bluuebunny/crossref_metadata_2025 huggingface dataset:
Technical Solutions to Mitigate Reliability Challenges due to Technology Scaling of Charge Storage NVM
Authors: Lee Meng Chuan , Wong Hin Yong
Published: October 2013

Charge storage nonvolatile memory (NVM) is one of the main driving forces in the evolution of IT handheld devices. Technology scaling of charge storage NVM has always been the strategy to achieve higher density NVM with lower cost per bit in order to meet the persistent consumer demand for larger storage space. However, conventional technology scaling of charge storage NVM has run into many critical reliability challenges related to fundamental device characteristics. Therefore, further technology scaling has to be supplemented with novel approaches in order to surmount these reliability issues to achieve desired reliability performance. This paper is focused on reviewing critical research findings on major reliability challenges and technical solutions to mitigate technology scaling challenges of charge storage NVM. Most of these technical solutions are still in research phase while a few of them are more mature and ready for production phase. Three of the mature technical solutions will be reviewed in detail, that is, tunnel oxide top/bottom nitridation, nanocrystal, and phase change memory (PCM). Key advantages and reported reliability challenges of these approaches are thoroughly reviewed in this paper. This paper will serve as a good reference to understand the future trend of innovative technical solutions to overcome the reliability challenges of charge storage NVM due to technology scaling.
A Note on Parabolic Homogenization with a Mismatch between the Spatial Scales
Authors: Flodén Liselott , Holmbom Anders , Olsson Lindberg Marianne , Persson Jens
Published: October 2013

We consider the homogenization of the linear parabolic problem which exhibits a mismatch between the spatial scales in the sense that the coefficient of the elliptic part has one frequency of fast spatial oscillations, whereas the coefficient of the time derivative contains a faster spatial scale. It is shown that the faster spatial microscale does not give rise to any corrector term and that there is only one local problem needed to characterize the homogenized problem. Hence, the problem is not of a reiterated type even though two rapid scales of spatial oscillation appear.
Singular Value Decomposition and Ligand Binding Analysis
Authors: Galo André Luiz , Colombo Márcio Francisco
Published: October 2013

Singular values decomposition (SVD) is one of the most important computations in linear algebra because of its vast application for data analysis. It is particularly useful for resolving problems involving least-squares minimization, the determination of matrix rank, and the solution of certain problems involving Euclidean norms. Such problems arise in the spectral analysis of ligand binding to macromolecule. Here, we present a spectral data analysis method using SVD (SVD analysis) and nonlinear fitting to determine the binding characteristics of intercalating drugs to DNA. This methodology reduces noise and identifies distinct spectral species similar to traditional principal component analysis as well as fitting nonlinear binding parameters. We applied SVD analysis to investigate the interaction of actinomycin D and daunomycin with native DNA. This methodology does not require prior knowledge of ligand molar extinction coefficients (free and bound), which potentially limits binding analysis. Data are acquired simply by reconstructing the experimental data and by adjusting the product of deconvoluted matrices and the matrix of model coefficients determined by the Scatchard and McGee and von Hippel equation.
The Fractional Quadratic-Form Identity and Hamiltonian Structure of an Integrable Coupling of the Fractional Broer-Kaup Hierarchy
Authors: Yue Chao , Xia Tiecheng , Liu Guijuan , Liu Jianbo
Published: October 2013

A fractional quadratic-form identity is derived from a general isospectral problem of fractional order, which is devoted to constructing the Hamiltonian structure of an integrable coupling of the fractional BK hierarchy. The method can be generalized to other fractional integrable couplings.
A Novel Approach to Sliding Mode Control of Time-Delay Systems
Authors: Xia Hongwei , Li Li , Wang Yanmin , Wu Aiguo , Ma Guangcheng
Published: October 2013

This paper is concerned with the sliding mode control for a class of linear systems with time-varying delays. By utilizing a novel Lyapunov-Krasovskii functional and combining it with the delay fractioning approach as well as the free-weighting matrix technology, a sufficient condition is established such that the resulting sliding mode dynamics is asymptotically stable. Then, a sliding mode controller for reaching motion is synthesized to guarantee that the trajectories of the resulting closed-loop system can be driven onto a prescribed sliding surface and maintained there for all subsequent time. A numerical example is provided to illustrate the effectiveness of the proposed design approach.
A Minimax Theorem forL-0-Valued Functions on Random Normed Modules
Authors: Zhao Shien , Zhao Yuan
Published: October 2013

We generalize the well-known minimax theorems toL¯0-valued functions on random normed modules. We first give some basic properties of anL0-valued lower semicontinuous function on a random normed module under the two kinds of topologies, namely, the (ε,λ)-topology and the locallyL0-convex topology. Then, we introduce the definition of random saddle points. Conditions for anL0-valued function to have a random saddle point are given. The most greatest difference between our results and the classical minimax theorems is that we have to overcome the difficulty resulted from the lack of the condition of compactness. Finally, we, using relations between the two kinds of topologies, establish the minimax theorem ofL¯0-valued functions in the framework of random normed modules and random conjugate spaces.
A Novel Image Mosaicking Algorithm for Wireless Multimedia Sensor Networks
Authors: Li Zhiyuan , Kong Weiting , Zhan Yongzhao , Bi Junlei
Published: October 2013

The wisdom tourism is an important application of internet of things industry, and many cities in China have paid attention to the development of wisdom tourism, such as the national historic city of Zhenjiang. How to take advantage of the cooperation among sensor nodes to obtain the panoramic information of scenic spots is a challenging issue for the wisdom tourism. However, the existing image mosaic algorithms are not suitable for wireless multimedia sensor networks (WMSNs) due to the resource-constrained multimedia sensor nodes, such as energy, computing, and storage space. And hence an image mosaic algorithm based on phase correlation and weighted average (IMBPW) is proposed in this paper. The IMBPW algorithm uses the phase correlation based on Fourier transform to achieve the registration of translation, rotation, and scaling images. After the image registration, the adaptive weighted average algorithm is proposed to do the image fusion. The simulation experiments show that compared with homogeneous algorithms, the IMBPW algorithm has higher real-time and fast convergence speed. Furthermore, the simulation results also show that the proposed algorithm can improve the accuracy of image registration, reduce the complexity of the image mosaic, and prolong the network lifetime while providing better image quality.
The Cohesive Zone Model for Fatigue Crack Growth
Authors: Liu Jinxiang , Li Jun , Wu Bo
Published: October 2013

In the past decade, the cohesive zone model has been receiving increasing attention as a powerful tool for the simulation of fatigue crack growth. When applying cohesive zone model to fatigue fracture problem, three aspects should generally be taken into account, that is, unloading-reloading path, damage evolution during cyclic loading, and crack surface contact and friction behavior. This paper addresses the critical views of these aspects. Before that, the formulation of cohesive zone model and identification of cohesive zone model parameters and its numerical implementation have been reviewed.
Novel Modeling of Cancer Cell Signaling Pathways Enables Systematic Drug Repositioning for Distinct Breast Cancer Metastases
Authors: Zhao Hong , Jin Guangxu , Cui Kemi , Ren Ding , Liu Timothy , Chen Peikai , Wong Solomon , Li Fuhai , Fan Yubo , Rodriguez Angel , Chang Jenny , Wong Stephen TC
Published: October 2013

A new type of signaling network element, called cancer signaling bridges (CSB), has been shown to have the potential for systematic and fast-tracked drug repositioning. On the basis of CSBs, we developed a computational model to derive specific downstream signaling pathways that reveal previously unknown target–disease connections and new mechanisms for specific cancer subtypes. The model enables us to reposition drugs based on available patient gene expression data. We applied this model to repurpose known or shelved drugs for brain, lung, and bone metastases of breast cancer with the hypothesis that cancer subtypes have their own specific signaling mechanisms. To test the hypothesis, we addressed specific CSBs for each metastasis that satisfy (i) CSB proteins are activated by the maximal number of enriched signaling pathways specific to a given metastasis, and (ii) CSB proteins are involved in the most differential expressed coding genes specific to each breast cancer metastasis. The identified signaling networks for the three types of breast cancer metastases contain 31, 15, and 18 proteins and are used to reposition 15, 9, and 2 drug candidates for the brain, lung, and bone metastases. We conducted both in vitro and in vivo preclinical experiments as well as analysis on patient tumor specimens to evaluate the targets and repositioned drugs. Of special note, we found that the Food and Drug Administration-approved drugs, sunitinib and dasatinib, prohibit brain metastases derived from breast cancer, addressing one particularly challenging aspect of this disease. Cancer Res; 73(20); 6149–63. ©2013 AACR.
Contribution of Bcl-2 Phosphorylation to Bak Binding and Drug Resistance
Authors: Dai Haiming , Ding Husheng , Meng X. Wei , Lee Sun-Hee , Schneider Paula A. , Kaufmann Scott H.
Published: October 2013

Bcl-2 is phosphorylated on Ser70 after treatment of cells with spindle poisons. On the basis of effects observed in cells overexpressing Bcl-2 S70E or S70A mutants, various studies have concluded that Ser70 phosphorylation either enhances or diminishes Bcl-2 function. In the present study, the ability of phosphorylated Bcl-2, as well as the S70E and S70A mutants, to bind and neutralize proapoptotic Bcl-2 family members under cell-free conditions and in intact cells was examined in an attempt to resolve this controversy. Surface plasmon resonance indicated that phosphorylated Bcl-2, Bcl-2 S70E, and Bcl-2 S70A exhibit enhanced binding to Bim and Bak compared with unmodified Bcl-2. This enhanced binding reflected a readily detectable conformation change in the loop domain of Bcl-2. Furthermore, Bcl-2 S70E and S70A bound more Bak and Bim than wild-type Bcl-2 in pull-downs and afforded greater protection against several chemotherapeutic agents. Importantly, binding of endogenous Bcl-2 to Bim also increased during mitosis, when Bcl-2 is endogenously phosphorylated, and disruption of this mitotic Bcl-2/Bim binding with navitoclax or ABT-199, like Bcl-2 downregulation, enhanced the cytotoxicity of paclitaxel. Collectively, these results provide not only a mechanistic basis for the enhanced antiapoptotic activity of phosphorylated Bcl-2, but also an explanation for the ability of BH3 mimetics to enhance taxane sensitivity. Cancer Res; 73(23); 6998–7008. ©2013 AACR.
RSK Isoforms in Cancer Cell Invasion and Metastasis
Authors: Sulzmaier Florian J. , Ramos Joe W.
Published: October 2013

Metastasis, the spreading of cancer cells from a primary tumor to secondary sites throughout the body, is the primary cause of death for patients with cancer. New therapies that prevent invasion and metastasis in combination with current treatments could therefore significantly reduce cancer recurrence and morbidity. Metastasis is driven by altered signaling pathways that induce changes in cell–cell adhesion, the cytoskeleton, integrin function, protease expression, epithelial-to-mesenchymal transition and cell survival. The ribosomal S6 kinase (RSK) family of kinases is a group of extracellular signal–regulated kinase/mitogen-activated protein kinase (ERK/MAPK) effectors that can regulate these steps of metastasis by phosphorylating both nuclear and cytoplasmic targets. However, our understanding of RSK function in metastasis remains incomplete and is complicated by the fact that the four RSK isoforms perform nonredundant, sometimes opposing functions. Although some isoforms promote cell motility and invasion by altering transcription and integrin activity, others impair cell motility and invasion through effects on the actin cytoskeleton. The mechanism of RSK action depends both on the isoform and the cancer type. However, despite the variance in RSK-mediated outcomes, chemical inhibition of this group of kinases has proven effective in blocking invasion and metastasis of several solid tumors in preclinical models. RSKs are therefore a promising drug target for antimetastatic cancer treatments that could supplement and improve current therapeutic approaches. This review highlights contradiction and agreement in the current data on the function of RSK isoforms in metastasis and suggests ways forward in developing RSK inhibitors as new antimetastasis drugs. Cancer Res; 73(20); 6099–105. ©2013 AACR.
Interleukin-6 Is Required for Pancreatic Cancer Progression by Promoting MAPK Signaling Activation and Oxidative Stress Resistance
Authors: Zhang Yaqing , Yan Wei , Collins Meredith A. , Bednar Filip , Rakshit Sabita , Zetter Bruce R. , Stanger Ben Z. , Chung Ivy , Rhim Andrew D. , di Magliano Marina Pasca
Published: October 2013

Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal—regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target. Cancer Res; 73(20); 6359–74. ©2013 AACR.
The Evolution of Melanoma Resistance Reveals Therapeutic Opportunities
Authors: Thakur Meghna Das , Stuart Darrin D.
Published: October 2013

The RAS–RAF–MEK–ERK pathway is a key driver of proliferation and survival signals in tumor cells and has been the focus of intense drug development efforts over the past 20 years. The recent regulatory approval of RAF inhibitors and a MAP–ERK kinase (MEK) inhibitor for metastatic melanoma provides clinical validation of tumor dependency on this pathway. Unfortunately, the therapeutic benefit of these agents is often short lived and resistance develops within a matter of months. Preclinical models of resistance to vemurafenib have provided critical insights into predicting, validating, and characterizing potential mechanisms. A key observation has been that vemurafenib-resistant tumor cells suffer a fitness deficit in the absence of drug treatment and this led to the predication that modulating the selective pressure of drug treatment through intermittent dosing could delay or prevent the emergence of resistant tumors. Most importantly, the preclinical data are supported by observations in vemurafenib-treated patients with melanoma providing a strong rationale for clinical testing of alternative dosing regimens. Cancer Res; 73(20); 6106–10. ©2013 AACR.
Twenty-fifth Annual Pezcoller Symposium: Metabolism and Tumorigenesis
Authors: Kaelin William , Livingston David , Loda Massimo , Vousden Karen , Mihich Enrico
Published: October 2013

Choking cancer via inhibition of metabolic enzymes essential for tumor but dispensable in normal tissues was discussed as was the altered metabolism in cancer cells related to: tumor suppressor protein (pVHL) function, the histone acetylation dependence upon glucose, the epigenomic reprogramming of acetyl CoA synthesis, the plasticity of aging mechanisms, and the metabolism orchestration in macrophage polarization. The p53 and p73 pathways role in metabolic adaptation, the effects on growth of AMP-dependent kinase, the growth regulation by the mTOR pathways, and the bioenergetics requirements of cancer cells were also discussed. A novel computational model of personalized metabolic changes in cancer was outlined with applications in patients with breast cancer. Imaging metabolic characteristics of tumors by MRI and 13C-nuclear magnetic resonance was described. The cancer metabolism regulation related to O-linked β-N-acetylglucosame was described. DNA hypermethylation and impaired hematopoietic differentiation in AML after isocitrate dehydrogenase 1/2 mutation and 2-hydroxyglutarate increases were outlined. Cancer Res; 73(20); 6124–7. ©2013 AACR.
Semaphorin 4F as a Critical Regulator of Neuroepithelial Interactions and a Biomarker of Aggressive Prostate Cancer
Authors: Ding Yi , He Dandan , Florentin Diego , Frolov Anna , Hilsenbeck Sue , Ittmann Michael , Kadmon Dov , Miles Brian , Rowley David , Ayala Gustavo
Published: October 2013

Background: Semaphorin 4F (S4F) has roles in embryologic axon guidance and is expressed in adults. S4F is involved in cancer-induced neurogenesis.

Methods: Prostate cells were transfected with S4F retrovirus. Cells and controls were used for a bromodeoxyuridine (BrdUrd) incorporation assay (proliferation) and in vitro scratch and Matrigel Transwell chamber invasion assay (migration). Monoclonal antibodies were developed using baculovirus-expressed recombinant GST-S4F and used to immunostain tissue microarrays. Slides were imaged using deconvolution and analyzed using tissue segmentation. Data were correlated with clinicopathologic parameters, other biomarkers and survival analysis conducted. Heterogeneity of S4F expression was analyzed with unsupervised clustering algorithms.

Results: Proliferation rates measured by BrdUrd incorporation were higher in all S4F-transfected cells. S4F overexpression was associated with increased motility of the cancer cells. S4F expression was overexpressed in high-grade prostatic intraepithelial neoplasia/prostate cancer than normal epithelium. S4F expression correlated with seminal vesicle invasion. Patients with high values of S4F in prostate cancer cytoplasm are at significantly higher risk of biochemical recurrence, by univariate and multivariate analyses. S4F cytoplasmic expression in prostate cancer cells also correlates with nerve density in prostate cancer and perineural invasion diameter. Correlations were identified with NF-κB and inversely with apoptosis in perineural invasion.

Conclusion: These data show that S4F is significantly involved in human prostate cancer progression. S4F is a key regulator of the interactions between nerves in the tumor microenvironment and cancer cells. Because of the importance of cancer nerve interaction in the biology of cancer and its clinical implication, S4F can be considered a major therapeutic target. Clin Cancer Res; 19(22); 6101–11. ©2013 AACR.
Ang-2-VEGF-A CrossMab, a Novel Bispecific Human IgG1 Antibody Blocking VEGF-A and Ang-2 Functions Simultaneously, Mediates Potent Antitumor, Antiangiogenic, and Antimetastatic Efficacy
Authors: Kienast Yvonne , Klein Christian , Scheuer Werner , Raemsch Romi , Lorenzon Erica , Bernicke Dirk , Herting Frank , Yu Sidney , The Huynh Hung , Martarello Laurent , Gassner Christian , Stubenrauch Kay-Gunnar , Munro Kate , Augustin Hellmut G. , Thomas Markus
Published: October 2013

Purpose: VEGF-A blockade has been clinically validated as a treatment for human cancers. Angiopoietin-2 (Ang-2) expression has been shown to function as a key regulator of tumor angiogenesis and metastasis.

Experimental Design: We have applied the recently developed CrossMab technology for the generation of a bispecific antibody recognizing VEGF-A with one arm based on bevacizumab (Avastin), and the other arm recognizing Ang-2 based on LC06, an Ang-2 selective human IgG1 antibody. The potency of Ang-2-VEGF CrossMab was evaluated alone and in combination with chemotherapy using orthotopic and subcutaneous xenotransplantations, along with metastasis analysis by quantitative real-time Alu-PCR and ex vivo evaluation of vessels, hypoxia, proliferation, and apoptosis. The mechanism of action was further elucidated using Western blotting and ELISA assays.

Results: Ang-2-VEGF-A CrossMab showed potent tumor growth inhibition in a panel of orthotopic and subcutaneous syngeneic mouse tumors and patient or cell line-derived human tumor xenografts, especially at later stages of tumor development. Ang-2-VEGF-A CrossMab treatment led to a strong inhibition of angiogenesis and an enhanced vessel maturation phenotype. Neoadjuvant combination with chemotherapy resulted in complete tumor regression in primary tumor-bearing Ang-2-VEGF-A CrossMab-treated mice. In contrast to Ang-1 inhibition, anti-Ang-2-VEGF-A treatment did not aggravate the adverse effect of anti-VEGF treatment on physiologic vessels. Moreover, treatment with Ang-2-VEGF-A CrossMab resulted in inhibition of hematogenous spread of tumor cells to other organs and reduced micrometastatic growth in the adjuvant setting.

Conclusion: These data establish Ang-2-VEGF-A CrossMab as a promising antitumor, antiangiogenic, and antimetastatic agent for the treatment of cancer. Clin Cancer Res; 19(24); 6730–40. ©2013 AACR.
Dual Targeting of HER2-Positive Cancer with Trastuzumab Emtansine and Pertuzumab: Critical Role for Neuregulin Blockade in Antitumor Response to Combination Therapy
Authors: Phillips Gail D. Lewis , Fields Carter T. , Li Guangmin , Dowbenko Donald , Schaefer Gabriele , Miller Kathy , Andre Fabrice , Burris Howard A. , Albain Kathy S. , Harbeck Nadia , Dieras Veronique , Crivellari Diana , Fang Liang , Guardino Ellie , Olsen Steven R. , Crocker Lisa M. , Sliwkowski Mark X.
Published: October 2013

Purpose: Targeting HER2 with multiple HER2-directed therapies represents a promising area of treatment for HER2-positive cancers. We investigated combining the HER2-directed antibody–drug conjugate trastuzumab emtansine (T-DM1) with the HER2 dimerization inhibitor pertuzumab (Perjeta).

Experimental Design: Drug combination studies with T-DM1 and pertuzumab were performed on cultured tumor cells and in mouse xenograft models of HER2-amplified cancer. In patients with HER2-positive locally advanced or metastatic breast cancer (mBC), T-DM1 was dose-escalated with a fixed standard pertuzumab dose in a 3+3 phase Ib/II study design.

Results: Treatment of HER2-overexpressing tumor cells in vitro with T-DM1 plus pertuzumab resulted in synergistic inhibition of cell proliferation and induction of apoptotic cell death. The presence of the HER3 ligand, heregulin (NRG-1β), reduced the cytotoxic activity of T-DM1 in a subset of breast cancer lines; this effect was reversed by the addition of pertuzumab. Results from mouse xenograft models showed enhanced antitumor efficacy with T-DM1 and pertuzumab resulting from the unique antitumor activities of each agent. In patients with mBC previously treated with trastuzumab, lapatinib, and chemotherapy, T-DM1 could be dosed at the maximum tolerated dose (MTD; 3.6 mg/kg every 3 weeks) with standard dose pertuzumab. Adverse events were mostly grade 1 and 2, with indications of clinical activity.

Conclusions: Dual targeting of HER2 with the combination of T-DM1 and pertuzumab in cell culture and mouse xenograft models resulted in enhanced antitumor activity. In patients, this combination showed an encouraging safety and tolerability profile with preliminary evidence of efficacy. Clin Cancer Res; 20(2); 456–68. ©2013 AACR.
A Novel Engineered Anti-CD20 Tracer Enables Early Time PET Imaging in a Humanized Transgenic Mouse Model of B-cell Non-Hodgkins Lymphoma
Authors: Natarajan Arutselvan , Hackel Benjamin J. , Gambhir Sanjiv Sam
Published: October 2013

Purpose: The aim of this article was to evaluate the use of a novel engineered anti-CD20 protein based on the 10 kDa human fibronectin type 3 domain (FN3) and subsequently compare with 64Cu-rituximab for positron emission tomography (PET) imaging of CD20.

Experimental Design: The engineered FN3CD20 and FN3WT were produced in Escherichia coli cells at 2 to 5 mg/L, conjugated to DOTA, labeled with 64Cu, and used for PET imaging of huCD20 expression in B cells. Humanized transgenic mice and subcutaneously xenografted mice each received intravenous 64Cu-FN3CD20 or FN3WT (3.7 MBq/4 μg Do-FN3 in 200 μL PBS). Control group received a blocking dose (50-fold excess) of unconjugated FN3CD20 two hours before radiotracer injection. PET imaging was carried out at 1 to 24 hours postinjections.

Results: In vitro assay demonstrated FN3 binds CD20 with 20 nmol/L affinity on CD20-expressing cells. 64Cu-FN3CD20 showed clear, high-contrast visualization of huCD20-expressing B cells in the spleen of transgenic mice as early as 1 hour postinjection [38 ± 3% injected dose (ID)/g] and exhibited a spleen-to-blood ratio of 13 by 4 hours. This is higher uptake (P = 0.04) and 10-fold greater signal-to-background (P = 0.04) than the 64Cu-rituximab antibody radiotracer. Tumor uptake (16.8 ± 1.6 vs. 5.6 ± 1.4%ID/g) and tumor:background ratios were superior for FN3CD20 relative to rituximab in xenograft studies as well.

Conclusions: The 64Cu-Do-FN3CD20 radiotracer represents a novel small, high-affinity binder for imaging human CD20, which may be well suited for B-cell non-Hodgkin's lymphoma imaging in patients at early time points. Clin Cancer Res; 19(24); 6820–9. ©2013 AACR.
Cabozantinib Inhibits Prostate Cancer Growth and Prevents Tumor-Induced Bone Lesions
Authors: Dai Jinlu , Zhang Honglai , Karatsinides Andreas , Keller Jill M. , Kozloff Kenneth M. , Aftab Dana T. , Schimmoller Frauke , Keller Evan T.
Published: October 2013

Purpose: Cabozantinib, an orally available multityrosine kinase inhibitor with activity against mesenchymal epithelial transition factor (MET) and VEGF receptor 2 (VEGFR2), induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases. The purpose of this study was to determine whether cabozantinib elicited a direct antitumor effect, an indirect effect through modulating bone, or both.

Experimental Design: Using human prostate cancer xenograft studies in mice, we determined the impact of cabozantinib on tumor growth in soft tissue and bone. In vitro studies with cabozantinib were performed using (i) prostate cancer cell lines to evaluate its impact on cell growth, invasive ability, and MET and (ii) osteoblast cell lines to evaluate its impact on viability and differentiation and VEGFR2.

Results: Cabozantinib inhibited progression of multiple prostate cancer cell lines (Ace-1, C4-2B, and LuCaP 35) in bone metastatic and soft tissue murine models of prostate cancer, except for PC-3 prostate cancer cells in which it inhibited only subcutaneous growth. Cabozantinib directly inhibited prostate cancer cell viability and induced apoptosis in vitro and in vivo and inhibited cell invasion in vitro. Cabozantinib had a dose-dependent biphasic effect on osteoblast activity and inhibitory effect on osteoclast production in vitro that was reflected in vivo. It blocked MET and VEGFR2 phosphorylation in prostate cancer cells and osteoblast-like cells, respectively.

Conclusion: These data indicate that cabozantinib has direct antitumor activity, and that its ability to modulate osteoblast activity may contribute to its antitumor efficacy. Clin Cancer Res; 20(3); 617–30. ©2013 AACR.
Bendamustine and Rituximab in Relapsed and Refractory Hairy Cell Leukemia
Authors: Burotto Mauricio , Stetler-Stevenson Maryalice , Arons Evgeny , Zhou Hong , Wilson Wyndham , Kreitman Robert J.
Published: October 2013

Purpose: To determine tolerability and for the first time explore efficacy of bendamustine–rituximab (BR) in multiply relapsed/refractory hairy cell leukemia (HCL), using two different dose levels of bendamustine.

Experimental Design: Patients with HCL with ≥2 prior therapies requiring treatment received rituximab 375 mg/m2 days 1 and 15 plus bendamustine 70 (n = 6) or 90 (n = 6) mg/m2, days 1 and 2, for six cycles at 4-week intervals.

Results: At 70 and 90 mg/m2/dose of bendamustine, overall response rate was 100%, with three (50%) and four (67%) complete remissions (CR) in each respective group. Minimal residual disease (MRD) was absent in 67% and 100% of CRs, respectively. All six without MRD remain in CR at 30 to 35 (median, 31) months of follow-up. Soluble CD22 and CD25 levels decreased with all responses, with median values decreasing from 17.7 and 42 ng/mL at baseline to undetectable and 2 ng/mL after CR, respectively (P < 0.001). Of 12 patients receiving 72 cycles of BR, the most common toxicities were hematologic, including thrombocytopenia (83%), lymphopenia (75%), leukopenia (58%), and neutropenia (42%). Grade III and IV hematologic toxicity included lymphopenia and thrombocytopenia (each 75%), leukopenia (58%), and neutropenia (25%). No significant dose-related differences were detected in response or toxicity.

Conclusion: BR has significant activity in HCL. Bendamustine at either 70 or 90 mg/m2/dose was highly effective in multiply relapsed/refractory HCL and could be considered for achieving durable CRs without MRD in patients after failure of standard therapies. As it was not dose-limiting, 90 mg/m2/dose was chosen for future testing. Clin Cancer Res; 19(22); 6313–21. ©2013 AACR.
Phase I Study of Panobinostat plus Everolimus in Patients with Relapsed or Refractory Lymphoma
Authors: Oki Yasuhiro , Buglio Daniela , Fanale Michelle , Fayad Luis , Copeland Amanda , Romaguera Jorge , Kwak Larry W. , Pro Barbara , de Castro Faria Silvana , Neelapu Sattva , Fowler Nathan , Hagemeister Fredrick , Zhang Jiexin , Zhou Shouhao , Feng Lei , Younes Anas
Published: October 2013

Purpose: To evaluate the safety and efficacy of panobinostat plus everolimus in patients with relapsed Hodgkin and non-Hodgkin lymphoma. The concept was supported by the single-agent clinical activity of histone deacetylase inhibitors and mTOR inhibitors, and on the in vitro mechanism-based synergistic antiproliferative activity.

Experimental Design: This was a phase I study in patients with relapsed or refractory Hodgkin and non-Hodgkin lymphoma using panobinostat orally on Monday/Wednesday/Friday and everolimus orally daily. Toxicity and responses were assessed in dose-escalation cohort followed by expansion cohort at maximum-tolerated dose. Exploratory analysis of serum cytokine levels was performed.

Results: Thirty patients were enrolled onto four dose levels. The dose-limiting toxicity was thrombocytopenia. The maximal tolerated dose was panobinostat 20 mg and everolimus 10 mg. Grade 3/4 toxicity included thrombocytopenia (64%), neutropenia (47%), anemia (20%), infection (10%), fatigue (7%), and dyspnea (7%). A total of 10 patients (33%; indolent lymphoma, T-cell lymphoma, mantle cell lymphoma, and Hodgkin lymphoma) achieved objective responses. In patients with Hodgkin lymphoma (n = 14), the overall response rate was 43% with complete response rate of 15%. In patients with Hodgkin lymphoma, multiple serum cytokine levels decreased significantly after treatment with this combination therapy. Of note, clinical responses were associated with a decrease in serum interleukin-5 levels (day 8, P = 0.013, and day 15, P = 0.021).

Conclusions: Our data suggest that the combination therapy is active but with significant thrombocytopenia. Future studies should explore alternate scheduling and different compounds that target the same pathways to improve the tolerability of this novel combination. Clin Cancer Res; 19(24); 6882–90. ©2013 AACR.
It Takes Two to Tango: Dual Inhibition of PI3K and MAPK in Rhabdomyosarcoma
Authors: Jahangiri Arman , Weiss William A.
Published: October 2013

The PI3K/AKT/mTOR and RAS/RAF/MAPK pathways play essential roles in rhabdomyosarcoma. Singular targeting of each pathway is ineffective due to extensive cross-talk and compensatory feedback between these two pathways. Dual blockade with inhibitors of PI3K and MAPK in combination synergistically inhibits growth of rhabdomyosarcoma both in vitro and in vivo. Clin Cancer Res; 19(21); 5811–3. ©2013 AACR.
Harnessing Immune Responses in the Tumor Microenvironment: All Signals Needed
Authors: Le Dung T. , Jaffee Elizabeth M.
Published: October 2013

An agonist CD40 monoclonal antibody (CP-870,893), in combination with gemcitabine, is well tolerated in patients with advanced pancreatic adenocarcinoma. The combination results in induction of cytokines, B cell activation, and clinical responses. These findings support testing of immunotherapies in combination with other established and targeted therapies. Clin Cancer Res; 19(22); 6061–3. ©2013 AACR.
Test-Firing Ammunition for Spliceosome Inhibition in Cancer
Authors: Dehm Scott M.
Published: October 2013

E7107 is a derivative of the pladienolide family of natural product spliceosome inhibitors, which targets the U2 small nuclear ribonucleoprotein (snRNP) subunit SF3b. The results of a first-in-human trial with E7107 have been reported, representing an important translational step toward the goal of modulating RNA splicing for cancer therapy. Clin Cancer Res; 19(22); 6064–6. ©2013 AACR.
Clinical, Electrocardiographic, Echocardiographic Characteristics and Long-Term Follow-Up of Elite Soccer Players With J-Point Elevation
Authors: Biasco Luigi , Cristoforetti Yvonne , Castagno Davide , Giustetto Carla , Astegiano Piero , Ganzit Gianpasquale , Gribaudo Carlo Gabriele , Gaita Fiorenzo
Published: October 2013

Background—

J-point elevation is common in athletes; nevertheless, the influence of structural changes associated with the athlete’s heart and its prognostic impact are still debated. Our aim was to investigate the prevalence of J-point elevation, the associated clinical, electrocardiographic, and echocardiographic characteristics and its impact on long-term outcome in elite soccer players.

Methods and Results—

Clinical, electrocardiographic, and cardiopulmonary exercise test data from 332 male professional soccer players were retrospectively analyzed. For 235 (70.7%) athletes echocardiographic data were also available. J-point elevation was defined as an elevation ≥1 mm in ≥2 contiguous leads. Long-term follow-up data were obtained for all athletes, whereas univariate and multivariable analyses were performed to assess the associated characteristics. Overall, 118 (35.6%) athletes showed a J-point elevation ≥1 mm. At multivariable analysis a significant direct association of interventricular septum thickness (odds ratio for 1 SD increase, 1.361; 95% confidence interval, 1.019–1.817;
P
=0.036) and Sokolow–Lyon index (odds ratio for 1 SD increase, 1.367; 95% confidence interval, 1.026–1.822;
P
=0.033) and an inverse association of baseline heart rate (odds ratio for 1 SD increase, 0.686; 95% confidence interval, 0.508–0.927;
P
=0.011) with J-point elevation were observed. During a long-term follow-up (median, 13.3 years; first and third quartiles, 10.1–17.0 years), a low mortality rate was observed, not related to cardiovascular causes.

Conclusions—

The correlation between J-point elevation and interventricular septum thickness suggests a possible mechanistic role of exercise-induced left ventricular hypertrophy as the basis for J-point elevation. After a long-term follow-up, no cardiac death was observed.
Unipolar Signal Modification as a Guide for Lesion Creation During Radiofrequency Application in the Left Atrium
Authors: Bortone Agustín , Appetiti Anthony , Bouzeman Abdeslam , Maupas Eric , Ciobotaru Vlad , Boulenc Jean-Marc , Pujadas-Berthault Pénélope , Rioux Philippe
Published: October 2013

Background—

In patients treated for paroxysmal atrial fibrillation, the pulmonary vein (PV) reconnection rate is substantial and may be related to the lack of transmurality achievement while performing PV isolation (PVI). It has been experimentally demonstrated that positive unipolar atrial electrogram completion, when applying radiofrequency energy, was associated with transmural lesions. In this regard, we seek to determine whether the unipolar signal modification may be an appropriate end point for point-by-point radiofrequency application and find out whether it could improve the paroxysmal atrial fibrillation ablation results in humans.

Methods and Results—

Fifty consecutive patients (61±8 years old, 41 men) with paroxysmal atrial fibrillation underwent PVI using Carto and Lasso. Each radiofrequency application lasted until development of a completely positive unipolar electrogram. Fifty patients (63±9 years old, 40 men), who previously underwent PVI following the standard approach of our institution, corresponded to the control group. All PVs were isolated in all patients of both groups. However, the procedural and ablation times were significantly lower in the unipolar group compared with those of the control group, whereas the PV reconnection rate, after 30 minutes of waiting time, was not significantly different. Overall, 21±4 months after 1 PVI session, the sinus rhythm maintenance rate without antiarrhythmic drugs was significantly higher (
P
=0.027) in the unipolar group (88%) compared with that of the control group (70%).

Conclusions—

Unipolar signal modification is a useful end point for radiofrequency energy delivery in patients with paroxysmal atrial fibrillation who undergo PVI and leads to a substantial midterm sinus rhythm maintenance rate.
Accuracy of Conventional Oximetry for Flow Estimation in Patients With Superior Cavopulmonary Connection
Authors: Downing Tacy E. , Whitehead Kevin K. , Dori Yoav , Gillespie Matthew J. , Harris Matthew A. , Fogel Mark A. , Rome Jonathan J. , Glatz Andrew C.
Published: October 2013

Background—

Cardiac catheterization is routinely used as a diagnostic tool in single ventricle patients with superior cavopulmonary connection. This physiology presents inherent challenges in applying the Fick principle to estimate flow. We sought to quantitatively define the error in oximetry-derived flow parameters using phase-contrast cardiac MRI (CMR) as a reference.

Methods and Results—

Thirty patients with superior cavopulmonary connection who underwent combined CMR and catheterization between July 2008 and June 2012 were retrospectively analyzed. Estimates of flow and resistance calculated using the Fick equation were compared with CMR measurements. Oximetry underestimated CMR-measured pulmonary blood flow (
Q
p
) by an average of 1.1 L/min per m
2
or 32% of the CMR value (
P
<0.0001). Oximetry overestimated systemic blood flow (
Q
s
) by an average of 0.5 L/min per m
2
or 15% of the CMR value (
P
=0.009). There was no correlation between the
Q
p
:
Q
s
ratio derived by Fick and that measured by CMR (
ρ
c
=0.01). The error in the Fick
Q
p
correlated moderately with the measured systemic-to-pulmonary arterial collateral flow (
r
=0.39). The median total oxygen consumption calculated using combined CMR and oximetry data was 173 mL/min per m
2
, higher than the assumed values used to calculate flows by the Fick equation. The upper body circulation received on average 51% of systemic blood flow while conducting only 39% of total body metabolism.

Conclusions—

Fick-derived estimates of flow are inherently unreliable in patients with superior cavopulmonary connections. Integrating flows measured by CMR and pressures measured by catheter will provide the best characterization of superior cavopulmonary connection physiology.
Occult Cardiotoxicity in Childhood Cancer Survivors Exposed to Anthracycline Therapy
Authors: Toro-Salazar Olga H. , Gillan Eileen , O’Loughlin Michael T. , Burke Georgine S. , Ferranti Joanna , Stainsby Jeffrey , Liang Bruce , Mazur Wojciech , Raman Subha V. , Hor Kan N.
Published: October 2013

Background—

More than 50% of >270 000 childhood cancer survivors in the United States have been treated with anthracyclines and are therefore at risk of developing cardiotoxicity. Cardiac magnetic resonance (CMR) has demonstrated utility to detect diffuse interstitial fibrosis and changes in regional myocardial function. We hypothesized that CMR would identify occult cardiotoxicity characterized by structural and functional myocardial abnormalities in a cohort of asymptomatic pediatric cancer survivors with normal global systolic function.

Methods and Results—

Forty-six long-term childhood cancer survivors with a cumulative anthracycline dose ≥200 mg/m
2
and normal systolic function were studied 2.5 to 26.9 years after anthracycline exposure. Subjects underwent transthoracic echocardiography, CMR with routine cine acquisition, tissue characterization, and left ventricular strain analysis using a modified 16-segment model. Extracellular volume was measured in 27 subjects, all of whom were late gadolinium enhancement negative. End-systolic fiber stress was elevated in 45 of 46 subjects. Low average circumferential strain magnitude (
ε
cc
) −14.9±1.4;
P
<0.001, longitudinal strain magnitude (
ε
ll
) −13.5±1.9;
P
<0.001, and regional peak circumferential strain were seen in multiple myocardial segments, despite normal global systolic function by transthoracic echocardiography and CMR. The mean T1 values of the myocardium were significantly lower than that of control subjects at 20 minutes (458±69 versus 487±44 milliseconds;
P
=0.01). Higher mean extracellular volume was observed in female subjects (0.34 versus 0.22;
P
=0.01).

Conclusions—

Asymptomatic postchemotherapy pediatric patients have abnormal myocardial characteristics and strain parameters by CMR despite normal global cardiac function by standard transthoracic echocardiography and CMR measures.
Macrophage Migration Inhibitory Factor for the Early Prediction of Infarct Size
Authors: Chan William , White David A. , Wang Xin‐Yu , Bai Ru‐Feng , Liu Yang , Yu Hai‐Yi , Zhang You‐Yi , Fan Fenling , Schneider Hans G. , Duffy Stephen J. , Taylor Andrew J. , Du Xiao‐Jun , Gao Wei , Gao Xiao‐Ming , Dart Anthony M.
Published: October 2013

Background

Early diagnosis and knowledge of infarct size is critical for the management of acute myocardial infarction (
MI
). We evaluated whether early elevated plasma level of macrophage migration inhibitory factor (
MIF
) is useful for these purposes in patients with
ST
‐elevation
MI
(
STEMI
).

Methods and Results

We first studied
MIF
level in plasma and the myocardium in mice and determined infarct size.
MI
for 15 or 60 minutes resulted in 2.5‐fold increase over control values in plasma
MIF
levels while
MIF
content in the ischemic myocardium reduced by 50% and plasma
MIF
levels correlated with myocardium‐at‐risk and infarct size at both time‐points (
P
<0.01). In patients with
STEMI
, we obtained admission plasma samples and measured
MIF
, conventional troponins (
TnI
,
TnT
), high sensitive
TnI
(
hsTnI
), creatine kinase (
CK
),
CK
‐
MB
, and myoglobin. Infarct size was assessed by cardiac magnetic resonance (
CMR
) imaging. Patients with chronic stable angina and healthy volunteers were studied as controls. Of 374
STEMI
patients, 68% had elevated admission
MIF
levels above the highest value in healthy controls (>41.6 ng/mL), a proportion similar to
hsTnI
(75%) and
TnI
(50%), but greater than other biomarkers studied (20% to 31%, all
P
<0.05 versus
MIF
). Only admission
MIF
levels correlated with
CMR
‐derived infarct size, ventricular volumes and ejection fraction (n=42, r=0.46 to 0.77, all
P
<0.01) at 3 day and 3 months post‐
MI
.

Conclusion

Plasma
MIF
levels are elevated in a high proportion of
STEMI
patients at the first obtainable sample and these levels are predictive of final infarct size and the extent of cardiac remodeling.
Physician Accuracy in Interpreting Potential ST‐Segment Elevation Myocardial Infarction Electrocardiograms
Authors: McCabe James M. , Armstrong Ehrin J. , Ku Ivy , Kulkarni Ameya , Hoffmayer Kurt S. , Bhave Prashant D. , Waldo Stephen W. , Hsue Priscilla , Stein John C. , Marcus Gregory M. , Kinlay Scott , Ganz Peter
Published: October 2013

Background

With adoption of telemedicine, physicians are increasingly asked to diagnose
ST
‐segment elevation myocardial infarctions (
STEMI
s) based on electrocardiograms (
ECG
s) with minimal associated clinical information. We sought to determine physicians' diagnostic agreement and accuracy when interpreting potential
STEMI ECG
s.

Methods and Results

A cross‐sectional survey was performed consisting of 36 deidentified
ECG
s that had previously resulted in putative
STEMI
diagnoses. Emergency physicians, cardiologists, and interventional cardiologists participated in the survey. For each
ECG
, physicians were asked, “based on the
ECG
above, is there a blocked coronary artery present causing a
STEMI
?” The reference standard for ascertaining the
STEMI
diagnosis was subsequent emergent coronary arteriography. Responses were analyzed with generalized estimating equations to account for nested and repeated measures. One hundred twenty‐four physicians interpreted a total of 4392
ECG
s. Among all physicians, interreader agreement (kappa) for
ECG
interpretation was 0.33, reflecting poor agreement. The sensitivity to identify “true”
STEMI
s was 65% (95%
CI
: 63 to 67) and the specificity was 79% (95%
CI
: 77 to 81). There was a 6% increase in the odds of accurate
ECG
interpretation for every 5 years of experience since medical school graduation (
OR
1.06, 95%
CI
: 1.02 to 1.10,
P
=0.01). After adjusting for experience, there was no significant difference in the odds of accurate interpretation by specialty—Emergency Medicine (reference), General Cardiology (
AOR
0.97, 95%
CI
: 0.79 to 1.2,
P
=0.80), or Interventional Cardiology physicians (
AOR
1.24, 95%
CI
: 0.93 to 1.7,
P
=0.15).

Conclusions

There is significant physician disagreement in interpreting
ECG
s with features concerning for
STEMI
. Such
ECG
s lack the necessary sensitivity and specificity to act as a suitable “stand‐alone” diagnostic test.