bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation
Authors: Leisegang Matthias , Engels Boris , Schreiber Karin , Yew Poh Yin , Kiyotani Kazuma , Idel Christian , Arina Ainhoa , Duraiswamy Jaikumar , Weichselbaum Ralph R. , Uckert Wolfgang , Nakamura Yusuke , Schreiber Hans 
Published: December 2015

Abstract
Purpose: Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic nonsynonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T-cell receptor (TCR) that is specific for a single AAS.
Experimental Design: By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy.
Results: When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intratumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T-cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar.
Conclusions: Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer, but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape. Clin Cancer Res; 22(11); 2734–43. ©2015 AACR.
See related commentary by Liu, p. 2602
Piperlongumine Suppresses Growth and Sensitizes Pancreatic Tumors to Gemcitabine in a Xenograft Mouse Model by Modulating the NF-kappa B Pathway
Authors: Wang Yongwei , Wu Xiangsong , Zhou Yinan , Jiang Hongchi , Pan Shangha , Sun Bei 
Published: December 2015

AbstractPancreatic cancer is an aggressive malignancy, which generally respond poorly to chemotherapy. Hence, novel agents that are safe and effective are highly needed. The aim of this study was to investigate whether piperlongumine, a natural product isolated from the fruit of the pepper Piper longum, has any efficacy against human pancreatic cancer when used either alone or in combination with gemcitabine in vitro and in a xenograft mouse model. In vitro, piperlongumine inhibited the proliferation of pancreatic cancer cell lines, potentiated the apoptotic effects of gemcitabine, inhibited the constitutive and inducible activation of NF-κB, and suppressed the NF-κB–regulated expression of c-Myc, cyclin D1, Bcl-2, Bcl-xL, Survivin, XIAP, VEGF, and matrix metalloproteinase-9 (MMP-9). Furthermore, in an in vivo xenograft model, we found piperlongumine alone significantly suppressed tumor growth and enhanced the antitumor properties of gemcitabine. These results were consistent with the downregulation of NF-κB activity and its target genes, decreased proliferation (PCNA and Ki-67), decreased microvessel density (CD31), and increased apoptosis (TUNEL) in tumor remnants. Collectively, our results suggest that piperlongumine alone exhibits significant antitumor effects against human pancreatic cancer and it further enhances the therapeutic effects of gemcitabine, possibly through the modulation of NF-κB– and NF-κB–regulated gene products. Cancer Prev Res; 9(3); 234–44. ©2015 AACR.
Double-Blind, Randomized Trial of Alternative Letrozole Dosing Regimens in Postmenopausal Women with Increased Breast Cancer Risk
Authors: López Ana Maria , Pruthi Sandhya , Boughey Judy C. , Perloff Marjorie , Hsu Chiu-Hsieh , Lang Julie E. , Ley Michele , Frank Denise , Taverna Josephine A. , Chow H-H. Sherry 
Published: December 2015

Abstract
Aromatase inhibitors (AI) profoundly suppress estrogen levels in postmenopausal women and are effective in breast cancer prevention among high-risk postmenopausal women. Unfortunately, AI treatment is associated with undesirable side effects that limit patient acceptance for primary prevention of breast cancer. A double-blind, randomized trial was conducted to determine whether low and intermittent doses of letrozole can achieve effective estrogen suppression with a more favorable side-effect profile. Overall, 112 postmenopausal women at increased risk for breast cancer were randomized to receive letrozole at 2.5 mg once daily (QD, standard dose arm), 2.5 mg every Monday, Wednesday, and Friday (Q-MWF), 1.0 mg Q-MWF, or 0.25 mg Q-MWF for 24 weeks. Primary endpoint was suppression in serum estradiol levels at the end of letrozole intervention. Secondary endpoints included changes in serum estrone, testosterone, C-telopeptide (marker of bone resorption), lipid profile, and quality-of-life measures (QoL) following treatment. Significant estrogen suppression was observed in all dose arms with an average of 75% to 78% and 86% to 93% reduction in serum estradiol and estrone levels, respectively. There were no differences among dose arms with respect to changes in C-telopeptide levels, lipid profile, adverse events (AE), or QoL measures. We conclude that low and intermittent doses of letrozole are not inferior to standard dose in estrogen suppression and resulted in a similar side-effect profile compared with standard dose. Further studies are needed to determine the feasibility of selecting an effective AI dosing schedule with better tolerability. Cancer Prev Res; 9(2); 142–8. ©2015 AACR.
No Benefit of Complex Fractionated Atrial Electrogram Ablation in Addition to Circumferential Pulmonary Vein Ablation and Linear Ablation
Authors: Wong Kelvin C.K. , Paisey John R. , Sopher Mark , Balasubramaniam Richard , Jones Michael , Qureshi Norman , Hayes Chris R. , Ginks Matthew R. , Rajappan Kim , Bashir Yaver , Betts Timothy R. 
Published: December 2015

Background—
The optimal ablation strategy for persistent atrial fibrillation (AF) remains unclear.

Methods and Results—

This multicentre randomized study compared circumferential pulmonary vein ablation+linear ablation (control arm) versus circumferential pulmonary vein ablation+linear ablation+complex fractionated atrial electrogram (CFAE) ablation (CFAE arm) in patients with persistent AF. Circumferential pulmonary vein ablation was performed followed by roof and mitral isthmus ablation, before CFAE ablation in the CFAE arm. Ablation strategy was maintained at the first redo procedure. Sixty-five patients were recruited in each arm. The mean age was 61±10 years, 75% were men, median AF duration was 2 years, 42% had long-lasting persistent AF, 68% had associated cardiovascular disease, mean left atrial dimension was 46±6 mm, and median CHA
2
DS
2
-VASc score was 2. Ablation and procedure times were significantly longer in the CFAE arm (70±20 versus 55±17; 201±35 versus 152±45 minutes;
P
<0.005). After a mean follow-up of 35±5 months, single-procedural success off antiarrhythmic drugs at 12 months (CFAE: 30/65 [46%] versus control: 37/65 [57%];
P
=0.29) and multiprocedural success (CFAE: 51/65 [78%] versus control: 52/65 [80%];
P
=1.0) were not significantly different. At the first redo procedure, patients in the CFAE arm had a higher incidence of organized atrial tachycardia/flutter (24/33 [73%] versus 11/31 [35%];
P
=0.005) and gap-related macro–re-entrant flutter (8/33[24%] versus 1/31[3%];
P
=0.03). Early recurrence of atrial arrhythmia was an independent predictor of late recurrence.

Conclusions—
CFAE ablation did not confer incremental benefit when performed in addition to circumferential pulmonary vein ablation and linear ablation. It was associated with a higher incidence of gap-related flutter.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01711047.
On the Consumption of Antarctic Bottom Water in the Abyssal Ocean
Authors: de Lavergne Casimir , Madec Gurvan , Le Sommer Julien , Nurser A. J. George , Naveira Garabato Alberto C. 
Published: December 2015

AbstractThe abyssal ocean is primarily filled by cold, dense waters formed around Antarctica and collectively referred to as Antarctic Bottom Water (AABW). At steady state, AABW must be consumed in the ocean interior at the same rate it is produced, but how and where this consumption is achieved remains poorly understood. Here, estimates of abyssal water mass transformation by geothermal heating and parameterized internal wave–driven mixing are presented. This study uses maps of the energy input to internal waves by tidal and geostrophic motions interacting with topography combined with assumptions about the distribution of energy dissipation to evaluate dianeutral transports induced by breaking internal tides and lee waves. Geothermal transformation is assessed based on a map of geothermal heat fluxes. Under the hypotheses underlying the constructed climatologies of buoyancy fluxes, the authors calculate that locally dissipating internal tides and geothermal heating contribute, respectively, about 8 and 5 Sverdrups (Sv; 1 Sv ≡ 106 m3 s−1) of AABW consumption (upwelling), mostly north of 30°S. In contrast, parameterized lee wave–driven mixing causes significant transformation only in the Southern Ocean, where it forms about 3 Sv of AABW, decreasing the mean density but enhancing the northward flow of abyssal waters. The possible role of remotely dissipating internal tides in complementing AABW consumption is explored based on idealized distributions of mixing energy. Depending mostly on the chosen vertical structure, such mixing could drive 1 to 28 Sv of additional AABW upwelling, highlighting the need to better constrain the spatial distribution of remote dissipation. Though they carry large uncertainties, these climatological transformation estimates shed light on the qualitative functioning and key unknowns of the diabatic overturning.
An Impact Study of GPS Radio Occultation Observations on Frontal Rainfall Prediction with a Local Bending Angle Operator
Authors: Huang Ching-Yuang , Chen Shu-Ya , Rao Anisetty S. K. A. V. Prasad , Yang Shu-Chih , Hsiao Ling-Feng 
Published: December 2015

Abstract
The impact of global positioning system (GPS) radio occultation (RO) soundings on the prediction of severe mei-yu frontal rainfall near Taiwan in June 2012 was investigated in this study using a developed local bending angle (LBA) operator. Two operators for local refractivity (REF) and nonlocal refractivity [excess phase (EPH)] were also used for comparisons. The devised LBA simplifies the calculation of the Abel transform in inverting model local refractivity without a loss of accuracy. These operators have been implemented into the three-dimensional variational data assimilation system of the Weather Research and Forecasting (WRF) Model to assimilate GPS RO soundings available from the Formosa Satellite Mission 3/Constellation Observing Systems for Meteorology, Ionosphere and Climate (FORMOSAT-3/COSMIC). The RO data are found to be beneficial to the WRF forecast of local severe rainfall in Taiwan. Characteristics of assimilation performance and innovation for the three operators are discussed. Both of the local operators performing assimilation at observation levels appear to produce mostly larger positive moisture increments than do the current nonlocal operators performing assimilation on the mean height of each model vertical level. As the information of the initial increments has propagated farther south with the frontal flow, the simulation for LBA shows better prediction of rainfall peaks in Taiwan on the second day than both REF and EPH, with a maximum improvement of about 25%. The positive impact of the RO data results partially from several RO observations near Mongolia and north China. This study provides an intercomparison among the three RO operators, and shows the feasibility of regional assimilation with LBA.
Local challenges and national concerns: municipal level responses to national refugee settlement policies in Denmark and Sweden
Authors: Myrberg Gunnar 
Published: December 2015

This article investigates how Danish and Swedish national policies vis-à-vis refugees and asylum seekers are perceived, and responded to, at the municipal level in the cities of Aarhus and Malmö. As will be spelled out in the article, municipal representatives raised their voices in both Denmark and Sweden during the middle of the 1990s, arguing that their municipalities had to carry a larger ‘burden of reception’ than they could manage, and they thus urged for changes in the national dispersal and migration policies. The response at the national level was dramatically different in Denmark than in Sweden, however. This is today apparent not only in the sheer numbers of newcomers but also in municipal introduction practices as well as in the institutional memories of municipal officials. Points for practitioners The findings presented in this study point both to the possibility for municipalities to have a direct impact on national policies, in this case mainly on refugee settlement policies, but also to how policy decisions at one point in time shapes the political opportunity structures at national as well as local levels at later points in time.
Influencing public sector performance: studying the impact of ability-, motivation- and opportunity-enhancing human resources practices on various performance outcomes in the public sector
Authors: Vermeeren Brenda 
Published: December 2015

Background In response to recent calls in the literature to decompose both the human resources system and performance, this study has examined the effects of ability-, motivation- and opportunity-enhancing human resources practices on the effectiveness, efficiency and fairness of public organizations, with job satisfaction considered as a mediating variable. Aim Insights from Human Resource Management and performance research, mostly conducted in the private sector, have been combined with public management literature in order to gain insight into the Human Resource Management–performance relationship in the public sector. Method Regression analysis with a bootstrapping method was used to test the mediating effects. Results The analysis showed that the three human resources components heterogeneously impact upon the three performance outcomes. Further, the results showed that ability-enhancing and opportunity-enhancing human resources practices are more strongly related to performance outcomes than motivation-enhancing human resources practices. Conclusion Decomposing Human Resource Management and performance provides greater insight into the Human Resource Management–performance relationship. Points for practitioners The results show that investing in Human Resource Management positively influences performance outcomes. Moreover, our results show that various aspects of public performance require different human resources approaches. Investing in ability-enhancing human resources practices seems to be particularly relevant if one wants to enhance effectiveness. All the human resources practices, but especially ability-enhancing ones, are relevant to enhancing efficiency. However, investing in motivation-enhancing human resources practices seems to make little sense if one is seeking to enhance fairness.
Anterior Cruciate Ligament Injuries in Professional Hockey Players
Authors: Sikka Robby , Kurtenbach Chad , Steubs J. Tyler , Boyd Joel L. , Nelson Bradley J. 
Published: December 2015

Background: Performance outcomes and return-to-play data have been reported after anterior cruciate ligament (ACL) injuries in professional football and basketball, but they have rarely been reported in professional hockey. Hypothesis: The hypothesis was that performance after ACL reconstruction would be comparable to prior levels of play in a series of National Hockey League (NHL) players. Study Design: Case series; Level of evidence, 4. Methods: The NHL Injury Surveillance System (ISS) was utilized to identify all players with an ACL injury between 2006 and 2010. Medical staff members for all NHL teams were surveyed regarding these injuries. The medical staff completed a questionnaire for each injury, and statistics were analyzed using multiple analyses of variance to compare outcomes, performance, and the complication rate. A control group was identified and matched based on performance, career length before injury, age, height, and weight. Results: There were 47 players identified by the NHL ISS. There were 3 goalies, 8 defensemen, and 36 wings or centers. The average age of these players was 27.69 years. The average length of time played after the injury was 2.8 years, which was less than that of the control group (4.4 years) ( P = .004). The presence of a meniscal injury was associated with a decreased length of career compared with the control group ( P = .012) and with patients with an isolated ACL injury ( P = .002). For wings and centers, the number of games played decreased from 71.2 to 58.2 in the first full season after the injury ( P = .05) and to 59.29 in the second season ( P = .03). In the first season after the injury, for forwards and wings, assists and total points decreased from 20.3 and 35.2 to 13.8 ( P = .005) and 25.9 ( P = .018), respectively. In the second season after the injury, assists and goals decreased to 10.0 ( P = .002) and 10.0 ( P = .013), respectively. Compared with controls, the per-season averages of goals ( P = .001), assists ( P = .010), and total points ( P = .004) decreased. Four players (8.5%) had subsequent failure of reconstruction, and there was a total reoperation rate of 20%. Five players (10.6%) did not return to play, and 4 (8.5%) were unable to return to play for a full season. Conclusion: Most players are able to return to play in the NHL after an ACL injury. However, career length and performance may be significantly decreased compared with controls. This may represent a more severe initial injury, and more focused return-to-play pathways may identify barriers to return to play.
Labeling quality and molecular characterization studies of products containing Lactobacillus spp. strains.
Authors: Blandino Giovanna , Fazio Davide , Petronio Giulio Petronio , Inturri Rosanna , Tempera Gianna , Furneri Pio Maria 
Published: December 2015

The objective of the study was to characterize at species level by phenotypic and different molecular methods the strains of Lactobacillus spp. used as constituents of five oral and four vaginal products. Susceptibilities to representative antibiotics were evaluated. In addition, total viable counts at mid and 3 months to deadline of shelf life, in the different formulations and the presence of eventual contaminant microorganisms were investigated. In all oral products the molecular characterization at species level of the strains of Lactobacillus spp. confirmed the strains stated on the label, except for one strain cited on the label as Lactobacillus casei, that our study characterized as Lactobacillus paracasei. In oral products total viable cell content complied with content claimed on the label. In three out four vaginal products (one product claimed “bacillo di Döderlein”), molecular characterization complied with the bacterial name stated on the label. Two vaginal products reported viable counts on the label that were confirmed by our study. The other vaginal products, which did not report bacterial counts on the label, showed a similar decrease of viable counts at different dates to deadline compared to the others. From all the tested products, contaminant microorganisms and acquired resistance to representative antibiotics by the probiotic strains were not detected.
Placebo-controlled study in neuromyelitis optica—Ethical and design considerations
Authors: Cree Bruce AC , Bennett Jeffrey L , Sheehan Mark , Cohen Jeffrey , Hartung Hans-Peter , Aktas Orhan , Kim Ho Jin , Paul Friedemann , Pittock Sean , Weinshenker Brian , Wingerchuk Dean , Fujihara Kazuo , Cutter Gary , Patra Kaushik , Flor Armando , Barron Gerard , Madani Soraya , Ratchford John N , Katz Eliezer 
Published: December 2015

Background: To date, no treatment for neuromyelitis optica (NMO) has been granted regulatory approval, and no controlled clinical studies have been reported. Objective: To design a placebo-controlled study in NMO that appropriately balances patient safety and clinical–scientific integrity. Methods: We assessed the “standard of care” for NMO to establish the ethical framework for a placebo-controlled trial. We implemented measures that balance the need for scientific robustness while mitigating the risks associated with a placebo-controlled study. The medical or scientific community, patient organizations, and regulatory authorities were engaged early in discussions on this placebo-controlled study, and their input contributed to the final study design. Results: The N-MOmentum study (NCT02200770) is a clinical trial that randomizes NMO patients to receive MEDI-551, a monoclonal antibody that depletes CD19+ B-cells, or placebo. The study design has received regulatory, ethical, clinical, and patient approval in over 100 clinical sites in more than 20 countries worldwide. Conclusion: The approach we took in the design of the N-MOmentum trial might serve as a roadmap for other rare severe diseases when there is no proven therapy and no established clinical development path.
Qualities of Inpatient Hospital Rooms
Authors: Devlin Ann Sloan , Andrade Cláudia Campos , Carvalho Diana 
Published: December 2015

Objectives: The aim of this qualitative study was to investigate what design features of hospital rooms are valued by inpatients. Background: Little research has explored how patients evaluate the physical environment of their hospital rooms. Most responses are captured by the Hospital Consumer Assessment of Healthcare Providers and Systems survey, which includes only two questions about the physical environment. Method: Two hundred thirty-six orthopedic patients (78 in the United States and 158 in Portugal) listed three features of their hospital room that influenced their level of satisfaction with their hospital stay, indicating whether the feature was positive or negative. Results: The comments were more positive (71.4%) than negative (28.6%). Using the framework of supportive design from Ulrich, over half the comments (64.31%) could be categorized in one of the three dimensions: 33.2% (positive distraction), 22.4% (perceived control), and 6.0% (social support). This total includes Internet (2.7%), which could be categorized as either social support or positive distraction. Comments called “other aspects” focused on overall environmental appraisals, cleanliness, and functionality and maintenance. Conclusions: The majority of comments could be accommodated by Ulrich’s theory, but it is noteworthy that other aspects emerge from patients’ comments and affect their experience. Cross-cultural differences pointed to the greater role of light and sun for Portuguese patients and health status whiteboard for U.S. patients. Qualitative research can add significantly to our understanding of the healthcare experience and may inform design decisions.