bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphoproteomic Characterization of Lung Squamous Cell Carcinoma Fragmentation, a Histological Marker of Increased Tumor Invasiveness
Authors: Casanova Ruben , Xia Daniel , Rulle Undine , Nanni Paolo , Grossmann Jonas , Vrugt Bart , Wettstein Reto , Ballester-Ripoll Rafael , Astolfo Alberto , Weder Walter , Moch Holger , Stampanoni Marco , Beck Andrew H. , Soltermann Alex 
Published: April 2017

Abstract
Accurate stratification of tumors is imperative for adequate cancer management. In addition to staging, morphologic subtyping allows stratification of patients into additional prognostic groups. In this study, we used an image-based computational method on pan-cytokeratin IHC stainings to quantify tumor fragmentation (TF), a measure of tumor invasiveness of lung squamous cell carcinoma (LSCC). In two independent clinical cohorts from tissue microarrays (TMA: n = 208 patients) and whole sections (WS: n = 99 patients), TF was associated with poor prognosis and increased risk of blood vessel infiltration. A third cohort from The Cancer Genome Atlas (TCGA: n = 335 patients) confirmed the poor prognostic value of TF using a similar human-based score on hematoxylin-eosin staining. Integration of RNA-seq data from TCGA and LC-MS/MS proteomics from WS revealed an upregulation of extracellular matrix remodeling and focal adhesion processes in tumors with high TF, supporting their increased invasive potential. This proposed histologic parameter is an independent and unfavorable prognostic marker that could be established as a new grading parameter for LSCC. Cancer Res; 77(10); 2585–93. ©2017 AACR.
Tissue-Specific Signaling Networks Rewired by Major Somatic Mutations in Human Cancer Revealed by Proteome-Wide Discovery
Authors: Zhao Junfei , Cheng Feixiong , Zhao Zhongming 
Published: April 2017

AbstractMassive somatic mutations discovered by large cancer genome sequencing projects provide unprecedented opportunities in the development of precision oncology. However, deep understanding of functional consequences of somatic mutations and identifying actionable mutations and the related drug responses currently remain formidable challenges. Dysfunction of protein posttranslational modification plays critical roles in tumorigenesis and drug responses. In this study, we proposed a novel computational oncoproteomics approach, named kinome-wide network module for cancer pharmacogenomics (KNMPx), for identifying actionable mutations that rewired signaling networks and further characterized tumorigenesis and anticancer drug responses. Specifically, we integrated 746,631 missense mutations in 4,997 tumor samples across 16 major cancer types/subtypes from The Cancer Genome Atlas into over 170,000 carefully curated nonredundant phosphorylation sites covering 18,610 proteins. We found 47 mutated proteins (e.g., ERBB2, TP53, and CTNNB1) that had enriched missense mutations at their phosphorylation sites in pan-cancer analysis. In addition, tissue-specific kinase–substrate interaction modules altered by somatic mutations identified by KNMPx were significantly associated with patient survival. We further reported a kinome-wide landscape of pharmacogenomic interactions by incorporating somatic mutation-rewired signaling networks in 1,001 cancer cell lines via KNMPx. Interestingly, we found that cell lines could highly reproduce oncogenic phosphorylation site mutations identified in primary tumors, supporting the confidence in their associations with sensitivity/resistance of inhibitors targeting EGF, MAPK, PI3K, mTOR, and Wnt signaling pathways. In summary, our KNMPx approach is powerful for identifying oncogenic alterations via rewiring phosphorylation-related signaling networks and drug sensitivity/resistance in the era of precision oncology. Cancer Res; 77(11); 2810–21. ©2017 AACR.
Development of a T-cell Receptor Mimic Antibody against Wild-Type p53 for Cancer Immunotherapy
Authors: Li Demin , Bentley Carol , Anderson Amanda , Wiblin Sarah , Cleary Kirstie L.S. , Koustoulidou Sofia , Hassanali Tasneem , Yates Jenna , Greig Jenny , Nordkamp Marloes Olde , Trenevska Iva , Ternette Nicola , Kessler Benedikt M. , Cornelissen Bart , Cragg Mark S. , Banham Alison H. 
Published: April 2017

Abstract
The tumor suppressor p53 is widely dysregulated in cancer and represents an attractive target for immunotherapy. Because of its intracellular localization, p53 is inaccessible to classical therapeutic monoclonal antibodies, an increasingly successful class of anticancer drugs. However, peptides derived from intracellular antigens are presented on the cell surface in the context of MHC I and can be bound by T-cell receptors (TCR). Here, we report the development of a novel antibody, T1-116C, that acts as a TCR mimic to recognize an HLA-A*0201–presented wild-type p53 T-cell epitope, p5365–73(RMPEAAPPV). The antibody recognizes a wide range of cancers, does not bind normal peripheral blood mononuclear cells, and can activate immune effector functions to kill cancer cells in vitro. In vivo, the antibody targets p5365–73 peptide–expressing breast cancer xenografts, significantly inhibiting tumor growth. This represents a promising new agent for future cancer immunotherapy. Cancer Res; 77(10); 2699–711. ©2017 AACR.
Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors
Authors: Kosaka Takayuki , Tanizaki Junko , Paranal Raymond M. , Endoh Hideki , Lydon Christine , Capelletti Marzia , Repellin Claire E. , Choi Jihyun , Ogino Atsuko , Calles Antonio , Ercan Dalia , Redig Amanda J. , Bahcall Magda , Oxnard Geoffrey R. , Eck Michael J. , Jänne Pasi A. 
Published: April 2017

Abstract
Insertion mutations in EGFR and HER2 both occur at analogous positions in exon 20. Non–small cell lung cancer (NSCLC) patients with tumors harboring these mutations seldom achieve clinical responses to dacomitinib and afatinib, two covalent quinazoline–based inhibitors of EGFR or HER2, respectively. In this study, we investigated the effects of specific EGFR and HER2 exon 20 insertion mutations from NSCLC patients that had clinically achieved a partial response after dacomitinib treatment. We identified Gly770 as a common feature among the drug-sensitive mutations. Structural modeling suggested that this mutation may facilitate inhibitor binding to EGFR. Introduction of Gly770 into two dacomitinib-resistant EGFR exon 20 insertion mutants restored sensitivity to dacomitinib. Based on these findings, we used afatinib to treat an NSCLC patient whose tumor harbored the HER2 V777_G778insGSP mutation and achieved a durable partial response. We further identified secondary mutations in EGFR (T790M or C797S) and HER2 (C805S) that mediated acquired drug resistance in drug-sensitive EGFR or HER2 exon 20 insertion models. Overall, our findings identified a subset of EGFR and HER2 exon 20 insertion mutations that are sensitive to existing covalent quinazoline–based EGFR/HER2 inhibitors, with implications for current clinical treatment and next-generation small-molecule inhibitors. Cancer Res; 77(10); 2712–21. ©2017 AACR.
Clinically Relevant Concentrations of Anticancer Drugs: A Guide for Nonclinical Studies
Authors: Liston Dane R. , Davis Myrtle 
Published: April 2017

Abstract
Approved and marketed drugs are frequently studied in nonclinical models to evaluate the potential application to additional disease indications or to gain insight about molecular mechanisms of action. A survey of the literature reveals that nonclinical experimental designs (in vitro or in vivo) often include evaluation of drug concentrations or doses that are much higher than what can be achieved in patients (i.e., above the maximally tolerated dose or much higher than the clinically relevant exposures). The results obtained with these high concentrations may be particularly helpful in elucidating off-target effects and toxicities, but it is critical to have a dose–response curve that includes the minimally effective or clinically effective concentration for comparison. We have reviewed the clinical literature and drug product labels for all small molecules and biological agents approved by the FDA for use in oncology to identify and compile the available pharmacokinetic parameters. The data summarized here can serve as a guide for selection of in vitro concentrations and in vivo plasma exposures for evaluation of drug effects in nonclinical studies. Inclusion of drug concentrations or exposures that are relevant to those observed in clinical practice can improve translation of nonclinical mechanism of action findings into potentially relevant clinical effects. Clin Cancer Res; 23(14); 3489–98. ©2017 AACR.
Cortical Superficial Siderosis in Different Types of Cerebral Small Vessel Disease
Authors: Wollenweber Frank Arne , Baykara Ebru , Zedde Marialuisa , Gesierich Benno , Achmüller Melanie , Jouvent Eric , Viswanathan Anand , Ropele Stefan , Chabriat Hugues , Schmidt Reinhold , Opherk Christian , Dichgans Martin , Linn Jennifer , Duering Marco 
Published: April 2017

Background and Purpose—
Cortical superficial siderosis (cSS) has emerged as a clinically relevant imaging feature of cerebral amyloid angiopathy (CAA). However, it remains unknown whether cSS is also present in nonamyloid-associated small vessel disease and whether patients with cSS differ in terms of other small vessel disease imaging features.

Methods—
Three hundred sixty-four CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) patients, 372 population-based controls, and 100 CAA patients with cSS (fulfilling the modified Boston criteria for possible/probable CAA) were included. cSS and cerebral microbleeds were visually rated on T2*-weighted magnetic resonance imaging. White matter hyperintensities were segmented on fluid-attenauted inversion recovery images, and their spatial distribution was compared between groups using colocalization analysis. Cerebral microbleeds location was determined in an observer-independent way using an atlas in standard space.

Results—
cSS was absent in CADASIL and present in only 2 population-based controls (0.5%). Cerebral microbleeds were present in 64% of CAA patients with cSS, 34% of patients with CADASIL, and 12% of population-based controls. Among patients with cerebral microbleeds, lobar location was found in 95% of CAA patients with cSS, 48% of CADASIL patients, and 69% of population-based controls. The spatial distribution of white matter hyperintensities was comparable between CAA with cSS and CADASIL as indicated by high colocalization coefficients.

Conclusions—
cSS was absent in CADASIL, whereas other small vessel disease imaging features were similar to CAA patients with cSS. Our findings suggest that cSS in combination with other small vessel disease imaging markers is highly indicative of CAA.
The Increasing Power of the European Parliament: Negotiating the eu-India Free Trade Agreement
Authors: Frennhoff Larsén Magdalena 
Published: April 2017

AbstractSince the Lisbon Treaty increased the legal role of the European Parliament (ep) ineutrade policy, there has been a debate about the extent to which these legal competencies have translated into actual influence over the content and outcome ofeutrade negotiations. Using the trade negotiations between theeuand India as a case study, this article argues that the impact of theephas indeed been significant. Through two-level game analysis, which extends its domestic focus to include theepas a domestic constituent, it demonstrates how theephas affected theeuwin-set in ways that have both hindered and facilitated agreement at the international level between theeuand India. It also shows how theephas affected the negotiating dynamics and how theeunegotiators have had their preferences somewhat compromised by theepin their attempt at reaching an agreement with India.
Parameter and contact force estimation of planar rigid-bodies undergoing frictional contact
Authors: Fazeli Nima , Kolbert Roman , Tedrake Russ , Rodriguez Alberto 
Published: April 2017

This paper addresses the identification of the inertial parameters and the contact forces associated with objects making and breaking frictional contact with the environment. Our goal is to explore under what conditions, and to what degree, the observation of physical interaction, in the form of motions and/or applied external forces, is indicative of the underlying dynamics that governs it. In this study we consider the cases of passive interaction, where an object free-falls under gravity, and active interaction, where known external perturbations act on an object at contact. We assume that both object and environment are planar and rigid, and exploit the well-known complementarity formulation for contact resolution to establish a constrained optimization-based problem to estimate inertial parameters and contact forces. We also show that when contact modes are known, or guessed, the formulation provides a closed-form relationship between inertial parameters, contact forces, and observed motions, that turns into a least squares problem. Consistent with intuition, the analysis indicates that without the application of known external forces, the identifiable set of parameters remains coupled, i.e. the ratio of mass moment of inertia to mass and the ratio of contact forces to the mass. Interestingly the analysis also shows that known external forces can lead to decoupling and identifiability of mass, mass moment of inertia, and normal and tangential contact forces. We evaluate the proposed algorithms both in simulation and with real experiments for the cases of a free falling square, ellipse, and rimless wheel interacting with the ground, as well as a disk interacting with a manipulator.
Assistive technology to enable sleep function in patients with acquired brain injury: Issues and opportunities
Authors: Biajar Anmol , Mollayeva Tatyana , Sokoloff Sandra , Colantonio Angela 
Published: April 2017

Introduction Sleep disorders in patients with acquired brain injury are highly burdensome and associated with disability. An assistive technology framework emphasises the need to develop and apply a broad range of devices, strategies, and practices to ameliorate disabilities. We aimed to summarise scientific evidence regarding the utility of assistive technology in managing sleep disorders in patients with various causes of acquired brain injury. Method We retrieved articles before January 2016, through database searches of Medline, Embase, PsycINFO, CINAHL, and various bibliographies. The person–environment–occupation framework was used to analyse complex data pertaining to technology application and utility. Results We found 21 studies that described seven assistive technologies (continuous positive airway pressure, adaptive servo ventilator, nasotracheal suction mechanical ventilation, positioning devices, cognitive behavioural therapy, light therapy, and acupuncture) utilised in patients with acquired brain injury to manage sleep disorders. Conclusion Assistive technologies demonstrated effectiveness in alleviating and/or managing sleep disorders after acquired brain injury. Adherence to using the technology is limited by the level of injury-induced cognitive and physical impairment, technological regime, and environmental support. Development of user-friendly sleep-assistive technologies that take into consideration functional limitations and practice guidelines on structural communication between the occupational therapist, patient, and caregiver may facilitate patients’ self-determination in managing sleep disorders.
The use of video-modelling as a method for improving the social play skills of children with attention deficit hyperactivity disorder (ADHD) and their playmates
Authors: Wilkes-Gillan Sarah , Cantrill Alycia , Cordier Reinie , Barnes Gabrielle , Hancock Nicola , Bundy Anita 
Published: April 2017

Introduction We investigated child outcomes and mothers' perspectives following technology-based intervention sessions aimed at improving children's social play skills. Method Participants in this multiple case study included five children with attention deficit hyperactivity disorder, their mothers and five typically developing playmates, who had completed a parent-delivered play-based intervention 18 months previously. The initial intervention included the use of a technology-based interactive DVD at home and clinic-based sessions involving video-modelling. In this study, children received two additional technology-based clinic sessions involving video-modelling. Children's social play skills were measured pre- to post-intervention using the Test of Playfulness. Trends in scores were descriptively analysed by case. Mothers' perspectives were explored through semi-structured interviews; data were descriptively analysed by group and case. Results Two children with attention deficit hyperactivity disorder showed an increase in their social play skills, and three a decrease in skills. Of the playmates, three showed consistent social play skills, one an increase and one a decrease. Qualitative findings suggest parents felt better able to support their child. Parents also suggested next steps for the intervention were necessary as their child continued to develop. Conclusion Additional intervention support using technology after initial intervention may need to be adapted to different developmental stages and for use across different contexts.
Kappa opioid receptor antagonists: A possible new class of therapeutics for migraine prevention
Authors: Xie Jennifer Y , De Felice Milena , Kopruszinski Caroline M , Eyde Nathan , LaVigne Justin , Remeniuk Bethany , Hernandez Pablo , Yue Xu , Goshima Naomi , Ossipov Michael , King Tamara , Streicher John M , Navratilova Edita , Dodick David , Rosen Hugh , Roberts Ed , Porreca Frank 
Published: April 2017

Background Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain. Methods Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA). Results KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR. Conclusions Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.
First Metatarsophalangeal Contact Properties Following Proximal Opening Wedge and Scarf Osteotomies for Hallux Valgus Correction: A Biomechanical Study
Authors: Kia Cameron , Yoshida Ryu , Cote Mark , DiVenere Jessica , Geaney Lauren E. 
Published: April 2017

Background: Proximal opening wedge osteotomy (POWO) is an established procedure for moderate to severe hallux valgus. A common concern of this procedure is that it results in lengthening of the first metatarsal, which could cause increased intra-articular pressure of the first metatarsophalangeal joint (MTP) and may ultimately lead to arthritis because of these altered mechanics. The purpose of this study was to use a cadaveric model to compare intra-articular pressures and articulating contact properties of the MTP joint following either scarf osteotomy or POWO. Methods: Fresh-frozen cadaveric below-knee specimens with pre-existing hallux valgus (n = 12) and specimens without hallux valgus (n = 6, control group) were used. The hallux valgus specimens were stratified into 2 groups (n = 6 each): POWO or scarf osteotomy. The groups were matched based on the degree of deformity. Peak intra-articular pressure, force, and area were measured in all normal, preoperative, and postoperative specimens with a simulated weightbearing model. These measurements were made with a pressure transducer placed within the first MTP joint. Results: Postoperatively POWO group had slightly higher contact forces and pressures compared to the scarf group and lower contact forces and pressures than those of the normal group but were not statistically significant ( P > .05). Normal specimens had higher intra-articular force, pressure, and area than postoperative specimens but the difference was not found to be significant. First metatarsal lengthening was found in both the scarf and POWO specimens; however, neither increase was found to be significant ( P > .05). Conclusion: The results from this study show that after operative correction, contact properties of the fist MTP joint among normal, POWO, and scarf osteotomy groups revealed no significant differences. First MTP joints in those with hallux valgus had significantly lower contact force and pressure compared to those without hallux valgus. Clinical Relevance: With little long-term outcomes of proximal opening wedge osteotomy, this study will help predict the possibility of future MTP joint arthritis.