bluuebunny/crossref_metadata_2025_split huggingface dataset:
Apoptosis Inhibitor ARC Promotes Breast Tumorigenesis, Metastasis, and Chemoresistance
Authors: Medina-Ramirez Christina M. , Goswami Sumanta , Smirnova Tatiana , Bamira Daniel , Benson Benjamin , Ferrick Neal , Segall Jeffrey , Pollard Jeffrey W. , Kitsis Richard N. 
Published: October 2011

Abstract
Apoptosis repressor with caspase recruitment domain (ARC) inhibits both death receptor- and mitochondrial/ER-mediated pathways of apoptosis. Although expressed mainly in terminally differentiated cells, ARC is markedly upregulated in a variety of human cancers, where its potential contributions have not yet been defined. In this study, we provide evidence of multiple critical pathophysiologic functions for ARC in breast carcinogenesis. In the polyoma middle T-antigen (PyMT) transgenic mouse model of breast cancer, in which endogenous ARC is strongly upregulated, deletion of the ARC-encoding gene nol3 decreased primary tumor burden without affecting tumor onset or multiplicity. More notably, ARC deficiency also limited tumor cell invasion and the number of circulating cancer cells, markedly reducing the number of lung metastases. Conversely, ectopic overexpression of ARC in a PyMT-derived metastatic breast cancer cell line increased invasion in vitro and lung metastasis in vivo. We confirmed these results in a humanized orthotopic model based on MDA-MB-231-derived LM2 metastatic breast cancer cells, in which RNAi-mediated knockdown of ARC levels was shown to reduce tumor volume, local invasion, and lung metastases. Lastly, we found that endogenous levels of ARC conferred chemoresistance in primary tumors and invading cell populations. Our results establish that ARC promotes breast carcinogenesis by driving primary tumor growth, invasion, and metastasis as well as by promoting chemoresistance in invasive cells. Cancer Res; 71(24); 7705–15. ©2011 AACR.
Phosphorylation of Carbonic Anhydrase IX Controls Its Ability to Mediate Extracellular Acidification in Hypoxic Tumors
Authors: Ditte Peter , Dequiedt Franck , Svastova Eliska , Hulikova Alzbeta , Ohradanova-Repic Anna , Zatovicova Miriam , Csaderova Lucia , Kopacek Juraj , Supuran Claudiu T. , Pastorekova Silvia , Pastorek Jaromir 
Published: October 2011

Abstract
In the hypoxic regions of a tumor, carbonic anhydrase IX (CA IX) is an important transmembrane component of the pH regulatory machinery that participates in bicarbonate transport. Because tumor pH has implications for growth, invasion, and therapy, determining the basis for the contributions of CA IX to the hypoxic tumor microenvironment could lead to new fundamental and practical insights. Here, we report that Thr443 phosphorylation at the intracellular domain of CA IX by protein kinase A (PKA) is critical for its activation in hypoxic cells, with the fullest activity of CA IX also requiring dephosphorylation of Ser448. PKA is activated by cAMP, which is elevated by hypoxia, and we found that attenuating PKA in cells disrupted CA IX-mediated extracellular acidification. Moreover, following hypoxia induction, CA IX colocalized with the sodium-bicarbonate cotransporter and other PKA substrates in the leading edge membranes of migrating tumor cells, in support of the concept that bicarbonate metabolism is spatially regulated at cell surface sites with high local ion transport and pH control. Using chimeric CA IX proteins containing heterologous catalytic domains derived from related CA enzymes, we showed that CA IX activity was modulated chiefly by the intracellular domain where Thr443 is located. Our findings indicate that CA IX is a pivotal mediator of the hypoxia-cAMP–PKA axis, which regulates pH in the hypoxic tumor microenvironment. Cancer Res; 71(24); 7558–67. ©2011 AACR.
Histone Deacetylase Inhibitors Induce Growth Arrest and Differentiation in Uveal Melanoma
Authors: Landreville Solange , Agapova Olga A. , Matatall Katie A. , Kneass Zachary T. , Onken Michael D. , Lee Ryan S. , Bowcock Anne M. , Harbour J. William 
Published: October 2011

Abstract
Purpose: Metastasis is responsible for the death of most cancer patients, yet few therapeutic agents are available which specifically target the molecular events that lead to metastasis. We recently showed that inactivating mutations in the tumor suppressor gene BAP1 are closely associated with loss of melanocytic differentiation in uveal melanoma (UM) and metastasis. The purpose of this study was to identify therapeutic agents that reverse the phenotypic effects of BAP1 loss in UM.
Experimental Design: In silico screens were done to identify therapeutic compounds predicted to differentiate UM cells using Gene Set Enrichment Analysis and Connectivity Map databases. Valproic acid (VPA), trichostatin A, LBH-589, and suberoylanilide hydroxamic acid were evaluated for their effects on UM cells using morphologic evaluation, MTS viability assays, bromodeoxyuridine incorporation, flow cytometry, clonogenic assays, gene expression profiling, histone acetylation and ubiquitination assays, and a murine xenograft tumorigenicity model.
Results: Histone deacetylase (HDAC) inhibitors induced morphologic differentiation, cell-cycle exit, and a shift to a differentiated, melanocytic gene expression profile in cultured UM cells. VPA inhibited the growth of UM tumors in vivo.
Conclusions: These findings suggest that HDAC inhibitors may have therapeutic potential for inducing differentiation and prolonged dormancy of micrometastatic disease in UM. Clin Cancer Res; 18(2); 408–16. ©2011 AACR.
Predicting IGF-1R Therapy Response in Bone Sarcomas: Immuno-SPECT Imaging with Radiolabeled R1507
Authors: Fleuren Emmy D.G. , Versleijen-Jonkers Yvonne M.H. , van de Luijtgaarden Addy C.M. , Molkenboer-Kuenen Janneke D.M. , Heskamp Sandra , Roeffen Melissa H.S. , van Laarhoven Hanneke W.M. , Houghton Peter J. , Oyen Wim J.G. , Boerman Otto C. , van der Graaf Winette T.A. 
Published: October 2011

AbstractPurpose: To investigate whether indium-111–labeled R1507 (111In-R1507) immuno-SPECT (single—photon emission computed tomography), a novel noninvasive, in vivo screening method to visualize membranous insulin-like growth factor 1 receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) response in bone sarcomas.Experimental Design: BALB/c nude mice were subcutaneously implanted with IGF-1R–expressing human bone sarcoma xenografts (OS-1, EW-5, and EW-8) which showed high, modest, or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R–negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well. Mice were injected with 111In-R1507. Biodistribution and immuno-SPECT/computed tomography imaging studies were carried out 1, 3, and 7 days p.i. in mice with OS-1 and EW-5 xenografts and 3 days p.i. in mice with EW-8 and OS-33 xenografts.Results: Biodistribution studies showed specific accumulation of 111In-R1507 in OS-1 and EW-5 xenografts (27.5 ± 6.5%ID/g and 14.0 ± 2.8%ID/g, 3 days p.i., respectively). Most importantly, 111In-R1507 uptake in IGF-1R positive, but unresponsive, EW-8 xenografts (6.5 ± 1.5%ID/g, 3 days p.i.) was similar to that of the IGF-1R–negative OS-33 tumor (5.5 ± 0.6%ID/g, 3 days p.i.). Uptake in normal tissues was low and nonspecific. Corresponding immuno-SPECT images clearly discriminated between high, modest, and nonresponding tumors by showing a homogeneous (OS-1), heterogeneous (EW-5), or nonspecific (EW-8 and OS-33) tumor uptake of 111In-R1507.Conclusions: 111In-R1507 immuno-SPECT is an excellent method to visualize membranous IGF-1R expression and target accessibility in vivo in human bone sarcoma xenografts and may serve as an independent marker to predict IGF-1R therapy (R1507) response in bone sarcoma patients. Clin Cancer Res; 17(24); 7693–703. ©2011 AACR.
Use of [11C]Choline PET-CT as a Noninvasive Method for Detecting Pelvic Lymph Node Status from Prostate Cancer and Relationship with Choline Kinase Expression
Authors: Contractor Kaiyumars , Challapalli Amarnath , Barwick Tara , Winkler Mathias , Hellawell Giles , Hazell Steve , Tomasi Giampaolo , Al-Nahhas Adil , Mapelli Paola , Kenny Laura M. , Tadrous Paul , Coombes R. Charles , Aboagye Eric O. , Mangar Stephen 
Published: October 2011

Abstract
Purpose: To evaluate the accuracy and biological basis for [11C]choline-PET-CT in the nodal staging of high risk localized prostate cancer patients.
Experimental Design: Twenty-eight patients underwent dynamic [11C]choline-PET-CT of the pelvis and lower abdomen prior to extended laparoscopic pelvic lymph node dissection (eLPL). The sensitivity and specificity of [11C]choline PET, [11C]choline PET-CT, and MRI for nodal detection were calculated. Average and maximal standardized uptake values (SUVave, SUVmax) were compared with choline kinase alpha (CHKα) and Ki67 immunohistochemistry scores.
Results: Four hundred and six lymph nodes (LN), in 26 patients, were assessable. Twenty-seven (6.7%) involved pelvic nodes at eLPL were detected in 9 patients. Seventeen of the 27 involved nodes were subcentimeter. The sensitivity and specificity on a per nodal basis were 18.5% and 98.7%, 40.7% and 98.4%, and 51.9% and 98.4% for MRI, [11C]choline PET, and [11C]choline PET-CT, respectively. Sensitivity was higher for [11C]choline PET-CT compared with MRI (P = 0.007). A higher nodal detection rate, including subcentimeter nodes, was seen with [11C]choline PET-CT than MRI. Malignant lesions showed CHKα expression in both cytoplasm and nucleus. SUVave and SUVmax strongly correlated with CHKα staining intensity (r = 0.68, P &lt; 0.0001 and r = 0.63, P = 0.0004, respectively). In contrast, Ki67 expression was generally low in all tumors.
Conclusion: This study establishes the relationship between [11C]choline PET-CT uptake with choline kinase expression in prostate cancer and allows it to be used as a noninvasive means of staging pelvic LNs, being highly specific and more sensitive than MRI, including the detection of subcentimeter disease. Clin Cancer Res; 17(24); 7673–83. ©2011 AACR.
In Vivo Functional and Transcriptional Profiling of Bone Marrow Stem Cells After Transplantation Into Ischemic Myocardium
Authors: Sheikh Ahmad Y. , Huber Bruno C. , Narsinh Kazim H. , Spin Joshua M. , van der Bogt Koen , de Almeida Patricia E. , Ransohoff Katherine J. , Kraft Daniel L. , Fajardo Giovanni , Ardigo Diego , Ransohoff Julia , Bernstein Daniel , Fischbein Michael P. , Robbins Robert C. , Wu Joseph C. 
Published: October 2011

Objective—
Clinical trials of bone marrow–derived stem cell therapy for the heart have yielded variable results. The basic mechanism(s) that underlies their potential efficacy remains unknown. In the present study, we evaluated the survival kinetics, transcriptional response, and functional outcome of intramyocardial bone marrow mononuclear cell (BMMC) transplantation for cardiac repair in a murine myocardial infarction model.

Methods and Results—
We used bioluminescence imaging and high-throughput transcriptional profiling to evaluate the in vivo survival kinetics and gene expression changes of transplanted BMMCs after their engraftment into ischemic myocardium. Our results demonstrate short-lived survival of cells following transplant, with less than 1% of cells surviving by 6 weeks posttransplantation. Moreover, transcriptomic analysis of BMMCs revealed nonspecific upregulation of various cell regulatory genes, with a marked downregulation of cell differentiation and maturation pathways. BMMC therapy caused limited improvement of heart function as assessed by echocardiography, invasive hemodynamics, and positron emission tomography. Histological evaluation of cell fate further confirmed findings of the in vivo cell tracking and transcriptomic analysis.

Conclusion—
Collectively, these data suggest that BMMC therapy, in its present iteration, may be less efficacious than once thought. Additional refinement of existing cell delivery protocols should be considered to induce better therapeutic efficacy.
Utility of Cardiovascular Magnetic Resonance in Identifying Substrate for Malignant Ventricular Arrhythmias
Authors: White James A. , Fine Nowell M. , Gula Lorne , Yee Raymond , Skanes Allan , Klein George , Leong-Sit Peter , Warren Heather , Thompson Terry , Drangova Maria , Krahn Andrew 
Published: October 2011

Background—
Sudden cardiac death (SCD) and sustained monomorphic ventricular tachycardia (SMVT) are frequently associated with prior or acute myocardial injury. Cardiovascular magnetic resonance (CMR) provides morphological, functional, and tissue characterization in a single setting. We sought to evaluate the diagnostic yield of CMR-based imaging versus non–CMR-based imaging in patients with resuscitated SCD or SMVT.

Methods and Results—

Eighty-two patients with resuscitated SCD or SMVT underwent routine non-CMR imaging, followed by a CMR protocol with comprehensive tissue characterization. Clinical reports of non-CMR imaging studies were blindly adjudicated and used to assign each patient to 1 of 7 diagnostic categories. CMR imaging was blindly interpreted using a standardized algorithm used to assign a patient diagnosis category in a similar fashion. The diagnostic yield of CMR-based and non–CMR-based imaging, as well as the impact of the former on diagnosis reclassification, was established. Relevant myocardial disease was identified in 51% of patients using non–CMR-based imaging and in 74% using CMR-based imaging (
P
=0.002). Forty-one patients (50%) were reassigned to a new or alternate diagnosis using CMR-based imaging, including 15 (18%) with unsuspected acute myocardial injury. Twenty patients (24%) had no abnormality by non-CMR imaging but showed clinically relevant myocardial disease by CMR imaging.

Conclusions—
CMR-based imaging provides a robust diagnostic yield in patients presenting with resuscitated SCD or SMVT and incrementally identifies clinically unsuspected acute myocardial injury. When compared with non–CMR-based imaging, a new or alternate myocardial disease process may be identified in half of these patients.
Improved Detection of Myocardial Involvement in Acute Inflammatory Cardiomyopathies Using T2 Mapping
Authors: Thavendiranathan Paaladinesh , Walls Michael , Giri Shivraman , Verhaert David , Rajagopalan Sanjay , Moore Sean , Simonetti Orlando P. , Raman Subha V. 
Published: October 2011

Background—
T2-weighted cardiac magnetic resonance imaging is useful in diagnosing acute inflammatory myocardial diseases, such as myocarditis and tako-tsubo cardiomyopathy (TTCM). We hypothesized that quantitative T2 mapping could better delineate myocardial involvement in these disorders versus T2-weighted imaging.

Methods and Results—

Thirty patients with suspected myocarditis or TTCM, referred for cardiac magnetic resonance imaging, who met established diagnostic criteria underwent myocardial T2 mapping. T2 values were averaged in involved and remote myocardial segments, both defined by a reviewer blinded to T2 data. In myocarditis, T2 was 65.2±3.2 ms in the involved myocardium versus 53.5±2.1 ms in the remote myocardium (
P
<0.001). In TTCM, T2 was 65.6±4.0 ms in the involved myocardium versus 53.6±2.7 ms in the remote segments (
P
<0.001). T2 values were similar across remote myocardial segments in patients and all myocardial segments in controls (
P
>0.05 for all). T2 maps provided diagnostic data even in patients with difficulty breath holding. A T2 cutoff of 59 ms identified areas of myocardial involvement, with sensitivity and specificity of 94% and 97%, respectively. T2 mapping revealed regions of abnormal T2 beyond those identified by wall motion abnormalities or late gadolinium-enhancement positivity. Conventional T2-weighted short tau inversion recovery images were uninterpretable in 7 patients because of artifact and unremarkable in 2 patients who had elevated T2 values. T2-prepared steady-state–free precession images showed areas of signal hyperintensity in only 17 of 30 patients.

Conclusions—
Quantitative T2 mapping reliably identifies myocardial involvement in patients with myocarditis and TTCM. T2 mapping delineated a greater extent of myocardial disease in both conditions compared with that identified by wall motion abnormalities, T2-weighted short tau inversion recovery imaging, T2-prepared steady-state–free precession, or late gadolinium enhancement. Quantitative T2 mapping warrants consideration as a robust technique to identify myocardial injury in patients with acute myocarditis or TTCM.
Age, Antipsychotics, and the Risk of Ischemic Stroke in the Veterans Health Administration
Authors: Wang Shirley , Linkletter Crystal , Dore David , Mor Vincent , Buka Stephen , Maclure Malcolm 
Published: October 2011

Background and Purpose—
Time-dependent effects of antipsychotics on risk of stroke and potential effect modification by age have not been fully investigated. A case–case–time–control design uses within- and between-case comparisons to evaluate short-term effects at the same time as adjusting for unmeasured time-invariant confounders and exposure-time trends.

Methods—
We conducted a case–case–time–control design study using data from the Veterans Health Administration. Veterans with inpatient hospitalizations for ischemic stroke between 2002 and 2007 were included. For every stroke case, the “current” exposure period was defined as 1 to 30 days before hospitalization and the “reference” period as 91 to 120 days before hospitalization. Exposure during the current period was compared with exposure during the reference period within cases. Exposure-time trend-adjusted estimates of the effect of antipsychotic exposure on risk of stroke were obtained by dividing exposure odds for antipsychotic exposure by average exposure odds for other medications over the same time period among the same cases.

Results—
After adjusting for exposure-time trends, odds of stroke were 1.8 (95% CI, (1.7–1.9) times higher when exposed to antipsychotics than when unexposed. Age-stratified estimates suggest a greater triggering effect of antipsychotics among older patients.

Conclusions—
Exposure to antipsychotics may be a proximal trigger for stroke. Elevation in risk is apparent after brief exposure to antipsychotics.
Risk of Stroke After Coronary Artery Bypass Grafting
Authors: Mérie Charlotte , Køber Lars , Olsen Peter Skov , Andersson Charlotte , Jensen Jan Skov , Torp-Pedersen Christian 
Published: October 2011

Background and Purpose—
The risk of stroke after coronary artery bypass grafting (CABG) is known to increase dramatically with age. During recent years, the age of patients operated on has increased and concomitant therapy has changed. Therefore, we have re-evaluated the risk of stroke after CABG.

Methods—
Through the Danish National Hospital Register, we identified all 25 159 patients with isolated CABG from 1997 through 2006. Stroke, comorbidities, and medication were further obtained. Risk factors of stroke were determined through regression models.

Results—

Overall, 1901 patients (7.6%) suffered a stroke after surgery, 477 patients (2.0%) within 30 days after CABG. Rates of stroke per 100 person-years (95% CI) within 30 days after surgery increased with age: <60 years, 10.1 (7.8–13.0); 60 to 64 years, 18.4 (14.3–23.5); 65 to 69 years, 27.7 (23.0–33.3); 70 to 74 years, 36.0 (30.4–42.6); 75 to 79 years, 36.1 (29.1–44.7); ≥80 years, 38.0 (25.2–57.1). Risks of stroke within 30 days after surgery adjusted for age (reference: age <60 years), sex, relevant comorbidities, and selected medication included: 60 to 64 years: HR, 1.7 (
P
=0.005; 95% CI, 1.2–2.4), 65 to 69 years: HR, 2.4 (
P
=0.001; 95% CI, 1.7–3.3), 70 to 74 years: HR, 2.8 (
P
=0.001; 95% CI, 2.1–3.8), 75 to 79 years: HR, 2.8 (
P
=0.001; 95% CI, 2.0–4.0), ≥80 years: HR, 3.0 (
P
=0.001; 95% CI, 1.8–4.9), previous stroke: HR, 4.2 (
P
=0.001; 95% CI, 3.3–5.4), diabetes: HR, 1.3 (
P
=0.019; 95% CI, 1.1–1.7), hypertension: HR, 1.4 (
P
=0.003; 95% CI, 1.1–1.7), peripheral vascular disease: HR, 1.6 (
P
=0.001; 95% CI, 1.3–2.1), renal failure: HR, 1.7 (
P
=0.012; 95% CI, 1.1–2.5), statins: HR, 0.8 (
P
=0.049; 95% CI, 0.7–1.0), clopidogrel: HR, 0.6 (
P
=0.032; 95% CI, 0.4–1.0).

Conclusions—
The increase in stroke with age after CABG is moderate and the relation uncertain in ages older than 70 years. Declining CABG in elderly patients because of risk of stroke purely on the basis of high age is debatable.
30-Day Mortality and Readmission After Hemorrhagic Stroke Among Medicare Beneficiaries in Joint Commission Primary Stroke Center-Certified and Noncertified Hospitals
Authors: Lichtman Judith H. , Jones Sara B. , Leifheit-Limson Erica C. , Wang Yun , Goldstein Larry B. 
Published: October 2011

Background and Purpose—
Ischemic stroke patients treated at Joint Commission Primary Stroke Center (JC-PSC)-certified hospitals have better outcomes. Data reflecting the impact of JC-PSC status on outcomes after hemorrhagic stroke are limited. We determined whether 30-day mortality and readmission rates after hemorrhagic stroke differed for patients treated at JC-PSC–certified versus noncertified hospitals.

Methods—
The study included all fee-for-service Medicare beneficiaries aged 65 years or older with a primary discharge diagnosis of subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH) in 2006. Covariate-adjusted logistic and Cox proportional hazards regression assessed the effect of care at a JC-PSC–certified hospital on 30-day mortality and readmission.

Results—

There were 2305 SAH and 8708 ICH discharges from JC-PSC–certified hospitals and 3892 SAH and 22 564 ICH discharges from noncertified hospitals. Unadjusted in-hospital mortality (SAH: 27.5% versus 33.2%,
P
<0.0001; ICH: 27.9% versus 29.6%,
P
=0.003) and 30-day mortality (SAH: 35.1% versus 44.0%,
P
<0.0001; ICH: 39.8% versus 42.4%,
P
<0.0001) were lower in JC-PSC hospitals, but 30-day readmission rates were similar (SAH: 17.0% versus 17.0%,
P
=0.97; ICH: 16.0% versus 15.5%,
P
=0.29). Risk-adjusted 30-day mortality was 34% lower (odds ratio, 0.66; 95% confidence interval, 0.58–0.76) after SAH and 14% lower (odds ratio, 0.86; 95% confidence interval, 0.80–0.92) after ICH for patients discharged from JC-PSC–certified hospitals. There was no difference in 30-day risk-adjusted readmission rates for SAH or ICH based on JC-PSC status.

Conclusions—
Patients treated at JC-PSC–certified hospitals had lower risk-adjusted mortality rates for both SAH and ICH but similar 30-day readmission rates as compared with noncertified hospitals.
The Level of Cortical Afferent Inhibition in Acute Stroke Correlates With Long-Term Functional Recovery in Humans
Authors: Di Lazzaro Vincenzo , Profice Paolo , Pilato Fabio , Capone Fioravante , Ranieri Federico , Florio Lucia , Colosimo Cesare , Pravatà Emanuele , Pasqualetti Patrizio , Dileone Michele 
Published: October 2011

Background and Purpose—
Using transcranial magnetic stimulation, we investigated short-interval intracortical inhibition and short-latency afferent inhibition in acute ischemic stroke.

Methods—
We evaluated short-interval intracortical inhibition and short-latency afferent inhibition in the affected hemisphere and unaffected hemisphere in 16 patients and correlated electrophysiological parameters with outcome at 6 months.

Results—
Affected hemisphere short-latency afferent inhibition was significantly reduced in patients, and short-latency afferent inhibition level correlated with functional outcome.

Conclusions—
Reduced afferent inhibition in acute stroke correlates with long-term recovery.