bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3934: Angiogenin and PlexinB2 promote glioblastoma progression by stimulating tumor angiogenesis, cancer cell survival and invasion
Authors: Yang Hailing , Hu Guo-fu
Published: May 2015

Glioblastoma (GBM) tumors secrete high level of angiogenic factors and feature vascular abnormality. Targeted therapy, such as Bevacizumab, which neutralizes VEGF and normalizes tumor vasculature, has been approved to treat recurrent GBM. However, it only marginally increases patients' overall survival with inevitable resistance. It suggests that therapy targeting complementary angiogenic pathway in GBM could suppress Bevacizumab resistance and extend patients' survival.

Angiogenin (ANG) is involved in tumor angiogenesis where it regulates ribosomal RNA transcription and functions downstream of VEGF and other related angiogenic factors. Like VEGF, ANG is also up-regulated in GBM patients. Inhibition of ANG by neutralizing monoclonal antibody delays U87 human GBM xenografts on nude mice. My preliminary data have shown that ANG is essential for GBM cell line s.c. vessel formation and tumor proliferation. In Rcas/tva orthotropic GBM model, Ang1 knockout mice show lower penetration and better survivals. ANG knockdown increases apoptosis during GBM cell line colony formation in agarose. Notably, ANG's role in tumor proliferation might extend beyond GBM, since oncogenic KRas transformed Ang1 knockout MEFs also fail to grow in agarose. Lastly, I have shown that PlexinB2, ANG cellular receptor, can mediate ANG cellular uptake and also modulate GBM apoptosis in agarose. In conclusion, inhibition of ANG inhibits GBM progression both in vitro and in vivo and thus represents a new molecular target for GBM treatment.

Citation Format: Hailing Yang, Guo-fu Hu. Angiogenin and PlexinB2 promote glioblastoma progression by stimulating tumor angiogenesis, cancer cell survival and invasion. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3934. doi:10.1158/1538-7445.AM2014-3934
Abstract 3939: Delineation of the ATM-Snail pathway in the DNA damage response
Authors: Boohaker Rebecca J. , Fried Joshua , Cui Xiaoli , Xu Bo
Published: May 2015

To cope with constant challenges toward the fidelity of genome by DNA damaging insults (both endogenous and exogenous), activation of the DNA damage response (DDR) is an essential step in preventing genomic instability. Studies of mammalian mechanisms have revealed that there are comprehensive, coordinated pathways that, when activated, serve to regulate the DDR. Recently, we have shown that hyperactive DDR mediated by the Ataxia-Telangiectasia Mutated (ATM) kinase is linked to activation of the Zinc finger protein SNAI1 (Snail). Activated Snail in metastasis is well-characterized by its role as transcriptional repressor of E-cadherin thereby inducing an epithelial-to-mesenchymal transition (EMT). Here we report that, in response to DNA damage, activation of the ATM-Snail pathway, mediated by Snail Serine 100 phosphorylation, also contributes to the regulation of the cellular sensitivity to ionizing radiation. Expression of a hyperactive Snail led to radioresistance. More interestingly, the Serine 100 to Glutamic Acid mutant variant of Snail displayed an enhanced invasion index after low dose radiation, independent of survival. Functional genomics and proteomics studies revealed downstream targets and interacting partners of Snail in the DDR. Together, we highlight the functional significance of the ATM-Snail pathway in the DDR.

Citation Format: Rebecca J. Boohaker, Joshua Fried, Xiaoli Cui, Bo Xu. Delineation of the ATM-Snail pathway in the DNA damage response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3939. doi:10.1158/1538-7445.AM2014-3939
Abstract 3947: Radiation treatment solubilizes membrane receptors in meningioma cells
Authors: Gogineni Venkateswara Rao , Maddirela Dilip R. , Chetty Chandramu , Rao Jasti S.
Published: May 2015

In our earlier studies we reported that radio-resistance was associated with soluble uPAR and uPARAP in meningioma cells. In the present study we show solubilization of a broad range of membrane-bound receptors induced by radiation treatment. Although the increase in radiation dosage beyond 10Gy increased the release of receptors, cell proliferation was adversely affected. Further, fractionated dosages (5Gy+5Gy) or a single dose (10Gy) radiation showed a significant surge in soluble receptors after 36 hours of treatment. Correspondingly, an initial lag in proliferation with G2-M arrest and subsequent recovery was seen in irradiated cells. Pretreatment of meningioma cells with N-acetyl cysteine before radiation treatment significantly quenched the solubilization of receptors. Conditioned media collected from irradiated cells promoted invasiveness and migration of meningioma cells compared to the controls. Later, screening for cell-free receptors in the brain sections of tumor-bearing mice also showed an increased incidence in irradiated groups. In conclusion, our study reveals an additional niche of receptor functioning in meningioma.

Citation Format: Venkateswara Rao Gogineni, Dilip R. Maddirela, Chandramu Chetty, Jasti S. Rao. Radiation treatment solubilizes membrane receptors in meningioma cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3947. doi:10.1158/1538-7445.AM2014-3947
Abstract 3950: Integrative analysis of acute and late radiotherapy effects using genome-wide transcriptomics and quantitative proteomics
Authors: Rackwitz Tilmann , Seidel Philipp , Winter Martin , Zhou Cheng , Mayer Ramona , Warnken Uwe , Hofner Peter , Debus Jürgen , Schnölzer Martina , Abdollahi Amir
Published: May 2015

Pulmonary microvascular endothelial cells are critically involved in development of radiation-induced acute inflammation and late fibrosis often limiting the delivery of sufficient dose to optimally treat lung cancer. Moreover, tumor-endothelium communication has emerged as a key target to augment radiotherapy by resensitizing endothelial-specific survival signals. Therefore, we aimed to employ high-throughput genome-wide gene expression and whole proteome analysis to uncover the molecular mechanisms governing tumor-vessel communication and radiation-induced normal tissue toxicity.

Human primary isolated pulmonary microvascular endothelial cells (HPMEC) were irradiated with 0 or 6Gy. Cells were harvested two hours (acute) and six days (late) after irradiation and proteins as well as RNA were extracted. Gene expression analysis was performed using 47k Illumina microarray (HumanHT-12 v4) platform. Mass spectrometry on an LTQ-Orbitrap instrument was employed for protein identification and relative quantification using label-free quantification techniques. An IMAC/TiO2 enrichment step to obtain phosphorylated peptides was carried out and analyzed by mass spectrometry as well. The regulation of candidate radiation-regulated genes and proteins were confirmed in-vitro and in irradiated lung specimen (C57BL/6 mouse) by real-time qRT-PCR, western blot and ELISA.

At the early timepoint a strong induction of genes involved in apoptosis and DNA-damage response such as GADD45A, PARP3 and DDB2 was identified. In contrast to the acute radiation response, cell adhesion (Integrins), pro-inflammatory (Interleukines), pro-angiogenic and matrix-remodeling related genes (MMPs, PDGFs, VEGFs) were induced late after irradiation. Integrative analysis of protein quantification, phosphorylation and gene-expression further revealed novel insights to an intricate gene/protein regulatory network underlying late radiation response in microvascular endothelium. The here identified genes and proteins involved in late radiation response constitute attractive targets for modulation of radiotherapy effects in tumor-endothelium or prevention of undesired radiotherapy-induced late side effects.

Citation Format: Tilmann Rackwitz, Philipp Seidel, Martin Winter, Cheng Zhou, Ramona Mayer, Uwe Warnken, Peter Hofner, Jürgen Debus, Martina Schnölzer, Amir Abdollahi. Integrative analysis of acute and late radiotherapy effects using genome-wide transcriptomics and quantitative proteomics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3950. doi:10.1158/1538-7445.AM2014-3950
Abstract 3952: Recurrent prostate cancer genomic alterations predict response to brachytherapy treatment
Authors: Fontugne Jacqueline , Lee Daniel , Cantaloni Chiara , Barbieri Christopher E. , Orazio Caffo , Hanspeter Esther , Mazzoleni Guido , Palma Paolo Dalla , Rubin Mark A. , Fellin Giovanni , Mosquera Juan Miguel , Barbareschi Mattia , Demichelis Francesca
Published: May 2015

Background

Discovery of ERG rearrangements and recurrent associated molecular alterations, such as PTEN deletions, has helped understand prostate carcinogenesis. However, prostate cancer (PCa) molecular stratification has not been well studied in response to different treatment modalities. The objective of this study was to evaluate the association of ERG rearrangements and PTEN deletions with oncologic outcomes in PCa patients treated with brachytherapy.

Material and methods

Ninety-two men underwent I-125 brachytherapy with a 145Gy delivered dose between 2000 and 2008. Pre-treatment prostate biopsies were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) for ERG rearrangement and overexpression, PTEN deletion and expression loss. Univariable and multivariable Cox-regression analyses evaluated association of ERG and PTEN status with biochemical recurrence (BCR).

Results

Within a median follow-up of 73 months, 11% of patients experienced BCR. Of 80 samples with both IHC and FISH performed for ERG, 46 (57.8%) demonstrated rearrangement by FISH and 45 (56.3%) by IHC. Of 77 samples with both IHC and FISH for PTEN, 14 (18.2%) had PTEN deletion by FISH and 22 (28.6%) by IHC. No significant associations were found between ERG, PTEN status and clinicopathologic features. Patients with concurrent ERG rearrangement and PTEN deletion demonstrated significantly worse relapse-free survival rates compared to those with ERG or PTEN wild-type (p<0.01). In multivariable Cox regression analysis adjusted for the effects of standard clinicopathologic features, combined ERG rearranged and PTEN deletion was independently associated with BCR (HR 2.6, p=0.02).

Conclusions

Concurrent ERG rearrangement and PTEN loss was independently associated with time to BCR in patients undergoing brachytherapy. Identifying patients in this molecular subclass may improve treatment personalization. Future studies are needed to validate PCa molecular subtyping for risk-stratification.

Citation Format: Jacqueline Fontugne, Daniel Lee, Chiara Cantaloni, Christopher E. Barbieri, Caffo Orazio, Esther Hanspeter, Guido Mazzoleni, Paolo Dalla Palma, Mark A. Rubin, Giovanni Fellin, Juan Miguel Mosquera, Mattia Barbareschi, Francesca Demichelis. Recurrent prostate cancer genomic alterations predict response to brachytherapy treatment. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3952. doi:10.1158/1538-7445.AM2014-3952
Abstract 3957: Analyzing the effects of radiotherapy on the metastatic phenotype: a role for combined therapeutic approaches incorporating Src and PI3K targeting
Authors: Rowling Emily J. , Telfer Brian , Elvin Paul , Williams Kaye J.
Published: May 2015

Background: Radiotherapy is used in the treatment of over 50% of cancer patients. Although seen as a positive intervention, there are reports of radiation enhancing the metastatic characteristics of cells. We have previously observed that radiotherapy activates a number of pathways associated with tumour metastases and aggressive phenotype including Src and phosphoinositide 3-kinase (PI3K). Here we wished to relate pathway activation to cellular phenotype and to investigate the impact of pharmacological inhibition on radiation response and metastases.

Methods: The effects of radiotherapy alone, and combined with Src (AZD0530) and/or PI3K (GDC-0941) inhibition, on cell adhesion, migration and clonogenic survival were assessed in vitro using well-characterised assays. Initial in vivo studies, using FTC133 xenografts, evaluated the effects of radiation treatment on the Src and PI3K pathways and inhibition thereof using pAKT (Ser473) and pFAK (Tyr861) as biomarkers. The effect of single versus combined pathway inhibition with radiation therapy (5x2Gy fractions) on primary tumour growth and lung metastasis (via ex vivo clonogenic assay) was then evaluated.

Results: In vitro, radiation combined with Src and/or PI3K inhibition resulted in a reduction in cell adhesion, cell spreading and cell migration compared to radiation alone, with the combined effects greater than either inhibitor alone. Radiation both in vivo and in vitro enhanced activity of the PI3K/AKT and the Src/FAK axis. In vivo, radiation combined with Src or PI3K inhibition showed little effect on tumour growth but did reduce metastatic lung colonisation, compared to radiation alone, with Src inhibition proving more efficacious. When radiation was combined with inhibition of both pathways a significant reduction in both primary tumour growth and metastatic lung colonisation was observed.

Conclusion: Radiation enhances multiple pathways, two predominant ones being PI3K and Src, and by using rationale drug combinations we saw improved local control and reduced metastatic spread. From these data we can suggest that the PI3K and Src pathways are involved in the radiation enhancement in metastatic phenotype and this provides potential for application of these therapies in the clinic.

Citation Format: Emily J. Rowling, Brian Telfer, Paul Elvin, Kaye J. Williams. Analyzing the effects of radiotherapy on the metastatic phenotype: a role for combined therapeutic approaches incorporating Src and PI3K targeting. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3957. doi:10.1158/1538-7445.AM2014-3957
Abstract 3994: Identifying molecular networks linked to colorectal liver metastasis progression during liver regeneration by RNA-seq
Authors: Simoneau Eve , Chicoine Jarred , Salman Ayat , Sladek Robert , Lazaris Anthoula , Amre Ramila , Metrakos Peter
Published: May 2015

The only potential cure for colorectal liver metastasis (CRCLM) is hepatic resection; portal vein embolization (PVE) is used as an adjunct to stimulate liver regeneration and increase the number of resectable patients. PVE has been shown to enhance CRCLM progression in most patients. The objective of this study is to determine the molecular networks involved in CRCLM progression during liver regeneration, by transcriptome analysis (RNA-Seq). CRCLM RNA was procured prospectively from patients prior to and after PVE. 14 patients with PVE underwent tumor volumetric analysis (blinded from the transcriptome analysis) to determine stable vs. progressive disease. A subgroup of 9 patients had tumor progression (median 45.3% (95%CI 10.6-192.5%) increase in tumor volume) while the remaining patients exhibited stable disease and continuous chemotherapy response (median 26.0%(95%CI -53.1-1.2%) decrease in tumor volume) (p=0.0121), which was consistent with our published series of 123 patients. RNA extracted from tumor tissue (pre and post PVE) in a subset (n=6) of patients (median RNA Integrity number (RIN) scores 7.1 (6.2 - 9.0)) was used to prepare Illumina rRNA-depleted TruSeq stranded cDNA libraries for HiSeq 100bp paired-end sequencing. An average of 150 million reads and 91.8% genomic alignment was achieved per sample. The analysis revealed that several genes known to act as tumor suppressors in CRC (e.g. NR1H4 and HRG) are consistently down regulated post-PVE in the progressive group. Several canonical pathways (including acute phase response, LXR/RXR signaling) showed statistical enrichment for transcripts that were differentially expressed in patients with disease progression. This work aims to establish a comprehensive view of the transcriptional changes associated with CRCLM progression during liver regeneration, to identify the molecular mechanisms that drive metastatic progression in this unique context. Highlighting such mechanisms is a critical first step towards developing targeted therapeutic strategies that may mitigate the unwanted effects of liver regeneration on tumor growth.

Citation Format: Eve Simoneau, Jarred Chicoine, Ayat Salman, Robert Sladek, Anthoula Lazaris, Ramila Amre, Peter Metrakos. Identifying molecular networks linked to colorectal liver metastasis progression during liver regeneration by RNA-seq. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3994. doi:10.1158/1538-7445.AM2014-3994
Abstract 3998: Network-based identification of gene signatures of epithelial-mesenchymal transition in breast cancer
Authors: CONG YANG , Zhan Ming , Wong Stephen T.
Published: May 2015

Metastasis is a major cause of death in breast cancer patients. Breast cancer cells at the primary site gain metastatic ability through epithelial-mesenchymal transition (EMT). During the process, cancer cells lose cell-cell adhesion mediated by E-cadherin repression and gain motility and invasive properties to penetrate the basement membrane and enter the bloodstream or lymphatic system in order to travel to distant metastatic sites. To investigate the underlying gene regulation mechanism of EMT, we established an EMT gene regulatory network. We first built and validated an EMT signal pathway by Ingenuity Knowledge Base, a repository of expertly curated biological interactions and functional annotations from literatures. Based on gene profiling data of 590 breast cancer patients from The Cancer Genome Atlas (TCGA) and over 370 breast cancer patients from Gene Expression Omnibus (GEO), we modeled the gene regulation mechanism of each gene and its expression regulators in the EMT signal pathway in a stochastic Markov Chain model. In order to identify biomarkers and to determine the dynamical transition process at molecular level during EMT, it is important to identify the corresponding gene expression patterns of epithelial and mesenchymal cells. Several studies have already demonstrated that stable gene expression patterns correspond to stable cell phenotypes. In this study, we reported a cost-efficient computational algorithm developed to identify these stable gene signatures and validate them with gene expression profiles of human mammary epithelial cells and transduced mesenchymal cells.

Citation Format: YANG CONG, Ming Zhan, Stephen T. Wong. Network-based identification of gene signatures of epithelial-mesenchymal transition in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3998. doi:10.1158/1538-7445.AM2014-3998
Abstract 4012: Large-scale characterization of DNA methylation changes in human gastric carcinomas with and without metastasis
Authors: Liu Zhaojun , Zhang Jun , Gao Yanhong , Pei Lirong , Hattori Naoko , Zhu Budong , Ji Jiafu , Yuasa Yasuhito , Kim Wooho , Ushijima Toshikazu , Shi Huidong , Deng Dajun
Published: May 2015

Metastasis is the leading cause of caner-related death for solid tumors including gastric carcinoma (GC). An epigenetic biomarker panel for prediction GC metastasis will have clinical impact on the care of GC patients. In order to characterize the methylation differences between GCs with and without metastasis, genome-wide DNA methylation profiles were compared between 4 metastatic and 4 non-metastatic GCs and their surgical margins (SM). The GC genome showed significantly higher proportions of hypomethylation in the promoter and exon-1 regions, as well as increased hypermethylation of intragenic fragments when compared to SMs. From the list of differentially methylated CpG islands (CGIs), 63 candidate genes and 10 known tumor-related genes were selected for further analysis based on their known functions. Significant differential methylation was validated in the CGIs of 15 genes (Ps<0.05) and confirmed using bisulfite-sequencing. These genes included BMP3, BNIP3, CDKN2A, ECEL1, ELK1, GFRA1, HOXD10, KCNH1, PSMD10, PTPRT, SIGIRR, SRF, TBX5, TFPI2, and ZNF382. Hypermethylation of CGIs in several genes resulted in inactivation of their transcription; however, hypomethylation of GFRA1 correlated with an increase in expression. Most importantly, the prevalence of GFRA1, SRF, and ZNF382 methylation alterations were inversely and coordinately associated with GC metastasis and the patients' overall survival throughout discovery and validation cohorts in China (n=108 and 222), and two independent validation cohorts in Japan and Korea (n=129 and 153). Multivariate analysis showed that the number of combined methylation changes of GFRA1, SRF, and ZNF382 was an independent predictor of overall survival for GC patients in the above 4 patient cohorts (n=246) after adjusting for the pTNM stage, GC location, differentiation, vascular embolus, age, and sex (HR=0.753; 95%CI [0.584-0.972]). The metastasis-prediction values of GFRA1 and SRF methylation are stronger than those of MMP7. In conclusion, methylation changes of GFRA1, SRF, and ZNF382 may be a potential biomarker set for prediction of GC metastasis.

Citation Format: Zhaojun Liu, Jun Zhang, Yanhong Gao, Lirong Pei, Naoko Hattori, Budong Zhu, Jiafu Ji, Yasuhito Yuasa, Wooho Kim, Toshikazu Ushijima, Huidong Shi, Dajun Deng. Large-scale characterization of DNA methylation changes in human gastric carcinomas with and without metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4012. doi:10.1158/1538-7445.AM2014-4012
Abstract 4016: Serum proteomics uncover possible biomarkers associated with progression of metastatic breast cancer
Authors: AlZaabi Adhari A. , Hansen Marc , Graves Steven
Published: May 2015

Despite the recognized advances in the treatment of breast cancer, it still accounts for 15% of all cancer-related deaths. Ninety percent of breast cancer deaths are due to unpredicted metastasis. There is neither successful treatment for metastatic patients nor a specific test to predict or detect secondary lesions. Patients with primary tumor will be either overtreated with cytotoxic side effects or undertreated and risk recurrence. This necessitates the need for personalized treatment, which is hard to offer for such heterogeneous disease. Obstacles in treating breast cancer metastasis are mainly due to the gaps exist in the understanding of the molecular mechanism of metastasis. The linear model of metastasis is supported by several observations that reflect an early crosstalk between the primary and secondary tumor, which in turn makes the secondary microenvironment fertile for the growth of disseminated cells. This communication occurs through circulation and utilizes molecules which have not been identified to date. Identifying such molecules may help in detecting initial stages of tumor colonization and predict the target organ of metastasis. Furthermore, these molecules may help to provide a personalized therapy that aims to tailor treatment according to the biology of the individual tumor. Advances in proteomics allows for more reproducible and sensitive biomarker discovery. Proteomic biomarkers are often more translatable to the clinic compared to biomarkers identified using other -omics approaches. Further, protein biomarkers can be found in biological fluids making them a non invasive way to treat or investigate cancer patients. In this study we are screening serum samples of stage I and stage III breast cancer patients using cLC-MS/MS, with a focus on characterizing the differential expression of small peptide biomarkers. We typically analyze 2500 individual small peptide biomarkers in a single serum sample. Comparisons between different sample types (from stage I and III breast cancer patients in this case) allows for the detection of unique short peptide biomarkers present in one sample type. In our preliminary analysis of 6 patients of each type, we find roughly 64 short peptide biomarkers to be upregulated in patients with metastatic breast cancer. We also see the downregulation of an addition 92 short peptides in these same patients. The serum expression pattern and identity of peptides in metastatic patients may provide clues about the biology underlying tumor cell dissemination and colonization to specific sites.

Citation Format: Adhari A. AlZaabi, Marc Hansen, Steven Graves. Serum proteomics uncover possible biomarkers associated with progression of metastatic breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4016. doi:10.1158/1538-7445.AM2014-4016
Abstract 4070: Functional differences of actinin isoforms in the formation of invadopodia by invasive cancer cells
Authors: Ito Yuumi , Yamaguchi Hideki , Fukami Kiyoko , Honda Kazufumi , Miura Nami , Yamada Tesshi , Sakai Ryuichi
Published: May 2015

Invadopodia are ventral membrane protrusions that are formed by invasive cancer cells cultured on physiological substrates. They are actin-based structures and promote the degradation of the extracellular matrix by focally localizing matrix metalloproteinases. Accumulating evidence suggests that invadopodia play an important role in local invasion and distant metastasis of malignant tumors. Actinin is an actin-binding protein that forms dimers and crosslinks actin filaments. There are four isoforms of actinin in mammals and they are divided into the muscle type (actinin-2 and -3) and the non-muscle type (actinin-1 and -4). Actinin-1 is ubiquitously expressed and involved in the formation of focal adhesions, while actinin-4 is strongly expressed at the invading front of advanced cancers and its expression is correlated with poor prognosis. Although actinin-4 is thought to regulate cell motility and invasion, the detailed molecular mechanisms remain unclear. Moreover, functional differences between the two isoforms have yet to be fully defined. In this study, we studied the roles of and functional differences between actinin-1 and -4 in invadopodia formation to determine the impact of actinin-4 expression on cancer cells. Immunofluorescence analysis showed that both actinin-1 and -4 clearly localized at invadopodia in RPMI-7951 human melanoma cells and there was no obvious difference in their localization patterns. Likewise, invadopodia formation and degradation of fluorescent gelatin matrix were blocked by siRNA-mediated knockdown of either actinin-1 or -4. In contrast, only actinin-4, but not actinin-1, promoted invadopodia-mediated gelatin degradation activity when overexpressed in RPMI7951 cells. Similar results were obtained when MDA-MB-231 human breast cancer cells and SCC61 human head and neck squamous cell carcinoma cells were analyzed in the same manner. These results indicate that both actinin-1 and -4 are essential components of invadopodia, but only actinin-4 possesses an ability to promote invadopodia formation. Therefore, further analysis is conducted now to identify the unique functions actinin-4 in invadopodia formation.

Citation Format: Yuumi Ito, Hideki Yamaguchi, Kiyoko Fukami, Kazufumi Honda, Nami Miura, Tesshi Yamada, Ryuichi Sakai. Functional differences of actinin isoforms in the formation of invadopodia by invasive cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4070. doi:10.1158/1538-7445.AM2014-4070
Abstract 4084: NKG2D receptor activation of mTOR and NFκB enhances antitumor immunity in effector CD8+ T cells
Authors: Whitman Emily , Barber Amorette E.
Published: May 2015

To induce strong anti-tumor immune responses, naïve CD8+ T cells require stimulation through the TCR and costimulatory receptors. Each costimulatory molecule can have a unique effect on the function of T cells due to differential activation of downstream signaling pathways and gene expression. However, the effect of stimulating costimulatory receptors on activated T cells is still unclear. One costimulation receptor that is likely to be engaged in the tumor microenvironment is NKG2D since the ligands for this receptor are expressed on over 80% of tumors. In order to determine how activation of costimulatory receptors in the tumor microenvironment affects CD8+ T cell functions, this study investigated the differential activation of signaling pathways by two costimulatory receptors, CD28 and NKG2D. Specifically, this study focused on the activation of mTORC1 and mTORC2 along with NFκB, all of which have been shown to have important roles in anti-tumor functions of CD8+ T cells. Stimulation through the CD3 and NKG2D receptors differentially activated the mTOR and NFκB pathways compared to the other receptors in our study. Activation of CD8+ T cells through CD3 and NKG2D lead to increased phosphorylation of signal transduction pathway members upstream of mTOR, including AKT, p70 S6K, and GSK3β. Also, expression of genes upstream and downstream of mTORC1 and mTORC2 were differentially activated after stimulation through NKG2D, indicating that activation of mTOR pathways are altered after CD3/NKG2D stimulation as compared to stimulation through CD3 or CD3/CD28. In addition, IKKα, IκBα, and NFκB phosphorylation and IκBα degradation was increased after CD3/NKG2D stimulation. This increased activation of the NFκB pathway also lead to increased gene expression and secretion of pro-inflammatory cytokines, including IFN-alpha and IFN-gamma, and decreased gene expression and secretion of anti-inflammatory cytokines, including IL-10 and VEGF-alpha. Together, these data show that stimulation through NKG2D leads to the differential activation of signaling pathways and alters the anti-tumor functions of effector CD8+ T cells.

Citation Format: Emily Whitman, Amorette E. Barber. NKG2D receptor activation of mTOR and NFκB enhances antitumor immunity in effector CD8+ T cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4084. doi:10.1158/1538-7445.AM2014-4084
What Physicians Need to Know About Renal Function in Outpatients with Heart Failure
Authors: Waldum-Grevbo Bård
Published: May 2015

The majority of outpatients with heart failure (HF) have chronic kidney disease (CKD) as an important comorbidity. Both glomerular filtration rate and abnormal urinary albumin excretion are major predictors of outcome in HF patients. Despite this, patients with renal dysfunction have been systematically excluded from the large randomized HF trials. There is lack of evidence for optimal treatment in these cardiorenal patients and treatment nihilism may account in part for their bad prognosis. Identifying and monitoring the progression of renal disease and making an effort to preserve renal function should be an important task in the management of all patients with HF. In this review, the current understanding of the pathophysiology of renal dysfunction in outpatients with HF will be summarized. Furthermore, important principles of the identification and management of cardiorenal patients will be described in order to make the physician more capable of managing outpatients with HF and renal dysfunction.
Sex Differences in Longevity and in Responses to Anti-Aging Interventions: A Mini-Review
Authors: Austad Steven N. , Bartke Andrzej
Published: May 2015

A robust, often underappreciated, feature of human biology is that women live longer than men not just in technologically advanced, low-mortality countries such as those in Europe or North America, but across low- and high-mortality countries of the modern world as well as through history. Women's survival advantage is not due to protection from one or a few diseases. Women die at lower rates than men from virtually all the top causes of death with the notable exception of Alzheimer's disease, to which women are particularly prone. Yet, despite this robust survival advantage, women across countries of the world suffer worse health throughout life. The biological mechanisms underlying either longer female survival or poorer female health remain elusive and understudied. Mechanisms of mammalian biology, particularly with respect to aging and disease, are most easily studied in laboratory mice. Although there are no consistent differences in longevity between mouse sexes even within single genotypes, there are often substantial differences in individual studies, sometimes favoring females, other times males. Investigating the environmental causes of this puzzling variation in longevity differences could prove illuminating. Sex differences in response to life-extending genetic or pharmacological interventions appear surprisingly often in mice. Longevity enhancement due to reduced signaling through IGF-1 or mTOR signaling typically favors females, whereas enhancement via a range of pharmacological treatments favors males. These patterns could be due to interactions of the interventions with sex steroids, with adiponectin or leptin levels, or with the sex differences in immune function or the regional distribution of body fat. Clearly, generalizations from one sex cannot be extended to the other, and inclusion of both sexes in biomedical studies of human or other animals is worth the effort and expense.
Whole-Slide Imaging of Pap Cellblock Preparations Is a Potentially Valid Screening Method
Authors: Tawfik Ossama , Davis Marilyn , Dillon Susan , Tawfik Laila , Diaz Francisco J. , Amin Khalid , Fan Fang
Published: May 2015

Objective: To date, the impact of digital imaging on routine cytology remains far from perfect. Cellblock (CB) preparations from Pap samples have been shown to be diagnostically valuable. We evaluated the validity of utilizing whole-slide imaging (WSI) prepared from Pap CBs as a screening tool. Study Design: A total of 1,110 CB slides prepared from residual Pap samples were analyzed - 563 normal, 282 atypical squamous cells of undetermined significance (ASCUS), 12 atypical squamous cells-cannot exclude high-grade squamous intraepithelial lesion, 188 low-grade squamous intraepithelial lesions (LSIL), 36 high-grade squamous intraepithelial lesions (HSIL), 25 atypical glandular cells of undetermined significance, 1 adenocarcinoma in situ, 2 invasive adenocarcinomas, and 1 squamous cell carcinoma. Virtual slides were obtained using the Aperio system. Test performance characteristics of liquid-based samples and WSI from CB samples were compared. Results: Average sensitivity and specificity of the five WSI reviewers was 58.3 and 85.1% for ASCUS, respectively, 54.1 and 93.9% for LSIL, and 51.8 and 98.8% for HSIL. Overall WSI sensitivity and specificity for detecting lesions was 82.1 and 86.2%, respectively. Agreement (kappa values) between WSI reviewers was 0.56 for ASCUS, 0.69 for LSIL, 0.67 for HSIL, and 0.74 for negative samples. Conclusions: WSI of CB preparations is a feasible method to achieve high-quality specimen preparations. It is as sensitive as liquid-based methods and appears to be highly specific for the detection of LSIL and HSIL.
Clínica de crianças com transtornos: quando a preocupação está para além do orgânico
Authors: Neuwald Marla Finkler , Ferrari Andrea Gabriela
Published: May 2015

Apesar de a constituiÃ§Ã£o do sujeito nÃ£o residir somente no orgÃ¢nico, nÃ£o podemos desconsiderar que limitaÃ§Ãµes no real do corpo podem impor obstÃ¡culos no processo de constituiÃ§Ã£o subjetiva. A partir de questionamentos da minha experiÃªncia clÃ­nica como fisioterapeuta neuropediÃ¡trica e do meu percurso acadÃªmico no curso de especializaÃ§Ã£o em atendimento clÃ­nico - Ãªnfase psicanÃ¡lise, alguns interrogantes sobre a prÃ¡tica clÃ­nica com crianÃ§as com transtornos neuromotores foram surgindo. Testemunhando uma carÃªncia na articulaÃ§Ã£o entre esses saberes, busquei encadear conhecimentos das duas especificidades objetivando propor uma clÃ­nica que tome a crianÃ§a como um sujeito em constituiÃ§Ã£o e nÃ£o apenas preocupada com o real orgÃ¢nico da lesÃ£o.
A prática psicanalítica de Françoise Dolto a partir de seus casos clínicos
Authors: Soler Vanessa Tramontin da , Bernardino Leda Mariza Fischer
Published: May 2015

Este artigo se embasa no trabalho e teoria de Françoise Dolto. Tivemos como objetivos compreender os pressupostos básicos de sua teoria; caracterizar as intervenções do psicanalista na análise com crianças; e exemplificar seu método através do recorte das principais intervenções realizadas no Caso Dominique e no caso Bernadette. Como resultado, constatamos que Dolto trabalhava com maestria o fenômeno da transferência e as situações de interpretação; providenciava a oferta de recursos adequados à condição da criança; conduzia o trabalho com os pais permitindo a efetivação do sentimento de confiança neles, em aderirem ao tratamento analítico de seus filhos.
O normal e o patológico na relação mãe-bebê: um estudo a partir de manuais de puericultura publicados no Brasil (1919-2009)
Authors: Lima Ana Laura Godinho
Published: May 2015

Este artículo pretende reflexionar sobre los criterios de normalidad que se aplican a la relación mamá-bebé. Las cuestiones que orientan el análisis son las siguientes: ¿cómo es la relación mamá-bebé considerada normal? Por otro lado, ¿qué se considera patológico en esa modalidad de relación? Mediante el examen de manuales de puericultura publicados desde las primeras décadas del siglo XX, se busca verificar cambios y permanencias en las maneras especializadas de evaluar las relaciones entre las madres y sus bebés como adecuadas o no. El análisis se fundamenta en los trabajos de Canguillem y Foucault sobre el concepto de normalización.
A psicanálise e o professor que amarelou
Authors: Riolfi Claudia Rosa
Published: May 2015

Frente à mercantilização da educação, experimentamos uma epidemia cujo sintoma é a perda de coragem dos professores. Essa se origina na dificuldade de suportar a angústia gerada pela distância entre o aluno empírico e o do passado mítico, que se interessava espontaneamente pelo conhecimento articulado. Seu resultado é a impossibilidade, por parte das novas gerações, de criar com ele uma relação que transcenda o mero uso pragmático. Ao privilegiar o real, a segunda clínica de Lacan permite fundar saídas não moralistas para este impasse e compreender que, além das que já estão prontas na cultura, soluções singulares e criativas são necessárias.
Ela se chama Sabine...
Authors: Vorcaro Angela , Rahme Mônica
Published: May 2015

Este artigo discute algumas questões decorrentes do filme documentário "O nome dela é Sabine (Elle s'appelle Sabine)", dirigido por Sandrine Bonnaire (França/2007). O filme apresenta um registro sobre o percurso de Sabine, irmã de Sandrine, que passou por um período de cinco anos de internação em hospital psiquiátrico. Recortando cenas de filmagens familiares e de imagens da irmã captadas nos anos de 2006 e 2007, Sandrine nos apresenta uma narrativa que permite indagar questões que atravessam a experiência dos sujeitos nas instituições e que faz emergir pontos relevantes sobre os efeitos subjetivos dos laços que se estabelecem na fratria.
I am Sam: deficiência mental e relação com o saber
Authors: Diniz Margareth
Published: May 2015

O filme I am Sam trata da deficiência mental e das representações sociais que a envolvem. Inicialmente, o artigo pretende apresentar a definição de deficiência mental em uma perspectiva universal e cotejar a diferença entre deficiência mental, debilidade e fracasso escolar na perspectiva da psicanálise, considerando a relação da criança com o saber. Usar do cinema e da filmografia disponível para interrogar diagnósticos fixos e segregadores, que excluem o sujeito e sua relação com o saber, é o objetivo deste trabalho.
O que resta da sexualidade infantil?
Authors: Bidaud Eric
Published: May 2015

O texto interroga a emergência e a importância no discurso atual da figura da criança maltratada e, mais ainda, da ideia da infância em risco. Examinamos a hipótese de que a pregnância da "criança maltratada", bem como da "criança abusada", implica a recusa da sexualidade infantil, paradigma da psicanálise. A denúncia da "pedofilia generalizada" visa de fato a silenciar o trauma sexual para assim eliminar toda causalidade psíquica, em beneficio de uma "realidade objetiva" que relegaria o fantasma do amor incestuoso à pedofilia.
Elementos para entender o transtorno de déficit de atenção e hiperatividade: TDAH
Authors: Matos Roberto Pires Calazans
Published: May 2015

Este artigo apresenta alguns elementos que podem permitir uma melhor compreensão do Transtorno de Déficit de Atenção e Hiperatividade. O primeiro elemento é determinar a função perturbada - a consciência - e a semiologia clássica dessa função; o segundo, apontar para uma ideologia naturalista que sustenta o diagnóstico em termos de transtorno; o terceiro é a maneira pela qual a psicanálise considera a consciência; e o quarto, uma breve consideração sobre como a inibição em Freud e Lacan podem auxiliar no entendimento desse transtorno.
Notas sobre algumas implicações psíquicas da desconstrução da maternidade no processo de luto: um caso de nascimento-morte
Authors: Lopes Cléa Maria Ballão , Pinheiro Nadja Nara Barbosa
Published: May 2015

O presente trabalho tem por objetivo discutir, a partir da psicanálise, questões relacionadas à maternidade em formação durante a gravidez, que é interrompida por ocasião da morte do bebê no momento ou logo após o parto. São feitas considerações sobre o efeito traumático desse evento para o psiquismo materno, no que se refere ao enfrentamento da ruptura e desconstrução do processo de maternidade, que durante o período gestacional estava se instalando e foi bruscamente interrompido e sobreposto pelo luto. O artigo encontra suporte em Winnicott e Freud e ancora-se nas noções de: preocupação materna primária, narcisismo, identificação e luto.
As problemáticas alimentares e a desnutrição na infância: contribuições psicanalíticas
Authors: Carvalho Ângela Sousa de , Lima Maria Celina Peixoto , Martins Karla Patrícia Holanda
Published: May 2015

Este artigo consiste em uma construção a partir da escuta de mães de crianças com desnutrição e queixas alimentares, tomando a psicanálise de Freud e Lacan como referencial teórico. Guardando as devidas particularidades, as crianças pesquisadas apresentam um quadro de desnutrição relacionado à recusa em se alimentar. O sintoma, então, se configura como uma recusa a qualquer alimento que não seja o leite materno, o que aponta para uma dificuldade em renunciar ao objeto seio e operar as devidas substituições para outros objetos/alimentos. Pode-se, desse modo, apontar que o diagnóstico da desnutrição infantil deve levar em consideração os fatores psíquicos relacionados ao âmbito da relação mãe-criança.
Transgressão e criatividade em sala de aula
Authors: Domingues Karen Geisel , Almeida Inês Maria Zanforlin Pires de , Cerqueira Teresa Cristina Siqueira
Published: May 2015

O artigo apresenta parte de uma pesquisa de mestrado que utilizou como referencial epistemológico a teoria da criatividade de Winnicott. A investigação aconteceu a partir de entrevistas com professores da 2a Fase do Ensino Fundamental de escolas da rede pública e particular de Brasília-DF, a fim de compreendermos a interpretação dos educadores sobre o processo de constituição do sujeito-aluno no entretecer de comportamentos transgressores e criativos no trabalho-educar. Concluiu-se que a transgressão pode ser considerada parte do processo criativo para o aluno, tanto em relação a ações e produções no mundo social quanto à criação da própria identidade do indivíduo.
A escuta de adolescentes na escola: a sexualidade como um sintoma escolar
Authors: Cunha Cristiane De Freitas , Lima Nádia Laguárdia de
Published: May 2015

Apresentamos uma reflexão sobre um trabalho realizado com adolescentes em uma escola particular. A demanda da escola surgiu quando o professor se deparou com a impossibilidade da transmissão de um saber sobre o corpo sexuado aos adolescentes. O professor se confrontou com as falhas na transmissão pedagógica, com o excedente pulsional intraduzível dos alunos, e com o próprio mal-estar e a perplexidade diante dessa situação. A eclosão da puberdade, o encontro com o outro sexo, o amor, o conflito entre as gerações, a imagem corporal cambiante geraram angústia e agitação. Nas conversações de orientação psicanalítica com um grupo de adolescentes na escola, emergiram perguntas e respostas, tornando possível uma simbolização do que aparecia como uma opacidade no saber e provocações linguageiras.
Para concluir um projeto de pesquisa
Authors: Falek Jussara
Published: May 2015

O artigo reflete sobre as atividades desenvolvidas em um projeto de pesquisa realizado na Universidade de São Paulo entre os anos de 2002 e 2007, enfocando em especial a modalidade de transferência que se desenvolveu na clínica com crianças diagnosticadas como autistas e as vicissitudes daí decorrentes, tendo por objetivo teorizar no campo da psicanálise de inspiração lacaniana.
Georg Friedrich Meier e os paraísos artificiais de Immanuel Kant
Authors: Suzuki Márcio
Published: May 2015

Este texto procura mostrar como G. F. Meier e Immanuel Kant veem a diversão e a distração como parte essencial do método filosófico.
El tiempo subjetivo como producto de la doctrina kantiana de la auto-afección
Authors: Orono Matías
Published: May 2015

El objetivo de este trabajo es demostrar que la doctrina kantiana de la auto-afección da lugar a la consciencia de un tiempo meramente subjetivo. En primer lugar, analizaremos los §§ 8 y 24 de la Crítica de la Razón Pura con el fin de comprender la distinción entre un nivel a priori y otro empírico de auto-afección. En segundo lugar, compararemos la doctrina de la auto-afección y el esquematismo trascendental, con el fin de señalar que la temporalidad a priori de la auto-afección no se identifica con el tiempo objetivo del esquematismo.
A construção política da identidade: um desafio feminista à distinção entre político e social
Authors: Bodziak Junior Paulo Eduardo
Published: May 2015

Se o hábito arendtiano de separar conceitos possibilitou importantes críticas à modernidade e promoveu um novo questionamento sobre o sentido da política, ele também possibilitou duras críticas ao pensamento da autora, de machista a nostálgico helênico. Compreender as distinções de modo a evitar compreensões rígidas é o exercício mais adequado para não perder as contribuições de Arendt ao debate político contemporâneo. Nesse sentido, autoras como Bonnie Honig e Hanna Pitkin lançam um desafio interessante às categorias arendtianas, extraindo delas uma possibilidade de leitura muito rica através dos conflitos de formação da identidade. Neste artigo, pretende-se mostrar como uma leitura específica, atitudinal e relacional, pode dar fôlego às distinções de Arendt, atenuando-as, porém sem fazer com que elas percam sua capacidade de traçar características próprias ao político e ao social.