bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rab27a Supports Exosome-Dependent and -Independent Mechanisms That Modify the Tumor Microenvironment and Can Promote Tumor Progression
Authors: Bobrie Angélique , Krumeich Sophie , Reyal Fabien , Recchi Chiara , Moita Luis F. , Seabra Miguel C. , Ostrowski Matias , Théry Clotilde 
Published: August 2012

Abstract
During progression from single cancer cells to a tumor mass and metastases, tumor cells send signals that can subvert their tissue microenvironment. These signals involve soluble molecules and various extracellular vesicles, including a particular type termed exosomes. The specific roles of exosomes secreted in the tumor microenvironment, however, is unclear. The small GTPases RAB27A and RAB27B regulate exocytosis of multivesicular endosomes, which lead to exosome secretion, in human HeLa cells. Here, we used mouse models to show that Rab27a blockade in mammary carcinoma cells decreased secretion of exosomes characterized by endocytic markers, but also of matrix metalloproteinase 9, which is not associated with exosomes. Rab27a blockade resulted in decreased primary tumor growth and lung dissemination of a metastatic carcinoma (4T1), but not of a nonmetastatic carcinoma (TS/A). Local growth of 4T1 tumors required mobilization of a population of neutrophil immune cells induced by Rab27a-dependent secretion of exosomes together with a specific combination of cytokines and/or metalloproteinases. Our findings offer in vivo validation of the concept that exosome secretion can exert key pathophysiologic roles during tumor formation and progression, but they also highlight the idiosyncratic character of the tumor context. Cancer Res; 72(19); 4920–30. ©2012 AACR.
Inactivation of the HIF-1α/PDK3 Signaling Axis Drives Melanoma toward Mitochondrial Oxidative Metabolism and Potentiates the Therapeutic Activity of Pro-Oxidants
Authors: Kluza Jérome , Corazao-Rozas Paola , Touil Yasmine , Jendoubi Manel , Maire Cyril , Guerreschi Pierre , Jonneaux Aurélie , Ballot Caroline , Balayssac Stéphane , Valable Samuel , Corroyer-Dulmont Aurélien , Bernaudin Myriam , Malet-Martino Myriam , de Lassalle Elisabeth Martin , Maboudou Patrice , Formstecher Pierre , Polakowska Renata , Mortier Laurent , Marchetti Philippe 
Published: August 2012

Abstract
Cancer cells can undergo a metabolic reprogramming from oxidative phosphorylation to glycolysis that allows them to adapt to nutrient-poor microenvironments, thereby imposing a selection for aggressive variants. However, the mechanisms underlying this reprogramming are not fully understood. Using complementary approaches in validated cell lines and freshly obtained human specimens, we report here that mitochondrial respiration and oxidative phosphorylation are slowed in metastatic melanomas, even under normoxic conditions due to the persistence of a high nuclear expression of hypoxia-inducible factor-1α (HIF-1α). Pharmacologic or genetic blockades of the HIF-1α pathway decreased glycolysis and promoted mitochondrial respiration via specific reduction in the expression of pyruvate dehydrogenase kinase-3 (PDK3). Inhibiting PDK3 activity by dichloroacetate (DCA) or siRNA-mediated attenuation was sufficient to increase pyruvate dehydrogenase activity, oxidative phosphorylation, and mitochondrial reactive oxygen species generation. Notably, DCA potentiated the antitumor effects of elesclomol, a pro-oxidative drug currently in clinical development, both by limiting cell proliferation and promoting cell death. Interestingly, this combination was also effective against BRAF V600E-mutant melanoma cells that were resistant to the BRAF inhibitor vemurafenib. Cotreatment of melanomas with DCA and elesclomol in vivo achieved a more durable response than single agent alone. Our findings offer a preclinical validation of the HIF-1/PDK3 bioenergetic pathway as a new target for therapeutic intervention in metastatic melanoma, opening the door to innovative combinations that might eradicate this disease. Cancer Res; 72(19); 5035–47. ©2012 AACR.
Effective Photothermal Chemotherapy Using Doxorubicin-Loaded Gold Nanospheres That Target EphB4 Receptors in Tumors
Authors: You Jian , Zhang Rui , Xiong Chiyi , Zhong Meng , Melancon Maritess , Gupta Sanjay , Nick Alpa M. , Sood Anil K. , Li Chun 
Published: August 2012

Abstract
Photothermal ablation (PTA) is an emerging technique that uses near-infrared (NIR) laser light–generated heat to destroy tumor cells. However, complete tumor eradication by PTA therapy alone is difficult because heterogeneous heat distribution can lead to sublethal thermal dose in some areas of the tumor. Successful PTA therapy requires selective delivery of photothermal conducting nanoparticles to mediate effective PTA of tumor cells, and the ability to combine PTA with other therapy modalities. Here, we synthesized multifunctional doxorubicin (DOX)-loaded hollow gold nanospheres (DOX@HAuNS) that target EphB4, a member of the Eph family of receptor tyrosine kinases overexpressed on the cell membrane of multiple tumors and angiogenic blood vessels. Increased uptake of targeted nanoparticles T-DOX@HAuNS was observed in three EphB4-positive tumors both in vitro and in vivo. In vivo release of DOX from DOX@HAuNS, triggered by NIR laser, was confirmed by dual-radiotracer technique. Treatment with T-DOX@HAuNS followed by NIR laser irradiation resulted in significantly decreased tumor growth when compared with treatments with nontargeted DOX@HAuNS plus laser or HAuNS plus laser. The tumors in 6 of the 8 mice treated with T-DOX@HAuNS plus laser regressed completely with only residual scar tissue by 22 days following injection, and none of the treatment groups experienced a loss in body weight. Together, our findings show that concerted chemo-photothermal therapy with a single nanodevice capable of mediating simultaneous PTA and local drug release may have promise as a new anticancer therapy. Cancer Res; 72(18); 4777–86. ©2012 AACR.
RNF8 Regulates Assembly of RAD51 at DNA Double-Strand Breaks in the Absence of BRCA1 and 53BP1
Authors: Nakada Shinichiro , Yonamine Rikako Miyamoto , Matsuo Koichi 
Published: August 2012

Abstract
The tumor suppressor protein BRCA1 localizes to sites of DNA double-strand breaks (DSB), promoting repair by homologous recombination through the recruitment of DNA damage repair proteins. In normal cells, homologous recombination largely depends on BRCA1. However, assembly of the pivotal homologous recombination regulator RAD51 can occur independently of BRCA1 in the absence of 53BP1, another DNA damage response protein. How this assembly process proceeds is unclear, but important to understand in tumor cell settings where BRCA1 is disabled. Here we report that RNF8 regulates BRCA1-independent homologous recombination in 53BP1-depleted cells. RNF8 depletion suppressed the recruitment of RAD51 to DSB sites without affecting assembly or phosphorylation of the replication protein RPA in neocarzinostatin-treated or X-ray-irradiated BRCA1/53BP1-depleted cells. Furthermore, RNF8/BRCA1/53BP1-depleted cells exhibited less efficient homologous recombination than BRCA1/53BP1-depleted cells. Intriguingly, neither RNF8 nor its relative RNF168 were required for RAD51 assembly at DSB sites in 53BP1-expressing cells. Moreover, RNF8-independent RAD51 assembly was found to be regulated by BRCA1. Together, our findings indicate a tripartite regulation of homologous recombination by RNF8, BRCA1, and 53BP1. In addition, our results predict that RNF8 inhibition may be a useful treatment of BRCA1-mutated/53BP1low cancers, which are considered resistant to treatment by PARP1 inhibitors and of marked current clinical interest. Cancer Res; 72(19); 4974–83. ©2012 AACR.
Cardiac Inflammation after Local Irradiation Is Influenced by the Kallikrein-Kinin System
Authors: Sridharan Vijayalakshmi , Tripathi Preeti , Sharma Sunil K. , Moros Eduardo G. , Corry Peter M. , Lieblong Benjamin J. , Kaschina Elena , Unger Thomas , Thöne-Reineke Christa , Hauer-Jensen Martin , Boerma Marjan 
Published: August 2012

AbstractRadiotherapy of intrathoracic and chest wall tumors may lead to exposure of the heart to ionizing radiation, resulting in radiation-induced heart diseases (RIHD). The main manifestations of RIHD become apparent many years after treatment and include cardiomyopathy and accelerated atherosclerosis. This study examines the role of the kallikrein-kinin system (KKS) in RIHD by investigating the cardiac radiation response in a kininogen-deficient Brown Norway Katholiek (BN/Ka) rat model. BN/Ka rats and wild-type Brown Norway (BN) rats were exposed to local heart irradiation with a single dose of 18 Gy or 24 Gy and were observed for 3 to 6 months. Examinations included in vivo and ex vivo cardiac function, histopathology, gene and protein expression measurements, and mitochondrial swelling assays. Upon local heart irradiation, changes in in vivo cardiac function were significantly less in BN/Ka rats. For instance, a single dose of 24 Gy caused a 35% increase in fractional shortening in BN rats compared with a 16% increase in BN/Ka rats. BN rats, but not BN/Ka rats, showed a 56% reduction in cardiac numbers of CD2-positive cells, and a 57% increase in CD68-positive cells, together with a 52% increase in phosphorylation of extracellular signal–regulated kinase 1/2 (Erk1/2). Local heart irradiation had similar effects on histopathology, mitochondrial changes, and left ventricular mRNA levels of NADPH oxidases in the two genotypes. These results suggest that the KKS plays a role in the effects of radiation on cardiac function and recruitment of inflammatory cells. The KKS may have these effects at least in part by altering Erk1/2 signaling. Cancer Res; 72(19); 4984–92. ©2012 AACR.
Roles for Endothelin Receptor B and BCL2A1 in Spontaneous CNS Metastasis of Melanoma
Authors: Cruz-Muñoz William , Jaramillo Maria L. , Man Shan , Xu Ping , Banville Myriam , Collins Catherine , Nantel Andre , Francia Giulio , Morgan Sherif S. , Cranmer Lee D. , O'Connor-McCourt Maureen D. , Kerbel Robert S. 
Published: August 2012

Abstract
Metastatic spread of melanoma to the central nervous system (CNS) is a common and devastating manifestation of disease progression, which, despite its clinical importance, remains poorly understood with respect to underlying molecular mechanisms. Using a recently developed preclinical model of spontaneous melanoma CNS metastasis, we have identified alterations in expression of endothelin receptor B (EDNRB) as a potential factor that influences brain metastatic potential. Induced overexpression of this gene mediated enhanced overall metastatic disease, and resulted in an increased incidence of spontaneous CNS metastases. In contrast, the overexpression of other highlighted genes, such as BCL2A1, did not affect the incidence of CNS metastases but nevertheless appears to facilitate intracranial tumor growth. The prometastatic effect in the CNS associated with EDNRB appears to be mediated by the interaction with its ligands resulting in enhanced tumor cell proliferation and thus intracranial melanoma growth. That EDNRB contributes to melanoma metastasis is underscored by the fact that its therapeutic inhibition by the EDNRB-specific inhibitor A192621 translated into improved outcomes when treating mice with either visceral metastases or intracranial tumors. The identification of an influential role of EDNRB in CNS melanoma spontaneous metastasis may provide both a target for therapeutic intervention as well as a potential prognostic marker for patients having an increased predisposition for incidence of CNS melanoma metastases. Cancer Res; 72(19); 4909–19. ©2012 AACR.
Mechanism of Drug Efficacy Within the EGF Receptor Revealed by Microsecond Molecular Dynamics Simulation
Authors: Wan Shunzhou , Wright David W. , Coveney Peter V. 
Published: August 2012

Abstract
The EGF receptor (EGFR) regulates important cellular processes including proliferation, differentiation, and apoptosis. EGFR is frequently overexpressed in a range of cancers and is associated with disease progression and treatment. Clinical studies have shown that EGFR mutations confer tumor sensitivity to tyrosine kinase inhibitors in patients with non–small cell lung cancer. In this study, we have conducted molecular dynamics simulations over several microseconds for wild-type and L858R mutant forms of EGFR in the ligand-free state. Close inspection of the conformations and interactions within the binding pocket reveals, converse to the wild type, that the mutant EGFR prefers to bind gefitinib, a targeted anticancer drug, rather than ATP, offering an explanation for why gefitinib is more effective in patients with EGFR mutations than those without. Mol Cancer Ther; 11(11); 2394–400. ©2012 AACR.
Myocardial Relaxation, Restoring Forces, and Early-Diastolic Load Are Independent Determinants of Left Ventricular Untwisting Rate
Authors: Opdahl Anders , Remme Espen W. , Helle-Valle Thomas , Edvardsen Thor , Smiseth Otto A. 
Published: August 2012

Background—
Peak left ventricular (LV) untwisting rate (UTR) has been introduced as a clinical marker of diastolic function. This study investigates if early-diastolic load and restoring forces are determinants of UTR in addition to the rate of LV relaxation.

Methods and Results—

In 10 anesthetized dogs we measured UTR by sonomicrometry and speckle tracking echocardiography at varying LV preloads, increased contractility, and myocardial ischemia. UTR was calculated as the time derivative of LV twist. Because preload modified end-diastolic twist, LV systolic twist was calculated in absolute terms with reference to the end-diastolic twist configuration at baseline. Relaxation rate was measured as the time constant (τ) of LV isovolumic pressure decay. Early-diastolic load was measured as LV pressure at the time of mitral valve opening. Circumferential-longitudinal shear strain was used as an index of restoring forces. In a multivariable mixed model analysis a strong association was observed between UTR and LV pressure at the time of mitral valve opening (parameter estimate [β]=6.9;
P
<0.0001), indicating an independent effect of early-diastolic load. Furthermore, the associations between UTR and circumferential-longitudinal shear strain (β=−11.3;
P
<0.0001) and τ (β=−1.6,
P
<0.003) were consistent with independent contributions from restoring forces and rate of relaxation. Maximal UTR before mitral valve opening, however, was determined only by relaxation rate and restoring forces.

Conclusions—
The present study indicates that early-diastolic load, restoring forces, and relaxation rate are independent determinants of peak UTR. However, only relaxation rate and restoring forces contributed to UTR during isovolumic relaxation.
Cyclooxygenase-2–Derived Prostacyclin Regulates Arterial Thrombus Formation by Suppressing Tissue Factor in a Sirtuin-1–Dependent-Manner
Authors: Barbieri Silvia S. , Amadio Patrizia , Gianellini Sara , Tarantino Eva , Zacchi Elena , Veglia Fabrizio , Howe Louise R. , Weksler Babette B. , Mussoni Luciana , Tremoli Elena 
Published: August 2012

Background—
Selective inhibitors of cyclooxygenase (COX)-2 increase the risk of myocardial infarction and thrombotic events, but the responsible mechanisms are not fully understood.

Methods and Results—
We found that ferric chloride–induced arterial thrombus formation was significantly greater in COX-2 knockout compared with wild-type mice. Cross-transfusion experiments excluded the likelihood that COX-2 knockout platelets, despite enhanced aggregation responses to collagen and thrombin, are responsible for increased arterial thrombus formation in COX-2 knockout mice. Importantly, we observed that COX-2 deletion decreased prostacyclin synthase and production and peroxisome proliferator-activated receptor- and sirtuin-1 (SIRT1) expression, with consequent increased upregulation of tissue factor (TF), the primary initiator of blood coagulation. Treatment of wild-type mice with a prostacyclin receptor antagonist or a peroxisome proliferator-activated receptor-δ antagonist, which predisposes to arterial thrombosis, decreased SIRT1 expression and increased TF activity. Conversely, exogenous prostacyclin or peroxisome proliferator-activated receptor-δ agonist completely reversed the thrombotic phenotype in COX-2 knockout mice, restoring normal SIRT1 levels and reducing TF activity. Furthermore, inhibition of SIRT1 increased TF expression and activity and promoted generation of occlusive thrombi in wild-type mice, whereas SIRT1 activation was sufficient to decrease abnormal TF activity and prothrombotic status in COX-2 knockout mice.

Conclusions—
Modulation of SIRT1 and hence TF by prostacyclin/peroxisome proliferator-activated receptor-δ pathways not only represents a new mechanism in controlling arterial thrombus formation but also might be a useful target for therapeutic intervention in the atherothrombotic complications associated with COX-2 inhibitors.
The Cell Motility Modulator Slit2 Is a Potent Inhibitor of Platelet Function
Authors: Patel Sajedabanu , Huang Yi-Wei , Reheman Adili , Pluthero Fred G. , Chaturvedi Swasti , Mukovozov Ilya M. , Tole Soumitra , Liu Guang-Ying , Li Ling , Durocher Yves , Ni Heyu , Kahr Walter H.A. , Robinson Lisa A. 
Published: August 2012

Background—
Vascular injury and atherothrombosis involve vessel infiltration by inflammatory leukocytes, migration of medial vascular smooth muscle cells to the intimal layer, and ultimately acute thrombosis. A strategy to simultaneously target these pathological processes has yet to be identified. The secreted protein, Slit2, and its transmembrane receptor, Robo-1, repel neuronal migration in the developing central nervous system. More recently, it has been appreciated that Slit2 impairs chemotaxis of leukocytes and vascular smooth muscle cells toward diverse inflammatory attractants. The effects of Slit2 on platelet function and thrombus formation have never been explored.

Methods and Results—
We detected Robo-1 expression in human and murine platelets and megakaryocytes and confirmed its presence via immunofluorescence microscopy and flow cytometry. In both static and shear microfluidic assays, Slit2 impaired platelet adhesion and spreading on diverse extracellular matrix substrates by suppressing activation of Akt. Slit2 also prevented platelet activation on exposure to ADP. In in vivo studies, Slit2 prolonged bleeding times in murine tail bleeding assays. Using intravital microscopy, we found that after mesenteric arteriolar and carotid artery injury, Slit2 delayed vessel occlusion time and prevented the stable formation of occlusive arteriolar thrombi.

Conclusions—
These data demonstrate that Slit2 is a powerful negative regulator of platelet function and thrombus formation. The ability to simultaneously block multiple events in vascular injury may allow Slit2 to effectively prevent and treat thrombotic disorders such as myocardial infarction and stroke.
Microbiological Characterization in Children with Aggressive Periodontitis
Authors: Shaddox L.M. , Huang H. , Lin T. , Hou W. , Harrison P.L. , Aukhil I. , Walker C.B. , Klepac-Ceraj V. , Paster B.J. 
Published: August 2012

The objective of this study was to characterize the subgingival microbiota of African-American children with Localized Aggressive Periodontitis (LAP). Fifty-one children were included. Subgingival plaque samples were taken from diseased (DD) and healthy sites (DH) in LAP and from healthy sites in HS and HC and analyzed by 16S rRNA-based microarrays. Aggregatibacter actinomycetemcomitans (Aa) was the only species found to be both more prevalent (OR = 8.3, p = 0.0025) and abundant (p < 0.01) in DD. Filifactor alocis (Fa) was also found to be more prevalent in DD (OR 2.31, CI 1.06-5.01, p = 0.03). Most prevalent species in healthy sites were Selenomonas spp, Veillonella spp, Streptococcus spp, Bergeyella sp, and Kingella oralis. Overall, Streptococcus spp, Campylobacter gracilis, Capnocytophaga granulosa, Haemophilus parainfluenzae, and Lautropia mirabilis were most abundant in healthy children, while Aa, Fa, Tannerella sp, Solobacterium moorei, Parvimonas micra, and Capnocytophaga sp were most abundant in LAP. Based on a comprehensive analysis with 16S rRNA-based microarrays, Aa was strongly associated and site-specific in LAP. In contrast, other species were found to be associated with healthy sites and individuals (ClinicalTrials.gov number CT01330719). Abbreviations: healthy site in healthy sibling (HS); healthy site in healthy control child (HC).
The Intersection of Gender and Ethnic Identities in the Cuzco–Machu Picchu Tourism Industry
Authors: Ypeij Annelou 
Published: August 2012

A large number of local people work in the lowest echelons of the tourist market in the Cuzco–Machu Picchu region. An examination of three groups—indigenous women who pose for tourists’ cameras in the village of Pisac, male tour guides who work on the Inca Trail, and women weavers in the village of Chinchero—reveals the ways in which ethnicity, gender, and tourism work are interrelated. In particular, it shows that ethnic identity should not be limited to indigenousness and women. Both indigenous people and mestizos, women and men use their ethnic identities in their tourism work. Further, it calls into question the division between staged and real identities that is often made in tourism studies, suggesting that tourism work has become an integral part of these people’s lives, social relations, and identities whether tourists are present or not. Un gran número de gente local trabaja en los eslabones inferiores del marcado turístico en la región Cuzco–Machu Picchu. Un examen de tres grupos—mujeres indígenas quienes posan para las cámaras de los turistas en la aldea de Pisac, hombres quienes fungen como guías turísticos en el camino Inca, y mujeres tejedoras en la aldea de Chincheros—revelan las formas por las cuales la etnia, género, y el empleo turístico están interrelacionados. En particular se demuestra que la identidad étnica no se puede limitar al indigenismo y las mujeres. Tanto los indígenas como mestizos, tanto mujeres como hombres usan su identidad indígena en su trabajo turístico. Además se cuestiona la división entre identidad efectuada y real que tanto se hace en los estudios del turismo, sugiriendo que el empleo turístico se ha convertido en parte integral de la vida de estas gentes, relaciones sociales e identidades estén o no presentes los turistas.