bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma
Authors: Brown Jennifer R. , Davids Matthew S. , Rodon Jordi , Abrisqueta Pau , Kasar Siddha N. , Lager Joanne , Jiang Jason , Egile Coumaran , Awan Farrukh T. 
Published: April 2015

Abstract
Purpose: This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma.
Patients and Methods: Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed.
Results: Twenty-five patients were included in the study: 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%), and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%), and anemia (16.0%). Pilaralisib exposure on cycle 1 day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and 3 patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥50%. Overall, 14 patients (56.0%; 7 patients with CLL and 7 patients with lymphoma) had progression-free survival ≥6 months.
Conclusions: Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development. Clin Cancer Res; 21(14); 3160–9. ©2015 AACR.
Inhibition of Homologous Recombination and Promotion of Mutagenic Repair of DNA Double-Strand Breaks Underpins Arabinoside–Nucleoside Analogue Radiosensitization
Authors: Magin Simon , Papaioannou Maria , Saha Janapriya , Staudt Christian , Iliakis George 
Published: April 2015

Abstract
In concurrent chemoradiotherapy, drugs are used to sensitize tumors to ionizing radiation. Although a spectrum of indications for simultaneous treatment with drugs and radiation has been defined, the molecular mechanisms underpinning tumor radiosensitization remain incompletely characterized for several such combinations. Here, we investigate the mechanisms of radiosensitization by the arabinoside nucleoside analogue 9-β-D-arabinofuranosyladenine (araA) placing particular emphasis on the repair of DNA double-strand breaks (DSB), and compare the results to those obtained with fludarabine (F-araA) and cytarabine (araC). Postirradiation treatment with araA strongly sensitizes cells to ionizing radiation, but leaves unchanged DSB repair by NHEJ in logarithmically growing cells, in sorted G1 or G2 phase populations, as well as in cells in the plateau phase of growth. Notably, araA strongly inhibits DSB repair by homologous recombination (HRR), as assessed by scoring ionizing radiation–induced RAD51 foci, and in functional assays using integrated reporter constructs. Cells compromised in HRR by RNAi-mediated transient knockdown of RAD51 show markedly reduced radiosensitization after treatment with araA. Remarkably, mutagenic DSB repair compensates for HRR inhibition in araA-treated cells. Compared with araA, F-araA and araC are only modestly radiosensitizing under the conditions examined. We propose that the radiosensitizing potential of nucleoside analogues is linked to their ability to inhibit HRR and concomitantly promote the error-prone processing of DSBs. Our observations pave the way to treatment strategies harnessing the selective inhibitory potential of nucleoside analogues and the development of novel compounds specifically utilizing HRR inhibition as a means of tumor cell radiosensitization. Mol Cancer Ther; 14(6); 1424–33. ©2015 AACR.
CD30 Downregulation, MMAE Resistance, and MDR1 Upregulation Are All Associated with Resistance to Brentuximab Vedotin
Authors: Chen Robert , Hou Jessie , Newman Edward , Kim Young , Donohue Cecile , Liu Xueli , Thomas Sandra H. , Forman Stephen J. , Kane Susan E. 
Published: April 2015

Abstract
Brentuximab vedotin (BV) is an antibody–drug conjugate that specifically delivers the potent cytotoxic drug monomethyl auristatin E (MMAE) to CD30-positive cells. BV is FDA approved for treatment of relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL); however, many patients do not achieve complete remission and develop BV-resistant disease. We selected for BV-resistant Hodgkin lymphoma (L428) and ALCL (Karpas-299) cell lines using either constant (ALCL) or pulsatile (Hodgkin lymphoma) exposure to BV. We confirmed drug resistance by MTS assay and analyzed CD30 expression in resistant cells by flow cytometry, qRT-PCR, and Western blotting. We also measured drug exporter expression, MMAE resistance, and intracellular MMAE concentrations in BV-resistant cells. In addition, tissue biopsy samples from 10 Hodgkin lymphoma and 5 ALCL patients who had relapsed or progressed after BV treatment were analyzed by immunohistocytochemistry for CD30 expression. The resistant ALCL cell line, but not the Hodgkin lymphoma cell line, demonstrated downregulated CD30 expression compared with the parental cell line. In contrast, the Hodgkin lymphoma cell line, but not the ALCL cell line, exhibited MMAE resistance and increased expression of the MDR1 drug exporter compared with the parental line. For both Hodgkin lymphoma and ALCL, samples from patients relapsed/resistant on BV persistently expressed CD30 by immunohistocytochemistry. One Hodgkin lymphoma patient sample expressed MDR1 by immunohistocytochemistry. Although loss of CD30 expression is a possible mode of BV resistance in ALCL in vitro models, this has not been confirmed in patients. MMAE resistance and MDR1 expression are possible modes of BV resistance for Hodgkin lymphoma both in vitro and in patients. Mol Cancer Ther; 14(6); 1376–84. ©2015 AACR.
Carperitide and Atrial Fibrillation After Coronary Bypass Grafting
Authors: Sezai Akira , Iida Mitsuru , Yoshitake Isamu , Wakui Shinji , Osaka Shunji , Kimura Haruka , Yaoita Hiroko , Hata Hiroaki , Shiono Motomi , Nakai Toshiko , Takayama Tadateru , Kunimoto Satoshi , Kasamaki Yuji , Hirayama Atsushi 
Published: April 2015

Background—
Occurrence of atrial fibrillation after cardiac surgery is associated with long-term mortality. We investigated whether infusion of human atrial natriuretic peptide (carperitide) could prevent postoperative atrial fibrillation.

Methods and Results—

A total of 668 patients who underwent isolated coronary artery bypass grafting were randomized to receive infusion of carperitide or physiological saline from the initiation of cardiopulmonary bypass. Patients were monitored continuously for 1 week after surgery to detect atrial fibrillation. The risk factors were investigated by Cox proportional hazard model. Postoperative atrial fibrillation occurred in 41 of 335 patients (12.2%) from the carperitide group versus 110 of 333 patients (32.7%) from the placebo group (
P
<0.0001). Postoperative levels of angiotensin-II, aldosterone, creatine kinase MB isoenzyme, human heart fatty acid–binding protein, and brain natriuretic peptide were all significantly lower in the carperitide group. The risk factors for postoperative atrial fibrillation by the Cox proportional hazard model were an age ≥70 years, emergency surgery, preoperative aldosterone level >150 ng/mL, preoperative nonuse of angiotensin receptor antagonists, preoperative use of calcium antagonists, postoperative nonuse of β-blockers, postoperative nonuse of aldosterone blockers, and nonuse of carperitide.

Conclusions

—
Perioperative carperitide infusion reduced the occurrence of postoperative atrial fibrillation. Accordingly, carperitide could be a useful option for preventing postoperative atrial fibrillation.

Clinical Trial Registration

—
URL:
http://www.umin.ac.jp
. Unique Identifier: UMIN000003958.
A Millennial Summer Temperature Reconstruction for the Eastern Tibetan Plateau from Tree-Ring Width*
Authors: Wang Jianglin , Yang Bao , Ljungqvist Fredrik Charpentier 
Published: April 2015

Abstract
Although tree-ring-width-based temperature reconstructions of centennial-to-millennial length have previously been published for many parts of the eastern Tibetan Plateau (ETP), a millennium-long regional-scale composite reconstruction with annual resolution has so far been lacking. Here, the authors present a reconstruction of June–August (JJA) temperature variability over the ETP for the period AD 1000–2005 using a nested composite-plus-scale (CPS) approach to 12 temperature-sensitive tree-ring width chronologies, including 946 individual tree-ring width series. The composite reconstruction reveals warm episodes occurring during much of the sixteenth, nineteenth, and twentieth centuries and cold episodes during much of the eleventh, seventeenth, and eighteenth centuries. The period AD 1996–2005 is likely the warmest decade in the context of the past millennium. The authors explore the influence of possible forcings, finding only a weak direct relationship of temperature changes over the ETP with solar forcing at multidecadal time scales but a robust in-phase relationship with the Atlantic multidecadal oscillation (AMO) during the past millennium. This suggests that the AMO may play an important role in controlling summer temperature variability over the ETP at multidecadal time scales. A comparison with temperature reconstructions from the higher latitudes of East Asia, central-eastern China, and the whole of the Northern Hemisphere shows that the cold eleventh century and the warm nineteenth century prevailing over ETP are somewhat unique, suggesting regional specific characteristics of the temperature variability in this region. This result highlights the need to further increase the number of millennium-long, high-resolution temperature records from East Asia.
Effect of Mesoscale Eddies on the Taiwan Strait Current
Authors: Chang Yu-Lin , Miyazawa Yasumasa , Guo Xinyu 
Published: April 2015

AbstractThis study shows that mesoscale eddies can alter the Taiwan Strait Current. The 20-yr data-assimilated Japan Coastal Ocean Predictability Experiment 2 (JCOPE2) reanalysis data are analyzed, and the results are confirmed with idealized experiments. The leading wind-forced seasonal cycle is excluded to focus on the effect of the eddy. The warm eddy southwest of Taiwan is shown to generate a northward flow, whereas the cold eddy produces a southward current. The effect of the eddy penetrates onto the shelf through the joint effect of baroclinicity and relief (JEBAR). The cross-isobath fluxes lead to shelfward convergence and divergence, setting up the modulation of the sea level slope. The resulting along-strait current anomaly eventually affects a wide area of the Taiwan Strait. The stronger eddy leads to larger modification of the cross-shelf flows and sea level slope, producing a greater transport anomaly. The composite Sea-Viewing Wide Field-of-View Sensor chlorophyll-a (Chl-a) serves as an indicator to show the change in Chl-a concentration in the strait in response to the eddy-induced current. During the warm eddy period, the current carries the southern water of lower concentration northward, reducing Chl-a concentration in the strait. In contrast, Chl-a is enhanced because the cold eddy–induced southward current carries the northern water of higher concentration southward into the strait.
A Comparison between a Generalized Beta–Advection Model and a Classical Beta–Advection Model in Predicting and Understanding Unusual Typhoon Tracks in Eastern China Seas
Authors: Huang Jing , Du Jun , Qian Weihong 
Published: April 2015

AbstractA total of 163 tropical cyclones (TCs) occurred in the eastern China seas during 1979–2011 with four types of tracks: left turning, right turning, straight moving, and irregular. The left-turning type is unusual and hard to predict. In this paper, 133 TCs from the first three types have been investigated. A generalized beta–advection model (GBAM) is derived by decomposing a meteorological field into climatic and anomalous components. The ability of the GBAM to predict tracks 1–2 days in advance is compared with three classical beta–advection models (BAMs). For both normal and unusual tracks, the GBAM apparently outperformed the BAMs. The GBAM’s ability to predict unusual TC tracks is particularly encouraging, while the BAMs have no ability to predict the left-turning and right-turning TC tracks. The GBAM was also used to understand unusual TC tracks because it can be separated into two forms: a climatic-flow BAM (CBAM) and an anomalous-flow BAM (ABAM). In the CBAM a TC vortex is steered by the large-scale climatic background flow, while in the ABAM, a TC vortex interacts with the surrounding anomalous flows. This decomposition approach can be used to examine the climatic and anomalous flows separately. It is found that neither the climatic nor the anomalous flow alone can explain unusual tracks. Sensitivity experiments show that two anomalous highs as well as a nearby TC played the major roles in the unusual left turn of Typhoon Aere (2004). This study demonstrates that a simple model can work well if key factors are properly included.
The Quality of Life Burden Associated With Voice Disorders in Sjögren’s Syndrome
Authors: Tanner Kristine , Pierce Jenny L. , Merrill Ray M. , Miller Karla L. , Kendall Katherine A. , Roy Nelson 
Published: April 2015

Objectives: This study examined quality of life burden of voice disorders in Sjögren’s syndrome (SS). Methods: Patients with SS (n = 101) completed interviews involving patient-reported histories of voice disorders, specific voice symptoms, SS disease severity, the Voice-Related Quality of Life (V-RQOL), and the general health-related quality of life Short Form 36 (SF-36) questionnaires. Relationships among voice symptoms, disease severity, and quality-of-life measures were examined and compared with patient-reported voice disorders. Results: Significant correlations were observed among voice symptoms, disease severity, V-RQOL, SF-36, and patient-reported voice disorders ( P < .05). Patients with SS who reported a voice disorder experienced a greater burden on general quality of life as compared with those without voice disorders. Specific voice symptoms significantly correlated with reduced SF-36 scores included frequent throat-clearing, throat soreness, difficulty projecting, and vocal discomfort. Despite the added burden of a voice disorder on quality of life in SS, voice-related treatment seeking was low (15.8%). However, the majority of patients who received voice treatment reported voice improvement. Conclusions: Individuals with SS frequently experience voice disorders and specific voice-related symptoms that are associated with reduced quality of life. These findings have important implications for voice referral practices and voice disorder symptom management in this population.
Activity of order n in continuous systems
Authors: Castro Rodrigo , Kofman Ernesto 
Published: April 2015

In this work we generalize the concept of activity of continuous time signals. We define the activity of order n of a signal and show that it allows us to estimate the number of sections of polynomials up to order n which are needed to represent that signal with a certain accuracy. Then we apply this concept to obtain a lower bound for the number of steps performed by quantization-based integration algorithms in the simulation of ordinary differential equations. We perform an exhaustive analysis over two examples, computing the activity of order n and comparing it with the number of steps performed by different integration methods. This analysis corroborates the theoretical predictions and also allows us to measure the suitability of the different algorithms depending on how close to the theoretical lower bound they perform.
Citizens’ Revolution and International Integration
Authors: Falconí Fander , Oleas-Montalvo Julio 
Published: April 2015

Can a country with an open economy tending toward reprimarization achieve a form of integration into the global economy other than the one determined by Latin America’s historical dependency? Dependency has created trade and technological gaps, among them the one generated by the physical balance (exporting more than is imported). In Ecuador, the Citizens’ Revolution government is attempting to overcome these structural problems by rejecting free-trade agreements and foreign investment that could yield negative balances or threaten national sovereignty. Its new productive model is based on the development of basic industry, the selective replacement of imports, and an intelligent diversification of the exportable supply. The idea is to achieve a society based more on producing services, less dependent on the extraction of natural resources, and with greater generation capacity in science, technology, and innovation. Although the plan faces an adverse international order, it could benefit from the new moment of political and financial integration in Latin America. ¿Puede un país con una economía abierta y una tendencia a la reprimarización lograr una forma de integración en la economía mundial que no esté determinada por la dependencia histórica de Latinoamérica? La dependencia ha creado brechas en el comercio y la tecnología, incluyendo aquella generada por el equilibrio fiscal (exportando más de lo que se importa). En Ecuador, el gobierno de la Revolución Ciudadana intenta superar estos problemas estructurales al rechazar los acuerdos de libre comercio e inversión extranjera que podrían producir saldos negativos o amenazar la soberanía nacional. Su nuevo modelo productivo se basa en el desarrollo de la industria básica, la sustitución selectiva de importaciones, y una inteligente diversificación de la oferta exportable. La idea es lograr una sociedad que se base preponderantemente en la producción de servicios, dependa menos de la extracción de recursos naturales, y tenga mayor capacidad de generación en las áreas de ciencia, tecnología e innovación. Aunque el plan se enfrenta a un orden internacional adverso, podría beneficiarse del nuevo momento de integración política y económica en América Latina.
A Pilot Study of Client Satisfaction: An Occupational Therapy Duty System in an Occupational Therapy Bureau
Authors: Dean Rachel 
Published: April 2015

The duty system is the telephone referral system for the Kent Occupational Therapy Bureau service for members of the public and health professionals. The duty rota is staffed by occupational therapists and rehabilitation coordinators. This evaluation aimed to determine the quality and equity of the service in relation to client satisfaction. Over a 2-week period, telephone interviews were conducted using a questionnaire. All members of the public who telephoned to make a referral and had had no prior contact with the bureau were eligible for the study. The duty system was shown to provide a consistently high level of service in all areas evaluated. However, those interviewed expressed dissatisfaction with the predicted time of wait for an assessment visit and the lack of accurate information regarding this wait. This pilot study demonstrates that an occupational therapist may not be needed to fulfil the role of duty officer. A trained duty officer with an occupational therapist available for consultation can provide the service, thereby freeing occupational therapists to undertake assessments and reduce waiting lists. More accurate information and regular contact from the bureau regarding the waiting time for an assessment is required to reduce dissatisfaction.
Innovation in Fieldwork Education: Working with Members of the Homeless Population in Glasgow
Authors: Totten Catherine , Pratt Joanne 
Published: April 2015

Occupational therapists are increasingly likely to come into contact with clients who have special needs associated with homelessness through acute or community care services. Given the degree of role loss often linked with homelessness, it could also be argued that occupational therapy has a part to play in the development and maintenance of the functional status of the members of this population. Statutory or voluntary sector day shelters might offer a new point of contact for service delivery with homeless people, representing nontraditional sites for occupational therapy services. The models of fieldwork supervision adopted by the College of Occupational Therapists could allow students to experience new forms of service delivery as undergraduates in novel practice settings. This opportunity could serve an adaptive function as health and social care services meet the demands of the changing political and social environment. This paper describes the perceptions of a student who undertook an elective placement in a day centre for homeless men in Glasgow. Conclusion In terms of educational development, this model of placement has since been incorporated into the curriculum at Glasgow Caledonian University. On revalidation of the BSc(Hons)OT degree in 1995, there was a decrease in the number of fieldwork hours in the curriculum structure, from 1200 to 1080 hours, and the elective placement was removed. The programme philosophy, however, embraced the learning opportunities provided by placements, such as the one described in this paper. As such, all second-year students have since been required to undertake a placement in the non-statutory, social care sector. In particular, these placements are seen to offer students a chance to develop a deeper understanding of social care needs and issues, and a chance to explore the occupational therapy process in nontraditional settings and thus to think more widely. In addition, they offer an opportunity for students to take much more responsibility for their learning, within a model of supervision where they get professional input, direction and support while developing their own sense of professional identity and autonomy.
A Review of the Use of Self-Report Assessment with Young Children
Authors: Sturgess Jennifer , Rodger Sylvia , Ozanne Anne 
Published: April 2015

In recent years, there has been an increase in the development of self-report assessments for children, for both clinical and research use. This increase is compatible with the increase in the use of client-centred practice and other frames of reference that give clients – including children – a greater voice in their therapy. Occupation, the focus of therapy, is best understood from the perspective of the child engaged in it (Primeau and Ferguson 1999). There is mounting evidence that the views of children are different from, but as valid as, those of their parents (Sturgess and Ziviani 1996, Bouman et al 1999). The purpose of this paper is to provide a contemporary analysis of self-report assessment for children. An extensive review of the self-report literature found a clear rationale for its use and also evidence about the features of effective self-report tools. The results of this literature review and a critique of some self-report assessments available for young children are included in this paper.