tbuckley/cabot-search huggingface dataset:
Abstract 2144: RasGRP1 induces autophagy in primary human epidermal keratinocytes resembling fail-safe mechanisms triggered by oncogenic Ras
Authors: Lauren L. Fonseca, Patricia S. Lorenzo
Journal: Cancer Research (2012)

Abstract RasGRP1 is a guanyl nucleotide exchange factor for Ras that is abundantly expressed in lymphocytes, regulating their maturation and activation. Its aberrant expression has been associated to transformation in various cell types, although the role in human cancer remains largely unexplored. Our lab has previously demonstrated expression of RasGRP1 in epidermal keratinocytes, followed by studies that showed a critical role in skin carcinogenesis in mouse models of cutaneous squamous cell carcinoma through its ability to increase the dosage of active Ras. To explore whether RasGRP1 could contribute to transformation of human keratinocytes, we utilized primary epidermal keratinocytes (HEK) isolated from neonatal foreskin. In a model of tissue reconstruct, or 3-D culture, HEK manipulated to overexpress RasGRP1 (RasGRP1+) failed at generating a stratified epithelium. In fact, the RasGRP1 + cells underwent changes resembling autophagy and cell death in culture, with vacuolated cytoplasm as well as rounded bodies. Autophagy was confirmed at the molecular level by measuring increases in the LC3-II species by Western blot and the formation of a LC3 punctate pattern by immunofluorescence. Surprisingly, there was no caspase-3 activation in the RasGRP1+ HEK despite the morphological signs of apoptosis, although we noticed an increase in the expression of the BH3-only protein NOXA as early as 48 hours post RasGRP1 overexpression. Since oncogenic signals are known to induce fail-safe mechanisms that restrict cell expansion, we presumed that the changes observed in the HEK cell overexpressing RasGRP1 were due to Ras hyperactivation (oncogenic)-induced cell death. As predicted, levels of active Ras-GTP were 3 times higher in the RasGRP1+ cells compared to the wild type HEK, with a preponderance of the H-Ras isoform being activated. In line with these observations, enforced expression of an oncogenic version of the H-Ras isoform (H-RasQ61L) also resulted in cytoplasmatic vacuolization of HEK and increases in LC3-II levels. In contrast to the RasGRP1+ cells, H-RasQ61L caused activation of caspase-3 while increases in NOXA were delayed compared to those caused by RasGRP1. While RasGRP1 and oncogenic H-RasQ61L differ in some aspect of their downstream molecular pathways, probably as a result of the magnitude of Ras activation, the present findings reveal a novel RasGRP1-Ras axis that can lead to oncogenic signals in human keratinocytes. This warrants further investigation into the potential participation of RasGRP1 in keratinocyte transformation, particularly contributing to cutaneous squamous cell carcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2144. doi:1538-7445.AM2012-2144
OP0126 Radiographic Progression is Less in Patients Achieving A Good Response to Treatment as Measured by New Composite Indices of Disease Activity in Psoriatic Arthritis: Data from an Interventional Study with Golimumab:
Authors: P.S. Helliwell, A. Kavanaugh
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> The purpose of this study was to compare radiographic outcomes according to the magnitude of the response utilizing 2 new psoriatic composite disease activity measures (the Psoriatic Arthritis Disease Activity Score (PASDAS),and the GRAPPA Composite Exercise (GRACE)) [1] with DAS28 as a comparator. The data were taken from the GO-REVEAL dataset, a large (N=324) randomised, double-blind, study which evaluated the safety and efficacy of 2 doses of golimumab in subjects with active PsA. <h3>Methods</h3> Data collected in the GO-REVEAL study was not sufficient to calculate all the components of the GRACE index, soimputation was used to obtain values for the PsA quality of life measure (PsAQoL). Response criteria at 24 weeks were applied across the whole dataset, irrespective of treatment group. Radiographic scores at baseline and 24 weeks were assessed. <h3>Results</h3> Radiographic progression was greater in subjects with a poor outcome with treatment, and less in those with a good outcome. Radiographic scores were intermediate for those with a moderate outcome (Table). Analysis of variance statistics were significant for all three measures but were more significant for the psoriatic arthritis specific indices. Data were also generated for the proportion of subjects in whom no radiographic progression was seen, and these data were compared across the outcome measures using chi-squared statistics: PASDAS, 82% in good outcome group did not have radiographic progression χ<sup>2</sup> =8.5, GRACE 80%, χ<sup>2</sup> =6.6, DAS28, 76% χ<sup>2</sup> =4.6. <h3>Conclusions</h3> Response criteria for disease specific composite measures enable better separation between groups in terms of radiographic progression and may therefore be used as suitable targets for interventional studies and in the clinic. <h3>References</h3> Helliwell PS, Fitzgerald O, Fransen J: Composite Disease Activity and Responder Indices for Psoriatic Arthritis: Development of Cut-offs for Both Disease Activity States and Response. J Rheum, in press (2014). <h3>Disclosure of Interest</h3> P. Helliwell Consultant for: Janssen, A. Kavanaugh Grant/research support: Janssen <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.4692
P1-12-20: The Safety and Tolerability of Vorinostat in Combination with Lapatinib in Advanced Solid Tumors.
Authors: S Chumsri, NS Tait, MM Medeiros, KS Bauer, K-MT Betts, JC Lewis, T Bao, SJ Feigenberg, SB Kesmodel, V Stearns, MJ Edelman, EA Sausville, KHR Tkaczuk
Journal: Cancer Research (2011)

Abstract Background: Lapatinib has been previously shown to markedly decrease cancer stem cells (CSC) in HER2−positive breast cancer. In preclinical models, we have demonstrated that histone deacetylase inhibitors (HDACi) such as vorinostat can induce differentiation and decrease CSC. The combination of vorinostat and lapatinib is synergistic with a combination index of 0.32 (synergism if CI &amp;lt;1). We therefore undertook a pilot study to evaluate the combination of these two drugs in advanced solid tumors. Method: Patients were eligible if they were: age ≥ 18 years with incurable solid tumors, ECOG PS 0–2, adequate organ function, and no prior exposure to HDACi. The first 3 patients received lapatinib at the dose of 1,250 mg continuous daily and vorinostat 300 mg 4 days on 3 days off. The second dose level with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off were administered in 6 patients. Cycles were repeated every 21 days until disease progression. Echocardiogram and radiologic evaluation were performed every 12 weeks. During the first cycle, pharmacokinetic (PK) evaluation was performed on days 18 and 21. Results: Nine consented patients (7 with metastatic breast cancer, 1 with non-small cell lung cancer, and 1 with thyroid cancer) have been enrolled with the median age of 52 (range 25–66). Patients received an average of 6 prior treatments (range 2–10). No dose limiting toxicity or drug related death have been observed. Grade 1–2 toxicities including diarrhea, fatigue, muscle cramps and stomatitis were observed. No grade 3 or 4 hepatic, renal or cardiac toxicity were observed (including no QTc prolongation and no significant reduction in the left ventricular ejection fraction). Patients have received the maximum of 7 cycles (median 3 cycles, range 2–7). Response: as of June 2011, 2 patients are still on treatment. Two patients achieved stable disease (triple negative metastatic breast cancer and HER2−positive breast cancer), 6 patients with progressive disease, and 1 patient is too early to evaluate for response. PK analysis will be presented at the time of the meeting. Conclusions: The combination of vorinostat and lapatinib is tolerable and has some antitumor activity in heavily pretreated advanced solid tumors. A phase II study in HER2−positive metastatic breast cancer is underway with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-20.
S103 Synthesis of gold-based nanomedicines to treat non-small cell lung cancer
Authors: AM Cryer, P Ruenraroengsak, TD Tetley, AJ Thorley
Journal: Thorax (2015)

<h3>Introduction</h3> Lung cancer is the leading cause of cancer death worldwide, with an average 5 yr survival rate of just 9.5% in the UK. The success of current chemotherapy regimens for non-small cell lung cancer (NSCLC), the predominant subtype of lung cancer, is hindered by poor tumour penetration and accumulation, and systemic side effects which significantly affect patient quality of life. The field of cancer nanomedicine seeks to overcome these problems by utilising the unique physicochemical properties of nanoparticles; gold-based nanomedicines (AuNPs) show particular promise as they may be able to offer multimodal therapeutics and diagnostics in a single formulation. <h3>Objectives</h3> This study aimed to conjugate cisplatin and pemetrexed, a first line therapy for NSCLC, to AuNPs, and investigate their efficacy on tumour cell proliferation compared to free drug. Furthermore, we investigated whether conjugation to AuNPs abrogated the inflammatory and toxic effects of these drugs on non-cancer human pulmonary epithelial cells. <h3>Methods</h3> Cisplatin and pemetrexed were conjugated to AuNPs using heterobifunctional polyethylene glycol (PEG) linkers and were characterised by electron microscopy, ICP-OES, dynamic light scattering and thermogravimetric analysis. The effect of conjugates in <i>in vitro</i> cancer (H226 and A549 cells) and non-cancer (human alveolar type I epithelial cells) cell models were measured by electric cell-substrate impedance sensing (ECIS), MTT assay, ELISA and confocal microscopy. <h3>Results</h3> Nanoparticle characterisation confirmed successful conjugation of cisplatin and pemetrexed to AuNPs. Confocal microscopy demonstrated that nanoparticles were internalised by cancer cells and distributed throughout the cytoplasm. Further studies showed that conjugates inhibited cancer cell proliferation significantly more than the respective free drug (Figure 1) and abrogated free drug cytotoxicity in non-cancer alveolar type I epithelial cells (0% cell death vs 30% respectively; 10 µM cisplatin; <i>P &lt; 0</i>.001). Conjugates also attenuated chemotherapy-induced IL-6 release in both cancer and non-cancer cells; 10 µM cisplatin induced 6.6-fold and 7-fold greater IL-6 release compared to equimolar conjugates in H226 and alveolar type I epithelial cells respectively (<i> P &lt; 0</i>.001). <h3>Conclusions</h3> We have synthesised gold-based nanomedicines that are more efficacious and biocompatible than free drug in <i>in vitro</i> cell models, suggesting these formulations could have enhanced therapeutic potency and improve patient quality of life.
Abstract 1488: SOX2 promotes tumor metastasis by stimulating the process of epithelial-mesenchymal transition
Authors: Xuefei Li, Xianpei Jia, Yingxi Xu, Yanan Chen, Si Chen, Rong Xiang, Na Li
Journal: Cancer Research (2011)

Abstract Ectopic expression of SOX2 has been reported in a variety of tumor tissues and contributes to cell proliferation and tumorigenesis by transcriptional regulation of the target genes; however the role of SOX2 in tumor metastasis and the underlying mechanisms remain largely elusive. Here we used immunohistochemistry to analyze the expression of SOX2 in the tissues of human breast and lymph nodes and found that SOX2 was highly expressed in breast cancer tissues and the metastasised lymph node, also the expression of SOX2 was closely correlated with the TNM stage and histological grade. We further demonstrated that SOX2 improved the migration and invasion properties of breast cancer and prostate cancer cells by facilitating the process of epithelial-mesenchymal transition (EMT). Investigation of the molecular mechanism revealed that SOX2 regulated EMT by β-catenin signaling pathway. Our findings prove that SOX2 plays a pivotal role in the metastasis of human breast cancer and prostate cancer and suggest that SOX2 has the potential to be developed as the diagnosis marker for breast and prostate cancer metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1488. doi:10.1158/1538-7445.AM2011-1488
PD01-05: Histone Deacetylase Inhibitor LBH589 (Panobinostat) Suppresses the Activated-NFκB Pathway in Acquired Aromatase Inhibitor Resistant Breast Cancer Cells.
Authors: M Kubo, N Kanaya, Z Liu, S Chen
Journal: Cancer Research (2011)

Abstract Background: Aromatase inhibitors (AIs) are effective in treating postmenopausal patients with estrogen receptor (ER)-positive breast cancer. However, resistance to endocrine therapies remains a major problem in the management of ER-positive breast cancer. Recently, histone deacetylase inhibitors (HDACis) show promise as cancer therapeutics, but the full scope of their utility remains unknown. Experimental Design: In order to search for critical genes in developing resistance to AI, a microarray study was performed on AI resistant cells derived from MCF-7aro cells that overexpress aromatase and on AI resistant tumors from our mouse experiments. Moreover, using MCF-7aro cells that are resistant to anastrozole (Ana-R), letrozole (Let-R), and exemestane (Exe-R), as well as LTEDaro, we evaluated the significance of NFKB1 and several regulatory genes in AI resistance, and the anti-NFκB1 activity of HDACi LBH589 in vitro and in vivo. Results: Significant changes (Fold change cutoff &amp;gt; 1.5, false discovery rate &amp;lt; 0.05) in the expression levels of 22 genes among three networks were identified from microarray analysis of our in vitro and in vivo models of acquired AI resistance. NFKB1 is a key player in one of three networks, including 11 genes, and is functionally up-regulated in all AI resistant cells. NFκB1 knockdown suppresses the proliferation of AI resistant cells more than that of MCF-7aro cells. Moreover, AI resistant cell lines are highly sensitive to LBH589 treatment and apoptosis is induced in these cell lines. LBH589 suppressed NFκB1 as demonstrated at both the mRNA and protein levels in LTEDaro and other AI resistant cell lines. Furthermore, the LBH589 treatment abrogated tumor growth in mice, and was associated with significant decreased levels of NFKB1 in tumors. Conclusions: Our findings provide new insights into how the NFκB1-mediated networks play roles in AI resistance, and strongly support that LBH589 offers a novel therapeutic strategy for patients with AI resistant breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-05.
A new instrument for endoscopic submucosal dissection: The “EndoDissector”
Authors: A Meining, D Roppenecker, A Schneider, T Lüth
Journal: Endoscopy (2012)

Background: Albeit, effective for treatment of early neoplasm, endoscopic submucosal dissection (ESD) can be technically demanding and time consuming. Furthermore, use of multiple instruments if often mandatory for performing various steps associated with the procedure. Hence, we aimed to design, create and evaluate a new instrument for ESD, the "Endo-Dissector".
AB0087 Tissue localisation of acid sensing proteins in synovial biopsies from patients with rheumatoid arthritis
Authors: F. S. Albloui, M. Muthana, A. G. Wilson, P. S. Grabowski
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In rheumatoid arthritis (RA), the hypoxic environment of the synovium leads to the generation of lactic acid as synoviocytes switch glucose metabolism from an aerobic pyruvate pathway towards an anaerobic glycolytic pathway for metabolic energy production. Fibroblast-like synoviocytes (FLS) have an aggressive phenotype that leads to cartilage damage and bone destruction in RA. Acidification of the synovial environment has been associated with radiological joint destruction, activation of cathepsin B in synoviocytes and subsequent collagen degeneration, and in animal models has been associated with pathological joint damage. In a preliminary study we have demonstrated that human (FLS) express mRNA for the acid sensing proteins Accn3, Gpr4, Gpr68 and Trpv1. In this study we now demonstrate and describe the tissue localisation of these four acid sensing proteins in synovial biopsies from patients with RA. <h3>Objectives</h3> To determine the tissue localisation of acid sensing proteins in synovium from patients with RA. <h3>Methods</h3> Histochemical methods were used to study the expression of acid sensing proteins in arthroscopic biopsies from RA patients. Paraffin-embedded specimens (5 micron) were stained with rabbit polyclonal primary antibodies to Accn3, Gpr4, Gpr68 and Sections of human lung tissue, known to express Trpv1 and Gpr68, were used as a positive control. <h3>Results</h3> Trpv1 was strongly expressed predominantly in synovial lining cells with a few positive cells localising around blood vessels. Gpr68 expression was highly restricted to the synovial lining, with few positive cells in deeper tissues. In contrast, Accn3 was distributed deeper within the synovium and around blood vessels but was absent from cells of the lining layer while Gpr4 was detected predominantly in adipose tissue. <h3>Conclusions</h3> These data demonstrate that acid sensing proteins are present with distinct patterns of distribution in the synovium of RA patients. Trpv1 was the most strongly expressed and was found in all the patient tissues analysed. Interestingly, while three of the four proteins were largely confined to the synovial lining layer where the FLS reside, Accn3 was not detected in these cells. It is clear that other cells deeper within the synovial tissue also express acid sensing proteins. Further studies are currently underway to characterise the cell types in which they are expressed and to determine the functional significance of acid sensing proteins in the pathology of RA. <h3>Disclosure of Interest</h3> None Declared
967 ROLES OF A CHOLINE UPTAKE TRANSPORTER, THE ORGANIC CATION TRANSPORTER 1 (OCT1), IN PATHOGENESIS OF PRIMARY BILIARY CIRRHOSIS: OCT1 EXPRESSION AND ITS SINGLE-NUCLEOTIDE POLYMORPHISM
Authors: M. Nakamuta, M. Kohjima, Y. Ohishi, N. Fukushima, T. Yoshimoto, K. Fukuizumi, M. Nakamura, H. Ishibashi, A. Honda, Y. Matsuzaki, Y. Nozaki, A. Nakajima, H. Nomura, M. Enjoji
Journal: Journal of Hepatology (2012)
P707Blockade of cystathionine gamma-lyase increases endothelium-dependent relaxation of aortic smooth muscles in old rats.
Authors: K Drachuk, A Kotsjuruba, V Sagach
Journal: Cardiovascular Research (2014)

Purpose. It is known that aging increases the risk of cardiovascular diseases. One of the reasons is a dysfunction of endothelium that aggravates with age. At the same time we can see more and more publications about cardio- and vasoprotective properties of hydrogen sulfide (H2S). This gas belongs to the family of gas transmitters, such as NO and CO. The uniqueness of gas transmitters consists in their ability to easily penetrate the cellular membranes without binding to any cell surface receptors and to interact directly with the intracellular structures. Cystathionine gamma-lyase (CSE) is the main enzyme for H2S synthesis in blood vessels. The aim of this study was to show the effect of blocking of CSE-associated H2S synthesis pathway upon endothelium-dependent relaxation of aortic smooth muscles (SM) in old animals.
A Heritable Disorder of Connective Tissue
Authors: Sheldon R. Pinnell, Stephen M. Krane, John E. Kenzora, Melvin J. Glimcher
Journal: New England Journal of Medicine (1972)

Two sisters nine and 12 years of age presented with a similar clinical picture consisting of severe scoliosis, recurrent joint dislocation and hyperextensible skin and joints. Amino acid analyses of dermal collagen revealed marked decrease in hydroxylysine content; skin from a clinically normal older sister and from the parents was normal in amino acid content. Collagen fibrils were normal morphologically. Dermal collagen from the affected children was more soluble in denaturing solvents than that derived from controls. Hydroxylysine content was also reduced in lumbodorsal fascia, variably reduced in bone and normal in a single sample of costal cartilage. The defect is probably inherited as an autosomal recessive and due to a deficiency of enzymatic hydroxylation of lysine in collagen, which in turn results in decreased structural integrity of this important protein.
The Types of Renal Disease in the Acquired Immunodeficiency Syndrome
Authors: T.K. Sreepada Rao, Eli A. Friedman, Anthony D. Nicastri
Journal: New England Journal of Medicine (1987)

Between January 1982 and December 1986, among the 750 patients with the acquired immunodeficiency syndrome (AIDS) who were treated at two adjacent hospitals in New York City, 78 (10.4 percent) needed evaluation for renal disorders. Reversible acute renal failure due to nephrotoxic injury, ischemic injury, or both was present in 23 patients (30 percent) (Group I). The remaining 55 (70 percent) had massive proteinuria, azotemia, or both (AIDS-associated nephropathy; Group II), and irreversible uremia developed in 43. In an additional 18 patients, all of whom had a history of intravenous narcotic drug use, AIDS was diagnosed after the initiation of maintenance hemodialysis for chronic renal failure (Group III). Survival for more than six months after the onset of chronic uremia occurred in only two subjects in Group II; all patients in Group III died within three months of the diagnosis of AIDS. Death in the patients in Groups II and III followed a syndrome of "failure to thrive" characterized by inanition unresponsive to intensive nutritional support and hemodialysis. In contrast, 8 of 17 patients with acute renal failure (Group I) and a serum creatinine concentration above 6 mg per deciliter regained renal function (serum creatinine level, less than 2.0 mg per deciliter). Four of the seven lived for 10 to 24 months, whereas the other four died of sepsis within a month. Our observations suggest that maintenance hemodialysis is not effective in prolonging life either in patients with AIDS-associated nephropathy and uremia or in patients with end-stage renal failure in whom AIDS develops during the course of maintenance dialysis. Hemodialysis may be useful in the management of potentially reversible acute renal failure in patients with AIDS.