bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genome-wide DNA Methylation Analysis of Lung Carcinoma Reveals One Neuroendocrine and Four Adenocarcinoma Epitypes Associated with Patient Outcome
Authors: Karlsson Anna , Jönsson Mats , Lauss Martin , Brunnström Hans , Jönsson Per , Borg Åke , Jönsson Göran , Ringnér Markus , Planck Maria , Staaf Johan 
Published: October 2014

Abstract
Purpose: Lung cancer is the worldwide leading cause of death from cancer. DNA methylation in gene promoter regions is a major mechanism of gene expression regulation that may promote tumorigenesis. However, whether clinically relevant subgroups based on DNA methylation patterns exist in lung cancer remains unclear.
Experimental Design: Whole-genome DNA methylation analysis using 450K Illumina BeadArrays was performed on 12 normal lung tissues and 124 tumors, including 83 adenocarcinomas, 23 squamous cell carcinomas (SqCC), 1 adenosquamous cancer, 5 large cell carcinomas, 9 large cell neuroendocrine carcinomas (LCNEC), and 3 small-cell carcinomas (SCLC). Unsupervised bootstrap clustering was performed to identify DNA methylation subgroups, which were validated in 695 adenocarcinomas and 122 SqCCs. Subgroups were characterized by clinicopathologic factors, whole-exome sequencing data, and gene expression profiles.
Results: Unsupervised analysis identified five DNA methylation subgroups (epitypes). One epitype was distinctly associated with neuroendocrine tumors (LCNEC and SCLC). For adenocarcinoma, remaining four epitypes were associated with unsupervised and supervised gene expression phenotypes, and differences in molecular features, including global hypomethylation, promoter hypermethylation, genomic instability, expression of proliferation-associated genes, and mutations in KRAS, TP53, KEAP1, SMARCA4, and STK11. Furthermore, these epitypes were associated with clinicopathologic features such as smoking history and patient outcome.
Conclusions: Our findings highlight one neuroendocrine and four adenocarcinoma epitypes associated with molecular and clinicopathologic characteristics, including patient outcome. This study demonstrates the possibility to further subgroup lung cancer, and more specifically adenocarcinomas, based on epigenetic/molecular classification that could lead to more accurate tumor classification, prognostication, and tailored patient therapy. Clin Cancer Res; 20(23); 6127–40. ©2014 AACR.
Hemoglobin α/eNOS Coupling at Myoendothelial Junctions Is Required for Nitric Oxide Scavenging During Vasoconstriction
Authors: Straub Adam C. , Butcher Joshua T. , Billaud Marie , Mutchler Stephanie M. , Artamonov Mykhaylo V. , Nguyen Anh T. , Johnson Tyler , Best Angela K. , Miller Megan P. , Palmer Lisa A. , Columbus Linda , Somlyo Avril V. , Le Thu H. , Isakson Brant E. 
Published: October 2014

Objective—
Hemoglobin α (Hb α) and endothelial nitric oxide synthase (eNOS) form a macromolecular complex at myoendothelial junctions; the functional role of this interaction remains undefined. To test if coupling of eNOS and Hb α regulates nitric oxide signaling, vascular reactivity, and blood pressure using a mimetic peptide of Hb α to disrupt this interaction.

Approach and Results—

In silico modeling of Hb α and eNOS identified a conserved sequence of interaction. By mutating portions of Hb α, we identified a specific sequence that binds eNOS. A mimetic peptide of the Hb α sequence (Hb α X) was generated to disrupt this complex. Using in vitro binding assays with purified Hb α and eNOS and ex vivo proximity ligation assays on resistance arteries, we have demonstrated that Hb α X significantly decreased interaction between eNOS and Hb α. Fluorescein isothiocyanate labeling of Hb α X revealed localization to holes in the internal elastic lamina (ie, myoendothelial junctions). To test the functional effects of Hb α X, we measured cyclic guanosine monophosphate and vascular reactivity. Our results reveal augmented cyclic guanosine monophosphate production and altered vasoconstriction with Hb α X. To test the in vivo effects of these peptides on blood pressure, normotensive and hypertensive mice were injected with Hb α X, which caused a significant decrease in blood pressure; injection of Hb α X into eNOS
-/-
mice had no effect.

Conclusions—
These results identify a novel sequence on Hb α that is important for Hb α/eNOS complex formation and is critical for nitric oxide signaling at myoendothelial junctions.
Mechanism of Race-Dependent Platelet Activation Through the Protease-Activated Receptor-4 and Gq Signaling Axis
Authors: Tourdot Benjamin E. , Conaway Stanley , Niisuke Katrin , Edelstein Leonard C. , Bray Paul F. , Holinstat Michael 
Published: October 2014

Objective—
Black individuals are at an increased risk of myocardial infarction and stroke, 2 vascular diseases with strong thrombotic components. Platelet activation is a key step in platelet clot formation leading to myocardial infarction and stroke, and recent work supports a racial difference in platelet aggregation through the thrombin protease-activated receptors (PARs). The underlying mechanism for this racial difference, however, has not been established. Determining where in the signaling cascade these racial differences emerge will aid in understanding why individuals of differing racial ancestry may possess an inherent difference in their responsiveness to antiplatelet therapies.

Approach and Results—

Washed human platelets from black volunteers were hyperaggregable in response to PAR4-mediated platelet stimulation compared with whites. Interestingly, the racial difference in PAR4-mediated platelet aggregation persisted in platelets treated ex vivo with aspirin and 2MeSAMP (2-methylthioadenosine 5′-monophosphate triethylammonium salt hydrate), suggesting that the racial difference is independent of secondary feedback. Furthermore, stimulation of platelets from black donors with PAR4-activating peptide showed a potentiated level of activation through the G
q
pathway compared with platelets from white donors. Differences in signaling included increased Ca
2+
mobilization, Rap1 (Ras-related protein 1) activation, and integrin α
IIb
β
3
activation with no observed difference in platelet protein expression between the groups tested.

Conclusions—

Our study is the first to demonstrate that the G
q
pathway is differentially regulated by race after PAR4 stimulation in human platelets. Furthermore, the racial difference in PAR4-mediated platelet aggregation persisted in the presence of cyclooxygenase and P2Y
12
receptor dual inhibition, suggesting that current antiplatelet therapy may provide less protection to blacks than whites.
β-Blocker Therapy Is Not Associated With Adverse Outcomes in Patients With Pulmonary Arterial Hypertension
Authors: Thenappan Thenappan , Roy Samit S. , Duval Sue , Glassner-Kolmin Cherylanne , Gomberg-Maitland Mardi 
Published: October 2014

Background—
The safety of β-blockers in patients with isolated right ventricular failure because of pulmonary arterial hypertension (PAH) is unclear.

Methods and Results—

We studied 564 PAH patients (total cohort) referred to our center from 1982 to 2013. Propensity score-matching was used to match pairs of PAH patients with and without β-blocker use (matched cohort). We compared all-cause mortality between the groups in the total cohort and the matched cohort using bootstrap validation, Kaplan–Meier, and Cox proportional hazard analyses. Seventy-one of the 564 patients in the total cohort were on β-blockers. They were older, had higher prevalence of comorbidities, and were more often on diuretics, digoxin, and angiotensin converting enzyme inhibitors. The severity of PAH and right ventricular failure was similar between those with and without β-blocker use. After propensity matching, 63 patients with β-blocker use were compared with 51 patients without β-blocker use. During a median follow-up time of 4.8 years, there were 339 (60%) deaths in the total cohort and 70 deaths (61%) in the matched cohort. There was no difference in absolute mortality between those with and without β-blockers (
P
=0.71). β-Blocker use was not associated with increased all-cause mortality in the total cohort after adjusting for propensity score (adjusted hazard ratio, 1.0; 95% confidence interval, 0.7–1.5) and in the matched cohort (hazard ratio, 1.2; 95% confidence interval, 0.8–2.0).

Conclusions—
There was no statistically significant difference in long-term mortality between propensity score-matched pairs of PAH patients with and without β-blocker use. These findings need further validation in prospective clinical trials.
Association of 10‐Year and Lifetime Predicted Cardiovascular Disease Risk With Subclinical Atherosclerosis in South Asians: Findings From the Mediators of Atherosclerosis in South Asians Living in America (MASALA) Study
Authors: Kandula Namratha R. , Kanaya Alka M. , Liu Kiang , Lee Ji Young , Herrington David , Hulley Stephen B. , Persell Stephen D. , Lloyd‐Jones Donald M. , Huffman Mark D. 
Published: October 2014

Background

Ten‐year and lifetime cardiovascular risk assessment algorithms have been adopted into atherosclerotic cardiovascular disease (
ASCVD
) prevention guidelines, but these prediction models are not based on South Asian populations and may underestimate the risk in Indians, Pakistanis, Bangladeshis, Nepali, and Sri Lankans in the United States. Little is known about
ASCVD
risk prediction and intermediate endpoints such as subclinical atherosclerosis in
US
individuals of South Asian ancestry.

Methods and Results

South Asians (n=893) from the Mediators of Atherosclerosis in South Asians Living in America (
MASALA
) study who were 40 to 79 years and free of
ASCVD
were included. Ten‐year
ASCVD
predicted risk was calculated using the 2013 Pooled Cohort Equations. Lifetime predicted risk was based on risk factor burden. Baseline levels of subclinical atherosclerosis (coronary artery calcium [
CAC
] and carotid intima media thickness [
CIMT
]) were compared across 10‐year and lifetime risk strata: (1) high (≥7.5%) 10‐year and low (<7.5%) 10‐year risk; (2) high (≥39%) lifetime and low (<39%) lifetime risk. South Asian men and women with high 10‐year predicted risk had a significantly greater
CAC
burden than those with low 10‐year risk. South Asians with high lifetime predicted risk had a significantly increased odds for
CAC
higher than 0 (odds ratio: men 1.97; 95%
CI
, 1.2 to 3.2; women 3.14; 95%
CI
, 1.5, 6.6). Associations between risk strata and
CIMT
were also present.

Conclusion

This study is the first to provide evidence that contemporary
ASCVD
risk assessment algorithms derived from non‐Hispanic white and African‐American samples can successfully identify substantial differences in atherosclerotic burden in
US
South Asians.
Increased Prevalence of Posttraumatic Stress Disorder in Patients After Transient Ischemic Attack
Authors: Kiphuth Ines C. , Utz Kathrin S. , Noble Adam J. , Köhrmann Martin , Schenk Thomas 
Published: October 2014

Background and Purpose—
A transient ischemic attack (TIA) involves temporary neurological symptoms but leaves a patient symptom-free. Patients are faced with an increased risk for future stroke, and the manifestation of the TIA itself might be experienced as traumatizing. We aimed to investigate the prevalence of posttraumatic stress disorder (PTSD) after TIA and its relation to patients’ psychosocial outcome.

Methods—
Patients with TIA were prospectively studied, and 3 months after the diagnosis, PTSD, anxiety, depression, quality of life, coping strategies, and medical knowledge were assessed via self-rating instruments.

Results—
Of 211 patients with TIA, data of 108 patients were complete and only those are reported. Thirty-two (29.6%) patients were classified as having PTSD. This rate is 10× as high as in the general German population. Patients with TIA with PTSD were more likely to show signs of anxiety and depression. PTSD was associated with the use of maladaptive coping strategies, subjectively rated high stroke risk, as well as with younger age. Finally, PTSD and anxiety were associated with decreased mental quality of life.

Conclusions—
The experience of TIA increases the risk for PTSD and associated anxiety, depression, and reduced mental quality of life. Because a maladaptive coping style and a subjectively overestimated stroke risk seem to play a crucial role in this adverse progression, the training of adaptive coping strategies and cautious briefing about the realistic stroke risk associated with TIA might be a promising approach. Despite the great loss of patients to follow-up, the results indicate that PTSD after TIA requires increased attention.
Biological and chemical dependent systemic resistance and their significance for the control of root-knot nematodes
Authors: Selim Mohamed E. , Mahdy Magdy E. , Sorial Mervat E. , Dababat Abdelfattah A. , Sikora Richard A. 
Published: October 2014

Inducing host plant-based systemic resistance is one of the modes of action involved in tri-trophic interactions between host plants, pests and mutualistic microorganisms. Two different types of systemic resistance – systemic acquired resistance (SAR) and induced systemic resistance (ISR) – were found to be functional against pathogens and plant-parasitic nematodes. In this study, the ability of Trichoderma harzianum isolate T10 and insecticidal active neem powder (NP) to induce systemic resistance in tomato against the root-knot nematode Meloidogyne javanica was compared with salicylic acid (SA) and jasmonic acid (JA) as standard elicitors for SAR and ISR, respectively. Results showed that, when the biotic and abiotic elicitors were applied to the inducer side of a split root plant system, a significant reduction in nematode infection was observed on the responder side. Physiological changes in the tomato plant due to the induction of SAR or ISA by these biotic and abiotic elicitors were further investigated using HPLC. Results demonstrated that T10 significantly increased the accumulation of different metabolites in the shoot of the tomato over the NP, JA and SA elicitors. Furthermore, the results demonstrated that several metabolic, physical and biochemical changes occurred in the shoots of the treated plants with both the biotic and abiotic elicitors. The percentage of membrane leakage (Ml) at nematode-infected tomato roots was significantly high, but the differences in percentage leakage were not significant in other treatments compared to the non-infested control. The best results were recorded with SA, T10 and NP, which gave the lowest MI% compared to the infested plants.
Systematics and DNA barcoding of free-living marine nematodes with emphasis on tropical desmodorids using nuclear SSU rDNA and mitochondrial COI sequences
Authors: Armenteros Maickel , Rojas-Corzo Ariadna , Ruiz-Abierno Alexei , Derycke Sofie , Backeljau Thierry , Decraemer Wilfrida 
Published: October 2014

The diversity and phylogenetic relationships of the Desmodoridae, a widespread tropical family of free-living marine nematodes, is hitherto poorly known both from molecular and taxonomic points of view. We performed a molecular phylogenetic analysis of marine nematodes to: i) disentangle relationships among tropical desmodorid species; and ii) compare the performance of the nuclear SSU rDNA and mitochondrial COI nucleotide sequences in 42 and 45 nominal species, respectively, to identify species. We generated 27 new sequences of SSU rDNA belonging to five genera not previously sequenced, and 34 new sequences of COI belonging to six genera and four families not previously sequenced. The SSU rDNA tree confirmed the Enoplida to be a monophyletic sister group to the Chromadorida. The family Comesomatidae is a sister group of the Xyalidae within the Monhysterida. Both DNA markers confirmed the congruence between the morphology- and molecular-based phylogenetic inferences for most of the families. Desmodoridae was a monophyletic group, but the relationships within the family could not be recovered; the subfamilies Desmodorinae and Spiriniinae were not monophyletic meanwhile the monophyly of Stilbonematinae was not fully supported due to a few specimens of questionable identity. COI performed better than SSU rDNA to disentangle relationships among closely related species and suggested the presence of cryptic diversity within Desmodoridae. COI is effective to explore cryptic diversity and barcode species within Nematoda, with a possible threshold of genetic distance of 5% between conspecific and interspecific sequences, but DNA barcoding is limited by the poor knowledge of the diversity and taxonomy of the group and the lack of a good reference database of vouchered COI sequences.
Midmembranous Vocal Fold Lamina Propria Proteoglycans across Selected Species
Authors: Hahn Mariah S. , Kobler James B. , Zeitels Steven M. , Langer Robert 
Published: October 2014

Objectives: We examined the proteoglycan (PG) and associated sulfated glycosaminoglycan (GAG) content of the midmembranous vocal fold lamina propria (LP) of humans, dogs, pigs, and ferrets. Methods: The LP PG levels were assessed indirectly by quantifying the associated sulfated GAGs, and immunohistochemical analyses of specific PGs and/or GAGs (PGs/GAGs) were conducted. Results: Sulfated GAGs constituted approximately (average ± SEM) 14.7 ±2.1 μg per milligram of tissue total protein in the human LP — similar to levels in canine, porcine, and ferret LPs (p > .05). Immunohistochemical analysis identified versican, chondroitin 4- and 6-sulfate, and heparan sulfate in the LP extracellular matrix — PGs/GAGs previously believed to be localized only intracellularly and in the basement membrane. Observations of PG/GAG staining patterns resulted in identification of microstructurally based subdivisions of canine, porcine, and ferret LPs. Conclusions: The sulfated GAG concentration in human LP was similar to that of dermis. In contrast to the interspecies similarity in LP sulfated GAG levels, immunohistochemical analysis indicated notable interspecies differences in specific PG/GAG distributions. Moreover, spatial variations in the presence of several PGs/GAGs were observed — variations that may be integral in maintaining normal LP physiology. Finally, the noted canine, porcine, and ferret LP subdivisions may yield insight into the adaptation of LP microstructure to the phonatory needs of each species.
Quality of Life following Small Fenestra Stapedotomy
Authors: Chandarana Shamir , Parnes Lorne , Agrawal Sumit , Fung Kevin 
Published: October 2014

Objectives: A cross-sectional observational study was designed to evaluate patient satisfaction after stapedotomy. Methods: Two validated questionnaires, the Psychosocial Impact of Assistive Devices Scale (PIADS) and the Hearing Handicap Inventory (HHI), were used to assess patients for whom audiometric data were available. Results: The response rate was 79%. The PIADS score showed that 96% of patients reported an improvement in quality of life. The HHI score, however, showed that 32% of patients still experienced a marked degree of handicap after surgery. The HHI scores correlated positively with postoperative audiometric data, and the PIADS scores correlated positively with the degree of change in audiometric data. Conclusions: The results of this study support the role of small fenestra stapedotomy as a primary treatment for otosclerosis. The study also identifies a certain subpopulation of patients with residual handicap who may require further aural rehabilitation.
Congenital Bilateral Vocal Cord Paralysis and the Role of Glycine
Authors: Berkowitz Robert G. , Sun Qi-Jian , Pilowsky Paul M. 
Published: October 2014

Objectives: We sought to modify normal laryngeal constrictor (LC) motoneuron activity to induce a pattern of aberrant LC muscle function that may serve as a model of congenital bilateral vocal cord paralysis. Methods: Single unit extracellular recordings of functionally identified LC motoneurons were made in anesthetized Sprague-Dawley rats, and the response to both intravenous and iontophoretic application of the glycine antagonist strychnine was studied. Results: The postinspiratory firing pattern of LC motoneurons became inspiratory after intravenous injection of strychnine (4 of 5 rats), but no change was recorded in response to strychnine iontophoresis (7 of 8 rats). Conclusions: Blockade of glycinergic inhibitory neurotransmission by strychnine, acting above the level of the LC motoneuron, causes LC motoneurons to fire during inspiration rather than after inspiration. This observation suggests that impaired glycine neurotransmission may be an underlying mechanism that explains the clinical manifestations of congenital bilateral vocal cord paralysis.
Vitamin A-Storing Stellate Cells in the Human Newborn Vocal Fold
Authors: Sato Kiminori , Nakashima Tadashi 
Published: October 2014

Objectives: Vocal fold stellate cells (VFSCs) in the newborn vocal fold were examined and compared with VFSCs in the adult vocal fold. Methods: Light and electron microscopic investigation of VFSCs was carried out on 5 human newborn larynges. Results: The VFSCs were distributed in human newborn maculae flavae. They were stellate or oval in shape, and possessed cytoplasmic processes. The VFSCs in some cells formed a gap junction with each other. A few lipid droplets were present in the cytoplasm, but they were much fewer than those of an adult. The nucleus-cytoplasm ratio was high, and the intracellular organelles were not very well developed. Free ribosomes were well developed in the cytoplasm. The VFSCs in some cells showed strong cytoplasm staining with periodic acid-Schiff stain and type III collagen. There were vesicles along the periphery of the cytoplasm of the VFSCs, and newly released amorphous materials were seen, but fewer were observed on the cell surface. The newborn VFSCs had started to synthesize extracellular matrices such as collagenous fibers, reticular fibers, elastic fibers, and glycosaminoglycan. Conclusions: The VFSCs in the newborn maculae flavae were immature, but had already started the synthesis of extracellular matrices essential for the viscoelastic properties of the vocal fold mucosa.
Endoscopic Treatment of cT2 Glottic Carcinoma: Prognostic Impact of Different pT Subcategories
Authors: Peretti Giorgio , Piazza Cesare , Mensi Maria C. , Magnoni Laura , Bolzoni Andrea 
Published: October 2014

Objectives: The cT2 glottic squamous cell carcinomas are a heterogeneous group of lesions in terms of superficial and deep extension. As a consequence, they differ greatly in treatment indications and prognosis. The aim of the present study was to divide cT2 glottic tumors into subcategories according to radiologic and postoperative histopathologic information, in order to identify risk factors connected with determinate survival, local-regional control, and laryngeal preservation rates. Methods: We retrospectively analyzed 55 cT2 glottic lesions treated at a single institution by carbon dioxide laser with at least 2 years of follow-up. Clinical, radiologic, surgical, and histopathologic data were reviewed, and the tumors were accordingly divided into 5 subcategories: I, or pT2 with lateral supraglottic extension (19 patients); II, or pT2 with lateral subglottic extension (6 patients); III, or pT2 with supracommissural and/or subcommissural extension (10 patients); IV, or pT2 with deep vocal muscle infiltration (14 patients); and V, or pT3, for superior and/or inferior paraglottic space invasion lateral to the thyroarytenoid muscle not detected before operation by computed tomographic scan (6 patients). Results: The disease-free survival, ultimate local control with laser alone, and laryngeal preservation rates were compared for each subcategory. Statistically significant differences were found only for the pT3 subgroup (2-year rates of 16.7%, 16.7%, and 16.7% for pT3 versus 5-year rates of 80.5%, 84.7%, and 93.3% for the entire pT2 group). Conclusions: Endoscopic treatment of cT2 glottic tumors can be considered effective when the pT2 stage has been confirmed. In cT2/pT3 patients, after the first endoscopic resection that allows the correct pT staging, additional treatment should always be considered.