bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mcl-1 Mediates TWEAK/Fn14-Induced Non–Small Cell Lung Cancer Survival and Therapeutic Response
Authors: Whitsett Timothy G. , Mathews Ian T. , Cardone Michael H. , Lena Ryan J. , Pierceall William E. , Bittner Michael , Sima Chao , LoBello Janine , Weiss Glen J. , Tran Nhan L. 
Published: January 2014

Abstract
Insensitivity to standard clinical interventions, including chemotherapy, radiotherapy, and tyrosine kinase inhibitor (TKI) treatment, remains a substantial hindrance towards improving the prognosis of patients with non–small cell lung cancer (NSCLC). The molecular mechanism of therapeutic resistance remains poorly understood. The TNF-like weak inducer of apoptosis (TWEAK)–FGF-inducible 14 (TNFRSF12A/Fn14) signaling axis is known to promote cancer cell survival via NF-κB activation and the upregulation of prosurvival Bcl-2 family members. Here, a role was determined for TWEAK–Fn14 prosurvival signaling in NSCLC through the upregulation of myeloid cell leukemia sequence 1 (MCL1/Mcl-1). Mcl-1 expression significantly correlated with Fn14 expression, advanced NSCLC tumor stage, and poor patient prognosis in human primary NSCLC tumors. TWEAK stimulation of NSCLC cells induced NF-κB–dependent Mcl-1 protein expression and conferred Mcl-1–dependent chemo- and radioresistance. Depletion of Mcl-1 via siRNA or pharmacologic inhibition of Mcl-1, using EU-5148, sensitized TWEAK-treated NSCLC cells to cisplatin- or radiation-mediated inhibition of cell survival. Moreover, EU-5148 inhibited cell survival across a panel of NSCLC cell lines. In contrast, inhibition of Bcl-2/Bcl-xL function had minimal effect on suppressing TWEAK-induced cell survival. Collectively, these results position TWEAK–Fn14 signaling through Mcl-1 as a significant mechanism for NSCLC tumor cell survival and open new therapeutic avenues to abrogate the high mortality rate seen in NSCLC.
Implications: The TWEAK–Fn14 signaling axis enhances lung cancer cell survival and therapeutic resistance through Mcl-1, positioning both TWEAK–Fn14 and Mcl-1 as therapeutic opportunities in lung cancer. Mol Cancer Res; 12(4); 550–9. ©2014 AACR.
CD74–NRG1 Fusions in Lung Adenocarcinoma
Authors: Fernandez-Cuesta Lynnette , Plenker Dennis , Osada Hirotaka , Sun Ruping , Menon Roopika , Leenders Frauke , Ortiz-Cuaran Sandra , Peifer Martin , Bos Marc , Daßler Juliane , Malchers Florian , Schöttle Jakob , Vogel Wenzel , Dahmen Ilona , Koker Mirjam , Ullrich Roland T. , Wright Gavin M. , Russell Prudence A. , Wainer Zoe , Solomon Benjamin , Brambilla Elisabeth , Nagy-Mignotte Hélène , Moro-Sibilot Denis , Brambilla Christian G. , Lantuejoul Sylvie , Altmüller Janine , Becker Christian , Nürnberg Peter , Heuckmann Johannes M. , Stoelben Erich , Petersen Iver , Clement Joachim H. , Sänger Jörg , Muscarella Lucia A. , la Torre Annamaria , Fazio Vito M. , Lahortiga Idoya , Perera Timothy , Ogata Souichi , Parade Marc , Brehmer Dirk , Vingron Martin , Heukamp Lukas C. , Buettner Reinhard , Zander Thomas , Wolf Jürgen , Perner Sven , Ansén Sascha , Haas Stefan A. , Yatabe Yasushi , Thomas Roman K. 
Published: January 2014

Abstract
We discovered a novel somatic gene fusion, CD74–NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P &lt; 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, CD74–NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment.
Significance: CD74–NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415–22. ©2014 AACR.
This article is highlighted in the In This Issue feature, p. 377
Elimination of NADPH Oxidase Activity Promotes Reductive Stress and Sensitizes the Heart to Ischemic Injury
Authors: Yu Qiujun , Lee Chi Fung , Wang Wang , Karamanlidis Georgios , Kuroda Junya , Matsushima Shouji , Sadoshima Junichi , Tian Rong 
Published: January 2014

Background

The
NADPH
oxidase family (Nox) produces reactive oxygen species by adding the electron donated by
NADPH
to oxygen. Excessive reactive oxygen species production under a variety of pathological conditions has been attributed to increased Nox activity. Here, we aimed at investigating the role of Nox in cardiac ischemic injury through gain‐ and loss‐of‐function approaches.

Methods and Results

We modulated Nox activity in the heart by cardiac‐specific expression of Nox4 and dominant negative Nox4. Modulation of Nox activity drastically changes the cellular redox status. Increasing Nox activity by cardiac‐specific overexpression of Nox4 imposed oxidative stress on the myocardium [increased
NAD
(P)
+
/
NAD
(P)H and decreased glutathione/glutathione disulfide ratio] and worsened cardiac energetics and contractile function after ischemia‐reperfusion. Overexpression of the dominant negative Nox4 (
DN
), which abolished the Nox function, led to a markedly reduced state [decreased
NAD
(P)
+
/
NAD
(P)H and increased glutathione/glutathione disulfide ratio] at baseline and paradoxically promoted mitochondrial reactive oxygen species production during ischemia resulting in no recovery of heart function after reperfusion. Limiting the generation of reducing equivalent through modulating carbon substrates availability partially restored the
NAD
+
/
NADH
ratio and protected dominant negative Nox4 hearts from ischemic injury.

Conclusions
This study reveals an important role of Nox in cardiac redox regulation and highlights the complexity of developing therapies that affect the intricately connected redox states.
Deletion of Krüppel‐Like Factor 4 in Endothelial and Hematopoietic Cells Enhances Neointimal Formation Following Vascular Injury
Authors: Yoshida Tadashi , Yamashita Maho , Horimai Chihiro , Hayashi Matsuhiko 
Published: January 2014

Background

Krüppel‐like factor 4 (Klf4) is involved in a variety of cellular functions by activating or repressing the transcription of multiple genes. Results of previous studies showed that tamoxifen‐inducible global deletion of the
Klf4
gene in mice accelerated neointimal formation following vascular injury, in part via enhanced proliferation of smooth muscle cells (
SMC
s). Because Klf4 is also expressed in non‐
SMC
s including endothelial cells (
EC
s), we determined if
Tie2
promoter‐dependent deletion of
Klf4
in
EC
s and hematopoietic cells affected injury‐induced neointimal formation.

Methods and Results

Klf4
conditional knockout (
cKO
) mice were generated by breeding
Tie2‐Cre
mice and
Klf4
floxed mice, and their phenotype was analyzed after carotid ligation injury. Results showed that injury‐induced repression of
SMC
differentiation markers was unaffected by
Tie2
promoter‐dependent
Klf4
deletion. However, of interest, neointimal formation was significantly enhanced in
Klf4
‐
cKO
mice 21 days following carotid injury. Moreover,
Klf4
‐
cKO
mice exhibited an augmented proliferation rate, enhanced accumulation of macrophages and T lymphocytes, and elevated expression of cell adhesion molecules including vascular cell adhesion molecule–1 (Vcam1) and E‐selectin in injured arteries. Mechanistic analyses in cultured ECs revealed that Klf4 inhibited tumor necrosis factor‐α–induced expression of
Vcam1
through blocking the binding of nuclear factor‐κB to the
Vcam1
promoter.

Conclusions

These results provide evidence that Klf4 in non‐
SMC
s such as
EC
s regulates neointimal formation by repressing arterial inflammation following vascular injury.
Equilibrium Tropical Cyclone Size in an Idealized State of Axisymmetric Radiative–Convective Equilibrium*
Authors: Chavas Daniel R. , Emanuel Kerry 
Published: January 2014

AbstractTropical cyclone size remains an unsolved problem in tropical meteorology, yet size plays a significant role in modulating damage. This work employs the Bryan cloud model (CM1) to systematically explore the sensitivity of the structure of an axisymmetric tropical cyclone at statistical equilibrium to the set of relevant model, initial, and environmental external parameters. The analysis is performed in a highly idealized state of radiative–convective equilibrium (RCE) governed by only four thermodynamic parameters, which are shown to modulate the storm structure primarily via modulation of the potential intensity.Using dimensional analysis, the authors find that the equilibrium radial wind profile is primarily a function of a single nondimensional parameter given by the ratio of the storm radial length scale to the parameterized eddy radial length scale. The former is found to be the ratio of the potential intensity to the Coriolis parameter, matching the prediction for the “natural” storm length scale embedded within prevailing axisymmetric tropical cyclone theory; the Rossby deformation radius is shown not to be fundamental. Beyond this primary scaling, a second nondimensional parameter representing the nondimensional Ekman suction velocity is found to modulate the far outer wind field. Implications of the primary nondimensional parameter are discussed, including the critical role of effective turbulence in modulating inner-core structure and new insight into empirical estimates of the radial mixing length.
A Global Analysis of Sverdrup Balance Using Absolute Geostrophic Velocities from Argo
Authors: Gray Alison R. , Riser Stephen C. 
Published: January 2014

Abstract
Using observations from the Argo array of profiling floats, the large-scale circulation of the upper 2000 decibars (db) of the global ocean is computed for the period from December 2004 to November 2010. The geostrophic velocity relative to a reference level of 900 db is estimated from temperature and salinity profiles, and the absolute geostrophic velocity at the reference level is estimated from the trajectory data provided by the floats. Combining the two gives the absolute geostrophic velocity on 29 pressure surfaces spanning the upper 2000 db of the global ocean. These velocities, together with satellite observations of wind stress, are then used to evaluate Sverdrup balance, the simple canonical theory relating meridional geostrophic transport to wind forcing. Observed transports agree well with predictions based on the wind field over large areas, primarily in the tropics and subtropics. Elsewhere, especially at higher latitudes and in boundary regions, Sverdrup balance does not accurately describe meridional geostrophic transports, possibly due to the increased importance of the barotropic flow, nonlinear dynamics, and topographic influence. Thus, while it provides an effective framework for understanding the zero-order wind-driven circulation in much of the global ocean, Sverdrup balance should not be regarded as axiomatic.
Forces and Trauma Associated with Minimally Invasive Image‐Guided Cochlear Implantation
Authors: Rohani Pooyan , Pile Jason , Kahrs Lueder A. , Balachandran Ramya , Blachon Grégoire S. , Simaan Nabil , Labadie Robert F. 
Published: January 2014

ObjectiveMinimally invasive image‐guided cochlear implantation (CI) utilizes a patient‐customized microstereotactic frame to access the cochlea via a single drill‐pass. We investigate the average force and trauma associated with the insertion of lateral wall CI electrodes using this technique.Study DesignAssessment using cadaveric temporal bones.SettingLaboratory setup.Subjects and MethodsMicrostereotactic frames for 6 fresh cadaveric temporal bones were built using CT scans to determine an optimal drill path following which drilling was performed. CI electrodes were inserted using surgical forceps to manually advance the CI electrode array, via the drilled tunnel, into the cochlea. Forces were recorded using a 6‐axis load sensor placed under the temporal bone during the insertion of lateral wall electrode arrays (2 each of Nucleus CI422, MED‐EL standard, and modified MED‐EL electrodes with stiffeners). Tissue histology was performed by microdissection of the otic capsule and apical photo documentation of electrode position and intracochlear tissue.ResultsAfter drilling, CT scanning demonstrated successful access to cochlea in all 6 bones. Average insertion forces ranged from 0.009 to 0.078 N. Peak forces were in the range of 0.056 to 0.469 N. Tissue histology showed complete scala tympani insertion in 5 specimens and scala vestibuli insertion in the remaining specimen with depth of insertion ranging from 360° to 600°. No intracochlear trauma was identified.ConclusionThe use of lateral wall electrodes with the minimally invasive image‐guided CI approach was associated with insertion forces comparable to traditional CI surgery. Deep insertions were obtained without identifiable trauma.
Imaging Prevalence of Sigmoid Sinus Dehiscence among Patients with and without Pulsatile Tinnitus
Authors: Schoeff Stephen , Nicholas Brian , Mukherjee Sugoto , Kesser Bradley W. 
Published: January 2014

ObjectiveDefine the radiographic prevalence of sigmoid sinus diverticulum or dehiscence (SSDD) in patients with and without pulsatile tinnitus (PT).Study DesignCase series with chart review.SettingTertiary care university medical center.SubjectsPatients imaged between January 1, 2003, and December 31, 2012.MethodsTwo groups were evaluated for SSDD. The first (“PT”) included patients whose radiology report indicated a clinical history of PT (n = 37 symptomatic ears in 30 patients). The second (“non‐PT”) included all patients undergoing temporal bone high resolution CT (HRCT) between November 2011 and November 2012 (n = 308 ears in 164 patients) for reasons other than pulsatile tinnitus. Primary outcome measure was the radiographic presence of SSDD. Covariates including age, gender, body mass index (BMI), and audiometric data were analyzed by independent t tests and Fisher's exact test.ResultsWithin the PT group, SSDD was identified in 24% of ears (9/37) and 23% of patients (7/30); all SSDD patients were female (P =. 024). Patients with SSDD were significantly younger (P =. 037). SSDD more frequently caused objective tinnitus (P =. 016). There was no difference in average BMI between those with and those without SSDD. In the non‐PT group, SSDD was identified in 2 (both female) of 164 patients (1.2%; 0.6% of ears). The difference in SSDD prevalence between groups was significant (P <. 0001).ConclusionsThe prevalence of SSDD in patients with PT was 23%. Among patients with PT, those with SSDD were younger, exclusively female, and presented with objective tinnitus. The prevalence of SSDD among asymptomatic patients in 1 year was 1.2%.
Aortic valve reconstruction using autologous pericardium for ages over 80 years
Authors: Ozaki Shigeyuki , Kawase Isamu , Yamashita Hiromasa , Uchida Shin , Nozawa Yukinari , Takatoh Mikio , Hagiwara So , Kiyohara Nagaki 
Published: January 2014

Background We performed original aortic valve reconstruction using autologous pericardium; the feasibility for elderly patients is reviewed. Methods From April 2007 through September 2011, aortic valve reconstruction was carried out in 86 patients over the age of 80 years. Twenty-seven patients were male and 59 were female. Mean age was 82.9 ± 2.5 years. Seventy-two patients had aortic stenosis and 14 had aortic regurgitation. Mean preoperative surgical annular diameter was 19.5 ± 2.5 mm. There were 80 (90.7%) cases of small aortic annulus. Mean preoperative logistic EuroSCORE was 22.9 ± 15.8. Results Isolated aortic valve reconstructions were performed in 51 patients. Concomitant procedures included coronary artery bypass grafting in 6, hemiarch aortic replacements in 6, 9 maze procedures, and some combinations. No conversion to valve replacement was required. Mean follow-up was 1243 days. There were 3 hospital deaths due to noncardiac causes. No reoperation was needed. Survival at 56 months was 87.0%. No thromboembolic event occurred. Echocardiography 3.5 years after surgery revealed an average peak pressure gradient of 14.6 ± 3.8 mm Hg. No moderate or severe regurgitation was recorded. Conclusions Aortic valve reconstruction is feasible for patients older than 80 years, resulting in good hemodynamics and a better quality of life, without anticoagulation.
Is continuation of antiplatelets until coronary artery bypass safe in Asians?
Authors: Duc Vu Thang , Zaw Min Htet , Chang Guohao , Hu Shu Lin Jesse , Tay Chee Wei Bobby , Ng Celene Wei Qi , Chia Daryl KA , Lee Chuen Neng , Kofidis Theo 
Published: January 2014

Background Controversies have arisen about the risks of discontinuing antiplatelets prior to coronary artery bypass grafting. Methods We retrospectively studied the effects of different strategies of antiplatelet discontinuation prior to coronary artery bypass on perioperative bleeding and major adverse cardiovascular events in Asian patients in a single center in Singapore. Results 402 patients were divided into 4 groups: group A had no antiplatelets before surgery; antiplatelets were stopped for 5–7 days in group B; 2–4 days in group C; and 0–1 day in group D. Compared to group B, group D had longer intensive care unit stays and more intraoperative transfusions of blood ( p = 0.006) and blood products ( p < 0.05). The 1-year major adverse cardiovascular event rate was higher in groups A and D ( p = 0.027). Stopping antiplatelets within 24 h of surgery was one of multiple independent predictors of intraoperative transfusion but not the 1-year major adverse cardiovascular event rate. Patients on aspirin alone had less intraoperative transfusion of platelets and postoperative minor bleeding than those on combined therapy. Conclusion Continuation of antiplatelets until 2 days before coronary artery bypass in Asian patients in our institution is unlikely to increase the risks of bleeding and perioperative transfusion. Taking antiplatelets within 24 h of surgery seems to be associated with a higher rate of 1-year major adverse cardiovascular events and bleeding, and an increased risk of blood product transfusion. Thirty-day and 1-year major adverse cardiovascular event rates were higher in patients without antiplatelet treatment.
Approximation of papillary muscles for ischaemic mitral regurgitation combined with coronary artery bypass grafting and left ventricular aneurysmectomy: a case report
Authors: Karapanagiotidis GT , Zakkar M , Gukop P , Sarsam MAI 
Published: January 2014

A 72-year-old female presented with severe ischaemic mitral regurgitation following a recent myocardial infarction. She had no significant past medical history. Pre-operative echocardiogram assessment demonstrated preserved tendinous cords of the mitral leaflets, a mitral valve annulus measuring 3.2 cm with end systolic coaptation of 0.3 cm, impaired left ventricular function with an ejection fraction of 35% and significant ventricular dilatation. Cardiac magnetic resonance imaging (MRI) showed delayed enhancement in the anterolateral, septal and lateral walls and confirmed the impairment of the left ventricle and a large aneurysmal deformation. On-table transoesophageal echo showed that the distance between the two papillary muscles was over 4 cm. We performed coronary artery bypass grafting combined with a Dor Procedure and papillary muscle approximation using a polytetrafluoroethylene (PTFE) vascular graft as a sling, without the insertion of a mitral annuloplasty ring. Postoperative echo and cardiac MRI showed improved left ventricular systolic function and reduced left ventricle volume associated with mild mitral regurgitation. We conclude that papillary muscles approximation as a method of mitral valve repair is a very effective procedure for functional ischaemic mitral regurgitation.
Evaluation of a partnership between primary and secondary care providing an accessible Level 1 sexual health service in the community
Authors: Kelly Carmel , Johnston Jillian , Carey Fiona 
Published: January 2014

Summary Comprehensive testing for asymptomatic sexually transmitted infections in Northern Ireland has traditionally been provided by genitourinary medicine clinics. As patient demand for services has increased while budgets have remained limited, there has been increasing difficulty in accommodating this demand. In May 2013, the newly commissioned specialist Sexual Health service in the South Eastern Trust sought to pilot a new model of care working alongside a GP partnership of 12 practices. A training programme to enable GPs and practice nurses to deliver Level 1 sexual health care to heterosexual patients aged >16 years, in accordance with the standards of BASHH, was developed. A comprehensive care pathway and dedicated community health advisor supported this new model with close liaison between primary and secondary care. Testing for Chlamydia, gonorrhoea, HIV and syphilis was offered. The aims of the pilot were achieved, namely to provide accessible, cost-effective sexual health care within a framework of robust clinical governance. Furthermore, it uncovered a high positivity rate for Chlamydia, especially in young men attending their general practice, and demonstrated a high level of patient satisfaction. Moreover the capacity of secondary care to deliver Levels 2 and 3 services was increased.
Different strategies of 25OH vitamin D supplementation in HIV-positive subjects
Authors: Falasca Katia , Ucciferri Claudio , Di Nicola Marta , Vignale Francesca , Di Biase Jessica , Vecchiet Jacopo 
Published: January 2014

Summary A high incidence of 25OH vitamin D deficiency has been observed in HIV-infected subjects. The objective of this study was to evaluate the effect of cholecalciferol administration on serum 25OH vitamin D levels in HIV-infected patients. This prospective cohort study included 153 HIV-positive subjects; 47 were treated with 300,000 IU intramuscular cholecalciferol, 67 with 25,000 IU oral cholecalciferol monthly, while the remaining 39 did not receive any treatment. The group treated orally had an increase of serum 25OH vitamin D concentration, changing from 15.7 ± 12.2 ng/mL to 27.4 ± 11.6 ng/mL after 10 months (T10). The group treated with intramuscular supplementation had an improvement, changing from 18.5 ± 10.5 ng/mL to 32.9.0 ± 12.2 ng/mL at T10. One-way repeated measures analysis of variance indicated a significant difference for 25OH vitamin D variation ( p = 0.002) among the three groups. A significant effect of time ( p < 0.001) and group × time interaction ( p < 0.001) was found: at T10, 25OH vitamin D values were significantly higher in the oral and intramuscular groups with respect to the control group. Our findings showed that the supplementation with cholecalciferol in patients with HIV-infection improved 25OH vitamin D serum levels, and suggest that the two types of administration are equivalent, but are insufficient for severe forms of hypovitaminosis.