bluuebunny/crossref_metadata_2025_split huggingface dataset:
Navitoclax (ABT-263) Accelerates Apoptosis during Drug-Induced Mitotic Arrest by Antagonizing Bcl-xL
Authors: Shi Jue , Zhou Yuan , Huang Hsiao-Chun , Mitchison Timothy J. 
Published: May 2011

Abstract
Combining microtubule-targeting antimitotic drugs with targeted apoptosis potentiators is a promising new chemotherapeutic strategy to treat cancer. In this study, we investigate the cellular mechanism by which navitoclax (previously called ABT-263), a Bcl-2 family inhibitor, potentiates apoptosis triggered by paclitaxel and an inhibitor of kinesin-5 (K5I, also called a KSP inhibitor), across a panel of epithelial cancer lines. By using time-lapse microscopy, we showed that navitoclax has little effect on cell death during interphase, but strongly accelerates apoptosis during mitotic arrest, and greatly increases the fraction of apoptosis-resistant cells that die. By systematically knocking down individual Bcl-2 proteins, we determined that Mcl-1 and Bcl-xL are the primary negative regulators of apoptosis during prolonged mitotic arrest. Mcl-1 levels decrease during mitotic arrest because of an imbalance between synthesis and turnover, and turnover depends in part on the MULE/HUWE1 E3 ligase. The combination of Mcl-1 loss with inhibition of Bcl-xL by navitoclax causes rapid apoptosis in all lines tested. Variation in expression levels of Mcl-1 and Bcl-xL largely determines variation in response to antimitotics alone, and antimitotics combined with navitoclax, across our panel. We concluded that Bcl-xL is a critical target of Bcl-2 family inhibitors for enhancing the lethality of antimitotic drugs in epithelial cancers, and combination treatment with navitoclax and a spindle specific antimitotic, such as a K5I, might be more effective than paclitaxel alone. Cancer Res; 71(13); 4518–26. ©2011 AACR.
Glycolytic Phenotype and AMP Kinase Modify the Pathologic Response of Tumor Xenografts to VEGF Neutralization
Authors: Nardo Giorgia , Favaro Elena , Curtarello Matteo , Moserle Lidia , Zulato Elisabetta , Persano Luca , Rossi Elisabetta , Esposito Giovanni , Crescenzi Marika , Casanovas Oriol , Sattler Ulrike , Mueller-Klieser Wolfgang , Biesalski Barbara , Thews Oliver , Canese Rossella , Iorio Egidio , Zanovello Paola , Amadori Alberto , Indraccolo Stefano 
Published: May 2011

Abstract
VEGF antagonists are now widely used cancer therapeutics, but predictive biomarkers of response or toxicity remain unavailable. In this study, we analyzed the effects of anti-VEGF therapy on tumor metabolism and therapeutic response by using an integrated set of imaging techniques, including bioluminescence metabolic imaging, 18-fluorodeoxyglucose positron emission tomography, and MRI imaging and spectroscopy. Our results revealed that anti-VEGF therapy caused a dramatic depletion of glucose and an exhaustion of ATP levels in tumors, although glucose uptake was maintained. These metabolic changes selectively accompanied the presence of large necrotic areas and partial tumor regression in highly glycolytic tumors. In addition, we found that the central metabolic protein kinase AMP-activated protein kinase (AMPK)—a cellular sensor of ATP levels that supports cell viability in response to energy stress—was activated by anti-VEGF therapy in experimental tumors. AMPK-α2 attenuation increased glucose consumption, tumor cell sensitivity to glucose starvation, and tumor necrosis following anti-VEGF therapy. Taken together, our findings reveal functional links between the Warburg effect and the AMPK pathway with therapeutic responses to VEGF neutralization in tumor xenograft models. Cancer Res; 71(12); 4214–25. ©2011 AACR.
In VivoPersistence, Tumor Localization, and Antitumor Activity of CAR-Engineered T Cells Is Enhanced by Costimulatory Signaling through CD137 (4-1BB)
Authors: Song De-Gang , Ye Qunrui , Carpenito Carmine , Poussin Mathilde , Wang Li-Ping , Ji Chunyan , Figini Mariangela , June Carl H. , Coukos George , Powell Daniel J. 
Published: May 2011

AbstractHuman T cells engineered to express a chimeric antigen receptor (CAR) specific for folate receptor-α (FRα) have shown robust antitumor activity against epithelial cancers in vitro but not in the clinic because of their inability to persist and home to tumor in vivo. In this study, CARs were constructed containing a FRα-specific scFv (MOv19) coupled to the T-cell receptor CD3ζ chain signaling module alone (MOv19-ζ) or in combination with the CD137 (4-1BB) costimulatory motif in tandem (MOv19-BBζ). Primary human T cells transduced to express conventional MOv19-ζ or costimulated MOv19-BBζ CARs secreted various proinflammatory cytokines, and exerted cytotoxic function when cocultured with FRα+ tumor cells in vitro. However, only transfer of human T cells expressing the costimulated MOv19-BBζ CAR mediated tumor regression in immunodeficient mice bearing large, established FRα+ human cancer. MOv19-BBζ CAR T-cell infusion mediated tumor regression in models of metastatic intraperitoneal, subcutaneous, and lung-involved human ovarian cancer. Importantly, tumor response was associated with the selective survival and tumor localization of human T cells in vivo and was only observed in mice receiving costimulated MOv19-BBζ CAR T cells. T-cell persistence and antitumor activity were primarily antigen-driven; however, antigen-independent CD137 signaling by CAR improved T-cell persistence but not antitumor activity in vivo. Our results show that anti-FRα CAR outfitted with CD137 costimulatory signaling in tandem overcome issues of T-cell persistence and tumor localization that limit the conventional FRα T-cell targeting strategy to provide potent antitumor activity in vivo. Cancer Res; 71(13); 4617–27. ©2011 AACR.
Advanced Drug Delivery Systems of Curcumin for Cancer Chemoprevention
Authors: Bansal Shyam S. , Goel Mehak , Aqil Farrukh , Vadhanam Manicka V. , Gupta Ramesh C. 
Published: May 2011

Abstract
Since ancient times, chemopreventive agents have been used to treat/prevent several diseases including cancer. They are found to elicit a spectrum of potent responses including anti-inflammatory, antioxidant, antiproliferative, anticarcinogenic, and antiangiogenic activity in various cell cultures and some animal studies. Research over the past 4 decades has shown that chemopreventives affect a number of proteins involved in various molecular pathways that regulate inflammatory and carcinogenic responses in a cell. Various enzymes, transcription factors, receptors, and adhesion proteins are also affected by chemopreventives. Although, these natural compounds have shown significant efficacy in cell culture studies, they elicited limited efficacy in various clinical studies. Their introduction into the clinical setting is hindered largely by their poor solubility, rapid metabolism, or a combination of both, ultimately resulting in poor bioavailability upon oral administration. Therefore, to circumvent these limitations and to ease their transition to clinics, alternate strategies should be explored. Drug delivery systems such as nanoparticles, liposomes, microemulsions, and polymeric implantable devices are emerging as one of the viable alternatives that have been shown to deliver therapeutic concentrations of various potent chemopreventives such as curcumin, ellagic acid, green tea polyphenols, and resveratrol into the systemic circulation. In this review article, we have attempted to provide a comprehensive outlook for these delivery approaches, using curcumin as a model agent, and discussed future strategies to enable the introduction of these highly potent chemopreventives into a physician's armamentarium. Cancer Prev Res; 4(8); 1158–71. ©2011 AACR.
Role of E-cadherin in Antimigratory and Antiinvasive Efficacy of Silibinin in Prostate Cancer Cells
Authors: Deep Gagan , Gangar Subhash Chander , Agarwal Chapla , Agarwal Rajesh 
Published: May 2011

Abstract
The epithelial-to-mesenchymal transition (EMT) in prostate cancer (PCA) cells is considered prerequisite for acquiring migratory/invasive phenotype, and subsequent metastasis. We hypothesized that promoting the E-cadherin expression in PCA cells by using nontoxic phytochemicals, like silibinin, would prevent EMT and consequently invasiveness. Our results showed that silibinin treatment (5–90 μmol/L) significantly inhibits migratory and invasive potential of advance human PCA PC3, PC3MM2, and C4–2B cells in in vitro assays. Importantly, the antimigratory/antiinvasive efficacy of silibinin was not due to its cytotoxicity toward PCA cells. Molecular analyses showed that silibinin increases E-cadherin level that was localized mainly at cellular membrane as evidenced by subcellular fractional and confocal analyses in PC3 cells, which might be responsible for morphologically observed shift toward epithelial character. Silibinin also decreased the levels of Slug, Snail, phospho-Akt(ser473), nuclear β-catenin, phospho-Src(tyr419) and Hakai; together they play an important role in regulating E-cadherin expression/function and EMT. Similar silibinin effects on E-cadherin, β-catenin, phospho-Src(tyr419), and Hakai levels were also observed in PC3MM2 and C4–2B PCA cells. Selective Src inhibition by dasatinib also showed increased E-cadherin expression in PC3 cells suggesting a possible involvement of Src inhibition in silibinin-caused increase in E-cadherin level. Additional studies in PC3 cells with stable knock-down of E-cadherin expression revealed that antimigratory/antiinvasive efficacy of silibinin is in-part dependent on E-cadherin expression. Together, our results showing antimigratory/antiinvasive effects of silibinin and associated mechanisms suggest that silibinin should be tested further in clinically relevant animal models toward exploiting its potential benefits against metastatic PCA. Cancer Prev Res; 4(8); 1222–32. ©2011 AACR.
Sterol Regulatory Element–Binding Protein-1 Determines Plasma Remnant Lipoproteins and Accelerates Atherosclerosis in Low-Density Lipoprotein Receptor–Deficient Mice
Authors: Karasawa Tadayoshi , Takahashi Akimitsu , Saito Ryo , Sekiya Motohiro , Igarashi Masaki , Iwasaki Hitoshi , Miyahara Shoko , Koyasu Saori , Nakagawa Yoshimi , Ishii Kiyoaki , Matsuzaka Takashi , Kobayashi Kazuto , Yahagi Naoya , Takekoshi Kazuhiro , Sone Hirohito , Yatoh Shigeru , Suzuki Hiroaki , Yamada Nobuhiro , Shimano Hitoshi 
Published: May 2011

Objective—
Sterol regulatory element–binding protein-1 (SREBP-1) is nutritionally regulated and is known to be a key transcription factor regulating lipogenic enzymes. The goal of this study was to evaluate the roles of SREBP-1 in dyslipidemia and atherosclerosis.

Methods and Results—
Transgenic mice that overexpress SREBP-1c in the liver and SREBP-1-deficient mice were crossed with low-density lipoprotein receptor (LDLR)–deficient mice, and the plasma lipids and atherosclerosis were analyzed. Hepatic SREBP-1c overexpression in LDLR-deficient mice caused postprandial hypertriglyceridemia, increased very-low-density lipoprotein (VLDL) cholesterol, and decreased high-density lipoprotein cholesterol in plasma, which resulted in accelerated aortic atheroma formation. Conversely, absence of SREBP-1 suppressed Western diet–induced hyperlipidemia in LDLR-deficient mice and ameliorated atherosclerosis. In contrast, bone marrow-specific SREBP-1 deficiency did not alter the development of atherosclerosis. The size of nascent VLDL particles secreted from the liver was increased in SREBP-1c transgenic mice and reduced in SREBP-1-deficient mice, accompanied by upregulation and downregulation of phospholipid transfer protein expression, respectively.

Conclusion—
Hepatic SREBP-1c determines plasma triglycerides and remnant cholesterol and contributes to atherosclerosis in hyperlipidemic states. Hepatic SREBP-1c also regulates the size of nascent VLDL particles.
Insulin-Like Growth Factor-1 Receptor Identifies a Pool of Human Cardiac Stem Cells With Superior Therapeutic Potential for Myocardial Regeneration
Authors: D'Amario Domenico , Cabral-Da-Silva Mauricio C. , Zheng Hanqiao , Fiorini Claudia , Goichberg Polina , Steadman Elisabeth , Ferreira-Martins João , Sanada Fumihiro , Piccoli Marco , Cappetta Donato , D'Alessandro David A. , Michler Robert E. , Hosoda Toru , Anastasia Luigi , Rota Marcello , Leri Annarosa , Anversa Piero , Kajstura Jan 
Published: May 2011

RETRACTION
This article has been retracted:

Circ Res
. 2018;123:e00. DOI: 10.1161/RES.0000000000000250.
Ischemic Stroke During Sleep
Authors: Kim Beom Joon , Lee Seung-Hoon , Shin Chae-Won , Ryu Wi-Sun , Kim Chi Kyung , Yoon Byung-Woo 
Published: May 2011

Background and Purpose—
Approximately one fourth of stroke occur during sleep. Despite the clinical and radiological similarities between wake-up stroke (WUS) and non-WUS, the functional outcomes of WUS are largely unknown.

Methods—
This retrospective analysis reviewed 2289 consecutive patients with acute ischemic stroke who were admitted between November 2002 and December 2009. We used 3 end-point analytic techniques to evaluate the association between WUS and functional outcomes: dichotomized analysis for “functional dependency” (a discharge modified Rankin Scale [mRS] score ≥2 regardless of initial stroke severity), severity-adjusted responder analysis for “unfavorable outcome” (a discharge mRS ≥1 for an admission National Institutes of Health Stroke Scale score 0 to 7; mRS ≥2 for National Institutes of Health Stroke Scale 8 to 14; or mRS ≥3 for National Institutes of Health Stroke Scale ≥15), and shift analysis for changes in overall distributions of discharge mRS scores.

Results—

The initial National Institutes of Health Stroke Scale score of patients with WUS was significantly higher than that of their non-WUS counterparts (median [interquartile range]; 4 [2 to 7] versus 3 [1 to 6];
P
<0.01). The dichotomized analysis strategy failed to detect a significant association between WUS and functional dependency at discharge (adjusted OR, 0.99; 95% CI, 0.76 to 1.28). However, the responder analysis showed that patients with WUS were more likely to have “unfavorable outcomes” (adjusted OR, 1.33; 95% CI, 1.02 to 1.72), and the shift analysis also detected significant effect of WUS on the mRS score distributions toward increased dependency (adjusted OR, 1.22; 95% CI, 1.01 to 1.48).

Conclusions—
From our study, we documented that WUS was associated with worse short-term outcomes after ischemic stroke. Careful selection of appropriate analytic techniques may help to detect modest associations in observational studies.
Associations of Edge-Detected and Manual-Traced Common Carotid Intima-Media Thickness Measurements With Framingham Risk Factors
Authors: Polak Joseph F. , Pencina Michael J. , Herrington David , O'Leary Daniel H. 
Published: May 2011

Background and Purpose—
Carotid intima-media thickness (IMT) is a marker of cardiovascular disease derived from ultrasound images of the carotid artery. In most outcome studies, human readers identify and trace the key IMT interfaces. We evaluate an alternate approach using automated edge detection.

Methods—
We studied a subset of 5640 participants with an average age 61.7 years (48% men) of the Multi-Ethnic Study of Atherosclerosis composed of whites, Chinese, Hispanic, and blacks that are part of the Multi-Ethnic Study of Atherosclerosis IMT progression study. Manual tracing IMT (mt-IMT) and edge-detected IMT (ed-IMT) measurements of the far wall of the common carotid artery served as outcome variables for multivariable linear regression models using Framingham cardiovascular risk factors and ethnicity as independent predictors.

Results—

Measurements of mt-IMT were obtainable in 99.9% (5633/5640) and measurements of ed-IMT were obtainable in 98.9% (5579/5640) of individuals. Average ed-IMT was 0.19 mm larger than mt-IMT. Inter-reader systematic differences (bias) in IMT measurements were apparent for mt-IMT but not ed-IMT. Based on complete data for 5538 individuals, associations of IMT with risk factors were stronger (
P
<0.0001) for mt-IMT (model
r
2
, 19.5%) than for ed-IMT (model
r
2
, 18.5%).

Conclusions—
We conclude that this edge-detection process generates IMT values equivalent to manually traced ones because it preserves key associations with cardiovascular risk factors. It also decreases inter-reader bias, potentially making it applicable for use in cardiovascular risk assessment.
Three-Month and Long-Term Outcomes and Their Predictors in Acute Basilar Artery Occlusion Treated With Intra-Arterial Thrombolysis
Authors: Jung Simon , Mono Marie-Luise , Fischer Urs , Galimanis Aekaterini , Findling Oliver , De Marchis Gian Marco , Weck Anja , Nedeltchev Krassen , Colucci Giuseppe , Mordasini Pasquale , Brekenfeld Caspar , El-Koussy Marwan , Gralla Jan , Schroth Gerhard , Mattle Heinrich P. , Arnold Marcel 
Published: May 2011

Background and Purpose—
Intra-arterial thrombolysis can be used for treatment of basilar artery occlusion. Predictors of outcome before initiation of treatment are of special interest.

Methods—
From 1992 to 2010, we treated 106 consecutive patients with basilar artery occlusion with intra-arterial thrombolysis. Baseline characteristics, treatment, clinical course, and 3-month and long-term outcomes (≥12 months) were assessed. Outcome parameters were vessel recanalization after treatment, complications, modified Rankin scale (mRS) score, and mortality after 3 months and in the long-term.

Results—

At 3 months, clinical outcome was good (mRS score, 0–2) in 33.0% of the patients and moderate (mRS score, 3) in 11.3%. Mortality was 40.6%. Partial or complete recanalization was achieved in 69.8% of the patients, and symptomatic intracranial hemorrhage occurred in 1 patient (0.9%). Between 3-month and long-term follow-up, 22 survivors (40.8%) showed clinical improvement of at least 1 point on the mRS score, 29 (53.7%) were functionally unchanged, and 3 (5.7%) showed functional worsening (
P
<0.0001). Multivariate analysis identified diabetes as a predictor of poor vessel recanalization (
P
=0.028). Low baseline National Institutes of Health Stroke Scale score was identified as a predictor of good or moderate clinical outcome (
P
<0.0001) and survival (
P
=0.001) at 3 months, and younger age was identified as an additional predictor of survival (
P
=0.012). For prediction of long-term clinical outcome, age was also an independent predictor (
P
=0.018).

Conclusions—
In our series, intra-arterial thrombolysis as treatment of basilar artery occlusion was safe. National Institutes of Health Stroke Scale score at admission and age were identified as predictors of outcome, and these predictors should be considered for treatment allocation in future randomized trials.
Resistin, but Not Adiponectin and Leptin, Is Associated With the Risk of Ischemic Stroke Among Postmenopausal Women
Authors: Rajpathak Swapnil N. , Kaplan Robert C. , Wassertheil-Smoller Sylvia , Cushman Mary , Rohan Thomas E. , McGinn Aileen P. , Wang Tao , Strickler Howard D. , Scherer Philipp E. , Mackey Rachel , Curb David , Ho Gloria Y.F. 
Published: May 2011

Background and Purpose—
Adipose tissue is considered an endocrine organ that secretes adipokines, which possibly mediate the effects of obesity on the risk of cardiovascular disease. However, there are yet limited prospective data on the association between circulating adipokine levels and the risk of ischemic stroke. We aimed to examine the associations of 3 adipokines (adiponectin, leptin, and resistin) with the risk of ischemic stroke.

Methods—
We conducted a prospective nested case–control study (972 stroke cases and 972 matched control subjects) within the Women's Health Initiative Observational Study cohort. The control subjects were matched to cases on age, race/ethnicity, date of study enrollment, and follow-up time.

Results—

Adipokine levels were associated with established stroke risk factors such as obesity and systolic blood pressure. Adjusted for body mass index, the ORs for incident ischemic stroke comparing the highest (Quartile 4) with the lowest quartile (Quartile 1) were 0.81 (95% CI, 0.61 to 1.08;
P
trend=0.068) for adiponectin, 1.15 (95% CI, 0.83 to 1.59;
P
trend
=
0.523) for leptin, and 1.57 (95% CI, 1.18 to 2.08;
P
trend=0.002) for resistin. The association for resistin remained significant even after accounting for established stroke risk factors (OR, 1.39; 95% CI, 1.01 to 1.90;
P
trend=0.036). Further adjustment for markers for inflammation, angiogenesis, and endothelial function also did not affect our results.

Conclusions—
Circulating levels of resistin, but not those of adiponectin or leptin, are associated with an increased risk of incident ischemic stroke in postmenopausal women, independent of obesity and other cardiovascular disease risk factors.
Dose Effect of Intraventricular Fibrinolysis in Ventricular Hemorrhage
Authors: Staykov Dimitre , Wagner Ingrid , Volbers Bastian , Huttner Hagen B. , Doerfler Arnd , Schwab Stefan , Bardutzky Juergen 
Published: May 2011

Background and Purpose—
The aim of the current study was to investigate the dose-dependent efficacy of intraventricular fibrinolysis (IVF) in patients with severe intraventricular hemorrhage (IVH).

Methods—
Patients with intracerebral hemorrhage, severe IVH, and obstructive hydrocephalus with the need for external ventricular drainage were treated with IVF through external ventricular drainage. The time course of IVH resolution and the safety profile were compared between patients treated with high-dose IVF (4 mg alteplase every 12 hours, maximum 20 mg; n=32) and low-dose IVF (1 mg alteplase every 8 hours, maximum 12 mg; n=22). CT scans on Days 1 to 4, 7±1 and 10±1 after admission, were analyzed volumetrically. Outcome was assessed after 3 months.

Results—

The overall effect of IVF dosage was not significantly different between the 2 groups (F=1.3,
P
=0.25). The course of IVH volume in the third and fourth ventricles was similar with high- and low-dose IVF. High-dose IVF resulted in lower total IVH volumes on Days 7 (4.4±4.2 mL versus 8.8±8.1 mL;
P
=0.01) and 10 (1.4±2.8 mL versus 4.9±65.8 mL;
P
=0.005). Total clot half-life was 78±43 hours in the low-dose and 56±25 hours in the high-dose group (
P
=0.02). One asymptomatic ventricular bleeding, 2 cases of ventriculitis, and 1 death due to pulmonary embolism occurred in the high-dose group. There was no difference in outcome at 3 months.

Conclusions—
Low-dose IVF (3 mg alteplase/day) has a similar effect on IVH clearance from the third and fourth ventricles and a similar safety profile when compared with high-dose IVF (8 mg alteplase/day).