bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oligodendrocyte Progenitor Cells Promote Neovascularization in Glioma by Disrupting the Blood–Brain Barrier
Authors: Huang Yujie , Hoffman Caitlin , Rajappa Prajwal , Kim Joon-Hyung , Hu Wenhuo , Huse Jason , Tang Zhongshu , Li Xuri , Weksler Babette , Bromberg Jacqueline , Lyden David C. , Greenfield Jeffrey P. 
Published: December 2013

Abstract
Enhanced platelet-derived growth factor (PDGF) signaling in glioma drives its development and progression. In this study, we define a unique role for stroma-derived PDGF signaling in maintaining tumor homeostasis within the glioma microenvironment. Large numbers of PDGF receptor-α (PDGFRα)–expressing stromal cells derived from oligodendrocytes progenitor cells (OPC) were discovered at the invasive front of high-grade gliomas, in which they exhibited a unique perivascular distribution. In PDGFRα-deficient host mice, in which orthotopic Gl261 tumors displayed reduced outgrowth, we found that tumor-associated blood vessels displayed smaller lumens and normalized vascular morphology, with tumors in host animals injected with the vascular imaging agent gadolinium also being enhanced less avidly by MRI. Notably, glioma-associated OPC promoted endothelial sprouting and tubule formation, in part by abrogating the inhibitory effect that perivascular astrocytes exert on vascular endothelial conjunctions. Stromal-derived PDGF-CC was crucial for the recruitment and activation of OPC, insofar as mice genetically deficient in PDGF-CC phenocopied the glioma/vascular defects observed in PDGFRα-deficient mice. Clinically, we showed that higher levels of PDGF-CC in glioma specimens were associated with more rapid disease recurrence and poorer overall survival. Our findings define a PDGFRα/PDGF-CC signaling axis within the glioma stromal microenvironment that contributes to vascular remodeling and aberrant tumor angiogenesis in the brain. Cancer Res; 74(4); 1011–21. ©2013 AACR.
Identification of Alternative Splicing Events Regulated by the Oncogenic Factor SRSF1 in Lung Cancer
Authors: de Miguel Fernando J. , Sharma Ravi D. , Pajares María J. , Montuenga Luis M. , Rubio Angel , Pio Ruben 
Published: December 2013

Abstract
Abnormal alternative splicing has been associated with cancer. Genome-wide microarrays can be used to detect differential splicing events. In this study, we have developed ExonPointer, an algorithm that uses data from exon and junction probes to identify annotated cassette exons. We used the algorithm to profile differential splicing events in lung adenocarcinoma A549 cells after downregulation of the oncogenic serine/arginine-rich splicing factor 1 (SRSF1). Data were generated using two different microarray platforms. The PCR-based validation rate of the top 20 ranked genes was 60% and 100%. Functional enrichment analyses found a substantial number of splicing events in genes related to RNA metabolism. These analyses also identified genes associated with cancer and developmental and hereditary disorders, as well as biologic processes such as cell division, apoptosis, and proliferation. Most of the top 20 ranked genes were validated in other adenocarcinoma and squamous cell lung cancer cells, with validation rates of 80% to 95% and 70% to 75%, respectively. Moreover, the analysis allowed us to identify four genes, ATP11C, IQCB1, TUBD1, and proline-rich coiled-coil 2C (PRRC2C), with a significantly different pattern of alternative splicing in primary non–small cell lung tumors compared with normal lung tissue. In the case of PRRC2C, SRSF1 downregulation led to the skipping of an exon overexpressed in primary lung tumors. Specific siRNA downregulation of the exon-containing variant significantly reduced cell growth. In conclusion, using a novel analytical tool, we have identified new splicing events regulated by the oncogenic splicing factor SRSF1 in lung cancer. Cancer Res; 74(4); 1105–15. ©2013 AACR.
A Preclinical Model of CD38-Pretargeted Radioimmunotherapy for Plasma Cell Malignancies
Authors: Green Damian J. , Orgun Nural N. , Jones Jon C. , Hylarides Mark D. , Pagel John M. , Hamlin Donald K. , Wilbur D.S. , Lin Yukang , Fisher Darrell R. , Kenoyer Aimee L. , Frayo Shani L. , Gopal Ajay K. , Orozco Johnnie J. , Gooley Theodore A. , Wood Brent L. , Bensinger William I. , Press Oliver W. 
Published: December 2013

Abstract
The vast majority of patients with plasma cell neoplasms die of progressive disease despite high response rates to novel agents. Malignant plasma cells are very radiosensitive, but the potential role of radioimmunotherapy (RIT) in the management of plasmacytomas and multiple myeloma has undergone only limited evaluation. Furthermore, CD38 has not been explored as a RIT target despite its uniform high expression on malignant plasma cells. In this report, both conventional RIT (directly radiolabeled antibody) and streptavidin–biotin pretargeted RIT (PRIT) directed against the CD38 antigen were assessed as approaches to deliver radiation doses sufficient for multiple myeloma cell eradication. PRIT demonstrated biodistributions that were markedly superior to conventional RIT. Tumor-to-blood ratios as high as 638:1 were seen 24 hours after PRIT, whereas ratios never exceeded 1:1 with conventional RIT. 90Yttrium absorbed dose estimates demonstrated excellent target-to-normal organ ratios (6:1 for the kidney, lung, liver; 10:1 for the whole body). Objective remissions were observed within 7 days in 100% of the mice treated with doses ranging from 800 to 1,200 μCi of anti-CD38 pretargeted 90Y–DOTA–biotin, including 100% complete remissions (no detectable tumor in treated mice compared with tumors that were 2,982% ± 2,834% of initial tumor volume in control animals) by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor xenografts treated with 800 μCi of anti-CD38 pretargeted 90Y–DOTA–biotin achieved long-term myeloma-free survival (&gt;70 days) compared with none (0%) of the control animals. Cancer Res; 74(4); 1179–89. ©2013 AACR.
Curcumin Targets Breast Cancer Stem–like Cells with Microtentacles That Persist in Mammospheres and Promote Reattachment
Authors: Charpentier Monica S. , Whipple Rebecca A. , Vitolo Michele I. , Boggs Amanda E. , Slovic Jana , Thompson Keyata N. , Bhandary Lekhana , Martin Stuart S. 
Published: December 2013

Abstract
Cancer stem–like cells (CSC) and circulating tumor cells (CTC) have related properties associated with distant metastasis, but the mechanisms through which CSCs promote metastasis are unclear. In this study, we report that breast cancer cell lines with more stem-like properties display higher levels of microtentacles (McTN), a type of tubulin-based protrusion of the plasma cell membrane that forms on detached or suspended cells and aid in cell reattachment. We hypothesized that CSCs with large numbers of McTNs would more efficiently attach to distant tissues, promoting metastatic efficiency. The naturally occurring stem-like subpopulation of the human mammary epithelial (HMLE) cell line presents increased McTNs compared with its isogenic non–stem-like subpopulation. This increase was supported by elevated α-tubulin detyrosination and vimentin protein levels and organization. Increased McTNs in stem-like HMLEs promoted a faster initial reattachment of suspended cells that was inhibited by the tubulin-directed drug, colchicine, confirming a functional role for McTNs in stem cell reattachment. Moreover, live-cell confocal microscopy showed that McTNs persist in breast stem cell mammospheres as flexible, motile protrusions on the surface of the mammosphere. Although exposed to the environment, they also function as extensions between adjacent cells along cell–cell junctions. We found that treatment with the breast CSC-targeting compound curcumin rapidly extinguished McTN in breast CSC, preventing reattachment from suspension. Together, our results support a model in which breast CSCs with cytoskeletal alterations that promote McTNs can mediate attachment and metastasis but might be targeted by curcumin as an antimetastatic strategy. Cancer Res; 74(4); 1250–60. ©2013 AACR.
Tumor Suppressor Alterations Cooperate to Drive Aggressive Mesotheliomas with Enriched Cancer Stem Cells via a p53–miR-34a–c-Met Axis
Authors: Menges Craig W. , Kadariya Yuwaraj , Altomare Deborah , Talarchek Jacqueline , Neumann-Domer Erin , Wu Yue , Xiao Guang-Hui , Shapiro Irina M. , Kolev Vihren N. , Pachter Jonathan A. , Klein-Szanto Andres J. , Testa Joseph R. 
Published: December 2013

Abstract
Malignant mesothelioma is a highly aggressive, asbestos-related cancer frequently marked by mutations of both NF2 and CDKN2A. We demonstrate that germline knockout of one allele of each of these genes causes accelerated onset and progression of asbestos-induced malignant mesothelioma compared with asbestos-exposed Nf2+/− or wild-type mice. Ascites from some Nf2+/−;Cdkn2a+/− mice exhibited large tumor spheroids, and tail vein injections of malignant mesothelioma cells established from these mice, but not from Nf2+/− or wild-type mice, produced numerous tumors in the lung, suggesting increased metastatic potential of tumor cells from Nf2+/−;Cdkn2a+/− mice. Intraperitoneal injections of malignant mesothelioma cells derived from Nf2+/−;Cdkn2a+/− mice into severe combined immunodeficient mice produced tumors that penetrated the diaphragm and pleural cavity and harbored increased cancer stem cells (CSC). Malignant mesothelioma cells from Nf2+/−;Cdkn2a+/− mice stained positively for CSC markers and formed CSC spheroids in vitro more efficiently than counterparts from wild-type mice. Moreover, tumor cells from Nf2+/−;Cdkn2a+/− mice showed elevated c-Met expression/activation, which was partly dependent on p53-mediated regulation of miR-34a and required for tumor migration/invasiveness and maintenance of the CSC population. Collectively, these studies demonstrate in vivo that inactivation of Nf2 and Cdkn2a cooperate to drive the development of highly aggressive malignant mesotheliomas characterized by enhanced tumor spreading capability and the presence of a CSC population associated with p53/miR-34a–dependent activation of c-Met. These findings suggest that cooperativity between losses of Nf2 and Cdkn2a plays a fundamental role in driving the highly aggressive tumorigenic phenotype considered to be a hallmark of malignant mesothelioma. Cancer Res; 74(4); 1261–71. ©2013 AACR.
Apoptosis Signal–Regulating Kinase 1 Is a Novel Target Molecule for Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion
Authors: Toyama Kensuke , Koibuchi Nobutaka , Uekawa Ken , Hasegawa Yu , Kataoka Keiichiro , Katayama Tetsuji , Sueta Daisuke , Ma Ming Jie , Nakagawa Takashi , Yasuda Osamu , Tomimoto Hidekazu , Ichijo Hidenori , Ogawa Hisao , Kim-Mitsuyama Shokei 
Published: December 2013

Objective—
There are currently no specific strategies for the treatment or prevention of vascular dementia. White matter lesions, a common pathology in cerebral small vessel disease, are a major cause of vascular dementia. We investigated whether apoptosis signal–regulating kinase 1 (ASK1) might be a key molecule in cerebral hypoperfusion, associated with blood–brain barrier breakdown and white matter lesions.

Approach and Results—

A mouse model of cognitive impairment was developed by inducing chronic cerebral hypoperfusion in white matter including the corpus callosum via bilateral common carotid artery stenosis (BCAS) surgery. BCAS-induced white matter lesions caused cognitive decline in C57BL/6J (wild-type) mice but not in ASK1-deficient (ASK1
−/−
) mice. Phosphorylated ASK1 increased in wild-type mouse brains, and phosphorylated p38 and tumor necrosis factor-α expression increased in corpus callosum cerebral endothelial cells after BCAS in wild-type mice but not in ASK1
−/−
mice. BCAS decreased claudin-5 expression and disrupted blood–brain barrier in the corpus callosum of wild-type but not ASK1
−/−
mice. Cerebral nitrotyrosine was increased in wild-type and ASK1
−/−
BCAS mice. Cerebral phosphorylated ASK1 did not increase in wild-type mice treated with NADPH-oxidase inhibitor. A p38 inhibitor and NADPH-oxidase inhibitor mimicked the protective effect of ASK1 deficiency against cognitive impairment. Specific ASK1 inhibitor prevented cognitive decline in BCAS mice. In vitro oxygen-glucose deprivation and tumor necrosis factor-α stimulation caused the disruption of endothelial tight junctions from wild-type mice but not ASK1
−/−
mice.

Conclusions—
Oxidative stress-ASK1-p38 cascade plays a role in the pathogenesis of cognitive impairment, through blood–brain barrier breakdown via the disruption of endothelial tight junctions. ASK1 might be a promising therapeutic target for chronic cerebral hypoperfusion–induced cognitive impairment.
Alpha-Chlorofatty Acid Accumulates in Activated Monocytes and Causes Apoptosis Through Reactive Oxygen Species Production and Endoplasmic Reticulum Stress
Authors: Wang Wen-yi , Albert Carolyn J. , Ford David A. 
Published: December 2013

Objective—
Myeloperoxidase-enriched monocytes play important roles in inflammatory disease, such as atherosclerosis. We previously demonstrated that α-chlorofatty aldehydes are produced as a result of plasmalogen targeting by myeloperoxidase-derived hypochlorous acid in activated monocytes. Here, we show α-chlorofatty acid (α-ClFA), a stable metabolite of α-chlorofatty aldehydes, accumulates in activated monocytes and mediates the molecular effects of α-ClFA on monocytes/macrophages.

Approach and Results—
Liquid chromatography-mass spectrometry revealed that α-ClFA is elevated 5-fold in phorbol myristate–stimulated human monocytes rising to ≈20 μmol/L when compared with unstimulated cells. Using human THP-1 monocytes and RAW 264.7 cells as in vitro models, we tested the hypothesis that α-ClFA is a cell death mediator that could potentially participate in pathophysiological roles of monocytes in diseases, such as atherosclerosis. Indeed, 2-chlorohexadecanoic acid, the 16-carbon molecular species of α-ClFA, caused significant apoptosis of primary monocytes. Similarly, 2-chlorohexadecanoic acid also caused apoptosis in THP-1 human monocytes and RAW 264.7 mouse macrophages as determined by annexin V-propidium iodide staining and terminal deoxynucleotidyl transferase dUTP nick end labeling staining, respectively. 2-Chlorohexadecanoic acid treatment also increased caspase-3 activity and poly (ADP-ribose) polymerase cleavage in THP-1 cells. 2-Chlorohexadecanoic acid likely elicits apoptosis by increasing both reactive oxygen species production and endoplasmic reticulum stress because antioxidants and CCAAT/enhancer-binding protein homologous protein block such induced cell apoptosis.

Conclusions—
The stable chlorinated lipid, α-ClFA, accumulates in activated primary human monocytes and elicits monocyte apoptosis through increased reactive oxygen species production and endoplasmic reticulum stress, providing a new insight into chlorinated lipids and monocytes in inflammatory disease.
Permanent Pacemaker Implantation After Transcatheter Aortic Valve Implantation
Authors: Urena Marina , Webb John G. , Tamburino Corrado , Muñoz-García Antonio J. , Cheema Asim , Dager Antonio E. , Serra Vicenç , Amat-Santos Ignacio J. , Barbanti Marco , Immè Sebastiano , Briales Juan H. Alonso , Benitez Luis Miguel , Al Lawati Hatim , Cucalon Angela Maria , García del Blanco Bruno , López Javier , Dumont Eric , DeLarochellière Robert , Ribeiro Henrique B. , Nombela-Franco Luis , Philippon François , Rodés-Cabau Josep 
Published: December 2013

Background—
Very few data exist on the clinical impact of permanent pacemaker implantation (PPI) after transcatheter aortic valve implantation. The objective of this study was to assess the impact of PPI after transcatheter aortic valve implantation on late outcomes in a large cohort of patients.

Methods and Results—

A total of 1556 consecutive patients without prior PPI undergoing transcatheter aortic valve implantation were included. Of them, 239 patients (15.4%) required a PPI within the first 30 days after transcatheter aortic valve implantation. At a mean follow-up of 22±17 months, no association was observed between the need for 30-day PPI and all-cause mortality (hazard ratio, 0.98; 95% confidence interval, 0.74–1.30;
P
=0.871), cardiovascular mortality (hazard ratio, 0.81; 95% confidence interval, 0.56–1.17;
P
=0.270), and all-cause mortality or rehospitalization for heart failure (hazard ratio, 1.00; 95% confidence interval, 0.77–1.30;
P
=0.980). A lower rate of unexpected (sudden or unknown) death was observed in patients with PPI (hazard ratio, 0.31; 95% confidence interval, 0.11–0.85;
P
=0.023). Patients with new PPI showed a poorer evolution of left ventricular ejection fraction over time (
P
=0.017), and new PPI was an independent predictor of left ventricular ejection fraction decrease at the 6- to 12-month follow-up (estimated coefficient, −2.26; 95% confidence interval, −4.07 to −0.44;
P
=0.013;
R
2
=0.121).

Conclusions—
The need for PPI was a frequent complication of transcatheter aortic valve implantation, but it was not associated with any increase in overall or cardiovascular death or rehospitalization for heart failure after a mean follow-up of ≈2 years. Indeed, 30-day PPI was a protective factor for the occurrence of unexpected (sudden or unknown) death. However, new PPI did have a negative effect on left ventricular function over time.
Extensive Leukoaraiosis Is Associated With High Early Risk of Recurrence After Ischemic Stroke
Authors: Kim Gyeong-Moon , Park Kwang-Yeol , Avery Ross , Helenius Johanna , Rost Natalia , Rosand Jonathan , Rosen Bruce , Ay Hakan 
Published: December 2013

Background and Purpose—
The integrity of white matter tracts connecting different parts of the brain is important for rapid compensation for the lost function from ischemic stroke. Impaired white matter reserve capacity secondary to leukoaraiosis may facilitate detection of new symptomatic ischemic events that would otherwise remain inconspicuous after an initial ischemic stroke. We sought to identify whether the extent of leukoaraiosis was a predictor of risk of early stroke recurrence.

Methods—
We used Cox regression analysis in consecutive patients with ischemic stroke to determine the relationship between leukoaraiosis burden and symptomatic stroke recurrence within 90 days. We graded total leukoaraiosis, periventricular leukoaraiosis, and subcortical leukoaraiosis using the Fazekas scale as mild (<2) and extensive (≥2) on fluid-attenuated inversion recovery images obtained within 72 hours of stroke onset in the hemisphere contralateral to acute stroke.

Results

—There were 106 recurrent events in 2378 patients. The cumulative incidence of recurrence was 5.9% at 90 days. Kaplan–Meier estimate of recurrence-free survival rate was lower in patients with extensive leukoaraiosis (
P
=0.04) and extensive periventricular leukoaraiosis (
P
=0.02) but not in extensive subcortical leukoaraiosis (
P
=0.09). Multivariable Cox regression analysis revealed a hazard ratio of 1.50 (95% confidence interval, 1.00–2.25) for extensive leukoaraiosis, 1.67 (95% confidence interval, 1.11–2.51) for extensive periventricular leukoaraiosis, and 1.42 (95% confidence interval, 0.94–2.12) for extensive subcortical leukoaraiosis.

Conclusions—
The extent of leukoaraiosis independently predicts 90-day recurrent stroke risk after ischemic stroke. This suggests that leukoaraiosis may be used for risk stratification in ischemic stroke.
Roles of Hypertension in the Rupture of Intracranial Aneurysms
Authors: Tada Yoshiteru , Wada Kosuke , Shimada Kenji , Makino Hiroshi , Liang Elena I. , Murakami Shoko , Kudo Mari , Kitazato Keiko T. , Nagahiro Shinji , Hashimoto Tomoki 
Published: December 2013

Background and Purpose—
Systemic hypertension has long been considered a risk factor of aneurysmal rupture. However, a causal link between systemic hypertension and the development of aneurysmal rupture has not been established. In this study, using a mouse model of intracranial aneurysm rupture, we examined the roles of systemic hypertension in the development of aneurysmal rupture.

Methods—
Aneurysms were induced by a combination of deoxycorticosterone acetate (DOCA)-salt and a single injection of elastase into the cerebrospinal fluid in mice. Antihypertensive treatment was started 6 days after aneurysm induction. Aneurysmal rupture was detected by neurological symptoms and confirmed by the presence of intracranial aneurysm with subarachnoid hemorrhage. Hydralazine (direct vasodilator) or discontinuation of DOCA-salt treatment was used to assess the roles of systemic hypertension. Captopril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin II type 1 receptor antagonist) was used to assess the roles of the local renin–angiotensin system in the vascular wall.

Results—
Normalization of blood pressure by hydralazine significantly reduced the incidence of ruptured aneurysms and the rupture rate. There was a dose-dependent relationship between reduction of blood pressure and prevention of aneurysmal rupture. Captopril and losartan were able to reduce rupture rate without affecting systemic hypertension induced by DOCA-salt treatment.

Conclusions—
Normalization of blood pressure after aneurysm formation prevented aneurysmal rupture in mice. In addition, we found that the inhibition of the local renin–angiotensin system independent from the reduction of blood pressure can prevent aneurysmal rupture.
Iodinated Contrast Does Not Alter Clotting Dynamics in Acute Ischemic Stroke as Measured by Thromboelastography
Authors: McDonald Mark M. , Archeval-Lao Joancy M. , Cai Chunyan , Peng Hui , Sangha Navdeep , Parker Stephanie A. , Wetzel Jeremy , Riney Stephen A. , Cherches Matt F. , Guthrie Greer J. , Roper Tiffany C. , Kawano-Castillo Jorge F. , Pandurengan Renga , Rahbar Mohammad H. , Grotta James C. 
Published: December 2013

Background and Purpose—
Iodinated contrast agents used for computed tomography angiography (CTA) may alter fibrin fiber characteristics and decrease fibrinolysis by tissue plasminogen activator (tPA). Thromboelastography (TEG) measures the dynamics of coagulation and correlates with thrombolysis in acute ischemic stroke patients. We hypothesized that receiving CTA before tPA will not impair thrombolysis as measured by TEG.

Methods—
Acute ischemic stroke patients receiving 0.9 mg/kg tPA <4.5 hours of symptom onset were prospectively enrolled. For CTA, 350 mg/dL of iohexol or 320 mg/dL of iodixanol at a dose of 2.2 mL/kg was administered. TEG was measured before tPA and 10 minutes after tPA bolus. CTA timing was left to the discretion of the treating physician.

Results—

Of 136 acute ischemic stroke patients who received tPA, 47 had CTA before tPA bolus, and 42 had either CTA after tPA and post–tPA TEG draw or no CTA (noncontrast group). Median change in clot lysis (LY30) after tPA was 95.3% in the contrast group versus 95.0% in the noncontrast group (
P
=0.74). Thus, tPA-induced thrombolysis did not differ between contrast and noncontrast groups. Additionally, there was no effect of contrast on any pre–tPA TEG value.

Conclusions—
Our data do not support an effect of iodinated contrast agents on clot formation or tPA activity.