bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intracrine VEGF Signaling Mediates the Activity of Prosurvival Pathways in Human Colorectal Cancer Cells
Authors: Bhattacharya Rajat , Ye Xiang-Cang , Wang Rui , Ling Xia , McManus Madonna , Fan Fan , Boulbes Delphine , Ellis Lee M. 
Published: March 2016

Abstract
The effects of vascular endothelial growth factor-A (VEGF-A/VEGF) and its receptors on endothelial cells function have been studied extensively, but their effects on tumor cells are less well defined. Studies of human colorectal cancer cells where the VEGF gene has been deleted suggest an intracellular role of VEGF as a cell survival factor. In this study, we investigated the role of intracrine VEGF signaling in colorectal cancer cell survival. In human colorectal cancer cells, RNAi-mediated depletion of VEGF decreased cell survival and enhanced sensitivity to chemotherapy. Unbiased reverse phase protein array studies and subsequent validation experiments indicated that impaired cell survival was a consequence of disrupted AKT and ERK1/2 (MAPK3/1) signaling, as evidenced by reduced phosphorylation. Inhibition of paracrine or autocrine VEGF signaling had no effect on phospho-AKT or phospho-ERK1/2 levels, indicating that VEGF mediates cell survival via an intracellular mechanism. Notably, RNAi-mediated depletion of VEGF receptor VEGFR1/FLT1 replicated the effects of VEGF depletion on phospho-AKT and phospho-ERK1/2 levels. Together, these studies show how VEGF functions as an intracrine survival factor in colorectal cancer cells, demonstrating its distinct role in colorectal cancer cell survival. Cancer Res; 76(10); 3014–24. ©2016 AACR.
Proteasomal Inhibition by Ixazomib Induces CHK1 and MYC-Dependent Cell Death in T-cell and Hodgkin Lymphoma
Authors: Ravi Dashnamoorthy , Beheshti Afshin , Abermil Nasséra , Passero Frank , Sharma Jaya , Coyle Michael , Kritharis Athena , Kandela Irawati , Hlatky Lynn , Sitkovsky Michail V. , Mazar Andrew , Gartenhaus Ronald B. , Evens Andrew M. 
Published: March 2016

Abstract
Proteasome-regulated NF-κB has been shown to be important for cell survival in T-cell lymphoma and Hodgkin lymphoma models. Several new small-molecule proteasome inhibitors are under various stages of active preclinical and clinical development. We completed a comprehensive preclinical examination of the efficacy and associated biologic effects of a second-generation proteasome inhibitor, ixazomib, in T-cell lymphoma and Hodgkin lymphoma cells and in vivo SCID mouse models. We demonstrated that ixazomib induced potent cell death in all cell lines at clinically achievable concentrations. In addition, it significantly inhibited tumor growth and improved survival in T-cell lymphoma and Hodgkin lymphoma human lymphoma xenograft models. Through global transcriptome analyses, proteasomal inhibition showed conserved overlap in downregulation of cell cycle, chromatin modification, and DNA repair processes in ixazomib-sensitive lymphoma cells. The predicted activity for tumor suppressors and oncogenes, the impact on “hallmarks of cancer,” and the analysis of key significant genes from global transcriptome analysis for ixazomib strongly favored tumor inhibition via downregulation of MYC and CHK1, its target genes. Furthermore, in ixazomib-treated lymphoma cells, we identified that CHK1 was involved in the regulation of MYC expression through chromatin modification involving histone H3 acetylation via chromatin immunoprecipitation. Finally, using pharmacologic and RNA silencing of CHK1 or the associated MYC-related mechanism, we demonstrated synergistic cell death in combination with antiproteasome therapy. Altogether, ixazomib significantly downregulates MYC and induces potent cell death in T-cell lymphoma and Hodgkin lymphoma, and we identified that combinatorial therapy with anti-CHK1 treatment represents a rational and novel therapeutic approach. Cancer Res; 76(11); 3319–31. ©2016 AACR.
Genotype–phenotype correlation in a cohort of Portuguese patients comprising the entire spectrum of VWD types: impact of NGS
Authors: Fidalgo Teresa , Salvado Ramon , Corrales Irene , Pinto Silva , Borràs Nina , Oliveira Ana , Martinho Patricia , Ferreira Gisela , Almeida Helena , Oliveira Cristina , Marques Dalila , Gonçalves Elsa , Diniz MJoão , Antunes Margarida , Tavares Alice , Caetano Gonçalo , Kjöllerström Paula , Maia Raquel , Sevivas Teresa , Vidal Francisco , Ribeiro Leticia 
Published: March 2016

SummaryThe diagnosis of von Willebrand disease (VWD), the most common inherited bleeding disorder, is characterised by a variable bleeding tendency and heterogeneous laboratory phenotype. The sequencing of the entire VWF coding region has not yet become a routine practice in diagnostic laboratories owing to its high costs. Nevertheless, nextgeneration sequencing (NGS) has emerged as an alternative to overcome this limitation. We aimed to determine the correlation of genotype and phenotype in 92 Portuguese individuals from 60 unrelated families with VWD; therefore, we directly sequenced VWF. We compared the classical Sanger sequencing approach and NGS to assess the value-added effect on the analysis of the mutation distribution in different types of VWD. Sixty-two different VWF mutations were identified, 27 of which had not been previously described. NGS detected 26 additional mutations, contributing to a broad overview of the mutant alleles present in each VWD type. Twenty-nine probands (48.3 %) had two or more mutations; in addition, mutations with pleiotropic effects were detected, and NGS allowed an appropriate classification for seven of them. Furthermore, the differential diagnosis between VWD 2B and platelet type VWD (n = 1), Bernard–Soulier syndrome and VWD 2B (n = 1), and mild haemophilia A and VWD 2N (n = 2) was possible. NGS provided an efficient laboratory workflow for analysing VWF. These findings in our cohort of Portuguese patients support the proposal that improving VWD diagnosis strategies will enhance clinical and laboratory approaches, allowing to establish the most appropriate treatment for each patient.
Release of the Inferior Crus in Antihelix Plasty
Authors: Raunig Hermann , Ofner Michael 
Published: March 2016

Objective: Protruding ears with a hypoplastic antihelix often have poorly developed inferior cura. Publications on this topic until now have only dealt with absent inferior crus and have neglected its importance in everyday antihelix plasty. This article describes a new surgical technique to improve treatment of the antihelix. Methods: Patients with protruding upper third ears received either standard otoplasty with crus superior remodeling (ST) or the newly developed surgical procedure including crus inferior release (STI). To evaluate the results, a survey containing 10 questions about different outcome parameters was conducted with the patients. Each question was given a score ranging from 0 to 10, where 10 meant the best outcome and 0 the worst. Results: From January 2013 to March 2014, 216 patients underwent otoplasty, of which 99 completed the questionnaire. No differences could be found between ST and STI patients except for their duration of pain, which was significantly less in group STI. Overall, the scores from the questionnaire were 89.85 in ST and 92.35 in STI. Mean values for satisfaction were 9.33 in group ST and 9.56 in group STI. Conclusion: When correcting the antihelix, the inferior crus must always be checked because the protruding upper third cannot be compensated only by overcorrecting the superior crus. It should be a matter of routine to recognize the degree of malformation and determine the best possible treatment. This novel technique is an additional valuable option in otoplasty to improve the upper third in a more natural way and create highly satisfactory results.
A Five-Year Analysis of Airway Foreign Body Management
Authors: Friedman Ellen M. , Anthony Benjamin 
Published: March 2016

Objective: To identify characteristics in patients who undergo positive and negative bronchoscopy for a suspected airway foreign body (AFB). Methods: Review medical records between 2008 and 2012. Results: There were 145 patients who went to the operating room with the pre-bronchoscopy diagnosis of suspected AFB during the study period. There was an overall negative bronchoscopy rate of an average of 37%, with an annual range between 21% and 50%. The findings of history or suspicion of choking, asymmetric breath sounds, and wheezing were statistically more common in patients with an AFB. Chest roentograms (CXR) had a sensitivity and specificity of 62% and 57%. Twenty patients had a chest computed tomography (CT) scan, and 100% were clinically significant. Four CT scans were diagnostic of an AFB, and 16 patients avoided bronchoscopy after negative CT. Conclusions: In current clinical practice, it is difficult to identify patients with an AFB without performing bronchoscopy. This results in a significant number of negative bronchoscopes. Certain elements in the history and physical exam were more common in patients who were found to have an AFB. Our preliminary data suggest that chest CT scans may be useful to decrease the number of negative bronchoscopies.
Non-cirrhotic portal fibrosis at a tertiary care centre in South India
Authors: Mukta V , Panicker Lakshmi C , Sivamani Kalaimani , Goel Amit , Basu Debdutta , Dhanapathi Halnayak 
Published: March 2016

Background Non-cirrhotic portal fibrosis (NCPF) is one of the important causes of upper gastrointestinal haemorrhage in patients in tropical countries. The aim of this study was to describe the clinical and laboratory profile of 68 patients with NCPF. Material and Methods NCPF is defined as liver disease with: (1) evidence of portal hypertension; (2) a liver biopsy showing no cirrhosis or a Tc-labelled sulphur colloid scan showing a pattern suggestive of NCPF; and (3) a patent splenoportal axis. The clinical, laboratory and demographic features of 68 patients with such criteria were studied and analysed. Results NCPF was common in women (73.5%) in the fourth decade of life. The median duration of illness was 24 months (range, 1 month–28 years). Patients presented to hospital with the sensation of a mass in the abdomen (50%) or with haematemesis (26.5%). They had splenomegaly (95.6%) and thrombocytopenia (88.2%). The majority of patients had normal liver function tests. Abdominal ultrasonography showed increased periportal and peri gallbladder echoes (72%), spontaneous collaterals (41.2%) and ascites (19.1%). Liver biopsy revealed portal venous sclerosis (76.3%) and periportal fibrosis (55.3%). Tc-labelled sulphur colloid scan was suggestive of NCPF in the remaining 30 cases. Conclusion NCPF is common in South India. Transient ascites occurs due to decompensation of liver function after variceal bleeding and in long standing cases of NCPF. Our study used Tc-sulphur scan for diagnosing NCPF in patients where liver biopsy was contraindicated in view of severe thrombocytopenia; however, the diagnostic utility of Tc-sulphur nuclear scan to diagnose NCPF in patients with severe hypersplenism needs to be further evaluated in future studies.
Analysis of killer cell immunoglobulin-like receptors and their human leukocyte antigen-ligands gene polymorphisms in Iranian patients with systemic lupus erythematosus
Authors: Akhtari M , Farazmand A , Mahmoudi M , Akbarian M , Ahmadzadeh N , Mirkazemi Z , Mostafaei S , Jamshidi A R 
Published: March 2016

Objective Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease. Natural killer (NK) cells play a critical role in the pathogenesis of autoimmune disorders that mainly express killer cell immunoglobulin-like receptors (KIRs). The present study was undertaken to determine the association of the KIR alleles, genotypes, and KIR–human leukocyte antigen ( HLA) ligand gene combinations with the susceptibility to SLE. Methods The genotyping of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method. The study population consisted of 230 SLE patients and 273 ethnical-, age-, and sex-matched healthy controls. The association of the polymorphisms with the prevalence of 11 clinical criteria in patients was analyzed. Results The carrier frequency of HLA-A-Bw4 was modestly decreased in the SLE patients. The prevalence of hematological and renal disorders was significantly increased in patients with combination of KIR3DL1+; HLA-B-Bw4Thr80+ and KIR2DS1+; HLA-C2+ genes, respectively. Female patients with combination of KIR2DL2+; HLA-C1− genes were more likely to develop serositis. In addition the prevalence of renal disorders, oral ulcer and serositis was significantly increased in male patients with KIR3DP1+, KIR2DS1+, and KIR2DS3+ genotypes respectively. Conclusion Our results showed that the presence of activating KIR receptors alone or in combination with their HLA ligands and the absence of inhibitory KIRs in combination with their HLA ligands may activate NK cells and are significantly correlated with the prevalence of renal disease, hematologic disorders, serositis, and oral ulcer in SLE patients.
Correlates of a single-item Self-Rated Mental Health Question in people with schizophrenia
Authors: Maguire Paul A , Reay Rebecca E , Raphael Beverley 
Published: March 2016

Objective: The objective of this study was to explore the correlates of a single-item Self-Rated Mental Health Question in people with schizophrenia, in order to achieve a better understanding of what it is measuring. Methods: A cross-sectional survey was conducted exploring the responses of 71 adults with schizophrenia to a single-item Self-Rated Mental Health Question and the relationship with psychological distress, illness perception, and self-rated general health. Measures included the 10-item Kessler Psychological Distress Scale, the Brief Illness Perception Questionnaire, and the single-item Self-Rated Health Question. Results: People with schizophrenia who reported poorer levels of mental health on a single-item Self-Rated Mental Health Question were more likely to have: higher levels of psychological distress; depressive and anxiety symptoms; and negative illness perceptions, especially a lack of perceived personal control over their illness. There was a moderate positive correlation between self-rated mental health and self-rated general health. Conclusion: The single-item Self-Rated Mental Health Question is a predictor of important clinical features in people with schizophrenia. As such, there are implications for health services, with a possible role as a brief, easily administered screening tool for the detection of clinical vulnerability.
Ankle Power and Endurance Outcomes Following Isolated Gastrocnemius Recession for Achilles Tendinopathy
Authors: Nawoczenski Deborah A. , DiLiberto Frank E. , Cantor Maxwell S. , Tome Josh M. , DiGiovanni Benedict F. 
Published: March 2016

Background: Studies have demonstrated improved ankle dorsiflexion and pain reduction following a gastrocnemius recession (GR) procedure. However, changes in muscle performance during functional activities are not known. The purpose of this study was to determine the effect of an isolated GR on ankle power and endurance in patients with Achilles tendinopathy. Methods: Fourteen patients with chronic unilateral Achilles tendinopathy and 10 healthy controls participated in this study. Patient group data were collected 18 months following GR. Pain was compared to preoperative values using a 10-cm visual analog scale (VAS). Patient-reported outcomes for activities of daily living (ADL) and sports were assessed using the Foot and Ankle Ability Measure (FAAM). Kinematic and kinetic data were collected during gait, stair ascent (standard and high step), and repetitive single-limb heel raises. Between-group and side-to-side differences in ankle plantarflexor muscle power and endurance were evaluated with appropriate t tests. Results: Compared with preoperative data, VAS pain scores were reduced (pre 6.8, post 1.6, P < .05). Significant differences were observed between GR and Control groups for FAAM scores for both ADL (GR 90.0, Control 98.3, P = .01) and Sports subscales (GR 70.6, Control 94.6, P = .01). When compared to controls, ankle power was reduced in the involved limb of the GR group for all activities (all P < .05). Between-group and side-to-side deficits (GR group only) were also found for ankle endurance. Conclusion: The gastrocnemius recession procedure provided significant pain reduction that was maintained at the 18-month follow-up for patients with chronic Achilles tendinopathy who failed nonoperative interventions. There were good patient-reported outcomes for activities of daily living. However, compared to controls, ankle plantarflexion power and endurance deficits in the GR group were noted. The functional implications of the muscle performance deficits are unclear, but may be reflective of patients’ self-reported difficulty during more challenging activities. Level of Evidence: Level III, comparative study.
Usefulness of quantitative peritumoural perfusion and proton spectroscopic magnetic resonance imaging evaluation in differentiating brain gliomas from solitary brain metastases
Authors: Sparacia Gianvincenzo , Gadde Judith A , Iaia Alberto , Sparacia Benedetta , Midiri Massimo 
Published: March 2016

Objectives The purpose of our study was to evaluate whether peritumoural perfusion weighted and proton spectroscopic magnetic resonance imaging can be used in differentiating between primary gliomas and solitary metastases. Methods Ten low-grade gliomas, eight high-grade gliomas and 10 metastases were prospectively evaluated with magnetic resonance imaging, dynamic susceptibility contrast enhanced perfusion imaging and single-voxel proton magnetic resonance spectroscopy before surgical resection or stereotactic biopsy. Maximal relative cerebral blood volume values were calculated drawing three regions of interest of 2 cm2 in the non-enhancing peritumoural areas. Maximal relative cerebral blood volume values were normalised to that of contralateral normal-appearing white matter. Maximal choline/creatine ratios were calculated from three voxels of 10 cm3 placed in the peritumoural areas defined as non-enhancing peritumoural white matter surrounding the tumour. The tumour grade presumed with these values was compared to histopathological grading. Differences in the study parameters between groups were assessed using the Mann–Whitney test. A receiver operating characteristic analysis was performed to determine cut-off values. Results A clear relative cerebral blood volume cut-off value of 1.88 was detected for differentiating low-grade gliomas from high-grade gliomas. A clear relative cerebral blood volume cut-off value of 1.20 was detected for differentiation of metastases from gliomas. The differences in the choline/creatine ratios in the peritumoural regions of high-grade gliomas and of solitary metastasis were statistically significant ( P < 0.001) but a clear cut-off value was not found. Conclusion Our preliminary data support the hypothesis that peritumoural perfusion-weighted imaging can assist in preoperative differentiation between a glioma and a solitary metastasis.
Implementation of a care pathway for infantile hypertrophic pyloric stenosis reduces length of stay and increases parent satisfaction
Authors: Wetherill Charlotte V , Melling James D , Rhodes Hannah L , Wilkinson David J , Kenny Simon E 
Published: March 2016

Introduction Infantile hypertrophic pyloric stenosis (IHPS) is a common surgical condition, but there are no guidelines regarding preoperative fluid resuscitation. Our aim was to evaluate a novel consensus care pathway for IHPS, incorporating a standardized fluid and electrolyte replacement regime. Methods One hundred patients were initially reviewed and compared to thirty-three patients following the introduction of a clinical pathway, whereby infants requiring electrolyte correction received 150 ml/kg/24 h of 0.45% saline, 5% dextrose and 10 mmol KCl, with systematic blood sampling until correction was achieved. We measured time to electrolyte correction, time to surgery and total length of hospitalization. Data were described using the median and interquartile range, and differences between the groups’ categorical and continuous data were described using Chi-squared and the Mann–Whitney U–tests, respectively. Results Time in hours taken to correct electrolytes was reduced: 25(16.5–42) versus 9.5(4.5–24.75) p = 0.004. Time to surgery from admission in uncorrected patients decreased from 50(40.25–66.75) to 39(28.75–41.75) p = 0.018. Subsequently, there was a reduction in total length of stay: 94(71–93.5) versus 75(64.5–93.5) p = 0.025. Parental satisfaction increased from 77% in the pre-pathway group to 83% in the pathway group. Conclusion A consensus care pathway for IHPS reduces the time taken to correct preoperative electrolyte abnormalities, decreases length of hospitalization and improves parental satisfaction.
New Fourth Generation of Innovation Management Theory & Practice: Part 2
Authors: Miller William L. 
Published: March 2016

This is the second article in a pair of articles in the Journal of Creating Value which identified the root cause of a group of wicked global problems as the lack of value creation from radical innovation. The root cause has existed over the last four decades following the large number of significant radical innovations that launched and initially propelled the Information Age. The first article described the essential part of a solution which is adoption of a new fourth generation of innovation management (4G) which has emerged as best practice since 2000 because 4G effectively enables radical innovation in addition to more effective and efficient incremental innovation. Radical innovation is required for sustained, adequate rates of economic growth driven by improvements in productivity, quality and cost in industries such as healthcare, education, construction and energy. As a result of inadequate radical innovation over the past four decades, a group of major economic, social and environmental wicked problems are unsolved such as income inequality and global warming and these problems exist in all countries including the United States. 4G is guided by 12 new principles and practices to effectively and efficiently create radical innovation based on new dominant designs while also improving the efficient creation of incremental innovation. The first article, Part 1, described the first four principles of 4G in detail. This article, Part 2, describes the remaining eight principles of 4G in detail.
Follicular lymphoma: evolving therapeutic strategies
Authors: Kahl Brad S. , Yang David T. 
Published: March 2016

AbstractFollicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. After decades of stagnation, the natural history of FL appears to have been favorably impacted by the introduction of rituximab. Randomized clinical trials have demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Maintenance rituximab strategies can improve progression-free survival. Even chemotherapy platforms have changed in the past 5 years, as bendamustine combined with rituximab has rapidly become a standard frontline strategy in North America and parts of Europe. Recent discoveries have identified patients at high risk for poor outcomes to first-line therapy (m7–Follicular Lymphoma International Prognostic Index [m7-FLIPI]) and for poor outcomes after frontline therapy (National LymphoCare Study). However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation. The development of targeted agents, exploiting our current understanding of FL biology, is a high research priority. A multitude of novel therapies are under investigation in both the frontline and relapsed/refractory settings. It will be critical to identify the most appropriate populations for new agents and to develop validated surrogate end points, so that novel agents can be tested (and adopted, if appropriate) efficiently.