bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY03-02: Preclinical assessment of JTX-2011, an agonist antibody targeting ICOS, supports evaluation in ICONIC clinical trial
Authors: Michaelson Jennifer S. , Harvey Christopher , Elpek Kutlu , Duong Ellen , Shallberg Lindsey , Wallace Matthew , Mabry Robert , Shu Jenny , Deshpande Amit , Zi Tong , Sazinsky Stephen , Apgar Joshua , Mounho-Zamora Barbara , Briskin Michael , Trehu Elizabeth , Reeves Jason , Hirsch Heather , Sathyanarayanan Sriram , Law Deborah 
Published: July 2017

Abstract
ICOS (the inducible T-cell co-stimulator) is a co-stimulatory molecule expressed on the surface of T cells and a member of the CD28 family, which includes clinically validated targets of cancer immunotherapies, such as PD-1 and CTLA-4. Clinical data identified ICOS as a potentially key molecule in providing optimal antitumor benefit following anti-CTLA-4 therapy. We have developed a species cross-reactive humanized IgG1 agonist antibody, JTX-2011, that binds ICOS and is designed to induce an antitumor immune response. Our preclinical data suggest that JTX-2011 functions through a dual mechanism of action, by stimulating T effector cells (Teff) and depleting intratumoral T regulatory cells (Tregs). The ICOS antibody is efficacious as a single agent in mouse syngeneic tumor models and demonstrates enhanced activity when administered in combination with anti-PD-1. Single-agent activity in the preclinical models appears to correlate with ICOS expression, with greater efficacy observed in tumor models that exhibit a higher percentage of ICOS-expressing immune cell infiltrate. An integrated expression analysis of human tumors identified non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC) as indications with higher percentages of ICOS-expressing cell infiltrate. Preclinical studies performed in rodent and monkeys evaluated safety, pharmacokinetics, and pharmacodynamics of JTX-2011 to inform the first in-human study. The ICONIC phase I/II clinical trial is currently ongoing for evaluation of JTX-2011 alone or in combination with the anti-PD-1 antibody Nivolumab in patients with advanced solid tumors and incorporates a patient enrichment strategy design based on the preclinical and translational findings.
Citation Format: Jennifer S. Michaelson, Christopher Harvey, Kutlu Elpek, Ellen Duong, Lindsey Shallberg, Matthew Wallace, Robert Mabry, Jenny Shu, Amit Deshpande, Tong Zi, Stephen Sazinsky, Joshua Apgar, Barbara Mounho-Zamora, Michael Briskin, Elizabeth Trehu, Jason Reeves, Heather Hirsch, Sriram Sathyanarayanan, Deborah Law. Preclinical assessment of JTX-2011, an agonist antibody targeting ICOS, supports evaluation in ICONIC clinical trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY03-02. doi:10.1158/1538-7445.AM2017-SY03-02
Abstract SY23-03: How does HTLV-1 cause leukemia
Authors: Bangham Charles 
Published: July 2017

Abstract
The retrovirus human T-lymphotropic virus type 1 (HTLV-1) causes an aggressive, rapidly fatal malignancy of CD4+ T cells, called adult T-cell leukemia/lymphoma (ATL), in 5% of infected individuals. Recent evidence on the clonal diversity and molecular virology of HTLV-1 and on the host genetic and immune response is changing the understanding of oncogenesis in HTLV-1 infection. It was previously believed that HTLV-1 was latent in vivo and persisted by continuous oligoclonal proliferation of about 100 clones of HTLV-1-infected CD4+ T cells, and that this oligoclonal proliferation predisposed to the malignancy ATL. However, we have shown that a typical individual carries between 104 and 105 clones and that the proviral load–the chief correlate of disease–is determined by the number of clones, not by oligoclonal proliferation. The central challenge remains to explain the regulation of HTLV-1 latency in vivo and the role of the host immune response in determining the set-point proviral load and the risk of ATL. I propose here three hypotheses. First, that ATL results from the accumulation of replicative mutations in HTLV-1-infected T-cell clones that persist for decades, typically over 40 years. Second, that the quality of the host immune response, chiefly the CTL response, determines the size and clonal diversity of the HTLV-1 reservoir, the net proliferation rate of HTLV-1-infected T cells, and therefore the risk of ATL. Third, that abnormal chromatin looping in the host genome caused by HTLV-1 can deregulate host gene expression and so contribute to the risk of ATL.
Citation Format: Charles Bangham. How does HTLV-1 cause leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY23-03. doi:10.1158/1538-7445.AM2017-SY23-03
Abstract SY25-02: Antigenic strength vs. tumor microenvironment in determining cancer immunosurveillance
Authors: Vonderheide Robert H. 
Published: July 2017

Abstract
We evaluated immune surveillance in pancreatic ductal adenocarcinoma (PDA), which exhibits far fewer missense mutations and potential neoepitopes than classically described carcinogen-induced, highly mutated tumors. In contrast to these immunogenic tumor models from which the theory of elimination-equilibrium-escape was determined, we found no evidence for immunoediting in a mutant Kras-driven murine model of PDA. These tumors progress the same with or without a functional adaptive immune system, similar to other mouse tumors that have also been shown to grow independently of T cells. Tumors arising in T cell–depleted mice grew unchecked in immune-competent hosts. We further show that KPC pancreatic tumors have few if any predicted neoepitopes derived from somatic tumor missense mutations and that an immunoediting phenotype can be rescued by ectopic expression of a neoantigen (OVA) in the same tumor model. Thus, the manifestations of cancer immune surveillance in the KPC model depend on tumor antigenic strength; the lack of neoepitopes is not a consequence of immunoediting in this model. These findings suggest an alternative biologic mechanism in which tumor outgrowth reflects immune quiescence, which is linked to, and regulated by, poor tumor antigenicity—a conclusion with potential relevance to human cancers with a low burden of mutations and minimal neoepitopes.
Citation Format: Robert H. Vonderheide. Antigenic strength vs. tumor microenvironment in determining cancer immunosurveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY25-02. doi:10.1158/1538-7445.AM2017-SY25-02
Abstract SY33-01: Targeting metabolism to enhance immunotherapy
Authors: Powell Jonathan D. , Leone Robert , Englert Judd , Rais Rana , Slusher Barbara 
Published: July 2017

Abstract
The extraordinary proliferative capacity of cancer necessitates specialized metabolic programming on the part of cancer cells. Indeed, this specialized metabolism not only facilitates growth but also creates a hypoxic, acidic, nutrient-deprived tumor microenvironment able to thwart immune destruction. We hypothesized that by targeting tumor metabolism we could not only slow down tumor growth but also “condition” tumors to be more susceptible to immunotherapy. Inherent to the specialized metabolism of tumors is a markedly increased requirement for glutamine. To this end we have devised a novel glutamine antagonist that is delivered as an inert prodrug that is converted to the active drug by enzymatic activity, which is enriched in tumors. In syngeneic mouse models of cancer our prodrug (JHU-083) markedly inhibited tumor growth, leading to cure of mice after only 14 days of monotherapy. Importantly, targeting glutamine metabolism led to a decreased extracellular acidification rate (ECAR), decreased hypoxia, and increased nutrient availability. Furthermore, we observed decreases in MDSC and fibrocytes with a concomitant increase in inflammatory (TNF-producing) tumor-associated macrophages (TAMs). Likewise, there was an increase in the CD8:Treg ratio and in some tumors a decrease in PDL1 expression on both tumors and infiltrating immune cells. Most importantly, JHU-083 markedly enhanced the efficacy of immunotherapy in the form of checkpoint blockade, adoptive cellular therapy (ACT), and A2aR blockade. Overall our studies define a novel compound for targeting metabolism as a means of enhancing immunotherapy for cancer.
Citation Format: Jonathan D. Powell, Robert Leone, Judd Englert, Rana Rais, Barbara Slusher. Targeting metabolism to enhance immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr SY33-01. doi:10.1158/1538-7445.AM2017-SY33-01
Association of Blood Pressure Control Level With Left Ventricular Morphology and Function and With Subclinical Cerebrovascular Disease
Authors: Nakanishi Koki , Jin Zhezhen , Homma Shunichi , Elkind Mitchell S. V. , Rundek Tatjana , Tugcu Aylin , Sacco Ralph L. , Di Tullio Marco R. 
Published: July 2017

Background

Left ventricular (
LV
) hypertrophy and subclinical cerebrovascular disease are early manifestations of cardiac and brain target organ damage caused by hypertension. This study aimed to investigate whether intensive office systolic blood pressure (
SBP
) control has beneficial effects on
LV
morphology and function and subclinical cerebrovascular disease in elderly patients with hypertension.

Methods and Results

We examined 420 patients treated for hypertension without history of heart failure and stroke from the
CABL
(Cardiovascular Abnormalities and Brain Lesions) study. All patients underwent 2‐dimensional echocardiographic examination and brain magnetic resonance imaging. Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume. Patients were divided into 3 groups: SBP <120 mm Hg (intensive control);
SBP
120 to 139 mm Hg (less intensive control); and
SBP
≥140 mm Hg (uncontrolled). Prevalence of
LV
hypertrophy and diastolic dysfunction were lowest in the intensive control, intermediate in the less intensive control, and highest in the uncontrolled groups (12.8%, 31.8%, and 44.7%, respectively [
P
<0.001], for
LV
hypertrophy; 46.8%, 61.7%, and 72.6%, respectively [
P
=0.003], for diastolic dysfunction). Patients with less intensive
SBP
control had greater risk of
LV
hypertrophy than those with intensive control (adjusted odds ratio, 3.26;
P
=0.013). A similar trend was observed for
LV
diastolic dysfunction but did not reach statistical significance (adjusted odds ratio, 1.65;
P
=0.144). Conversely, intensive
SBP
control was not significantly associated with reduced risk of silent brain infarcts and white matter hyperintensity volume compared with less intensive control.

Conclusions

Compared with less intensive control, intensive
SBP
control may have a stronger beneficial effect on cardiac than cerebral subclinical disease.
Influence of Pycnocline Smoothing and Subgrid-Scale Variability of Density Profiles on the Determination of Mixed Layer Depth
Authors: Ok Hyejin , Noh Yign , Choi Yeonju 
Published: July 2017

AbstractThis study investigates how pycnocline smoothing and subgrid-scale variability of density profiles influence the determination of the mixed layer depth (MLD) in the global ocean, and applies the results of analysis to assess the ability of ocean general circulation models (OGCM) to simulate the MLD. For this purpose, individual, monthly mean, and climatological profiles are analyzed over a horizontal resolution of 1° × 1° for both observation data (Argo) and eddy-resolving OGCM (OFES) results. It is found that the MLDs from averaged profiles are generally smaller than those from individual profiles because of pycnocline smoothing induced by the averaging process. A correlation is found between the decrease in MLD Δh and the increase in pycnocline thickness Δδ of averaged profiles, except during winter in the high-latitude ocean. The relation is estimated as Δh = −αΔδ − β, where α ≃ 0.7 in all cases, but β increases with the subgrid-scale variability of density profiles. A correlation is also found between Δh and the standard deviation of the MLD within a grid. The results are applied to estimate how much of the MLD bias of OFES is due to prediction error and how much is due to profile error, induced by different pycnocline smoothing and the subgrid-scale variability of density profiles. The study also shows how profile error varies with the threshold density difference criterion.
Global risk governance: what role for public administrations: the paradigm of the EU food safety control and alert systems
Authors: Iurato Andrea 
Published: July 2017

This study explores crucial issues arising from the increasing establishment of supranational risk-governance systems that pursue a compromise between the need for effective governance and the necessity to avoid obstacles regarding trade. In these contexts, national public administrations become a peripheral module in a multilevel system where they see their organization altered and the legitimacy of their actions questioned. The analysis uses as a paradigm the systems on food safety controls and rapid alert in the EU and tries to answer the following questions: How do we give public administrations an effective role in the global scene? Are national administrations destined to become mere executors of supranational-set rules? Outcomes show that legal systems whose multilevel integration reached a high level suggest positive implications deriving from a new model of global governance not involving a reduction in state sovereignty, but leading it to a new role, guaranteeing the accomplishment of supranational-set goals and safeguarding the autonomy of national public administrations. Points for practitioners Practitioners, especially those who hold managerial positions, may often find themselves disoriented when acting in a multilevel context because of the shrinking of their autonomy as well as their submission to external rules and controls. Starting from the analysis of the elected paradigm, practitioners could find that in a well-functioning multilevel regulatory system, national public administrations are able to use their remaining range of discretion, even if minimal, in order to realize innovative organizational models, through which they may avoid direct intervention from upper levels and propose themselves as a model to be borrowed and applied in the whole system.
Physicochemical properties of keratin extracted from wool by various methods
Authors: Rajabinejad Hossein , Zoccola Marina , Patrucco Alessia , Montarsolo Alessio , Rovero Giorgio , Tonin Claudio 
Published: July 2017

Keratin from wool fibers was extracted with different extraction methods, for example oxidation, reduction, sulfitolysis, and superheated water hydrolysis. Different samples of extracted keratin were characterized by molecular weight determination, FT-IR and NIR spectroscopy, amino acid analysis, and thermal behavior. While using oxidation, reduction, and sulfitolysis, only the cleavage of disulfide bonds takes place; keratin hydrolysis leads to the breaking of peptide bonds with the formation of low molecular weight proteins and peptides. In the FT-IR spectra of keratoses, the formation of cysteic acid appears, as well as the formation of Bunte salts (–S–SO3–) after the cleavage of disulfide bonds by sulfitolysis. The amino acid composition confirms the transformation of amino acid cystine, which is totally converted into cysteic acid following oxidative extraction and almost completely destroyed during superheated water hydrolysis. Thermal behavior shows that keratoses, which are characterized by stronger ionic interaction and higher molecular weight, are the most temperature stable keratin, while hydrolyzed wool shows a poor thermal stability.
The Effects of Injury Prevention Programs on the Biomechanics of Landing Tasks: A Systematic Review With Meta-analysis
Authors: Lopes Thiago Jambo Alves , Simic Milena , Myer Gregory D. , Ford Kevin R. , Hewett Timothy E. , Pappas Evangelos 
Published: July 2017

Background: Anterior cruciate ligament (ACL) tear is a common injury in sports and often occurs during landing from a jump. Purpose: To synthesize the evidence on the effects of injury prevention programs (IPPs) on landing biomechanics as they relate to the ligament, quadriceps, trunk, and leg dominance theories associated with ACL injury risk. Study Design: Meta-analysis. Methods: Six electronic databases were searched for studies that investigated the effect of IPPs on landing task biomechanics. Prospective studies that reported landing biomechanics at baseline and post-IPP were included. Results from trunk, hip, and knee kinematics and kinetics related to the ACL injury theories were extracted, and meta-analyses were performed when possible. Results: The criteria were met by 28 studies with a total of 466 participants. Most studies evaluated young females, bilateral landing tasks, and recreational athletes, while most variables were related to the ligament and quadriceps dominance theories. An important predictor of ACL injury, peak knee abduction moment, decreased ( P = .01) after the IPPs while other variables related to the ligament dominance theory did not change. Regarding the quadriceps dominance theory, after the IPPs, angles of hip flexion at initial contact ( P = .009), peak hip flexion ( P = .002), and peak knee flexion ( P = .007) increased, while knee flexion at initial contact did not change ( P = .18). Moreover, peak knee flexion moment decreased ( P = .005) and peak vertical ground-reaction force did not change ( P = .10). Conclusion: The exercises used in IPPs might have the potential to improve landing task biomechanics related to the quadriceps dominance theory, especially increasing peak knee and hip flexion angles. Importantly, peak knee abduction moment decreased, which indicates that IPPs influence a desired movement strategy to help athletes overcome dangerous ligament dominance loads arising from lack of frontal plane control during dynamic tasks. The lack of findings for some biomechanical variables suggests that future IPPs may be enhanced by targeting participants’ baseline profile deficits, highlighting the need to deliver an individualized and task-specific IPP.
Personalized, bilateral whole-body somatosensory cortex stimulation to relieve fatigue in multiple sclerosis
Authors: Cancelli Andrea , Cottone Carlo , Giordani Alessandro , Migliore Simone , Lupoi Domenico , Porcaro Camillo , Mirabella Massimiliano , Rossini Paolo Maria , Filippi Maria Maddalena , Tecchio Franca 
Published: July 2017

Background: The patients suffering from multiple sclerosis (MS) often consider fatigue the most debilitating symptom they experience, but conventional medicine currently offers poorly efficacious therapies. Objective: We executed a replication study of an innovative approach for relieving MS fatigue. Methods: According to the sample size estimate, we recruited 10 fatigued MS patients who received 5-day transcranial direct current stimulation (tDCS) in a randomized, double-blind, Sham-controlled, crossover study, with modified Fatigue Impact Scale (mFIS) score reduction at the end of the treatment as primary outcome. A personalized anodal electrode, shaped on the magnetic resonance imaging (MRI)-derived individual cortical folding, targeted the bilateral whole-body primary somatosensory cortex (S1) with an occipital cathode. Results: The amelioration of fatigue symptoms after Real stimulation (40% of baseline) was significantly larger than after Sham stimulation (14%, p = 0.012). Anodal whole body S1 induced a significant fatigue reduction in mildly disabled MS patients when the fatigue-related symptoms severely hampered their quality of life. Conclusion: This second result in an independent group of patients supports the idea that neuromodulation interventions that properly select a personalized target might be a suitable non-pharmacological treatment for MS fatigue.
Treatment of ruptured blood blister aneurysms using primary flow-diverter stenting with considerations for adjunctive coiling: A single-centre experience and literature review
Authors: Yang Cunli , Vadasz Agnes , Szikora István 
Published: July 2017

Objective The objective of this article is to conduct a single-centre evaluation and quick literature review of the effectiveness of primary flow-diverter (FD) treatment of ruptured blood blister aneurysms (BBAs), with additional relevance of adjunctive coiling. Methods Patients presenting with subarachnoid haemorrhage (SAH) due to ruptured BBAs and subsequently treated with FDs were retrospectively selected from June 2010 to January 2017. Treatment techniques, angiographic data on occlusion rates and procedural success as well as clinical outcomes using the modified Rankin Scale (mRS) were collated. Cross-reference of results were made with available literature. Results Thirteen patients harbouring 14 BBAs were recruited. Of the 14 aneurysms, five (35.7%) showed immediate complete occlusion after the procedure (four of these five patients had adjunctive coiling). All of the aneurysms showed complete occlusion by the six- to nine-month control diagnostic angiogram. No rebleed or retreatment was experienced. Twelve of 13 (92%) patients had an mRS score of 0–1 at the last clinical follow-up. From the pooled data of the literature review, eventual aneurysm occlusion was achieved in 48/56 patients, with five patients requiring further endovascular treatment. In the clinical follow-up period, an mRS of 0–2 was recorded for 83.3% (45/54) of patients. Conclusion Endovascular reconstruction of BBAs using FD treatment is an effective method with good final clinical outcomes. Adjunctive use of coiling achieves higher incidence of immediate complete occlusion of BBAs.
Pipeline embolization device retraction and foreshortening after internal carotid artery blister aneurysm treatment
Authors: Heit Jeremy J , Telischak Nicholas A , Do Huy M , Dodd Robert L , Steinberg Gary K , Marks Michael P 
Published: July 2017

Background Subarachnoid hemorrhage (SAH) secondary to rupture of a blister aneurysm (BA) results in high morbidity and mortality. Endovascular treatment with the pipeline embolization device (PED) has been described as a new treatment strategy for these lesions. We present the first reported case of PED retraction and foreshortening after treatment of a ruptured internal carotid artery (ICA) BA. Case description A middle-aged patient presented with SAH secondary to ICA BA rupture. The patient was treated with telescoping PED placement across the BA. After 5 days from treatment, the patient developed a new SAH due to re-rupture of the BA. Digital subtraction angiography revealed an increase in caliber of the supraclinoid ICA with associated retraction and foreshortening of the PED that resulted in aneurysm uncovering and growth. Conclusions PED should be oversized during ruptured BA treatment to prevent device retraction and aneurysm regrowth. Frequent imaging follow up after BA treatment with PED is warranted to ensure aneurysm occlusion.