bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIMP-1 via TWIST1 Induces EMT Phenotypes in Human Breast Epithelial Cells
Authors: D'Angelo Rosemarie Chirco , Liu Xu-Wen , Najy Abdo J. , Jung Young Suk , Won Joshua , Chai Karl X. , Fridman Rafael , Kim Hyeong-Reh Choi 
Published: June 2014

AbstractTissue inhibitor of metalloproteinase-1 (TIMP-1) regulates intracellular signaling networks for inhibition of apoptosis. Tetraspanin (CD63), a cell surface binding partner for TIMP-1, was previously shown to regulate integrin-mediated survival pathways in the human breast epithelial cell line MCF10A. In the current study, we show that TIMP-1 expression induces phenotypic changes in cell morphology, cell adhesion, cytoskeletal remodeling, and motility, indicative of an epithelial–mesenchymal transition (EMT). This is evidenced by loss of the epithelial cell adhesion molecule E-cadherin with an increase in the mesenchymal markers vimentin, N-cadherin, and fibronectin. Signaling through TIMP-1, but not TIMP-2, induces the expression of TWIST1, an important EMT transcription factor known to suppress E-cadherin transcription, in a CD63-dependent manner. RNAi-mediated knockdown of TWIST1 rescued E-cadherin expression in TIMP-1–overexpressing cells, demonstrating a functional significance of TWIST1 in TIMP-1–mediated EMT. Furthermore, analysis of TIMP-1 structural mutants reveals that TIMP-1 interactions with CD63 that activate cell survival signaling and EMT do not require the matrix metalloproteinase (MMP)–inhibitory domain of TIMP-1. Taken together, these data demonstrate that TIMP-1 binding to CD63 activates intracellular signal transduction pathways, resulting in EMT-like changes in breast epithelial cells, independent of its MMP-inhibitory function.Implications: TIMP-1′s function as an endogenous inhibitor of MMP or as a “cytokine-like” signaling molecule may be a critical determinant for tumor cell behavior. Mol Cancer Res; 12(9); 1324–33. ©2014 AACR.
AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer
Authors: Cross Darren A.E. , Ashton Susan E. , Ghiorghiu Serban , Eberlein Cath , Nebhan Caroline A. , Spitzler Paula J. , Orme Jonathon P. , Finlay M. Raymond V. , Ward Richard A. , Mellor Martine J. , Hughes Gareth , Rahi Amar , Jacobs Vivien N. , Brewer Monica Red , Ichihara Eiki , Sun Jing , Jin Hailing , Ballard Peter , Al-Kadhimi Katherine , Rowlinson Rachel , Klinowska Teresa , Richmond Graham H.P. , Cantarini Mireille , Kim Dong-Wan , Ranson Malcolm R. , Pao William 
Published: June 2014

Abstract
First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm+) non–small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm+ sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino–pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm+ and EGFRm+/T790M+ mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm+ T790M+ NSCLC is described as proof of principle.
Significance: We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M+ mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented. Cancer Discov; 4(9); 1046–61. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 973
A Comparison of Clinical Outcomes From Carotid Artery Stenting Among US Hospitals
Authors: Epstein Andrew J. , Yang Lin , Yang Feifei , Groeneveld Peter W. 
Published: June 2014

Background—
The Centers for Medicare and Medicaid Services require hospitals performing carotid artery stenting (CAS) to recertify the quality of their programs every 2 years, but currently this involves no explicit comparisons of postprocedure mortality across hospitals. Hence, the current recertification process may fail to identify hospitals that are performing poorly in relation to peer institutions. Our objective was to compare risk-standardized procedural outcomes across US hospitals that performed CAS and to identify hospitals with statistically high postprocedure mortality rates.

Methods and Results—

We conducted a retrospective cohort study of Medicare beneficiaries who underwent CAS from July 2009 to June 2011 at 927 US hospitals. Thirty-day risk-standardized mortality rates were calculated using the Hospital Compare statistical method, a well-validated hierarchical generalized linear model that included both patient-level and hospital-level predictors. Claims were examined from 22 708 patients undergoing CAS, with a crude 30-day mortality rate of 2.0%. Risk-standardized 30-day mortality rates after CAS varied from 1.1% to 5.1% (
P
<0.001 for the difference). Thirteen hospitals had risk-standardized mortality rates that were statistically (
P
<0.05) higher than the national mean. Conversely, 5 hospitals had risk-standardized mortality rates that were statistically (
P
<0.05) lower than the national mean.

Conclusions—
We used administrative claims to identify several CAS hospitals with excessively high 30-day mortality after carotid stenting. When combined with information currently used by Medicare for CAS recertification, such as clinical registry data and program reports, clinical outcomes comparisons could enhance Medicare’s ability to identify hospitals that are questionable candidates for recertification.
Oscillatory Responses to Semantic and Syntactic Violations
Authors: Kielar Aneta , Meltzer Jed A. , Moreno Sylvain , Alain Claude , Bialystok Ellen 
Published: June 2014

Abstract
EEG studies employing time–frequency analysis have revealed changes in theta and alpha power in a variety of language and memory tasks. Semantic and syntactic violations embedded in sentences evoke well-known ERPs, but little is known about the oscillatory responses to these violations. We investigated oscillatory responses to both kinds of violations, while monolingual and bilingual participants performed an acceptability judgment task. Both violations elicited power decreases (event-related desynchronization, ERD) in the 8–30 Hz frequency range, but with different scalp topographies. In addition, semantic anomalies elicited power increases (event-related synchronization, ERS) in the 1–5 Hz frequency band. The 1–5 Hz ERS was strongly phase-locked to stimulus onset and highly correlated with time domain averages, whereas the 8–30 Hz ERD response varied independently of these. In addition, the results showed that language expertise modulated 8–30 Hz ERD for syntactic violations as a function of the executive demands of the task. When the executive function demands were increased using a grammaticality judgment task, bilinguals but not monolinguals demonstrated reduced 8–30 Hz ERD for syntactic violations. These findings suggest a putative role of the 8–30 Hz ERD response as a marker of linguistic processing that likely represents a separate neural process from those underlying ERPs.
Reward Acts on the pFC to Enhance Distractor Resistance of Working Memory Representations
Authors: Fallon Sean James , Cools Roshan 
Published: June 2014

Abstract
Working memory and reward processing are often thought to be separate, unrelated processes. However, most daily activities involve integrating these two types of information, and the two processes rarely, if ever, occur in isolation. Here, we show that working memory and reward interact in a task-dependent manner and that this task-dependent interaction involves modulation of the pFC by the ventral striatum. Specifically, BOLD signal during gains relative to losses in the ventral striatum and pFC was associated not only with enhanced distractor resistance but also with impairment in the ability to update working memory representations. Furthermore, the effect of reward on working memory was accompanied by differential coupling between the ventral striatum and ignore-related regions in the pFC. Together, these data demonstrate that reward-related signals modulate the balance between cognitive stability and cognitive flexibility by altering functional coupling between the ventral striatum and the pFC.
A 10-Year Survey of Extreme Rainfall Events in the Central and Eastern United States Using Gridded Multisensor Precipitation Analyses
Authors: Stevenson Stephanie N. , Schumacher Russ S. 
Published: June 2014

AbstractExtreme rainfall events in the central and eastern United States during 2002–11 were identified using NCEP stage-IV precipitation analyses. Precipitation amounts were compared against established 50- and 100-yr recurrence interval thresholds for 1-, 6-, and 24-h durations. The authors identified points where analyzed precipitation exceeded the threshold, and combined points associated with the same weather system into events. At shorter durations, points exceeding the thresholds were most common in the Southeast, whereas points were more uniformly distributed for the 24-h duration. Most 24-h events have more points than the other durations, reflecting the importance of organized precipitation systems on longer temporal scales. Though monthly peaks varied by region, the maximum (minimum) usually occurred during the summer (winter); however, the 24-h point maximum occurred in September owing to tropical cyclones. The maximum (minimum) in hourly extreme rainfall points occurred at 2300 (1100) LST, though there were regional differences in the timing of the diurnal maxima and minima. Over half of 100-yr, 24-h events were a result of mesoscale convective systems (MCS), with synoptic and tropical systems responsible for nearly one-third and one-tenth, respectively. Of the 10 events with the most points exceeding this threshold, 5 were associated with tropical cyclones, 3 were synoptic events, and 2 were MCSs. Among the MCS events, 7 of the top 10 were training line/adjoining stratiform (TL/AS). While the 49 TL/AS events investigated further had similar moisture availability, the more widespread events had stronger low-level winds, stronger warm air advection, and stronger and more expansive frontogenesis in the inflow.
Success of Salvage Treatment: A Critical Appraisal of Salvage Rates for Different Subsites of HNSCC
Authors: Matoscevic Katja , Graf Nicole , Pezier Thomas F. , Huber Gerhard F. 
Published: June 2014

ObjectiveDespite advances in interdisciplinary treatment protocols, the chance of cure for recurrent head and neck squamous cell carcinoma (HNSCC) following failed primary therapy is poor and often entails a high morbidity. Recurrence rates vary widely in the literature depending on tumor localization, primary tumor stage, and treatment modality, and only a minority of patients can be salvaged.Study DesignHistorical cohort study.SettingThis study valuates the outcomes of patients treated for recurrent squamous cell carcinoma of the larynx, pharynx, and oral cavity in the largest tertiary referral center of Switzerland to find predictors for survival in salvage surgery with curative intent.Subjects and MethodsIncluded were 176 consecutive patients with recurrent disease after primary curative treatment of HNSCC, in locations mentioned previously. Kaplan‐Meier survival analyses with log‐rank testing were performed depending on T and N stage, gender, treatment, and location of first relapse to evaluate the impact on overall survival, disease specific survival, and recurrence free survival.ResultsOverall successful salvage rates were 49.2% for laryngeal recurrence, 35.1% for oral cavity, 32.7% for oropharyngeal, and a mere 17.4% for hypopharyngeal recurrences. Predictive factors for better outcome were location of recurrence, female gender, lymph node status, and extent of salvage treatment.ConclusionIn case of recurrent disease, laryngeal cancers showed the best salvage rates, whereas in hypopharyngeal relapses, very few patients could be successfully salvaged. Patients therefore should be carefully selected and counseled for salvage treatment according to patient motivation, age, type of previous treatment, surgical resectability, and exclusion of distant recurrence.
Medication Associated with Hearing Loss: 25 Years of Medical Malpractice Cases in the United States
Authors: Ruhl Douglas S. , Cable Benjamin B. , Martell David W. 
Published: June 2014

ObjectivesMany medications have the potential for ototoxicity. To potentiate management of this risk, this study examines malpractice litigation trends of lawsuits involving hearing loss associated with medication use. As experts in hearing loss, it may benefit otolaryngologists to be familiar with this information.Study DesignRetrospective review.SettingAll US civil trials.Subjects and MethodsCourt records of legal trials from 1987 to 2012 were obtained from 2 major computerized databases. Data were compiled on the demographics of the defendant and plaintiff, use of otolaryngologists as expert witnesses, medication used, legal allegations, verdicts, and judgments.ResultsForty‐six unique cases met inclusion criteria and were selected for review. Antibiotics (72%), specifically aminoglycosides (47%), were the most common medications cited as causing hearing loss. Eleven (22%) cases were resolved through a settlement before a verdict was reached. Verdicts in favor of the plaintiffs (37%) were awarded an average of $1,134,242. Pediatric patients were more likely to have outcomes in their favor (P =. 03) compared to adults. Of the cases found in favor of the plaintiff, the most common reasons cited were inappropriate medication, dose, or duration (59%); failure to properly monitor (39%); and failure to choose a less toxic medication (18%).ConclusionsPhysicians must be aware of the potential effects of the medications they prescribe. An understanding of potential drug interactions, proper monitoring, and appropriate substitution with less toxic medications are important to improve patient care. Analyzing litigation trends may be used to prevent future lawsuits and improve physician awareness.
Minimizing the perfusion system by integration of the components. Does it affect the hematocrit drop and transfused red blood cells? A retrospective audit
Authors: Boks RH , van Pelt C , Takkenberg JJM , Bogers Ad JJC 
Published: June 2014

Background: We evaluate the affect on the hematocrit (Hct) drop and the amount of transfused red blood cells (RBCs) during cardiopulmonary bypass (CPB) in adult cardiac surgery patients due to minimizing the CPB circuit by using integrated components. Methods: Two hundred and seventy-two patients were included in this retrospective audit. Patients were assigned to three cohorts: the first cohort consisted of patients operated on with a CPB circuit volume of 1630 ml in 2008; the second cohort of such patients in 2010, with 1380 ml; and the third cohort of such patients in 2011, with 1250 ml. Results: There were no significant differences with respect to patient demographics. The priming volume was consecutively significantly reduced; (1635 ± 84 ml, 1384 ± 72 ml and 1256 ± 130 ml, p<0.0001). A trend of decreased amount of RBCs during CPB was visible (cohort 1630: 98 ± 195 ml, cohort 1380: 35 ± 151 ml and cohort 1250: 48 ± 113 ml, p=0.02). Also, the amount of RBCs during the total CPB procedure shows a decreased trend (cohort 1630: 122 ± 230 ml, cohort 1380: 52 ± 180 ml and cohort 1250: 71 ± 156 ml, p=0.04). Blood loss during CPB was significantly lower in cohorts 1380 and 1250 (1630: 922 ± 378 ml, 1380: 706 ± 347 ml and 1250: 708 ± 418 ml, p<0.0001). The volume of diuresis was significantly larger in cohort 1630 (1630: 1166 ± 800 ml, 1380: 477 ± 530 ml and 1250: 523 ± 504 ml, p<0.0001). The Hct drop at the start and end of CPB was significantly reduced comparing cohort 1630 with cohort 1250 (1630: 32 ± 7%, 1380: 30 ± 7% and 1250: 28 ± 10%, p=0.002) at the start of CPB and (1630: 31 ± 7%, 1380: 29 ± 7% and 1250: 28 ± 8%, p=0.016) at the end of CPB. The Hct values at the start and end of CPB were significantly different between the cohorts (1680: 0.23 ± 0.03 L/L - 0.22 ± 0.02 L/L, 1380: 0.25 ± 0.03 L/L - 0.25 ± 0.03 L/L and 1250: 0.25 ± 0.03 L/L- 0.25 ± 0.03 L/L, p= 0.001 and 0.0001). Conclusions: Minimizing our CPB circuit by using integrated components has affected the drop of Hct and the amount of transfused RBCs.
Task-specific balance training improves self-assessed function in community-dwelling older adults with balance deficits and fear of falling: a randomized controlled trial
Authors: Roaldsen Kirsti Skavberg , Halvarsson Alexandra , Sahlström Theres , Ståhle Agneta 
Published: June 2014

Objective: To evaluate the effects of a 12-week balance training programme on self-assessed function and disability in healthy community-dwelling older adults with self-perceived balance deficits and fear of falling. Design: A prospective, randomized controlled trial. Setting: Stockholm County, Sweden. Participants: A total of 59 community-dwelling older adults (42 women and 17 men) aged 67–93 were randomized to either an intervention group ( n = 38) or to serve as controls ( n = 21) after baseline testing. Intervention: The intervention was a 12-week, three times per week, progressive, specific and individually adjusted group balance-training programme. Main measures: Self-perceived function and disability measured with Late Life Function and Disability Instrument. Results: The intervention group reported improvement in overall function ( p = 0.016), as well as in basic ( p = 0.044) and advanced lower extremity function ( p = 0.025) compared with the control group. The study showed no improvement in overall disability or upper extremity function. Conclusion: This group balance training programme improves self-assessed function in community-dwelling older adults with balance deficits and fear of falling.
Comparing the effects of hydrotherapy and land-based therapy on balance in patients with Parkinson’s disease: a randomized controlled pilot study
Authors: Volpe Daniele , Giantin Maria Giulia , Maestri Roberto , Frazzitta Giuseppe 
Published: June 2014

Objective: Our aim was to evaluate the feasibility of a hydrotherapy treatment in patients with Parkinson’s disease and the effectiveness of this treatment on balance parameters in comparison to a traditional land-based physical therapy. Design: A randomized single-blind controlled trial. Setting: Outpatients. Subjects: Thirty-four patients with Parkinson’s disease in Hoehn-Yahr stage 2.5–3. Intervention: Group 1 hydrotherapy treatment, group 2 land-based rehabilitation treatment. The two groups underwent the same rehabilitation period (60 minutes of treatment, five days a week for two months). Main measures: The primary outcome measures were the centre of the pressure sway area recorded with open and closed eyes, using a stabilometric platform. Secondary outcome measures were Unified Parkinson’s Disease Rating Scale II and III, Timed Up and Go Test, Berg Balance Scale, Activities-specific Balance Confidence Scale, Falls Efficacy Scale, Falls diary and Parkinson’s Disease Questionnaire-39. Results: Hydrotherapy treatment proved to be feasible and safe. Patients in both groups had a significant improvement in all outcome variables. There was a better improvement in patients who underwent hydrotherapy than in patients treated with land-based therapy in the centre of pressure sway area closed eyes (mean SD change: 45.4 SD64.9 vs. 6.9 SD45.3, p = 0.05), Berg Balance Scale (51.2 SD3.1 vs. 6.0 SD3.1, p = 0.005), Activities-specific Balance Confidence Scale (16.8 SD10.6 vs. 4.1 SD5.4, p = 0.0001), Falls Efficacy Scale (−5.9 SD4.8 vs. −1.9 SD1.4, p = 0.003), Parkinson’s Disease Quetionnaire-39 (−18.4 SD12.9 vs. −8.0 SD7.0, p = 0.006) and falls diary (−2.4 SD2.2 vs. −0.4 SD0.5, p = 0.001). Conclusion: Our study suggests that hydrotherapy may constitute a possible treatment for balance dysfunction in Parkinsonian patients with moderate stage of disease.
Surgically Relevant Bony and Soft Tissue Anatomy of the Proximal Femur
Authors: Philippon Marc J. , Michalski Max P. , Campbell Kevin J. , Goldsmith Mary T. , Devitt Brian M. , Wijdicks Coen A. , LaPrade Robert F. 
Published: June 2014

Background: Hip endoscopy facilitates the treatment of extra-articular disorders of the proximal femur. Unfortunately, current knowledge of proximal femur anatomy is limited to qualitative descriptions and lacks surgically relevant landmarks. Purpose: To provide a quantitative and qualitative analysis of proximal femur anatomy in reference to surgically relevant bony landmarks. Study Design: Descriptive laboratory study. Methods: Fourteen cadaveric hemipelvises were dissected. A coordinate measuring device measured dimensions and interrelationships of the gluteal muscles, hip external rotators, pectineus, iliopsoas, and joint capsule in reference to osseous landmarks. Results: The vastus tubercle, superomedial border of the greater trochanter, and femoral head-neck junction were distinct and reliable osseous landmarks. The anteroinferior tip of the vastus tubercle was 17.1 mm (95% CI: 14.5, 19.8 mm) anteroinferior to the center of the gluteus medius lateral insertional footprint and was 22.9 mm (95% CI: 20.1, 25.7 mm) inferolateral to the center of the gluteus minimus insertional footprint. The insertions of the piriformis, conjoint tendon of the hip (superior gemellus, obturator internus, and inferior gemellus), and obturator externus were identified relative to the superomedial border of the greater trochanter. The relationship of the aforementioned footprints were 49% (95% CI: 43%, 54%), 42% (95% CI: 33%, 50%), and 64% (95% CI: 59%, 69%) from the anterior (0%) to posterior (100%) margins of the superomedial border of the greater trochanter, respectively. The hip joint capsule attached distally on the proximal femur 18.2 mm (95% CI: 14.2, 22.2 mm) from the head-neck junction medially on average. Conclusion: The vastus tubercle, superomedial border of the greater trochanter, and the femoral head-neck junction were reliable osseous landmarks for the identification of the tendinous and hip capsular insertions on the proximal femur. Knowledge of the interrelationships between these structures is essential for endoscopic navigation and anatomic surgical repair and reconstruction. Clinical Relevance: The qualitative and quantitative clinically relevant anatomic data presented here will aid in the diagnosis of proximal femur pathology and will provide a template for anatomic repair or reconstruction.
Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation
Authors: Hervier Baptiste , Haroche Julien , Arnaud Laurent , Charlotte Frédéric , Donadieu Jean , Néel Antoine , Lifermann François , Villabona Carles , Graffin Bruno , Hermine Olivier , Rigolet Aude , Roubille Camille , Hachulla Eric , Carmoi Thierry , Bézier Maud , Meignin Véronique , Conrad Marie , Marie Laurence , Kostrzewa Elise , Michot Jean-Marie , Barete Stéphane , Taly Valerie , Cury Karine , Emile Jean-François , Amoura Zahir 
Published: June 2014

Key PointsThe association of both Langerhans cell histiocytosis and Erdheim-Chester disease is not exceptional. This association is linked to BRAFV600E mutation.