tbuckley/cabot-search huggingface dataset:
Abstract 1715: IRES-transactivating factors (ITAFs) as therapeutic targets in breast and colorectal cancer
Authors: Toby M. Ward, Jessica Bockhorn, J C. Harrell, Xiaofei Liu, Mark D. Pegram
Journal: Cancer Research (2015)

Abstract Background: The majority of cellular mRNAs are translated in a cap-dependent manner, via ribosome assembly at 5′ methylguanosine caps followed by initiation at a nearby favorable AUG codon. Alternatively, internal ribosome entry sites (IRESs) facilitate translation in a cap-independent manner, particularly during cell stress, and have been identified in mRNAs encoding many canonical cellular oncogenes, including c-MYC, c-SRC, XIAP, Aurora-A kinase, and IGF1R. IRES trans-activating factors (ITAFs) are accessory proteins that augment or inhibit translation of client IRES-containing mRNAs, and were found to be upregulated in many cancer types including breast and colorectal cancers. Methods and Results: Analysis of microarray datasets from cancer and normal tissue specimens (The Cancer Genome Atlas, METABRIC, and University of North Carolina datasets) revealed that expression of several ITAFs is upregulated in malignant tissues compared to normal controls. mRNAs encoding ITAFs were significantly upregulated (p &amp;lt; 0.05) in cancer specimens, and ITAF protein levels were increased as measured by immunohistochemistry on tissue microarrays made up of malignant and healthy tissue specimens. To investigate biological impact of ITAF silencing, gene knockdown was accomplished using pGIPZ and pTRIPZ lentiviral shRNA vectors. Silencing of ITAFs and concomitant reduction in protein levels (measured by western blot) led to significant proliferation impairment in MDA-MB-231, MCF7 and DLD1 cancer cells in 2-D culture (as measured by counting assays, p&amp;lt;0.05) as well as in soft agar assays (p&amp;lt; 0.05). In cancer cell lines, treatment with TNF-related apoptosis inducing ligand (TRAIL) led relocalization of ITAFs from cell nuclei to the endoplasmic reticulum (assayed by immunofluorescence), with increased translation of client IRES-harboring mRNAs encoding BAG-1 and c-MYC oncoproteins, despite impaired global cap-dependent translation. Conclusions and future directions: Future experiments will include expanded investigation of protein-level ITAF expression in archival human specimens using immunohistochemistry, as well as investigation of the effects of ITAF silencing in cancer cell xenografts in immunocompromised mice. Based on their increased expression in malignant tissues and activity in translation of oncoproteins, cellular ITAF genes may represent novel therapeutic targets for intervention. Citation Format: Toby M. Ward, Jessica Bockhorn, J C. Harrell, Xiaofei Liu, Mark D. Pegram. IRES-transactivating factors (ITAFs) as therapeutic targets in breast and colorectal 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 1715. doi:10.1158/1538-7445.AM2015-1715
Feasiblity and Implication of Bidirectional Sequencing Using a Multiplex Framework 2 Region Primer for Somatic Mutation Analysis of the Immunoglobulin (IgH) Heavy Chain in Chronic Lymphocytic Leukemia (CLL).
Authors: Adin Nelson, Ivelise Rijo, Zhigang Zhang, Andrew D. Zelenetz, Ariela Noy
Journal: Blood (2007)
OC-079 Do patients who failed to attend their first bowel cancer screening clinic visit warrant further follow-up?
Authors: S Tran, T Jackson, J Adams, S Singh, G R Lipscomb
Journal: Gut (2010)

<h3>Introduction</h3> The second round of the national bowel cancer screening pilot found that 17% of those with positive faecal occult blood testing did not attend for colonoscopy.1 Some of these individuals may have good reasons for non-attendance (eg, under colonoscopic screening already or electing for private colonoscopy). However, the question remains whether non-attenders harbour the same pathology and need to be pursued. The aim of our study was to assess the incidence of adenomas and cancers in those who did not attend for their first screening clinic visit as part of the Bowel Cancer Screening Programme. <h3>Methods</h3> We prospectively collected data from the Bolton screening area between 1 March 2007 and 30 September 2009. The Bolton Screening Centre (BSC) covers a population of approx 800 000 and started screening in Feb 2007. Those who failed to attend their initial clinic visit were sent a second appointment and we identified the proportion where colonoscopy was indicated and the subsequent incidence of adenoma and cancer. <h3>Results</h3> One hundred and twenty-four thousand and five individuals were invited for stool testing. 67 420 were returned and 1321 were positive with a subsequent invitation to a bowel cancer screening clinic visit. One hundred and ten patients (8.3%) did not attend their initial appointment. In the early stages of the programme some patients were not offered a second appointment. However, ninety-seven were offered a second appointment. Seventy-eight (80%) attended and 60 went on to colonoscopy. Adenomas were identified in 23 individuals (38% of those investigated) and six patients were found to have colourectal cancer (10%). Two cancers were Dukes A, one was Dukes B and two were Dukes C. One patient was not classified because of his poor general health limiting the indication for staging/surgery. The proportion of patients with colourectal cancer was slightly higher in this group than our overall figures (8.6%) but the proportion of patients with adenomas was slightly lower compared to our overall figures (56%). <h3>Conclusion</h3> Although, it might be speculated that non-attenders are self-selecting as those without significant pathology, our data would suggest otherwise. The majority of those offered a second screening visit took up the opportunity. Colonoscopy was indicated in most and the incidence of adenomas and cancer in this group was significant. We conclude that second appointments should be offered to individuals who fail to attend their initial visit as part of the National Bowel Cancer Screening Programme.
The Role of Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (Allo-SCT) in Patients with Acute Myeloid Leukemia (AML): A Donor vs. No Donor Comparison.
Authors: Hugue de la Vallade, Mohamad Mohty, Catherine Faucher, Norbert Vey, Diane Coso, Anne-Marie Stoppa, Jean-Albert Gastaut, Patrick Ladaique, Christian Chabannon, Didier Blaise
Journal: Blood (2004)
30. Modulation of Intracellular Calcium Enhances AAV Transduction in the CNS
Authors: Garrett Berry, Giridhar Murlidharan, Aravind Asokan
Journal: Molecular Therapy (2016)

Recent preclinical studies and clinical trials utilizing recombinant AAV vectors have highlighted vector dose-related toxicity as a potential safety concern. Therefore, strategies to enhance AAV transduction may mitigate this toxicity, as they may allow for administration of lower vector doses. While some strategies rely on modification of the capsid to achieve such, pharmacological modulation of the cellular environment often has the benefit of enhancing AAV transduction independent of capsid serotype. Intracellular calcium is important in the life cycles of several viruses, such as Ebola virus and rotavirus. Several small molecule drugs and biologics exist that can modify intracellular calcium levels in a specific manner. In the current study, we sought to determine if modulation of intracellular calcium levels affects AAV transduction. Increasing intracellular calcium levels using either thapsigargin or ionomycin decreased AAV transduction by an order of magnitude. Conversely, decreasing intracellular calcium levels using the cell permanent calcium chelator BAPTA-AM increased transduction by 10 to 100-fold in a cell independent fashion. In addition, the effects of modification of intracellular calcium are not dependent on AAV serotype. Furthermore, in vivo studies performed in mice demonstrate that BAPTA-AM augments transduction by different AAV serotypes, when administered intracranially. In summary, our results support the preclinical evaluation of drugs and biologics that modulate intracellular calcium in the CNS and evaluate their potential for affecting AAV transduction. Results from ongoing studies in mouse models of disease will be presented.
Dasatinib (SPRYCEL®) in Patients (pts) with Chronic Myelogenous Leukemia in Accelerated Phase (AP-CML) That Is Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results of the CA180–005 ’START-A’ Phase II Study.
Authors: Jorge Cortes, D.W. Kim, F. Guilhot, G. Rosti, R.T. Silver, A. Gollerkeri, P. Agarwal, S. Branford, J.F. Apperley
Journal: Blood (2006)
357. Blood-Brain Interface Opening By Ultrasound in Adult Common Marmoset To Induce Brain Pathology With rAAV
Authors: Hironori Okada, Hidetoshi Ishibashi, Chiaki Masuda, Hiromi Hayashita-Kinoh, Tomoko Chiyo, Yuko Nitahara-Kasahara, Yoko Endo-Takahashi, Koichi Kato, Yoichi Negishi, Shin'ichi Takeda, Takashi Okada
Journal: Molecular Therapy (2015)

Background: The common marmoset (Callithrix jacchus) could provide an appropriate model for neuromuscular diseases because of its higher brain function and physiological resemblance to human. Although production of transgenic marmosets from zygote transduced with lentiviral vector were reported, this strategy is too costly and not efficient with various reasons. In contrast, an adeno-associated virus vector (rAAV) has great advantages to induce pathology in the aged animals. However, fully maturated blood-brain interface (BBI) significantly limits passive rAAV transport from circulation to the brain. To overcome this issue, we investigated BBI opening, which is a promising technology to make cerebral capillary open by transiently disrupting tight junction in BBI with ultrasound irradiation (UI) just after i.v. injection of microbubble (MB). Methods: Commercially available MB or homemade bubbleliposome (BL) mixed with evans blue were i.v. injected into the femoral vein of the anesthetized adult marmosets. rAAV1 was also injected simultanously in certain trials. Subsequently, transcranial (TC) UI to the brain was performed for several minutes. The brain was removed 24 hrs after the UI. To visualize the leakage of albumin (ALB) in more detail, cryosections were immunologically stained with antibodies against ALB and CD31. Thin coronal slice of the brain was pieced into various parts, and genome DNA was extracted from the each pieces. Then relative rAAV genome copies were measured by qPCR. For live imaging analysis, BL mixed with carbon 11-labeled aminoisobutyric acid were i.v. injected into the tail vein. Subsequently, TCUI and positron emission tomography (PET) scan were performed. Results: In TCUI from the temporal region, ALB mainly leaked at the temporal cortex and hippocampus. In TCUI from circumference, ALB leakage seemed to occur at whole brain except for white matter. Microscopically, ALB leakage was found around the blood vessels of 10-50 mm in diameter. Especially, leakage in hippocampus was prominent. Relative rAAV genome copies were imbalanced between symmetrical piece pair. PET revealed ALB leakage not only in hippocampus but also in the anterior cingulate cortex, basal ganglia, optic tract, amygdala, and superior temporal gyrus. Conclusion: UI-mediated MB-assisted TC-BBI opening is promising approach in the generation of the disease model based on adult common marmoset.
A possible prognostic significance of c-Kit receptor expression and angiogenesis in early breast cancer patients: a pilot study
Authors: M. Ammendola, I. Marech, C. Leporini, R. Patruno, M. Luposella, R. Sacco, G. Sammarco, V. Zuccalà, N. Zizzo, E. Russo, C.D. Gadaleta, G. Ranieri
Journal: Annals of Oncology (2015)
Altered mitochondrial metabolism as a target in acute myeloid leukemia.
Authors: T. S. Pardee, D. A. Levitan, D. D. Hurd
Journal: Journal of Clinical Oncology (2011)

6590 Background: Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow. AML disproportionally affects the elderly with a median age of onset of 72. Patients over 60 have less than 10% survival at 5 years. This is a result of resistant disease and treatment related mortality. There is a desperate need for novel targets and agents. Nearly all tumor cells will preferentially utilize anaerobic glycolysis, a phenomenon known as the Warburg effect. This altered mitochondrial metabolism represents a possible therapeutic target. CPI-613 is a first in class agent that targets 2 key mitochondrial enzymes involved in this aberrant metabolism, pyruvate dehydrogenase and α-ketoglutarate dehydrogenase. Methods: CPI-613 was tested against several leukemia cell lines in vitro and is the subject of a phase I clinical trial for patients with relapsed and refractory hematologic malignancies at the Wake Forest University Comprehensive Cancer Center. Results: CPI-613 was active against HL60, Jurkat and K562 cells with an average IC50 value of 14 μM (range 12.2 – 16.4). In preliminary studies CPI-613 was found to be synergistic with doxorubicin with Combinatorial Index values between 0.478 and 0.765. In vivo, 5 patients have been treated on trial. CPI-613 appears well tolerated with no adverse events > grade 2 definitely associated with drug. Two of the patients had a diagnosis of relapsed AML. CPI-613 at the initial dosing level concurrent with hydroxyurea resulted in a transient reduction in peripheral blood blasts in the first AML patient. Treatment at the next dosing level resulted in a raise in the platelet count from 35 to 73 after two cycles of therapy in the second AML patient. However there was no reduction in marrow blasts seen in this patient following the first cycle of therapy. Conclusions: These data suggest that altered mitochondrial metabolism is a viable target in AML. The novel agent CPI-613 has activity against several acute leukemia cell lines and may have activity in patients with relapsed disease. The therapeutic index appears quite high with only minor toxicities seen. The phase I trial continues to enroll patients. The mode of cytotoxicity and degree of synergy with other agents remains a focus of ongoing study.
Abstract POSTER-BIOL-1336: Investigating the role of phosphodiesterase 10A as a novel target in ovarian cancer
Authors: Luciana Madeira da Silva, Kevin Lee, Gary A. Piazza, Lavanya Bachaboina, Rodney P. Rocconi, Jennifer Scalici
Journal: Clinical Cancer Research (2015)

Abstract Cyclic nucleotide phosphodiesterases (PDEs) play major roles regulating cell signaling by hydrolyzing the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP). Phosphodiesterase 10A (PDE10A) is one of 21 PDEs encoded in the human genome. Its predominant expression in the brain striatum has guided intensive investigations on the therapeutic potential of PDE10A in psychiatric and neurological disorders, leading to several PDE10A inhibitors in clinical trials for schizophrenia and Hungtington's disease. Recently, we described for the first time an oncogenic role for PDE10A in colorectal cancer (N. Li et al. 2014 Oncogene 1-11). Our published data showed that PDE10A is overexpressed in colon tumor cells when compared to normal colonocytes, and that pharmacological inhibition or genetic knockdown of PDE10A suppresses colon tumor growth. Here, we are investigating the role of PDE10A in ovarian cancer and its potential as a novel therapeutic target. We detected expression of PDE10A in several ovarian cancer cell lines (SKOV3, SKOV3ip1, A2780, A2780-CP70, OV-90, ES-2 and TOV112D) by western-blotting and quantitative RT-PCR. In addition, our preliminary analysis revealed PDE10A expression in tumors and matched normal tissues from eight patients of ovarian cancer. Finally, we developed novel small molecule compounds targeting PDE10A which potently inhibit growth of all these ovarian cancer cell lines at low micromolar or sub-micromolar concentrations. Future work will focus on i) expanding the cohort of ovarian cancer patient tissues to analyze expression levels of PDE10A by western-blotting, quantitative RT-PCR and immunohistochemistry; ii) genetic silencing of PDE10A by siRNA/shRNA to investigate its role regulating cell proliferation, apoptosis, and cGMP/cAMP cell signaling in ovarian cancer; iii) investigate the signaling pathways suppressed by our novel PDE10A inhibitors. Our studies will determine the potential of using PDE10A as a novel therapeutic target for the treatment and chemoprevention of ovarian cancer. Citation Format: Luciana Madeira da Silva, Kevin Lee, Gary A. Piazza, Lavanya Bachaboina, Rodney P. Rocconi, Jennifer Scalici. Investigating the role of phosphodiesterase 10A as a novel target in ovarian cancer [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1336.
S9 The role of LRIG1-dependent EGFR signalling in airway homoeostasis and squamous cell lung cancer development
Authors: L Succony, KHC Gowers, RE Hynds, R Thakrar, A Giangreco, D Davies, S Janes
Journal: Thorax (2016)

<h3>Background</h3> Aberrations of EGFR signalling drive cancer development. In squamous cell lung cancer (SqCLC), EGFR is overexpressed. LRIG1 is a negative regulator of EGFR and patient pre-invasive SqCLC samples show LRIG1 loss, suggesting involvement in early disease pathogenesis. In skin and gut homeostasis, LRIG1 regulates stem cells. In the upper airway, basal cells act as stem cells and are the putative origin of SqCLC. We hypothesise LRIG1 has a key role in airway homeostasis and its loss promotes pre-invasive SqCLC development. <h3>Methods</h3> <i>Lrig1</i> EGFP-ires-CreERT2 mice were used to delineate airway LRIG1 expression. Flow sorted LRIG1-positive and -negative murine basal cells were used in 2D and 3D colony-forming, spheroid and proliferation assays. A murine SqCLC model was set up through application of N-Nitrosotris-(2-chloroethyl)urea (NTCU). Pre-invasive lesions and tumour development were compared between wild-type (WT), heterozygous and LRIG1-knockout (KO) animals. Human basal cells obtained from bronchoscopy were sorted according to LRIG1 expression and used directly in colony-forming assays or maintained in primary culture to assess the effect of shRNA knockdown of LRIG1. LRIG1-knockdown cells were assessed in colony-forming and proliferation assays, and differentiation and invasion were assessed using organotypic models. <h3>Results</h3> LRIG1 is expressed by 40% of airway basal cells. LRIG1-expressing murine basal cells exhibit increased colony-forming capacity (p = 0.0286), spheroid formation (p = 0.0043) and proliferation (p = 0.0043) compared with LRIG1-negative cells. Similarly, LRIG1-expressing human airway basal cells isolated from endobronchial brush biopsy samples exhibit increased colony-forming capacity (p = 0.0469). Topical application of NTCU to mice recapitulates the development of human pre-invasive and SCLC lesions after 23 weeks. Results show lesions in LRIG1-KO mice to be larger than those of WT animals. Knock down of LRIG1 in cultured human airway basal cells alters cell phenotype, leading to an increased colony-forming efficiency and greater proliferation at cell confluence. <h3>Conclusions</h3> LRIG1 has an important role in stem cell homeostasis of the human and murine airway epithelium. Loss of LRIG1 promotes pre-cancerous lesion development in a murine SqCLC mouse model and behaviour of human epithelial cells in culture, indicating a potential target for chemoprevention of SqCLC in humans.
Abstract A2-67: Live cell imaging of ERK reveals unique inhibitor-specific adaptive responses
Authors: Taryn E. Gillies, Kevin Distor, Marta Minguet Sànchez, Michael Pargett, John Albeck
Journal: Cancer Research (2015)

Abstract Defects in cell-to-cell signaling pathways can result in developmental abnormalities as well as cancer. The Ras/MAPK pathway is a central regulator of gene expression, cellular proliferation, and differentiation that is frequently de-regulated in cancer. While this pathway is a promising target for cancer therapeutics, a major obstacle is the tendency of the pathway to become re-activated via feedback within hours following inhibition. This adaptive response is important because the timing and duration of Ras/MAPK activity are known to determine the resulting cellular response and gene expression pattern. We have developed a new live-cell reporter, EKAR3, that allows ERK activity to be monitored with high temporal precision and resolution of heterogeneous individual cell behavior. To track the detailed pattern of adaptation to Ras/MAPK pathway inhibitors, we imaged over 10,000 individual cells responding to specific inhibitors of EGFR, Raf, MEK, and ERK. ERK activity was immediately reduced upon inhibition, but returned after a period of time ranging from 1-12 hours, depending on the inhibitor and its concentration. Strikingly, different inhibitors were found to induce distinct ERK recovery patterns, ranging from frequent, high-amplitude pulses to extended steady-state activity. We then statistically analyzed the effect of these differential ERK responses on cell behavior to dissect elements of the temporal signal relevant for information transmission in the cell. Our results indicate that, at the level of individual cells, targeted inhibitors induce kinetically distinct adaptive responses, which are likely to determine their effectiveness in controlling different aspects of cellular proliferation, survival, and migration. Citation Format: Taryn E. Gillies, Kevin Distor, Marta Minguet Sànchez, Michael Pargett, John Albeck. Live cell imaging of ERK reveals unique inhibitor-specific adaptive responses. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-67.
Primary Prevention of Sexually Transmitted Diseases
Authors: Katherine M. Stone
Journal: JAMA (1986)

With the advent of sexually transmitted infections for which curative therapy is not available, primary prevention has assumed greater importance. The spectrum of sexually transmitted diseases (STDs) has broadened, and clinicians need to understand the mechanisms of their transmission and prevention. Modifying selection of sexual partners and avoiding certain sexual practices should theoretically reduce the risk of infection. Clinical and laboratory studies indicate that the use of condoms, diaphragms, and spermicides reduces the risk of acquiring certain infections. At present, hepatitis B is the only STD for which a safe, effective vaccine is available. Use of oral antibiotics cannot be recommended. Postcoital washing or urination have not been shown to have a protective effect against infection. Because of the potential benefits, persons at risk for STDs should be encouraged to modify their sexual behavior and use barrier methods and spermicides to protect themselves against sexually transmitted infections. (<i>JAMA</i>1986;255:1763-1766)