tbuckley/cabot-search huggingface dataset:
Abstract 2369: SOX11 promotes protective microenviromental nixes in agressive MCL
Authors: Virginia Amador
Journal: Cancer Research (2015)

Abstract Mantle cell lymphoma (MCL) is considered one of the most aggressive lymphoid neoplasms and althought MCL represents only a 5-10% of all non-Hodgkins lymphomas, the aggressive clinical evolution with short responses to treatment, frequent relapses and the poor response to current therapies of the MCL patients, makes this lymphoma one of the tumors most studied internationally. Recent clinical observations have identified some patients with a more indolent form of this disease that have a long survival even without the need for treatment. Gene expression profiling (GEP) studies have identified the aberrant expression of the transcription factor SOX11 in aggressive MCL and absent in MCL with an indolent outcome, other lymphomas or normal B-cells, suggesting that SOX11 might play a relevant pathogenic role in the development and progression of this tumor. We have recently demonstrated in experimental studies that SOX11 blocks the maturation of the MCL cells and promotes the growth and angiogenesis of these tumors confirming the clinical observations that SOX11 may play an important role in the aggressive behavior of MCL. We have now generated preliminary results suggesting that SOX11 may regulate the migration and adhesion of the tumor cells increasing tumor dissemination and homing to different tissues compartments, protective microenvironment niches, the proliferation of new vessels bringing nutrients to the tumor and modulating an immature cellular status with more stemness capacity and drugs resistance known as cancer stem cell status. The understanding of these mechanisms will provide new potential candidates for therapeutic interventions. Citation Format: Virginia Amador. SOX11 promotes protective microenviromental nixes in agressive MCL. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2369. doi:10.1158/1538-7445.AM2015-2369
Abstract 2060: DUSP6 phosphatase as a tumor suppressor in non-small cell lung cancer
Authors: Rosario Perona, Veronica Moncho-Amor, Inmaculada Ibanez de Caceres, Laura Pintado-Berninches, Ester Martin, Miguel Quintanilla, María Cortes-Sempere, Leandro Sastre, Cristobal Belda-Iniesta
Journal: Cancer Research (2015)

Abstract DUSP6/MKP3 a Map Kinase phosphatase involved in dephosphorylation and inactivation of ERK1/2 is a key gene whose expression in NSCLC is regulated by the DUSP1 Map Kinase phosphatase. Here we show that DUSP6 plays a major role in the regulation of cell migration, motility and tumor growth. We have found upregulation in the expression of several genes involved in Epidermal to mesenchimal transition in NSCLC-DUSP6 depleted cells. Furthermore ERK5 expression and phosphorylation, but not ERK1/2 is greatly enhanced in these cells. Finally the data obtained in RNAseq studies carried out in DUSP6 depleted cells identified several genes such as VAV3, RUNXR2, LEF1, FGFR2 whose expression is upregulated in these cells and affecting cellular functions such as integrin mediated cell adhesion and focal adhesion supporting the changes in cell adhesion and motility observed in DUSP6 depleted cells. TGFβ pathway is activated in these cells as we have observed phosphorylation of SMAD3 and consequently inhibition of TGFβ reduces the expression of EMT genes. Finally in silico studies from Gene Expression Omnibus and The Cancer Genome Atlas databases indicates that those NSCLC patients with low expression of DUSP6 are those with the worst prognosis. Citation Format: Rosario Perona, Veronica Moncho-Amor, Inmaculada Ibanez de Caceres, Laura Pintado-Berninches, Ester Martin, Miguel Quintanilla, María Cortes-Sempere, Leandro Sastre, Cristobal Belda-Iniesta. DUSP6 phosphatase as a tumor suppressor in non-small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2060. doi:10.1158/1538-7445.AM2015-2060
Potential role of orexin and sleep modulation in the pathogenesis of Alzheimer’s disease
Authors: Jee Hoon Roh, Hong Jiang, Mary Beth Finn, Floy R. Stewart, Thomas E. Mahan, John R. Cirrito, Ashish Heda, B. Joy Snider, Mingjie Li, Masashi Yanagisawa, Luis de Lecea, David M. Holtzman
Journal: The Journal of Experimental Medicine (2014)
Modulation of breast cancer development in MMTV-PyVT mice by adiponectin: A perspective on tumor microenvironment.
Authors: Yu Wang
Journal: Journal of Clinical Oncology (2015)

34 Background: The survival and growth of epithelial carcinoma cells are critically dependent on the interactions with the neighboring stromal cells. Adiponectin, a molecule exclusively produced by adipose tissue, possesses potent anti-inflammatory and anti-tumorigenic activities. Its expression and production are inversely associated with breast cancer risks in pre- and post-menopausal women. Reduced or completely loss of adiponectin expression enhances the development of mammary tumors in MMTV-PyVT mice. Despite these evidences, the mechanisms underlying the anti-breast cancer activity of adiponectin remain poorly understood. Methods: Adiponectin-deficient MMTV-PyVT mice that show distinct basal epithelial-like features of mammary tumors are used for analyzing the stromal vascular fractions (SVF) of the adipose tissues in tumor microenvironment. Results: Flow cytometric analyses demonstrate that adiponectin deficiency significantly alters the composition of cells in SVF isolated from the mammary adipose tissues. Adiponectin-deficient SVF contribute to the metaplastic features of the basal epithelial-like breast cancers. Co-implantation of SVF derived from adiponectin-deficient mice accelerates mammary tumor development and metastasis in NOD/SCID mice engrafted with MDA-MB-231 human breast cancer cells. Fluorescence Activated Cell Sorting isolates a population of CD44+CD25-CD100+ cells that are enriched in both thymus and SVF of mice lacking the expression of adiponectin. Upregulated CD100 expression interrupts early T-cell development and maturation. In mammary tissues, CD44+CD25-CD100+ cells facilitate the development of metaplastic basal epithelial-like breast cancers. Adiponectin treatment down-regulates CD100 expression, in turn enhancing Notch signaling and T-cell maturation in the thymus, and reduces the accumulation of CD44+CD25-CD100+ cells in the tumor microenvironment. Conclusions: These results support a pivotal role of adiponectin in mediating the epithelial-stroma crosstalk to prevent mammary carcinogenesis and shed new lights on the development of immuno-therapeutics for breast cancer diseases.
Duration of Antibiotic Therapy for Community-Acquired Pneumonia in the Era of Personalized Medicine
Authors: Jonathan S. Lee, Daniel L. Giesler, Michael J. Fine
Journal: JAMA (2016)

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Abstract 4178: L1CAM and integrin αvβ3 mediate direct cell contact between cancer stem cells and endothelial cells: Promotion of endothelial cell migration and survival
Authors: Monica E. Burgett, Justin D. Lathia, Patrick Roth, Amy S. Nowacki, Ping Huang, Amit Vasanji, Meizhang Li, Tatiana Byzova, Tom Mikkelsen, Shideng Bao, Jeremy Rich, Michael Weller, Candece L. Gladson
Journal: Cancer Research (2015)

Abstract Sprouting angiogenesis requires endothelial cell (EC) migration. In glioblastoma (GBM), cancer stem cells (CSC) in the perivascular niche secrete factors that promote EC migration. Here, we identify a direct interaction between the CSCs and ECs that is mediated by RGD-peptide-dependent binding of L1CAM on CSCs with integrin αvβ3 on ECs. Using in vitro assays, we found that this interaction increased migration-associated signaling events in ECs, including activation of integrin αvβ3, ERK, JNK and Akt, and VCAM-1 and E-selectin mRNA expression. Comparison of the effects of co-culturing CSCs with ECs versus the effects of conditioned media from CSCs co-cultured with ECs indicated that the effects of the direct interaction and soluble factors differed quantitatively and qualitatively. The direct interactions stimulated the migration of ECs and primed them to the migratory effects of soluble factors produced by the CSCs. The direct interaction also enhanced expression of pro-survival genes in CSCs and ECs. In GBM biopsies, Sox2-positive tumor cells were localized in close proximity to ECs and injection of β3-negative ECs or L1CAM-negative CSCs into brain slices in organotypic culture resulted in reduced interactions between ECs and CSCs. RGD-peptide treatment of mice with established intracerebral GBM xenografts increased the mean distance of Sox2-positive tumor cells from ECs, decreased integrin αvβ3 activation and decreased vessel surface area. These data show that direct interactions between CSCs and ECs have potent effects on EC migration and angiogenesis in GBM and have implications for the design of angiogenesis-targeted therapies. Citation Format: Monica E. Burgett, Justin D. Lathia, Patrick Roth, Amy S. Nowacki, Ping Huang, Amit Vasanji, Meizhang Li, Tatiana Byzova, Tom Mikkelsen, Shideng Bao, Jeremy Rich, Michael Weller, Candece L. Gladson. L1CAM and integrin αvβ3 mediate direct cell contact between cancer stem cells and endothelial cells: Promotion of endothelial cell migration and survival. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4178. doi:10.1158/1538-7445.AM2015-4178
273. MMPs-Responsive Release of siRNA from 4-Arm PEG siRNA Conjugate
Authors: Hye Sung Kim, Hyuk Sang Yoo
Journal: Molecular Therapy (2015)

Small interfering RNA (siRNA) has drawn much attention for its unique and effective gene silencing mechanism although its poor cellular membrane permeability, limited stability and low flexibility still remain major concerns. In particular, when siRNAs are complexed with the cationic carriers, the resultant complexes shows much lower physical stability than those prepared with plasmid DNA due to the low charge density of siRNA. Thus, we conjugated siRNAs to 4-arm polyethylene glycol (PEG) via a matrix metalloproteinases (MMPs)-cleavable peptide to enhance complexation with linear polyethyleneimine (LPEI). In addition, release of siRNA/LPEI complex from 4-arm PEG-siRNA/LPEI and subsequent gene silencing efficacy were investigated in diabetic ulcers. After synthesis of 4PEG-siRNA conjugate, the conjugation amount of siRNA per 4-arm PEG was 2.6 (mol/mol). According to gel retardation assay, 4PEG-siRNA/LPEI showed superior association to siRNA/LPEI at the same N/P ratio, which suggests the flexible structure of 4PEG-siRNA conjugate is more favorable for complexation with LPEI than naked siRNA. The particle size and zeta potential of 4PEG-siRNA/LPEI was 1415.5±73.1nm and 13.8±1.9mV, respectively. However, those values were changed similarly to those of siRNA/LPEI in the presence of MMP-2 because the MMPs-cleavable linker between 4-arm PEG and siRNA was digested by MMP-2. In addition, 4PEG-siRNA/LPEI complexes could not be uptaken by cells before dissociation by MMP-2 due to their huge size. In diabetic ulcers, 4PEG-siRNA/LPEI was rapidly cleaved and separated to siRNA/LPEI fraction and showed higher gene silencing of MMP-2 for 14 days. Thus, wound recovery was subsequently enhanced by inhibiting MMP-2 expression in diabetic ulcers.
Abstract 1576: Analysis of HSP10 as a putative biomarker of breast cancer
Authors: Sadr-ul Shaheed, Andreas Hadjisavvas, Kleitos Sokratous, Paul Loadman, Chris Sutton, Kyriacos Kyriacou
Journal: Cancer Research (2015)

Abstract Introduction. Detection of the very earliest stages of breast cancer remain challenging and the differentiation of those carcinomas that develop into aggressive invasive forms from those that remain benign has not been achieved. Consequently, removal of the tumor by total mastectomy, local excision (LE) plus adjuvant radiotherapy (RT), or LE alone remain the main treatments, even if they prove unnecessary. Previously, using proteomics analysis, we identified proteins that were significantly changed in expression between matched normal and tumor tissues from Cypriot patients with different stages of the disease. Heat shock protein 10 (HSP10), which is responsible for the mitochondrial protein folding, was one of the proteins identified. A range of methods were used to verify HSP10 as a possible biomarker for breast cancer. Materials and Methods. Protein extracts from breast cancer cell lines and breast tissue biopsies from Cypriot patients with different stages of the disease were analysed by (i) Western Blotting (WB) and (ii) multiple reaction monitoring mass spectrometry (MRM MS) using two proteotypic peptides unique to HSP10, in proteins extracted form fresh frozen as well as from FFPE breast tissues. Tissue microarray analysis (TMA) was carried out on core biopsies from the Leeds Breast Tissue Bank. Results. WB indicated that HSP10 was ubiquitously and evenly expressed across breast cancer cell lines representative of different phenotypes. WB and MRM MS revealed that expression was significantly increased in invasive carcinoma compared to normal tissue, but was patient specific for fibroadenoma and DCIS cases. TMA of 360 samples indicated a strong correlation between staining and type of breast cancer (invasive ductal and lobular), grade and ER positive phenotype. Discussion. Proteomics analysis using iTRAQ quantitation indicated an average of 1.6 fold increase in HSP10 in invasive carcinomas compared to matched normal tissue. By comparison, WB and MRM MS analysis indicated a significantly amplified discrimination in the expression of HSP10 as has been observed with other biomarker candidates. HSP10 protein levels were in agreement with mRNA results observed in breast cancer cell lines reported in the Cancer Cell Line Encyclopaedia. In conclusion, HSP10 represents an excellent biomarker candidate for further validation. Citation Format: Sadr-ul Shaheed, Andreas Hadjisavvas, Kleitos Sokratous, Paul Loadman, Chris Sutton, Kyriacos Kyriacou. Analysis of HSP10 as a putative biomarker of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1576. doi:10.1158/1538-7445.AM2015-1576
PTCA with STENTING compared to off-pump coronary surgery with a left internal mammary artery in patients with single vessel disease of the left anterior descending artery; 6 months angiographic follow-up results of a prospective clinical trial
Authors: PW Boonstra, AJ van Boven, JG Grandjean, Massimo Mariani, DJ Drenth, Tjark Ebels
Journal: Circulation (1998)
Abstract 1026: Role of Group I Paks in MPNST cell proliferation, migration and invasion
Authors: Galina Semenova, Jonathan Chernoff
Journal: Cancer Research (2015)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas that arise in patients with neurofibromatosis (NF1) or sporadically. MPNSTs are typically chemoresistant, while surgical removal is limited due to invasiveness of the tumors. Recent studies that attempted to discover rational MPNST therapies identified MEK/ERK, PI3K/mTORC1 and Wnt/β-catenin pathways among the most critical for MPNST development and progression. As Group I p21-activated kinases (Paks) are known to regulate all three of these signaling pathways in many cell types, we proposed assess the potential of these kinases as potential therapeutic target for MPNST. Using genetic and biochemical approaches we showed that loss of PAK1-3 activity significantly suppressed MPNST cell proliferation, as well as migration and invasion capacity. Treatment with specific small molecule PAK1-3 inhibitors Frax1036 and IPA-3 caused reduction of mTORC1 and β-catenin signaling in MPNST cells. MEK/ERK signaling, however, appeared to be intact or upregulated upon chemical Pak inhibition in most of the MPNST cell lines analyzed. Dual inhibition of PAK and MEK (PD0325901) resulted in synergistic cytotoxic effect on MPNST cells. Collectively, these findings suggest that Pak inhibitors might be useful for MPNST therapy, as single agents or in combinatorial treatment strategies. Citation Format: Galina Semenova, Jonathan Chernoff. Role of Group I Paks in MPNST cell proliferation, migration and invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1026. doi:10.1158/1538-7445.AM2015-1026
99. A Novel Mechanism of Transduction of Human Cells By Recombinant AAV Vectors
Authors: Zifei Yin, George V. Aslanidi, Chen Ling, Yuanhui Zhang, Changquan Ling, Mengqun Tan, Mervin C. Yoder, Arun Srivastava
Journal: Molecular Therapy (2015)

The human embryonic kidney cell line, HEK293, is readily transduced by the most commonly used AAV2 serotype vectors because these adherent cells abundantly express the cell surface receptor, heparan sulfate proteoglycan (HSPG), and one of the co-receptors, human fibroblast growth factor receptor 1 (FGFR1) for AAV2. However, a human erythroleukemia cell line, K562, commonly used as a model for human hematopoietic cell transduction, is not transduced as efficiently, although these cells grown in suspension, express both HSPG and FGFR1 only at modestly lower levels. We reasoned that the lack of proximity of HSPG and FGFR1 on K562 cells might account for the suboptimal transduction of these cells, and hypothesized that if the transduction was performed at high cell density, presumably allowing for HSPG on one cell to come in close proximity to FGFR1 on the neighboring cell, then AAV2 bound to HSPG on one cell could utilize FGFR1 on the neighboring cell to gain entry in the latter, and vice versa, thus leading to increased transduction. To test this hypothesis, HEK293 and K562 cells were transduced with 3×103 vgs/cell of scAAV2-EGFP vectors either at low-density (60,000 cells in 50 ml) or at high-density (480,000 cells in 50 ml). Transgene expression was evaluated by flow cytometry 48 hrs post-transduction. Whereas ~90% of HEK293 cells expressed the transgene at low-density, the transduction efficiency at high-density increased up to ~95%. On the other hand, only ~35% of K562 cells were transduced at low-density, but interestingly, the transduction efficiency at high-density increased to ~65%, thus corroborating that close cell-cell contact facilitated vector entry into these cells. That the initial cell-cell contact was critical in achieving improved transduction, was further corroborated by experiments in which cells were transduced at low-density, and subsequently pooled together to reach high-density, and conversely, cells were transduced at high-density, and soon after transduction, were diluted to low-density. The increased transduction was observed only under the latter condition. Similar results were obtained with two additional human cell lines, M07e and Raji, which express low to extremely low levels of HSPG and FGFR1, respectively, and consequently, are transduced extremely poorly by AAV2 vectors. These studies were also extended to include primary human CD34+ hematopoietic stem/progenitor cells (HSPCs), also grown in suspension, and known to be transduced sub-optimally by AAV2 vectors. In these studies also, whereas only~5% of these cells were transduced at low-density, the transduction efficiency increased up to ~20% at high-density. Taken together, our studies have revealed a novel mechanism, which we have termed "cross-transduction", which AAV vectors exploit to gain entry into target cells, and which may have implications in the optimal use of AAV vectors in human gene therapy applications.
Association of peripheral blood guanylyl cyclase C (GCC) expressions with prognostic parameters and response to therapy in patients with colorectal cancer.
Authors: Celalettin Camci, Alper Sevinc, Akif Sahin, Mehmet Emin Kalender, Serdar Oztuzcu, Ozlem nuray Sever, Esma Ozyazgan, Abdullah Tuncay Demiryurek
Journal: Journal of Clinical Oncology (2012)

508 Background: Guanylyl cyclase C (GCC) is expressed exclusively in normal intestinal mucosal cells, primary and metastatic colorectal cancers (CRC). The aim of this study was to determine the possible association between the GCC expressions in peripheral blood, prognostic parameters and response to chemotherapy in CRC patients. Methods: Forty-nine metastatic CRC patients and 41 healthy controls with similar age and sex were included to this study. Peripheral blood GCC expressions are measured by the reverse transcriptase-polymerase chain reaction (RT-PCR) method. Results: No GCC expression was measured in healthy controls but GCC expressions of the patients were detectable. Although there was a significant reduction in GCC expressions in 30 patients with regression (from 5.46 ± 4.12 to 0.06 ± 0.03, p &lt; 0.0001), marked increase in GCC expressions was observed in 19 patients with progression following chemotherapy (from 0.43 ± 0.19 to 1.38 ± 0.52, p = 0.0174). Significant correlation was found between the GCC expressions and carbohydrate antigen 19-9 (CA19-9) levels (p = 0.0041) in 30 patients with regression before chemotherapy. Marked correlation was also detected between the GCC expressions and carcinoembryonic antigen (CEA) levels (p = 0.0072) in 19 patients with progression before chemotherapy. Conclusions: The results of the present study suggest that peripheral blood GCC expressions along with CEA and CA19-9 can be used to determine the early respose to chemotherapy in patients with metastatic CRC. These findings imply that higher expression of GCC in peripheral blood seems to be an indicator of good therapeutic response to chemotherapy and remission. Monitoring the peripheral blood GCC expressions may allow employing different treatment options to metastatic CRC patients.