bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA18: Adoptive T-cell transfer for metastatic melanoma: What are the relevant antigens?
Authors: Yang James C. 
Published: July 2015

Abstract
The transfer of cultured tumor-reactive T-cells into patients with metastatic melanoma can cause tumor regressions when other immunotherapies have failed. A single transfer of T-cells can mediate complete and durable regressions in some patients. The two main sources of T-cells for transfer have been from the native T-cells infiltrating the tumor (tumor infiltrating lymphocytes; TIL) or from peripheral blood lymphocytes retrovirally engineered with a tumor-reactive T-cell receptor (TCR). In the latter situation, a variety of tumor-associated antigens have been targeted with cloned receptors and although responses are seen, in some cases unacceptable toxicity has occurred due to on-target, off-tumor immune recognition. Although melanoma TIL often contain T-cells that also target the same nominal antigens, their transfer is rarely associated with such undesirable toxicities. In addition, melanoma TIL frequently contain T-cells which recognize the autochthonous tumor, while TIL from other tumors infrequently show this reactivity. Recent data have implicated the presence of abundant tumor-specific mutations in melanoma as the explanation for these various observations. These appear to be significant antigenic targets in therapeutic TIL that cause no collateral damage, and their high frequency as shown by tumor exomic sequencing of melanomas may explain that tumor's high degree of natural immunogenicity. These lessons learned from studying T-cell transfer for melanoma can now be applied to other cancers and a recent example has demonstrated the potential and promise of this approach.
Citation Format: James C. Yang. Adoptive T-cell transfer for metastatic melanoma: What are the relevant antigens? [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA18.
Abstract IA21: Skin pigmentation pathways and melanoma risk
Authors: Fisher David E. 
Published: July 2015

Abstract
Melanoma risk is well known to be strongly linked to UV exposure. Yet despite this important linkage, melanoma incidence increases relentlessly, at one of the steepest rates of all human cancers. Prevention approaches that include education, sunscreen, avoidance of tanning beds, and sun-safe behavior messages are excellent in principal, but have not as yet produced sufficient decreases in melanoma incidence. Here we present studies which explore cutaneous responses to ultraviolet radiation exposure. These results indicate the presence of multiple cutaneous responses and pathways that are triggered by UV and which modulate not only skin signaling, but also systemic effects of this cutaneous UV exposure. These pathways include pigmentation or tanning. Other studies will describe a murine “redhair/lightskin” melanoma model of melanoma which identifies roles for pigmentation intermediates in melanoma formation. Finally, the MITF transcription factor plays central roles in both melanocyte and melanoma growth, survival, and differentiation. Studies will be described which characterize several MITF transcriptional targets, some of which may represent novel therapeutic opportunities.
Citation Format: David E. Fisher. Skin pigmentation pathways and melanoma risk. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA21.
Abstract IA22: The immunobiology of the melanoma tumor microenvironment and efficacy of immunotherapies
Authors: Gajewski Thomas F. 
Published: July 2015

Abstract
Two major categories of melanoma metastases have been observed based on gene expression profiling and confirmatory assays. One subgroup of patients has an inflamed phenotype that includes expression of chemokines, T cell markers, and other immunoregulatory factors. In contrast, the other major subset lacks this phenotype and appears to display immune “exclusion”. The optimal immunotherapeutic interventions may be distinct in these two global subsets. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3+ Tregs, and evidence for T cell-intrinsic anergy has also emerged aided by a recently defined functional role of EGR2. In addition, the mechanism of induction of these inhibitory mechanisms has been elucidated—PD-L1 and IDO are induced by IFN-γ, and Tregs are largely recruited by the chemokine CCL22, both being produced by activated CD8+ effector T cells. Preclinical experiments have confirmed a critical role for each of these mechanisms in limiting anti-tumor T cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic. These include anti-PD-1/PD-L1 mAbs, IDO inhibitors, and approaches to deplete CD25+ Tregs and/or reverse anergy. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous. Preclinical data have indicated synergy between anti-CTLA-4 +/- anti-PD-L1 +/- IDO inhibition. The mechanism of synergy is striking, as it correlates with a marked improvement of IL-2 production and proliferation of tumor-infiltrating CD8+ T cells. Clinical translation of these combination immunotherapies is promising and ongoing. In contrast to the T cell-inflamed melanomas, a new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8α+ DCs. New strategies are being developed to engage or mimic this pathway as a therapeutic endeavor. The molecular mechanisms that mediate the presence or absence of the T cell-inflamed tumor microenvironment in patients are being elucidated and should open up additional new treatment approaches.
Citation Format: Thomas F. Gajewski. The immunobiology of the melanoma tumor microenvironment and efficacy of immunotherapies. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA22.
Abstract IA31: Combining targeted therapy and immune checkpoint blockade to improve responses
Authors: Wargo Jennifer A. 
Published: July 2015

Abstract
There have been significant advances in treatment of metastatic melanoma over the past several years through the use of targeted therapy and immune checkpoint blockade. Oncogenic mutations in the BRAF gene occur in over half of melanoma tumors, and treatment with agents targeting this mutation results in objective responses in the majority of patients. However significant limitations exist as responses are not durable, with the majority of patients progressing on therapy within 6-10 months. Another area of significant progress involves the use of immune checkpoint blockade, such as with monoclonal antibodies blocking CTLA-4 and the PD-1 pathway. In contrast, treatment of patients with immune checkpoint inhibitors results in a lower response rate than those observed with targeted therapy, but ones that tend to be more durable. With these advances, we are posed with therapeutic dilemmas with regard to timing and sequence of therapy. Namely, there is significant debate as to whether to begin treatment with targeted therapy versus immune checkpoint blockade upfront, and at which point to change treatment strategy.
There is growing evidence of potential synergy in combining treatment with BRAF-targeted therapy and immune checkpoint blockade, and this concept is being empirically tested in clinical trials. There a strong scientific rationale for combining these therapies, as treatment with BRAF inhibitors is associated with increased immunogenicity of melanoma tumors within 2 weeks of therapy - with increased melanoma antigens and CD8+ T cell infiltrate, and decreased immunosuppressive cytokines and VEGF. BRAF inhibitors may also directly activate T cells through paradoxical activation of the MAPK pathway. However there is a concurrent increase in expression of immunomodulatory molecules (such as PD-L1) within 2 weeks of therapy which is likely related to T cell infiltrate, though also suggest a possible immune mechanism of resistance. Clinical trials and studies in murine models are currently underway to explore synergy between these therapies, and insights gained will be discussed herein. It is becoming increasingly apparent that complexities exist regarding appropriate timing and sequence in these combination strategies to optimize responses and minimize toxicity. Ultimately, ideal approaches using combined BRAF-targeted therapy and immune checkpoint blockade will be built on a deep understanding of the molecular and immune effects of each of these therapies in isolation, as well as in combination.
Citation Format: Jennifer A. Wargo. Combining targeted therapy and immune checkpoint blockade to improve responses. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr IA31.
Gestural Control in the English Past-Tense Suffix: An Articulatory Study Using Real-Time MRI
Authors: Lammert Adam , Goldstein Louis , Ramanarayanan Vikram , Narayanan Shrikanth 
Published: July 2015

AbstractThe English past tense allomorph following a coronal stop (e.g., /bɑndəd/) includes a vocoid that has traditionally been transcribed as a schwa or as a barred i. Previous evidence has suggested that this entity does not involve a specific articulatory gesture of any kind. Rather, its presence may simply result from temporal coordination of the two temporally adjacent coronal gestures, while the interval between those two gestures remains voiced and is acoustically reminiscent of a schwa. The acoustic and articulatory characteristics of this vocoid are reexamined in this work using real-time MRI with synchronized audio which affords complete midsagittal views of the vocal tract. A novel statistical analysis is developed to address the issue of articulatory targetlessness based on previous models that predict articulatory action from segmental context. Results reinforce the idea that this vocoid is different, both acoustically and articulatorily, than lexical schwa, but its targetless nature is not supported. Data suggest that an articulatory target does exist, especially in the pharynx where it is revealed by the new data acquisition methodology. Moreover, substantial articulatory differences are observed between subjects, which highlights both the difficulty in characterizing this entity previously, and the need for further study with additional subjects.
Inverse Relationship of Blood Pressure to Long-Term Outcomes and Benefit of Cardiac Resynchronization Therapy in Patients With Mild Heart Failure
Authors: Biton Yitschak , Moss Arthur J. , Kutyifa Valentina , Mathias Andrew , Sherazi Saadia , Zareba Wojciech , McNitt Scott , Polonsky Bronislava , Barsheshet Alon , Brown Mary W. , Goldenberg Ilan 
Published: July 2015

Background—
Previous studies have shown that low blood pressure is associated with increased mortality and heart failure (HF) in patients with left ventricular dysfunction. Cardiac resynchronization therapy (CRT) was shown to increase systolic blood pressure (SBP). Therefore, we hypothesized that treatment with CRT would provide incremental benefit in patients with lower SBP values.

Methods and Results—

The independent contribution of SBP to outcome was analyzed in 1267 patients with left bundle brunch block enrolled in Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). SBP was assessed as continuous measures and further categorized into approximate quintiles. The risk of long-term HF or death and CRT with defibrillator versus implantable cardioverter defibrillator benefit was assessed in multivariate Cox proportional hazards regression models. Multivariate analysis showed that in the implantable cardioverter defibrillator arm, each 10-mm Hg decrement of SBP was independently associated with a significant 21% (
P
<0.001) increased risk for HF or death, and patients with lower quintile SBP (<110 mm Hg) experienced a corresponding >2-fold risk-increase. CRT with defibrillator provided the greatest HF or mortality risk reduction in patients with SBP<110 mm Hg hazard ratio of 0.34,
P
<0.001, when compared with hazard ratio of 0.52,
P
<0.001, in those with 110>SBP≥136 mm Hg and hazard ratio of 0.94,
P
=0.808, with SBP>136 mm Hg (
P
for trend=0.001).

Conclusions—
In patients with mild HF, prolonged QRS, and left bundle brunch block, low SBP is related to higher risk of mortality or HF with implantable cardioverter defibrillator therapy alone. Treatment with CRT is associated with incremental clinical benefits in patients with lower baseline SBP values.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00180271.
On the Rapid Intensification of Hurricane Wilma (2005). Part III: Effects of Latent Heat of Fusion
Authors: Miller William , Chen Hua , Zhang Da-Lin 
Published: July 2015

Abstract
The impacts of the latent heat of fusion on the rapid intensification (RI) of Hurricane Wilma (2005) are examined by comparing a 72-h control simulation (CTL) of the storm to a sensitivity simulation in which the latent heat of deposition is reduced by removing fusion heating (NFUS). Results show that, while both storms undergo RI, the intensification rate is substantially reduced in NFUS. At peak intensity, NFUS is weaker than CTL by 30 hPa in minimum central pressure and by 12 m s−1 in maximum surface winds. The reduced rate of surface pressure falls in NFUS appears to result hydrostatically from less upper-level warming in the eye. It is shown that CTL generates more inner-core convective bursts (CBs) during RI, with higher altitudes of peak vertical motion in the eyewall, compared to NFUS. The latent heat of fusion contributes positively to sufficient eyewall conditional instability to support CB updrafts. Slantwise soundings taken in CB updraft cores reveal moist adiabatic lapse rates until 200 hPa, where the updraft intensity peaks. These results suggest that CBs may impact hurricane intensification by inducing compensating subsidence of the lower-stratospheric air, and the authors conclude that the development of more CBs inside the upper-level radius of maximum wind and at the higher altitude of latent heating all appear to be favorable for the RI of Wilma.
On the Convective Coupling and Moisture Organization of East Pacific Easterly Waves
Authors: Rydbeck Adam V. , Maloney Eric D. 
Published: July 2015

Abstract
Processes associated with the local amplification of easterly waves (EWs) in the east Pacific warm pool are explored. Developing EWs favor convection in the southwest and northeast quadrants of the disturbance. In nascent EWs, convection favors the southwest quadrant. As the EW life cycle progresses, convection in the northeast quadrant becomes increasingly prominent and southwest quadrant convection wanes. The EW moisture budget reveals that anomalous meridional winds acting on the mean meridional moisture gradient of the ITCZ produce moisture anomalies supportive of convection in the southwest quadrant early in the EW life cycle. As EWs mature, moisture anomalies on the poleward side of the EW begin to grow and are supported by the advection of anomalous moisture by the mean zonal wind.
In the southwest and northeast portions of the wave, where convection anomalies are favored, lower-tropospheric vorticity is generated locally through vertical stretching that supports a horizontal tilt of the wave from the southwest to the northeast. EWs with such tilts are then able to draw energy via barotropic conversion from the background cyclonic zonal wind shear present in the east Pacific. Convection anomalies associated with EWs vary strongly with changes in the background intraseasonal state. EWs during westerly and neutral intraseasonal periods are associated with robust convection anomalies. Easterly intraseasonal periods are, at times, associated with very weak EW convection anomalies because of weaker moisture and diluted CAPE variations.
Considerations for Oversampling in Azimuth on the Phased Array Weather Radar
Authors: Borowska Lesya , Zhang Guifu , Zrnić Dusan S. 
Published: July 2015

AbstractWhen spectral moments in the azimuth are spaced by less than a beamwidth, it is called oversampling. Superresolution is a type of oversampling that refers to sampling at half a beamwidth on the national network of Doppler weather radars [Weather Surveillance Radar-1988 Doppler (WSR-88D)]. Such close spacing is desirable because it extends the range at which small severe weather features, such as tornadoes or microbursts, can be resolved. This study examines oversampling for phased array radars. The goal of the study is to preserve the same effective beamwidth as on the WSR-88D while obtaining smaller spectral moment estimate errors at the same or faster volume update times. To that effect, a weighted average of autocorrelations of radar signals from three consecutive radials is proposed. Errors in three spectral moments obtained from these autocorrelations are evaluated theoretically. Methodologies on how to choose weights that preserve the desirable effective beamwidth are presented. The results are demonstrated on the fields of spectral moments obtained with the National Weather Radar Testbed (NWRT), a phased array weather radar at NOAA’s National Severe Storms Laboratory (NSSL).
Effects of Acetabular Rim Trimming on Hip Joint Contact Pressures
Authors: Bhatia Sanjeev , Lee Simon , Shewman Elizabeth , Mather Richard C. , Salata Michael J. , Bush-Joseph Charles A. , Nho Shane J. 
Published: July 2015

Background: In patients with femoroacetabular impingement (FAI), acetabular rim trimming removes the offending area of the acetabular deformity in patients with pincer-type and mixed-type FAI to improve hip joint kinematics. Although the rationale for arthroscopic acetabular rim trimming in patients with FAI is well established, the amount of rim resection has not been quantified, and the threshold at which excessive rim resection results in abnormal hip contact pressures has not been described. Purpose: To investigate the changes in contact areas, contact pressures, and peak forces within the hip joint with sequential acetabular rim trimming. Study Design: Controlled laboratory study. Methods: Six fresh-frozen, nondysplastic, human cadaveric hemipelvises were analyzed utilizing thin-film piezoresistive load sensors to measure the contact area, contact pressure, and peak force after anterosuperior acetabular rim trimming at depths of 0 mm (intact), 2 mm, 4 mm, 6 mm, and 8 mm. Each specimen was examined at 20° of extension and 60° of flexion. Analysis was performed on 2 regions of interest: the acetabular rim and the acetabular base (deep part of the acetabulum). After each experimental condition, the acetabulum was normalized with respect to the intact state to account for specimen variability. Statistical analysis was conducted through 1-way analysis of variance with post hoc Games-Howell tests. Results: At the acetabular base, there were significant increases in the contact area after 4-mm resection (60°: 169.12% ± 30.64%; P = .0138), contact pressure after 6-mm resection (60°: 292.76% ± 79.07%; P = .009), and peak force after 6-mm resection (60°: 166.00% ± 34.40%; P = .027). At the acetabular rim, there were significant decreases in the contact area after 6-mm resection (60°: 66.32% ± 18.80%; P = .0354) (20°: 65.47% ± 15.87%; P = .0127), contact pressure after 6-mm resection (60°: 50.77% ± 11.49%; P < .001) (20°: 58.01% ± 23.10%; P = .0335), and peak force after 6-mm resection (60°: 60.67% ± 9.29%; P < .001) (20°: 74.44% ± 9.84%; P = .007). Conclusion: Resecting more than 4 to 6 mm of the acetabular rim during hip arthroscopic surgery to address a pincer deformity may dramatically increase contact pressures by 3-fold at the acetabular base. The study suggests that excessive rim resection may lead to increased loads in the hip joint and may predispose to premature joint degeneration. Clinical Relevance: Resecting more than 4 to 6 mm of the acetabular rim may significantly alter hip joint biomechanics, increasing joint reactive forces and subsequent chondrolabral degeneration.
Evaluation of antioxidant, enzyme inhibition, and cytotoxic activity of three anthraquinones (alizarin, purpurin, and quinizarin)
Authors: Zengin G , Degirmenci NS , Alpsoy L , Aktumsek A 
Published: July 2015

Objective: The aim of this work was to investigate the cytotoxic, antioxidative, and enzyme inhibition effects of alizarin, quinizarin, and purpurin, which are anthraquinones (AQ). Methods: Cytotoxic effects were evaluated with cell inhibition rate by 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide assay. Different chemical assays, including free radical scavenging activity (1,1-diphenyl-2-picrylhydrazyl and 2,2-azino-bis(3-ethylbenzothiazloine-6-sulfonic acid)), phosphomolybdenum and reducing power (ferric reducing antioxidant power and cupric ion reducing activity), were used to evaluate the antioxidant properties. Moreover, enzyme inhibitory activities were analyzed against acetylcholinesterase, butrylcholinesterase, tyrosinase, α-amylase, and α-glucosidase. Results: These components have antioxidant and enzyme inhibition activity. Especially, purpurin showed the strongest antioxidant and good enzyme inhibitory effects. According to our cytotoxicity results, alizarin, purpurin, and quinizarin induced dose- and time-dependent cell proliferation. Furthermore, when we applied AQs with mitomycin C (MC) on L929 cell line, we demonstrated that cell proliferation in MC-AQ groups compared with MC group was increased. The most effective component was alizarin at 100 µM concentration. These AQs showed positive effects on L929 cell lines with high half-maximal inhibitory concentration values. Conclusion: Our results demonstrate that AQs may be used as antioxidative compounds in food and medicinal applications.