bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of prostaglandins and COX-inhibiting drugs on skeletal muscle adaptations to exercise
Authors: Trappe Todd A. , Liu Sophia Z.
Published: March 2013

It has been ∼40 yr since the discovery that PGs are produced by exercising skeletal muscle and since the discovery that inhibition of PG synthesis is the mechanism of action of what are now known as cyclooxygenase (COX)-inhibiting drugs. Since that time, it has been established that PGs are made during and after aerobic and resistance exercise and have a potent paracrine and autocrine effect on muscle metabolism. Consequently, it has also been determined that orally consumed doses of COX inhibitors can profoundly influence muscle PG synthesis, muscle protein metabolism, and numerous other cellular processes that regulate muscle adaptations to exercise loading. Although data from acute human exercise studies, as well as animal and cell-culture data, would predict that regular consumption of a COX inhibitor during exercise training would dampen the typical muscle adaptations, the chronic data do not support this conjecture. From the studies in young and older individuals, lasting from 1.5 to 4 mo, no interfering effects of COX inhibitors on muscle adaptations to resistance-exercise training have been noted. In fact, in older individuals, a substantial enhancement of muscle mass and strength has been observed. The collective findings of the PG/COX-pathway regulation of skeletal muscle responses and adaptations to exercise are compelling. Considering the discoveries in other areas of COX regulation of health and disease, there is certainly an interesting future of investigation in this re-emerging area, especially as it pertains to older individuals and the condition of sarcopenia, as well as exercise training and performance of individuals of all ages.
Pulmonary chemoreflex responses are potentiated by tumor necrosis factor-alpha in mice
Authors: Lin Ruei-Lung , Lin Yu-Jung , Geer Marcus J. , Kryscio Richard , Lee Lu-Yuan
Published: March 2013

Inhalation of tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine, induces airway hyperresponsiveness, and the underlying mechanism is not fully understood. Hypersensitivity of vagal bronchopulmonary C-fiber afferents is known to contribute to the airway hyperresponsiveness during an airway inflammatory reaction. Because activation of these afferents can elicit pulmonary chemoreflexes, this study was designed to determine if a pretreatment with TNF-α induced airway inflammation and enhanced the pulmonary chemoreflex sensitivity in anesthetized mice; and if so, whether the effect was mediated through activation of either or both of the TNF receptors, p55 and p75. Our results showed that TNF-α instilled into the lung caused an increased sensitivity of pulmonary chemoreflex responses to various chemical stimulants of the vagal bronchopulmonary C-fiber afferents. The increased sensitivity was found 24 h later, persisted at 48 h, and then gradually declined after several days. The TNF-α-induced airway hypersensitivity was accompanied by airway inflammation as shown by a striking elevation of the levels of eosinophils and neutrophils, several potent bronchoactive inflammatory mediators, and proinflammatory cytokines in the bronchoalveolar lavage fluid. Furthermore, the increase in pulmonary chemoreflex response caused by TNF-α was partially abrogated in both p55-null and p75-null mice, but completely abolished in p55/p75-null mice. In conclusion, TNF-α pretreatment induced airway inflammation and a sustained elevation of pulmonary chemoreflex sensitivity, which was mediated through an activation of both types of TNF receptors.
Elevated ALCAM Shedding in Colorectal Cancer Correlates with Poor Patient Outcome
Authors: Hansen Amanda G. , Freeman Tanner J. , Arnold Shanna A. , Starchenko Alina , Jones-Paris Celestial R. , Gilger Michael A. , Washington Mary K. , Fan Kang-Hsien , Shyr Yu , Beauchamp Robert D. , Zijlstra Andries
Published: March 2013

Molecular biomarkers of cancer are needed to assist histologic staging in the selection of treatment, outcome risk stratification, and patient prognosis. This is particularly important for patients with early-stage disease. We show that shedding of the extracellular domain of activated leukocyte cell adhesion molecule (ALCAM) is prognostic for outcome in patients with colorectal cancer (CRC). Previous reports on the prognostic value of ALCAM expression in CRC have been contradictory and inconclusive. This study clarifies the prognostic value of ALCAM by visualizing ectodomain shedding using a dual stain that detects both the extracellular and the intracellular domains in formalin-fixed tissue. Using this novel assay, 105 patients with primary CRCs and 12 normal mucosa samples were evaluated. ALCAM shedding, defined as detection of the intracellular domain in the absence of the corresponding extracellular domain, was significantly elevated in patients with CRC and correlated with reduced survival. Conversely, retention of intact ALCAM was associated with improved survival, thereby confirming that ALCAM shedding is associated with poor patient outcome. Importantly, analysis of patients with stage II CRC showed that disease-specific survival is significantly reduced for patients with elevated ALCAM shedding (P = 0.01; HR, 3.0), suggesting that ALCAM shedding can identify patients with early-stage disease at risk of rapid progression. Cancer Res; 73(10); 2955–64. ©2013 AACR.
Booster Vaccinations against Cancer Are Critical in Prophylactic but Detrimental in Therapeutic Settings
Authors: Ricupito Alessia , Grioni Matteo , Calcinotto Arianna , Hess Michelini Rodrigo , Longhi Renato , Mondino Anna , Bellone Matteo
Published: March 2013

Although cancer vaccines are in the clinic, several issues remain to be addressed to increase vaccine efficacy. In particular, whether how and how frequently a patient should be boosted remains to be defined. Here, we have assessed the ability of dendritic cell (DC)-based vaccines to induce a long-lasting tumor-specific CTL response in either prophylactic or therapeutic settings by taking advantage of transplantable and spontaneous mouse tumor models. Implementing a 24-hour ex vivo intracellular cytokine production assay, we have found that priming with a DC-based vaccine induced a long-lasting CTL response in wild-type mice, and homologous boosting better sustained the pool of central memory T cells, which associated with potent protection against B16F1 melanoma challenge. Appropriate timing of booster vaccination was also critical, as a tight boosting schedule hindered persistence of IFN-γ–competent memory CD8+ T cells and mice survival in prophylactic settings. Conversely, prime/boost vaccination proved to be of no advantage or even detrimental in therapeutic settings in B16F1 and transgenic adenocarcinoma of the mouse prostate (TRAMP) models, respectively. Although DC priming was indeed needed for tumor shrinkage, restoration of immune competence, and prolonged survival of TRAMP mice, repeated boosting did not sustain the pool of central memory CTLs and was detrimental for mice overall survival. Thus, our results indicate that booster vaccinations impact antitumor immunity to different extents, depending on their prophylactic or therapeutic administration, and suggest evaluating the need for boosting in any given patient with cancer depending on the state of the disease. Cancer Res; 73(12); 3545–54. ©2013 AACR.
Fibroblast-Specific Protein 1/S100A4–Positive Cells Prevent Carcinoma through Collagen Production and Encapsulation of Carcinogens
Authors: Zhang Jinhua , Chen Lin , Liu Xiaoman , Kammertoens Thomas , Blankenstein Thomas , Qin Zhihai
Published: March 2013

Stromal restraints to cancer are critical determinants of disease but they remain incompletely understood. Here, we report a novel mechanism for host surveillance against cancer contributed by fibroblast-specific protein 1 (FSP1)+/S100A4+ fibroblasts. Mechanistic studies of fibrosarcoma formation caused by subcutaneous injection of the carcinogen methylcholanthrene (MCA) had suggested that IFN-γ receptor signaling may restrict MCA diffusion by inducing expression of collagen (foreign body reaction). We tested the hypothesis that this reaction encapsulated MCA and limited carcinogenesis by determining whether its ability to induce fibrosarcomas was impaired in the absence of proliferating fibroblasts. We found that FSP1+/S100A4+ fibroblasts accumulated around the carcinogen where they produced collagens, encapsulating MCA and protecting epithelial cells from DNA damage. Ablation of these cells at the site of MCA injection by local administration of ganciclovir in FSP-TK transgenic mice altered tumor morphology to an epithelial phenotype, indicating that, in the absence of encapsulating fibroblasts, MCA targeted epithelial cells. Notably, we showed that destruction of the fibrous capsule around the MCA by local injection of collagenase induced rapid tumor development in mice that were otherwise durably tumor free. Our findings demonstrate that the FSP1+/S100A4+ fibroblasts prevent epithelial malignancy and that collagen encapsulation of carcinogens protects against tumor development. Together, this study provides a novel mechanism for host surveillance against cancer. Cancer Res; 73(9); 2770–81. ©2013 AACR.
NEDD9 Depletion Destabilizes Aurora A Kinase and Heightens the Efficacy of Aurora A Inhibitors: Implications for Treatment of Metastatic Solid Tumors
Authors: Ice Ryan J. , McLaughlin Sarah L. , Livengood Ryan H. , Culp Mark V. , Eddy Erik R. , Ivanov Alexey V. , Pugacheva Elena N.
Published: March 2013

Aurora A kinase (AURKA) is overexpressed in 96% of human cancers and is considered an independent marker of poor prognosis. While the majority of tumors have elevated levels of AURKA protein, few have AURKA gene amplification, implying that posttranscriptional mechanisms regulating AURKA protein levels are significant. Here, we show that NEDD9, a known activator of AURKA, is directly involved in AURKA stability. Analysis of a comprehensive breast cancer tissue microarray revealed a tight correlation between the expression of both proteins, significantly corresponding with increased prognostic value. A decrease in AURKA, concomitant with increased ubiquitination and proteasome-dependent degradation, occurs due to depletion or knockout of NEDD9. Reexpression of wild-type NEDD9 was sufficient to rescue the observed phenomenon. Binding of NEDD9 to AURKA is critical for AURKA stabilization, as mutation of S296E was sufficient to disrupt binding and led to reduced AURKA protein levels. NEDD9 confers AURKA stability by limiting the binding of the cdh1–substrate recognition subunit of APC/C ubiquitin ligase to AURKA. Depletion of NEDD9 in tumor cells increases sensitivity to AURKA inhibitors. Combination therapy with NEDD9 short hairpin RNAs and AURKA inhibitors impairs tumor growth and distant metastasis in mice harboring xenografts of breast tumors. Collectively, our findings provide rationale for the use of AURKA inhibitors in treatment of metastatic tumors and predict the sensitivity of the patients to AURKA inhibitors based on NEDD9 expression. Cancer Res; 73(10); 3168–80. ©2013 AACR.
β-Catenin/POU5F1/SOX2 Transcription Factor Complex Mediates IGF-I Receptor Signaling and Predicts Poor Prognosis in Lung Adenocarcinoma
Authors: Xu Chuan , Xie Dan , Yu Shi-Cang , Yang Xiao-Jun , He Li-Ru , Yang Jing , Ping Yi-Fang , Wang Bin , Yang Lang , Xu Sen-Lin , Cui Wei , Wang Qing-Liang , Fu Wen-Juan , Liu Qing , Qian Cheng , Cui You-Hong , Rich Jeremy N. , Kung Hsiang-Fu , Zhang Xia , Bian Xiu-Wu
Published: March 2013

Cancer stem-like cells (CSLC) are crucial in tumor initiation and progression; however, the underlying mechanism for the self-renewal of cancer cells remains undefined. In the study, immunohistochemical analysis of specimens freshly excised from patients with lung adenocarcinoma showed that high expression of insulin-like growth factor I receptor (IGF-IR) in lung adenocarcinoma cells was positively correlated with the expressions of cancer stem cell markers CD133 and aldehyde dehydrogenase 1 family member A1 (ALDH1A1). IGF-IR activation enhanced POU class 5 homeobox 1 (POU5F1) expression on human lung adenocarcinoma stem-like cells (LACSLC) through PI3K/AKT/GSK3β/β-catenin cascade. POU5F1 could form a novel complex with β-catenin and SOX2 to bind Nanog promoter for transcription to maintain self-renewal of LACSLCs, which was dependent on the functional IGF-IR. Genetic and pharmacologic inhibition of IGF-IR abrogated LACSLC capabilities for self-renewal and tumorigenicity in vitro. In an in vivo xenograft tumor model, knockdown of either IGF-IR or POU5F1 impeded tumorigenic potentials of LACSLCs. By analyzing pathologic specimens excised from 200 patients with lung adenocarcinoma, we found that colocalization of highly expressed IGF-IR with β-catenin and POU5F1 predicted poor prognosis. Taken together, we show that IGF-IR—mediated POU5F1 expression to form a complex with β-catenin and SOX2 is crucial for the self-renewal and oncogenic potentials of LACSLCs, and the integrative clinical detection of the expressions of IGF-IR, β-catenin, and POU5F1 is indicatory for predicting prognosis in the patients of lung adenocarcinoma. Cancer Res; 73(10); 3181–9. ©2013 AACR.
A Novel Tankyrase Small-Molecule Inhibitor Suppresses APC Mutation–Driven Colorectal Tumor Growth
Authors: Lau Ted , Chan Emily , Callow Marinella , Waaler Jo , Boggs Jason , Blake Robert A. , Magnuson Steven , Sambrone Amy , Schutten Melissa , Firestein Ron , Machon Ondrej , Korinek Vladimir , Choo Edna , Diaz Dolores , Merchant Mark , Polakis Paul , Holsworth Daniel D. , Krauss Stefan , Costa Mike
Published: March 2013

Most colorectal cancers (CRC) are initiated by mutations of APC, leading to increased β-catenin–mediated signaling. However, continued requirement of Wnt/β-catenin signaling for tumor progression in the context of acquired KRAS and other mutations is less well-established. To attenuate Wnt/β-catenin signaling in tumors, we have developed potent and specific small-molecule tankyrase inhibitors, G007-LK and G244-LM, that reduce Wnt/β-catenin signaling by preventing poly(ADP-ribosyl)ation-dependent AXIN degradation, thereby promoting β-catenin destabilization. We show that novel tankyrase inhibitors completely block ligand-driven Wnt/β-catenin signaling in cell culture and display approximately 50% inhibition of APC mutation–driven signaling in most CRC cell lines. It was previously unknown whether the level of AXIN protein stabilization by tankyrase inhibition is sufficient to impact tumor growth in the absence of normal APC activity. Compound G007-LK displays favorable pharmacokinetic properties and inhibits in vivo tumor growth in a subset of APC-mutant CRC xenograft models. In the xenograft model most sensitive to tankyrase inhibitor, COLO-320DM, G007-LK inhibits cell-cycle progression, reduces colony formation, and induces differentiation, suggesting that β-catenin–dependent maintenance of an undifferentiated state may be blocked by tankyrase inhibition. The full potential of the antitumor activity of G007-LK may be limited by intestinal toxicity associated with inhibition of Wnt/β-catenin signaling and cell proliferation in intestinal crypts. These results establish proof-of-concept antitumor efficacy for tankyrase inhibitors in APC-mutant CRC models and uncover potential diagnostic and safety concerns to be overcome as tankyrase inhibitors are advanced into the clinic. Cancer Res; 73(10); 3132–44. ©2013 AACR.
High Phospho-Stathmin(Serine38) Expression Identifies Aggressive Endometrial Cancer and Suggests an Association with PI3K Inhibition
Authors: Wik Elisabeth , Birkeland Even , Trovik Jone , Werner Henrica M.J. , Hoivik Erling A. , Mjos Siv , Krakstad Camilla , Kusonmano Kanthida , Mauland Karen , Stefansson Ingunn M. , Holst Frederik , Petersen Kjell , Oyan Anne M. , Simon Ronald , Kalland Karl H. , Ricketts William , Akslen Lars A. , Salvesen Helga B.
Published: March 2013

Purpose: High Stathmin expression has recently been associated with clinical progress in endometrial cancers. Stathmin protein activity is modulated by phosphorylation, and the Serine38 site is one of four Stathmin phospho-sites. The presence and significance of pStathmin(S38) is largely unknown in human cancers, and we here examined the associations between this marker and tumor cell proliferation, clinicopathologic phenotype, and survival impact in endometrial cancer. A relationship with possible treatment targets was explored by integrated analysis of transcriptional alterations.

Experimental Design: Primary endometrial cancers from two independent patient series (n = 518/n = 286) were analyzed. Biomarkers were assessed by immunohistochemistry, FISH, flow cytometry, DNA oligonucleotide microarray, single-nucleotide polymorphism array, and Sanger sequencing, and related to clinicopathologic annotations and follow-up information.

Results: High pStathmin(S38) level was associated with poor prognosis, independent of other features, and correlated to increased tumor cell proliferation as well as high Stathmin levels. On the basis of transcriptional differences between high/low pStathmin(S38) tumors, phosphoinositide 3-kinase (PI3K)/mTOR/HSP90 were suggested as possible targets in pStathmin(S38)-high cases. High pStathmin(S38) was associated with several PI3K pathway alterations: amplification of the 3q26 region, increased PIK3CA copy number (FISH) and a PI3K activation score (all P < 0.05).

Conclusions: High pStathmin(S38) is a novel biomarker of increased tumor cell proliferation and impaired prognosis as reported here for independent cohorts of endometrial cancer and not previously shown in human cancer. Our data support a rationale for further studies exploring effects of drugs inhibiting the PI3K signaling pathway in pStathmin(S38)-high endometrial cancer, including a potential value of pStathmin(S38) in predicting response to PI3K/mTOR/HSP90 inhibitors. Clin Cancer Res; 19(9); 2331–41. ©2013 AACR.
Inhibition of Wee1, AKT, and CDK4 Underlies the Efficacy of the HSP90 Inhibitor XL888 in an In Vivo Model of NRAS-Mutant Melanoma
Authors: Haarberg H. Eirik , Paraiso Kim H.T. , Wood Elizabeth , Rebecca Vito W. , Sondak Vernon K. , Koomen John M. , Smalley Keiran S.M.
Published: March 2013

The HSP90 inhibitor XL888 is effective at reversing BRAF inhibitor resistance in melanoma, including that mediated through acquired NRAS mutations. The present study has investigated the mechanism of action of XL888 in NRAS-mutant melanoma. Treatment of NRAS-mutant melanoma cell lines with XL888 led to an inhibition of growth, G2–M phase cell-cycle arrest, and the inhibition of cell survival in three-dimensional spheroid and colony formation assays. In vitro, HSP90 inhibition led to the degradation of ARAF, CRAF, Wee1, Chk1, and cdc2 and was associated with decreased mitogen-activated protein kinase (MAPK), AKT, mTOR, and c-jun NH2 kinase (JNK) signaling. Apoptosis induction was associated with increased BIM expression and a decrease in the expression of the prosurvival protein Mcl-1. The critical role of increased BIM and decreased Mcl-1 expression in the survival of NRAS-mutant melanoma cell lines was shown through siRNA knockdown and overexpression studies. In an animal xenograft model of NRAS-mutant melanoma, XL888 treatment led to reduced tumor growth and apoptosis induction. Important differences in the pattern of client degradation were noted between the in vivo and in vitro studies. In vivo, XL888 treatment led to degradation of CDK4 and Wee1 and the inhibition of AKT/S6 signaling with little or no effect observed upon ARAF, CRAF, or MAPK. Blockade of Wee1, using either siRNA knockdown or the inhibitor MK1775, was associated with significant levels of growth inhibition and apoptosis induction. Together, these studies have identified Wee1 as a key target of XL888, suggesting novel therapeutic strategies for NRAS-mutant melanoma. Mol Cancer Ther; 12(6); 901–12. ©2013 AACR.
ERK and AKT Signaling Drive MED1 Overexpression in Prostate Cancer in Association with Elevated Proliferation and Tumorigenicity
Authors: Jin Feng , Irshad Shazia , Yu Wei , Belakavadi Madesh , Chekmareva Marina , Ittmann Michael M. , Abate-Shen Cory , Fondell Joseph D.
Published: March 2013

MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.

Visual Overview: http://mcr.aacrjournals.org/content/11/7/736/F1.large.jpg.

Mol Cancer Res; 11(7); 736–47. ©2013 AACR.
Oncogenic MUC1-C Promotes Tamoxifen Resistance in Human Breast Cancer
Authors: Kharbanda Akriti , Rajabi Hasan , Jin Caining , Raina Deepak , Kufe Donald
Published: March 2013

Tamoxifen resistance of estrogen receptor-positive (ER+) breast cancer cells has been linked in part to activation of receptor tyrosine kinases, such as HER2, and the PI3K-AKT pathway. Mucin 1 (MUC1) is aberrantly overexpressed in about 90% of human breast cancers, and the oncogenic MUC1-C subunit is associated with ERα. The present studies using HER2 overexpressing BT-474 breast cancer cells, which are constitutively resistant to tamoxifen, demonstrate that silencing MUC1-C is associated with (i) downregulation of p-HER2 and (ii) sensitivity to tamoxifen-induced growth inhibition and loss of clonogenic survival. In contrast, overexpression of MUC1-C in tamoxifen-sensitive MCF-7 breast cancer cells resulted in upregulation of p-AKT and tamoxifen resistance. We show that MUC1-C forms complexes with ERα on the estrogen-responsive promoter of Rab31 and that MUC1-C blocks tamoxifen-induced decreases in ERα occupancy. MUC1-C also attenuated tamoxifen-induced decreases in (i) recruitment of the coactivator CREB binding protein, (ii) Rab31 promoter activation, and (iii) Rab31 mRNA and protein levels. The importance of MUC1-C is further supported by the demonstration that targeting MUC1-C with the cell-penetrating peptide inhibitor, GO-203, sensitized tamoxifen-resistant cells to tamoxifen treatment. Moreover, we show that targeting MUC1-C in combination with tamoxifen is highly synergistic in the treatment of tamoxifen-resistant breast cancer cells. Combined, these findings indicate that MUC1-C contributes to tamoxifen resistance. Mol Cancer Res; 11(7); 714–23. ©2013 AACR.
Essential Role of SH3-domain GRB2-like 3 for Vascular Lumen Maintenance in Zebrafish
Authors: Zhao Yan , Lin Shuo
Published: March 2013

Objective—

Studying the underlying molecular mechanisms for maintaining stereotyped vascular lumen diameters should help toward a comprehensive understanding of vascular homeostasis and function. We aimed to determine the role of SH3-domain GRB2-like 3 (Sh3gl3) and its interacting pathways in dorsal aorta (DA) maintenance in zebrafish.

Approach and Results—

Sh3gl3 and its binding partner, Cbl-interacting protein of 85K (Cin85), together regulate endocytosis and were expressed in the developing vasculature. Morpholino knockdown of either gene resulted in shrinkage of the DA lumen, although artery/vein specification and the initial formation of vascular lumens were unaffected. In addition,
sh3gl3
and
cin85
morpholinos exerted a synergistic effect in causing the vascular phenotypes. To identify the signaling pathways in which Sh3gl3/Cin85 may participate, we screened several candidate inhibitors for their ability to induce similar circulatory defects. Chemical inhibition of the epidermal growth factor receptor and the phosphatidylinositol 3-kinase/Akt cascade led to a loss of circulation and shrunken DA in zebrafish embryos. Furthermore, inhibition of the epidermal growth factor receptor/phosphatidylinositol 3-kinase pathway showed a functional cooperation with Sh3gl3 deficiency in impairing DA lumens.

Conclusions—

These results identify 2 new factors, Sh3gl3 and Cin85, which are essential for DA lumen maintenance, and suggest that endocytosis, possibly involving epidermal growth factor receptor and phosphatidylinositol 3-kinase, is implicated in Sh3gl3/Cin85 function.
Liver Kinase B1 Is Required for Thromboxane Receptor-Dependent Nuclear Factor-κB Activation and Inflammatory Responses
Authors: He Jinlong , Zhou Yanhong , Xing Junjie , Wang Qilong , Zhu Huaiping , Zhu Yi , Zou Ming-Hui
Published: March 2013

Objective—

Thromboxane A
2
receptor (TPr) has been reported to trigger vascular inflammation. Nuclear factor κ B (NF-κB) is a known transcription factor. The aims of the present study were to determine the contributions of NF-κB activation to TPr-triggered vascular inflammation and elucidate the mechanism(s) underlying TPr activation of NF-κB.

Approach and Results—

The effects of TPr activators, [1S-[1alpha,2alpha(Z),3beta(1E,3S*), 4alpha]]-7-[3-[3-hydroxy-4-(4-iodophenoxy)-1-butenyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (I-BOP) and U46619, on NF-κB activation, phosphorylation of rhoA/rho-associated kinases and liver kinase B1, cell adhesion and migration, proliferation, and endothelium-dependent vasorelaxation were assayed in cultured human umbilical vein endothelial cells, human monocytes, or isolated mouse aortas. Exposure of human umbilical vein endothelial cells to TPr agonists I-BOP and U46619 induced dose-dependent and time-dependent phosphorylation of inhibitor of κB α in parallel with aberrant expression of inflammatory markers cyclooxygenase-2, inducible nitric oxide synthase, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1. Inhibition of NF-κB by pharmacological or genetic means abolished TPr-triggered expression of inflammatory markers. Consistently, exposure of human umbilical vein endothelial cells to either I-BOP or U46619 significantly increased phosphorylation of inhibitor of κB α, IkappaB kinase, rhoA, rho-associated kinases, and liver kinase B1. Pretreatment of human umbilical vein endothelial cells with the TPr antagonist SQ29548 or rho-associated kinases inhibitor Y27632 or silencing of the LKB1 blocked TPr-enhanced phosphorylation of inhibitor of κB α and its upstream kinase, IkappaB kinase. Finally, exposure of isolated mouse aortas to either U46619 or I-BOP enhanced NF-κB activation and vascular inflammation in parallel with reduced endothelium-dependent relaxation in intact vessels.

Conclusions—

TPr stimulation instigates aberrant inflammation and endothelial dysfunction via rho-associated kinases/liver kinase B1/IkappaB kinase-dependent NF-κB activation in vascular endothelial cells.
Fluorescence Tomography of Rapamycin-Induced Autophagy and Cardioprotection In Vivo
Authors: Chen Howard H. , Mekkaoui Choukri , Cho Hoonsung , Ngoy Soeun , Marinelli Brett , Waterman Peter , Nahrendorf Matthias , Liao Ronglih , Josephson Lee , Sosnovik David E.
Published: March 2013

Background—

Autophagy is a biological process during which cells digest organelles in their cytoplasm and recycle the constituents. The impact of autophagy in the heart, however, remains unclear in part because of the inability to noninvasively image this process in living animals.

Methods and Results—

Here, we report the use of fluorescence molecular tomography and a cathepsin-activatable fluorochrome to image autophagy in the heart in vivo after ischemia/reperfusion and rapamycin (RAP) therapy. We show that cathepsin-B activity in the lysosome is upregulated by RAP and that this allows the expanded lysosomal compartment in autophagy to be imaged in vivo with fluorescence molecular tomography. We further demonstrate that the delivery of diagnostic nanoparticles to the lysosome by endocytosis is enhanced during autophagy. The upregulation of autophagy by RAP was associated with a 23% reduction (
P
<0.05) of apoptosis in the area at risk and a 45% reduction in final infarct size (19.6±5.6% of area at risk with RAP versus 35.9±9.1% of area at risk without RAP;
P
<0.05).

Conclusions—

The ability to perform noninvasive tomographic imaging of autophagy in the heart has the potential to provide valuable insights into the pathophysiology of autophagy, particularly its role in cardiomyocyte salvage. Although additional data are needed, our study supports the investigation of RAP therapy in patients with acute coronary syndromes.
Berlin Heart EXCOR Pediatric Ventricular Assist Device for Bridge to Heart Transplantation in US Children
Authors: Almond Christopher S. , Morales David L. , Blackstone Eugene H. , Turrentine Mark W. , Imamura Michiaki , Massicotte M. Patricia , Jordan Lori C. , Devaney Eric J. , Ravishankar Chitra , Kanter Kirk R. , Holman William , Kroslowitz Robert , Tjossem Christine , Thuita Lucy , Cohen Gordon A. , Buchholz Holger , St. Louis James D. , Nguyen Khanh , Niebler Robert A. , Walters Henry L. , Reemtsen Brian , Wearden Peter D. , Reinhartz Olaf , Guleserian Kristine J. , Mitchell Max B. , Bleiweis Mark S. , Canter Charles E. , Humpl Tilman
Published: March 2013

Background—

Recent data suggest that the Berlin Heart EXCOR Pediatric ventricular assist device is superior to extracorporeal membrane oxygenation for bridge to heart transplantation. Published data are limited to 1 in 4 children who received the device as part of the US clinical trial. We analyzed outcomes for all US children who received the EXCOR to characterize device outcomes in an unselected cohort and to identify risk factors for mortality to facilitate patient selection.

Methods and Results—

This multicenter, prospective cohort study involved all children implanted with the Berlin Heart EXCOR Pediatric ventricular assist device at 47 centers from May 2007 through December 2010. Multiphase nonproportional hazards modeling was used to identify risk factors for early (<2 months) and late mortality. Of 204 children supported with the EXCOR, the median duration of support was 40 days (range, 1–435 days). Survival at 12 months was 75%, including 64% who reached transplantation, 6% who recovered, and 5% who were alive on the device. Multivariable analysis identified lower weight, biventricular assist device support, and elevated bilirubin as risk factors for early mortality and bilirubin extremes and renal dysfunction as risk factors for late mortality. Neurological dysfunction occurred in 29% and was the leading cause of death.

Conclusions—

Use of the Berlin Heart EXCOR has risen dramatically over the past decade. The EXCOR has emerged as a new treatment standard in the United States for pediatric bridge to transplantation. Three-quarters of children survived to transplantation or recovery; an important fraction experienced neurological dysfunction. Smaller patient size, renal dysfunction, hepatic dysfunction, and biventricular assist device use were associated with mortality, whereas extracorporeal membrane oxygenation before implantation and congenital heart disease were not.
“Faith(fulness) of the Son of God”? Galatians 2:20b Reconsidered
Authors: Jermo van Nes
Published: March 2013

Abstract

For more than a century, contributors to the πίστις Χριστοῦ debate have focused primarily on the linguistic and theological issues involved without recognizing the potential relevance of a text-critical variant of Gal 2:20b. It is argued that if preference is to be given to the variant reading ἐν πίστει ζῶ τῇ τοῦ θεοῦ καὶ Χριστοῦ as based on both external and internal evidence, its immediate context encourages an objective genitive understanding—“I live by faith in God and Christ.” As such, Gal 2:20b might offer an interpretative clue to the other πίστις Χριστοῦ expressions in the Pauline corpus.
Judaean Apocalypticism and the Unmasking of Ideology: Foreign and National Rulers in the Testament of Moses
Authors: Keddie G. Anthony
Published: March 2013

Abstract

The current study attempts to move beyond the fashionable scholarly opinion that apocalyptic literature is essentially posed “against empire” by critically analyzing the ideologies evaluated and advanced by the Testament of Moses. The author employs a theoretical framework derived from the work of the Marxist philosopher Louis Althusser to argue that the schematization of history in the Testament of Moses exposes and criticizes the domination of national rulers and foreign rulers, but for different reasons. While ideology is depicted as a strategy of domination used by both types of rulers, repressive physical violence is typically only associated with foreign domination. Yet, the text is not simply “against empire.” Rather, the ideology of the Testament of Moses is primarily opposed to the priestly ruling class of Judaea, the group thought to be responsible for the socioeconomic hardships experienced by the Judaean masses in the early first century C.E.
Galenic Medicine and Social Stability in Early Modern Florence and the Islamic Empires
Authors: Syros Vasileios
Published: March 2013

Abstract

Modern perceptions of cross-cultural encounters between Europe and the Islamic empires have centered around the differences between the European and Islamic systems of political organization in an effort to valorize Western political values and styles of rulership. The present article challenges some of the assumptions that inform scholarship on contacts between Europe and the Islamic world in the early modern period by pointing to hitherto unexplored affinities between the Florentine and Islamic traditions of political thought. In particular, it investigates the use of ancient Greek theories of the four humors/elements of the human body in an extensive corpus of writings produced by seminal political theorists, historians, and figures of intellectual and political life in early modern Florentine (Niccolò Machiavelli, Francesco Guicciardini, Donato Giannotti), Persian (Ṭūsī, Dawwānī, Kāshifī), Mughal (Khwāndamīr, Abūʾl-Fazl), and Ottoman (Kınalızâde, Kâtib Çelebi) traditions from the thirteenth to the seventeenth centuries. My analysis demonstrates that Galen’s humoral theory served the aforementioned writers as a conceptual tool for identifying the mutual dependency of the component parts of the body politic as one of the key determinants of domestic balance and harmony and for theorizing remedies against strife and friction.
The Problematic Jurisprudence on Instigation under the Statute of the ICTR: The Consistencies, Inconsistencies and Misgivings of the Trial and Appeal Chambers of the ICTR
Authors: Agbor Avitus Agbor
Published: March 2013

As affirmed by international instruments, instigation is a recognised mode of participation in international crimes. The UN Convention on the Prevention and Punishment of the Crime of Genocide made punishable the inchoate crime of direct and public incitement to commit genocide. The Statute of the International Criminal Tribunal for Rwanda (ICTR) imported this inchoate crime. Furthermore, it included instigation as a mode of participation under Article 6(1) (which would lead to the imposition of criminal responsibility for the crimes). This double appearance of instigation under the Statute of the ICTR has been problematic to both the Trial and Appeal Chambers of the ICTR. Their jurisprudence on instigation is not just flawed, but also inconsistent and does not contribute to the evolution of instigation as a mode of participation in international criminal law.
Equal treatment or equal opportunity? Male attitudes towards women in the Norwegian and US armed forces
Authors: Gustavsen Elin
Published: March 2013

This article examines men’s attitudes towards women in the Norwegian and US armed forces. The military is one of society’s most gendered institutions, and this study investigates how men in the armed forces feel about serving alongside women. Building on interviews with 34 men in the Norwegian and US air forces, the article finds that men in both countries have a positive attitude towards female service members, and that the majority prefer to serve in gender-mixed units. When discussing their attitudes on more concrete topics, however, the participants employed two different concepts of equality. The Norwegian men argued for the importance of equal treatment of men and women, while the American men thought it was more important to create equal opportunities for women in the armed forces. These different understandings are embedded in the two national cultures, which provide the men with the different cultural resources they relied on to frame their opinions.
The Influence of Institutional Logics on Corporate Responsibility Toward Employees
Authors: Westermann-Behaylo Michelle , Berman Shawn L. , Van Buren Harry J.
Published: March 2013

Focusing on corporate responsibility (CR) toward employees, this article discusses how multilayered institutional logics affect the relationship between the firm and its employee stakeholders. It considers what constitutes CR toward employees and explores the institutional logics that can shape whether employers treat their employees as merely means to a strategic end or as ends in themselves. Specifically, the article examines market-, state-, professional-, and firm-based institutional logics that influence how employers treat their employees. The conclusion suggests that external institutional logics both enable and constrain firms to adopt a more instrumental relationship with their employees. However, some forms of organizational identity may generate firm-based institutional logics that enable firms to resist these pressures. Suggestions for future research focusing on the institutional and organizational drivers behind understanding CR toward employees are offered.
Advanced BMP Gene Therapies for Temporal and Spatial Control of Bone Regeneration
Authors: Wilson C.G. , Martín-Saavedra F.M. , Vilaboa N. , Franceschi R.T.
Published: March 2013

Spatial and temporal patterns of bone morphogenetic protein (BMP) signaling are crucial to the assembly of appropriately positioned and shaped bones of the face and head. This review advances the hypothesis that reconstitution of such patterns with cutting-edge gene therapies will transform the clinical management of craniofacial bone defects attributed to trauma, disease, or surgical resection. Gradients in BMP signaling within developing limbs and orofacial primordia regulate proliferation and differentiation of mesenchymal progenitors. Similarly, vascular and mesenchymal cells express BMPs in various places and at various times during normal fracture healing. In non-healing fractures of long bones, BMP signaling is severely attenuated. Devices that release recombinant BMPs promote healing of bone in spinal fusions and, in some cases, of open fractures, but cannot control the timing and localization of BMP release. Gene therapies with regulated expression systems may provide substantial improvements in efficacy and safety compared with protein-based therapies. Synthetic gene switches, activated by pharmacologics or light or hyperthermic stimuli, provide several avenues for the non-invasive regulation of the expression of BMP transgenes in both time and space. Through new gene therapy platforms such as these, active control over BMP signaling can be achieved to accelerate bone regeneration.
Nonalcoholic Fatty Liver Disease
Authors: Li Ding‐You , Yang Min , Edwards Sarah , Ye Shui‐Qing
Published: March 2013

Nonalcoholic fatty liver disease (NAFLD) is a major clinical consequence for people with obesity and metabolic syndrome and is also associated with enteral and parenteral nutrition. Early studies suggested that altered gut microbiota might contribute to obesity by affecting energy harvest from the diet and energy storage in the host. Recent evidence in humans as well as in animal models has linked gut microbiota to the development of NAFLD through the gut‐liver axis. With bacterial overgrowth and increased intestinal permeability observed in patients with NAFLD and in animal models, gut‐derived bacterial products such as endotoxin (lipopolysaccharide) and bacterial DNA are being delivered to the liver through the portal vein and then activate Toll‐like receptors (TLRs), mainly TLR4 and TLR9, and their downstream cytokines and chemokines, leading to the development and progression of NAFLD. Given the limited data in humans, the role of gut microbiota in the pathogenesis of NAFLD is still open to discussion. Prebiotics and probiotics have been attempted to modify the microbiota as preventive or therapeutic strategies on this pathological condition. Their beneficial effects on NALFD have been demonstrated in animal models and limited human studies. However, prospective, appropriately powered, randomized, controlled clinical trials are needed to determine whether prebiotics and probiotics and other integrated strategies to modify intestinal microbiota are efficacious therapeutic modalities to treat NALFD.
Prognostic value of epidermal growth factor receptor, p53 and galectin-3 expression in papillary thyroid carcinoma
Authors: Lee Yu Mi , Lee Jae Bok
Published: March 2013

Objective

The aim of this study was to determine the protein expression and prognostic value of epidermal growth factor receptor (EGFR), p53 and galectin-3 in papillary thyroid carcinoma (PTC).

Methods

A retrospective analysis was performed using tumour specimens from patients with PTC who underwent thyroidectomy between July 2007 and December 2008. The percentages of tumour cells staining positively for EGFR, galectin-3 and p53 were determined by immunohistochemistry. Associations between protein expression and age, sex, extrathyroidal extension and lymph node metastasis were assessed, together with the total Metastasis, Age, Completeness of resection, Invasion, Size (MACIS) score (a marker of prognosis). MACIS prognostic scores were categorized into four groups.

Results

Data from 168 patients with PTC (mean follow-up, 35 months) were included. EGFR expression was significantly associated with male sex and lymph node metastasis; p53 expression was higher in males than in females; galectin-3 expression was not significantly associated with age, sex, extrathyroidal extension, lymph node metastasis or total MACIS score category, however.

Conclusion

Immunohistochemical evaluation of EGFR and p53 expression in patients with PTC may be useful for determining prognosis, in PTC patients.
Decolonizing Bourdieu
Authors: Go Julian
Published: March 2013

While new scholarship on Pierre Bourdieu has recovered his early work on Algeria, this essay excavates his early thoughts on colonialism. Contrary to received wisdom, Bourdieu did in fact offer a theory of colonialism and a systematic understanding of its effects and logics. Bourdieu portrayed colonialism as a racialized system of domination, backed by force, which restructures social relations and creates hybrid cultures. His theory entailed insights on the limits and promises of colonial reform, anticolonial revolution, and postcolonial liberation. Bourdieu’s early thinking on colonialism drew upon but extended French colonial studies of the time. It also contains the seeds of later concepts like habitus, field, and reflexive sociology while prefiguring more recent disciplinary postcolonial studies. Bourdieusian sociology in this sense originates not just as a study of Algeria but more specifically a critique of colonialism. It can be seen as contributing to the larger project of postcolonial sociology.
The Thickness of Musical Pitch
Authors: Dolscheid Sarah , Shayan Shakila , Majid Asifa , Casasanto Daniel
Published: March 2013

Do people who speak different languages think differently, even when they are not using language? To find out, we used nonlinguistic psychophysical tasks to compare mental representations of musical pitch in native speakers of Dutch and Farsi. Dutch speakers describe pitches as high ( hoog) or low ( laag), whereas Farsi speakers describe pitches as thin ( na-zok) or thick ( koloft). Differences in language were reflected in differences in performance on two pitch-reproduction tasks, even though the tasks used simple, nonlinguistic stimuli and responses. To test whether experience using language influences mental representations of pitch, we trained native Dutch speakers to describe pitch in terms of thickness, as Farsi speakers do. After the training, Dutch speakers’ performance on a nonlinguistic psychophysical task resembled the performance of native Farsi speakers. People who use different linguistic space-pitch metaphors also think about pitch differently. Language can play a causal role in shaping nonlinguistic representations of musical pitch.
The Experience of HIV Diagnosis Among Aboriginal People Living With HIV/AIDS and Depression
Authors: Cain Roy , Jackson Randy , Prentice Tracey , Collins Evan , Mill Judy , Barlow Kevin
Published: March 2013

In this article, we consider how the broad context of Aboriginal people’s lives can shape their experience and understanding of their HIV diagnosis. We conducted interviews across Canada with 72 Aboriginal people living with HIV who also reported feelings of depression. Consistent with what has been found in previous studies, participants responded to their HIV diagnosis with shock, disbelief, and often anger. Prior depression, drug and alcohol use, multiple losses, stigma, and social isolation also shaped how participants experienced their diagnosis. We consider how the history of colonization of Aboriginal communities in Canada relates to the experience of HIV diagnosis, and end with a discussion of the service implications of our findings.
Already on the Shelf
Authors: Ryan Caitlin L. , Hermann-Wilmarth Jill M.
Published: March 2013

This essay explores what it might mean to read children’s literature in elementary school classrooms through a queer lens. The authors argue that because queer theory has a history as a literary theory that destabilizes normative associations among gender, sexuality, bodies, and desire, it provides a set of analytical tools classroom communities can draw on to create alternative readings of a wide range of familiar texts. Such readings of books already on the shelves of elementary school libraries and classrooms can highlight experiences and subjectivities of nonnormative sexualities and gender identities in the hopes of making classrooms more inclusive. Specifically, we argue that four high-quality, award-winning children’s books already included in many schools and classrooms—Sendak’s (1963) Where the Wild Things Are, Woodson’s (2001) The Other Side, DiCamillo’s (2003) Tale of Despereaux, and Patterson’s (1977) Bridge to Terabithia—can be fruitful sites for opening up these more inclusive readings and conversations. The article offers possible queer readings of these texts as well as suggestions for how to encourage elementary-aged students to think about both books and the socially constructed norms of real life through a queered lens. By first queering on-the-shelf texts and then asking students to think about how that queering connects to larger social issues, elementary classrooms can become places where strict identity categories—categories that can marginalize queer students and families—are made visible, are questioned, are stretched, and can even fall apart.