bluuebunny/crossref_metadata_2025 huggingface dataset:
Campaign Finance and American Democracy
Authors: Dawood Yasmin
Published: April 2015

This article considers the vast academic literature on campaign finance regulation in the United States, drawing on the fields of political theory, American politics, election law, constitutional law, and economics. The scholarly treatment of campaign finance regulation has become increasingly focused on fundamental questions about democratic governance and democratic values, and it has generated profound debates about participation, representation, free speech, political equality, liberty, and the organization and distribution of political power in government and society. This article reviews the original debate about campaign finance regulation and traces its evolution in both political theory and constitutional law, identifying current areas of inquiry and new directions in research. In particular, the article focuses on corruption, political equality and representation, electoral exceptionalism, and the post–Citizens United landscape. It also surveys empirical findings from political science and economics.
Income Inequality and Policy Responsiveness
Authors: Erikson Robert S.
Published: April 2015

The growing concern about economic inequality leads to a similar concern about political inequality. This article explores the seeming contradiction between the literature pointing to inequality in political representation in the United States and the literature showing that public policy does tend to represent public opinion in general. Low-income voters are much less likely to vote or to be politically knowledgeable than high-income voters, which limits their influence and creates an upper-income bias to effective public opinion. Considerable research suggests that low-income voters' opinions count for even less than would be implied by their low participation rate, a matter that should continue to be the subject of research. Seemingly contrary to any upper-income bias to policy making, major legislation usually moves policy in the direction favored by low-income voters (e.g., redistribution, government programs). Upper-income voters and interest groups, however, are able to slow the pace of liberal change.
International Environmental Agreements
Authors: de Zeeuw Aart
Published: April 2015

The regulation of environmental externalities at the global level requires international agreements between sovereign states. Game theory provides an appropriate theoretical tool for analysis. However, game theory can result in a wide range of outcomes, and therefore it is important to discuss the assumptions and mechanisms of the different approaches and to relate these with what is observed in practice. The basic picture is not optimistic: If there are large gains of cooperation, the stable coalition is small. This grim picture challenges the perspective and design of international agreements. This article discusses and compares the different approaches: noncooperative, cooperative, dynamic, and evolutionary. Asymmetries and the options for side payments are considered. At the end, some more optimistic ways forward are presented.
New Directions for the Sociology of Development
Authors: Viterna Jocelyn , Robertson Cassandra
Published: April 2015

At the close of World War II, “development” began to evolve along two paths. On the first path, scholars aimed to generate theoretical understandings of social change, especially at the national level (development studies). On the second path, policy makers in governments and other development-focused organizations initiated actions to promote positive social change, especially in poor or war-torn nations (development practice). In this article, we review the recent trajectory of “development” in sociology, paying close attention to the intersections between development studies and development practice. Through explicit comparisons to economics and political science, we demonstrate how the prominence of development sociology has varied historically in relation to its proposed policy prescriptions. We conclude by highlighting five uniquely sociological contributions that could powerfully improve contemporary interdisciplinary development conversations, and by calling for greater sociological attention to the complex ways in which a growing transnational field of development practitioners is shaping a multiplicity of development outcomes.
Intersectionality's Definitional Dilemmas
Authors: Collins Patricia Hill
Published: April 2015

The term intersectionality references the critical insight that race, class, gender, sexuality, ethnicity, nation, ability, and age operate not as unitary, mutually exclusive entities, but rather as reciprocally constructing phenomena. Despite this general consensus, definitions of what counts as intersectionality are far from clear. In this article, I analyze intersectionality as a knowledge project whose raison d'être lies in its attentiveness to power relations and social inequalities. I examine three interdependent sets of concerns: (a) intersectionality as a field of study that is situated within the power relations that it studies; (b) intersectionality as an analytical strategy that provides new angles of vision on social phenomena; and (c) intersectionality as critical praxis that informs social justice projects.
miR-21-mediated decreased neutrophil apoptosis is a determinant of impaired coronary collateral growth in metabolic syndrome
Authors: Hutcheson Rebecca , Terry Russell , Hutcheson Brenda , Jadhav Rashmi , Chaplin Jennifer , Smith Erika , Barrington Robert , Proctor Spencer D. , Rocic Petra
Published: April 2015

Coronary collateral growth (CCG) is impaired in metabolic syndrome. microRNA-21 (miR-21) is a proproliferative and antiapoptotic miR, which we showed to be elevated in metabolic syndrome. Here we investigate whether impaired CCG in metabolic syndrome involved miR-21-mediated aberrant apoptosis. Normal Sprague-Dawley (SD) and metabolic syndrome [J. C. Russel (JCR)] rats underwent transient, repetitive coronary artery occlusion [repetitive ischemia (RI)]. Antiapoptotic Bcl-2, phospho-Bad, and Bcl-2/Bax dimers were increased on days 6 and 9 RI, and proapoptotic Bax and Bax/Bax dimers and cytochrome- c release concurrently decreased in JCR versus SD rats. Active caspases were decreased in JCR versus SD rats (∼50%). Neutrophils increased transiently on day 3 RI in the collateral-dependent zone of SD rats but remained elevated in JCR rats, paralleling miR-21 expression. miR-21 downregulation by anti-miR-21 induced neutrophil apoptosis and decreased Bcl-2 and Bcl-2/Bax dimers (∼75%) while increasing Bax/Bax dimers, cytochrome- c release, and caspase activation (∼70, 400, and 400%). Anti-miR-21 also improved CCG in JCR rats (∼60%). Preventing neutrophil infiltration with blocking antibodies resulted in equivalent CCG recovery, confirming a major role for deregulated neutrophil apoptosis in CCG impairment. Neutrophil and miR-21-dependent CCG inhibition was in significant part mediated by increased oxidative stress. We conclude that neutrophil apoptosis is integral to normal CCG and that inappropriate prolonged miR-21-mediated survival of neutrophils plays a major role in impaired CCG, in part via oxidative stress generation.
Aortic perivascular adipose-derived interleukin-6 contributes to arterial stiffness in low-density lipoprotein receptor deficient mice
Authors: Du Bing , Ouyang An , Eng Jason S. , Fleenor Bradley S.
Published: April 2015

We tested the hypothesis that aortic perivascular adipose tissue (PVAT) from young low-density lipoprotein receptor-deficient (LDLr−/−) mice promotes aortic stiffness and remodeling, which would be mediated by greater PVAT-derived IL-6 secretion. Arterial stiffness was assessed by aortic pulse wave velocity and with ex vivo intrinsic mechanical properties testing in young (4–6 mo old) wild-type (WT) and LDLr−/− chow-fed mice. Compared with WT mice, LDLr−/− mice had increased aortic pulse wave velocity (407 ± 18 vs. 353 ± 13 cm/s) and intrinsic mechanical stiffness (5,308 ± 623 vs. 3,355 ± 330 kPa) that was associated with greater aortic protein expression of collagen type I and advanced glycation end products (all P < 0.05 vs. WT mice). Aortic segments from LDLr−/− compared with WT mice cultured in the presence of PVAT had greater intrinsic mechanical stiffness (6,092 ± 480 vs. 3,710 ± 316 kPa), and this was reversed in LDLr−/− mouse arteries cultured without PVAT (3,473 ± 577 kPa, both P < 0.05). Collagen type I and advanced glycation end products were increased in LDLr−/− mouse arteries cultured with PVAT ( P < 0.05 vs. WT mouse arteries), which was attenuated when arteries were cultured in the absence of PVAT ( P < 0.05). PVAT from LDLr−/− mice secreted larger amounts of IL-6 (3.4 ± 0.1 vs. 2.3 ± 0.7 ng/ml, P < 0.05), and IL-6 neutralizing antibody decreased intrinsic mechanical stiffness in LDLr−/− aortic segments cultured with PVAT ( P < 0.05). Collectively, these data provide evidence for a role of PVAT-derived IL-6 in the pathogenesis of aortic stiffness and remodeling in chow-fed LDLr−/− mice.
Collagen and elastin cross-linking is altered during aberrant late lung development associated with hyperoxia
Authors: Mižíková Ivana , Ruiz-Camp Jordi , Steenbock Heiko , Madurga Alicia , Vadász István , Herold Susanne , Mayer Konstantin , Seeger Werner , Brinckmann Jürgen , Morty Rory E.
Published: April 2015

Maturation of the lung extracellular matrix (ECM) plays an important role in the formation of alveolar gas exchange units. A key step in ECM maturation is cross-linking of collagen and elastin, which imparts stability and functionality to the ECM. During aberrant late lung development in bronchopulmonary dysplasia (BPD) patients and animal models of BPD, alveolarization is blocked, and the function of ECM cross-linking enzymes is deregulated, suggesting that perturbed ECM cross-linking may impact alveolarization. In a hyperoxia (85% O2)-based mouse model of BPD, blunted alveolarization was accompanied by alterations to lung collagen and elastin levels and cross-linking. Total collagen levels were increased (by 63%). The abundance of dihydroxylysinonorleucine collagen cross-links and the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio were increased by 11 and 18%, respectively, suggestive of a profibrotic state. In contrast, insoluble elastin levels and the abundance of the elastin cross-links desmosine and isodesmosine in insoluble elastin were decreased by 35, 30, and 21%, respectively. The lung collagen-to-elastin ratio was threefold increased. Treatment of hyperoxia-exposed newborn mice with the lysyl oxidase inhibitor β-aminopropionitrile partially restored normal collagen levels, normalized the dihydroxylysinonorleucine-to-hydroxylysinonorleucine ratio, partially normalized desmosine and isodesmosine cross-links in insoluble elastin, and partially restored elastin foci structure in the developing septa. However, β-aminopropionitrile administration concomitant with hyperoxia exposure did not improve alveolarization, evident from unchanged alveolar surface area and alveoli number, and worsened septal thickening (increased by 12%). These data demonstrate that collagen and elastin cross-linking are perturbed during the arrested alveolarization of developing mouse lungs exposed to hyperoxia.
STAT3-dependent CXC chemokine formation and neutrophil migration in streptococcal M1 protein-induced acute lung inflammation
Authors: Zhang Songen , Hwaiz Rundk , Luo Lingtao , Herwald Heiko , Thorlacius Henrik
Published: April 2015

Streptococcus pyogenes cause infections ranging from mild pharyngitis to severe streptococcal toxic shock syndrome (STSS). The M1 serotype of Streptococcus pyogenes is most frequently associated with STSS. Herein, it was hypothesized that STAT3 signaling might be involved in M1 protein-evoked lung inflammation. The STAT3 inhibitor, S3I-201, was administered to male C57Bl/6 mice before iv challenge with M1 protein. Bronchoalveolar fluid and lung tissue were harvested for quantification of STAT3 activity, neutrophil recruitment, edema, and CXC chemokine formation. Neutrophil expression of Mac-1 was quantified by use of flow cytometry. Levels of IL-6 and HMGB1 were determined in plasma. CXCL2-induced neutrophil chemotaxis was studied in vitro. Administration of S3I-201 markedly reduced M1 protein-provoked STAT3 activity, neutrophil recruitment, edema formation, and inflammatory changes in the lung. In addition, M1 protein significantly increased Mac-1 expression on neutrophils and CXC chemokine levels in the lung. Treatment with S3I-201 had no effect on M1 protein-induced expression of Mac-1 on neutrophils. In contrast, inhibition of STAT3 activity greatly reduced M1 protein-induced formation of CXC chemokines in the lung. Interestingly, STAT3 inhibition markedly decreased plasma levels of IL-6 and HMGB1 in animals exposed to M1 protein. Moreover, we found that S3I-201 abolished CXCL2-induced neutrophil migration in vitro. In conclusion, these novel findings indicate that STAT3 signaling plays a key role in mediating CXC chemokine production and neutrophil infiltration in M1 protein-induced acute lung inflammation.
Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients
Authors: Hoffmann Julia , Marsh Leigh M. , Pieper Mario , Stacher Elvira , Ghanim Bahil , Kovacs Gabor , König Peter , Wilkens Heinrike , Haitchi Hans Michael , Hoefler Gerald , Klepetko Walter , Olschewski Horst , Olschewski Andrea , Kwapiszewska Grazyna
Published: April 2015

Alterations in extracellular matrix (ECM) have been implicated in the pathophysiology of pulmonary hypertension. Here, we have undertaken a compartment-specific study to elucidate the expression profile of collagens and their processing enzymes in donor and idiopathic pulmonary arterial hypertension (IPAH) pulmonary arteries. Predominant intimal, but also medial and perivascular, remodeling and reduced lumen diameter were detected in IPAH pulmonary arteries. Two-photon microscopy demonstrated accumulation of collagen fibers. Quantification of collagen in pulmonary arteries revealed collagen accumulation mainly in the intima of IPAH pulmonary arteries compared with donors. Laser capture-microdissected pulmonary artery profiles (intima+media and perivascular tissue) were analyzed by real-time PCR for ECM gene expression. In the intima+media of IPAH vessels, collagens ( COL4A5, COL14A1, and COL18A1), matrix metalloproteinase (MMP) 19, and a disintegrin and metalloprotease (ADAM) 33 were higher expressed, whereas MMP10, ADAM17, TIMP1, and TIMP3 were less abundant. Localization of COLXVIII, its cleavage product endostatin, and MMP10, ADAM33, and TIMP1 was confirmed in pulmonary arteries by immunohistochemistry. ELISA for collagen XVIII/endostatin demonstrated significantly elevated plasma levels in IPAH patients compared with donors, whereas circulating MMP10, ADAM33, and TIMP1 levels were similar between the two groups. Endostatin levels were correlated with pulmonary arterial wedge pressure, and established prognostic markers of IPAH, right atrial pressure, cardiac index, 6-min walking distance, NH2-terminal pro-brain natriuretic peptide, and uric acid. Expression of unstudied collagens, MMPs, ADAMs, and TIMPs were found to be significantly altered in IPAH intima+media. Elevated levels of circulating collagen XVIII/endostatin are associated with markers of a poor prognosis.
Innate and ozone-induced airway hyperresponsiveness in obese mice: role of TNF-α
Authors: Williams Alison Suzanne , Mathews Joel Andrew , Kasahara David Itiro , Wurmbrand Allison Patricia , Chen Lucas , Shore Stephanie Ann
Published: April 2015

Innate airway hyperresponsiveness (AHR) and augmented responses to ozone, an asthma trigger, are characteristics of obese mice. Systemic inflammation, a condition of increased circulating concentrations of inflammatory moieties, occurs in obesity. We hypothesized that TNF-α, via its effects as a master effector of this systemic inflammation, regulates innate AHR and augmented responses to ozone in obese mice. Therefore, we examined pulmonary inflammation and airway responsiveness in unexposed or ozone-exposed (2 ppm for 3 h) lean wild-type and obese Cpefatmice that were TNF-α sufficient or deficient. Cpefatmice lack carboxypeptidase E, which regulates satiety. Compared with wild type, Cpefatmice had elevated serum IL-17A, G-CSF, KC, MCP-1, IL-9, MIG, and leptin, indicating systemic inflammation. Despite reductions in most of these moieties in TNF-α-deficient vs. -sufficient Cpefatmice, we observed no substantial difference in airway responsiveness in these two groups of mice. Ozone-induced increases in bronchoalveolar lavage (BAL) neutrophils and macrophages were lower, but ozone-induced AHR and increases in BAL hyaluronan, osteopontin, IL-13, and protein carbonyls, a marker of oxidative stress, were augmented in TNF-α-deficient vs. -sufficient Cpefatmice. Our data indicate that TNF-α has an important role in promoting the systemic inflammation but not the innate AHR of obesity, suggesting that the systemic inflammation of obesity is not the major driver of this AHR. TNF-α is required for the augmented effects of acute ozone exposure on pulmonary inflammatory cell recruitment in obese mice, whereas TNF-α protects against ozone-induced AHR in obese mice, possibly by suppressing ozone-induced oxidative stress.
Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis
Authors: Sadok Amine , McCarthy Afshan , Caldwell John , Collins Ian , Garrett Michelle D. , Yeo Maggie , Hooper Steven , Sahai Erik , Kuemper Sandra , Mardakheh Faraz K. , Marshall Christopher J.
Published: April 2015

There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion, impairing both “amoeboid-like” and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest that inhibition of ROCK reduces the ability of melanoma cells to efficiently colonize the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis. Cancer Res; 75(11); 2272–84. ©2015 AACR.
Effective Eradication of Glioblastoma Stem Cells by Local Application of an AC133/CD133-Specific T-cell–Engaging Antibody and CD8 T Cells
Authors: Prasad Shruthi , Gaedicke Simone , Machein Marcia , Mittler Gerhard , Braun Friederike , Hettich Michael , Firat Elke , Klingner Kerstin , Schüler Julia , Wider Dagmar , Wäsch Ralph M. , Herold-Mende Christel , Elsässer-Beile Ursula , Niedermann Gabriele
Published: April 2015

Cancer stem cells (CSC) drive tumorigenesis and contribute to genotoxic therapy resistance, diffuse infiltrative invasion, and immunosuppression, which are key factors for the incurability of glioblastoma multiforme (GBM). The AC133 epitope of CD133 is an important CSC marker for GBM and other tumor entities. Here, we report the development and preclinical evaluation of a recombinant AC133×CD3 bispecific antibody (bsAb) that redirects human polyclonal T cells to AC133+ GBM stem cells (GBM-SC), inducing their strong targeted lysis. This novel bsAb prevented the outgrowth of AC133-positive subcutaneous GBM xenografts. Moreover, upon intracerebral infusion along with the local application of human CD8+ T cells, it exhibited potent activity in prophylactic and treatment models of orthotopic GBM-SC–derived invasive brain tumors. In contrast, normal hematopoietic stem cells, some of which are AC133-positive, were virtually unaffected at bsAb concentrations effective against GBM-SCs and retained their colony-forming abilities. In conclusion, our data demonstrate the high activity of this new bsAb against patient-derived AC133-positive GBM-SCs in models of local therapy of highly invasive GBM. Cancer Res; 75(11); 2166–76. ©2015 AACR.
Leptin–STAT3–G9a Signaling Promotes Obesity-Mediated Breast Cancer Progression
Authors: Chang Chao-Ching , Wu Meng-Ju , Yang Jer-Yen , Camarillo Ignacio G. , Chang Chun-Ju
Published: April 2015

Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem–like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBRhi). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBRhi population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy. Cancer Res; 75(11); 2375–86. ©2015 AACR.
Global Transcriptional Changes Following Statin Treatment in Breast Cancer
Authors: Bjarnadottir Olöf , Kimbung Siker , Johansson Ida , Veerla Srinivas , Jönsson Mats , Bendahl Pär-Ola , Grabau Dorthe , Hedenfalk Ingrid , Borgquist Signe
Published: April 2015

Background: Statins purportedly exert antitumoral effects, but the underlying mechanisms are currently not fully elucidated. The aim of this study was to explore potential statin-induced effects on global gene expression profiles in primary breast cancer.

Experimental Design: This window-of-opportunity phase II trial enrolled 50 newly diagnosed breast cancer patients prescribed atorvastatin (80 mg/day) for 2 weeks presurgically. Pre- and posttreatment tumor samples were analyzed using Significance Analysis of Microarrays (SAM) to identify differentially expressed genes. Similarly, SAM and gene ontology analyses were applied to gene expression data derived from atorvastatin-treated breast cancer cell lines (MCF7, BT474, SKBR3, and MDAMB231) comparing treated and untreated cells. The Systematic Motif Analysis Retrieval Tool (SMART) was used to identify enriched transcription factor-binding sites. Literature Vector Analysis (LitVAn) identified gene module functionality, and pathway analysis was performed using GeneGo Pathways Software (MetaCore; https://portal.genego.com/).

Results: Comparative analysis of gene expression profiles in paired clinical samples revealed 407 significantly differentially expressed genes (FDR = 0); 32 upregulated and 375 downregulated genes. Restricted filtration (fold change ≥1.49) resulted in 21 upregulated and 46 downregulated genes. Significantly upregulated genes included DUSP1, RHOB1, GADD45B, and RGS1. Pooled results from gene ontology, LitVAn and SMART analyses identified statin-induced effects on the apoptotic and MAPK pathways among others. Comparative analyses of gene expression profiles in breast cancer cell lines showed significant upregulation of the mevalonate and proapoptotic pathways following atorvastatin treatment.

Conclusions: We report potential statin-induced changes in global tumor gene expression profiles, indicating MAPK pathway inhibition and proapoptotic events. Clin Cancer Res; 21(15); 3402–11. ©2015 AACR.
A Novel Anti-CD22 Anthracycline-Based Antibody–Drug Conjugate (ADC) That Overcomes Resistance to Auristatin-Based ADCs
Authors: Yu Shang-Fan , Zheng Bing , Go MaryAnn , Lau Jeff , Spencer Susan , Raab Helga , Soriano Robert , Jhunjhunwala Suchit , Cohen Robert , Caruso Michele , Polakis Paul , Flygare John , Polson Andrew G.
Published: April 2015

Purpose: We are interested in identifying mechanisms of resistance to the current generation of antibody–drug conjugates (ADC) and developing ADCs that can overcome this resistance.

Experimental Design: Pinatuzumab vedotin (anti-CD22-vc-MMAE) and polatuzumab vedotin (anti-CD79b-vc-MMAE) are ADCs that contain the microtubule inhibitor monomethyl auristatin E (MMAE) attached to the antibody by the protease-cleavable linker maleimidocaproyl-valine-citrulline-p-aminobenzoyloxycarbonyl (MC-vc-PAB). Early clinical trial data suggest that these ADCs have promising efficacy for the treatment of non-Hodgkin lymphoma (NHL); however, some patients do not respond or become resistant to the ADCs. Anthracyclines are very effective in NHL, but ADCs containing the anthracycline doxorubicin were not clinically efficacious probably due to the low drug potency and inadequate linker technology. The anthracycline analogue PNU-159682 is thousands of times more cytotoxic than doxorubicin, so we used it to develop a new class of ADCs. We used the same MC-vc-PAB linker and antibody in pinatuzumab vedotin but replaced the MMAE with a derivative of PNU-159682 to make anti-CD22-NMS249 and tested it for in vivo efficacy in xenograft tumors resistant to MMAE-based ADCs.

Results: We derived cell lines from in vivo xenograft tumors that were made resistant to anti-CD22-vc-MMAE and anti-CD79b-vc-MMAE. We identified P-gp (ABCB1/MDR1) as the major driver of resistance to the vc-MMAE–based conjugates. Anti-CD22-NMS249 was at least as effective as anti-CD22-vc-MMAE in xenograft models of the parental cell lines and maintained its efficacy in the resistant cell lines.

Conclusions: These studies provide proof of concept for an anthracycline-based ADC that could be used to treat B-cell malignancies that are resistant to vc-MMAE conjugates. Clin Cancer Res; 21(14); 3298–306. ©2015 AACR.
Biological Activities of RUNX1 Mutants Predict Secondary Acute Leukemia Transformation from Chronic Myelomonocytic Leukemia and Myelodysplastic Syndromes
Authors: Tsai Shu-Chun , Shih Lee-Yung , Liang Sung-Tzu , Huang Ying-Jung , Kuo Ming-Chung , Huang Chein-Fuang , Shih Yu-Shu , Lin Tung-Huei , Chiu Ming-Chun , Liang Der-Cherng
Published: April 2015

Purpose: Transcription factor RUNX1 is essential for normal hematopoiesis. High mutation frequencies of RUNX1 gene in chronic myelomonocytic leukemia (CMML) and myelodysplastic syndromes (MDS) have been described, whereas the biologic significances of the mutations were not investigated. Here, we aimed to correlate the biologic activities of the RUNX1 mutants with the clinical outcomes of patients.

Experimental Design: We examined the mutational status of RUNX1 in 143 MDS and 84 CMML patients. Then, we studied the DNA and CBFβ binding abilities of all the RUNX1 mutants identified by using electrophoretic mobility shift assay and co-immunoprecipitation assay, and also determined their activities on target C-FMS gene induction by Western blotting and luciferase reporter assay. Using luciferase reporter assay, the relative biologic activities of each RUNX1 mutant could be quantified and correlated with the patient outcomes by statistical analyses.

Results: We observed that most RUNX1 mutants had reduced abilities in DNA binding, CBFβ heterodimerization, and C-FMS gene induction. The relative biologic activities of RUNX1 mutants were grouped into high- and low-activity mutations. Correlation of the activities of RUNX1 mutants with the clinical outcomes revealed that patients harboring lower activities of RUNX1 mutants had a higher risk and shorter time to secondary acute myeloid leukemia transformation in MDS and CMML. In multivariate analysis, low RUNX1 activity remained an independent predictor for secondary acute myeloid leukemia–free survival in MDS patients.

Conclusions: The biologic activity rather than the mutational status of RUNX1 might be an indicator in predicting outcome of patients with MDS and CMML. Clin Cancer Res; 21(15); 3541–51. ©2015 AACR.
Phase I Trial of the Pan-PI3K Inhibitor Pilaralisib (SAR245408/XL147) in Patients with Chronic Lymphocytic Leukemia (CLL) or Relapsed/Refractory Lymphoma
Authors: Brown Jennifer R. , Davids Matthew S. , Rodon Jordi , Abrisqueta Pau , Kasar Siddha N. , Lager Joanne , Jiang Jason , Egile Coumaran , Awan Farrukh T.
Published: April 2015

Purpose: This phase I expansion-cohort study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of the pan-PI3K inhibitor pilaralisib (SAR245408/XL147) in patients with chronic lymphocytic leukemia (CLL) or relapsed or refractory lymphoma.

Patients and Methods: Patients were treated with the maximum tolerated dose of pilaralisib previously determined in patients with solid tumors (600 mg capsules once daily). Adverse events (AE) and response were evaluated. Plasma pharmacokinetics and pharmacodynamic effects on cytokines and chemokines were also assessed.

Results: Twenty-five patients were included in the study: 10 with CLL and 15 with lymphoma. The most frequent AEs of any grade were diarrhea (92.0%), pyrexia (52.0%), and fatigue (44.0%). The most frequent grade ≥3 AEs were neutropenia (32.0%), diarrhea (20.0%), and anemia (16.0%). Pilaralisib exposure on cycle 1 day 28 was similar to exposure in patients with solid tumors. In patients with CLL, pilaralisib significantly reduced plasma levels of several cytokines and chemokines involved in B-cell trafficking. Five patients (50.0%) with CLL and 3 patients (20.0%) with lymphoma had a partial response. Six patients (60.0%) with CLL had nodal shrinkage ≥50%. Overall, 14 patients (56.0%; 7 patients with CLL and 7 patients with lymphoma) had progression-free survival ≥6 months.

Conclusions: Pilaralisib demonstrated an acceptable safety profile in patients with CLL and lymphoma, generally consistent with findings in patients with solid tumors. Single-agent pilaralisib showed preliminary clinical activity in patients with CLL and lymphoma, supporting further development. Clin Cancer Res; 21(14); 3160–9. ©2015 AACR.
Inhibition of Homologous Recombination and Promotion of Mutagenic Repair of DNA Double-Strand Breaks Underpins Arabinoside–Nucleoside Analogue Radiosensitization
Authors: Magin Simon , Papaioannou Maria , Saha Janapriya , Staudt Christian , Iliakis George
Published: April 2015

In concurrent chemoradiotherapy, drugs are used to sensitize tumors to ionizing radiation. Although a spectrum of indications for simultaneous treatment with drugs and radiation has been defined, the molecular mechanisms underpinning tumor radiosensitization remain incompletely characterized for several such combinations. Here, we investigate the mechanisms of radiosensitization by the arabinoside nucleoside analogue 9-β-D-arabinofuranosyladenine (araA) placing particular emphasis on the repair of DNA double-strand breaks (DSB), and compare the results to those obtained with fludarabine (F-araA) and cytarabine (araC). Postirradiation treatment with araA strongly sensitizes cells to ionizing radiation, but leaves unchanged DSB repair by NHEJ in logarithmically growing cells, in sorted G1 or G2 phase populations, as well as in cells in the plateau phase of growth. Notably, araA strongly inhibits DSB repair by homologous recombination (HRR), as assessed by scoring ionizing radiation–induced RAD51 foci, and in functional assays using integrated reporter constructs. Cells compromised in HRR by RNAi-mediated transient knockdown of RAD51 show markedly reduced radiosensitization after treatment with araA. Remarkably, mutagenic DSB repair compensates for HRR inhibition in araA-treated cells. Compared with araA, F-araA and araC are only modestly radiosensitizing under the conditions examined. We propose that the radiosensitizing potential of nucleoside analogues is linked to their ability to inhibit HRR and concomitantly promote the error-prone processing of DSBs. Our observations pave the way to treatment strategies harnessing the selective inhibitory potential of nucleoside analogues and the development of novel compounds specifically utilizing HRR inhibition as a means of tumor cell radiosensitization. Mol Cancer Ther; 14(6); 1424–33. ©2015 AACR.
CD30 Downregulation, MMAE Resistance, and MDR1 Upregulation Are All Associated with Resistance to Brentuximab Vedotin
Authors: Chen Robert , Hou Jessie , Newman Edward , Kim Young , Donohue Cecile , Liu Xueli , Thomas Sandra H. , Forman Stephen J. , Kane Susan E.
Published: April 2015

Brentuximab vedotin (BV) is an antibody–drug conjugate that specifically delivers the potent cytotoxic drug monomethyl auristatin E (MMAE) to CD30-positive cells. BV is FDA approved for treatment of relapsed/refractory Hodgkin lymphoma and anaplastic large cell lymphoma (ALCL); however, many patients do not achieve complete remission and develop BV-resistant disease. We selected for BV-resistant Hodgkin lymphoma (L428) and ALCL (Karpas-299) cell lines using either constant (ALCL) or pulsatile (Hodgkin lymphoma) exposure to BV. We confirmed drug resistance by MTS assay and analyzed CD30 expression in resistant cells by flow cytometry, qRT-PCR, and Western blotting. We also measured drug exporter expression, MMAE resistance, and intracellular MMAE concentrations in BV-resistant cells. In addition, tissue biopsy samples from 10 Hodgkin lymphoma and 5 ALCL patients who had relapsed or progressed after BV treatment were analyzed by immunohistocytochemistry for CD30 expression. The resistant ALCL cell line, but not the Hodgkin lymphoma cell line, demonstrated downregulated CD30 expression compared with the parental cell line. In contrast, the Hodgkin lymphoma cell line, but not the ALCL cell line, exhibited MMAE resistance and increased expression of the MDR1 drug exporter compared with the parental line. For both Hodgkin lymphoma and ALCL, samples from patients relapsed/resistant on BV persistently expressed CD30 by immunohistocytochemistry. One Hodgkin lymphoma patient sample expressed MDR1 by immunohistocytochemistry. Although loss of CD30 expression is a possible mode of BV resistance in ALCL in vitro models, this has not been confirmed in patients. MMAE resistance and MDR1 expression are possible modes of BV resistance for Hodgkin lymphoma both in vitro and in patients. Mol Cancer Ther; 14(6); 1376–84. ©2015 AACR.
Carperitide and Atrial Fibrillation After Coronary Bypass Grafting
Authors: Sezai Akira , Iida Mitsuru , Yoshitake Isamu , Wakui Shinji , Osaka Shunji , Kimura Haruka , Yaoita Hiroko , Hata Hiroaki , Shiono Motomi , Nakai Toshiko , Takayama Tadateru , Kunimoto Satoshi , Kasamaki Yuji , Hirayama Atsushi
Published: April 2015

Background—

Occurrence of atrial fibrillation after cardiac surgery is associated with long-term mortality. We investigated whether infusion of human atrial natriuretic peptide (carperitide) could prevent postoperative atrial fibrillation.

Methods and Results—

A total of 668 patients who underwent isolated coronary artery bypass grafting were randomized to receive infusion of carperitide or physiological saline from the initiation of cardiopulmonary bypass. Patients were monitored continuously for 1 week after surgery to detect atrial fibrillation. The risk factors were investigated by Cox proportional hazard model. Postoperative atrial fibrillation occurred in 41 of 335 patients (12.2%) from the carperitide group versus 110 of 333 patients (32.7%) from the placebo group (
P
<0.0001). Postoperative levels of angiotensin-II, aldosterone, creatine kinase MB isoenzyme, human heart fatty acid–binding protein, and brain natriuretic peptide were all significantly lower in the carperitide group. The risk factors for postoperative atrial fibrillation by the Cox proportional hazard model were an age ≥70 years, emergency surgery, preoperative aldosterone level >150 ng/mL, preoperative nonuse of angiotensin receptor antagonists, preoperative use of calcium antagonists, postoperative nonuse of β-blockers, postoperative nonuse of aldosterone blockers, and nonuse of carperitide.

Conclusions

—
Perioperative carperitide infusion reduced the occurrence of postoperative atrial fibrillation. Accordingly, carperitide could be a useful option for preventing postoperative atrial fibrillation.

Clinical Trial Registration

—
URL:
http://www.umin.ac.jp
. Unique Identifier: UMIN000003958.
TREM-1 Mediates Inflammatory Injury and Cardiac Remodeling Following Myocardial Infarction
Authors: Boufenzer Amir , Lemarié Jérémie , Simon Tabassome , Derive Marc , Bouazza Youcef , Tran Nguyen , Maskali Fatiha , Groubatch Frédérique , Bonnin Philippe , Bastien Claire , Bruneval Patrick , Marie Pierre-Yves , Cohen Raphael , Danchin Nicolas , Silvestre Jean-Sébastien , Ait-Oufella Hafid , Gibot Sébastien
Published: April 2015

Rationale:

Optimal outcome after myocardial infarction (MI) depends on a coordinated healing response in which both debris removal and repair of the myocardial extracellular matrix play a major role. However, adverse remodeling and excessive inflammation can promote heart failure, positioning leucocytes as central protagonists and potential therapeutic targets in tissue repair and wound healing after MI.

Objective:

In this study, we examined the role of triggering receptor expressed on myeloid cells-1(TREM-1) in orchestrating the inflammatory response that follows MI. TREM-1, expressed by neutrophils and mature monocytes, is an amplifier of the innate immune response.

Methods and Results:

After infarction, TREM-1 expression is upregulated in ischemic myocardium in mice and humans. Trem-1 genetic invalidation or pharmacological inhibition using a synthetic peptide (LR12) dampens myocardial inflammation, limits neutrophils recruitment and monocyte chemoattractant protein-1 production, thus reducing classical monocytes mobilization to the heart. It also improves left ventricular function and survival in mice (n=20–22 per group). During both permanent and transient myocardial ischemia, Trem-1 blockade also ameliorates cardiac function and limits ventricular remodeling as assessed by fluorodeoxyglucose-positron emission tomographic imaging and conductance catheter studies (n=9–18 per group). The soluble form of TREM-1 (sTREM-1), a marker of TREM-1 activation, is detectable in the plasma of patients having an acute MI (n=1015), and its concentration is an independent predictor of death.

Conclusions:

These data suggest that TREM-1 could constitute a new therapeutic target during acute MI.
“Quite a Genteel and Extreamly Commodious House”
Authors: Scribner Vaughn
Published: April 2015

When investigated through the tavern space, the processes of social differentiation so often associated with more populated northern “urban crucibles” appear less geographically determined than previously supposed. Colonial elites throughout British North America attempted to impose order and control over society during the eighteenth century. Elites’ quest for social differentiation and public order thus went beyond place. Whether patricians’ efforts occurred in Williamsburg or New York, such endeavors centered around the colonies’ most popular, accessible, and numerous public space—the tavern. This article will use Chesapeake and Low Country taverns to demonstrate, through outwardly broad but nonetheless effective comparisons with taverns in the northern colonies, that colonists throughout the eastern seaboard experienced very similar processes of social differentiation despite living thousands of miles apart. The tavern places Chesapeake and Low Country urban centers on an equal footing with their northern counterparts in their contributions to elites’ attempts at order and control.
Small scale endemism in Brazil’s Atlantic Forest: 14 new species of Mesabolivar (Araneae, Pholcidae), each known from a single locality
Authors: HUBER BERNHARD A.
Published: April 2015

In an ongoing mega-transect project that aims at analyzing pholcid spider diversity and distribution in the Atlantic Forest of Brazil, many species appear restricted to small geographic ranges. Of the 84 species collected between 2003 and 2011 at 17 sites between Bahia and Santa Catarina, 51 species (61%) were found at only one locality. The present paper focuses on such species in the genus Mesabolivar, and compares diversity and distribution patterns of this genus within and outside the Atlantic Forest. The percentage of species known from single localities is higher in the Atlantic Forest (34 of 52 species; 65%) than outside the Atlantic Forest (10 of 25; 40%). Distribution rages of species in the Atlantic Forest are significantly smaller than of species outside the Atlantic Forest (mean maximum distances between localities: 184 versus 541 km; medians: 10 km versus 220 km). The following species are newly described (arranged from north to south), each currently known from the respective type locality only: M. caipora; M. kathrinae; M. bonita; M. pau (Bahia); M. monteverde; M. perezi (Espírito Santo); M. giupponii; M. goitaca; M. sai (Rio de Janeiro); M. tamoio; M. unicornis; M. gabettae; M. inornatus (São Paulo); M. itapoa (Santa Catarina).
Brevipalpus phoenicis (Geijskes) species complex (Acari: Tenuipalpidae)—a closer look
Authors: BEARD JENNIFER J. , OCHOA RONALD , BRASWELL W. EVAN , BAUCHAN GARY R.
Published: April 2015

Brevipalpus phoenicis sensu stricto (Geijskes) is redescribed and the species diagnosis established. Two former synonyms of B. phoenicis sensu lato, B. yothersi Baker and B. papayensis Baker, are resurrected and redescribed and their species diagnoses established. Brevipalpus hondurani Evans is also redescribed and diagnosed. Four new species, previously misidentified as B. phoenicis sensu lato or B. obovatus Donnadieu, are described—B. azores sp. nov., B. feresi sp. nov., B. ferraguti sp. nov., and B. tucuman sp. nov. Four new junior synonyms of B. yothersi are listed—Brevipalpus amicus Chaudhri and B. recula Chaudhri (new synonymies), and B. mcbridei Baker and B. deleoni Pritchard and Baker (misidentifications). A key is provided to separate these species. New morphological characters significant for species separation are presented and discussed.
A Millennial Summer Temperature Reconstruction for the Eastern Tibetan Plateau from Tree-Ring Width*
Authors: Wang Jianglin , Yang Bao , Ljungqvist Fredrik Charpentier
Published: April 2015

Although tree-ring-width-based temperature reconstructions of centennial-to-millennial length have previously been published for many parts of the eastern Tibetan Plateau (ETP), a millennium-long regional-scale composite reconstruction with annual resolution has so far been lacking. Here, the authors present a reconstruction of June–August (JJA) temperature variability over the ETP for the period AD 1000–2005 using a nested composite-plus-scale (CPS) approach to 12 temperature-sensitive tree-ring width chronologies, including 946 individual tree-ring width series. The composite reconstruction reveals warm episodes occurring during much of the sixteenth, nineteenth, and twentieth centuries and cold episodes during much of the eleventh, seventeenth, and eighteenth centuries. The period AD 1996–2005 is likely the warmest decade in the context of the past millennium. The authors explore the influence of possible forcings, finding only a weak direct relationship of temperature changes over the ETP with solar forcing at multidecadal time scales but a robust in-phase relationship with the Atlantic multidecadal oscillation (AMO) during the past millennium. This suggests that the AMO may play an important role in controlling summer temperature variability over the ETP at multidecadal time scales. A comparison with temperature reconstructions from the higher latitudes of East Asia, central-eastern China, and the whole of the Northern Hemisphere shows that the cold eleventh century and the warm nineteenth century prevailing over ETP are somewhat unique, suggesting regional specific characteristics of the temperature variability in this region. This result highlights the need to further increase the number of millennium-long, high-resolution temperature records from East Asia.
Effect of Mesoscale Eddies on the Taiwan Strait Current
Authors: Chang Yu-Lin , Miyazawa Yasumasa , Guo Xinyu
Published: April 2015

This study shows that mesoscale eddies can alter the Taiwan Strait Current. The 20-yr data-assimilated Japan Coastal Ocean Predictability Experiment 2 (JCOPE2) reanalysis data are analyzed, and the results are confirmed with idealized experiments. The leading wind-forced seasonal cycle is excluded to focus on the effect of the eddy. The warm eddy southwest of Taiwan is shown to generate a northward flow, whereas the cold eddy produces a southward current. The effect of the eddy penetrates onto the shelf through the joint effect of baroclinicity and relief (JEBAR). The cross-isobath fluxes lead to shelfward convergence and divergence, setting up the modulation of the sea level slope. The resulting along-strait current anomaly eventually affects a wide area of the Taiwan Strait. The stronger eddy leads to larger modification of the cross-shelf flows and sea level slope, producing a greater transport anomaly. The composite Sea-Viewing Wide Field-of-View Sensor chlorophyll-a (Chl-a) serves as an indicator to show the change in Chl-a concentration in the strait in response to the eddy-induced current. During the warm eddy period, the current carries the southern water of lower concentration northward, reducing Chl-a concentration in the strait. In contrast, Chl-a is enhanced because the cold eddy–induced southward current carries the northern water of higher concentration southward into the strait.
A Comparison between a Generalized Beta–Advection Model and a Classical Beta–Advection Model in Predicting and Understanding Unusual Typhoon Tracks in Eastern China Seas
Authors: Huang Jing , Du Jun , Qian Weihong
Published: April 2015

A total of 163 tropical cyclones (TCs) occurred in the eastern China seas during 1979–2011 with four types of tracks: left turning, right turning, straight moving, and irregular. The left-turning type is unusual and hard to predict. In this paper, 133 TCs from the first three types have been investigated. A generalized beta–advection model (GBAM) is derived by decomposing a meteorological field into climatic and anomalous components. The ability of the GBAM to predict tracks 1–2 days in advance is compared with three classical beta–advection models (BAMs). For both normal and unusual tracks, the GBAM apparently outperformed the BAMs. The GBAM’s ability to predict unusual TC tracks is particularly encouraging, while the BAMs have no ability to predict the left-turning and right-turning TC tracks. The GBAM was also used to understand unusual TC tracks because it can be separated into two forms: a climatic-flow BAM (CBAM) and an anomalous-flow BAM (ABAM). In the CBAM a TC vortex is steered by the large-scale climatic background flow, while in the ABAM, a TC vortex interacts with the surrounding anomalous flows. This decomposition approach can be used to examine the climatic and anomalous flows separately. It is found that neither the climatic nor the anomalous flow alone can explain unusual tracks. Sensitivity experiments show that two anomalous highs as well as a nearby TC played the major roles in the unusual left turn of Typhoon Aere (2004). This study demonstrates that a simple model can work well if key factors are properly included.