bluuebunny/crossref_metadata_2025 huggingface dataset:
The geodetic precession as a 3D Schouten precession and a gravitational Thomas precession
Authors: de Haas E.P.J. (Paul)
Published: January 2014

The Gravity Probe B (GP-B) experiment measured the geodetic precession due to parallel transport in a curved space–time metric, as predicted by de Sitter, Fokker, and Schiff. The Schiff treatment included Thomas precession and argued that it should be zero in a free fall orbit. We review the existing interpretations regarding the relation between the Thomas precession and the geodetic precession for a gyroscope in a free fall orbit. Schiff and Parker had contradictory views on the status of the Thomas precession in a free fall orbit, a contradiction that continues to exist in the literature. In the second part of this paper we derive the geodetic precession as a global Thomas precession by use of the equivalent principle and some elements of hyperbolic geometry, a derivation that allows the treatment of GP-B physics in between special and general relativity courses.
Emotional and Behavioral Symptoms in Neurodegenerative Disease: A Model for Studying the Neural Bases of Psychopathology
Authors: Levenson Robert W. , Sturm Virginia E. , Haase Claudia M.
Published: January 2014

Disruptions in emotional, cognitive, and social behavior are common in neurodegenerative disease and in many forms of psychopathology. Because neurodegenerative diseases have patterns of brain atrophy that are much clearer than those of psychiatric disorders, they may provide a window into the neural bases of common emotional and behavioral symptoms. We discuss five common symptoms that occur in both neurodegenerative disease and psychopathology (i.e., anxiety, dysphoric mood, apathy, disinhibition, and euphoric mood) and their associated neural circuitry. We focus on two neurodegenerative diseases (i.e., Alzheimer's disease and frontotemporal dementia) that are common and well characterized in terms of emotion, cognition, and social behavior and in patterns of associated atrophy. Neurodegenerative diseases provide a powerful model system for studying the neural correlates of psychopathological symptoms; this is supported by evidence indicating convergence with psychiatric syndromes (e.g., symptoms of disinhibition associated with dysfunction in orbitofrontal cortex in both frontotemporal dementia and bipolar disorder). We conclude that neurodegenerative diseases can play an important role in future approaches to the assessment, prevention, and treatment of mental illness.
Attention-Deficit/Hyperactivity Disorder and Risk of Substance Use Disorder: Developmental Considerations, Potential Pathways, and Opportunities for Research
Authors: Molina Brooke S.G. , Pelham William E.
Published: January 2014

Many opportunities to explain attention-deficit/hyperactivity disorder (ADHD)-related risk of substance use disorder (SUD) remain available for study. We detail these opportunities by considering characteristics of children with ADHD and factors affecting their outcomes side by side with overlapping variables in the developmental literature on SUD etiology. Although serious conduct problems are a known contributor to ADHD-related risk of SUD, few studies have considered their emergence developmentally and in relation to other candidate mediators and moderators that could also explain risk and be intervention targets. Common ADHD-related impairments, such as school difficulties, are in need of research. Heterogeneous social impairments have the potential for predisposing, and buffering, influences. Research on neurocognitive domains should move beyond standard executive function batteries to measure deficits in the interface between cognitive control, reward, and motivation. Ultimately, maximizing prediction will depend, as it has in the SUD literature, on simultaneous consideration of multiple risk factors.
Improving Care for Depression and Suicide Risk in Adolescents: Innovative Strategies for Bringing Treatments to Community Settings
Authors: Asarnow Joan Rosenbaum , Miranda Jeanne
Published: January 2014

This article reviews the literature on interventions and services for depression and suicide prevention among adolescents, with the goals of placing this science within the context of currently changing health care environments and highlighting innovative models for improving health and mental health. We examine the challenges and opportunities offered by new initiatives and legislation designed to transform the US health and mental health care systems; summarize knowledge regarding the treatment of depression and suicidality/self-harm in adolescents; and describe innovative models for partnering with health systems and communities. This review demonstrates that treatment models and service delivery strategies are currently available for increasing evidence-based care, particularly for depression, and concludes with recommendations for future research and quality improvement initiatives aimed at inspiring additional efforts to put science to work, bridge science and community practice, and develop strategies for partnering with communities to improve care, mental health, and well-being among adolescents.
State and Local Government Finance: The New Fiscal Ice Age
Authors: Kiewiet D. Roderick , McCubbins Mathew D.
Published: January 2014

The Great Recession that began in late 2007 had devastating consequences for the fiscal health of state and local governments, and many remain in a precarious financial position. Several cities have declared bankruptcy, and more will do so in coming years. The future, however, promises no long-term relief. Due primarily to the aging population of the United States, state and local governments are allocating large and increasing shares of their budgets to expenditures on Medicaid and on retirement benefits that they have promised to their past and current employees. As these expenditures consume more of their budgets, there is less to spend on transportation, parks and recreation, education, public safety, and all the other services that these governments provide. We are thus experiencing the onset of a New Fiscal Ice Age, a period in which a given level of tax revenue purchases a considerably lower level of current services.
Role of GATA factors in development, differentiation, and homeostasis of the small intestinal epithelium
Authors: Aronson Boaz E. , Stapleton Kelly A. , Krasinski Stephen D.
Published: January 2014

The small intestinal epithelium develops from embryonic endoderm into a highly specialized layer of cells perfectly suited for the digestion and absorption of nutrients. The development, differentiation, and regeneration of the small intestinal epithelium require complex gene regulatory networks involving multiple context-specific transcription factors. The evolutionarily conserved GATA family of transcription factors, well known for its role in hematopoiesis, is essential for the development of endoderm during embryogenesis and the renewal of the differentiated epithelium in the mature gut. We review the role of GATA factors in the evolution and development of endoderm and summarize our current understanding of the function of GATA factors in the mature small intestine. We offer perspective on the application of epigenetics approaches to define the mechanisms underlying context-specific GATA gene regulation during intestinal development.
Dissociation of hepatic insulin resistance from susceptibility of nonalcoholic fatty liver disease induced by a high-fat and high-carbohydrate diet in mice
Authors: Asai Akihiro , Chou Pauline M. , Bu Heng-Fu , Wang Xiao , Rao M. Sambasiva , Jiang Anthony , DiDonato Christine J. , Tan Xiao-Di
Published: January 2014

Liver steatosis in nonalcoholic fatty liver disease is affected by genetics and diet. It is associated with insulin resistance (IR) in hepatic and peripheral tissues. Here, we aimed to characterize the severity of diet-induced steatosis, obesity, and IR in two phylogenetically distant mouse strains, C57BL/6J and DBA/2J. To this end, mice (male, 8 wk old) were fed a high-fat and high-carbohydrate (HFHC) or control diet for 16 wk followed by the application of a combination of classic physiological, biochemical, and pathological studies to determine obesity and hepatic steatosis. Peripheral IR was characterized by measuring blood glucose level, serum insulin level, homeostasis model assessment of IR, glucose intolerance, insulin intolerance, and AKT phosphorylation in adipose tissues, whereas the level of hepatic IR was determined by measuring insulin-triggered hepatic AKT phosphorylation. We discovered that both C57BL/6J and DBA/2J mice developed obesity to a similar degree without the feature of liver inflammation after being fed an HFHC diet for 16 wk. C57BL/6J mice in the HFHC diet group exhibited severe pan-lobular steatosis, a marked increase in hepatic triglyceride levels, and profound peripheral IR. In contrast, DBA/2J mice in the HFHC diet group developed only a mild degree of pericentrilobular hepatic steatosis that was associated with moderate changes in peripheral IR. Interestingly, both C57BL/6J and DBA/2J developed severe hepatic IR after HFHC diet treatment. Collectively, these data suggest that the severity of diet-induced hepatic steatosis is correlated to the level of peripheral IR, not with the severity of obesity and hepatic IR. Peripheral rather than hepatic IR is a dominant factor of pathophysiology in nonalcoholic fatty liver disease.
Macrophage migration inhibitory factor deficiency in chronic obstructive pulmonary disease
Authors: Sauler Maor , Leng Lin , Trentalange Mark , Haslip Maria , Shan Peiying , Piecychna Marta , Zhang Yi , Andrews Nathaniel , Mannam Praveen , Allore Heather , Fried Terri , Bucala Richard , Lee Patty J.
Published: January 2014

The pathogenesis of chronic obstructive pulmonary disease (COPD) remains poorly understood. Cellular senescence and apoptosis contribute to the development of COPD; however, crucial regulators of these underlying mechanisms remain unknown. Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine that antagonizes both apoptosis and premature senescence and may be important in the pathogenesis of COPD. This study examines the role of MIF in the pathogenesis of COPD. Mice deficient in MIF ( Mif −/−) or the MIF receptor CD74 ( Cd74 −/−) and wild-type (WT) controls were aged for 6 mo. Both Mif −/− and Cd74 −/− mice developed spontaneous emphysema by 6 mo of age compared with WT mice as measured by lung volume and chord length. This was associated with activation of the senescent pathway markers p53/21 and p16. Following exposure to cigarette smoke, Mif −/− mice were more susceptible to the development of COPD and apoptosis compared with WT mice. MIF plasma concentrations were measured in a cohort of 224 human participants. Within a subgroup of older current and former smokers ( n = 72), MIF concentrations were significantly lower in those with COPD [8.8, 95%CI (6.7–11.0)] compared with those who did not exhibit COPD [12.7 ng/ml, 95%CI (10.6–14.8)]. Our results suggest that both MIF and the MIF receptor CD74 are required for maintenance of normal alveolar structure in mice and that decreases in MIF are associated with COPD in human subjects.
Computed tomographic measures of airway morphology in smokers and never-smoking normals
Authors: Washko G. R. , Diaz A. A. , Kim V. , Barr R. G. , Dransfield M. T. , Schroeder J. , Reilly J. J. , Ramsdell J. W. , McKenzie A. , Van Beek E. J. R. , Lynch D. A. , Butler J. P. , Han M. K.
Published: January 2014

Bronchial wall area percent (WA% = 100 × wall area/total bronchial cross sectional area) is a standard computed tomographic (CT) measure of central airway morphology utilized in smokers with chronic obstructive pulmonary disease (COPD). Although it provides significant clinical correlations, the range of reported WA% is narrow. This suggests limited macroscopic change in response to smoking or that remodeling proportionally affects the airway wall and lumen dimensions such that their ratio is preserved. The objective of this study is to assess central airway wall area (WA), lumen area (Ai), and total bronchial area (Ao) from CT scans of 5,179 smokers and 92 never smoking normal subjects. In smokers, WA, Ai, and Ao were positively correlated with forced expiratory volume in 1 s (FEV1) expressed as a percent of predicted (FEV1%), and the WA% was negatively correlated with FEV1% ( P < 0.0001 for all comparisons). Importantly, smokers with lower FEV1% tended to have airways of smaller cross-sectional area with lower WA. The increases in the WA% across GOLD stages of chronic obstructive pulmonary disease (COPD) can therefore not be due to increases in WA. The data suggest two possible origins for the WA% increases: 1) central airway remodeling resulting in overall reductions in airway caliber in excess of the decreased WA or 2) those with COPD had smaller native airways before they began smoking. In both cases, these observations provide an explanation for the limited range of values of WA% across stages of COPD.
Perturbed and spontaneous regional cerebral blood flow responses to changes in blood pressure after high-level spinal cord injury: the effect of midodrine
Authors: Phillips Aaron A. , Krassioukov Andrei V. , Ainslie Philip N. , Warburton Darren E. R.
Published: January 2014

Individuals with spinal cord injury (SCI) above the T6 spinal segment suffer from orthostatic intolerance. How cerebral blood flow (CBF) responds to orthostatic challenges in SCI is poorly understood. Furthermore, it is unclear how interventions meant to improve orthostatic tolerance in SCI influence CBF. This study aimed to examine 1) the acute regional CBF responses to rapid changes in blood pressure (BP) during orthostatic stress in individuals with SCI and able-bodied (AB) individuals; and 2) the effect of midodrine (alpha1-agonist) on orthostatic tolerance and CBF regulation in SCI. Ten individuals with SCI >T6, and 10 age- and sex-matched AB controls had beat-by-beat BP and middle and posterior cerebral artery blood velocity (MCAv, PCAv, respectively) recorded during a progressive tilt-test to quantify the acute CBF response and orthostatic tolerance. Dynamic MCAv and PCAv to BP relationships were evaluated continuously in the time domain and frequency domain (via transfer function analysis). The SCI group was tested again after administration of 10 mg midodrine to elevate BP. Coherence (i.e., linearity) was elevated in SCI between BP-MCAv and BP-PCAv by 35% and 22%, respectively, compared with AB, whereas SCI BP-PCAv gain (i.e., magnitudinal relationship) was reduced 30% compared with AB (all P < 0.05). The acute (i.e., 0–30 s after tilt) MCAv and PCAv responses were similar between groups. In individuals with SCI, midodrine led to improved PCAv responses 30–60 s following tilt (10 ± 3% vs. 4 ± 2% decline; P < 0.05), and a 59% improvement in orthostatic tolerance ( P < 0.01). The vertebrobasilar region may be particularly susceptible to hypoperfusion in SCI, leading to increased orthostatic intolerance.
Research-Based PAM50 Subtype Predictor Identifies Higher Responses and Improved Survival Outcomes in HER2-Positive Breast Cancer in the NOAH Study
Authors: Prat Aleix , Bianchini Giampaolo , Thomas Marlene , Belousov Anton , Cheang Maggie C.U. , Koehler Astrid , Gómez Patricia , Semiglazov Vladimir , Eiermann Wolfgang , Tjulandin Sergei , Byakhow Mikhail , Bermejo Begoña , Zambetti Milvia , Vazquez Federico , Gianni Luca , Baselga José
Published: January 2014

Purpose: We report a retrospective exploratory analysis of the association of the research-based prediction analysis of microarray 50 (PAM50) subtype predictor with pathologic complete response (pCR) and event-free survival (EFS) in women enrolled in the NeOAdjuvant Herceptin (NOAH) trial.

Experimental Design: Gene expression profiling was performed using RNA from formalin-fixed paraffin-embedded core biopsies from 114 pretreated patients with HER2-positive (HER2+) tumors randomized to receive neoadjuvant doxorubicin/paclitaxel (AT) followed by cyclophosphamide/methotrexate/fluorouracil (CMF), or the same regimen in combination with trastuzumab for one year. A control cohort of 42 patients with HER2-negative tumors treated with AT-CMF was also included. The PAM50 subtypes, the PAM50 proliferation score, and the PAM50 risk of relapse score based on subtype (RORS) and subtype and proliferation (RORP) were evaluated.

Results: HER2-enriched (HER2-E) tumors predominated within HER2+ disease, although all PAM50 intrinsic subtypes were identified across the three cohorts. The OR for achieving pCR with trastuzumab-based chemotherapy for HER2+/HER2-E and HER2+/RORP-high were 5.117 (P = 0.009) and 8.469 (P = 0.025), respectively, compared with chemotherapy only. The pCR rates of HER2+/HER2-E and HER2+/RORP-high after trastuzumab-based chemotherapy were 52.9% and 75.0%, respectively. A statistically nonsignificant trend was observed for more pronounced survival benefit with trastuzumab in patients with HER2+/HER2-E and HER2+/RORP-high tumors compared with patients with HER2+/non-HER2-E and HER2+/non-RORP-high tumors, respectively.

Conclusions: As determined by EFS and pCR, patients with HER2+/HER2-E tumors, or HER2+/RORP-high tumors, benefit substantially from trastuzumab-based chemotherapy. The clinical value of this genomic test within HER2+ disease warrants further investigation. Clin Cancer Res; 20(2); 511–21. ©2014 AACR.
“Quitting Smoking Will Benefit Your Health”: The Evolution of Clinician Messaging to Encourage Tobacco Cessation
Authors: Toll Benjamin A. , Rojewski Alana M. , Duncan Lindsay R. , Latimer-Cheung Amy E. , Fucito Lisa M. , Boyer Julie L. , O'Malley Stephanie S. , Salovey Peter , Herbst Roy S.
Published: January 2014

Illnesses that are caused by smoking remain as the world's leading cause of preventable death. Smoking and tobacco use constitute approximately 30% of all cancer-related deaths and nearly 90% of lung cancer–related deaths. Thus, improving smoking cessation interventions is crucial to reduce tobacco use and assist in minimizing the burden of cancer and other diseases in the United States. This review focuses on the existing research on framed messages to promote smoking cessation. Consistent with the tenets of prospect theory and recent meta-analysis, gain-framed messages emphasizing the benefits of quitting seem to be preferable when working with adult patients who smoke tobacco products. The evidence also suggests that moderators of treatment should guide framed statements made to patients. Meta-analyses have provided consistent moderators of treatment such as need for cognition, but future studies should further define the specific framed interventions that would be most helpful for subgroups of smokers. In conclusion, instead of using loss-framed statements like “Smoking will harm your health by causing problems like lung and other cancers, heart disease, and stroke,” as a general rule, physicians should use gain-framed statements like “Quitting smoking will benefit your health by preventing problems like lung and other cancers, heart disease, and stroke.” Clin Cancer Res; 20(2); 301–9. ©2014 AACR.
Antagonism of SET Using OP449 Enhances the Efficacy of Tyrosine Kinase Inhibitors and Overcomes Drug Resistance in Myeloid Leukemia
Authors: Agarwal Anupriya , MacKenzie Ryan J. , Pippa Raffaella , Eide Christopher A. , Oddo Jessica , Tyner Jeffrey W. , Sears Rosalie , Vitek Michael P. , Odero María D. , Christensen Dale J. , Druker Brian J.
Published: January 2014

Purpose: The SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A), is overexpressed in leukemia. We evaluated the efficacy of SET antagonism in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cell lines, a murine leukemia model, and primary patient samples using OP449, a specific, cell-penetrating peptide that antagonizes SET's inhibition of PP2A.

Experimental Design: In vitro cytotoxicity and specificity of OP449 in CML and AML cell lines and primary samples were measured using proliferation, apoptosis, and clonogenic assays. Efficacy of target inhibition by OP449 was evaluated by immunoblotting and PP2A assay. In vivo antitumor efficacy of OP449 was measured in human HL-60 xenografted murine model.

Results: We observed that OP449 inhibited growth of CML cells including those from patients with blastic phase disease and patients harboring highly drug-resistant BCR-ABL1 mutations. Combined treatment with OP449 and ABL1 tyrosine kinase inhibitors was significantly more cytotoxic to K562 cells and primary CD34+ CML cells. SET protein levels remained unchanged with OP449 treatment, but BCR-ABL1–mediated downstream signaling was significantly inhibited with the degradation of key signaling molecules such as BCR-ABL1, STAT5, and AKT. Similarly, AML cell lines and primary patient samples with various genetic lesions showed inhibition of cell growth after treatment with OP449 alone or in combination with respective kinase inhibitors. Finally, OP449 reduced the tumor burden of mice xenografted with human leukemia cells.

Conclusions: We demonstrate a novel therapeutic paradigm of SET antagonism using OP449 in combination with tyrosine kinase inhibitors for the treatment of CML and AML. Clin Cancer Res; 20(8); 2092–103. ©2014 AACR.
Enhancement of the Tumor Penetration of Monoclonal Antibody by Fusion of a Neuropilin-Targeting Peptide Improves the Antitumor Efficacy
Authors: Shin Tae-Hwan , Sung Eun-Sil , Kim Ye-Jin , Kim Ki-Su , Kim Se-Ho , Kim Seok-Ki , Lee Young-Don , Kim Yong-Sung
Published: January 2014

The limited localization and penetration of monoclonal antibodies (mAb) into solid tumors restricts their antitumor efficacy. Here, we describe a solid tumor–targeting antibody with enhanced tumor penetration activity. We designed a 22-residue peptide (A22p), which was extracted from the C-terminal basic region of semaphorin 3A (Sema3A) but modified to have higher affinity with neuropilin receptors (NRP), and genetically fused it to the C-terminus of Fc of human immunoglobulin G1 via a 15-residue (G4S)3 linker, generating Fc-A22p, for the bivalent binding to NRPs. In contrast to Fc or the monovalent A22p peptide alone, Fc-A22p homed to tumor vessels and induced vascular permeability through VE-cadherin downregulation and penetrated tumor tissues by interacting with NRPs in mice bearing human tumor xenografts. We extended the Fc-A22p platform by generating mAb-A22p antibodies of two clinically approved solid tumor–targeting mAbs, the anti-EGF receptor mAb cetuximab (erbitux), and the anti-Her2 mAb trastuzumab (herceptin). The mAb-A22p antibodies retained the intrinsic antigen binding, natural Fc-like biophysical properties, and productivity in mammalian cell cultures, comparable with those of the parent mAbs. In mouse xenograft tumor models, the mAb-A22p antibodies more efficiently homed to tumor vessels and spread into the extravascular tumor parenchyma, which significantly enhanced antitumor efficacy compared with the parent mAbs. Our results suggest that mAb-A22p is a superior format for solid tumor–targeting antibodies due to its enhanced tumor tissue penetration and greater antitumor efficacy compared with conventional mAbs. Mol Cancer Ther; 13(3); 651–61. ©2014 AACR.
Highly Active Combination of BRD4 Antagonist and Histone Deacetylase Inhibitor against Human Acute Myelogenous Leukemia Cells
Authors: Fiskus Warren , Sharma Sunil , Qi Jun , Valenta John A. , Schaub Leasha J. , Shah Bhavin , Peth Karissa , Portier Bryce P. , Rodriguez Melissa , Devaraj Santhana G.T. , Zhan Ming , Sheng Jianting , Iyer Swaminathan P. , Bradner James E. , Bhalla Kapil N.
Published: January 2014

The bromodomain and extra-terminal (BET) protein family members, including BRD4, bind to acetylated lysines on histones and regulate the expression of important oncogenes, for example, c-MYC and BCL2. Here, we demonstrate the sensitizing effects of the histone hyperacetylation-inducing pan–histone deacetylase (HDAC) inhibitor panobinostat on human acute myelogenous leukemia (AML) blast progenitor cells (BPC) to the BET protein antagonist JQ1. Treatment with JQ1, but not its inactive enantiomer (R-JQ1), was highly lethal against AML BPCs expressing mutant NPM1c+ with or without coexpression of FLT3-ITD or AML expressing mixed lineage leukemia fusion oncoprotein. JQ1 treatment reduced binding of BRD4 and RNA polymerase II to the DNA of c-MYC and BCL2 and reduced their levels in the AML cells. Cotreatment with JQ1 and the HDAC inhibitor panobinostat synergistically induced apoptosis of the AML BPCs, but not of normal CD34+ hematopoietic progenitor cells. This was associated with greater attenuation of c-MYC and BCL2, while increasing p21, BIM, and cleaved PARP levels in the AML BPCs. Cotreatment with JQ1 and panobinostat significantly improved the survival of the NOD/SCID mice engrafted with OCI-AML3 or MOLM13 cells (P < 0.01). These findings highlight cotreatment with a BRD4 antagonist and an HDAC inhibitor as a potentially efficacious therapy of AML. Mol Cancer Ther; 13(5); 1142–54. ©2014 AACR.
Targeting Microtubules by Natural Agents for Cancer Therapy
Authors: Mukhtar Eiman , Adhami Vaqar Mustafa , Mukhtar Hasan
Published: January 2014

Natural compounds that target microtubules and disrupt the normal function of the mitotic spindle have proven to be one of the best classes of cancer chemotherapeutic drugs available in clinics to date. There is increasing evidence showing that even minor alteration of microtubule dynamics can engage the spindle checkpoint, arresting cell-cycle progression at mitosis and subsequently leading to cell death. Our improved understanding of tumor biology and our continued appreciation for what the microtubule targeting agents (MTAs) can do have helped pave the way for a new era in the treatment of cancer. The effectiveness of these agents for cancer therapy has been impaired, however, by various side effects and drug resistance. Several new MTAs have shown potent activity against the proliferation of various cancer cells, including resistance to the existing MTAs. Sustained investigation of the mechanisms of action of MTAs, development and discovery of new drugs, and exploring new treatment strategies that reduce side effects and circumvent drug resistance could provide more effective therapeutic options for patients with cancer. This review focuses on the successful cancer chemotherapy from natural compounds in clinical settings and the challenges that may abort their usefulness. Mol Cancer Ther; 13(2); 275–84. ©2014 AACR.
Functional Heterogeneity of PAX5 Chimeras Reveals Insight for Leukemia Development
Authors: Fortschegger Klaus , Anderl Stefanie , Denk Dagmar , Strehl Sabine
Published: January 2014

PAX5, a transcription factor pivotal for B-cell commitment and maintenance, is one of the most frequent targets of somatic mutations in B-cell precursor acute lymphoblastic leukemia. A number of PAX5 rearrangements result in the expression of in-frame fusion genes encoding chimeric proteins, which at the N-terminus consistently retain the PAX5 DNA-binding paired domain fused to the C-terminal domains of a markedly heterogeneous group of fusion partners. PAX5 fusion proteins are thought to function as aberrant transcription factors, which antagonize wild-type PAX5 activity. To gain mechanistic insight into the role of PAX5 fusion proteins in leukemogenesis, the biochemical and functional properties of uncharacterized fusions: PAX5–DACH1, PAX5–DACH2, PAX5–ETV6, PAX5–HIPK1, and PAX5–POM121 were ascertained. Independent of the subcellular distribution of the wild-type partner proteins, ectopic expression of all PAX5 fusion proteins showed a predominant nuclear localization, and by chromatin immunoprecipitation all of the chimeric proteins exhibited binding to endogenous PAX5 target sequences. Furthermore, consistent with the presence of potential oligomerization motifs provided by the partner proteins, the self-interaction capability of several fusion proteins was confirmed. Remarkably, a subset of the PAX5 fusion proteins conferred CD79A promoter activity; however, in contrast with wild-type PAX5, the fusion proteins were unable to induce Cd79a transcription in a murine plasmacytoma cell line. These data show that leukemia-associated PAX5 fusion proteins share some dominating characteristics such as nuclear localization and DNA binding but also show distinctive features.

Implications: This comparative study of multiple PAX5 fusion proteins demonstrates both common and unique properties, which likely dictate their function and impact on leukemia development. Mol Cancer Res; 12(4); 595–606. ©2014 AACR.
Rapid Induction of Apoptosis by PI3K Inhibitors Is Dependent upon Their Transient Inhibition of RAS–ERK Signaling
Authors: Will Marie , Qin Alice Can Ran , Toy Weiyi , Yao Zhan , Rodrik-Outmezguine Vanessa , Schneider Claudia , Huang Xiaodong , Monian Prashant , Jiang Xuejun , de Stanchina Elisa , Baselga José , Liu Ningshu , Chandarlapaty Sarat , Rosen Neal
Published: January 2014

The effects of selective phosphoinositide 3-kinase (PI3K) and AKT inhibitors were compared in human tumor cell lines in which the pathway is dysregulated. Both caused inhibition of AKT, relief of feedback inhibition of receptor tyrosine kinases, and growth arrest. However, only the PI3K inhibitors caused rapid induction of cell death. In seeking a mechanism for this phenomenon, we found that PI3K inhibition, but not AKT inhibition, causes rapid inhibition of wild-type RAS and of RAF–MEK–ERK signaling. Inhibition of RAS–ERK signaling is transient, rebounding a few hours after drug addition, and is required for rapid induction of apoptosis. Combined MEK and AKT inhibition also promotes cell death, and in murine models of HER2+ cancer, either pulsatile PI3K inhibition or combined MEK and AKT inhibition causes tumor regression. We conclude that PI3K is upstream of RAS and AKT and that pulsatile inhibition of both pathways is sufficient for effective antitumor activity.

Significance: We show that the RAS–ERK pathway is a key downstream effector pathway of oncogenic PI3K. Coordinate downregulation of AKT and ERK is necessary for induction of apoptosis and antitumor activity and can be accomplished with pulsatile dosing, which will likely decrease toxicity and allow administration of therapeutic doses. Cancer Discov; 4(3); 334–47. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 259
Polypoidal Choroidal Vasculopathy: Clinical Features and Genetic Predisposition
Authors: Honda Shigeru , Matsumiya Wataru , Negi Akira
Published: January 2014

Polypoidal choroidal vasculopathy (PCV) is currently recognized as a phenotype of age-related macular degeneration (AMD). PCV is believed to be a type of choroidal neovascularization, although some cases of PCV show a distinct vascular abnormality of the choroidal vessels. PCV often shows several unique clinical manifestations which are apparently different from typical neovascular AMD (tAMD). In addition, the natural course and response to treatment are often different between tAMD and PCV. Moreover, recent genetic studies suggested a possible difference in the genetic susceptibility to disease between tAMD and PCV, as well as the existence of heterogeneity among PCV cases. In viewing the accumulation of knowledge about PCV, we have summarized the recent literature regarding PCV in this review article to improve the understanding of this clinical entity including possible susceptibility genes. We will also discuss the optimal treatment strategies for PCV in accordance with the results of recent clinical and genetic studies.
Safety and Outcome of Patients Treated with a Modified Outpatient Intraperitoneal Regimen for Epithelial Ovarian, Primary Peritoneal or Fallopian Tube Cancer
Authors: Battelli Chiara , Campo Meghan , Buss Mary K. , Awtrey Christopher S. , Konstantinopoulos Panagiotis A.
Published: January 2014

Background: Despite the survival benefit of intraperitoneal (IP) chemotherapy observed in GOG172, significant toxicity and poor treatment completion rates have prevented the widespread acceptance of this regimen. Here, we report our experience with a modified outpatient GOG172 regimen. Methods: Eligible patients had stage III, optimally debulked epithelial ovarian, fallopian tube or primary peritoneal cancer that underwent IP port placement for administration of a modified GOG172 regimen consisting of: (i) intravenous paclitaxel 135 mg/m2 on day 1 over 3 h; (ii) intraperitoneal cisplatin 75 mg/m2 on day 2, and (iii) intraperitoneal paclitaxel 60 mg/m2 on day 8. Day 8 IP paclitaxel was omitted until tolerance of the first cycle of IP cisplatin had been established. Results: Four or more cycles of IP chemotherapy were completed by 72.5% (29) of 40 eligible patients; 20% of patients exhibited catheter-related complications requiring port removal and discontinuation of IP chemotherapy. Grade 3-4 hematologic, metabolic and gastrointestinal toxicities occurred in 36, 8 and 21% of the patients, respectively. With a median follow-up of 47.7 months, progression-free and overall survival was comparable to GOG172. Conclusions: This modified outpatient GOG172 regimen is associated with less toxicity and improved completion rates compared to the original GOG172 regimen.
Paricalcitol Ameliorates Epithelial-to-Mesenchymal Transition in the Peritoneal Mesothelium
Authors: Kang Seok Hui , Kim San Ok , Cho Kyu Hyang , Park Jong Won , Yoon Kyung Woo , Do Jun Young
Published: January 2014

Background: The purpose of the present study was to examine the effectiveness of paricalcitol for the prevention of epithelial-to-mesenchymal transition (EMT). Materials and Methods: Human peritoneal mesothelial cells (HPMCs) were cultured in media containing transforming growth factor β1 (TGF-β1) with or without paricalcitol. Forty-two male Sprague-Dawley rats were divided into three groups. In the control group, the catheter was inserted but no dialysate was infused. The peritoneal dialysis (PD) group was infused with a conventional 4.25% dialysis solution. The paricalcitol group was infused with 4.25% dialysis solution and cotreated with paricalcitol. Results: Exposure of HPMCs to TGF-β1 decreased the protein level of the epithelial cell marker and increased the expression levels of the mesenchymal markers. Cotreatment with paricalcitol increased the protein levels of the epithelial cell marker and decreased those of mesenchymal markers compared with their levels in cells treated with TGF-β1 alone. Exposure of HPMCs to TGF-β1 significantly increased the phosphorylation of Smad2 and Smad3. Cotreatment with paricalcitol significantly decreased the phosphorylation of Smad2 and Smad3 compared with that of cells treated with TGF-β1 alone. After 8 weeks of experimental PD in rats, the thickness of the peritoneal membrane in the PD group was significantly increased compared with that of the control group. Cotreatment with paricalcitol decreased peritoneal thickness. Conclusion: The present study showed that paricalcitol attenuates the TGF-β1-induced EMT in peritoneal mesothelial cells. We suggest that paricalcitol may preserve peritoneal mesothelial cells during PD and could thus be of value for the success of long-term PD.
Angiographic Outcomes Contradict Platelet Data in the PLATO Trial: Confusion over Official Trial Substudies
Authors: Serebruany Victor L.
Published: January 2014

Major indication-seeking phase 3 clinical trials usually include numerous subanalyses and substudies designed to facilitate the interpretation of results, often providing putative mechanisms that might explain clinical outcomes. Such subanalyses and/or substudies may focus on socioeconomic implications, cost-effectiveness, biomarker applicability, subgroup analyses, etc. Novel antiplatelet agents may benefit from substudies aimed at elucidating the effects on platelets, while angiographic data are also essential for the adequate assessment of coronary flow. Ideally, the data yielded from substudies should correlate well with the main results of the trial. However, in the PLATO (PLATelet Inhibition and Clinical Outcomes) trial, official angiographic data (PLATO-A) contradict platelet (PLATO-P) substudy results. While the large (n = 2,616) PLATO-A concluded that coronary flow and myocardial perfusion were almost identical after ticagrelor or clopidogrel, the small (n = 24) single-center PLATO-P suggested that ticagrelor achieved a highly significantly greater antiplatelet effect compared to clopidogrel after loading in patients enrolled in the same trial and at similar time points. In contrast to PLATO-P, PLATO-A corresponds well with clinical outcomes including the early percutaneous coronary intervention ‘ticagrelor death paradox' in PLATO-USA patients and the lack of an early ticagrelor benefit in the overall invasive PLATO cohort reported by the FDA. The discrepancy between PLATO-A and PLATO-P is obvious and lacks a reasonable explanation: platelet activity and coronary flow are generally inversely related, as consistently shown for other antiplatelet regimens, and should be particularly matched when assessed in the frame of the same trial.
Gefitinib Enhances the Antitumor Activity of CPT-11 in vitro and in vivo by Inhibiting ABCG2 but Not ABCB1: A New Clue to Circumvent Gastrointestinal Toxicity Risk
Authors: Inoue Yutaka , Ikegami Yoji , Sano Kazumi , Suzuki Toshihiro , Yoshida Hisahiro , Nakamura Yoichi , Nakagawa Hiroshi , Ishikawa Toshihisa
Published: January 2014

Background: Despite the potent antitumor activity of CPT-11, late-onset diarrhea owing to enterohepatic circulation of SN-38 is a critical issue. Methods: We aimed to evaluate the inhibitory potency of gefitinib against the ABCB1- or ABCG2-mediated excretion of CPT-11 and its active metabolite SN-38 in vitro and in vivo. Results: Gefitinib dose-dependently enhanced the antiproliferation activity of SN-38 in vitro by inhibiting ABCG2. The inhibitory effect of gefitinib on ABCB1 was marginal. When both CPT-11 and gefitinib were administered orally to nude mice bearing human lung cancer PC-6 cells, tumor growth was markedly suppressed. By gefitinib coadministration, the lactone forms of both CPT-11 and SN-38 in the tumor tissue increased more than 2-fold. Conclusions: Gefitinib significantly enhances the antitumor efficacy of CPT-11 and its tumor distribution in vivo. Coadministration of gefitinib may provide a new means to reduce the dose of CPT-11 and to circumvent the gastrointestinal toxicity risk.
Protective Role for Toll-Like Receptor-9 in the Development of Atherosclerosis in Apolipoprotein E–Deficient Mice
Authors: Koulis Christine , Chen Yung-Chih , Hausding Christian , Ahrens Ingo , Kyaw Tin Soe , Tay Christopher , Allen Terri , Jandeleit-Dahm Karin , Sweet Matthew J. , Akira Shizuo , Bobik Alexander , Peter Karlheinz , Agrotis Alex
Published: January 2014

Objective—

Atherosclerosis is driven by inflammatory reactions that are shared with the innate immune system. Toll-like receptor-9 (TLR9) is an intracellular pattern recognition receptor of the innate immune system that is currently under clinical investigation as a therapeutic target in inflammatory diseases. Here, we investigated whether TLR9 has a role in the development of atherosclerosis in apolipoprotein E–deficient (ApoE
−/−
) mice.

Approach and Results—

Newly generated double-knockout ApoE
−/−
:TLR9
−/−
mice and control ApoE
−/−
mice were fed a high-fat diet from 8 weeks and effects on lesion size, cellular composition, inflammatory status, and plasma lipids were assessed after 8, 12, 15, and 20 weeks. All 4 time points demonstrated exacerbated atherosclerotic lesion severity in ApoE
−/−
:TLR9
−/−
mice, with a corresponding increase in lipid deposition and accumulation of macrophages, dendritic cells, and CD4
+
T cells. Although ApoE
−/−
:TLR9
−/−
mice exhibited an increase in plasma very low-density lipoprotein/low-density-lipoprotein cholesterol, the very low-density lipoprotein/low-density lipoprotein:high-density lipoprotein ratio was unaltered because of a parallel increase in plasma high-density lipoprotein cholesterol. As a potential mechanism accounting for plaque progression in ApoE
−/−
:TLR9
−/−
mice, CD4
+
T-cell accumulation was further investigated and depletion of these cells in ApoE
−/−
:TLR9
−/−
mice significantly reduced lesion severity. As a final translational approach, administration of a TLR9 agonist (type B CpG oligodeoxynucleotide 1668) to ApoE
−/−
mice resulted in a reduction of lesion severity.

Conclusions—

Genetic deletion of the innate immune receptor TLR9 exacerbated atherosclerosis in ApoE
−/−
mice fed a high-fat diet. CD4
+
T cells were identified as potential mediators of this effect. A type B CpG oligodeoxynucleotide TLR9 agonist reduced lesion severity, thus identifying a novel therapeutic approach in atherosclerosis.
Functional Analysis of Two Haplotypes of the Human Endothelial Protein C Receptor Gene
Authors: Medina P. , Navarro S. , Bonet E. , Martos L. , Estellés A. , Bertina R.M. , Vos H.L. , España F.
Published: January 2014

Objective—

To confirm the effect of the endothelial protein receptor gene (
PROCR
) haplotypes H1 and H3 on venous thromboembolism (VTE), to study their effect on endothelial protein C receptor (EPCR) expression in human umbilical vein endothelial cells, and to investigate the functionality of H1 tagging single-nucleotide polymorphisms in an in vitro model.

Approach and Results—

Protein C (PC), activated PC, and soluble EPCR (sEPCR) levels were measured in 702 patients with VTE and 518 healthy individuals. All subjects were genotyped for
PROCR
H1 and H3. Human umbilical vein endothelial cells isolated from 111 umbilical cords were used to study the relation between
PROCR
haplotypes,
PROCR
mRNA, cellular distribution of EPCR, and rate of PC activation. Finally, the functionality of the intragenic
PROCR
H1 single-nucleotide polymorphisms was analyzed using a luciferase-based method. We confirmed that individuals carrying H1 have reduced VTE risk, increased plasma activated PC levels, and reduced plasma sEPCR levels and that individuals with the H3H3 genotype have an increased VTE risk and increased plasma sEPCR levels. In cultured human umbilical vein endothelial cells, H1 is associated with increased membrane-bound EPCR, increased rate of PC activation, and reduced sEPCR in conditioned medium, but does not significantly influence
PROCR
mRNA levels. In contrast, H3 is associated with reduced membrane-bound EPCR and increased sEPCR in human umbilical vein endothelial cell–conditioned medium, higher levels of a truncated mRNA isoform, and a lower rate of PC activation. Finally, we identified the g.2132T>C single-nucleotide polymorphism in intron 1 as an intragenic H1-specific functional single-nucleotide polymorphism.

Conclusions—

These results support a protective role of
PROCR
H1 against VTE and an increased risk of VTE associated with the H3 haplotype.
Multilocus Genetic Risk Score Associates With Ischemic Stroke in Case–Control and Prospective Cohort Studies
Authors: Malik Rainer , Bevan Steve , Nalls Michael A. , Holliday Elizabeth G. , Devan William J. , Cheng Yu-Ching , Ibrahim-Verbaas Carla A. , Verhaaren Benjamin F.J. , Bis Joshua C. , Joon Aron Y. , de Stefano Anita L. , Fornage Myriam , Psaty Bruce M. , Ikram M. Arfan , Launer Lenore J. , van Duijn Cornelia M. , Sharma Pankaj , Mitchell Braxton D. , Rosand Jonathan , Meschia James F. , Levi Christopher , Rothwell Peter M. , Sudlow Cathie , Markus Hugh S. , Seshadri Sudha , Dichgans Martin
Published: January 2014

Background and Purpose—

Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

Methods—

Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

Results—

A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case–control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

Conclusions—

A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.
Predicting Stroke Through Genetic Risk Functions
Authors: Ibrahim-Verbaas Carla A. , Fornage Myriam , Bis Joshua C. , Choi Seung Hoan , Psaty Bruce M. , Meigs James B. , Rao Madhu , Nalls Mike , Fontes Joao D. , O’Donnell Christopher J. , Kathiresan Sekar , Ehret Georg B. , Fox Caroline S. , Malik Rainer , Dichgans Martin , Schmidt Helena , Lahti Jari , Heckbert Susan R. , Lumley Thomas , Rice Kenneth , Rotter Jerome I. , Taylor Kent D. , Folsom Aaron R. , Boerwinkle Eric , Rosamond Wayne D. , Shahar Eyal , Gottesman Rebecca F. , Koudstaal Peter J. , Amin Najaf , Wieberdink Renske G. , Dehghan Abbas , Hofman Albert , Uitterlinden André G. , DeStefano Anita L. , Debette Stephanie , Xue Luting , Beiser Alexa , Wolf Philip A. , DeCarli Charles , Ikram M. Arfan , Seshadri Sudha , Mosley Thomas H. , Longstreth W.T. , van Duijn Cornelia M. , Launer Lenore J.
Published: January 2014

Background and Purpose—

Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

Methods—

The study includes 4 population-based cohorts with 2047 first incident strokes from 22 720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case–control study of ischemic stroke.

Results—

In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016,
P
=2.3×10
−6
; ischemic stroke: Δjoint area under the curve=0.021,
P
=3.7×10
−7
), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (
P
<10
−4
).

Conclusions—

The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.