bluuebunny/crossref_metadata_2025 huggingface dataset:
Human Suppressor of Cytokine Signaling 1 Controls Immunostimulatory Activity of Monocyte-Derived Dendritic Cells
Authors: Hong Bangxing , Ren Wenhong , Song Xiao-Tong , Evel-Kabler Kevin , Chen Si-Yi , Huang Xue F.
Published: September 2009

Dendritic cell (DC)–based tumor vaccines have only achieved limited clinical efficacy, underscoring the limitation of stimulatory strategies to elicit effective cytotoxic T lymphocyte (CTL) responses against self-tumor–associated antigens. Here, we investigate the role of human suppressor of cytokine signaling 1 (SOCS1), a feedback inhibitor of the Janus-activated kinase/signal transducer and activator of transcription signaling pathway, in regulating antigen presentation by human DCs (hDC). We find that human SOCS1 (hSOCS1)–silenced DCs have an enhanced stimulatory ability to prime self-antigen–specific CTLs in vitro and in a severe combined immunodeficient-hu mouse model. Human CTLs activated by SOCS1-silenced DCs, but not wild-type DCs, have an active lytic activity to natural antigen-expressing tumor cells. We further find that the capacity of hDCs to prime CTLs is likely controlled by SOCS1-restricted production and signaling of proinflammatory cytokines, such as interleukin-12. These results indicate a critical role of hSOCS1 in negatively regulating the immunostimulatory capacity of DCs and imply a translational potential of this alternative SOCS1 silencing strategy to develop effective DC vaccines. [Cancer Res 2009;69(20):8076–84]
Extracellular Signal-Regulated Kinase Positively Regulates the Oncogenic Activity of MCT-1 in Diffuse Large B-Cell Lymphoma
Authors: Dai Bojie , Zhao X. Frank , Hagner Patrick , Shapiro Paul , Mazan-Mamczarz Krystyna , Zhao Shuchun , Natkunam Yasodha , Gartenhaus Ronald B.
Published: September 2009

The MCT-1 oncogene was originally identified from lymphoma cell lines. Herein we establish that MCT-1 is highly expressed in 85% of human diffuse large B-cell lymphomas (DLBCL) and that knocking down MCT-1 by a specific short hairpin RNA in DLBCL cells induces apoptosis, supporting a critical role for MCT-1 in DLBCL cell survival. However, the mechanism underlying MCT-1 regulation is largely unknown. We find that MCT-1 is phosphorylated and up-regulated by extracellular signal-regulated kinase (ERK). Furthermore, by using a small inhibitory molecule targeting ERK, we interrupted MCT-1 phosphorylation and stability. Significantly, cells with distinct levels of MCT-1 protein displayed differential sensitivity to ERK inhibitor–induced apoptosis. Treatment with the ERK inhibitor showed marked in vivo antitumor activity in a human DLBCL xenograft model. Our findings establish a functional molecular interaction between MCT-1 and the MEK/ERK signaling pathway and suggest that the activation of MCT-1 function by its upstream kinase ERK plays an important role in lymphomagenesis. [Cancer Res 2009;69(19):7835–43]
RAS Mutations Affect Tumor Necrosis Factor–Induced Apoptosis in Colon Carcinoma Cells via ERK-Modulatory Negative and Positive Feedback Circuits Along with Non-ERK Pathway Effects
Authors: Kreeger Pamela K. , Mandhana Roli , Alford Shannon K. , Haigis Kevin M. , Lauffenburger Douglas A.
Published: September 2009

More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-α (TNFα)–induced apoptosis. When the dynamics of phosphorylated ERK response to TNFα were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-α. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-α autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNFα treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence. [Cancer Res 2009;69(20):8191–9]
Proinflammatory Mediators Upregulate Snail in Head and Neck Squamous Cell Carcinoma
Authors: St. John Maie A. , Dohadwala Mariam , Luo Jie , Wang Guanyu , Lee Gina , Shih Hubert , Heinrich Eileen , Krysan Kostantyn , Walser Tonya , Hazra Saswati , Zhu Li , Lai Chi , Abemayor Elliot , Fishbein Michael , Elashoff David A. , Sharma Sherven , Dubinett Steven M.
Published: September 2009

Purpose: Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1β (IL-1β) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC.

Experimental Design: We evaluated the effect of IL-1β on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model was used to assess the effects of Snail overexpression.

Results: Cyclooxygenase-2 (COX-2)-dependent pathways contribute to the modulation of E-cadherin expression in HNSCC. An inverse relationship between COX-2 and E-cadherin was shown in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL-1β caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 small hairpin RNA. IL-1β–treated HNSCC cell lines showed a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1β exposure led to enhanced Snail binding at the chromatin level. Small hairpin RNA–mediated knockdown of Snail interrupted the capacity of IL-1β to downregulate E-cadherin. In a SCID xenograft model, HNSCC Snail-overexpressing cells showed significantly increased primary and metastatic tumor burdens.

Conclusions: IL-1β modulates Snail and thereby regulates COX-2–dependent E-cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy. (Clin Cancer Res 2009;15(19):6018–27)
Associations of a Polymorphism in the Ornithine Decarboxylase Gene with Colorectal Cancer Survival
Authors: Zell Jason A. , Ziogas Argyrios , Ignatenko Natalia , Honda Jane , Qu Ning , Bobbs Alexander S. , Neuhausen Susan L. , Gerner Eugene W. , Anton-Culver Hoda
Published: September 2009

Purpose: Activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is required for normal growth and is elevated in many cancers, including colorectal cancer. We examined associations of the +316 ODC1 single nucleotide polymorphism (SNP) with colorectal cancer–specific survival among colorectal cancer cases, and then investigated its functional significance in colon cancer cells.

Experimental Design: The study included 400 incident stage I-III colorectal cancer cases from the population-based University of California Irvine Gene-Environment Study of Familial Colorectal Cancer (diagnosed from 1994 to 1996 with follow-up through March 2008). The primary outcome was colorectal cancer–specific survival dependent on ODC1 (rs2302615) genotype (GG versus GA/AA). In human colon cancer cell lines, ODC1 allele-specific binding of E-box transcription factors was determined via Western blotting and chromatin immunoprecipitation assays. ODC1 allele-specific promoter activity was determined using promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MAD1.

Results: Genotype-specific survival differences were observed among colorectal cancer cases: compared with cases with the ODC1 GG genotype (hazards ratio, 1; reference) the adjusted colorectal cancer–specific survival hazards ratio was 2.02 (95% confidence interval, 1.17-3.50) for ODC1 GA/AA cases (P = 0.012). In colon cancer cells, the ODC1 SNP, flanked by two E-boxes, predicts ODC1 promoter activity. The E-box activator c-MYC and repressors MAD1 and MAD4 preferentially bind to ODC1 minor A-alleles, compared with major G-alleles, in cultured cells.

Conclusions: These results have implications for conditional regulation of polyamine homeostasis and suggest a model in which the ODC1 SNP may be protective for colon adenoma recurrence and detrimental for survival after colon cancer diagnosis. (Clin Cancer Res 2009;15(19):6208–16)
Lymph Node–Targeted Immunotherapy Mediates Potent Immunity Resulting in Regression of Isolated or Metastatic Human Papillomavirus–Transformed Tumors
Authors: Smith Kent A. , Meisenburg Brenna L. , Tam Victor L. , Pagarigan Robb R. , Wong Raymond , Joea Diljeet K. , Lantzy Liz , Carrillo Mayra A. , Gross Todd M. , Malyankar Uriel M. , Chiang Chih-Sheng , Da Silva Diane M. , Kündig Thomas M. , Kast W. Martin , Qiu Zhiyong , Bot Adrian
Published: September 2009

Purpose: The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic human papillomavirus 16–transformed murine tumors.

Experimental Design: Animals bearing E7-expressing tumors were coimmunized by lymph node injection with E7 49-57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and antitumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease.

Results: In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen–specific T lymphocytes in the range of 1/10 CD8+ T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with antitumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T-cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization.

Conclusions: This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells. (Clin Cancer Res 2009;15(19):6167–76)
Blockade of MGMT Expression by O6 Benzyl Guanine Leads to Inhibition of Pancreatic Cancer Growth and Induction of Apoptosis
Authors: Konduri Santhi D. , Ticku Jonathan , Bobustuc George C. , Sutphin Robert M. , Colon Jimmie , Isley Beth , Bhakat Kishor K. , Kalkunte Srivenugopal S. , Baker Cheryl H.
Published: September 2009

Purpose: We sought to determine whether administration of a MGMT blocker, O6-benzyl guanine (O6BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth.

Experimental Design: Human pancreatic cancer L3.6pl and PANC1 cells were treated with O6BG, either alone or in combination with gemcitabine, and the therapeutic efficacy and biological activity of these drug combinations were investigated.

Results: O6BG sensitized pancreatic cancer cells to gemcitabine. Protein and mRNA expression of MGMT, cyclin B1, cyclin B2, cyclin A, and ki-67 were significantly decreased in the presence of O6BG. In sharp contrast, protein expression and mRNA message of p21cip1 were significantly increased. Interestingly, O6BG increases p53-mediated p21cip1 transcriptional activity and suppresses cyclin B1. In addition, our results indicate that p53 is recruited to p21 promoter. Furthermore, an increase in p21cip1 and a decrease in cyclin transcription are p53 dependent. The volume of pancreatic tumors was reduced by 27% in mice treated with gemcitabine alone, by 47% in those treated with O6BG alone, and by 65% in those mice given combination. Immunohistochemical analysis showed that O6BG inhibited expression of MGMT and cyclins, and increased expression of p21cip1. Furthermore, there was a significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis.

Conclusions: Collectively, our results show that decreased MGMT expression is correlated with p53 activation, and significantly reduced primary pancreatic tumor growth. These findings suggest that O6BG either alone or in combination with gemcitabine may provide a novel and effective approach for the treatment of human pancreatic cancer. (Clin Cancer Res 2009;15(19):6087–95)
Rapid Development of Hypertension by Sorafenib: Toxicity or Target?
Authors: Humphreys Benjamin D. , Atkins Michael B.
Published: September 2009

Blood pressure elevation is likely a pharmacodynamic marker of VEGF signaling pathway (VSP) inhibition and could be useful for optimizing safe and effective VSP inhibitor dosing. Blood pressure rises on the first day of treatment, facilitating design and interpretation of future trials aiming to correlate blood pressure changes with clinical outcomes. (Clin Cancer Res 2009;15(19):5947–9)
Oltipraz and dithiolethione congeners inhibit hypoxia-inducible factor-1α activity through p70 ribosomal S6 kinase-1 inhibition and H2O2-scavenging effect
Authors: Lee Woo Hyung , Kim Young Woo , Choi Jae Hoon , Brooks Samuel Carroll , Lee Mi-Ock , Kim Sang Geon
Published: September 2009

Hypoxia-inducible factor-1α (HIF-1α) induces tumor proliferation, angiogenesis and metastasis. Reactive oxygen species, hypoxia, and growth factor stimulation induce HIF-1α, and the augmented HIF-1α activity confers upon cancer cells the ability to adapt to microenvironments. Oltipraz is a cancer chemopreventive agent and has an inhibitory effect on angiogenesis and tumor growth. Nonetheless, the molecular mechanism of tumor inhibition is as yet unclear. This study investigated whether oltipraz and its congeners inhibit HIF-1α activity and, if so, the molecular basis of inhibition. Oltipraz and other 1,2-dithiole-3-thiones have the ability to prevent insulin- or hypoxia-induced HIF-1α expression through an increase in ubiquitination, thereby accelerating HIF-1α degradation and inhibiting HIF-1α–dependent gene transcription. Transfection of cells with a constitutively active mutant of p70 ribosomal S6 kinase-1 (CA-S6K1) increased the basal and insulin-inducible HIF-1α activity. CA-S6K1 overexpression reversed HIF-1α inhibition by rapamycin (a mammalian target of rapamycin/S6K1 inhibitor). However, the inhibitory effect of oltipraz on HIF-1α was not reversed by CA-S6K1 despite its S6K1 inhibition. The failure of dominant negative mutant AMP-activated protein kinase-α to restore the ability of insulin to increase HIF-1α against oltipraz excluded the possible role of AMP-activated protein kinase activation in the action of oltipraz. Oltipraz treatment abrogated insulin-induced H2O2 production, thereby preventing H2O2-enhanced HIF-1α expression and promoting its ubiquitination and degradation. In an animal model, tumor regression by oltipraz was accompanied by decreases in microvessel density and vascular endothelial growth factor induction. Oltipraz inhibits HIF-1α activity and HIF-1α–dependent tumor growth, which may result from a decrease in HIF-1α stability through S6K1 inhibition in combination with an H2O2-scavenging effect. [Mol Cancer Ther 2009;8(10):2791–802]
Pharmacokinetics-pharmacodynamics and antitumor activity of mercaptoacetamide-based histone deacetylase inhibitors
Authors: Konsoula Zacharoula , Cao Hong , Velena Alfredo , Jung Mira
Published: September 2009

Structurally diverse histone deacetylase inhibitors (HDACI) have emerged as chemotherapeutic agents. Here, we report the first mercaptoacetamide HDACIs (coded 6MAQH and 5MABMA) for use in treatment against prostate cancer cells in vitro and in vivo and correlate their plasma pharmacokinetics and tissue-pharmacodynamics with tumor sensitivity. HDACIs were assessed for in vitro microsomal stability and growth inhibition against prostate cancer and nonmalignant cells. Antitumor activity was determined following i.p. administration of 6MAQH and 5MABMA (0.5 and 5 mg/Kg) using mice bearing PC3 tumor xenografts (n = 10). The plasma pharmacokinetics of 6MAQH and 5MABMA and their effects on the acetylation of histone H4 in tissues were determined in athymic mice. Both HDACIs significantly inhibited the growth of cancer cells while exerting limited effect on nonmalignant cells. They exhibited stability in human, dog, and rat microsomes [t1/2 (min) = 83, 72, and 66 for 6MAQH and 68, 43, and 70 for 5MABMA, respectively]. Both HDACIs (0.5 mg/Kg) led to tumor regression (P < 0.01), which was sustained for at least 60 days. In vivo data show favorable plasma pharmacokinetics with the area under the curve of 4.97 ± 0.6 μmol/L × h for 6MAQH and 4.23 ± 0.43 μmol/L × h for 5MABMA. The clearance rates for 6MAQH and 5MABMA were 4.05 ± 0.15 and 4.87 ± 0.2 L/h, whereas the half-lives were 2.2 ± 0.33 and 1.98 ± 0.21 h, respectively. Both HDACIs markedly enhanced the acetylation of histone H4 within 30 minutes in tissues, including the brain, liver, and spleen. Taken together, the results provide a rationale for further investigation of these mercaptoacetamide HDACIs as potent anticancer agents. [Mol Cancer Ther 2009;8(10):2844–51]
A Model of Gene-Environment Interaction Reveals Altered Mammary Gland Gene Expression and Increased Tumor Growth following Social Isolation
Authors: Williams J. Bradley , Pang Diana , Delgado Bertha , Kocherginsky Masha , Tretiakova Maria , Krausz Thomas , Pan Deng , He Jane , McClintock Martha K. , Conzen Suzanne D.
Published: September 2009

Clinical studies have revealed that social support improves the outcome of cancer patients, whereas epidemiologic studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise molecular consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible preclinical models are needed to study the mechanisms whereby an adverse environment affects gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a preclinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the premalignant mammary gland. Chronic social isolation was associated with up-regulated lipid synthesis and glycolytic pathway gene expression—both pathways are known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes in premalignant mammary tissue, isolated mice subsequently developed a significantly larger mammary gland tumors burden compared with group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared with group-housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways gene expression favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g., fatty acid synthesis) for preventive intervention in breast cancer.
Positive Feedback Loop between Plasminogen Activator Inhibitor-1 and Transforming Growth Factor-Beta1 during Renal Fibrosis in Diabetes
Authors: Seo Ji Yeon , Park Jehyun , Yu Mi Ra , Kim Yu Seun , Ha Hunjoo , Lee Hi Bahl
Published: September 2009

Background/Aims: Plasminogen activator inhibitor (PAI)-1 is increasingly recognized as a profibrotic factor but the mechanisms are not entirely clear. The present study examined the profibrotic mechanism of PAI-1 focusing on its effect on transforming growth factor (TGF)-β1 in experimental diabetes. Methods: PAI-1 knockout (KO) mesangial cells cultured under high glucose (HG) in addition to streptozotocin-induced diabetic PAI-1 KO mice were used. Results: PAI-1 deficiency did not affect plasma glucose significantly but reduced the fractional mesangial area, fibronectin and collagen I expression in the renal cortex after 20 weeks of diabetes as well as in HG-stimulated mesangial cells along with suppression of TGF-β1 mRNA expression. PAI-1 deficiency also reduced HG-induced βig-h3, a TGF-β1-induced gene product, mRNA expression. All these losses-of-function in PAI-1 KO mesangial cells were effectively gained by recombinant PAI-1. Recombinant PAI-1-induced fibronectin and collagen I expression was abrogated by TGF-β1 receptor inhibitor or anti-TGF-β antibody suggesting that the effect of PAI-1 was mediated by TGF-β1. In a similar context, recombinant PAI-1 stimulated TGF-β1 promoter activity to the same extent as TGF-β1 itself. Conclusion: Since TGF-β1 is well known to stimulate the PAI-1 promoter, we suggest that TGF-β1 and PAI-1 together constitute a positive feedback loop in the development of renal fibrosis in diabetes.
A Protein That Inhibits Surfactant in Respiratory Distress Syndrome
Authors: Ikegami Machiko , Jobe Alan , Berry David
Published: September 2009

A protein that interferes with surfactant function is present in the airways and alveoli of infants with respiratory distress syndrome (RDS). This inhibitor is also found in serum and amniotic fluid and presumably appears in the alveoli because of the abnormal protein leak present in the lungs of infants with RDS. This protein has a molecular weight of about 110,000 and is resistant to boiling or lipid extraction. As measured by radioimmunoassay, the ratio of inhibitor to phosphatidylcholine decreased from 8.1 ± 2.3 early in the course of RDS to 0.7 ± 0.1 on the day of extubation. The value at extubation was the same as that measured for preterm infants without RDS. The inhibitor to phosphatidylcholine ratio in airway samples from infants with RDS correlated significantly with simultaneously recorded PO2/FiO2 ratios and the peak inspiratory pressures used to normalized pCO2 values. These results are consistent with the concept that the inhibitor contributes to surfactant dysfunction and thus the respiratory failure characteristic of RDS.
Postprandial Glucose and Insulin Responses to Glucose Polymers by Premature Infants
Authors: Tucker Neil T. , Hodge Charles , Choi Tai-Soon , Lee Ping-Cheung , Prihoda Thomas J. , Lebenthal Emanuel
Published: September 2009

Previous studies have questioned whether neonatal infants can digest and absorb glucose polymers (GP). Thirteen infants of 33–42 weeks of corrected gestational age were fed two glucose polymers with different dextrose equivalents (DE) and glucose. Postprandial glucose and insulin responses were measured consecutively after each feeding. At 60 min, glucose, glucose polymer DE 15 and glucose polymer DE 24 produced serum glucose responses of 138.1, 111.6 and 120 mg/100 ml, respectively. Differences in mean serum glucose and insulin levels were found when glucose or glucose polymers were used as the test carbohydrate. Glucose polymer DE 24 produced a hormonal response closer to that of glucose. This suggests that glucose polymers were hydrolyzed and absorbed and evoked a sufficient glucose and insulin response. Therefore, these glucose polymers would seem to be suitable for use in feeding neonatal infants.
Effect of a Popular Chinese Herb on Neonatal Bilirubin Protein Binding
Authors: Yeung C.Y. , Lee F.T. , Wong H.N.
Published: September 2009

A study on the effects of a popular Chinese herb commonly given to newborn infants was undertaken. ‘Chuen-Lin’, Coptis chinensus/japonicum, which is consumed by 28–51% of Chinese infants, was found to have a significant effect in displacing bilirubin from its serum protein binding as assessed by the peroxidase oxidation method. Taking this herbal tea may thus increase the risk of brain damage by free bilirubin in jaundiced infants. As neonatal hyperbilirubinaemia is highly prevalent among Southern Chinese, the use of Chuen-Lin in the perinatal period must be strongly discouraged.
Molecular MRI of Cardiomyocyte Apoptosis With Simultaneous Delayed-Enhancement MRI Distinguishes Apoptotic and Necrotic Myocytes In Vivo
Authors: Sosnovik David E. , Garanger Elisabeth , Aikawa Elena , Nahrendorf Matthias , Figuiredo Jose-Luiz , Dai Guangping , Reynolds Fred , Rosenzweig Anthony , Weissleder Ralph , Josephson Lee
Published: September 2009

Background—

A novel dual-contrast molecular MRI technique to image both cardiomyocyte apoptosis and necrosis in vivo within 4 to 6 hours of ischemia is presented. The technique uses the annexin-based nanoparticle AnxCLIO-Cy5.5 (apoptosis) and simultaneous delayed-enhancement imaging with a novel gadolinium chelate, Gd-DTPA-NBD (necrosis).

Methods and Results—

Mice with transient coronary ligation were injected intravenously at the onset of reperfusion with AnxCLIO-Cy5.5 (n=7) or the control probe Inact_CLIO-Cy5.5 (n=6). T2*-weighted MR images (9.4 T) were acquired within 4 to 6 hours of reperfusion. The contrast-to-noise ratio between injured and uninjured myocardium was measured. The mice were then injected with Gd-DTPA-NBD, and delayed-enhancement imaging was performed within 10 to 30 minutes. Uptake of AnxCLIO-Cy5.5 was most prominent in the midmyocardium and was significantly greater than that of Inact_CLIO-Cy5.5 (contrast-to-noise ratio, 8.82�1.5 versus 3.78�1.1;
P
<0.05). Only 21�3% of the myocardium with accumulation of AnxCLIO-Cy5.5 showed delayed-enhancement of Gd-DTPA-NBD. Wall thickening was significantly reduced in segments with delayed enhancement and/or transmural accumulation of AnxCLIO-Cy5.5 (
P
<0.001). Fluorescence microscopy of AnxCLIO-Cy5.5 and immunohistochemistry of Gd-DTPA-NBD confirmed the presence of large numbers of apoptotic but potentially viable cardiomyocytes (AnxCLIO-Cy5.5 positive, Gd-DTPA-NBD negative) in the midmyocardium.

Conclusions—

A novel technique to image cardiomyocyte apoptosis and necrosis in vivo within 4 to 6 hours of injury is presented and reveals large areas of apoptotic but viable myocardium in the midmyocardium. Strategies to salvage the numerous apoptotic but potentially viable cardiomyocytes in the midmyocardium in acute ischemia should be investigated.
Long Time Going: Religion and the Duration of Crusading
Authors: Horowitz Michael C.
Published: September 2009

Scholars have argued for centuries about the relative importance of religion in determining behavior. Do actors with genuine religious beliefs, both leaders and foot soldiers, actually fight wars and commit atrocities in the name of religion and religious institutions? Or is religion a proxy for materialist variables such as land grabs or wealth creation? A case study of the Catholic Crusading movement and an evaluation of Crusading as an institution demonstrate that religiously motivated military campaigns, when decisive conclusions are not possible, may last longer than other campaigns because of the nonmaterial reasons for continuing to fight. Despite spectacular failures and rising costs, Crusading continued for centuries. The evidence shows that it is impossible to comprehend the persistence of Crusading over a several-hundred-year period without understanding the religious devotion at the heart of this institution. This research contributes to growing work in international relations on the importance of identity attributes and helps to explain how factors such as religion can influence processes such as crisis bargaining and war termination.
Bad Debts: Assessing China's Financial Influence in Great Power Politics
Authors: Drezner Daniel W.
Published: September 2009

Commentators and policymakers have articulated growing concerns about U.S. dependence on China and other authoritarian capitalist states as a source of credit to fund the United States' trade and budget deficits. What are the security implications of China's creditor status? If Beijing or another sovereign creditor were to flex its financial muscles, would Washington buckle? The answer can be drawn from the existing literature on economic statecraft. An appraisal of the ability of creditor states to convert their financial power into political power suggests that the power of credit has been moderately exaggerated in policy circles. To use the argot of security studies, China's financial power increases its deterrent capabilities, but it has little effect on its compellence capabilities. China can use its financial power to resist U.S. entreaties, but it cannot coerce the United States into changing its policies. Financial power works best when a concert of creditors (or debtors) can be maintained. Two case studies—the contestation over regulating sovereign wealth funds and the protection of Chinese financial investments in the United States—demonstrate the constraints on China's financial power.
What's in a Line? Is Partition a Solution to Civil War?
Authors: Sambanis Nicholas , Schulhofer-Wohl Jonah
Published: September 2009

Does territorial partition of countries in civil wars help to end these wars, reducing the risk of recurrence? Researchers have proposed territorial partition with or without formal recognition of sovereignty as a solution to civil wars and a way to create self-enforcing peace. Quantitative studies of the effect of partition on the risk of renewed civil war, however, suffer several main shortcomings, including conflicting results in the extant literature that result mainly from data coding differences, selective use of case histories, and methodological problems. A new data set and a benchmark empirical analysis find that, on average, partition is unlikely to reduce the risk of a return to civil war and, in some cases, may increase that risk.
Genre without a Name: Was There a Hebrew Term for “Apocalypse”?
Authors: Kulik Alexander
Published: September 2009

Although the term for “apocalypse” is not attested as a title or genre definition in the extant corpus of Hebrew or Jewish Aramaic documents, some early Hebrew, Syriac, and Arabic texts may contain rudimentary evidence in favor of the existence of a Hebrew or Jewish Aramaic equivalent for the term. Moreover, its reconstruction can contribute to better understanding of certain wide spread apocalyptic imagery, which must be closely connected to the semantics of this term.
Partisan Thought
Authors: Toscano Alberto
Published: September 2009

What is the relationship between materialism and partisanship today? Starting with an outline of the elements of Lenin's understanding of the partisan character of truth, this intervention outlines some of the challenges posed to a Marxist understanding of partisanship by the influential positions of Michel Foucault and Carl Schmitt, as well as by the recent turn to vitalism and complexity in social theory. On the basis of the confrontation between a Leninist conception of materialist partisanship and its contemporary challengers, the article considers Alain Badiou's recent attempt to revive a 'materialist dialectic' in order to think through the present conditions for formulating a partisan and universalist conception of political truth that would not collapse into mere partiality or outright dogmatism.
Why Did Latife Cover Her Hair?
Authors: Bakan Birol
Published: September 2009

This paper uncovers the Orientalist assumptions dominating studies of Ataturk reforms as to women's rights in Turkey and proposes an alternative approach, which drops messianic approach to Ataturk reforms and calls for situating them within a broader historical strategic context. It argues that Ataturk's clique was one of the many contenders competing for political power in post-WWI Turkey. In an effort to pacify and eliminate its opponents, the political regime pursued a policy of corporatist regime construction, by which no autonomous social institution was left alone. Such a reading of early Republican history suggests that granting women certain rights was part of authoritarian regime consolidation. This essay argues the case further; suggesting that being contained within an authoritarian regime caused the nascent feminist movement to lose its potential to reach to broader women groups in Turkey.
Inexpensive Time-Lapse Digital Cameras for Studying Transient Meteorological Phenomena: Dust Devils and Playa Flooding
Authors: Lorenz Ralph D. , Jackson Brian , Barnes Jason W.
Published: September 2009

The authors describe the design and performance of inexpensive and compact time-lapse cameras suitable for field deployment in remote locations for long periods and their application to studying two time-variable meteorological phenomena in arid regions: desert dust devils and transient flooding of playa lakes. The camera units (with a total parts cost of ∼$80) are based around commercial “point and shoot” digital cameras, storing ∼1500 images on a solid-state memory card over a period between an hour to several months powered by alkaline batteries. A microcontroller can trigger image acquisition based on sensor inputs or at regular intervals. Some example results are presented, showing an association of cumulus clouds with thermals from dust devils, a region of dust enhancement around a dust devil, and a dramatic range of conditions at Racetrack Playa in Death Valley National Park. Alternative systems and applications are also discussed.
Household Evacuation Decision Making and the Benefits of Improved Hurricane Forecasting: Developing a Framework for Assessment
Authors: Lazo Jeffrey K. , Waldman Donald M. , Morrow Betty Hearn , Thacher Jennifer A.
Published: September 2009

Hurricane warnings are the primary sources of information that enable the public to assess the risk and develop responses to threats from hurricanes. These warnings have significantly reduced the number of hurricane-related fatalities in the last several decades. Further investment in the science and implementation of the warning system is a primary mission of the National Weather Service and its partners. It is important that the weather community understand the public’s preferences and values for such investments; yet, there is little empirical information on the use of forecasts in evacuation decision making, the economic value of current forecasts, or the potential use or value for improvements in hurricane forecasts. Such information is needed to evaluate whether improved forecast provision and dissemination offer more benefit to society than alternative public investments.

Fundamental aspects of households’ perceptions of hurricane forecasts and warnings and their potential uses of and values for improved hurricane forecast information are examined. The study was designed in part to examine the viability of survey research methods for exploring evacuation decision making and for eliciting values for improved hurricane forecasts and warnings. First, aspects that affect households’ stated likelihood of evacuation are explored, because informing such decisions is one of the primary purposes of hurricane forecasts and warnings. Then, stated-choice valuation methods are used to analyze choices between potential forecast-improvement programs and the accuracy of existing forecasts. From this, the willingness to pay (WTP) for improved forecasts is derived from survey respondents.
Financial Crises, Politics and Financial Sector Restructuring
Authors: Konoe Sara
Published: September 2009

This article analyzes and compares the financial sector restructuring process after the financial crises in Japan and the United States. As these financial crises deepened, countries shifted their policies away from postponing financial sector restructuring toward more thorough reforms. The impacts of different political structures are examined through the Small-N Case Study method. Cases include: the bursting of the financial bubble in the 1990s in Japan and the Savings and Loan crisis in the 1980s in the USA, both of which are analyzed through a review of academic literature, journalistic writings, and statistical data from the World Wide Web.
NGOs as Political Institutions
Authors: Ghosh Sujay
Published: September 2009

Institutions are essentially broadly agreed norms, rules and routines. They might have arisen out of social conflicts with strong influence of power relations, but they also face the demands of democracy. While studying NGOs as political institutions, particularly in the context of a number of developing countries, this article argues that the political context of their action is determined by their relationship with the donors and social movements. Second, NGOs promote democracy when they redefine participation in terms of their relationship with state and society; and contribute to improve the quality of participation, although with much less success in promoting internal democracy.
Controlling Violent Offenders Released to the Community: An Evaluation of the Boston Reentry Initiative
Authors: Braga Anthony A. , Piehl Anne M. , Hureau David
Published: September 2009

Despite the high level of funding and policy interest in prisoner reentry, there is still little rigorous scientific evidence to guide jurisdictions in developing reentry programs to enhance public safety, particularly for managing those who pose the greatest safety risks. The Boston Reentry Initiative (BRI) is an interagency initiative to help transition violent adult offenders released from the local jail back to their Boston neighborhoods through mentoring, social service assistance, and vocational development.This study uses a quasi-experimental design and survival analyses to evaluate the effects of the BRI on the subsequent recidivism of program participants relative to an equivalent control group. The authors find that the BRI was associated with significant reductions—on the order of 30 percent—in the overall and violent arrest failure rates.
Effect of the Bile Acid Sequestrant Colesevelam on the Pharmacokinetics of Pioglitazone, Repaglinide, Estrogen Estradiol, Norethindrone, Levothyroxine, and Glyburide
Authors: Brown Karen S. , Armstrong Ingrid C. , Wang Antonia , Walker Joseph R. , Noveck Robert J. , Swearingen Dennis , Allison Mark , Kissling James C. , Kisicki James , Salazar Daniel E.
Published: September 2009

The purpose of this study was to assess effects of colesevelam on the pharmacokinetics of glyburide, levothyroxine, estrogen estradiol (EE), norethindrone (NET), pioglitazone, and repaglinide in healthy volunteers. Six drugs with a potential to interact with colesevelam were studied in open‐label, randomized clinical studies. The presence of a drug interaction was concluded if the 90% confidence intervals for the geometric least squares mean ratios of AUC0‐t (AUC0–48 for levothyroxine) and Cmax fell outside the no‐effect limits of (80.0%, 125.0%). Concomitant administration of colesevelam had no effect on the AUC0‐t or Cmax of pioglitazone but significantly decreased the AUC0‐t and Cmax of glyburide, levothyroxine, and EE and the Cmax of repaglinide and NET. AUC0‐t and Cmax of glyburide and EE, but not repaglinide or NET, were significantly decreased when the drug was given 1 hour before colesevelam. When glyburide, EE, or levothyroxine was given 4 hours before colesevelam, no drug interaction was observed. Although colesevelam has a cleaner drug interaction profile than other bile acid sequestrants, it does interfere with absorption of some drugs. A 4‐hour window appears sufficient to eliminate these interactions.
Long-Term Test-Retest Reliability of Baseline Cognitive Assessments Using ImPACT
Authors: Schatz Philip
Published: September 2009

Background

Computer-based assessment programs are commonly used to document baseline cognitive performance for comparison with postconcussion testing. There are currently no guidelines for how often baseline assessments should be updated, and no data documenting the test-retest stability of baseline measures over relevant time periods.

Purpose

To establish long-term test-retest reliability of baseline assessments using ImPACT, and to compare various statistical methods for establishing test-retest reliability.

Study Design

Case series; Level of evidence, 4.

Methods

Participants were 95 collegiate varsity athletes completing baseline cognitive testing at 2 time periods, approximately 2 years apart. No participant sustained a concussion between assessments. All athletes completed the ImPACT test battery; dependent measures were the composite scores and total symptom scale score.

Results

Intraclass correlation coefficient estimates for visual memory (.65), processing speed (.74), and reaction time (.68) composite scores reflected stability over the 2-year period, with greater variability in verbal memory (.46) and symptom scale (.43) scores. Using reliable change indices and regression-based methods, only a small percentage of participants’ scores showed “reliable” or “significant” change on the composite scores (0%-6%), or symptom scale scores (5%-10%).

Conclusion

The current results suggest that college athletes’ cognitive performance at baseline remains considerably stable over a 2-year period. These data help establish the effects of longer, clinically pragmatic testing intervals on test-retest reliability.

Clinical Implications

The current results suggest that stretching the time between baseline assessments from 1 to 2 years may have little effect on the clinical management of concussions in collegiate athletes. These results should not be generalized to collegiate football players, who were not included in this sample. Youth athletes (high school and younger) should continue to receive annually updated baseline assessments until prospective study of the stability of baseline assessments for this younger age group can be completed.
Can Science Communication Workshops Train Scientists for Reflexive Public Engagement?
Authors: Miller Steve , Fahy Declan ,   The ESConet Team
Published: September 2009

The European Science Communication Network, between 2005 and 2008, created and delivered original communication training workshops to more than 170 researchers, primarily early-career scientists, to empower them to perform reflexive public engagement activities in various communication situations. The program designed 12 original teaching modules for science communication that not only delivered skills training, including writing for popular audiences and media interview skills, but also developed capacity in, among other areas, risk communication, communicating science in dialogue, and examining controversies within the scientific community. The workshops aimed to encourage scientists to reflect critically on the social, historical, cultural, and ethical dimensions of science.
Microcapsules of a Casein Hydrolysate: Production, Characterization, and Application in Protein Bars
Authors: Rocha G.A. , Trindade M.A. , Netto F.M. , Favaro-Trindade C.S.
Published: September 2009

The aim of this work was to encapsulate a casein hydrolysate by spray drying using maltodextrins (DE 10 and 20) as wall materials and to evaluate the efficiency of the microencapsulation in attenuating the bitter taste of the hydrolysate using protein bars as the model system. Microcapsules were evaluated for morphology (SEM), particle size, hygroscopicity, solubility, thermal behavior (DSC), and bitter taste with a trained sensory panel by a paired comparison test (nonencapsulated samples vs. encapsulated samples). Bars were prepared with the addition of 3% casein hydrolysate at free or both encapsulated forms, and were then evaluated for their moisture, water activity (aw) and for their bitter taste by a ranking test. Microcapsules were of the matrix type, having continuous surfaces with no apparent porosity for both coatings. Both encapsulated casein hydrolysates had similar hygroscopicity, and lower values than free encapsulated hydrolysates. The degree of hydrolysis of the maltodextrin influenced only the particle size and Tg. The sensory panel considered the protein bars produced with both encapsulated materials less bitter (p < 0.05) than those produced with the free casein hydrolysates. Microencapsulation by spray drying with maltodextrin DE 10 and 20 was successful to attenuate the bitter taste and the hygroscopicity of casein hydrolysates.
GPs’ perceptions of the service needs of South Asian people with chronic pain
Authors: Patel S. , Peacock S.M. , Mckinley R.K. , Clark-Carter D. , Watson P.J.
Published: September 2009

This qualitative study describes GPs’ experiences of and needs for management of people from a South Asian community who have chronic pain. Semi-structured interviews were conducted with 18 GPs from practices in two PCTs in Leicester. The data was analysed using grounded theory. The results indicate that managing patients from a South Asian community with chronic pain can be challenging due to differing pain expression and presentation. Emerging themes refer to shortages of services for these patients including the need for CBT, counselling, community support and GP education and training. Potential implications of the results for service provision are discussed.
Oh Stuff It! The Experience and Explanation of Diet Failure
Authors: Green A.R. , Larkin M. , Sullivan V.
Published: September 2009

Successful long-term weight-loss is exceptional, even with the best dietary and psychological interventions. Nomothetic accounts of diet failure focus on cognitive processes and emotional regulation. However, qualitative research suggests that successful dieters draw on wider understandings in explaining their success; this study extends this literature to address diet failure. Individual interviews with 10 self-selected UK dieters are analysed using IPA. Understandings of diet failure are explored and situated within wider cultural discourses. Five themes are identified: ‘Dieting mode’; ‘Multime’; ‘Not me’; ‘Modern life’; and ‘Challenges of emotional and social eating’. Implications for weight-loss interventions are explored.
Pleasure and Distance: Exploring Sexual Cultures in the Classroom
Authors: Smith Clarissa
Published: September 2009

Teaching sexually explicit materials to undergraduate students is fraught with questions of what ought to be taught when we introduce sessions on pornography, cybersex, explicit representations of gay and lesbian sexuality and the politics of representation more generally. This article will address some of those concerns through a meditation on some of my own teaching experiences offered, not as an example of best practice, but as a further contribution to the provocative discussions elsewhere in this issue. I argue that teaching about sexually explicit representations has the potential for reaching beyond the examination of hegemonic meanings or the exposition of generic repetitions to more innovative exploration of the cultural discourses of sexuality.