bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multifunctional Polymeric Micelles Co-loaded with Anti–Survivin siRNA and Paclitaxel Overcome Drug Resistance in an Animal Model of Ovarian Cancer
Authors: Salzano Giuseppina , Navarro Gemma , Trivedi Malav S. , De Rosa Giuseppe , Torchilin Vladimir P. 
Published: February 2015

Abstract
Ovarian cancer is a dreadful disease estimated to be the second most common gynecologic malignancy worldwide. Its current therapy, based on cytoreductive surgery followed by the combination of platinum and taxanes, is frequently complicated by the onset of multidrug resistance (MDR). The discovery that survivin, a small antiapoptotic protein, is involved in chemoresistance provided a new prospect to overcome MDR in cancer, because siRNA could be used to inhibit the expression of survivin in cancer cells. With this in mind, we have developed self-assembly polymeric micelles (PM) able to efficiently co-load an anti–survivin siRNA and a chemotherapeutic agent, such as paclitaxel (PXL; survivin siRNA/PXL PM). Previously, we have successfully demonstrated that the downregulation of survivin by using siRNA-containing PM strongly sensitizes different cancer cells to paclitaxel. Here, we have evaluated the applicability of the developed multifunctional PM in vivo. Changes in survivin expression, therapeutic efficacy, and biologic effects of the nanopreparation were investigated in an animal model of paclitaxel-resistant ovarian cancer. The results obtained in mice xenografed with SKOV3-tr revealed a significant downregulation of survivin expression in tumor tissues together with a potent anticancer activity of survivin siRNA/PXL PM, while the tumors remained unaffected with the same quantity of free paclitaxel. These promising results introduce a novel type of nontoxic and easy-to-obtain nanodevice for the combined therapy of siRNA and anticancer agents in the treatment of chemoresistant tumors. Mol Cancer Ther; 14(4); 1075–84. ©2015 AACR.
Targeting Integrin-Linked Kinase Suppresses Invasion and Metastasis through Downregulation of Epithelial-to-Mesenchymal Transition in Renal Cell Carcinoma
Authors: Han Kyung Seok , Li Na , Raven Peter A. , Fazli Ladan , Ettinger Susan , Hong Sung Joon , Gleave Martin E. , So Alan I. 
Published: February 2015

Abstract
Renal cell carcinoma (RCC) is the most common malignancy in the kidney. Antiangiogenic targeted therapies inhibit the progression of RCC, but have limited impacts on invasion or metastasis of tumor cells. Integrin-linked kinase (ILK) is a serine/threonine kinase implicated in the regulation of cell growth/survival, cell-cycle progression, epithelial–mesenchymal transition (EMT), invasion/migration, and angiogenesis. However, the role of ILK in RCC has not been evaluated. We investigated the role of ILK on cancer progression and metastasis and the therapeutic potential of ILK inhibition in RCC. Our investigation reveals that ILK is expressed at a low level in normal cells and low-stage RCC cells and is highly expressed in advanced and metastatic cells. Caki-1, a metastatic RCC cell line, showed higher expression of molecular EMT markers, including Snail and Zeb1, but decreased activity of GSK3β. Knockdown of ILK using small interference (si)-ILK minimally inhibited tumor proliferation and cell-cycle progression was not significantly affected. However, ILK knockdown suppressed the formation of stress fibers and focal adhesions and impeded phenotypic EMT markers, including cell migration and invasion, in Caki-1 and UMRC-3 cells. Finally, in vivo knockdown of ILK suppressed the progression, invasion, and metastasis of primary RCC in nude mice by downregulation of EMT markers (Snail, Zeb1, vimentin, and E-cadherin). Our results show that ILK may be essential for invasion and metastasis in RCC and regulates vimentin and E-cadherin expression by regulating the EMT-related transcription factors Snail and Zeb1. These results suggest that ILK may be a potential target in RCC. Mol Cancer Ther; 14(4); 1024–34. ©2015 AACR.
Magnetic Resonance Spectroscopy for Detection of Choline Kinase Inhibition in the Treatment of Brain Tumors
Authors: Kumar Manoj , Arlauckas Sean P. , Saksena Sona , Verma Gaurav , Ittyerah Ranjit , Pickup Stephen , Popov Anatoliy V. , Delikatny Edward J. , Poptani Harish 
Published: February 2015

AbstractAbnormal choline metabolism is a hallmark of cancer and is associated with oncogenesis and tumor progression. Increased choline is consistently observed in both preclinical tumor models and in human brain tumors by proton magnetic resonance spectroscopy (MRS). Thus, inhibition of choline metabolism using specific choline kinase inhibitors such as MN58b may be a promising new strategy for treatment of brain tumors. We demonstrate the efficacy of MN58b in suppressing phosphocholine production in three brain tumor cell lines. In vivo MRS studies of rats with intracranial F98-derived brain tumors showed a significant decrease in tumor total choline concentration after treatment with MN58b. High-resolution MRS of tissue extracts confirmed that this decrease was due to a significant reduction in phosphocholine. Concomitantly, a significant increase in poly-unsaturated lipid resonances was also observed in treated tumors, indicating apoptotic cell death. MRI-based volume measurements demonstrated a significant growth arrest in the MN58b-treated tumors in comparison with saline-treated controls. Histologically, MN58b-treated tumors showed decreased cell density, as well as increased apoptotic cells. These results suggest that inhibition of choline kinase can be used as an adjuvant to chemotherapy in the treatment of brain tumors and that decreases in total choline observed by MRS can be used as an effective pharmacodynamic biomarker of treatment response. Mol Cancer Ther; 14(4); 899–908. ©2015 AACR.
Microbiota Modulation of Myeloid Cells in Cancer Therapy
Authors: Goldszmid Romina S. , Dzutsev Amiran , Viaud Sophie , Zitvogel Laurence , Restifo Nicholas P. , Trinchieri Giorgio 
Published: February 2015

AbstractMyeloid cells represent a major component of the tumor microenvironment, where they play divergent dual roles. They can induce antitumor immune responses, but mostly they promote immune evasion, tumor progression, and metastasis formation. Thus, strategies aiming at reprogramming the tumor microenvironment represent a promising immunotherapy approach. Myeloid cells respond to environmental factors including signals derived from commensal microbes. In this Cancer Immunology at the Crossroads overview, we discuss recent advances on the effects of the commensal microbiota on myeloid-cell functions and how they affect the response to cancer therapy. Cancer Immunol Res; 3(2); 103–9. ©2015 AACR.
P-Selectin Inhibition Therapeutically Promotes Thrombus Resolution and Prevents Vein Wall Fibrosis Better Than Enoxaparin and an Inhibitor to von Willebrand Factor
Authors: Diaz Jose A. , Wrobleski Shirley K. , Alvarado Christine M. , Hawley Angela E. , Doornbos Nichole K. , Lester Patrick A. , Lowe Suzan E. , Gabriel Joy E. , Roelofs Karen J. , Henke Peter K. , Schaub Robert G. , Wakefield Thomas W. , Myers Daniel D. 
Published: February 2015

Objective—
Aptamers are oligonucleotides targeting protein–protein interactions with pharmacokinetic profiles and activity reversal options. Although P-selectin and von Willebrand factor (vWF) have been implicated in the development of venous thrombosis (VT), no studies have directly compared aptamer efficacy with standard of care in VT. In this study, ARC5692, an anti-P-selectin aptamer, and ARC15105, an anti-vWF aptamer, were compared with low–molecular-weight heparin, enoxaparin, to test the efficacy of P-selectin or vWF inhibition in promoting thrombus resolution and preventing vein wall fibrosis, in a baboon model of VT.

Approach and Results—
Groups were as follows: treatment arm: animals received P-selectin or vWF aptamer inhibitors or enoxaparin (n=3 per group). Controls received no treatment (n=3). Prophylactic arm: animals received P-selectin inhibitor (n=4) or vWF inhibitor (n=3). Treatment arm: P-selectin-inhibitor demonstrated a significant improvement in vein recanalization by magnetic resonance venography (73% at day 21), and significantly decreased vein wall collagen, compared with all groups. Anti–P-selectin equaled enoxaparin in maintaining valve competency by ultrasound. All control animals had compromised valve competency post thrombosis. Prophylactic arm: animals receiving P-selectin and vWF inhibitors demonstrated improved vein recanalization by magnetic resonance venography versus controls (80% and 85%, respectively, at day 21). Anti–P-selectin protected iliac valve function better than anti-vWF, and both improved valve function versus controls. No adverse bleeding events were observed.

Conclusions—
The P-selectin inhibitor aptamer promoted iliac vein recanalization, preserved valve competency, and decreased vein wall fibrosis. The results of this work suggest that P-selectin inhibition maybe an ideal target in the treatment and prophylaxis of deep VT, warranting clinical trials.
Sleep Apnea Is Independently Associated With Peripheral Arterial Disease in the Hispanic Community Health Study/Study of Latinos
Authors: Shah Neomi , Allison Matthew , Teng Yanping , Wassertheil-Smoller Sylvia , Sotres-Alvarez Daniela , Ramos Alberto R. , Zee Phyllis C. , Criqui Michael H. , Yaggi Henry K. , Gallo Linda C. , Redline Susan , Kaplan Robert C. 
Published: February 2015

Objective—
Sleep apnea (SA) has been linked with various forms of cardiovascular disease, but little is known about its association with peripheral artery disease (PAD) measured using the ankle–brachial index. This relationship was evaluated in the Hispanic Community Health Study/Study of Latinos.

Approach and Results—

We studied 8367 Hispanic Community Health Study/Study of Latinos participants who were 45 to 74 years of age. Sleep symptoms were examined with the self-reported Sleep Health Questionnaire. SA was assessed using an in-home sleep study. Systolic blood pressure was measured in all extremities to compute the ankle–brachial index. PAD was defined as ankle–brachial index <0.90 in either leg. Multivariable logistic regression was used to investigate the association between moderate-to-severe SA, defined as apnea–hypopnea index ≥15, and the presence of PAD. Analyses were adjusted for covariates. The prevalence of PAD was 4.7% (n=390). The mean apnea–hypopnea index was significantly higher among adults with PAD compared with those without (11.1 versus 8.6 events/h;
P
=0.046). After adjusting for covariates, moderate-to-severe SA was associated with a 70% increase in the odds of PAD (odds ratio, 1.7; 95% confidence interval, 1.1–2.5;
P
=0.0152). This association was not modified by sex (
P
=0.8739). However, there was evidence that the association between moderate-to-severe SA and PAD varied by Hispanic/Latino background (
P
<0.01). Specifically, the odds were stronger in Mexican (adjusted odds ratio, 2.9; 95% confidence interval, 1.3–6.2) and in Puerto Rican Americans (adjusted odds ratio, 2.0; 95% confidence interval, 0.97–4.2) than in other backgrounds.

Conclusions—
Moderate-to-severe SA is associated with higher odds of PAD in Hispanic/Latino adults.
Sex Differences in Platelet Toll-Like Receptors and Their Association With Cardiovascular Risk Factors
Authors: Koupenova Milka , Mick Eric , Mikhalev Ekaterina , Benjamin Emelia J. , Tanriverdi Kahraman , Freedman Jane E. 
Published: February 2015

Objective—
Platelets contribute to thrombosis, and platelet toll-like receptors (TLRs) are central in pathogen detection, potentially mediating infection-induced vascular occlusion. Using a large community-based cohort study, we sought to examine if platelets express all known TLR transcripts and analyze their association with cardiovascular risk factors.

Approach and Results—
mRNA levels for TLRs were measured in isolated platelets by high-throughput quantitative reverse transcriptase polymerase chain reaction in 1625 participants (mean age, 66.6±9; 54% women) of the Framingham Heart Study. We measured circulating inflammatory and thrombotic markers (C-reactive protein, interleukin-6, monocyte chemoattractant protein 1, intracellular cell adhesion molecule 1, soluble tumor necrosis factor-α receptor 1, and soluble p-selectin) and analyzed TLRs and their association with sex and cardiovascular risk factors by multivariable logit regression model adjusted for confounding factors. Platelets expressed all 10 TLR transcripts, and all TLRs were coexpressed. Women had higher platelet TLR expression, which associated with different cardiovascular risk factors, compared with men. In women, TLR1, TLR3, TLR6, and TLR7 were associated with body mass index and TLR5, TLR7, and TLR10 were associated with total cholesterol to high-density lipoprotein ratio. In men, TLR1, TLR2, and TLR3 were associated with lipid and TLR8 with hypertension treatment. Similarly, TLR expression in men was more commonly associated with circulating inflammatory markers (soluble tumor necrosis factor-α receptor 1 and intracellular cell adhesion molecule 1), whereas in women, TLR expression was associated with soluble p-selectin levels.

Conclusions—
We report the first study to demonstrate that platelets express all TLR transcripts using a large community-based observational cohort. These transcripts are more abundant in women and have distinct associations with cardiovascular risk and inflammatory biomarkers that vary by sex.
Noninvasive Molecular Imaging of Apoptosis in a Mouse Model of Anthracycline-Induced Cardiotoxicity
Authors: Su Helen , Gorodny Natalia , Gomez Luis Felipe , Gangadharmath Umesh , Mu Fanrong , Chen Gang , Walsh Joseph C. , Szardenings Katrin , Kolb Hartmuth C. , Tamarappoo Balaji 
Published: February 2015

Background—
Anthracycline-induced cardiotoxicity and myocardial dysfunction may be associated with apoptosis. Caspase 3 catalyzes a terminal step in apoptosis, and its expression may serve as a marker of cardiomyocyte apoptosis. We synthesized 18F-CP18, a caspase-3 substrate and evaluated cardiac 18F-CP18 uptake in a mouse model of anthracycline cardiotoxicity.

Methods and Results—

For 12 weeks, mice were injected with doxorubicin, 3 mg/kg/week, or vehicle (control). Left ventricular fractional shortening was quantified by echocardiography. CP18 uptake after intravenous injection of 250 μCi of 18F-CP18, 24 hours post-doxorubicin treatment was quantified by microPET, autoradiography, and gamma counting. Apoptosis was assessed by enzymatic assay of myocardial caspase 3 and TUNEL staining of tissue sections. Compared with controls, at 6 and 12 weeks of doxorubicin treatment, fractional shortening was reduced (20.7%±2.5% versus 31%±3.5%,
P
=0.010; and 20.3%±3.1% versus 32.4%±2.1%,
P
=0.011). Doxorubicin treatment was associated with increased 18F-CP18 uptake in %ID/g by gamma counting from 0.36±0.01 (week 1) to 0.78±0.01 (week 12),
P
=0.003. A similar increase in 18F-CP18 uptake was observed by microPET (0.41±0.04 versus 0.73±0.1,
P
=0.014) and autoradiography (1.1±0.3 versus 2.8±0.2
P
=0.001). Caspase 3 enzymatic activity and apoptosis by TUNEL staining were also increased after 12 weeks of doxorubicin compared with weeks 1 and 3. CP18 uptake in controls was relatively unchanged at weeks 1, 3, and 12.

Conclusions—
In a mouse model of cardiotoxicity, doxorubicin treatment is associated with increased myocardial caspase 3 expression and an increase in CP18 uptake. 18F-CP18 may be useful for detection of anthracycline-induced myocardial apoptosis.
Impact of Mitral Regurgitation on Clinical Outcomes of Patients With Low-Ejection Fraction, Low-Gradient Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation
Authors: O’Sullivan Crochan J. , Stortecky Stefan , Bütikofer Anne , Heg Dik , Zanchin Thomas , Huber Christoph , Pilgrim Thomas , Praz Fabien , Buellesfeld Lutz , Khattab Ahmed A. , Blöchlinger Stefan , Carrel Thierry , Meier Bernhard , Zbinden Stephan , Wenaweser Peter , Windecker Stephan 
Published: February 2015

Background—
Up to 1 in 6 patients undergoing transcatheter aortic valve implantation (TAVI) present with low-ejection fraction, low-gradient (LEF-LG) severe aortic stenosis and concomitant relevant mitral regurgitation (MR) is present in 30% to 55% of these patients. The effect of MR on clinical outcomes of LEF-LG patients undergoing TAVI is unknown.

Methods and Results—

Of 606 consecutive patients undergoing TAVI, 113 (18.7%) patients with LEF-LG severe aortic stenosis (mean gradient ≤40 mm Hg, aortic valve area <1.0 cm
2
, left ventricular ejection fraction <50%) were analyzed. LEF-LG patients were dichotomized into ≤mild MR (n=52) and ≥moderate MR (n=61). Primary end point was all-cause mortality at 1 year. No differences in mortality were observed at 30 days (
P
=0.76). At 1 year, LEF-LG patients with ≥moderate MR had an adjusted 3-fold higher rate of all-cause mortality (11.5% versus 38.1%; adjusted hazard ratio, 3.27 [95% confidence interval, 1.31–8.15];
P
=0.011), as compared with LEF-LG patients with ≤mild MR. Mortality was mainly driven by cardiac death (adjusted hazard ratio, 4.62;
P
=0.005). As compared with LEF-LG patients with ≥moderate MR assigned to medical therapy, LEF-LG patients with ≥moderate MR undergoing TAVI had significantly lower all-cause mortality (hazard ratio, 0.38; 95% confidence interval, 0.019–0.75) at 1 year.

Conclusions—
Moderate or severe MR is a strong independent predictor of late mortality in LEF-LG patients undergoing TAVI. However, LEF-LG patients assigned to medical therapy have a dismal prognosis independent of MR severity suggesting that TAVI should not be withheld from symptomatic patients with LEF-LG severe aortic stenosis even in the presence of moderate or severe MR.
Effect of a Stable Angiotensin‐(1–7) Analogue on Progenitor Cell Recruitment and Cardiovascular Function Post Myocardial Infarction
Authors: Pessôa Bruno Sevá , Becher Peter Moritz , Van Veghel Richard , De Vries René , Tempel Dennie , Sneep Stefan , Van Beusekom Heleen , Van Der Velden Vincent H. J. , Westermann Dirk , Danser A. H. Jan , Roks Anton J. M. 
Published: February 2015

Background
Angiotensin‐(1–7) improves cardiac function and remodeling after myocardial infarction (MI). This may involve recruitment of hematopoietic progenitor cells that support angiogenesis. However, angiotensin‐(1–7) is rapidly metabolized in plasma and tissue. The authors investigated in mice the effect of a metabolically stable angiotensin‐(1–7) analogue, cyclic angiotensin‐(1–7), on progenitor cell recruitment and on the heart post MI, when given in the angiogenesis phase of remodeling.

Methods and Results
Angiogenic progenitor cell recruitment was measured by using flow cytometry 24 and 72 hours after a daily bolus injection of cyclic angiotensin‐(1–7) in healthy C57BL/6 mice. Further, mice underwent MI or sham surgery and subsequently received saline or 2 different doses of cyclic angiotensin‐(1–7) for 3 or 9 weeks. Cyclic angiotensin‐(1–7) increased circulating hematopoietic progenitor cells at 24 hours but not 72 hours. Post MI, cyclic angiotensin‐(1–7) diminished cardiomyocyte hypertrophy and reduced myogenic tone, without altering cardiovascular function or cardiac histology at 9 weeks. Importantly, cyclic angiotensin‐(1–7)–treated mice had reduced cardiac capillary density at 3 weeks after MI but not after 9 weeks. Finally, cyclic angiotensin‐(1–7) decreased tube formation by cultured human umbilical vein endothelial cells.

Conclusions
Our results suggest that cyclic angiotensin‐(1–7), when given early after MI, recruits progenitor cells but does not lead to improved angiogenesis, most likely because it simultaneously exerts antiangiogenic effect in adult endothelial cells. Apparently, optimal treatment with cyclic angiotensin‐(1–7) depends on the time point of onset of application after MI.
No Relationship of Lipid-Lowering Agents to Hematoma Growth
Authors: Priglinger Miriam , Arima Hisatomi , Anderson Craig , Krause Martin 
Published: February 2015

Background and Purpose—
Controversy persists over statins and risk of intracerebral hemorrhage. We determined associations of premorbid lipid-lowering therapy and outcomes among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT).

Methods—
The pooled data of INTERACT 1 and 2 (international, multicenter, prospective, open, blinded end point, randomized controlled trials of patients with intracerebral hemorrhage [<6 hours] and elevated systolic blood pressure) were analyzed with regard to associations of baseline lipid-lowering treatment and clinical outcomes of 3184 participants in a multivariate model. Associations of lipid-lowering therapy and hematoma growth (baseline to 24 hours) in computed tomographic substudies participants (n=1310) were estimated in ANCOVA.

Results—

Among 204 patients (6.5%) with baseline lipid-lowering treatment, 90-day clinical outcomes were not significantly different after adjustment for confounding variables including region and age. In the computed tomographic substudy, 24-hour hematoma growth was greater in 124 patients (9%) with, compared with those without, prior lipid-lowering therapy. However, this association was not significant between groups (9.2 versus 6.8 mL;
P
<0.13), after adjustment for prior antithrombotic therapy.

Conclusions—
No independent associations were found between lipid-lowering medication and adverse outcomes in patients with intracerebral hemorrhage.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00226096 and NCT00716079.
Methodological Factors in Determining Rates of Dementia in Transient Ischemic Attack and Stroke
Authors: Pendlebury Sarah T. , Chen Ping-Jen , Bull Linda , Silver Louise , Mehta Ziyah , Rothwell Peter M. 
Published: February 2015

Background and Purpose—
Many previous studies on dementia in stroke have restrictive inclusion criteria, which may result in underestimation of dementia rates. We undertook a large prospective population-based study of all transient ischemic attack and stroke to determine the impact of study entry criteria on measured rates of pre- and postevent dementia.

Methods—
All patients with acute transient ischemic attack or stroke from a defined population of 92 728 are referred from primary care or at hospital admission to the Oxford Vascular Study (2002–2007) and have baseline clinical and cognitive assessment and follow-up. We examined the impact of early death, other nonavailability, and commonly used selection criteria, on measured rates of dementia.

Results—

Among 1236 patients (mean age/SD 75.2/12.1 years, 582 men, 403 transient ischemic attack), 139 died or were otherwise unavailable for baseline assessment, 319 had prior dependency, 425 had comorbidity, 512 were aged ≥80 years, 85 were dysphasic, and 502 were hospitalized. Pre-event dementia was 3-fold higher in patients dying preascertainment (10/47, 21%) and twice as high in other nonassessed (14/92, 15%) versus assessed patients (69/1097, 6%;
P
=0.0006 and
P
=0.002) and was several-fold higher in those with prior functional impairment (24% versus 3%;
P
<0.0001), age >80 years (13% versus 3%;
P
<0.0001), dysphasia (11% versus 7%;
P
<0.0001), and comorbidity (10% versus 6%;
P
=0.04). Findings for postevent dementia were similar: prior functional impairment (40% versus 13%;
P
<0.0001), age >80 years (28% versus 10%;
P
<0.0001), dysphasia (39% versus 15%; P<0.0001), and comorbidity (20% versus 15%; P=0.04).

Conclusions—
Exclusion of patients unavailable for assessment, and other widely used selection criteria, results in underestimation of the measured rate of dementia associated with transient ischemic attack and stroke.