proves to be a simpler and efficient technology to implement IoT at various levels. Since IoT is greatly imapcting the lives of people, one of the major concerns of IoT is the security. IoT will have millions of devices and users connected to each other.
It is important to authenticate both users and devices to prevent any breach of information. With the limitations in RFID technology, various authentication protocols have been developed to provide optimal solutions.
Evaluation of object utilization through statistical model in Software development process
Authors: Rahul Kumar , Sinha Brijesh , Kumar Vijay
Published: March 2017

Objects needs verification through statistical model in software development process which are important in software industries now a day. Software development process consist of several steps right from analysis to deployment and maintenance, therefore statistical model would certainly analyses object(s) and its various qualities and its relationship during software development process. Earlier, we have designed a TMS where, object(s) being available for various purposes like accessibility, reusability in a development of software product or embedded product, thus statistical model justify the level of accessibility in terms of profitability and quantity of access. So far various statistical models have been implemented to identify and established the relationship but not all statistical model are used to analyses and calculate the parametric standard and determine the reusability factor in software development process model. In fact, this statistical model justified at various level of development and would help in determine cost of accessibility (CoA) and cost of reusability (CoR)
Performance Investigation of Antivirus - A Comparative Analysis
Authors: Thomas Remya , Nachamai M
Published: March 2017

Antivirus as name implies prevent the devices such as computers, mobiles and pen-drive from viruses. All gadgets which interact with open network are prone to virus. Virus is a malicious software program which replicates by copying its code multiple times or by infecting any computer program (like modifying the existing program) which can affect its process. Virus perform harmful task on affected host computer such as possessing on hard disk, CPU time, accessing private information etc. This paper specifies the performance of (McAFee, Avast, Avira, Bitdefender, Norton) antivirus and its effectiveness on the computer. The performance is tested based on the time acquired by each antivirus to act on a computer. The parameters used to analyze the performance are quick scan, full scan and custom scan with respect to time. Through the analysis Bitdefender performance is better than other selected antivirus.
Spinal osteotomies: indications, limits and pitfalls
Authors: Kose Kamil Cagri , Bozduman Omer , Yenigul Ali Erkan , Igrek Servet
Published: March 2017

The aims of spinal deformity surgery are to achieve balance, relieve pain and prevent recurrence or worsening of the deformity. The main types of osteotomies are the Smith-Petersen osteotomy (SPO), pedicle subtraction osteotomy (PSO), bone-disc-bone osteotomy (BDBO) and vertebral column resection (VCR), in order of increasing complexity. SPO is a posterior column osteotomy in which the posterior ligaments and the facet joints are removed and correction is performed through the disc space. A mobile anterior disc is essential. SPO is best in patients with +6-8 cm C7 plumbline. The amount of correction is 9.3° to 10.7°/level (1°/mm bone). PSO is a technique where the posterior elements and pedicles are removed. Then a triangular wedge through the pedicles is removed and the posterior spine is shortened using the anterior cortex as a hinge. The ideal candidates are patients with a severe sagittal imbalance. A single level osteotomy can produce 30° 40° of correction. A single level osteotomy may restore global sagittal balance by an average of 9 cm with an upper limit of 19 cm. BDBO is an osteotomy done above and below a disc level. A BDBO provides correction rates in the range of 35° to 60°. The main indications are deformities with the disc space as the apex and severe sagittal plane deformities. VCR is indicated for rigid multi-planar deformities, sharp angulated deformities, hemivertebra resections, resectable spinal tumours, post-traumatic deformities and spondyloptosis. The main indication for a VCR is fixed coronal plane deformity. The type of osteotomy must be chosen mainly according to the aetiology, type and apex of the deformity. One may start with SPOs and may gradually advance to complex osteotomies.

Cite this article: EFORT Open Rev 2017;2:73-82.

DOI: 10.1302/2058-5241.2.160069
Subjects of, or subject to, policy reform? A Foucauldian discourse analysis of regulation and resistance in UK narratives of educational impacts of welfare cuts: The case of the ‘bedroom tax’
Authors: Burman Erica , Greenstein Anat , Bragg Joanna , Hanley Terry , Kalambouka Afroditi , Lupton Ruth , McCoy Lauren , Sapin Kate , Winter Laura
Published: March 2017

This paper draws on material generated from a qualitative study of educational impacts of a British welfare reform affecting housing rent subsidy, size and location commonly known as ‘the bedroom tax’ (Bragg et al., 2015), which was partly taken as a topic for study specifically because of its iconic status as a controversial and unpopular welfare ‘reform’ (or cut). The analysis draws on Foucauldian understandings of subjectification or subject-formation - as elaborated both from within and in relation to the social (Foucault, 1970; 1983; Ball, 1990; Olssen, 2006; Popkewitz & Brennan, 1998), read through new and newly available perspectives (Allen, 2015; Pêcheux, 2014). This approach is applied to discuss how those addressed by educational policy, and also as research participants, are both subject to prevailing political and practice-oriented discourses (of educational ‘problems’, and of the neoliberal frameworks by which poverty and welfare cuts are discussed), but also – at times – how they can become the subject of – in the sense of reformulating – these discourses in their accounts of everyday activities. After outlining our approach and the context for the study, we focus on four examples drawn from the narratives of the various stakeholders in the study – parents/carers, school staff and other community-based organisations as illustrations of how this discursive approach can provide rich readings of relevance to educational policy debates. From these we not only take further discussions of the production and regulation of subjectivities via social and educational policy practices, but also offer indicative glimpses of resistance to this as expressed by those who are its primary subjects, and where in one case such resistance brings our own research commitments under critical scrutiny.  As such, the contribution of this article is both topic-related (concerning the educational impacts of policy) but, crucially, also conceptual and methodological, in motivating for a Foucauldian-influenced discursive approach that is sensitive to struggle and resistance.
LAND PRICE MAPPING OF JABODETABEK, INDONESIA
Authors: Elmanisa Adisti Madella , Kartiva An An , Fernando Alfaret , Arianto Rama , Winarso Haryo , Zulkaidi Denny
Published: March 2017

Land provision is one of the biggest challenges for development in urban area. Most of the available urban land will be the object of speculation to be resold at a higher price when the time is right. In Jabodetabek, where the pace of urban development is faster than other parts of Indonesia, the prices of land show an abnormal increase; they seem to rise too fast. This paper discusses the increasing land prices in Jabodetabek area and argues that the increasing land price has encourages the private developer to bank the land in the area. Based on land price survey in Jabodetabek, urban activity is moving to south Jakarta. The highest land prices were found at East Kuningan, Setiabudi, and South Jakarta. By constrast, the lowest prices were observed in Sumur Batu and Cimuning (Bantar Gebang, Bekasi).It can be concluded that the land price increase also triggered land banking practice in Jabodetabek reaching in total approximately 60% of total area of Jakarta.
Intentionality, Privilege and World Pluralism: Reply to Beillard
Authors: Nulty Timothy J.
Published: March 2017

I respond to Julian Beillard’s (2016) critique of my arguments (2009, 2015) for a plurality of worlds. My initial arguments deployed the notions of relevant similarity and primitive triangulation found in the later writings of Donald Davidson. More specifically, I address Beillard’s claims that my use of intentionality to develop further Davidson’s concept of primitive triangulation is incoherent and leads to empirically absurd results. I argue that Beillard’s two main arguments—the causal objection and the coherence objection – fail due to a limited and erroneous understanding of the forms of intentionality relevant to primitive triangulation. I argue Beillard unjustifiably privileges one form of intentionality as the standard for what counts as real in a given world. Some of Beillard’s claims might in fact commit him to the world pluralism I advocate.
Human Nature and the Limits of Plasticity: Revisiting the Debate Concerning the Supernatural
Authors: Rivera Joseph
Published: March 2017

Kathryn Tanner’s recent work rehabilitates the decades-long debate concerning the supernatural, in which the church fathers feature as principal interlocutors. It is her particular
Stability of 25 mg/mL Azacitidine Suspensions Kept in Fridge after Freezing
Authors: Balouzet Clara , Chanat Cédric , Jobard Marion , Brandely-Piat Marie-Laure , Chast François
Published: March 2017

Azacitidine is supplied as lyophilized powder to be reconstituted with sterile water for injection. The molecule is very unstable in aqueous medium (temperature-dependent process). Advance preparation and leftover management are made difficult by such poor stability. This study evaluates the stability of 25 mg/mL azacitidine suspensions kept for a 1-month period at –20 °C, followed by a 5-day period at 5 °C. Three batches of 7 polypropylene syringes were filled with 2 mL of Vidaza
The unappreciated roles of the cholecystokinin receptor CCK(1) in brain functioning
Authors: Ballaz Santiago
Published: March 2017

The CCK(1) receptor is a G-protein-coupled receptor activated by the sulfated forms of cholecystokinin (CCK), a gastrin-like peptide released in the gastrointestinal tract and mammal brain. A substantial body of research supports the hypothesis that CCK(1)r stimulates gallbladder contraction and pancreatic secretion in the gut, as well as satiety in brain. However, this receptor may also fulfill relevant roles in behavior, thanks to its widespread distribution in the brain. The strategic location of CCK(1)r in mesolimbic structures and specific hypothalamic and brainstem nuclei lead to complex interactions with neurotransmitters like dopamine, serotonin, and glutamate, as well as hypothalamic hormones and neuropeptides. The activity of CCK(1)r maintains adequate levels of dopamine and regulates the activity of serotonin neurons of raphe nuclei, which makes CCK(1)r an interesting therapeutic target for the development of adjuvant treatments for schizophrenia, drug addiction, and mood disorders. Unexplored functions of CCK(1)r, like the transmission of interoceptive sensitivity in addition to the regulation of hypothalamic hormones and neurotransmitters affecting emotional states, well-being, and attachment behaviors, may open exciting roads of research. The absence of specific ligands for the CCK(1) receptor has complicated the study of its distribution in brain so that research about its impact on behavior has been published sporadically over the last 30 years. The present review reunites all this body of evidence in a comprehensive way to summarize our knowledge about the actual role of CCK in the neurobiology of mental illness.
Investigation of lactose hydrolysis by crude extract of Trichoderma viride ATCC 32098
Authors: Bilkay Isil Seyis
Published: March 2017

Objective

Aim of this study was to find the optimum pH, temperature and incubation conditions for efficient lactose hydrolysis by beta-galactosidase produced by Trichoderma viride ATCC 32098. In addition, enzymatic lactose hydrolysis in milk, whey and lactose solutions were studied and compared.

Material and methods

Trichoderma viride ATCC 32098 was incubated at 30°C for 8 days on a rotary shaker. Lactose hydrolysis was calculated based on the amount of glucose measured. Hydrolysis was carried out in lactose solution, milk and whey.

Results

Maximum efficiency was observed at pH 5.0 and at 60°C. Agitation increases lactose hydrolysis slightly. When enzymatic lactose hydrolysis in milk, whey and lactose solutions were studied, it was observed that after 26 h, hydrolyses in lactose solution and whey were almost 100% and hydrolysis in milk was 92%.

Conclusion

It can be concluded that the enzyme produced from T. viride ATCC 32098 in this study is a good alternative for use in lactose hydrolysis.
Transgenic Monkey Model of the Polyglutamine Diseases Recapitulating Progressive Neurological Symptoms
Authors: Tomioka Ikuo , Ishibashi Hidetoshi , Minakawa Eiko N. , Motohashi Hideyuki H. , Takayama Osamu , Saito Yuko , Popiel H. Akiko , Puentes Sandra , Owari Kensuke , Nakatani Terumi , Nogami Naotake , Yamamoto Kazuhiro , Noguchi Satoru , Yonekawa Takahiro , Tanaka Yoko , Fujita Naoko , Suzuki Hikaru , Kikuchi Hisae , Aizawa Shu , Nagano Seiichi , Yamada Daisuke , Nishino Ichizo , Ichinohe Noritaka , Wada Keiji , Kohsaka Shinichi , Nagai Yoshitaka , Seki Kazuhiko
Published: March 2017

Age-associated neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and the polyglutamine (polyQ) diseases, are becoming prevalent as a consequence of elongation of the human lifespan. Although various rodent models have been developed to study and overcome these diseases, they have limitations in their translational research utility owing to differences from humans in brain structure and function and in drug metabolism. Here, we generated a transgenic marmoset model of the polyQ diseases, showing progressive neurological symptoms including motor impairment. Seven transgenic marmosets were produced by lentiviral introduction of the human ataxin 3 gene with 120 CAG repeats encoding an expanded polyQ stretch. Although all offspring showed no neurological symptoms at birth, three marmosets with higher transgene expression developed neurological symptoms of varying degrees at 3–4 months after birth, followed by gradual decreases in body weight gain, spontaneous activity, and grip strength, indicating time-dependent disease progression. Pathological examinations revealed neurodegeneration and intranuclear polyQ protein inclusions accompanied by gliosis, which recapitulate the neuropathological features of polyQ disease patients. Consistent with neuronal loss in the cerebellum, brain MRI analyses in one living symptomatic marmoset detected enlargement of the fourth ventricle, which suggests cerebellar atrophy. Notably, successful germline transgene transmission was confirmed in the second-generation offspring derived from the symptomatic transgenic marmoset gamete. Because the accumulation of abnormal proteins is a shared pathomechanism among various neurodegenerative diseases, we suggest that this new marmoset model will contribute toward elucidating the pathomechanisms of and developing clinically applicable therapies for neurodegenerative diseases.