bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optimization of T-cell Reactivity by Exploiting TCR Chain Centricity for the Purpose of Safe and Effective Antitumor TCR Gene Therapy
Authors: Ochi Toshiki , Nakatsugawa Munehide , Chamoto Kenji , Tanaka Shinya , Yamashita Yuki , Guo Tingxi , Fujiwara Hiroshi , Yasukawa Masaki , Butler Marcus O. , Hirano Naoto 
Published: May 2015

AbstractAdoptive transfer of T cells redirected by a high-affinity antitumor T-cell receptor (TCR) is a promising treatment modality for cancer patients. Safety and efficacy depend on the selection of a TCR that induces minimal toxicity and elicits sufficient antitumor reactivity. Many, if not all, TCRs possess cross-reactivity to unrelated MHC molecules in addition to reactivity to target self-MHC/peptide complexes. Some TCRs display chain centricity, in which recognition of MHC/peptide complexes is dominated by one of the TCR hemi-chains. In this study, we comprehensively studied how TCR chain centricity affects reactivity to target self-MHC/peptide complexes and alloreactivity using the TCR, clone TAK1, which is specific for human leukocyte antigen-A*24:02/Wilms tumor 1235–243 (A24/WT1235) and cross-reactive with B*57:01 (B57). The TAK1β, but not the TAK1α, hemi-chain possessed chain centricity. When paired with multiple clonotypic TCRα counter-chains encoding TRAV12-2, 20, 36, or 38-2, the de novo TAK1β-containing TCRs showed enhanced, weakened, or absent reactivity to A24/WT1235 and/or to B57. T cells reconstituted with these TCRα genes along with TAK1β possessed a very broad range (&gt;3 log orders) of functional and structural avidities. These results suggest that TCR chain centricity can be exploited to enhance desired antitumor TCR reactivity and eliminate unwanted TCR cross-reactivity. TCR reactivity to target MHC/peptide complexes and cross-reactivity to unrelated MHC molecules are not inextricably linked and are separable at the TCR sequence level. However, it is still mandatory to carefully monitor for possible harmful toxicities caused by adoptive transfer of T cells redirected by thymically unselected TCRs. Cancer Immunol Res; 3(9); 1070–81. ©2015 AACR.
Survival Outcomes of Sipuleucel-T Phase III Studies: Impact of Control-Arm Cross-Over to Salvage Immunotherapy
Authors: George Daniel J. , Nabhan Chadi , DeVries Todd , Whitmore James B. , Gomella Leonard G. 
Published: May 2015

Abstract
Sipuleucel-T is an autologous cellular immunotherapy for asymptomatic/minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). After disease progression, control-arm patients on three double-blind, randomized phase III sipuleucel-T trials were offered, in nonrandomized open-label protocols, APC8015F, an autologous immunotherapy made from cells cryopreserved at the time of control manufacture. These exploratory analyses evaluated potential effects on survival outcomes associated with such treatment. Of 249 control-treated patients, 165 (66.3%) received APC8015F. We explored the effects of APC8015F on the overall survival (OS; Cox regression) of control-arm patients and treatment effects of sipuleucel-T versus control adjusted for APC8015F treatment [iterative parameter estimation model (IPE)]. The median time to first APC8015F infusion was 5.2 months (range, 1.8–33.1) after randomization and 2.2 months (0.5–14.6) after progression. After disease progression, median survival was longer for APC8015F-treated versus control-only treated patients [20.0 vs. 9.8 months; HR, 0.53; 95% confidence interval (CI), 0.38–0.74; P &lt; 0.001]; however, baseline characteristics were more favorable for APC8015F-treated patients. Multivariate regression analyses identified lactate dehydrogenase, alkaline phosphatase, hemoglobin, ECOG status, age, and number of bone metastases as potential (P &lt; 0.1) independent predictors of postprogression survival. After adjusting for these predictors, APC8015F (HR, 0.78; 95% CI, 0.54–1.11; P = 0.17) treatment trended toward improved survival. Estimated median OS benefit for sipuleucel-T versus control adjusted for APC8015F treatment was 3.9 months if APC8015F had no effect and was 8.1 months if APC8015F was equally as effective as sipuleucel-T. Exploratory analyses indicate that APC8015F treatment may have extended patient survival, suggesting the sipuleucel-T OS advantage in CRPC may be more robust than previously estimated. Cancer Immunol Res; 3(9); 1063–9. ©2015 AACR.
Long-Term Cost-Effectiveness of Providing Full Coverage for Preventive Medications After Myocardial Infarction
Authors: Ito Kouta , Avorn Jerry , Shrank William H. , Toscano Michele , Spettel Claire , Brennan Troyen , Choudhry Niteesh K. 
Published: May 2015

Background—
Adherence to drugs that are prescribed after myocardial infarction remains suboptimal. Although eliminating patient cost sharing for secondary prevention increases adherence and reduces rates of major cardiovascular events, the long-term clinical and economic implications of this approach have not been adequately evaluated.

Methods and Results—
We developed a Markov model simulating a hypothetical cohort of commercially insured patients who were discharged from the hospital after myocardial infarction. Patients received β-blockers, renin–angiotensin system antagonists, and statins without cost sharing (full coverage) or at the current level of insurance coverage (usual coverage). Model inputs were extracted from the Post Myocardial Infarction Free Rx Event and Economic Evaluation trial and other published literature. The main outcome was an incremental cost-effectiveness ratio as measured by cost per quality-adjusted life year gained. Patients receiving usual coverage lived an average of 9.46 quality-adjusted life years after their event and incurred costs of $171 412. Patients receiving full coverage lived an average of 9.60 quality-adjusted life years and incurred costs of $167 401. Compared with usual coverage, full coverage would result in greater quality-adjusted survival (0.14 quality-adjusted life years) and less resource use ($4011) per patient. Our results were sensitive to alterations in the risk reduction for post-myocardial infarction events from full coverage.

Conclusions—
Providing full prescription drug coverage for evidence-based pharmacotherapy to commercially insured post-myocardial infarction patients has the potential to improve health outcomes and save money from the societal perspective over the long-term.

Clinical Trial Registration Information—

https://www.clinicaltrials.gov
. Unique identifier: NCT00566774.
Insulin Resistance and Risk of Cardiovascular Disease in Postmenopausal Women
Authors: Schmiegelow Michelle D. , Hedlin Haley , Stefanick Marcia L. , Mackey Rachel H. , Allison Matthew , Martin Lisa W. , Robinson Jennifer G. , Hlatky Mark A. 
Published: May 2015

Background—
Insulin resistance is associated with diabetes mellitus, but it is uncertain whether it improves cardiovascular disease (CVD) risk prediction beyond traditional cardiovascular risk factors.

Methods and Results—
We identified 15 288 women from the Women’s Health Initiative Biomarkers studies with no history of CVD, atrial fibrillation, or diabetes mellitus at baseline (1993–1998). We assessed the prognostic value of adding fasting serum insulin, HOMA-IR (homeostasis model assessment–insulin resistance), serum-triglyceride-to-serum-high-density lipoprotein-cholesterol ratio TG/HDL-C, or impaired fasting glucose (serum glucose ≥110 mg/dL) to traditional risk factors in separate Cox multivariable analyses and assessed risk discrimination and reclassification. The study end point was major CVD events (nonfatal and fatal coronary heart disease and ischemic stroke) within 10 years, which occurred in 894 (5.8%) women. Insulin resistance was associated with CVD risk after adjusting for age and race/ethnicity with hazard ratios (95% confidence interval [CI]) per doubling in insulin of 1.21 (CI, 1.12–1.31), in HOMA-IR of 1.19 (CI, 1.11–1.28), in TG/HDL-C of 1.35 (CI, 1.26–1.45), and for impaired fasting glucose of 1.31 (CI, 1.05–1.64). Although insulin, HOMA-IR, and TG/HDL-C remained associated with increased CVD risk after adjusting for most CVD risk factors, none remained significant after adjusting for HDL-C: hazard ratios for insulin, 1.06 (CI, 0.98–1.16); for HOMA-IR, 1.06 (CI, 0.98–1.15); for TG/HDL-C, 1.11 (CI, 0.99–1.25); and for glucose, 1.20 (CI, 0.96–1.50). Insulin resistance measures did not improve CVD risk discrimination and reclassification.

Conclusions—
Measures of insulin resistance were no longer associated with CVD risk after adjustment for high-density lipoprotein-cholesterol and did not provide independent prognostic information in postmenopausal women without diabetes mellitus.

Clinical Trial Registration Information—

URL:
http://www.clinicaltrial.gov
. Unique identifier: NCT00000611.
Clinical and Hemodynamic Outcomes up to 7 Years After Transcatheter Pulmonary Valve Replacement in the US Melody Valve Investigational Device Exemption Trial
Authors: Cheatham John P. , Hellenbrand William E. , Zahn Evan M. , Jones Thomas K. , Berman Darren P. , Vincent Julie A. , McElhinney Doff B. 
Published: May 2015

Background—
Studies of transcatheter pulmonary valve (TPV) replacement with the Melody valve have demonstrated good short-term outcomes, but there are no published long-term follow-up data.

Methods and Results—
The US Investigational Device Exemption trial prospectively enrolled 171 pediatric and adult patients (median age, 19 years) with right ventricular outflow tract conduit obstruction or regurgitation. The 148 patients who received and were discharged with a TPV were followed up annually according to a standardized protocol. During a median follow-up of 4.5 years (range, 0.4–7 years), 32 patients underwent right ventricular outflow tract reintervention for obstruction (n=27, with stent fracture in 22), endocarditis (n=3, 2 with stenosis and 1 with pulmonary regurgitation), or right ventricular dysfunction (n=2). Eleven patients had the TPV explanted as an initial or second reintervention. Five-year freedom from reintervention and explantation was 76±4% and 92±3%, respectively. A conduit prestent and lower discharge right ventricular outflow tract gradient were associated with longer freedom from reintervention. In the 113 patients who were alive and reintervention free, the follow-up gradient (median, 4.5 years after implantation) was unchanged from early post-TPV replacement, and all but 1 patient had mild or less pulmonary regurgitation. Almost all patients were in New York Heart Association class I or II. More severely impaired baseline spirometry was associated with a lower likelihood of improvement in exercise function after TPV replacement.

Conclusions—
TPV replacement with the Melody valve provided good hemodynamic and clinical outcomes up to 7 years after implantation. Primary valve failure was rare. The main cause of TPV dysfunction was stenosis related to stent fracture, which was uncommon once prestenting became more widely adopted.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00740870.
Minocycline Reduces Spontaneous Hemorrhage in Mouse Models of Cerebral Amyloid Angiopathy
Authors: Yan Ping , Zhu Alec , Liao Fan , Xiao Qingli , Kraft Andrew W. , Gonzales Ernie , Perez Ron , Greenberg Steven M. , Holtzman David M. , Lee Jin-Moo 
Published: May 2015

Background and Purpose—
Cerebral amyloid angiopathy (CAA) is a common cause of recurrent intracerebral hemorrhage in the elderly. Previous studies have shown that CAA induces inflammation and expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 (gelatinases) in amyloid-laden vessels. Here, we inhibited both using minocycline in CAA mouse models to determine whether spontaneous intracerebral hemorrhage could be reduced.

Methods—
Tg2576 (n=16) and 5xFAD/ApoE4 knockin mice (n=16), aged 17 and 12 months, respectively, were treated with minocycline (50 mg/kg, IP) or saline every other day for 2 months. Brains were extracted and stained with X-34 (to quantify amyloid), Perls’ blue (to quantify hemorrhage), and immunostained to examined β-amyloid peptide load, gliosis (glial fibrillary acidic protein [GFAP], Iba-1), and vascular markers of blood–brain barrier integrity (zonula occludins-1 [ZO-1] and collagen IV). Brain extracts were used to quantify mRNA for a variety of inflammatory genes.

Results—
Minocycline treatment significantly reduced hemorrhage frequency in the brains of Tg2576 and 5xFAD/ApoE4 mice relative to the saline-treated mice, without affecting CAA load. Gliosis (GFAP and Iba-1 immunostaining), gelatinase activity, and expression of a variety of inflammatory genes (matrix metalloproteinase-9, NOX4, CD45, S-100b, and Iba-1) were also significantly reduced. Higher levels of microvascular tight junction and basal lamina proteins were found in the brains of minocycline-treated Tg2576 mice relative to saline-treated controls.

Conclusions—
Minocycline reduced gliosis, inflammatory gene expression, gelatinase activity, and spontaneous hemorrhage in 2 different mouse models of CAA, supporting the importance of matrix metalloproteinase–related and inflammatory pathways in intracerebral hemorrhage pathogenesis. As a Food and Drug Administration–approved drug, minocycline might be considered for clinical trials to test efficacy in preventing CAA-related intracerebral hemorrhage.
Obesity Increases Risk of Ischemic Stroke in Young Adults
Authors: Mitchell Andrew B. , Cole John W. , McArdle Patrick. F. , Cheng Yu-Ching , Ryan Kathleen A. , Sparks Mary J. , Mitchell Braxton D. , Kittner Steven J. 
Published: May 2015

Background and Purpose—
Body mass index has been associated with ischemic stroke in older populations, but its association with stroke in younger populations is not known. In light of the current obesity epidemic in the United States, the potential impact of obesity on stroke risk in young adults deserves attention.

Methods—
A population-based case–control study design with 1201 cases and 1154 controls was used to investigate the relationship of obesity and young onset ischemic stroke. Stroke cases were between the ages of 15 and 49 years. Logistic regression analysis was used to evaluate the association between body mass index and ischemic stroke with and without adjustment for comorbid conditions associated with stroke.

Results—

In analyses adjusted for age, sex, and ethnicity, obesity (body mass index >30 kg/m
2
) was associated with an increased stroke risk (odds ratio, 1.57; 95% confidence interval, 1.28–1.94) although this increased risk was highly attenuated and not statistically significant after adjustment for smoking, hypertension, and diabetes mellitus.

Conclusions—
These results indicate that obesity is a risk factor for young onset ischemic stroke and suggest that this association may be partially mediated through hypertension, diabetes mellitus, or other variables associated with these conditions.
Questions, Answers and Pleas in Portuguese Exams During Seven Decades
Authors: Silva M. C. , Teodoro V. D. 
Published: May 2015

Keeping in mind the central part national exams have been performing in the design and implementation of learning and curricula, the analysis of the evolution of national exams shows the dynamic implications between the exams and the curricula, in the realm of the curricular reforms that happened in Portugal.
As it is never too much to highlight, it is not possible to reflect on the exams focusing exclusively around the students and the technical concern of measuring their performance without keeping in mind the factors in play regarding learning, such as curriculum, Portuguese cultural characteristics, the organization of the School Community, and the educational legislation driven by several national and international historical factors.
The Anatomy of the Key Codices and the Ontogeny of Prosvetitel’
Authors: Goldfrank David 
Published: May 2015

The textual development of Iosif Volotskii’s influential Book against the Novgorod Heretics or Prosvetitel’ remains in dispute. Aleksei Alekseev (2010/2012) has recently challenged Iakov Lur’e’s scheme (1955/1960): from Iosif’s discourses and epistles, to Brief with 11 discourses, to more discourses and epistles, to Extended with 16 discourses. Alekseev proposes instead: Extended with 13 discourses, to both Prosv-11 (this essay’s shorthand) and Prosv-16, and from these to all of Iosif’s relevant, cognate discourses and epistles. Differences in applying literary, textual, editorial, and historical criticism may be unresolvable. But evidence from the structural hints within the texts and the actual physical anatomy – the quires and individually glued pieces of paper, whose analysis Andrei Pliguzov pursued to special advantage (1986/1992–1993) – indicate a progression from a Brief Prosv-11, or maybe Prosv-10 at first, to an imaginable Prosv-12 or -13, to Prosv-16, as well as other earlier and intermediary possibilities.
Nonlinear Wind Analysis of Single-Doppler Radar Observations within a DVAD Framework
Authors: Tang Xiaowen , Lee Wen-Chau , Wang Yuan 
Published: May 2015

AbstractThe application of the distance velocity azimuth display (DVAD) method to the retrieval of vertical wind profiles from single-Doppler radar observations is presented in this study. It was shown that Doppler velocity observations at a constant altitude can be expressed as a single polynomial function for both linear and nonlinear wind fields in DVAD. Only a one-step least squares fitting of a polynomial function is required to obtain the vertical wind profile of a real wind field. The mathematic formulation of DVAD results in two advantages over the traditional nonlinear VAD method used for the nonlinear analysis of single-Doppler observations. First, the requirement of only one-step least squares fitting leads to robust performance when Doppler velocity observations are contaminated by unevenly distributed data noise and voids. Second, the degree of nonlinearity to properly represent a real wind field can be directly estimated in DVAD instead of being empirically determined in the traditional method. A proper nonlinear wind model for approximating the real wind field can be objectively derived using the DVAD method. The merits of DVAD as a quantitative single-Doppler analysis method were compared with the traditional method using both idealized and real datasets. Results show that the simplicity and robust performance of DVAD make it a good candidate for single-Doppler retrieval in operational use.
Aspects of Potential Vorticity Fluxes: Climatology and Impermeability
Authors: Egger Joseph , Hoinka Klaus-Peter , Spengler Thomas 
Published: May 2015

Abstract
Some aspects of the dynamics of generalized potential vorticity (PV) density P = ω ⋅ ∇χ are discussed with the main emphasis on P fluxes, where ωa is absolute vorticity and χ is a scalar. The impermeability theorem claims that there is no net P flux across a χ surface. Various forms of the flux are presented that mostly cross χ surfaces. As these fluxes are as dynamically relevant as the one chosen for the theorem, P fluxes through a surface element are inherently multivalued and there is no best choice on physical grounds. Nevertheless, the net P flux is unique for closed surfaces. This point is illustrated by P integrals over the volume between the earth’s surface and an isentropic surface. Reanalysis data are used to present mean advective and some nonadvective P fluxes for χ = θ in height coordinates. The extratropical tropopause appears to be supported by advective P fluxes. A satisfactorily closed P budget cannot, however, be presented.
Synoptic-Scale Influences on Tropical Cyclone Formation within the Western North Pacific Monsoon Trough
Authors: Zong Huijun , Wu Liguang 
Published: May 2015

Abstract
Tropical cyclones (TCs) always develop from synoptic-scale disturbances. While early studies suggested that the presence of synoptic-scale disturbances may enhance large-scale conditions for TC formation, recent studies argued that TC-precursor disturbances can establish a rotation-dominant area, which can play a crucial role in organizing convective activity and converting convective heating to rotational energy for storm-scale intensification. To demonstrate the synoptic-scale influence of TC-precursor disturbances, 91 TC formation events within the monsoon trough over the western North Pacific during 2000–10 were examined by separating TC-precursor disturbances from the low-frequency background. The composite analysis shows that the synoptic disturbances indeed enhance the mid- and low-level relative vorticity and convergence, but contribute little to reducing vertical wind shear.
The dynamic composite that is conducted with respect to disturbance centers indicates that TC-precursor disturbances within the monsoon trough establish a rotation-dominant region with a radius of less than 550 km. The cyclonic rotation increases with time 72 h prior to TC formation and nearly all air particles keep recirculating in the core area with a radius of about 220 km. Analysis of a specific case suggests that vorticity increase occurs through the merger of mesoscale convective systems in the rotation-dominant area. The enhancing rotation in the core area may efficiently convert diabatic heating to kinetic energy for TC formation. Thus, it is suggested that the important role of TC-precursor disturbances in TC formation is the establishment of a limited, rotation-dominant area.
The Effect of Arytenoidectomy on Functional and Oncologic Results of Supracricoid Partial Laryngectomy
Authors: Basaran Bora , Unsaler Selin , Ulusan Murat , Aslan Ismet 
Published: May 2015

Objective: The effect of arytenoid resection was investigated in patients who had undergone supracricoid partial laryngectomy (SCPL) by comparing functional and oncologic results between patients with both arytenoids preserved with those with one arytenoid resected. Methods: Patients were divided into 2 groups: (1) both arytenoids preserved SCPL (BASCL) cases and (2) one arytenoid preserved SCPL (OASCL). The functional outcomes of the 2 groups were compared in terms of nasogastric tube removal time, decannulation time, incidence of aspiration pneumonia, and Performance Status Scale Scores for Head and Neck Cancer Patients for the late postoperative period. Additionally, the oncologic outcomes of both groups were compared using the 5-year local control rate, overall survival, disease-specific survival, and larynx preservation rate. Results: Of the 68 patients who were enrolled in the study, 20 of them were in the OASCL group and 48 in BASCL group. There was no statistically significant difference in the early and late functional outcomes, and the oncologic outcomes were also similar. Conclusion: In addition to the proven oncologic safety, arytenoid resection does not increase the functional morbidity of the SCPL.