bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma
Authors: Liu Xian-De , Hoang Anh , Zhou Lijun , Kalra Sarathi , Yetil Alper , Sun Mianen , Ding Zhiyong , Zhang Xuesong , Bai Shanshan , German Peter , Tamboli Pheroze , Rao Priya , Karam Jose A. , Wood Christopher , Matin Surena , Zurita Amado , Bex Axel , Griffioen Arjan W. , Gao Jianjun , Sharma Padmanee , Tannir Nizar , Sircar Kanishka , Jonasch Eric 
Published: May 2015

Abstract
Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy. We assessed the interaction between antiangiogenic therapy and the tumor immune microenvironment and determined their impact on clinical outcome. We found that antiangiogenic therapy–treated RCC primary tumors showed increased infiltration of CD4+ and CD8+ T lymphocytes, which was inversely related to patient overall survival and progression-free survival. Furthermore, specimens from patients treated with antiangiogenic therapy showed higher infiltration of CD4+FOXP3+ regulatory T cells and enhanced expression of checkpoint ligand programed death-ligand 1 (PD-L1). Both immunosuppressive features were correlated with T-lymphocyte infiltration and were negatively related to patient survival. Treatment of RCC cell lines and RCC xenografts in immunodeficient mice with sunitinib also increased tumor PD-L1 expression. Results from this study indicate that antiangiogenic treatment may both positively and negatively regulate the tumor immune microenvironment. These findings generate hypotheses on resistance mechanisms to antiangiogenic therapy and will guide the development of combination therapy with PD-1/PD-L1–blocking agents. Cancer Immunol Res; 3(9); 1017–29. ©2015 AACR.
Differential Expression of PD-L1 between Primary and Metastatic Sites in Clear-Cell Renal Cell Carcinoma
Authors: Callea Marcella , Albiges Laurence , Gupta Mamta , Cheng Su-Chun , Genega Elizabeth M. , Fay André P. , Song Jiaxi , Carvo Ingrid , Bhatt Rupal S. , Atkins Michael B. , Hodi F. Stephen , Choueiri Toni K. , McDermott David F. , Freeman Gordon J. , Signoretti Sabina 
Published: May 2015

Abstract
PD-L1 expression in primary clear-cell renal cell carcinoma (ccRCC) increases the likelihood of response to anti–PD-1 inhibition, but fails to identify all responders. We hypothesized that PD-L1 levels assessed in randomly selected areas of the primary tumors may not accurately reflect expression levels in metastatic lesions, which are the target of systemic therapy. Therefore, we compared PD-L1 expression in a series of primary ccRCC and their metastases. Tissue blocks from 53 primary ccRCCs and 76 corresponding metastases were retrieved. Areas with predominant and highest nuclear grade were selected. Slides were immunostained with a validated anti–PD-L1 antibody (405.9A11). Membranous expression in tumor cells was quantified using H-score. Expression in tumor-infiltrating mononuclear cells (TIMC) was quantified using a combined score. Discordant tumor cell PD-L1 staining between primary tumors and metastases was observed in 11 of 53 cases (20.8%). Overall, tumor cell PD-L1 levels were not different in primary tumors and metastases (P = 0.51). Tumor cell PD-L1 positivity was associated with higher T stage (P = 0.03) and higher Fuhrman nuclear grade (P &lt; 0.01). Within individual lesions, PD-L1 positivity was heterogeneous and almost exclusively detected in high nuclear grade areas (P &lt; 0.001). No difference was found in PD-L1 levels in TIMCs between primary tumors and metastases (P = 0.82). The heterogeneity of PD-L1 expression in ccRCC suggests that its assessment as a predictive biomarker for PD-1 blockade may require analysis of metastatic lesions. Notably, because PD-L1 expression was mostly detected in high nuclear grade areas, to avoid false-negative results, these areas should be specifically selected for assessment. Cancer Immunol Res; 3(10); 1158–64. ©2015 AACR.
Performance of T1 and T2 Mapping Cardiovascular Magnetic Resonance to Detect Active Myocarditis in Patients With Recent-Onset Heart Failure
Authors: Bohnen Sebastian , Radunski Ulf K. , Lund Gunnar K. , Kandolf Reinhard , Stehning Christian , Schnackenburg Bernhard , Adam Gerhard , Blankenberg Stefan , Muellerleile Kai 
Published: May 2015

Background—
This study evaluated the performance of novel quantitative T1 and T2 mapping cardiovascular magnetic resonance (CMR) techniques to identify active myocarditis in patients with recent-onset heart failure.

Methods and Results—

Thirty-one consecutive patients with recent-onset heart failure, reduced left ventricular function and clinically suspected myocarditis underwent endomyocardial biopsy and CMR at 1.5 Tesla. The CMR protocol included standard Lake-Louise parameters as well as T1 mapping using a modified Look-Locker inversion recovery sequence and T2 mapping using a hybrid gradient and spin-echo sequence. Short-axis maps were generated using an OsiriX plug-in to calculate global myocardial T1, T2, and extracellular volume fraction. Active myocarditis was defined by ongoing inflammation on endomyocardial biopsy. Endomyocardial biopsy revealed active myocarditis in 16 (52%) of 31 patients. Neither clinical characteristics, standard Lake-Louise CMR parameters, global myocardial T1 nor extracellular volume fraction differed significantly between patients with and without active myocarditis. However, median global myocardial T2 was significantly higher in patients with active myocarditis (65 ms [Q1–Q3, 61–70 ms]) than in patients without active myocarditis (59 ms [Q1–Q3, 55–64 ms];
P
<0.01). A cutoff value for global myocardial T2 of ≥60 ms provided a sensitivity, specificity, accuracy, negative and positive predictive value of 94% (70%–100%), 60% (32%–84%), 77% (60%–89%), 90% (56%–100%), and 71% (48%–89%) for active myocarditis, respectively.

Conclusions—
T2 mapping seems to be superior when compared with standard CMR parameters, global myocardial T1, and extracellular volume fraction values for assessing the activity of myocarditis in patients with recent-onset heart failure and reduced left ventricular function.
Use of Whole Exome Sequencing for the Identification of
I
to
‐Based Arrhythmia Mechanism and Therapy
Authors: Sturm Amy C. , Kline Crystal F. , Glynn Patric , Johnson Benjamin L. , Curran Jerry , Kilic Ahmet , Higgins Robert S. D. , Binkley Philip F. , Janssen Paul M. L. , Weiss Raul , Raman Subha V. , Fowler Steven J. , Priori Silvia G. , Hund Thomas J. , Carnes Cynthia A. , Mohler Peter J. 
Published: May 2015

Background
Identified genetic variants are insufficient to explain all cases of inherited arrhythmia. We tested whether the integration of whole exome sequencing with well‐established clinical, translational, and basic science platforms could provide rapid and novel insight into human arrhythmia pathophysiology and disease treatment.

Methods and Results

We report a proband with recurrent ventricular fibrillation, resistant to standard therapeutic interventions. Using whole‐exome sequencing, we identified a variant in a previously unidentified exon of the dipeptidyl aminopeptidase‐like protein‐6 (

DPP
6

) gene. This variant is the first identified coding mutation in

DPP
6

and augments cardiac repolarizing current (
I
to
) causing pathological changes in
I
to
and action potential morphology. We designed a therapeutic regimen incorporating dalfampridine to target
I
to
. Dalfampridine, approved for multiple sclerosis, normalized the
ECG
and reduced arrhythmia burden in the proband by >90‐fold. This was combined with cilostazol to accelerate the heart rate to minimize the reverse‐rate dependence of augmented
I
to
.

Conclusions

We describe a novel arrhythmia mechanism and therapeutic approach to ameliorate the disease. Specifically, we identify the first coding variant of

DPP
6

in human ventricular fibrillation. These findings illustrate the power of genetic approaches for the elucidation and treatment of disease when carefully integrated with clinical and basic/translational research teams.
Cost-Effectiveness of Intra-Arterial Treatment as an Adjunct to Intravenous Tissue-Type Plasminogen Activator for Acute Ischemic Stroke
Authors: Leppert Michelle H. , Campbell Jonathan D. , Simpson Jennifer R. , Burke James F. 
Published: May 2015

Background and Purpose—
The objective of this study was to determine the cost-effectiveness of intra-arterial treatment within the 0- to 6-hour window after intravenous tissue-type plasminogen activator within 0- to 4.5-hour compared with intravenous tissue-type plasminogen activator alone, in the US setting and from a social perspective.

Methods—
A decision analytic model estimated the lifetime costs and outcomes associated with the additional benefit of intra-arterial therapy compared with standard treatment with intravenous tissue-type plasminogen activator alone. Model inputs were obtained from published literature, the Multicenter Randomized Clinical Trial of Endovascular Therapy for Acute Ischemic Stroke in the Netherlands (MR CLEAN) study, and claims databases in the United States. Health outcomes were measured in quality-adjusted life years (QALYs). Treatment benefit was assessed by calculating the cost per QALY gained. One-way and probabilistic sensitivity analyses were performed to estimate the overall uncertainty of model results.

Results—
The addition of intra-arterial therapy compared with standard treatment alone yielded a lifetime gain of 0.7 QALY for an additional cost of $9911, which resulted in a cost of $14 137 per QALY. Multivariable sensitivity analysis predicted cost-effectiveness (≤$50 000 per QALY) in 97.6% of simulation runs.

Conclusions—
Intra-arterial treatment after intravenous tissue-type plasminogen activator for patients with anterior circulation strokes within the 6-hour window is likely cost-effective. From a societal perspective, increased investment in access to intra-arterial treatment for acute stroke may be justified.
Comparison of Gravity Waves in the Southern Hemisphere Derived from Balloon Observations and the ECMWF Analyses
Authors: Jewtoukoff Valérian , Hertzog Albert , Plougonven Riwal , Cámara Alvaro de la , Lott François 
Published: May 2015

Abstract
The increase of spatial resolution allows the ECMWF operational model to explicitly resolve a significant portion of the atmospheric gravity wave (GW) field, but the realism of the simulated GW field in the ECMWF analyses still needs to be precisely evaluated. Here the authors use data collected during the Concordiasi stratospheric balloon campaign to assess the representation of GWs in the ECMWF analyses over Antarctica and the Southern Ocean in spring 2010. The authors first compare the balloonborne GW momentum fluxes with those in ECMWF analyses throughout the campaign and find a correct agreement of the geographical and seasonal patterns. However, the authors also note that ECMWF analyses generally underestimate the balloon fluxes by a factor of 5, which may be essentially due to the spatial truncation of the ECMWF model. Intermittency of wave activity in the analyses and observations are found comparable. These results are confirmed on two case studies dealing with orographic and nonorographic waves, which thus supports that the ECMWF analyses can be used to study the geographical and seasonal distribution of GW momentum fluxes. The authors then used both datasets to provide insights on the missing GW drag at 60°S in general circulation models in the Southern Hemisphere spring. These datasets suggest that a significant part of the missing drag may be associated with nonorographic GWs generated by weather systems above the Southern Ocean.
Impact of Tropical Pacific Precipitation Anomaly on the East Asian Upper-Tropospheric Westerly Jet during the Boreal Winter
Authors: Guo Yuanyuan , Wen Zhiping , Wu Renguang , Lu Riyu , Chen Zesheng 
Published: May 2015

Abstract
The leading mode of boreal winter precipitation variability over the tropical Pacific for the period 1980–2010 shows a west–east dipole pattern with one center over the western North Pacific (WNP) and Maritime Continent and the other center over the equatorial central Pacific (CP). Observational evidence shows that the variability of the East Asian upper-tropospheric subtropical westerly jet (EAJ) has a significant correlation with precipitation anomalies over the WNP and CP and that tropical precipitation anomalies over WNP and CP have a distinct influence on the variation of the EAJ. A series of numerical experiments based on a linear baroclinic model are performed to confirm the influence of the heating anomalies associated with precipitation perturbations over the WNP and CP on the EAJ. The results of numerical experiments indicate that a heat source over the WNP can excite a northward-propagating Rossby wave train in the upper troposphere over East Asia and facilitate a poleward eddy momentum flux. It results in the acceleration of the westerlies between 30° and 45°N, which favors a northward displacement of the EAJ. The response induced by a heat sink over the CP features a zonal easterly band between 25° and 40°N, suggesting that the response to heat sink associated with negative precipitation anomalies over the CP may weaken the EAJ. A strengthened relationship was found between tropical Pacific precipitation and the EAJ since 1979. The modeling results suggest that the shift of mean states might be responsible for the strengthened EAJ–rainfall relationship after 1979.
Ferumoxytol as an intraprostatic MR contrast agent for lymph node mapping of the prostate: a feasibility study in non-human primates
Authors: Sankineni Sandeep , Smedley Jeremy , Bernardo Marcelino , Brown Anna M , Johnson Linda , Muller Berrend , Griffiths Gary L , Kobayashi Hisataka , Rais-Bahrami Soroush , Pinto Peter A , Wood Bradford J , Keele Brandon , Choyke Peter L , Turkbey Baris 
Published: May 2015

Background A variety of magnetic resonance (MR) lymphographic agents have been proposed for mapping the lymph nodes draining the prostate. Purpose To investigate the feasibility of using ferumoxytol (an FDA-approved iron oxide agent) for lymph node mapping of the prostate on imaging (MRI) in a non-human primate (NHP) Macaque model. Material and Methods Four NHPs weighing 5–13 kg underwent injection of ferumoxytol after a needle was introduced transrectally under MRI guidance into the prostate using a commercially available intrarectal MRI biopsy guide. Ferumoxytol was administered at dosage in the range of 0.15–0.75 mg Fe/kg in a fixed injection volume of 0.2 mL. T1-weighted MRI was performed at 3 T starting immediately and extending at least 45 min post-injection. Two readers evaluated the images in consensus. The NHPs tolerated the ferumoxytol injections at all doses with no evident side effects. Results It was determined that the lowest dose of 0.15 mg Fe/kg produced the best outcome in terms of lymph node visualization and draining nodes were reliably visualized at this dose and volume. Conclusion Thus, MRI with intraprostatic injection of ferumoxytol may be considered an effective T1 contrast agent for prospective mapping of lymph nodes draining the prostate and, thus, for attempted sentinel lymph node identification in prostate cancer. Large clinical trials to determine safety and efficacy are needed.
The inability of an early post-transplantation intrarenal resistive index to predict renal allograft function at 12 weeks after engraftment in young adults
Authors: Shakeri Bavil Abolhassan , Mirfakhraei Alirezal , Tayebi Khosroshahi Hamid , Chokhachizadeh Moghadam Reihaneh , Fouladi Daniel Fadaei 
Published: May 2015

Background The intrarenal resistive index (RI) is a promising tool for predicting renal graft outcomes. Due to the complexity of graft function and the presence of diverse contributing factors, however, the available data are inconclusive. Purpose To examine the performance of the RI 1 week after transplant in predicting allograft function at week 12, with an emphasis on the type of intrarenal artery used in the examination. Material and Methods A total of 58 first-time living-donor kidney-allograft-transplantation patients aged less than 50 years underwent Doppler ultrasonography (US) of the intrarenal arteries 1 week after engraftment. The RI was calculated for both the segmental (RI-C) and interlobar-arcuate (RI-P) arteries. Serum creatinine level and the creatinine reduction ratio (CRR) were determined at weeks 1 and 12 post transplantation. Results While the RI did not correlate with serum creatinine level and CRR at week 1, significant correlations were present between the RI and serum creatinine level (r = 0.28, P = 0.03 for both RI-C and RI-P) and CRR (r = –0.25, P = 0.05 for both RI-C and RI-P) at week 12. The sensitivity, specificity, positive predictive value, and negative predictive value of using RI-C in predicting abnormal 12-week serum creatinine level were 51.2%, 52.9%, 72.4%, and 31.3%, respectively; and 53.7%, 47.1%, 70.9%, and 29.6% for RI-P, respectively ( P > 0.99 for all comparisons). Conclusion Early post-transplantation RI correlates significantly with both serum creatinine level and creatinine reduction ratio 12 weeks after engraftment with intermediate predictive accuracy.
Is there an additive value of 18 F-FDG PET-CT to CT/MRI for detecting nodal metastasis in oropharyngeal squamous cell carcinoma patients with palpably negative neck?
Authors: Sohn Beomseok , Koh Yoon Woo , Kang Won Jun , Lee Jae-Hoon , Shin Na-Young , Kim Jinna 
Published: May 2015

Background Cervical node metastasis is one of the most significant prognostic factors in patients with oropharyngeal squamous cell carcinoma (SCC). There is little information regarding the comparison of histopathologic analysis following neck dissection with imaging results in oropharyngeal SCC. Purpose To investigate the clinical utility of PET-CT compared with computed tomography (CT) or magnetic resonance imaging (MRI) for detecting nodal metastasis in oropharyngeal SCC patients with palpably negative neck and to investigate whether pretreatment imaging modalities support the rationale for elective neck treatment. Material and Methods A total of 49 oropharyngeal SCC patients with palpably negative neck (42 men, 7 women; average age, 59.1 years) underwent primary tumor resection and neck dissection as a primary treatment. All patients were preoperatively evaluated with PET-CT and CT/MRI, and the diagnostic accuracy of each imaging modality was assessed by comparison with histopathologic results of the surgical specimen. Results Twenty-five (51.0%) of our 49 patients had neck metastases. On a level-by-level analysis, the sensitivity of PET-CT, CT/MRI, and a combination of PET-CT and CT/MRI was 54.6%, 54.6%, and 60.6%, respectively, at all neck levels. The area under the ROC showed that the diagnostic performance of the combined interpretation was not significantly different from that of CT/MRI alone (0.780 vs. 0.750, respectively; P = 0.158) and PET-CT alone (0.780 vs. 0.765, respectively; P = 0.501). Conclusion Addition of PET-CT to CT/MRI did not provide better diagnostic accuracy for detecting nodal metastasis in preoperative evaluation of oropharyngeal SCC patients with palpably negative neck, suggesting that current imaging studies might not replace elective neck dissection.
Squamous cell carcinoma of the oral cavity and oropharynx: what does the apparent diffusion coefficient tell us about its histology?
Authors: Bonello Luke , Preda Lorenzo , Conte Giorgio , Giannitto Caterina , Raimondi Sara , Ansarin Mohssen , Maffini Fausto , Summers Paul , Bellomi Massimo 
Published: May 2015

Background Diffusion-weighted imaging obtained with magnetic resonance (DW-MRI) is a non-invasive imaging tool potentially able to provide information about microstructural tumor characteristics. Purpose To prospectively analyze the correlation between the apparent diffusion coefficient (ADC) and clinical-histologic characteristics of squamous cell carcinoma (SCCA) of the oral cavity and oropharynx. Material and Methods Sixty-seven patients with untreated, histologically proven SCCA of the oral cavity and oropharynx underwent conventional and diffusion-weighted (b-values 0, 50, 250, 500, and 900 s/mm2) MRI. Tumor ADC was calculated from regions of interest drawn manually on the highest b-value images using ImageJ (ImageJ, NIH) and fsl (fsl 4, University of Oxford) image processing packages. ADC was calculated in two ways: standard ADC using all b-values; and ADCHigh using only b-values ≥ 250 s/mm2. We assessed the correlations between both ADC and ADCHigh and the clinical-histological characteristics of SCCA. Results Fifty-two patients (36 men, 16 women; mean age, 55 ± 13 years) were suitable for ADC calculation. Mean ADC was 1136.0 ± 108.5 × 10–6 mm2/s. Mean tumor ADCHigh was 991.2 ± 152.1 × 10–6 mm2/s. Mean tumor size was 32.3 ± 13.4 mm (range, 14.0–69.0 mm). We observed no correlation of either ADC or ADCHigh values with any of the clinical-histological tumor characteristics. Undifferentiated tumors (G3) showed lower apparent diffusion coefficient values compared to differentiated ones (G1-G2), without reaching statistical significance. Conclusion We did not observe any statistically significant correlation between ADC values and clinical-histological characteristics of SCCA of the oral cavity and oropharynx.
Platelet-Rich Plasma for Arthroscopic Repair of Medium to Large Rotator Cuff Tears
Authors: Jo Chris Hyunchul , Shin Ji Sun , Shin Won Hyoung , Lee Seung Yeon , Yoon Kang Sup , Shin Sue 
Published: May 2015

Background: Two main questions about the use of platelet-rich plasma (PRP) for regeneration purposes are its effect on the speed of healing and the quality of healing. Despite recent numerous studies, evidence is still lacking in this area, especially in a representative patient population with medium to large rotator cuff tears. Purpose: To assess the efficacy of PRP augmentation on the speed and quality of healing in patients undergoing arthroscopic repair for medium to large rotator cuff tears. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 74 patients scheduled for arthroscopic repair of medium to large rotator cuff tears were randomly assigned to undergo either PRP-augmented repair (PRP group) or conventional repair (conventional group). In the PRP group, 3 PRP gels (3 × 3 mL) were applied to each patient between the torn end and the greater tuberosity. The primary outcome was the Constant score at 3 months after surgery. Secondary outcome measures included the visual analog scale (VAS) for pain, range of motion (ROM), muscle strength, overall satisfaction and function, functional scores, retear rate, and change in the cross-sectional area (CSA) of the supraspinatus muscle. Results: There was no difference between the 2 groups in the Constant score at 3 months ( P > .05). The 2 groups had similar results on the VAS for pain, ROM, muscle strength, overall satisfaction and function, and other functional scores (all P > .05) except for the VAS for worst pain ( P = .043). The retear rate of the PRP group (3.0%) was significantly lower than that of the conventional group (20.0%) ( P = .032). The change in 1-year postoperative and immediately postoperative CSAs was significantly different between the 2 groups: –36.76 ± 45.31 mm2 in the PRP group versus −67.47 ± 47.26 mm2 in the conventional group ( P = .014). Conclusion: Compared with repairs without PRP augmentation, the current PRP preparation and application methods for medium to large rotator cuff repairs significantly improved the quality, as evidenced by a decreased retear rate and increased CSA of the supraspinatus, but not the speed of healing. However, further studies may be needed to investigate the effects of PRP on the speed of healing without risking the quality.