bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-Suppressive miR148a Is Silenced by CpG Island Hypermethylation in IDH1-Mutant Gliomas
Authors: Li Sichen , Chowdhury Reshmi , Liu Fei , Chou Arthur P. , Li Tie , Mody Reema R. , Lou Jerry J. , Chen Weidong , Reiss Jean , Soto Horacio , Prins Robert , Liau Linda M. , Mischel Paul S. , Nghiemphu Phioanh L. , Yong William H. , Cloughesy Timothy F. , Lai Albert 
Published: September 2014

Abstract
Purpose: IDH1/2-mutant gliomas harbor a distinct glioma-CpG island methylation phenotype (G-CIMP) that may promote the initiation and progression of secondary pathway gliomas by silencing tumor-suppressive genes. The potential role of tumor-suppressive microRNAs (miRNA; miR) in this process is not understood.
Experimental Design: To identify potential tumor-suppressive miRNA hypermethylated in glioma, the methylation profiles of IDH1/2WT gliomas (n = 11) and IDH1MUT glioma (n = 20) were compared by using massively parallel reduced representation bisulfite sequencing (RRBS). The methylation status of selected miRNA was validated by using targeted bisulfite sequencing (BiSEQ) in a large cohort of glioma tissue samples including 219 IDH1WT and 72 IDH1/2MUT samples. The expression of selected miRNAs was determined by using the TaqMan qPCR. Functional analyses of miR148a were conducted and target genes were identified.
Results: We identify miR148a as a novel, G-CIMP–associated miRNA whose methylation is tightly correlated with IDH1 mutation and associated with improved survival in patients with malignant glioma. We confirm that downregulation of miR148a can occur via DNA methylation. We demonstrate that IDH1 mutation provides a mechanism of miR148a methylation and downregulation, and that restoration of miR148a reduced tumorigenic properties of glioma cells, possibly by targeting DNMT1.
Conclusions: We identify miR148a as a novel G-CIMP–associated miRNA, and provide results suggesting that miR148a restoration may have therapeutic implications. Clin Cancer Res; 20(22); 5808–22. ©2014 AACR.
Alteration of Cell–Cell and Cell–Matrix Adhesion in Urothelial Cells: An Oncogenic Mechanism for Mutant FGFR3
Authors: di Martino Erica , Kelly Gavin , Roulson Jo-An , Knowles Margaret A. 
Published: September 2014

Abstract
Activating mutations of FGFR3 are a common and early event in bladder cancer. Ectopic expression of mutant FGFR3 in normal urothelial cells has both pro-proliferative and antiapoptotic effects at confluence, suggesting that mutant cells are insensitive to cell–cell contact inhibition. Herein, detailed analysis revealed that these cells have reduced cell–cell adhesion, with large intercellular spaces observable at confluence, and diminished cell–substrate adhesion to collagen IV, collagen I, and fibronectin. These phenotypic alterations are accompanied by changes in the expression of genes involved in cell adhesion and extracellular matrix remodeling. Silencing of endogenous mutant FGFR3 in bladder cancer cells induced converse changes in transcript levels of CDH16, PLAU, MMP10, EPCAM, TNC, and HAS3, confirming them as downstream gene targets of mutant FGFR3. Overexpression of EPCAM, HAS3, and MMP10 transcripts was found in a large fraction of primary bladder tumors analyzed, supporting their key role in bladder tumorigenesis in vivo. However, no correlation was found between their protein and/or mRNA expression and FGFR3 mutation status in tumor specimens, indicating that these genes may be targeted by several converging oncogenic pathways. Overall, these results indicate that mutant FGFR3 favors the development and progression of premalignant bladder lesions by altering key genes regulating the cell–cell and cell–matrix adhesive properties of urothelial cells.
Implications: The ability of mutant FGFR3 to drive transcriptional expression profiles involved in tumor cell adhesion suggests a mechanism for expansion of premalignant urothelial lesions. Mol Cancer Res; 13(1); 138–48. ©2014 AACR.
Human Fecal Microbiome–Based Biomarkers for Colorectal Cancer
Authors: Narayanan Vilvapathy , Peppelenbosch Maikel P. , Konstantinov Sergey R. 
Published: September 2014

Abstract
Colorectal cancer may develop slowly over years from precursor lesions, and thus screening combined with early diagnosis is the key to disease prevention. Recent studies have elucidated specific traits in the gut microbiome associated with colorectal cancer and suggested that the microbiome may be useful in screening for colorectal cancer purposes but failed to provide protocols that can be applied in a practical situation. A recent study by Zackular and colleagues, presented on page 1112, provides an important way forward here in showing that specific analysis of multiple aspects of the microbiome composition in toto provides reliable detection of both precancerous and cancerous lesions. This important achievement when combined with other noninvasive techniques promises to provide highly effective tools for early colorectal cancer diagnosis and its prevention. Cancer Prev Res; 7(11); 1108–11. ©2014 AACR.
Genomic Landscape of Ewing Sarcoma Defines an Aggressive Subtype with Co-Association of STAG2 and TP53 Mutations
Authors: Tirode Franck , Surdez Didier , Ma Xiaotu , Parker Matthew , Le Deley Marie Cécile , Bahrami Armita , Zhang Zhaojie , Lapouble Eve , Grossetête-Lalami Sandrine , Rusch Michael , Reynaud Stéphanie , Rio-Frio Thomas , Hedlund Erin , Wu Gang , Chen Xiang , Pierron Gaelle , Oberlin Odile , Zaidi Sakina , Lemmon Gordon , Gupta Pankaj , Vadodaria Bhavin , Easton John , Gut Marta , Ding Li , Mardis Elaine R. , Wilson Richard K. , Shurtleff Sheila , Laurence Valérie , Michon Jean , Marec-Bérard Perrine , Gut Ivo , Downing James , Dyer Michael , Zhang Jinghui , Delattre Olivier 
Published: September 2014

Abstract
Ewing sarcoma is a primary bone tumor initiated by EWSR1–ETS gene fusions. To identify secondary genetic lesions that contribute to tumor progression, we performed whole-genome sequencing of 112 Ewing sarcoma samples and matched germline DNA. Overall, Ewing sarcoma tumors had relatively few single-nucleotide variants, indels, structural variants, and copy-number alterations. Apart from whole chromosome arm copy-number changes, the most common somatic mutations were detected in STAG2 (17%), CDKN2A (12%), TP53 (7%), EZH2, BCOR, and ZMYM3 (2.7% each). Strikingly, STAG2 mutations and CDKN2A deletions were mutually exclusive, as confirmed in Ewing sarcoma cell lines. In an expanded cohort of 299 patients with clinical data, we discovered that STAG2 and TP53 mutations are often concurrent and are associated with poor outcome. Finally, we detected subclonal STAG2 mutations in diagnostic tumors and expansion of STAG2-immunonegative cells in relapsed tumors as compared with matched diagnostic samples.
Significance: Whole-genome sequencing reveals that the somatic mutation rate in Ewing sarcoma is low. Tumors that harbor STAG2 and TP53 mutations have a particularly dismal prognosis with current treatments and require alternative therapies. Novel drugs that target epigenetic regulators may constitute viable therapeutic strategies in a subset of patients with mutations in chromatin modifiers. Cancer Discov; 4(11); 1342–53. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 1243
Long-Term Clinical Outcome of Major Adverse Cardiac Events in Survivors of Infective Endocarditis
Authors: Shih Chia-Jen , Chu Hsi , Chao Pei-Wen , Lee Yi-Jung , Kuo Shu-Chen , Li Szu-Yuan , Tarng Der-Cherng , Yang Chih-Yu , Yang Wu-Chang , Ou Shuo-Ming , Chen Yung-Tai 
Published: September 2014

Background—
Substantial infective endocarditis (IE)–related morbidity and mortality may occur even after successful treatment. However, no previous study has explored long-term hard end points (ie, stroke, myocardial infarction, heart failure, cardiovascular death) in addition to all-cause mortality in IE survivors.

Methods and Results—
A nationwide population-based cohort study was conducted among IE survivors identified with the use of the Taiwan National Health Insurance Research Database during 2000 to 2009. IE survivors were defined as those who survived after discharge from first hospitalization with a diagnosis of IE. A total of 10 116 IE survivors were identified. IE survivors were matched to control subjects without IE at a 1:1 ratio through the use of propensity scores. The primary outcomes were stroke, myocardial infarction, readmission for heart failure, and sudden cardiac death or ventricular arrhythmia. The secondary outcomes were repeat IE and all-cause mortality. Compared with the matched cohort, IE survivors had higher risks of ischemic stroke (adjusted hazard ratio [aHR], 1.59; 95% confidence interval [CI], 1.40–1.80), hemorrhagic stroke (aHR, 2.37; 95% CI, 1.90–2.96), myocardial infarction (aHR, 1.44; 95% CI, 1.17–1.79), readmission for heart failure (aHR, 2.24; 95% CI, 2.05–2.43), sudden death or ventricular arrhythmia (aHR, 1.69; 95% CI, 1.44–1.98), and all-cause death (aHR, 2.27; 95% CI, 2.14–2.40). Risk factors for repeat IE were older age, male sex, drug abuse, and valvular replacement after an initial episode of IE.

Conclusion—
Despite treatment, the risk of long-term major adverse cardiac events was substantially increased in IE survivors.
Precipitation Estimates from MSG SEVIRI Daytime, Nighttime, and Twilight Data with Random Forests
Authors: Kühnlein Meike , Appelhans Tim , Thies Boris , Nauß Thomas 
Published: September 2014

AbstractA new rainfall retrieval technique for determining rainfall rates in a continuous manner (day, twilight, and night) resulting in a 24-h estimation applicable to midlatitudes is presented. The approach is based on satellite-derived information on cloud-top height, cloud-top temperature, cloud phase, and cloud water path retrieved from Meteosat Second Generation (MSG) Spinning Enhanced Visible and Infrared Imager (SEVIRI) data and uses the random forests (RF) machine-learning algorithm. The technique is realized in three steps: (i) precipitating cloud areas are identified, (ii) the areas are separated into convective and advective-stratiform precipitating areas, and (iii) rainfall rates are assigned separately to the convective and advective-stratiform precipitating areas. Validation studies were carried out for each individual step as well as for the overall procedure using collocated ground-based radar data. Regarding each individual step, the models for rain area and convective precipitation detection produce good results. Both retrieval steps show a general tendency toward elevated prediction skill during summer months and daytime. The RF models for rainfall-rate assignment exhibit similar performance patterns, yet it is noteworthy how well the model is able to predict rainfall rates during nighttime and twilight. The performance of the overall procedure shows a very promising potential to estimate rainfall rates at high temporal and spatial resolutions in an automated manner. The near-real-time continuous applicability of the technique with acceptable prediction performances at 3–8-hourly intervals is particularly remarkable. This provides a very promising basis for future investigations into precipitation estimation based on machine-learning approaches and MSG SEVIRI data.
Orographic Signature on Extreme Precipitation of Short Durations
Authors: Avanzi Francesco , De Michele Carlo , Gabriele Salvatore , Ghezzi Antonio , Rosso Renzo 
Published: September 2014

Abstract
This paper investigates how atmospheric circulation and orography affect the spatial variability of extreme precipitation in terms of depth–duration–frequency (DDF) curve parameters. To this aim, the Italian territory was considered because it is characterized by a complex orography and different precipitation dynamics and regimes. A database of 1494 time series with more than 20 years of maximum annual precipitation data was collected for the durations of 1, 3, 6, 12, and 24 h. For each data series, the parameters of DDF curves were estimated using a statistical simple scale invariance model. Hence, the combined effect of orography and atmospheric fields on parameter variability was investigated considering the spatial distribution of the parameters and their relation with elevation. The vertically integrated atmospheric moisture flux J was used as a measurement of the principal direction of the vapor transport at a given location. The analysis highlights the variability of DDF parameters and quantiles according to orography and precipitation climatology. This is confirmed by the evaluation of J modal direction over the study area. The variability of DDF parameters with mere elevation shows that maxima at high elevations seem to be upper bounded and more variable than those at lower elevations. Moreover, the mean of maximum annual precipitation of unit duration decreases with elevation. This last phenomenon is defined as “reverse orographic effect” on extreme precipitation of short durations.
A 10-Year Study on the Characteristics of Thunderstorms in Belgium Based on Cloud-to-Ground Lightning Data
Authors: Poelman Dieter R. 
Published: September 2014

Abstract
Temporal and spatial distributions of cloud-to-ground (CG) lightning in Belgium are analyzed. Based on data from the European Cooperation for Lightning Detection (EUCLID) network, spanning a period of 10 years between 2004 and 2013, mean CG flash densities vary between 0.3 km−2 yr−1 in the west up to 2.4 km−2 yr−1 toward the east of Belgium, with an average flash density of 0.7 km−2 yr−1. The same behavior is found in terms of thunderstorm days and hours, where in the east most of the activity is observed, with a drop-off toward the coast. The majority of lightning activity takes place in the summer months between May and August, accounting for nearly 90% of the total activity. Furthermore, the thunderstorm season reaches its highest activity in July in terms of CG detections, while the diurnal cycle peaks between 1500 and 1600 UTC. A correlation is found between the estimated peak currents and altitude, with on average higher absolute peak currents at lower elevations and vice versa. In addition, a cell tracking algorithm is applied to the data to monitor the behavior of the individual cells. It is found that the lightning cells travel at an average speed of about 25 km h−1, with a preferred northeasterly direction of movement. At last, CG flash rates are strongly related to the cell area.
Three Layer Interlocking
Authors: Kaya Ercan , Cingi Cemal , Olgun Yüksel , Soken Hakan , Pinarbasli Özgür 
Published: September 2014

Objective: Many techniques to repair a septal perforation using local flaps with or without an interpositioning graft with various rates of success have been described. Our aim was to describe a new and relatively easy technique for repairing these perforations. Methods: Twenty-two patients with nasal septal perforations smaller than 2 cm in diameter were operated on between 2010 and 2012 at Eskişehir Osmangazi University. The described 3-layer interlocking method was applied to repair the septal perforation in all of the cases. Results: Twenty-two patients were operated on using this technique. The follow-up time ranged from 30 months to 10 months, with a mean follow-up time of 20.9 months. In 19 of the 22 patients, complete closure of the perforation was achieved (86.3%). We did not encounter any early or late postoperative complications. Conclusion: A novel technique that uses a temporalis fascia-conchal cartilage complex as an interpositioning material to repair septal perforations is described. This complex was endoscopically introduced to the perforation after elevating the edges of the perforation. We concluded that the low morbidity, short operating time, and high success rate make this technique a good choice for repairing small- to medium-sized perforations.
Ghrelin and obestatin plasma levels and ghrelin/obestatin prepropeptide gene polymorphisms in small for gestational age infants
Authors: Zhang Shulian , Zhai Guanpeng , Zhang Jinping , Zhou Jianguo , Chen Chao 
Published: September 2014

Objectives To investigate plasma ghrelin and obestatin levels, and ghrelin/obestatin prepropeptide gene polymorphisms, in sequentially enrolled small for gestational age (SGA) infants. Methods Neonates were sequentially enrolled into this study and were then subdivided into different groups, according to different study aims and availability of study materials. Consequently, plasma ghrelin and obestatin levels were measured in term SGA, term appropriate for gestational age (AGA), term large for gestational age (LGA), preterm SGA and preterm AGA neonates. Levels of both peptides were also measured in AGA infants of different gestational ages, and in term AGA neonates at different days following birth. Three ghrelin/obestatin prepropeptide gene single nucleotide polymorphisms (SNPs), Arg51Gln, Leu72Met, and Gln90Leu, were measured in neonates. Results The study involved a total cohort of 581neonates. Out of 150 neonates (30 term AGA, 30 term SGA, 30 term LGA, 30 preterm AGA, and 30 preterm SGA), plasma obestatin levels were significantly higher in term SGA versus term LGA neonates (0.21 ± 0.02 ng/ml versus 0.17 ± 0.01 ng/ml, respectively). Out of a wider cohort, there were no significant differences in genotypes and allele frequencies of Arg51Gln, Leu72Met, and Gln90Leu SNPs between term SGA and AGA neonates, or between preterm SGA and AGA neonates. Conclusions Ghrelin/obestatin prepropeptide polymorphisms were not found to be associated with SGA status in neonates; however, ghrelin and obestatin levels may be involved in growth and development. Further studies are required to understand the relationship between ghrelin, obestatin and prenatal development.
Knotted Versus Knotless Suture Bridge Repair of the Achilles Tendon Insertion
Authors: Cox Joseph T. , Shorten Peter L. , Gould Gregory C. , Markert Ronald J. , Barnett Michael D. , Laughlin Richard T. 
Published: September 2014

Background: Surgical treatment of insertional Achilles tendinopathy often involves detachment and debridement of the Achilles tendon insertion. A recent study has shown that knotted suture bridge fixation of the Achilles to the calcaneus is biomechanically superior to single-row fixation, but there is an absence of literature on the use of different suture bridge constructs to repair the Achilles tendon. Hypothesis: There will be no significant difference in the load to failure, mode of failure, tendon strain, tendon stiffness, repair site gapping, or footprint size when comparing knotted suture bridge repair to knotless suture bridge repair of the Achilles tendon after detachment for insertional Achilles tendinopathy. Study Design: Controlled laboratory study. Methods: A single specimen from each pair of 10 cadaveric Achilles tendons was randomized to 1 of 2 Achilles insertion repair groups: knotted (n = 10) or knotless (n = 10) suture bridge repair. Repaired footprint size was measured, and then cyclic testing from 10 to 100 N for 2000 cycles was performed. This was followed by measurement of tendon strain, repair site displacement, load to failure, and tendon stiffness. Results: The knotted suture bridge repair had a significantly higher load to failure compared with the knotless suture bridge (mean ± SD, 317.8 ± 93.6 N vs 196.1 ± 12.1 N, respectively; P = .001). All constructs failed at the tendon-suture interface. Tendon strain after cyclic testing was significantly greater in the knotless (1.20 ± 1.05) compared with the knotted (0.39 ± 0.4) suture repair groups ( P = .011). There was no significant difference in footprint size between the knotted (230.3 ± 63.3 mm2) and knotless (248.5 ± 48.8 mm2) groups ( P = .40). There was also no significant difference in stiffness (knotted = 76.4 ± 8.0 N/mm; knotless = 69.6 ± 10.9 N/mm; P = .17) and repair site displacement after cyclic testing (knotted = 2.8 ± 1.2 mm; knotless = 3.6 ± 1.1 mm; P = .17). Conclusion: During suture bridge repair of the Achilles tendon after detachment, knots at the proximal suture anchors significantly improve the biomechanical strength of the repair. Clinical Relevance: This study demonstrated that the knotless suture bridge repair had a significantly lower load to failure than the knotted suture bridge. Surgeons should be aware of these biomechanical differences, as they influence the postoperative rehabilitation protocol and may lead to higher surgical complication rates.
Biomechanical Comparison of Arthroscopic Repair Constructs for Meniscal Root Tears
Authors: Anz Adam W. , Branch Eric A. , Saliman Justin D. 
Published: September 2014

Background: Complete meniscal root tears render the meniscus nonfunctional. Repair constructs have been presented and tested; however, prior studies have evaluated suture patterns placed ex vivo without simulating an in vivo surgical setting. This study introduces a new double-locking loop suture pattern and compares its biomechanical properties and execution time with commonly used suture patterns. All constructs were performed using an all-inside arthroscopic technique. Hypothesis: Complex suture repair constructs have higher failure loads, stiffness, and execution times compared with simple constructs. Study Design: Controlled laboratory study. Methods: Sutures were placed arthroscopically into the posterior horn root region of the medial and lateral menisci in 21 cadaveric knees. Four repair constructs were evaluated: 2 simple sutures (2SS), 1 inverted mattress suture (1MS), 1 double-locking loop suture (1DLS), and 2 double-locking loop sutures (2DLS). In total, 40 posterior meniscal roots were tested, with 10 trials for each construct. After arthroscopic placement of the root repair constructs, each meniscus was explanted and tested to failure on a uniaxial materials testing machine. The Kruskal-Wallis test was used to evaluate for the significance of maximum failure loads and stiffness between groups. Results: The mean maximum failure loads were 137 ± 49 N (2SS), 126 ± 44 N (1MS), 186 ± 43 N (1DLS), and 368 ± 76 N (2DLS). Interconstruct comparison revealed a statistical difference between 2DLS and all 3 remaining constructs ( P < .01) and 1DLS when compared with 2SS and 1MS ( P < .01 for both). Statistical significance was not found between 2SS and 1MS ( P = .8). The mean times for repair of the 4 fixation techniques were 1.8 ± 0.9 minutes (2SS), 2.4 ± 1.9 minutes (1MS), 4.7 ± 2.0 minutes (1DLS), and 5.4 ± 0.6 minutes (2DLS). Conclusion: The double-locking loop suture repair technique had significantly higher failure loads compared with the 3 other methods tested. As the complexity of repair constructs increases, failure loads and surgical times increase. Clinical Relevance: Complex suture patterns can be placed via an all-inside arthroscopic technique delivering higher failure loads for meniscal root repair with little increase in surgical time.