bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Targeting of STAT3/NF-κB/COX-2/EP4 for Effective Management of Pancreatic Cancer
Authors: Gong Jingjing , Xie Jianping , Bedolla Roble , Rivas Paul , Chakravarthy Divya , Freeman James W. , Reddick Robert , Kopetz Scott , Peterson Amanda , Wang Huamin , Fischer Susan M. , Kumar Addanki P. 
Published: February 2014

Abstract
Purpose: Near equal rates of incidence and mortality emphasize the need for novel targeted approaches for better management of patients with pancreatic cancer. Inflammatory molecules NF-κB and STAT3 are overexpressed in pancreatic tumors. Inhibition of one protein allows cancer cells to survive using the other. The goal of this study is to determine whether targeting STAT3/NF-κB crosstalk with a natural product Nexrutine can inhibit inflammatory signaling in pancreatic cancer.
Experimental Design: HPNE, HPNE-Ras, BxPC3, Capan-2, MIA PaCa-2, and AsPC-1 cells were tested for growth, apoptosis, cyclooxygenase-2 (COX-2), NF-κB, and STAT3 level in response to Nexrutine treatment. Transient expression, gel shift, chromatin immunoprecipitation assay was used to examine transcriptional regulation of COX-2. STAT3 knockdown was used to decipher STAT3/NF-κB crosstalk. Histopathologic and immunoblotting evaluation was performed on BK5–COX-2 transgenic mice treated with Nexrutine. In vivo expression of prostaglandin receptor E-prostanoid 4 (EP4) was analyzed in a retrospective cohort of pancreatic tumors using a tissue microarray.
Results: Nexrutine treatment inhibited growth of pancreatic cancer cells through induction of apoptosis. Reduced levels and activity of STAT3, NF-κB, and their crosstalk led to transcriptional suppression of COX-2 and subsequent decreased levels of prostaglandin E2 (PGE2) and PGF2. STAT3 knockdown studies suggest STAT3 as negative regulator of NF-κB activation. Nexrutine intervention reduced the levels of NF-κB, STAT3, and fibrosis in vivo. Expression of prostaglandin receptor EP4 that is known to play a role in fibrosis was significantly elevated in human pancreatic tumors.
Conclusions: Dual inhibition of STAT3–NF-κB by Nexrutine may overcome problems associated with inhibition of either pathway. Clin Cancer Res; 20(5); 1259–73. ©2014 AACR.
Combination Immunotherapy after ASCT for Multiple Myeloma Using MAGE-A3/Poly-ICLC Immunizations Followed by Adoptive Transfer of Vaccine-Primed and Costimulated Autologous T Cells
Authors: Rapoport Aaron P. , Aqui Nicole A. , Stadtmauer Edward A. , Vogl Dan T. , Xu Yin Yan , Kalos Michael , Cai Ling , Fang Hong-Bin , Weiss Brendan M. , Badros Ashraf , Yanovich Saul , Akpek Gorgun , Tsao Patricia , Cross Alan , Mann Dean , Philip Sunita , Kerr Naseem , Brennan Andrea , Zheng Zhaohui , Ruehle Kathleen , Milliron Todd , Strome Scott E. , Salazar Andres M. , Levine Bruce L. , June Carl H. 
Published: February 2014

AbstractPurpose: Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells.Experimental Design: In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28–costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8+ T cells, and ELISA performed serially after transplant.Results: T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in &gt;90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3–specific CD8 T cells in 7 of 8 evaluable HLA-A2+ patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%–100%] and 2-year event-free survival was 56% (95% CI, 37%–85%).Conclusions: A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF–primed MAGE-A3 vaccine. Clin Cancer Res; 20(5); 1355–65. ©2013 AACR.
CD4+ T Lymphocyte Ablation Prevents Pancreatic Carcinogenesis in Mice
Authors: Zhang Yaqing , Yan Wei , Mathew Esha , Bednar Filip , Wan Shanshan , Collins Meredith A. , Evans Rebecca A. , Welling Theodore H. , Vonderheide Robert H. , di Magliano Marina Pasca 
Published: February 2014

Abstract
Pancreatic cancer, one of the deadliest human malignancies, is associated with oncogenic Kras and is most commonly preceded by precursor lesions known as pancreatic intraepithelial neoplasias (PanIN). PanIN formation is accompanied by the establishment of an immunotolerant microenvironment. However, the immune contribution to the initiation of pancreatic cancer is currently poorly understood. Here, we genetically eliminate CD4+ T cells in the iKras* mouse model of pancreatic cancer, in the context of pancreatitis, to determine the functional role of CD4+ T cells during mutant Kras-driven pancreatic carcinogenesis. We show that oncogenic Kras-expressing epithelial cells drive the establishment of an immunosuppressive microenvironment through the recruitment and activity of CD4+ T cells. Furthermore, we show that CD4+ T cells functionally repress the activity of CD8+ T cells. Elimination of CD4+ T cells uncovers the antineoplastic function of CD8+ T cells and blocks the onset of pancreatic carcinogenesis. Thus, our studies uncover essential and opposing roles of immune cells during PanIN formation and provide a rationale to explore immunomodulatory approaches in pancreatic cancer. Cancer Immunol Res; 2(5); 423–35. ©2014 AACR.
Physical Activity Measured With Implanted Devices Predicts Patient Outcome in Chronic Heart Failure
Authors: Conraads Viviane M. , Spruit Martijn A. , Braunschweig Frieder , Cowie Martin R. , Tavazzi Luigi , Borggrefe Martin , Hill Michael R.S. , Jacobs Sandra , Gerritse Bart , van Veldhuisen Dirk J. 
Published: February 2014

Background—
Physical activity (PA) predicts cardiovascular mortality in the population at large. Less is known about its prognostic value in patients with chronic heart failure (HF).

Methods and Results—

Data from 836 patients with implantable cardioverter defibrillator without or with cardiac resynchronization therapy enrolled in the Sensitivity of the InSync Sentry OptiVol feature for the prediction of Heart Failure (SENSE-HF)

1

study and the Diagnostic Outcome Trial in Heart Failure (DOT-HF) were pooled. The devices continuously measured and stored total daily active time (single-axis accelerometer). Early PA (average daily activity over the earliest 30-day study period) was studied as a predictor of time to death or HF-related hospital admission (primary end point). Data from 781 patients were analyzed (65±10 years; 85% men; left ventricular ejection fraction, 26±7%). Older age, shorter height, ischemic cause, peripheral artery disease, atrial fibrillation, diabetes mellitus, rales, peripheral edema, higher New York Heart Association class, lower diastolic blood pressure, and no angiotensin II receptor blocker/angiotensin-converting enzyme inhibitor use were associated with reduced early PA. The primary end point occurred in 135 patients (15±7 months of follow-up). In multivariable analysis including baseline variables, early PA predicted death or HF hospitalization, with a 4% reduction in risk for each 10 minutes per day additional activity (hazard ratio [HR], 0.96; confidence interval [CI], 0.94–0.98;
P
=0.0002 compared with a model with the same baseline variables but without PA). PA also predicted death (HR, 0.93; CI, 0.90–0.96;
P
<0.0001) and HF hospitalization (HR, 0.97; CI, 0.95–0.99;
P
=0.011).

Conclusions—
Early PA, averaged over a 30-day window early after defibrillator implantation or cardiac resynchronization therapy in patients with chronic HF, predicted death or HF hospitalization, as well as mortality and HF hospitalization separately, accounting for baseline HF severity.

Clinical Trial Registration Information—

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00400985, NCT00480077.
Cyclooxygenase-2 in Endothelial and Vascular Smooth Muscle Cells Restrains Atherogenesis in Hyperlipidemic Mice
Authors: Tang Soon Yew , Monslow James , Todd Leslie , Lawson John , Puré Ellen , FitzGerald Garret A. 
Published: February 2014

Background—
Placebo-controlled trials of nonsteroidal anti-inflammatory drugs selective for inhibition of cyclooxygenase-2 (COX-2) reveal an emergent cardiovascular hazard in patients selected for low risk of heart disease. Postnatal global deletion of COX-2 accelerates atherogenesis in hyperlipidemic mice, a process delayed by selective enzyme deletion in macrophages.

Methods and Results—

In the present study, selective depletion of COX-2 in vascular smooth muscle cells and endothelial cells depressed biosynthesis of prostaglandin I
2
and prostaglandin E
2
, elevated blood pressure, and accelerated atherogenesis in Ldlr knockout mice. Deletion of COX-2 in vascular smooth muscle cells and endothelial cells coincided with an increase in COX-2 expression in lesional macrophages and increased biosynthesis of thromboxane. Increased accumulation of less organized intimal collagen, laminin, α-smooth muscle actin, and matrix-rich fibrosis was also apparent in lesions of the mutants.

Conclusions—
Although atherogenesis is accelerated in global COX-2 knockouts, consistent with evidence of risk transformation during chronic nonsteroidal anti-inflammatory drug administration, this masks the contrasting effects of enzyme depletion in macrophages versus vascular smooth muscle cells and endothelial cells. Targeting delivery of COX-2 inhibitors to macrophages may conserve their efficacy while limiting cardiovascular risk.
Microtubule-Mediated Defects in Junctophilin-2 Trafficking Contribute to Myocyte Transverse-Tubule Remodeling and Ca
2+
Handling Dysfunction in Heart Failure
Authors: Zhang Caimei , Chen Biyi , Guo Ang , Zhu Yanqi , Miller Jordan D. , Gao Shan , Yuan Can , Kutschke William , Zimmerman Kathy , Weiss Robert M. , Wehrens Xander H. T. , Hong Jiang , Johnson Frances L. , Santana Luis F. , Anderson Mark E. , Song Long-Sheng 
Published: February 2014

Background—
Cardiac dysfunction in failing hearts of human patients and animal models is associated with both microtubule densification and transverse-tubule (T-tubule) remodeling. Our objective was to investigate whether microtubule densification contributes to T-tubule remodeling and excitation–contraction coupling dysfunction in heart disease.

Methods and Results—

In a mouse model of pressure overload–induced cardiomyopathy by transaortic banding, colchicine, a microtubule depolymerizer, significantly ameliorated T-tubule remodeling and cardiac dysfunction. In cultured cardiomyocytes, microtubule depolymerization with nocodazole or colchicine profoundly attenuated T-tubule impairment, whereas microtubule polymerization/stabilization with taxol accelerated T-tubule remodeling. In situ immunofluorescence of heart tissue sections demonstrated significant disorganization of junctophilin-2 (JP2), a protein that bridges the T-tubule and sarcoplasmic reticulum membranes, in transaortic banded hearts as well as in human failing hearts, whereas colchicine injection significantly preserved the distribution of JP2 in transaortic banded hearts. In isolated mouse cardiomyocytes, prolonged culture or treatment with taxol resulted in pronounced redistribution of JP2 from T-tubules to the peripheral plasma membrane, without changing total JP2 expression. Nocodazole treatment antagonized JP2 redistribution. Moreover, overexpression of a dominant-negative mutant of kinesin 1, a microtubule motor protein responsible for anterograde trafficking of proteins, protected against JP2 redistribution and T-tubule remodeling in culture. Finally, nocodazole treatment improved Ca
2+
handling in cultured myocytes by increasing the amplitude of Ca
2+
transients and reducing the frequency of Ca
2+
sparks.

Conclusion—
Our data identify a mechanistic link between microtubule densification and T-tubule remodeling and reveal microtubule-mediated JP2 redistribution as a novel mechanism for T-tubule disruption, loss of excitation–contraction coupling, and heart failure.
Intakes of Potassium, Magnesium, and Calcium and Risk of Stroke
Authors: Sluijs Ivonne , Czernichow Sebastien , Beulens Joline W.J. , Boer Jolanda M.A. , van der Schouw Yvonne T. , Verschuren W. Monique M. , Grobbee Diederick E. 
Published: February 2014

Background and Purpose—
We aimed to investigate the associations of dietary and total potassium, magnesium, and calcium intakes with stroke occurrence.

Methods—
A prospective cohort study was conducted among 36 094 participants aged 21 to 70 years. Dietary intake was assessed with a food frequency questionnaire.

Results—
During 12 years of follow-up, 631 strokes occurred. After adjustment for confounders, magnesium intake was associated with reduced stroke risk (hazard ratio [95% confidence interval] per 100 mg/d, 0.80 [0.67–0.97] dietary magnesium; 0.78 [0.65–0.93] total magnesium). Potassium and calcium intakes were not associated with stroke.

Conclusions—
This study supports an association between high magnesium intake and a reduced stroke risk.
A new species of sponge-dwelling Oukuriella (Chironomidae) from Brazil
Authors: FUSARI LÍVIA MARIA , BELLODI CAROLINA FERRAZ , LAMAS CARLOS JOSÉ EINICKER 
Published: February 2014

Oukuriella Epler, 1986 is an exclusively Neotropical genus that comprises two well supported clades: inhabitants of freshwater sponges and inhabitants of immersed wood (saproxylophilic). In this work, males of a new chironomid species, Oukuriella froehlichi sp. n., are described and illustrated. Specimens were collected near stream in the Brazilian Atlantic Forest. Phylogenetic analyses performed in this study show that the newly discovered species belongs in the clade of freshwater sponge inhabitants.
A study of the psychological distress in family caregivers of patients with prolonged disorders of consciousness during in-hospital rehabilitation
Authors: Moretta Pasquale , Estraneo Anna , De Lucia Lucia , Cardinale Viviana , Loreto Vincenzo , Trojano Luigi 
Published: February 2014

Objectives: To study psychological distress in a sample of caregivers of patients affected by prolonged disorders of consciousness during hospital stay in the Neurorehabilitation Unit. Materials and methods: Twenty-four caregivers of 22 patients affected by prolonged disorders of consciousness admitted to postacute rehabilitation center, completed self-reported questionnaires for assessment of depressive symptoms, state and trait anxiety, psychophysiological disturbances, prolonged grief disorder, psychological coping strategies, quality of perceived needs, perceived social support, and caregiver burden; at admission, and after four and eight months. Results: At admission depressive symptoms were found in 20/24 caregivers, high levels of anxiety in 16, and relevant psychophysiological disturbances in 10 participants; eight caregivers (32%) met criteria for prolonged grief disorder. The scores on questionnaires did not differ as a function of relatives’ diagnosis (vegetative state vs. minimally conscious state). The longitudinal study ( n = 18) showed a progressive and statistically significant increase of “emotional burden” during the hospital stay, whereas the remaining variables did not change significantly. Conclusions: Data confirmed the presence of severe psychological problems in caregivers of patients with prolonged disorders of consciousness. The levels of psychological distress tend to be constant over time, while the emotional burden increases.
Endovascular embolization is applicable for large and giant intracranial aneurysms: experience in one center with long-term angiographic follow-up
Authors: Wang Bing , Gao Bu-Lang , Xu Guo-Ping , Xiang Cheng , Liu Xiao-Sheng 
Published: February 2014

Background Endovascular treatment of large and giant intracranial aneurysms and long-term results of angiographic follow-up of these aneurysms treated endovascularly are not known currently. Purpose To investigate the outcome of endovascular treatment of large and giant aneurysms and the long-term angiographic follow-up results. Material and Methods A retrospective analysis of all patients with endovascular treatment of large and giant aneurysms between 1998 and 2009 was performed. There were 90 large or giant aneurysms treated with coiling alone, stent-assisted coiling, covered-stent deployment, or parent artery occlusion (PAO) in 88 patients (female/male, 54/34; age range, 23–92 years; mean age, 56 years). Results Immediately after the initial endovascular embolization procedure, complete occlusion was achieved in 56.7%, near complete occlusion in 37.8%, and incomplete occlusion in 5.5%. The total periprocedural complication rate excluding subarachnoid hemorrhage (SAH)-induced vasospasm was 10.2% with a mortality rate of 2.3%. Follow-up angiography was performed in all of the aneurysms with the longest follow-up duration of 131 months. Among 38 aneurysms initially treated with coiling alone and 17 initially treated with stent-assisted coiling, 22 (57.9%) and four (23.5%) recurred, respectively, during follow-up. No recurrence occurred in aneurysms initially treated with covered-stent deployment or PAO. Aneurysm recurrence was predominantly seen in older and female patients, in larger aneurysms, and in aneurysms treated with coiling alone. Twenty-three aneurysms were successfully retreated endovascularly. Conclusion Endovascular intervention with coiling alone or stent-assisted coiling for large and giant cerebral aneurysms is not very effective, while covered stents are more promising. Better endovascular devices are needed to obtain more secure closure.
Ephrin B2 and EphB4 selectively mark arterial and venous vessels in cerebral arteriovenous malformation
Authors: Bai Jie , Wang Ya-jie , Liu Li , Zhao Yuan-li 
Published: February 2014

Objectives Ephrin type B receptor 4 (EphB4, Eph receptor) selectively binds ephrin B2 (Eph ligand). EphB4/ephrin B2 is involved in embryonic vessel development, vascular remodelling and pathological vessel formation in adults (including tumour angiogenesis). Binding of vascular endothelial growth factor (VEGF)-A to the endothelial-specific receptor VEGF receptor-2 is the main extracellular signal triggering angiogenic response. Little is known about the role of EphB4/ephrin B2 during angiogenesis and arteriovenous plasticity in cerebral arteriovenous malformation (cAVM). This study investigated EphB4 and ephrin B2 expression in cAVM. Methods Haemorrhagic (H-AVM) and nonhaemorrhagic (NH-AVM) specimens of AVM nidus, obtained after microsurgical cAVM resection, and normal superficial temporal artery (STA) specimens, were analysed retrospectively. VEGF-A, EphB4 and ephrin B2 expression were studied by immunohistochemistry and immunoblotting. Results In cAVM (10 H-AVM; 10 NH-AVM), VEGF-A was immunocytochemically localized to endothelial cells; strong endothelial cell staining was found for EphB4 in veins and ephrin B2 in arteries. Normal STA ( n = 10) did not express EphB4 or ephrin B2. EphB4 and ephrin B2 expression was greater in H-AVM than in NH-AVM. Conclusions Endothelial cells are more active in H-AVM than NH-AVM. EphB4 and ephrin B2 play important roles in neovascularization and arteriovenous differentiation/plasticity. These data provide new insights into the aetiology of cAVM and lay a foundation for further study. The notch pathway induced by VEGF-A may be a key signalling pathway in this process.
Adolescent cervical disc degeneration in MRI does not predict adult headache or neck pain: A 5-year follow-up of adolescents with and without headache
Authors: Laimi Katri , Pitkänen Johanna , Metsähonkala Liisa , Vahlberg Tero , Mikkelsson Marja , Erkintalo Minna , Aromaa Minna , Rautava Päivi , Anttila Pirjo , Oksanen Airi , Saltychev Mikhail , Sillanpää Matti 
Published: February 2014

Aim The impact of early degenerative changes of the cervical spine on pain in adulthood is unknown. The objective was to determine whether degeneration in adolescence predicts headache or neck pain in young adulthood. Methods As part of a follow-up of schoolchildren with and without headache, 17-year-old adolescents with headache at least three times a month ( N = 47) and adolescents with no headache ( N = 22) participated in a magnetic resonance imaging (MRI) study of the cervical spine. The same adolescents were re-examined by phone interview at the age of 22 years ( N = 60/69, 87%). Results Mild disc degeneration at the age of 17 years was common, but was not associated with either frequent or intensive headache or neck pain at the age of 22 years. Conclusion: Mild degenerative changes of the cervical spine in 17-year-old adolescents cannot be regarded as a cause of future headache or neck pain.
Intraganglionic injection of a nitric oxide donator induces afferent mechanical sensitization that is attenuated by palmitoylethanolamide
Authors: Cairns Brian E , Laursen Jens C , Dong Xu-Dong , Gazerani Parisa 
Published: February 2014

Aim The aim of this article is to investigate whether the nitric oxide (NO) donator diethylenetriamine/nitric oxide (DETA/NO) affects trigeminal sensory processing through the trigeminal ganglion in part by activating trigeminal satellite glial cells (SGCs) and whether this effect is attenuated by the anti-inflammatory compound palmitoylethanolamide (PEA). Methods DETA/NO was administered to isolated rat trigeminal SGCs in vitro, and injected into the rat trigeminal ganglion in vivo, in the presence or absence of PEA. Results Administration of DETA/NO (1000 µM) increased the release of prostaglandin E2 by SGCs. PEA (1 and 10 µM) significantly attenuated prostaglandin E2 release. Two intraganglionic injections of DETA/NO (10 mM, 3 µl) or prostaglandin E2 at a 30-minute interval did not evoke discharge in trigeminal ganglion neurons that innervate the rat jaw-closer muscles, but did reduce the mechanical activation threshold of their peripheral endings by 30%–50%. Intravenous administration of PEA (1 mg/kg) or ketorolac (0.5 mg/kg) prevented DETA/NO-induced afferent mechanical sensitization. Conclusions Elevation of NO in the trigeminal ganglion results in the sensitization of the peripheral endings of masticatory muscle nociceptors to mechanical stimulation through a mechanism that involves prostaglandin E2 release from SGCs. Attenuation of this sensitization by PEA suggests a possible option for acute management of craniofacial pain and headache.