bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activation of IL6/IGFIR Confers Poor Prognosis of HBV-Related Hepatocellular Carcinoma through Induction of OCT4/NANOG Expression
Authors: Chang Te-Sheng , Wu Yu-Chih , Chi Ching-Chi , Su Wei-Chi , Chang Pey-Jium , Lee Kam-Fai , Tung Tao-Hsin , Wang Jui , Liu Jun-Jen , Tung Shui-Yi , Kuo Liang-Mou , Ho Hong-Nerng , Ling Thai-Yen , Huang Yen-Hua 
Published: January 2015

Abstract
Purpose: To unravel the role of interleukin (IL)-6 and insulin-like growth factor (IGF)-I receptor (IGFIR) in expressing stemness-related properties and to evaluate the prognostic values of pluripotent transcription factor OCT4/NANOG, and IGFIR in hepatocellular carcinoma (HCC).
Experimental Design: Serum levels of IL6 were detected using ELISA assays (n = 120). The effects of IL6/IGFI on stemness expression in HCC were examined using OCT4/NANOG promoter luciferase reporter, RNA interference, secondary sphere formation, side population, and xenograft animal models. The OCT4/NANOG protein and phospho-IGFI receptor (p-IGFIR) in tissues were detected by Western blotting (n = 8) and immunohistochemical staining (n = 85). OCT4, NANOG, and IGFIR expression levels in tissues (n = 191) were analyzed by real-time qRT-PCR and was correlated with early tumor recurrence using the Kaplan–Meier survival analysis.
Results: A high positive correlation between the expression levels of OCT4/NANOG and IGFIR/p-IGFIR in human HCC tissues was observed. The concurrent expression of OCT4/NANOG/IGFIR was mostly confined to hepatitis B virus (HBV)–related HCC (HBV-HCC) and was significantly correlated with early tumor recurrence. High serum levels of IL6 were significantly correlated with high OCT4/NANOG expression. IL6 stimulated an autocrine IGFI/IGFIR expression STAT3 dependently, which stimulated stemness-related properties in both the cell lines and the xenografted mouse tumors. The inhibition of IGFIR activation by either RNA interference or by treatment with the inhibitor picropodophyllin (PPP) significantly suppressed the IL6-induced stemness-related properties both in vitro and in vivo.
Conclusions: The expression of pluripotency-related genes is associated with early tumor recurrence and is regulated by IL6-induced IGF/IGFIR activation, particularly in HBV-HCC. Clin Cancer Res; 21(1); 201–10. ©2014 AACR.
Development of a Prognostic Genetic Signature to Predict the Metastatic Risk Associated with Cutaneous Melanoma
Authors: Gerami Pedram , Cook Robert W. , Wilkinson Jeff , Russell Maria C. , Dhillon Navneet , Amaria Rodabe N. , Gonzalez Rene , Lyle Stephen , Johnson Clare E. , Oelschlager Kristen M. , Jackson Gilchrist L. , Greisinger Anthony J. , Maetzold Derek , Delman Keith A. , Lawson David H. , Stone John F. 
Published: January 2015

Abstract
Purpose: The development of a genetic signature for the identification of high-risk cutaneous melanoma tumors would provide a valuable prognostic tool with value for stage I and II patients who represent a remarkably heterogeneous group with a 3% to 55% chance of disease progression and death 5 years from diagnosis.
Experimental Design: A prognostic 28-gene signature was identified by analysis of microarray expression data. Primary cutaneous melanoma tumor tissue was evaluated by RT-PCR for expression of the signature, and radial basis machine (RBM) modeling was performed to predict risk of metastasis.
Results: RBM analysis of cutaneous melanoma tumor gene expression reports low risk (class 1) or high risk (class 2) of metastasis. Metastatic risk was predicted with high accuracy in development (ROC = 0.93) and validation (ROC = 0.91) cohorts of primary cutaneous melanoma tumor tissue. Kaplan–Meier analysis indicated that the 5-year disease-free survival (DFS) rates in the development set were 100% and 38% for predicted classes 1 and 2 cases, respectively (P &lt; 0.0001). DFS rates for the validation set were 97% and 31% for predicted classes 1 and 2 cases, respectively (P &lt; 0.0001). Gene expression profile (GEP), American Joint Committee on Cancer stage, Breslow thickness, ulceration, and age were independent predictors of metastatic risk according to Cox regression analysis.
Conclusions: The GEP signature accurately predicts metastasis risk in a multicenter cohort of primary cutaneous melanoma tumors. Preliminary Cox regression analysis indicates that the signature is an independent predictor of metastasis risk in the cohort presented. Clin Cancer Res; 21(1); 175–83. ©2015 AACR.
Tadalafil Augments Tumor Specific Immunity in Patients with Head and Neck Squamous Cell Carcinoma
Authors: Califano Joseph A. , Khan Zubair , Noonan Kimberly A. , Rudraraju Lakshmi , Zhang Zhe , Wang Hao , Goodman Steven , Gourin Christine G. , Ha Patrick K. , Fakhry Carole , Saunders John , Levine Marshall , Tang Mei , Neuner Geoffrey , Richmon Jeremy D. , Blanco Ray , Agrawal Nishant , Koch Wayne M. , Marur Shanthi , Weed Donald T. , Serafini Paolo , Borrello Ivan 
Published: January 2015

AbstractPurpose: To determine if phosphodiesterase 5 (PDE5) inhibitors can augment immune function in patients with head and neck cancer through inhibition of myeloid-derived suppressor cells (MDSC).Experimental Design: We performed a randomized, prospective, double blinded, placebo controlled, phase II clinical trial to determine the in vivo effects of systemic PDE5 inhibition on immune function in patients with head and neck squamous cell carcinoma (HNSCC).Results: Tadalafil augmented immune response, increasing ex vivo T-cell expansion to a mean 2.4-fold increase compared with 1.1-fold in control patients (P = 0.01), reducing peripheral MDSC numbers to mean 0.81-fold change compared with a 1.26-fold change in control patients (P = 0.001), and increasing general immunity as measured by delayed type hypersensitivity response (P = 0.002). Tumor-specific immunity in response to HNSCC tumor lysate was augmented in tadalafil-treated patients (P = 0.04).Conclusions: These findings demonstrate that tadalafil augments general and tumor-specific immunity in patients with HNSCC and has therapeutic potential in HNSCC. Evasion of immune surveillance and suppression of systemic and tumor-specific immunity is a significant feature of head and neck cancer development. This study demonstrates that a PDE5 inhibitor, tadalafil, can reverse tumor-specific immune suppression in patients with head and neck cancer, with potential for therapeutic application. Clin Cancer Res; 21(1); 30–38. ©2015 AACR.
Circulating Cholesteryl Ester Transfer Protein and Coronary Heart Disease
Authors: Niu Wenquan , Qi Yue 
Published: January 2015

Background—

The cholesteryl ester transfer protein (CETP) plays a central role in reverse cholesterol transport. Currently, it remains unresolved whether circulating CETP is causally associated with coronary heart disease (CHD). We aimed to investigate this causal association using
CETP
gene rs708272 polymorphism as an instrument in a Mendelian randomization meta-analysis.

Methods and Results—

We searched PubMed and EMBASE before May 2014. Data and study quality were assessed in duplicate. Thirty-four articles (17 813 CHD patients and 22 203 controls) were qualified. Overall analyses revealed a significant association of rs708272-B1 allele with a reduced CHD risk compared with B2 allele under allelic (odds ratio and 95% confidence interval: 0.87 and 0.82–0.92;
P
<0.001), homozygous genotypic (0.74 and 0.66–0.83;
P
<0.001), and dominant (0.87 and 0.80–0.94;
P
<0.001) models. Carriers of rs708272-B1B1 genotype (weighted mean difference and 95% confidence interval: −0.21 and −0.41 to 0.00 μg/dL;
P
=0.052) or B1 allele (−0.15 and −0.30 to 0.00 μg/dL;
P
=0.056) had a marginally lower circulating CETP level compared with B2B2 genotype carriers. In Mendelian randomization analysis, there was a 25% (odds ratio and 95% confidence interval: 0.75 and 0.19–0.91) and a 17% (0.83 and 0.41–0.96) significantly reduced risk of CHD by a reduction of 0.2 μg/mL in circulating CETP for the comparison of B1B1 genotype and B1 allele with B2B2 genotype, respectively. There were low probabilities of publication bias.

Conclusions—
Our findings demonstrate that the long-term genetically reduced circulating CETP might be causally associated with the low risk of CHD.
Genome-Wide Association Analysis of Plasma B–Type Natriuretic Peptide in Blacks
Authors: Musani Solomon K. , Fox Ervin R. , Kraja Aldi , Bidulescu Aurelian , Lieb Wolfgang , Lin Honghuang , Beecham Ashley , Chen Ming-Huei , Felix Janine F. , Fox Caroline S. , Kao W.H. Linda , Kardia Sharon L.R. , Liu Ching-Ti , Nalls Mike A. , Rundek Tatjana , Sacco Ralph L. , Smith Jennifer , Sun Yan V. , Wilson Gregory , Zhang Zhaogong , Mosley Thomas H. , Taylor Herman A. , Vasan Ramachandran S. 
Published: January 2015

Background—
Numerous experimental studies suggest that B-type natriuretic peptide (BNP) is cardioprotective; however, in clinical studies, higher plasma BNP concentrations have been associated with incident cardiovascular disease and higher left ventricular mass. Genetic association studies may allow us to determine the true causal directions without confounding by compensatory mechanisms.

Methods and Results—

We performed a meta-analysis of 2 genome-wide association results from a total of 2790 blacks. We assumed an additive genetic model in an association analysis of imputed 2.5 million single-nucleotide polymorphism dosages with residuals generated from multivariable-adjusted logarithmically transformed BNP controlling for relevant covariates and population stratification. Two loci were genome-wide significant, a candidate gene locus
NPPB
(rs198389,
P
=1.18×10
−09
) and a novel missense variant in the
KLKB1
locus (rs3733402,
P
=1.75×10
−11
) that explained 0.4% and 1.9% of variation in log BNP concentration, respectively. The observed increase in BNP concentration was proportional to the number of effect allele copies, and an average of 8.1 pg/mL increase was associated with 2 allele copies. In a companion study, single-nucleotide polymorphisms in this loci were cross-checked with genome-wide association results for the aldosterone/renin ratio in individuals of European ancestry, and rs3733402 was genome-wide significant (
P
<5.0×10
−8
), suggesting possible shared genetic architecture for these 2 pathways. Other statistically significant relations for these single-nucleotide polymorphisms included the following: rs198389 with systolic blood pressure in blacks (COGENT consortium) and rs198389 and rs3733402 with left ventricular mass in whites (EchoGEN consortium).

Conclusions—
These findings improve our knowledge of the genetic basis of BNP variation in blacks, demonstrate a possible shared allelic architecture for BNP with aldosterone-renin ratio, and motivate further studies of underlying mechanisms.
Meox2/Tcf15 Heterodimers Program the Heart Capillary Endothelium for Cardiac Fatty Acid Uptake
Authors: Coppiello Giulia , Collantes Maria , Sirerol-Piquer María Salomé , Vandenwijngaert Sara , Schoors Sandra , Swinnen Melissa , Vandersmissen Ine , Herijgers Paul , Topal Baki , van Loon Johannes , Goffin Jan , Prósper Felipe , Carmeliet Peter , García-Verdugo Jose Manuel , Janssens Stefan , Peñuelas Iván , Aranguren Xabier L. , Luttun Aernout 
Published: January 2015

Background—
Microvascular endothelium in different organs is specialized to fulfill the particular needs of parenchymal cells. However, specific information about heart capillary endothelial cells (ECs) is lacking.

Methods and Results—

Using microarray profiling on freshly isolated ECs from heart, brain, and liver, we revealed a genetic signature for microvascular heart ECs and identified Meox2/Tcf15 heterodimers as novel transcriptional determinants. This signature was largely shared with skeletal muscle and adipose tissue endothelium and was enriched in genes encoding fatty acid (FA) transport–related proteins. Using gain- and loss-of-function approaches, we showed that Meox2/Tcf15 mediate FA uptake in heart ECs, in part, by driving endothelial CD36 and lipoprotein lipase expression and facilitate FA transport across heart ECs. Combined
Meox2
and
Tcf15
haplodeficiency impaired FA uptake in heart ECs and reduced FA transfer to cardiomyocytes. In the long term, this combined haplodeficiency resulted in impaired cardiac contractility.

Conclusions—
Our findings highlight a regulatory role for ECs in FA transfer to the heart parenchyma and unveil 2 of its intrinsic regulators. Our insights could be used to develop new strategies based on endothelial Meox2/Tcf15 targeting to modulate FA transfer to the heart and remedy cardiac dysfunction resulting from altered energy substrate usage.
Central and Eastern U.S. Surface Pressure Variations Derived from the USArray Network
Authors: Jacques Alexander A. , Horel John D. , Crosman Erik T. , Vernon Frank L. 
Published: January 2015

Abstract
Large-magnitude pressure signatures associated with a wide range of atmospheric phenomena (e.g., mesoscale gravity waves, convective complexes, tropical disturbances, and synoptic storm systems) are examined using a unique set of surface pressure sensors deployed as part of the National Science Foundation EarthScope USArray Transportable Array. As part of the USArray project, approximately 400 seismic stations were deployed in a pseudogrid fashion across a portion of the United States for 1–2 yr, then retrieved and redeployed farther east. Surface pressure observations at a sampling frequency of 1 Hz were examined during the period 1 January 2010–28 February 2014 when the seismic array was transitioning from the central to eastern continental United States. Surface pressure time series at over 900 locations were bandpass filtered to examine pressure perturbations on three temporal scales: meso- (10 min–4 h), subsynoptic (4–30 h), and synoptic (30 h–5 days) scales.
Case studies of strong pressure perturbations are analyzed using web tools developed to visualize and track tens of thousands of such events with respect to archived radar imagery and surface wind observations. Seasonal assessments of the bandpass-filtered variance and frequency of large-magnitude events are conducted to identify prominent areas of activity. Large-magnitude mesoscale pressure perturbations occurred most frequently during spring in the southern Great Plains and shifted northward during summer. Synoptic-scale pressure perturbations are strongest during winter in the northern states with maxima located near the East Coast associated with frequent synoptic development along the coastal storm track.
The Decline of Tracheotomy among Otolaryngologists
Authors: Patel Hetal H. , Siltumens Aldis , Bess Leah , Camacho Fabian , Goldenberg David 
Published: January 2015

ObjectiveTo determine the trend of number of tracheotomies performed by otolaryngologists.Study DesignCase series with chart review.SettingTertiary referral center in central Pennsylvania.SubjectsAll patients undergoing tracheotomy between 2000 and 2013.MethodsData were gathered from billing records and operative reports to determine the service performing the tracheotomy. In addition, the surgical technique and indication for surgery were recorded. Negative binomial regressions were conducted to examine the number of tracheotomies performed by each specialty as a function of year.ResultsIn 2000, 44% of tracheotomies were being performed by the otolaryngology service, compared with only 25% in 2013. This is a decline of 22% over time. Since 2000, general surgery steadily increased the number of tracheotomies performed in comparison to the steady decrease performed by otolaryngology. Since 2008, general surgeons have significantly increased the number of percutaneous tracheotomies they perform (76% per year). Over the same period, the number of tracheotomies performed by the cardiothoracic surgery service has steadily increased by 26% per year. Most of the tracheotomies performed by cardiothoracic surgery are percutaneous tracheotomies.ConclusionThis study illustrates that otolaryngologists at our institution are performing fewer tracheotomies over time. If this trend continues, the experience of our trainees may become diluted through reduction in surgical volume. While multi‐institutional studies are warranted, this review provides a summary of data collected at a tertiary care institution, which may reflect national trends.
Lack of Association between Human Herpesvirus and Vestibular Schwannoma
Authors: Bhimrao Sanjiv K. , Maguire John , Garnis Cathie , Tang Patrick , Lea Jane , Akagami Ryojo , Westerberg Brian D. 
Published: January 2015

ObjectiveTo assess for the presence of human herpesvirus (HHV) using immunohistochemical and polymerase chain reaction (PCR) assay in surgically excised vestibular schwannoma (VS) samples.Study DesignCross‐sectional study.SettingA retrospective laboratory‐based study of tumors from patients with vestibular schwannoma.Subjects and MethodsTissue microarrays (TMAs) representing sporadic and NF2‐associated VS from 121 patients, as well as appropriate positive and negative controls, were studied. TMA sections were immunostained using antibodies directed against HHV‐1, HHV‐2, HHV‐3, HHV‐4, HHV‐5, and HHV‐8. PCR was used for the detection of all 8 known human herpesviruses.ResultsThere was no detectable HHV (HHV‐1, HHV‐2, HHV‐3, HHV‐4, HHV‐5, HHV‐8) by immunohistochemistry in any of the 121 cases of sporadic and NF2 cases analyzed. These data were further validated by DNA sequence analyses using PCR in a subset of the VS samples, all of which were found to be negative for all HHV.ConclusionsThe data offer no support for an association between HHV and the development of sporadic or NF2‐associated VS in humans.
Treatment Outcomes of Temporal Bone Osteoradionecrosis
Authors: Kammeijer Quinten , van Spronsen Erik , Mirck Piet G. B. , Dreschler Wouter A. 
Published: January 2015

ObjectiveTo investigate the clinical relevance of the classification systems used for temporal bone osteoradionecrosis (ORN) and to define a treatment protocol for temporal bone ORN.Study DesignRetrospective case series.SettingAmsterdam, department of otorhinolaryngology and head and neck surgery.Subjects and MethodsClassification of temporal bone ORN was performed through use of clinical data and radiologic imaging. Outcomes of conservative and surgical treatment were investigated and compared for different grades of ORN.ResultsOf the 49 ears included in this study, 35 were primarily treated conservatively. At start of conservative treatment, 23 were classified as a localized and 8 as a diffuse form of ORN; 4 could not be classified. There was a significant difference in clinical outcome between the localized and diffuse forms of ORN (χ2 = 5.862, P =. 015), and mastoid air cell destruction on preoperative computed tomography scan was found to be a significant predictor for a negative outcome of conservative treatment (χ2 = 4.34, P =. 037). Fourteen ears with diffuse ORN were primarily treated surgically, and 11 were secondarily treated surgically following a period of conservative treatment. Twenty‐two patients were treated with subtotal petrosectomy, of which 20 were cured. Three patients were treated with canal wall down mastoidectomy, and 2 had recurrence of disease.ConclusionRamsden’s classification system is clinically relevant in predicting conservative treatment outcomes. Mastoid air cell destruction on computed tomography differentiates between the localized and diffuse forms of ORN. Given our results and experience with treating temporal bone ORN, we propose a treatment protocol.
Agreement Between Athlete-Recalled and Clinically Documented Concussion Histories in Former Collegiate Athletes
Authors: Kerr Zachary Y. , Mihalik Jason P. , Guskiewicz Kevin M. , Rosamond Wayne D. , Evenson Kelly R. , Marshall Stephen W. 
Published: January 2015

Background: Athlete-recalled and clinically documented concussion histories have been used in research on former athletes, but both have limitations. Comparisons of these 2 types of concussion histories are needed to improve the accuracy of estimates of concussion history for future research and clinical care. Purpose: To estimate the agreement between athlete-recalled and clinically documented concussion histories during college and to explore reasons for differences. Study: Cohort study (diagnosis); Level of evidence, 3. Methods: Athlete-recalled concussion histories were provided by a convenience sample of 130 former collegiate athletes using an online questionnaire, and they were individually linked to previously collected clinical data that tracked medically diagnosed concussions at the host institution from 1996 to 2012. The intraclass correlation coefficient (ICC2,1) was used to assess agreement between athlete-recalled and clinically documented concussion histories. Descriptive analyses were performed to assess reasons for disagreement. Results: Agreement between athlete-recalled and clinically documented concussion histories was low (ICC2,1 = 0.21; 95% confidence interval, 0.05-0.37), but it was higher for women (ICC2,1 = 0.65; 95% confidence interval, 0.44-0.79) and for athletes playing more recently (2005-2012; ICC2,1 = 0.39; 95% confidence interval, 0.01-0.67). Of the 53 athletes who self-reported college sports–related concussions, 40% believed that they sustained impacts that should have been diagnosed as concussions but were undetected, and 21% admitted nondisclosure of suspected concussions. Common reasons for nondisclosure included the following: did not think injury was serious enough (91%), did not know it was a concussion (73%), and did not want to leave the game/practice (73%). Conclusion: Given the low agreement between athlete-recalled and clinically documented concussion histories, methodologic research is needed to improve the quality of tools used to assess concussion histories in former athletes.
Surgical Treatment of Clavicle Fractures in the Adolescent Athlete
Authors: Fanter Nathan J. , Kenny Ryan M. , Baker Champ L. , Baker Champ L. 
Published: January 2015

Context: Current literature has clearly shown that the indications for surgical treatment of clavicle fractures in adults are expanding. Although clavicle fractures in children and adolescents have traditionally been treated nonoperatively, surgical treatment of displaced clavicle fractures may be indicated for adolescent athletes. Evidence Acquisition: A review of relevant articles published between 1970 and 2013 was completed using MEDLINE and the terms clavicle fracture and adolescent athlete. Study Design: Clinical review. Level of Evidence: Level 3. Results: Excellent outcomes and rapid return to competition can be achieved with surgical management of displaced clavicle fractures in the adolescent athlete with high functional demands similar to those of their adult counterparts. Complications include hardware irritation, screw loosening, pin migration, peri-incisional numbness, and refracture. Athletes and families must be counseled regarding complications and potential need for secondary surgery to remove hardware. Conclusion: The adolescent athlete with a displaced, shortened, or comminuted clavicle fracture presents a unique, controversial dilemma for the surgeon. Earlier return to competition can be achieved with surgical management to restore length and alignment and may prevent malunion, nonunion, and poor outcomes.