bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased Expression of HER2, HER3, and HER2:HER3 Heterodimers in HPV-Positive HNSCC Using a Novel Proximity-Based Assay: Implications for Targeted Therapies
Authors: Pollock Netanya I. , Wang Lin , Wallweber Gerald , Gooding William E. , Huang Weidong , Chenna Ahmed , Winslow John , Sen Malabika , DeGrave Kara A. , Li Hua , Zeng Yan , Grandis Jennifer R. 
Published: July 2015

Abstract
Purpose: In other cancer types, HPV infection has been reported to coincide with overexpression of HER2 (ERBB2) and HER3 (ERBB3); however, the association between HER2 or HER3 expression and dimer formation in HNSCC has not been reported. Overexpression of HER2 and HER3 may contribute to resistance to EGFR inhibitors, including cetuximab, although the contribution of HPV in modulating cetuximab response remains unknown. Determination of heterodimerization of HER receptors is challenging and has not been reported in HNSCC. The present study aimed to determine the expression of HER proteins in HPV+ versus HPV− HNSCC tumors using a proximity-based protein expression assay (VeraTag), and to determine the efficacy of HER-targeting agents in HPV+ and HPV− HNSCC cell lines.
Experimental Design: Expression of total HER1, HER2, and HER3, p95HER2, p-HER3, HER1:HER1 homodimers, HER2:HER3 heterodimers, and the HER3–PI3K complex in 88 HNSCC was determined using VeraTag, including 33 baseline tumors from individuals treated in a trial including cetuximab. Inhibition of cell growth and protein activation with cetuximab and afatinib was compared in HPV+ and HPV− cetuximab-resistant cell lines.
Results: Expression of total HER2, total HER3, HER2:HER3 heterodimers, and the HER3:PI3K complex were significantly elevated in HPV+ HNSCC. Total EGFR was significantly increased in HPV− HNSCC where VeraTag assay results correlated with IHC. Afatinib significantly inhibited cell growth when compared with cetuximab in the HPV+ and HPV− cetuximab-resistant HNSCC cell lines.
Conclusions: These findings suggest that agents targeting multiple HER proteins may be effective in the setting of HPV+ HNSCC and/or cetuximab resistance. Clin Cancer Res; 21(20); 4597–606. ©2015 AACR.
CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer
Authors: Higuchi Tomoe , Flies Dallas B. , Marjon Nicole A. , Mantia-Smaldone Gina , Ronner Lukas , Gimotty Phyllis A. , Adams Sarah F. 
Published: July 2015

Abstract
Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA− ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1− cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P &lt; 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1− cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1− tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer. Cancer Immunol Res; 3(11); 1257–68. ©2015 AACR.
Senescent Vascular Smooth Muscle Cells Drive Inflammation Through an Interleukin-1α–Dependent Senescence-Associated Secretory Phenotype
Authors: Gardner Sarah E. , Humphry Melanie , Bennett Martin R. , Clarke Murray C.H. 
Published: July 2015

Objective—
Vascular smooth muscle cells (VSMCs) that become senescent are both present within atherosclerotic plaques and thought to be important to the disease process. However, senescent VSMCs are generally considered to only contribute through inaction, with failure to proliferate resulting in VSMC- and collagen-poor unstable fibrous caps. Whether senescent VSMCs can actively contribute to atherogenic processes, such as inflammation, is unknown.

Approach and Results—
We find that senescent human VSMCs develop a proinflammatory state known as a senescence-associated secretory phenotype. Senescent human VSMCs release high levels of multiple cytokines and chemokines driven by secreted interleukin-1α acting in an autocrine manner. Consequently, the VSMC senescence-associated secretory phenotype promotes chemotaxis of mononuclear cells in vitro and in vivo. In addition, senescent VSMCs release active matrix metalloproteinase-9, secrete less collagen, upregulate multiple inflammasome components, and prime adjacent endothelial cells and VSMCs to a proadhesive and proinflammatory state. Importantly, maintaining the senescence-associated secretory phenotype places a large metabolic burden on senescent VSMCs, such that they can be selectively killed by inhibiting glucose utilization.

Conclusions—
Senescent VSMCs may actively contribute toward the chronic inflammation associated with atherosclerosis through the interleukin-1α–driven senescence-associated secretory phenotype and the priming of adjacent cells to a proatherosclerotic state. These data also suggest that inhibition of this potentially important source of chronic inflammation in atherosclerosis requires blockade of interleukin-1α and not interleukin-1β.
Proangiogenic Properties of Thrombospondin-4
Authors: Muppala Santoshi , Frolova Ella , Xiao Roy , Krukovets Irene , Yoon Suzy , Hoppe George , Vasanji Amit , Plow Edward , Stenina-Adognravi Olga 
Published: July 2015

Objective—
Thrombospondin-4 (TSP-4) is 1 of the 5 members of the thrombospondin protein family. TSP-1 and TSP-2 are potent antiangiogenic proteins. However, angiogenic properties of the 3 other TSPs, which do not contain the domains associated with the antiangiogeneic activity of TSP-1 and TSP-2, have not been explored. In our previous studies, we found that TSP-4 is expressed in the vascular matrix of blood vessels of various sizes and is especially abundant in capillaries. We sought to identify the function of TSP-4 in the regulation of angiogenesis.

Approach and Results—

The effect of TSP-4 in in vivo angiogenesis models and its effect on angiogenesis-related properties in cultured cells were assessed using
Thbs4
−/−
mice, endothelial cells (EC) derived from these mice, and recombinant TSP-4. Angiogenesis was decreased in
Thbs4
−/−
mice compared with wild-type mice. TSP-4 was detected in the lumen of the growing blood vessels. Mice expressing the P387 TSP-4 variant, which was previously associated with coronary artery disease and found to be more active in its cellular interactions, displayed greater angiogenesis compared with A387 form. Lung EC from
Thbs4
−/−
mice exhibited decreased adhesion, migration, and proliferation capacities compared with EC from wild-type mice. Recombinant TSP-4 promoted proliferation and the migration of EC. Integrin α
2
and gabapentin receptor α
2
δ-1 were identified as receptors involved in regulation of EC adhesion, migration, and proliferation by TSP-4.

Conclusion—
TSP-4, an extracellular matrix protein previously associated with tissue remodeling, is now demonstrated to possess proangiogenic activity.
Cerebral Microbleeds Are Associated With an Increased Risk of Stroke
Authors: Akoudad Saloua , Portegies Marileen L.P. , Koudstaal Peter J. , Hofman Albert , van der Lugt Aad , Ikram M. Arfan , Vernooij Meike W. 
Published: July 2015

Background—
Cerebral microbleeds are highly prevalent in people with clinically manifest cerebrovascular disease and have been shown to increase the risk of stroke recurrence. Microbleeds are also frequently found in healthy elderly, a population in which the clinical implication of microbleeds is unknown.

Methods and Results—
In the population-based Rotterdam Study, the presence, number, and location of microbleeds were assessed at baseline on brain MRI of 4759 participants aged ≥45 years. Participants were followed for incident stroke throughout the study period (2005–2013). We used Cox proportional hazards to investigate if people with microbleeds were at increased risk of stroke in comparison with those without microbleeds, adjusting for demographic, genetic, and cardiovascular risk, and cerebrovascular imaging markers. Microbleed prevalence was 18.7% (median count 1 [1–111]). During mean follow-up of 4.9 years (standard deviation, 1.6) 93 strokes occurred (72 ischemic, 11 hemorrhagic, and 10 unspecified). Microbleed presence was associated with an increased risk of all strokes (hazard ratio, 1.93; 95% confidence interval, 1.25–2.99). The risk increased with greater microbleed count. In comparison with those without microbleeds, participants with microbleeds in locations suggestive of cerebral amyloid angiopathy (lobar with or without cerebellar microbleeds) were at increased risk of intracerebral hemorrhage (hazard ratio, 5.27; 95% confidence interval, 1.38–20.23). Microbleeds at other locations were associated with an increased risk of both ischemic stroke and intracerebral hemorrhage.

Conclusions—
Microbleeds on MRI are associated with an increased risk of stroke in the general population. Our results strengthen the notion that microbleeds mark progression of cerebrovascular pathology and represent a precursor of stroke.
Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage
Authors: Yagi Kenji , Lidington Darcy , Wan Hoyee , Fares Jessica C. , Meissner Anja , Sumiyoshi Manabu , Ai Jinglu , Foltz Warren D. , Nedospasov Sergei A. , Offermanns Stefan , Nagahiro Shinji , Macdonald R. Loch , Bolz Steffen-Sebastian 
Published: July 2015

Background and Purpose—
Subarachnoid hemorrhage (SAH) is a complex stroke subtype characterized by an initial brain injury, followed by delayed cerebrovascular constriction and ischemia. Current therapeutic strategies nonselectively curtail exacerbated cerebrovascular constriction, which necessarily disrupts the essential and protective process of cerebral blood flow autoregulation. This study identifies a smooth muscle cell autocrine/paracrine signaling network that augments myogenic tone in a murine model of experimental SAH: it links tumor necrosis factor-α (TNFα), the cystic fibrosis transmembrane conductance regulator, and sphingosine-1-phosphate signaling.

Methods—
Mouse olfactory cerebral resistance arteries were isolated, cannulated, and pressurized for in vitro vascular reactivity assessments. Cerebral blood flow was measured by speckle flowmetry and magnetic resonance imaging. Standard Western blot, immunohistochemical techniques, and neurobehavioral assessments were also used.

Results—
We demonstrate that targeting TNFα and sphingosine-1-phosphate signaling in vivo has potential therapeutic application in SAH. Both interventions (1) eliminate the SAH-induced myogenic tone enhancement, but otherwise leave vascular reactivity intact; (2) ameliorate SAH-induced neuronal degeneration and apoptosis; and (3) improve neurobehavioral performance in mice with SAH. Furthermore, TNFα sequestration with etanercept normalizes cerebral perfusion in SAH.

Conclusions—
Vascular smooth muscle cell TNFα and sphingosine-1-phosphate signaling significantly enhance cerebral artery tone in SAH; anti-TNFα and anti–sphingosine-1-phosphate treatment may significantly improve clinical outcome.
Adopting a Patient-Centered Approach to Primary Outcome Analysis of Acute Stroke Trials Using a Utility-Weighted Modified Rankin Scale
Authors: Chaisinanunkul Napasri , Adeoye Opeolu , Lewis Roger J. , Grotta James C. , Broderick Joseph , Jovin Tudor G. , Nogueira Raul G. , Elm Jordan J. , Graves Todd , Berry Scott , Lees Kennedy R. , Barreto Andrew D. , Saver Jeffrey L. ,   Additional contributors from DAWN Trial Steering Committee:, Furlan Anthony , Baxter Blaise , Lutsep Helmi L. , Ribo Marc , Jansen Olav , Gupta Rishi , Pereira Vitor Mendes 
Published: July 2015

Background and Purpose—
Although the modified Rankin Scale (mRS) is the most commonly used primary end point in acute stroke trials, its power is limited when analyzed in dichotomized fashion and its indication of effect size challenging to interpret when analyzed ordinally. Weighting the 7 Rankin levels by utilities may improve scale interpretability while preserving statistical power.

Methods—
A utility-weighted mRS (UW-mRS) was derived by averaging values from time-tradeoff (patient centered) and person-tradeoff (clinician centered) studies. The UW-mRS, standard ordinal mRS, and dichotomized mRS were applied to 11 trials or meta-analyses of acute stroke treatments, including lytic, endovascular reperfusion, blood pressure moderation, and hemicraniectomy interventions.

Results—
Utility values were 1.0 for mRS level 0; 0.91 for mRS level 1; 0.76 for mRS level 2; 0.65 for mRS level 3; 0.33 for mRS level 4; 0 for mRS level 5; and 0 for mRS level 6. For trials with unidirectional treatment effects, the UW-mRS paralleled the ordinal mRS and outperformed dichotomous mRS analyses. Both the UW-mRS and the ordinal mRS were statistically significant in 6 of 8 unidirectional effect trials, whereas dichotomous analyses were statistically significant in 2 to 4 of 8. In bidirectional effect trials, both the UW-mRS and ordinal tests captured the divergent treatment effects by showing neutral results, whereas some dichotomized analyses showed positive results. Mean utility differences in trials with statistically significant positive results ranged from 0.026 to 0.249.

Conclusions—
A UW-mRS performs similar to the standard ordinal mRS in detecting treatment effects in actual stroke trials and ensures the quantitative outcome is a valid reflection of patient-centered benefits.
Effect of Antibiotic Class on Stroke Outcome
Authors: Zierath Dannielle , Kunze Allison , Fecteau Leia , Becker Kyra 
Published: July 2015

Background and Purpose—
Infections are common after stroke and associated with worse outcome. Clinical trials evaluating the benefit of prophylactic antibiotics have produced mixed results. This study explores the possibility that antibiotics of different classes may differentially affect stroke outcome.

Methods—
Lewis rats were subjected to transient cerebral ischemia (2 hours) and survived for 1 month. The day after stroke they were randomized to therapy with ceftiofur (a β-lactam antibiotic), enrofloxacin (a fluoroquinolone antibiotic), or vehicle (as controls) and underwent the equivalent of 7 days of treatment. Behavioral tests were performed weekly until euthanization. In a subset of animals, histology was done.

Results—
There were no differences in outcomes at 24 hours or 1 week after stroke among the different groups. At 1 month after stroke, however, performance on the rotarod was worse in enrofloxacin-treated animals when compared with control animals.

Conclusions—
Independent of infection, the antibiotic enrofloxacin was associated with worse stroke outcome. These data echo the clinical observations to date and suggest that the secondary effects of antibiotics on stroke outcome should be considered when treating infection in subjects with stroke. The mechanism by which this antibiotic affects outcome needs to be elucidated.
Pediatric Acute Stroke Protocol Activation in a Children’s Hospital Emergency Department
Authors: Ladner Travis R. , Mahdi Jasia , Gindville Melissa C. , Gordon Angela , Harris Zena Leah , Crossman Kristen , Pruthi Sumit , Abramo Thomas J. , Jordan Lori C. 
Published: July 2015

Background and Purpose—
Pediatric acute stroke teams are a new phenomenon. We sought to characterize the final diagnoses of children with brain attacks in the emergency department where the pediatric acute stroke protocol was activated and to describe the time to neurological evaluation and neuroimaging.

Methods—
Clinical and demographic information was obtained from a quality improvement database and medical records for consecutive patients (age, ≤20 years) presenting to a single institution’s pediatric emergency department where the acute stroke protocol was activated between April 2011 and October 2014. Stroke protocol activation means that a neurology resident evaluates the child within 15 minutes, and urgent magnetic resonance imaging is available.

Results—
There were 124 stroke alerts (age, 11.2±5.2 years; 63 boys/61 girls); 30 were confirmed strokes and 2 children had a transient ischemic attack. Forty-six of 124 (37%) cases were healthy children without any significant medical history. Nonstroke neurological emergencies were found in 17 children (14%); the majority were meningitis/encephalitis (n=5) or intracranial neoplasm (n=4). Other common final diagnoses were complex migraine (17%) and seizure (15%). All children except 1 had urgent neuroimaging. Magnetic resonance imaging was the first study in 76%. The median time from emergency department arrival to magnetic resonance imaging was 94 minutes (interquartile range, 49–151 minutes); the median time to computed tomography was 59 minutes (interquartile range, 40–112 minutes).

Conclusions—
Of pediatric brain attacks, 24% were stroke, 2% were transient ischemic attack, and 14% were other neurological emergencies. Together, 40% had a stroke or other neurological emergency, underscoring the need for prompt evaluation and management of children with brain attacks.
Firefighting to Innovation
Authors: Hignett Sue , Wolf Laurie , Taylor Ellen , Griffiths Paula 
Published: July 2015

Objective: The aim of this study was to use a theoretical model (bench) for human factors and ergonomics (HFE) and a comparison with occupational slips, trips, and falls (STFs) risk management to discuss patient STF interventions (bedside). Background: Risk factors for patient STFs have been identified and reported since the 1950s and are mostly unchanged in the 2010s. The prevailing clinical view has been that STF events indicate underlying frailty or illness, and so many of the interventions over the past 60 years have focused on assessing and treating physiological factors (dizziness, illness, vision/hearing, medicines) rather than designing interventions to reduce risk factors at the time of the STF. Method: Three case studies are used to discuss how HFE has been, or could be, applied to STF risk management as (a) a design-based (building) approach to embed safety into the built environment, (b) a staff- (and organization-) based approach, and (c) a patient behavior–based approach to explore and understand patient perspectives of STF events. Results and Conclusion: The results from the case studies suggest taking a similar HFE integration approach to other industries, that is, a sustainable design intervention for the person who experiences the STF event—the patient. Application: This paper offers a proactive problem-solving approach to reduce STFs by patients in acute hospitals. Authors of the three case studies use HFE principles (bench/book) to understand the complex systems for facility and equipment design and include the perspective of all stakeholders (bedside).
Shoulder Dysfunction after Selective Neck Dissection in Recurrent Nasopharyngeal Carcinoma
Authors: Chan Jimmy Yu Wai , Wong Stanley Thian Sze , Chan Richie Chiu Lung , Wei William Ignace 
Published: July 2015

ObjectiveTo investigate the incidence of occult nodal metastasis and severity of shoulder dysfunction after selective neck dissection (SND) for recurrent nasopharyngeal carcinoma (NPC) with N0 status.Study DesignProspective, single‐group, pre/post test design.SettingAcademic medical center.Subjects and MethodsBetween 1998 and 2012, 46 patients who had recurrent NPC and N0 status were recruited. They subsequently received salvage nasopharyngectomy and SND, removing ipsilateral level I to III and V lymphatics. The incidence of occult nodal metastasis was noted. All patients underwent standardized physiotherapy after surgery. Postoperative shoulder function was measured using the Disability of Arm, Shoulder, and Hand (DASH) questionnaire.ResultsThe incidence of microscopic nodal metastasis was 15.2%. For first year posttreatment, the mean DASH score was 44.2. With time, there was no improvement in shoulder function despite targeted physiotherapy (P =. 09), and the second postoperative year mean DASH score was 46.3. The degree of daily activity affected was rated as moderate to very limited, and 30% of the patients had at least moderate shoulder pain at rest.ConclusionShoulder dysfunction after SND for recurrent NPC is significant and persistent. Given the low incidence of microscopic nodal metastasis in such circumstances, routine SND is not recommended.
Neural Response Telemetry Thresholds in Patients with Cochlear Nerve Canal Stenosis
Authors: Han Shuguang , Wang Line , Zhang Daoxing , Peng Kevin 
Published: July 2015

ObjectiveTo explore neural response telemetry (NRT) thresholds in patients with stenotic versus normal cochlear nerve canals.Study DesignCase series with chart review.SettingTertiary referral center.Subjects and MethodsThirty pediatric patients with profound sensorineural hearing loss in at least 1 ear and no benefit from amplification underwent computed tomography imaging of the temporal bones. They were divided into 3 groups according to the diameter of the cochlear nerve canal: group A, <1.5 mm; group B, 1.5 to 1.7 mm; group C, 1.8 to 2.1 mm. All patients underwent cochlear implantation with full insertion of all electrodes. NRT was performed both intraoperatively and 6 months postoperatively in all patients; thresholds of electrodes 1, 11, and 22 were compared.ResultsPer analysis of variance, intraoperative and 6‐month postoperative NRT thresholds were both significantly different among groups A, B, and C at electrodes 1 and 22 but not at electrode 11. On intergroup analysis, group A showed statistically higher thresholds than those of groups B and C; however, no difference was found between groups B and C.ConclusionCochlear nerve canal stenosis, defined as a canal diameter <1.5 mm, is associated with significantly increased NRT thresholds, which may play a role in postimplant performance.