bluuebunny/crossref_metadata_2025 huggingface dataset:
Modifying Bodily Self-Awareness during Acupuncture Needle Stimulation Using the Rubber Hand Illusion
Authors: Chang Dong-Seon , Kim Yun-Ji , Lee Soon-Ho , Lee Hyejung , Lee In-Seon , Park Hi-Joon , Wallraven Christian , Chae Younbyoung
Published: April 2013

Background. The rubber hand illusion (RHI) is an experimental paradigm that manipulates important aspects of body self-awareness.Objectives. We were interested in whether modifying bodily self-awareness by manipulation of body ownership and visual expectations using the RHI would change the subjective perception of pain as well as the autonomic response to acupuncture needle stimulation.Methods. Acupuncture needle stimulation was applied to the real hand during the RHI with (experiment 1) or without (experiment 2) visual expectation while measuring concurrent autonomic changes such as the skin conductance response (SCR). Subjective responses such as perception of the RHI and perceived pain were measured by questionnaires.Results. In experiment 1, the amplitude of the increase in SCR was visibly higher during the synchronous session compared with that of the asynchronous session. In experiment 2, the amplitude of the increase of SCR was lower for the synchronous session compared with that for the asynchronous session. Comparing these two experiments, the visual expectation of needle stimulation produced a greater autonomic response to acupuncture stimulation.Conclusions. Our findings suggest that the sympathetic response to acupuncture needle stimulation is primarily influenced by visual expectation rather than by modifications of body ownership.
Mobitz Type II Atrioventricular Block Followed by Remifentanil in a Patient with Severe Aortic Stenosis
Authors: Taghavi Gilani Mehryar , Razavi Majid
Published: April 2013

Opioids have been considered for their hemodynamic stability. Remifentanil is an opioid analgesic with rapid metabolism and fast primary effect and recovery. In this paper, a very rare effect of using remifentanil along with propofol was presented. An 84-year-old male patient with severe aortic stenosis underwent general anesthesia. In order to induce anesthesia and maintain it, fentanyl, pancuronium, and propofol, along with a combination of propofol and remifentanil, were used, respectively. At beginning of remifentanil infusion, bradycardia and then Mobitz type II conduction block with a hemodynamic disorder occurred for the patient. The decreased blood pressure responded to injection of atropine and ephedrine; however, dysrhythmia only improved after cessation of remifentanil. Therefore remifentanil should be used with caution in aortic stenosis.
Boehmeria niveaStimulates Glucose Uptake by Activating Peroxisome Proliferator-Activated Receptor Gamma in C2C12 Cells and Improves Glucose Intolerance in Mice Fed a High-Fat Diet
Authors: Kim Sung Hee , Sung Mi Jeong , Park Jae Ho , Yang Hye Jeong , Hwang Jin-Taek
Published: April 2013

We examined the antidiabetic property ofBoehmeria nivea(L.) Gaud. Ethanolic extract ofBoehmeria nivea(L.) Gaud. (EBN) increased the uptake of 2-[N-(nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose in C2C12 myotubes. To examine the mechanisms underlying EBN-mediated increase in glucose uptake, we examined the transcriptional activity and expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), a pivotal target for glucose metabolism in C2C12 myotubes. We found that the EBN increased both the transcriptional activity and mRNA expression levels of PPAR-γ. In addition, we measured phosphorylation and expression levels of other targets of glucose metabolism, such as AMP-activated protein kinase (AMPK) and protein kinase B (Akt/PKB). We found that EBN did not alter the phosphorylation or expression levels of these proteins in a time- or dose-dependent manner, which suggested that EBN stimulates glucose uptake through a PPAR-γ-dependent mechanism. Further, we investigated the antidiabetic property of EBN using mice fed a high-fat diet (HFD). Administration of 0.5% EBN reduced the HFD-induced increase in body weight, total cholesterol level, and fatty liver and improved the impaired fasting glucose level, blood insulin content, and glucose intolerance. These results suggest that EBN had an antidiabetic effect in cell culture and animal systems and may be useful for preventing diabetes.
Travelling Waves of a Diffusive Epidemic Model with Latency and Relapse
Authors: Wang Zhiping , Xu Rui
Published: April 2013

An SEIR epidemic model with relapse and spatial diffusion is studied. By analyzing the corresponding characteristic equations, the local stability of each of the feasible steady states to this model is discussed. The existence of a travelling wave solution is established by using the technique of upper and lower solutions and Schauder's fixed point theorem. Numerical simulations are carried out to illustrate the main results.
Application of Optimal HAM for Finding Feedback Control of Optimal Control Problems
Authors: Saberi Nik H. , Shateyi Stanford
Published: April 2013

An optimal homotopy-analysis approach is described for Hamilton-Jacobi-Bellman equation (HJB) arising in nonlinear optimal control problems. This optimal approach contains at most three convergence-control parameters and is computationally rather efficient. A kind of averaged residual error is defined. By minimizing the averaged residual error, the optimal convergence-control parameters can be obtained. This optimal approach has general meanings and can be used to get fast convergent series solutions of different types of equations with strong nonlinearity. The closed-loop optimal control is obtained using the Bellman dynamic programming. Numerical examples are considered aiming to demonstrate the validity and applicability of the proposed techniques and to compare with the existing results.
Pulsating Different Curves of Zero Velocity around Triangular Equilibrium Points in Elliptical Restricted Three-Body Problem
Authors: Narayan A. , Shrivastava Amit
Published: April 2013

The oblateness and the photogravitational effects of both the primaries on the location and the stability of the triangular equilibrium points in the elliptical restricted three-body problem have been discussed. The stability of the triangular points under the photogravitational and oblateness effects of both the primaries around the binary systems Achird, Lyeten, Alpha Cen-AB, Kruger 60, and Xi-Bootis, has been studied using simulation techniques by drawing different curves of zero velocity.
miR145 Targets the SOX9/ADAM17 Axis to Inhibit Tumor-Initiating Cells and IL-6–Mediated Paracrine Effects in Head and Neck Cancer
Authors: Yu Cheng-Chia , Tsai Lo-Lin , Wang Mong-Lien , Yu Chuan-Hang , Lo Wen-Liang , Chang Yun-Ching , Chiou Guang-Yuh , Chou Ming-Yung , Chiou Shih-Hwa
Published: April 2013

ALDH1+CD44+ cells are putative tumor-initiating cells (TIC) in head and neck squamous cell carcinomas (HNC). miR-145 regulates tumorigenicity in various cancers but the breadth of its mechanistic contributions and potential therapeutic applications are not completely known. Here, we report that ALDH1+CD44+-HNC cells express reduced levels of miR145. SPONGE-mediated inhibition of miR-145 (Spg-miR145) was sufficient to drive tumor-initiating characteristics in non-TICs/ALDH1−CD44-negative HNC cells. Mechanistic analyses identified SOX9 and ADAM17 as two novel miR145 targets relevant to this process. miR-145 expression repressed TICs in HNC in a manner associated with SOX9 interaction with the ADAM17 promoter, thereby activating ADAM17 expression. Notably, the SOX9/ADAM17 axis dominated the TIC-inducing activity of miR-145. Either miR-145 suppression or ADAM17 overexpression in non-TICs/ALDH1−CD44−-HNC cells increased expression and secretion of interleukin (IL)-6 and soluble-IL-6 receptor (sIL-6R). Conversely, conditioned medium from Spg-miR145–transfected non-TICs/ALDH1−CD44−-HNC cells was sufficient to confer tumor-initiating properties in non-TICs/ALDH1−CD44−-HNC and this effect could be abrogated by an IL-6–neutralizing antibody. We found that curcumin administration increased miR-145 promoter activity, thereby decreasing SOX9/ADAM17 expression and eliminating TICs in HNC cell populations. Delivery of lentivral-miR145 or orally administered curcumin blocked tumor progression in HNC-TICs in murine xenotransplant assays. Finally, immunohistochemical analyses of patient specimens confirmed that an miR-145low/SOX9high/ADAM17high phenotype correlated with poor survival. Collectively, our results show how miR-145 targets the SOX9/ADAM17 axis to regulate TIC properties in HNC, and how altering this pathway may partly explain the anticancer effects of curcumin. By inhibiting IL-6 and sIL-6R as downstream effector cytokines in this pathway, miR-145 seems to suppress a paracrine signaling pathway in the tumor microenvironment that is vital to maintain TICs in HNC. Cancer Res; 73(11); 3425–40. ©2013 AACR.
Null Association between Tamoxifen Use and Dementia in Danish Breast Cancer Patients
Authors: Ording Anne Gulbech , Jensen Anders Bonde , Cronin-Fenton Deirdre , Pedersen Lars , Sørensen Henrik Toft , Lash Timothy L.
Published: April 2013

Background: Concerns have been raised about the risk of dementia associated with antiestrogen adjuvant therapy in breast cancer, but study results have been inconsistent. We examined whether tamoxifen or other endocrine therapy was associated with dementia risk in a large population of patients with breast cancer.

Methods: We used Danish nationwide medical registries to identify patients with breast cancer diagnosed between 1990 and 2004, use of endocrine therapy, and subsequent diagnoses of dementia. We used Cox regression to estimate the risk of dementia among patients who received five years of tamoxifen or other endocrine therapies.

Results: The study included 16,419 patients with breast cancer. In this cohort, 37% were unexposed to endocrine therapy, 9% had five years of tamoxifen therapy, and 54% had other endocrine regimens, some of them containing tamoxifen for less than five years with subsequent aromatase inhibitor therapy. Tamoxifen therapy was associated with a near-null risk of dementia [HR, 1.4; 95% confidence interval (CI), 1.0–1.9], and a null association was observed after death was taken into account as a competing risk (sub-HR, 1.0; 95% CI, 0.76–1.4).

Conclusions: No clinically relevant association between use of tamoxifen or other endocrine therapy and risk of dementia was observed.

Impact: Our result contradicts earlier research findings suggesting tamoxifen and other endocrine therapies increase the risk of dementia in breast cancer patients. Cancer Epidemiol Biomarkers Prev; 22(5); 993–6. ©2013 AACR.
Molecular Pathways: The Complex Roles of Inflammation Pathways in the Development and Treatment of Liver Cancer
Authors: Nikolaou Kostas , Sarris Michalis , Talianidis Iannis
Published: April 2013

Inflammatory signals from the surrounding microenvironment play important roles in tumor promotion. Key inflammatory mediators and pathways that induce and sustain tumorigenesis have recently been identified in many different cancers. Hepatocellular carcinoma is a paradigm for inflammation-induced cancer, as it most frequently develops in the setting of chronic hepatitis, consecutive cellular damage, and compensatory regeneration. Recent studies revealed that liver damage–mediated inflammation and carcinogenesis are triggered by a complex cross-talk between NF-κB, c-jun-NH2-kinase, and STAT3 signaling pathways. Molecular dissection of the mechanisms involved in the interplay between these pathways identified promising new targets for therapeutic intervention. Targeting different components of the signaling cascades may provide efficient means for blocking the apparently irreversible sequence of events initiated by chronic liver inflammation and culminating in liver cancer. Clin Cancer Res; 19(11); 2810–6. ©2013 AACR.
Altered DNA Methylation Landscapes of Polycomb-Repressed Loci Are Associated with Prostate Cancer Progression and ERG Oncogene Expression in Prostate Cancer
Authors: Kron Ken , Trudel Dominique , Pethe Vaijayanti , Briollais Laurent , Fleshner Neil , van der Kwast Theodorus , Bapat Bharati
Published: April 2013

Purpose: To assess differentially methylated “landscapes” according to prostate cancer Gleason score (GS) and ERG oncogene expression status, and to determine the extent of polycomb group (PcG) target gene involvement, we sought to assess the genome-wide DNA methylation profile of prostate cancer according to Gleason score and ERG expression.

Experimental Design: Genomic DNA from 39 prostate cancer specimens was hybridized to CpG island microarrays through differential methylation hybridization. We compared methylation profiles between Gleason score and ERG expression status as well as Gleason score stratified by ERG expression status. In addition, we compared results from our dataset to publicly available datasets of histone modifications in benign prostate cells.

Results: We discovered hundreds of distinct differentially methylated regions (DMR) associated with increasing Gleason score and ERG. Furthermore, the number of DMRs associated with Gleason score was greatly expanded by stratifying samples into ERG-positive versus ERG-negative, with ERG-positive/GS–associated DMRs being primarily hypermethylated as opposed to hypomethylated. Finally, we found that there was a significant overlap between either Gleason score–related or ERG-hypermethylated DMRs and distinct regions in benign epithelial cells that have PcG signatures (H3K27me3, SUZ12) and lack active gene expression signatures (H3K4me3, RNA pol II).

Conclusions: This work defines methylation landscapes of prostate cancer according to Gleason score, and suggests that initiating genetic events may influence the prostate cancer epigenome, which is further perturbed as prostate cancer progresses. Moreover, CpG islands with silent chromatin signatures in benign cells are particularly susceptible to prostate cancer–related hypermethylation. Clin Cancer Res; 19(13); 3450–61. ©2013 AACR.
Predictive Biomarkers for Bevacizumab: Are We There Yet?
Authors: Maru Dipen , Venook Alan P. , Ellis Lee M.
Published: April 2013

Therapy targeting VEGF has become the standard of care in several solid malignancies. Early investigations attempting to identify predictive markers for the efficacy of therapy failed to identify any predictive markers that could help oncologists decide who should—and, more importantly, who should not—receive VEGF-targeted therapies. However, interest has been renewed in predictive biomarkers for VEGF-targeted therapies, especially in light of the fact that the U.S. Food and Drug Administration withdrew approval for use of bevacizumab, an antibody to VEGF, in patients with metastatic breast cancer. In a recent publication in the Journal of Clinical Oncology, investigators identified circulating VEGF and tumor neuropilin-1 expression as potential predictive biomarkers for bevacizumab. From this perspective, we provide a critical evaluation of the use of these markers and the need for validation in prospective clinical trials. Clin Cancer Res; 19(11); 2824–7. ©2013 AACR.
Molecular Pathways: Environmental Estrogens Activate Nongenomic Signaling to Developmentally Reprogram the Epigenome
Authors: Wong Rebecca Lee Yean , Walker Cheryl Lyn
Published: April 2013

Exposure to environmental xenoestrogens is a major health concern because of the ability of these compounds to perturb estrogen receptor (ER) signaling and act as endocrine disrupting compounds (EDC). Inappropriate exposure to EDCs during development, even at low doses, can predispose individuals to an increased lifetime risk of disease, including cancer. Recent data indicate that perinatal exposure to EDCs increases cancer risk by (re)programming the epigenome via alterations in DNA and histone methylation. We and others have begun to dissect the mechanisms by which xenoestrogens disrupt the epigenetic machinery to reprogram the epigenome and induce developmental reprogramming. Our studies revealed that xenoestrogens induce nongenomic ER signaling to activate PI3K/AKT, resulting in AKT phosphorylation and inactivation of the histone methyltransferase EZH2, thus providing a direct link to disruption of the epigenome. Other epigenetic “readers, writers, and erasers” may also be targeted by nongenomic signaling, suggesting this is a central mechanism by which xenoestrogens and other EDCs disrupt the epigenome to induce developmental reprogramming. Elucidating mechanisms of developmental reprogramming of the epigenome is important for understanding how environmental exposures increase cancer risk, and provides a rationale for developing epigenetic interventions that can reverse the effects of environmental exposures to reduce cancer risk. Clin Cancer Res; 19(14); 3732–7. ©2013 AACR.
Abstract A29: Notch-dependent modulation of microRNAs in rhabdomyosarcoma
Authors: Rota Rossella , Ciarapica Roberta , Da Sacco Letizia , De Salvo Maria , Masotti Andrea , Miele Lucio , Locatelli Franco
Published: April 2013

Rhabdomyosarcoma (RMS) is a pediatric tumor that originates from skeletal muscle precursors. Therapeutic strategies aimed at restoring the differentiation potential of RMS tumor cells are accepted as anti-cancer approaches. Therefore, pathways involved in skeletal muscle determination are good potential targets. We have recently demonstrated that Notch3 signaling is over-activated in RMS cell lines of both embryonal and alveolar subtype. Down-regulation of Notch3 expression resulted in cell cycle inhibition of RMS alveolar and embryonal cell lines that showed the appearance of multinucleated structures indicative of skeletal muscle-like myotubes in vitro. Moreover, Notch3 knockdown impaired tumor growth in vivo. Here we expand this study evaluating, through microarrays profiling, the expression of microRNAs 48 hours after Notch3 siRNA treatment compared to that of control siRNA. Several up- or down-regulated microRNAs were detected in both RH30 alveolar and RD embryonal cells. The up-regulation of muscle-specific microRNAs such as miR-1, miR-133 and miR-206 was confirmed 24 and 48 hours post-Notch3 depletion by RT-qPCR. Moreover, non-muscle-specific microRNAs such as miR-26a and miR-214 that cooperate to myogenesis were up-regulated as well. Altogether, these preliminary results indicate that Notch3 prevents the differentiation of RMS cells also through down-regulation of pro-myogenic microRNAs. More deep studies are in course to dissect the Notch3-dependent modulation of these small non-coding RNAs in this soft tissue sarcoma.

Citation Format: Rossella Rota, Sr., Roberta Ciarapica, Jr., Letizia Da Sacco, Jr., Maria De Salvo, Jr., Andrea Masotti, Sr., Lucio Miele, Sr., Franco Locatelli, Sr. Notch-dependent modulation of microRNAs in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A29.
Abstract A31: Differential processing of let-7a precursors influences gemcitabine chemosensitivity in pancreatic cancer: Role of ribonucleotide reductase subunit M2
Authors: Govindarajan Rajgopal
Published: April 2013

Ribonucleotide reductase subunit M2 (RRM2) involved in deoxyribonucleotide synthesis acts as a key determinant of chemoresistance to nucleoside drugs (e.g., gemcitabine) used in treating pancreatic cancer. While silencing RRM2 expression by synthetic means (e.g., siRNA) improves the chemosensitivity of pancreatic cancer cells to gemcitabine, targeting endogenous molecules to advance gemcitabine chemotherapeutic responses has never been explored. Based on existing evidence and computational predictions, we hypothesized that the let-7 tumor suppressor microRNAs will inhibit RRM2-mediated gemcitabine chemoresistance in pancreatic cancer. Reduced expression of the majority of let-7 miRNAs with an inverse relationship to RRM2 expression was identified in inherently gemcitabine-resistant pancreatic cancer cells. Direct binding of let-7 miRNA to the 3′-UTR of RRM2 transcripts identified post-transcriptional repression of RRM2 as a novel phenomenon influencing gemcitabine chemosensitivity. Intriguingly, overexpression of human precursor-let-7 miRNAs led to differential RRM2 expression and gemcitabine chemosensitization in a poorly differentiated gemcitabine-resistant pancreatic cancer cell line MIA PaCa-2. Defective processing of the let-7a precursors to mature forms explained, in part, the discrepancies observed with let-7a expressional outcomes. Screening putative regulators of let-7a biogenesis in MIA PaCa-2 cells identified LIN-28 and SET oncoprotein to differentially modulate let-7 biogenesis and chemosensitivity in gemcitabine-sensitive versus-resistant pancreatic cancer cells. Additionally, acquired gemcitabine chemoresistance was found to be independent of let-7 alterations. These data demonstrate an intricate post-transcriptional regulation of RRM2 expression by let-7 and that the manipulation of let-7 processing machinery may provide a mechanism for improving gemcitabine chemosensitivity in innately-resistant pancreatic cancer cells.

Citation Format: Rajgopal Govindarajan. Differential processing of let-7a precursors influences gemcitabine chemosensitivity in pancreatic cancer: Role of ribonucleotide reductase subunit M2 [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr A31.
Abstract B15: Repression of PDGFRA-targeting miR-34a promotes tumorigenesis in proneural malignant gliomas
Authors: Silber Joachim , Jacobsen Anders , Ozawa Tatsuya , Harinath Girish , Holland Eric C. , Sander Chris , Huse Jason T.
Published: April 2013

Malignant gliomas - particularly glioblastoma (GBM) - continue to cause a disproportionate degree of morbidity and mortality within human oncology. Recent integrated genomics has demonstrated biologically distinct subclasses within malignant glioma that transcend conventional histopathological boundaries. Perhaps the broadest of these subclassess has been termed “proneural” and includes both a large fraction of GBMs along with most of their lower-grade astrocytic and oligodendroglial counterparts. The pathogenesis of proneural gliomas has been strongly linked to dysregulated PDGF signaling; but although genomic amplification or activating mutations involving the PDGF receptor (PDGFRA) characterize a significant subset of proneural GBMs, the mechanisms driving dysregulated PDGF signaling and downstream oncogenic networks in non-amplified/mutated tumors remain unclear. MicroRNAs (miRNAs) are a class of small, noncoding RNAs that regulate gene expression on a pre-translational level by binding loosely to complimentary sequences in target mRNAs. The role of miRNA biology in numerous cancer variants is well established. In an analysis of miRNA involvement in the phenotypic expression and regulation of oncogenic PDGF signaling, we found that expression of miR-34a is responsive to PDGF pathway activation in vitro. Similarly, analysis of data from the Cancer Genome Atlas (TCGA) revealed that expression of miR-34a is highly negatively correlated in proneural gliomas and in gliomas harboring amplified PDGFRA compared to other tumor subtypes. Using primary GBM cells maintained under neurosphere conditions, we then demonstrated that miR-34a specifically affects growth of proneural GBM cells in vitro and in vivo. Using data from TCGA, we identified PDGFRA as a direct target of miR-34a and validated this interaction experimentally. Finally, we provided evidence for a p53-independent mechanism mediated by PDGF signaling for negative regulation of miR-34a in proneural tumors. Taken together, our data suggest reciprocal negative feedback regulation of miR-34 and PDGFRA expression in proneural gliomas and, as such, identify a subtype specific therapeutic potential for miR-34a.

Citation Format: Joachim Silber, Anders Jacobsen, Tatsuya Ozawa, Girish Harinath, Eric C. Holland, Chris Sander, Jason T. Huse. Repression of PDGFRA-targeting miR-34a promotes tumorigenesis in proneural malignant gliomas [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B15.
Abstract B30: Exogenous miR-128 Enforced HNSCC Inhibits Proliferation
Authors: Hauser Belinda , Hao Yubin , Califano Joseph , Gu Xinbin
Published: April 2013

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease with complex molecular abnormalities. There are more than 65,000 Americans diagnosed with head and neck cancer and 25,000 die from this disease. microRNAs are 22~nucleotide-long endogenously expressed, highly conserved noncoding RNAs with important regulatory functions in proliferation, apoptosis, and metastasis. miR-128 a brain-enriched microRNA most commonly in gliomas that have shown to function as a tumor suppressor which decreases cell proliferation and cell invasiveness in prostate cancer. miR-128 has been shown to target BMI-1 in squamous cell carcinoma; however we believe miR-128 functions by targeting multiple targets in HNSCC.

Methods: We established HNSCC cell lines that stably expressed individual members of the miR-128 using a lentiviral delivery system. The levels of miR-128 and their targeted proteins were analyzed by qRT-PCR and Western blot. miR-128 affinity was elucidated by MTT, colony formation, flow cytometry, and a tumor xenograft model.

Results: Enforced transfection of miR-128 in HNSCC (JHU-22) expression was stable in vitro and in vivo. We identified five specific targets of miR-128 (BMI-1, BAG2, BAX, H3f3b, and Paip2). BMI-1 and H3f3b were shown to be a more dominant targeted of miR-128. Overexpression of miR-128, lead to the down regulation of these targets including decrease cell viability (30%), decrease of proliferation (55%), and significantly reduced solid tumor formation in tumor xenografts models.

Conclusions: miR-128 exhibits anti-proliferative effects and phenotypic alteration in HNSCC by targeting multiple predicted conserved targets activity function in apoptosis, cell cycle, transcription, and translation. Therefore, screening for differentially expressed targets of miR-128 help elucidate the possible mechanisms underlining the function of miR-128.Our results indicate that miR-128 has the potential to serve as a therapeutic approach.

Citation Format: Belinda Hauser, Yubin Hao, Joseph Califano, Xinbin Gu. Exogenous miR-128 Enforced HNSCC Inhibits Proliferation [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B30.
Abstract B7: microRNA regulation of cell viability and drug sensitivity in lung cancer
Authors: Du Liqin , DeSevo Christopher , Robert Borkowski , Michael Baker , Gazdar Adi F. , Minna John D. , Pertsemlidis Alexander
Published: April 2013

Introduction: Lung cancer is the leading cause of cancer-related deaths, with the majority of deaths due to failed therapy from tumor drug resistance. Third-generation chemotherapeutic agents represent the standard first-line treatment for advanced small cell (SCLC) and non-small cell (NSCLC) lung cancer patients. Response rates are poor (20–40%) with a median survival of 8–10 months.

Methods: In an unbiased and comprehensive approach, we have combined a high-throughput screening platform with a library of chemically synthesized microRNA mimics and inhibitors. We have used this platform to identify mimics and inhibitors that reduce cell viability in general, and those that specifically sensitize cells to taxanes.

Results: We have identified several miRNAs for which over-expression or inhibition has a dramatic and selective effect on cell viability or drug response. We have demonstrated that miR-337-3p mimic sensitizes NSCLC cells to taxanes. By combining in vitro and in silico approaches, we identified STAT3 and RAP1A as direct targets that mediate the effect of miR-337-3p by enhancing taxane-induced arrest in the G2 phase of the cell cycle. We have also identified an inhibitor of miR-139-5p as a potent and selective regulator of SCLC cell viability. Inhibiting miR-139-5p decreases SCLC cell viability by over 80%, but has a minimal cytotoxic effect on that of NSCLCs or immortalized human bronchial epithelial cells. We are currently investigating the targets of miR-139-5p that mediate its effect on SCLC cell viability.

Conclusion: We have identified miR-337-3p as a regulator of taxane sensitivity in NSCLC, and miR-139-5p as a modulator of viability in SCLC. Increasing levels of miR-337-3p and inhibiting miR-139-5p may therefore provide novel therapeutic tools for the treatment of NSCLC and SCLC lung tumors, respectively.

Citation Format: Liqin Du, Christopher DeSevo, Borkowski Robert, Baker Michael, Adi F. Gazdar, John D. Minna, Alexander Pertsemlidis. microRNA regulation of cell viability and drug sensitivity in lung cancer [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr B7.
Abstract IA15: MicroRNA reprogramming in cancer: mechanisms and consequences
Authors: Mendell Joshua T.
Published: April 2013

miRNA gain- and loss-of-function can potently influence cellular behavior in normal physiologic states and in diseases such as cancer. The regulation of miRNA expression and activity by cellular signaling cascades can therefore result in dramatic phenotypic outputs. We previously demonstrated extensive control of miRNA expression by well-characterized oncogenic and tumor suppressor networks including the Myc, Kras, and p53 pathways. We are now employing novel mouse models with gain and loss of miRNA function to investigate the roles of the miRNAs embedded within these signaling pathways and the pathologic consequences when their functions are disrupted. Insights gained from these functional studies have led to the development of novel therapeutic strategies for cancer and other pathologic states based on miRNA delivery. I will present our latest findings related to miRNA regulation in cancer and exploitation of these findings for the development of novel therapeutic approaches.

Citation Format: Joshua T. Mendell. MicroRNA reprogramming in cancer: mechanisms and consequences [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA15.
Abstract IA2: Navigating the balance of INK4/ARF expression in cancer: ncRNAs as sensors and regulators of transcription
Authors: Walsh Martin J. , Aguilo Francesca , Li SiDe , Yap Kyoko , Gil Jesus , Zhou Ming-Ming
Published: April 2013

The INK/ARF (CDKN2A) locus expresses p15Ink4B, p16Ink4A, p14Arf and is under control of Polycomb Repressive Complexes PRC1 and PRC2 to impose transcriptional silencing to bypass cellular senescence upon oncogenic stress. Previously, we had identified a constituent member of human PRC1, known as the chromobox protein 7 (CBX7), is endowed the capacity to bind specifically to elements of the long non-coding RNA identified as the non-coding anti-sense RNA of the INK locus (ANRIL) RNA transcript as a mature processed polyadenylated RNA transcript. ANRIL represent a large heterogeneous population of individual transcripts and their isoforms arising from the localized genomic region overlapping INK/ARF. These transcripts reveal independent patterns of expression dependent on the state of cell growth and differentiation. Moreover, specific transcripts overlapping the ANRIL region of chromosome 9p21.3 provide strict correlation to human embryonic stem cell pluripotency and self-renewal versus differentiation. We recently identify specific ANRIL transcripts and isoforms that are correlative with human prostate tumor stages and states of malignancy. We had previously shown that certain transcripts correlate with PRC1 is organized on the INK/ARF locus through the interaction between CBX7 and the nascent ANRIL transcript to help establish and maintain repressive histone H3K27 methylation and H2AK119 monoubiquitination. Both PRC1 and PRC2 can interact with different ANRIL transcript regions and it remains unclear whether this activity is cooperative. This activity is abrogated in the absence of RNA polymerase II activity thereby requiring nascent transcription of anti-sense transcripts of INK/ARF by RNA polymerase II (RNA POLII). Interestingly, TAF15/TAFII68 can be tethered to CBX7 in prostate carcinoma cells where the ANRIL ncRNA transcripts are elevated. Our recent finding is that specific ANRIL transcripts directed by RNAPOLII are influenced by RNA polymerase III (RNA POLIII) as measured through the depletion of the core RNA POLIII factor BRF1. This evidence suggests that RNA POLIII may populate RNA synthesis of shorter transcripts to influence PRC1 and PRC2 binding thereby instructing the behavior of RNA POLII synthesis. This provides a rational mechanism whereby RNA POLIII with RNAPOLIII provide the genomic RNA context to instruct PRC1 and PRC2 to exert antisense transcription at the expense of transcriptional activity of INK/ARF.

Citation Format: Martin J. Walsh, Francesca Aguilo, SiDe Li, Kyoko Yap, Jesus Gil, Ming-Ming Zhou. Navigating the balance of INK4/ARF expression in cancer: ncRNAs as sensors and regulators of transcription [abstract]. In: Proceedings of the AACR Special Conference on Noncoding RNAs and Cancer; 2012 Jan 8-11; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Res 2012;72(2 Suppl):Abstract nr IA2.
Chemoprevention of Lung Squamous Cell Carcinoma by Ginseng
Authors: Pan Jing , Zhang Qi , Li Kezhen , Liu Qian , Wang Yian , You Ming
Published: April 2013

Ginseng has been used as a medicinal herb to maintain physical vitality for thousands of years, and it has also been shown to be a nonorgan-specific cancer preventive agent by several epidemiologic studies. However, the chemopreventive effects of Korea white ginseng (KWG) in lung squamous cell carcinoma (SCC) have not been tested. In this study, we investigated the chemopreventive activity of KWG in a mouse lung SCC model. N-nitroso-trischloroethylurea (NTCU) was used to induce lung tumors in female Swiss mice, and KWG was given orally. KWG significantly reduced the percentage of lung SCCs from 26.5% in the control group to 9.1% in the KWG group and in the meantime, increased the percentage of normal bronchial and hyperplasia. KWG was also found to greatly reduce squamous cell lung tumor area from an average of 9.4% in control group to 1.5% in the KWG group. Treatment with KWG decreased Ki-67 staining, suggesting that the lung tumor inhibitory effects of KWG were partly through inhibition of proliferation. High-performance liquid chromatography/mass spectrometry identified 10 ginsenosides from KWG extracts, Rb1 and Rd being the most abundant as detected in mouse blood and lung tissue. The tumor inhibitory effects of KWG are mediated by inhibition of activator protein (AP-1), as showed by in vitro study conducted on AP-1/NF-κB–dependent mouse non–small cell lung carcinoma cell lines. Western blotting of lung tissues also indicated that NTCU upregulated AP-1 through phosphorylation of c-jun-NH2-kinase, which was downregulated by KWG in concurrence with its chemoprevention function. These results suggest that KWG could be a potential chemopreventive agent for lung SCC. Cancer Prev Res; 6(6); 530–9. ©2013 AACR.
Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor
Authors: Killian J. Keith , Kim Su Young , Miettinen Markku , Smith Carly , Merino Maria , Tsokos Maria , Quezado Martha , Smith William I. , Jahromi Mona S. , Xekouki Paraskevi , Szarek Eva , Walker Robert L. , Lasota Jerzy , Raffeld Mark , Klotzle Brandy , Wang Zengfeng , Jones Laura , Zhu Yuelin , Wang Yonghong , Waterfall Joshua J. , O'Sullivan Maureen J. , Bibikova Marina , Pacak Karel , Stratakis Constantine , Janeway Katherine A. , Schiffman Joshua D. , Fan Jian-Bing , Helman Lee , Meltzer Paul S.
Published: April 2013

Gastrointestinal stromal tumors (GIST) harbor driver mutations of signal transduction kinases such as KIT, or, alternatively, manifest loss-of-function defects in the mitochondrial succinate dehydrogenase (SDH) complex, a component of the Krebs cycle and electron transport chain. We have uncovered a striking divergence between the DNA methylation profiles of SDH-deficient GIST (n = 24) versus KIT tyrosine kinase pathway–mutated GIST (n = 39). Infinium 450K methylation array analysis of formalin-fixed paraffin-embedded tissues disclosed an order of magnitude greater genomic hypermethylation relative to SDH-deficient GIST versus the KIT-mutant group (84.9 K vs. 8.4 K targets). Epigenomic divergence was further found among SDH-mutant paraganglioma/pheochromocytoma (n = 29), a developmentally distinct SDH-deficient tumor system. Comparison of SDH-mutant GIST with isocitrate dehydrogenase-mutant glioma, another Krebs cycle–defective tumor type, revealed comparable measures of global hypo- and hypermethylation. These data expose a vital connection between succinate metabolism and genomic DNA methylation during tumorigenesis, and generally implicate the mitochondrial Krebs cycle in nuclear epigenomic maintenance.

Significance: This study shows that SDH deficiency underlies pervasive DNA hypermethylation in multiple tumor lineages, generally defining the Krebs cycle as mitochondrial custodian of the methylome. We propose that this phenomenon may result from a failure of maintenance CpG demethylation, secondary to inhibition of the TET 5-methylcytosine dioxgenase demethylation pathway, by inhibitory metabolites that accumulate in tumors with Krebs cycle dysfunction. Cancer Discov; 3(6); 648–57. ©2013 AACR.

This article is highlighted in the In This Issue feature, p. 591
Delayed Intracranial Hypertension and Cerebral Edema in Severe Pediatric Head Injury: Risk Factor Analysis
Authors: Bennett Colomer Carlos , Solari Vergara Felipe , Tapia Perez Felipe , Miranda Vasquez Francisca , Horlacher Kunstmann Andres , Parra Fierro Gilda , Salazar Zenkovich Cristián
Published: April 2013

Introduction: Diffuse brain edema has been described as a major cause of intracranial hypertension (IH) following traumatic brain injury (TBI), and several studies suggest that it may be more frequent in children than in adults. While most cases of IH following TBI are present from the beginning, several studies have described a subgroup of patients with delayed elevations in intracranial pressure (ICP). Methods: Retrospective review of severe pediatric TBI cases admitted to a single institution during a 6-year period. Patients were classified into three groups, based on the temporal evolution of ICP: patients who evolved without IH, patients who had IH at admission and patients with delayed IH. A risk factor analysis was performed to find differences between these groups. Results: 31 cases of severe pediatric TBI were analyzed. 13 patients were female and 18 male, with an average age of 8.9 years. 4 patients met the described criteria for delayed IH; the only significant risk factor was presence of edema at the initial brain CT (p = 0.008). 3 additional patients presented clinical deterioration after 48 h and signs of brain edema in the CT, after ICP monitoring had been discontinued. Conclusions: Late-onset IH is a relatively common clinical condition in the pediatric population with severe TBI (present in 13% of the cases in our series), and the presence of a Marshall III CT scan at admission is a significant risk factor for this condition. Pediatric patients may benefit from a more prolonged period of ICP monitoring than adults, and the lack of amelioration of brain edema at follow-up brain CT (even with normal ICP values) may be an indication that more prolonged monitoring is needed.
Specific Binding of Paraprotein to Platelet Receptors as a Cause of Platelet Dysfunction in Monoclonal Gammopathies
Authors: Djunic I. , Elezovic I. , Vucic M. , Srdic-Rajic T. , Konic-Ristic A. , Ilic V. , Milic N. , Bila Jelena , Suvajdzic-Vukovic Nada , Virijevic Marijana , Antic Darko , Vidovic Ana , Tomin D.
Published: April 2013

The study included 48 untreated patients with monoclonal gammopathies (MG). Paraprotein was isolated from the serum of 10 patients with decreased platelet aggregation. Platelet aggregation was measured before and after the addition of the isolated paraprotein to platelet-rich plasma (PRP) from 10 healthy donors, in vitro. Expression of platelet von Willebrand factor (vWF) receptor glycoprotein (GP)Ib and platelet collagen receptor GPVI was determined by flow cytometry in the PRP of healthy donors before and after the addition of isolated paraprotein using the monoclonal antibodies, CD42b (for GPIb) and CD36 (for GPVI). Flowcytometry showed that expression of CD42b and CD36 positive cells was reduced after the addition of isolated paraprotein to PRP from healthy donors (p < 0.001). These investigations demonstrated that paraprotein causes platelet dysfunction in patients with MG due to specific binding to the platelet vWF receptor GPIb and platelet collagen receptor GPVI.
Human Amnion Epithelial Cells Reduce Fetal Brain Injury in Response to Intrauterine Inflammation
Authors: Yawno Tamara , Schuilwerve Joyce , Moss Timothy J.M. , Vosdoganes Patricia , Westover Alana J. , Afandi Ezzat , Jenkin Graham , Wallace Euan M. , Miller Suzanne L.
Published: April 2013

Intrauterine infection, such as occurs in chorioamnionitis, is a principal cause of preterm birth and is a strong risk factor for neurological morbidity and cerebral palsy. This study aims to examine whether human amnion epithelial cells (hAECs) can be used as a potential therapeutic agent to reduce brain injury induced by intra-amniotic administration of lipopolysaccharide (LPS) in preterm fetal sheep. Pregnant ewes underwent surgery at approximately 110 days of gestation (term is approx. 147 days) for implantation of catheters into the amniotic cavity, fetal trachea, carotid artery and jugular vein. LPS was administered at 117 days; hAECs were labeled with carboxyfluorescein succinimidyl ester and administered at 0, 6 and 12 h, relative to LPS administration, into the fetal jugular vein, trachea or both. Control fetuses received an equivalent volume of saline. Brains were collected 7 days later for histological assessment of brain injury. Microglia (Iba-1-positive cells) were present in the brain of all fetuses and were significantly increased in the cortex, subcortical and periventricular white matter in fetuses that received LPS, indicative of inflammation. Inflammation was reduced in fetuses that received hAECs. In LPS fetuses, the number of TUNEL-positive cells was significantly elevated in the cortex, periventricular white matter, subcortical white matter and hippocampus compared with controls, and reduced in fetuses that received hAECs in the cortex and periventricular white matter. Within the fetal brains studied there was a significant positive correlation between the number of Iba-1-immunoreactive cells and the number of TUNEL-positive cells (R2 = 0.19, p < 0.001). The administration of hAECs protects the developing brain when administered concurrently with the initiation of intrauterine inflammation.
Trastuzumab-Induced Hepatotoxicity: A Case Report
Authors: Vucicevic Darko , Carey Elizabeth J. , Karlin Nina J.
Published: April 2013

Background: Trastuzumab is a humanized monoclonal antibody approved for the treatment of breast cancer with HER2 amplification and/or overexpression. There are only 2 prior cases of trastuzumab-related hepatotoxicity reported in the literature. Case Report: We report the case of a 60-year-old woman who was treated with trastuzumab for stage I invasive ductal carcinoma of the right breast. She successfully completed 6 months of therapy when an increase in liver transaminases was noted on routine examination. A full work-up for causes of acute and chronic liver disease was negative. After review of the patient's medication list, trastuzumab was thought to be the most likely culprit for the liver injury, based on timing of administration and rise in liver enzymes.
Rapid On-Site Cytologic Evaluation during Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Diagnosing Lung Cancer: A Randomized Study
Authors: Oki Masahide , Saka Hideo , Kitagawa Chiyoe , Kogure Yoshihito , Murata Naohiko , Adachi Takashi , Ando Masahiko
Published: April 2013

Background: Although rapid on-site cytologic evaluation (ROSE) is widely used during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), its role remains unclear. Objectives: The purpose of the present study was to evaluate the efficacy of ROSE during EBUS-TBNA in the diagnosis of lung cancer. Methods: One hundred and twenty patients highly suspected of having lung cancer who had hilar/mediastinal lymphadenopathy or a tumor adjacent to the central airway were enrolled in this study and randomized to undergo EBUS-TBNA with or without ROSE. Results: Twelve patients with visible endobronchial lesions were excluded in the analysis. Thus, a total of 108 patients (55 in the ROSE group, 53 in the non-ROSE group) were analyzed. Additional procedures including EBUS-TBNA for lesions other than the main target lesion and/or transbronchial biopsy in the same setting were performed in 11% of patients in the ROSE group and 57% in the non-ROSE group (p < 0.001). Mean puncture number was significantly lower in the ROSE group (2.2 vs. 3.1 punctures, p < 0.001), and mean bronchoscopy time was similar between both groups (22.3 vs. 22.1 min, p = 0.95). The sensitivity and accuracy for diagnosing lung cancer were 88 and 89% in the ROSE group, and 86 and 89% in the non-ROSE group, respectively. No complications were associated with the procedures. Conclusions: ROSE during EBUS-TBNA is associated with a significantly lower need for additional bronchoscopic procedures and puncture number.
The Relation between Decreased Glomerular Filtration Rate and Nonvalvular Atrial Fibrillation
Authors: Balta Sevket , Demirkol Sait , Arslan Zekeriya , Sahin Mehmet Ali , Yesil Fahri Gurkan , Kucuk Ugur
Published: April 2013

No abstract available
Dasatinib Maintenance Therapy after Allogeneic Hematopoietic Stem Cell Transplantation for an Isolated Central Nervous System Blast Crisis in Chronic Myelogenous Leukemia
Authors: Nishimoto Mitsutaka , Nakamae Hirohisa , Koh Ki-Ryang , Kosaka Saori , Matsumoto Kana , Morita Kunihiko , Koh Hideo , Nakane Takahiko , Ohsawa Masahiko , Hino Masayuki
Published: April 2013

A 22-year-old male with Ph-positive chronic myelogenous leukemia (CML) was started on treatment with imatinib. After 12 months of therapy, he achieved a complete cytogenetic response (CCyR). Although the CCyR persisted in his bone marrow, he developed an isolated CML blast crisis in his central nervous system (CNS) after 29 months of therapy. He underwent allogeneic hematopoietic stem cell transplantation (HSCT) following combination therapy with dasatinib, intrathecal chemotherapy and cranial irradiation. Subsequently, 168 days after allogeneic HSCT, he was started on dasatinib maintenance therapy to prevent a CNS relapse. Thirty-eight months after allogeneic HSCT, he has sustained a complete molecular response in both bone marrow and CNS. We believe dasatinib has the potential to prevent CNS relapse if used for maintenance therapy after allogeneic HSCT.