tbuckley/cabot-search huggingface dataset:
Abstract 1313: Mutually exclusive somatic mutations in WNT pathway medulloblastomas reveal a critical interaction between DDX3X and SMARCA4
Authors: Shyamal D. Weeraratne, Tenley Archer, Trevor J. Pugh, Diana Hargreaves, Furong Yu, Amanda Kautzman, David T.W. Jones, Natalie Jaeger, Pablo Tamayo, Jill P. Mesirov, Stefan M. Pfister, Peter Lichter, Gerald Crabtree, Matthew Meyerson, Scott L. Pomeroy, Yoon-Jae Cho
Journal: Cancer Research (2012)

Abstract DDX3X is an ATP-dependent RNA helicase that belongs to an extended family of D-E-A-D motif (DEAD-box) containing proteins whose functions have been implicated in key biological processes ranging from RNA transcription and splicing to the regulation of translation initiation. Through whole exome sequencing of 94 primary medulloblasotmas, we have identified DDX3X as one of the most common recurrently mutated genes in medulloblastoma. These mutations predominantly occur in WNT pathway medulloblastomas which concurrently harbor stabilized forms of mutant beta-catenin. Interestingly, we have also identified SMARCA4 mutations in WNT pathway tumors that are mutually exclusive of DDX3X mutations. In addition, two WNT pathway tumors that have neither DDX3X nor SMARCA4 gene mutations have mutations in genes known to encode for direct binding partners of DDX3X and SMARCA4 (EIF3E and ACTL6A, respectively). This mutual exclusivity of DDX3X and SMARCA4 mutations suggests either a direct interaction between the DDX3X and SMARCA4 gene products or an overlap of the biological processes regulated by each. Here we reveal the direct interaction between DDX3X and SMARCA4 in normal physiological conditions and further investigate the impact of somatic mutations in DDX3X and SMARCA4 on this interaction in WNT pathway associated medulloblastomas. Our results point to a critical link between RNA helicases and the SWI/SNF chromatin remodeling complex in WNT/beta-catenin signaling and disease. 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 1313. doi:1538-7445.AM2012-1313
A8.12 Decreased expression of MIR-125A in psoriatic arthritis. Implications for joint pathogenesis
Authors: S Wade, M Connolly, C Orr, DJ Veale, U Fearon
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and aims</h3> Psoriatic Arthritis (PsA) is a chronic immune-mediated inflammatory disease, characterised by proliferation of synovial tissue and destruction of articular cartilage/bone with associated psoriasis. Dysregulated angiogenesis is one of the key early pathogenic processes in PsA. These processes may be governed by microRNA (miRNA), a class of evolutionary conserved short non-coding RNAs which function as post-transcriptional repressors of gene expression. On such miRNA is miR-125a-5p which, in cancer, has been previously associated with altered angiogenesis, invasion and migration. <h3>Objectives</h3> To examine the expression and angiogenic associations of miR-125a-5p in PsA. <h3>Methods</h3> Synovial tissue biopsies and peripheral blood mononuclear cells were obtained from patients with PsA, osteoarthritis (OA) and/or healthy controls (HC). MiR-125a-5p levels were analysed by real-time PCR using RNU48 as an endogenous control. To examine possible factors involved in regulating miR125a-5p expression, primary synovial fibroblasts (SFC) and microvascular endothelial cells (HMVEC) microvascular endothelial cells (HMVEC) were cultured with candidate pro-inflammatory stimuli including; TLR ligands (PAM, PolyIC, LPS), pro-inflammatory cytokines (TNFa, IL-1b, IL-17) and growth factors (VEGF, Ang2). Immunoistochemical analysis was performed using factor VIII (DAKO) and appropriate IgG controls, on cryostat synovial tissue sections. Clinical markers, including synovitis, vascularity, ESR, CRP, DAS28, ascertained at the time of arthroscopy were correlated with synovial miRNA expression. <h3>Results</h3> Expression of miR-125a-5p was significantly decreased in PsA synovial biopsies (n = 8) compared to OA (n = 4) (p &lt; 0.05). No significant difference was observed at the PBMC level across PsA (n = 6), RA (n = 5) and Healthy controls (n = 5). Angiogenic growth factor, Ang2, induced miR-125a-5p in HMVEC (p &lt; 0.05). Lower synovial expression of miR-125a-5p displayed a higher degree of factor VIII staining compared to patients with higher miR-125a-5p expression. This was further demonstrated in representative arthroscopic images. <h3>Conclusion</h3> Decreased expression of miR-125a-5p in the joint and it's association with vascularity, which is a hallmark of PsA, suggests it may be important in mediating key pro-angiogenic/pro-inflammatory mechanisms in the synovium. Correcting these microRNA deficiencies, either by conventional pharmacological agents or as novel targets, may provide a therapeutic benefit, especially in early disease stages.
In the Thick of It
Authors: Deepak A. Rao, Neal K. Lakdawala, Amy Leigh Miller, Joseph Loscalzo
Journal: New England Journal of Medicine (2013)

A 52-year-old man presented to the emergency department with an acute onset of palpitations and chest pressure. He had felt well until 2 days earlier, when epigastric burning, fatigue, weakness, and emesis had developed.
PTU-173 Neuroepithelial cell transforming gene 1 in adenocarcinoma of the oesophago-gastric junction: expression, biology and prognostic significance in a large well characterised cohort
Authors: C Lahiff, D Murray, P MacMathuna, G Pidgeon, J Reynolds
Journal: Gut (2012)

<h3>Introduction</h3> Neuroepithelial Transforming Gene 1 (NET1) is a protein involved in tumour invasion and metastasis and is associated with poor prognosis in a number of human cancers. We aimed to determine NET1 expression status and its prognostic significance in a large, well characterised cohort of patients with oesophageal cancer and cancer of the oesophago-gastric junction. <h3>Methods</h3> NET1 expression was measured by immunohistochemistry in a 210 patient tissue micro-array (TMA). The TMA was constructed from bio-banked tissue using a comprehensive and prospectively maintained clinical database which includes demographic, clinical, histopathological and survival data on all patients. <h3>Results</h3> Of 210 patients in the original cohort, 89 had a post-operative diagnosis of oesophageal adenocarcinoma and did not receive neoadjuvant chemotherapy or radiotherapy. Five patients had oesophageal adenocarcinoma, 81 had cancer of the oesophago-gastric junction and three had gastric adenocarcinoma. Of the 89 patients 51% were NET1 positive. NET1 staining was variable across tumour subtpes. Using the Siewert classification for OGJ tumours, significantly more type I tumours were NET1 positive (p=0.008) and there was significantly more Barrett9s in the NET1 positive group (59% vs 30%, p=0.009). Median disease specific survival for the overall group was 37 months for NET1 negative patients compared with 23 months for NET1 positive. In patients with gastric and OGJ type III tumours, NET1 positivity was associated with worse median survival (23 vs 15 months, p=0.02). Within this subgroup (n=31), NET1 positive patients were more likely to be female (p=0.04), have advanced stage cancer (p=0.03), had a higher number of transmural cancers (p=0.006) and a significantly higher median number of positive lymph nodes (p=0.03). <h3>Conclusion</h3> There is growing recognition of the heterogeneity of the different subtypes of OGJ tumours. While existing data shows differences in clinical and prognostic indices in these patients, there are no studies showing differences in tumour biology between OGJ sub-types. Our data suggests NET1, a known mediator of an aggressive tumour phenotype in numerous human cancers, is differentially expressed across OGJ sub-types and may be of prognostic significance in the clinical management of this disease. <h3>Competing interests</h3> None declared.
Pharmacology of Dichloromethotrexate
Authors: J. R. BERTINO
Journal: JNCI Journal of the National Cancer Institute (1989)

Journal Article Pharmacology of Dichloromethotrexate Get access JOSEPH R. BERTINO JOSEPH R. BERTINO Developmental Therapy and Clinical Investigation Sloan-Kettering Institute1274 York Ave. New York N.Y. 10021 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 81, Issue 10, 22 May 1989, Page 815, https://doi.org/10.1093/jnci/81.10.815 Published: 22 May 1989
Abstract 2005: Identification of Bcl2L13 as a novel GBM oncoprotein
Authors: Samuel A. Jensen, Andrea Calvert, Janina Luciano, Alexander Stegh
Journal: Cancer Research (2012)

Abstract Using in silico analysis of 272 GBM samples in the TGCA data set to find important cell death mechanisms in gliomapathogenesis, we identified differential expression of the novel Bcl2-Like13 protein (Bcl2L13). Bcl2L13 shares significant structural homology with Bcl-2 and Bcl-xL, but contains a unique 250 amino acid sequence that may point to unique, non-classical functions. Several studies have shown that Bcl2L13 expression correlates with increased chemotherapeutic resistance and unfavorable treatment outcome in leukemia and ZIC1-driven liposarcomas. These clinical data suggests that Bcl2L13 likely acts as an onco-protein in multiple cancers and may act in a similar manner in GBM. Using qRT-PCR and immunohistochemical analyses, we found that Bcl2L13 was highly overexpressed in &amp;gt;90% of GBM samples, but absent in adjacent normal brain. Using RNAi-loss- and cDNA complementation studies in glioma cell lines and glioma stem cells (GSCs), we determined that Bcl2L13 potently inhibits therapy-induced apoptosis by inhibiting mitochondrial outer membrane permeabalization (MOMP) and post-mitochondrial caspase-3 and -7 cleavage, likely acting in a similar manner as canonical Bcl-2 family proteins. Bcl2L13 overexpression also greatly increased cellular proliferation, and immunofluorescence and cell fractionalization experiments revealed that Bcl2L13 is localized at the mitochondria. To study the impact of Bcl2L13 on the progression of gliomagenesis in vivo, we orthotopically injected glioma cell lines with enforced expression of Bcl2L13-targeting shRNAs into immunocompromised SCID mice. Strikingly, neutralization of Bcl2L13 signaling increased overall glioma-free survival, which was associated with enhanced intratumoral apoptosis and decreased proliferative indices. To molecularly elucidate the mechanism by which Bcl2L13 exerts its anti-apoptotic effects, we performed a Yeast Two Hybrid screen and identified a select number of tumor suppressors and onco-proteins including ceramide synthase 2 (CerS2), (a regulator of MOMP) and O-6-methylguanine-DNA methyltransferase (MGMT), (an important prognostic indicator of telozolomide effectiveness) as Bcl2L13 interaction partners. Co-immunoprecipitations confirmed the interactions between Bcl2L13 and these proteins. Taken together, these results reveal that Bcl2L13 represents a novel anti-apoptotic, Bcl-2-like GBM oncoprotein that inhibits apoptosis progression and promotes tumor growth by impacting mitochondrial membrane physiology. 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 2005. doi:1538-7445.AM2012-2005
<i>BRCA1</i>Mutations in Women Attending Clinics That Evaluate the Risk of Breast Cancer
Authors: Fergus J. Couch, Michelle L. DeShano, M. Anne Blackwood, Kathleen Calzone, Jill Stopfer, Lisa Campeau, Arupa Ganguly, Timothy Rebbeck, Barbara L. Weber, Lisa Jablon, Melody A. Cobleigh, Kent Hoskins, Judy E. Garber
Journal: New England Journal of Medicine (1997)

To define the incidence of BRCA1 mutations among patients seen in clinics that evaluate the risk of breast cancer, we analyzed DNA samples from women seen in this setting and constructed probability tables to provide estimates of the likelihood of finding a BRCA1 mutation in individual families.
Abstract 4024: ING4 tumor suppressor binds to estrogen receptor-complex and modulates estrogen-dependent cell growth and gene expression in breast cancer
Authors: Katherine J. Dempsey, Timothy G. Whitsett, Suwon Kim
Journal: Cancer Research (2011)

Abstract The tumor suppressor ING4 (Inhibitor of Growth family member 4) has been shown to play a role in diverse cancer-related cellular processes, including gene regulation, apoptosis, cell migration, contact inhibition, and angiogenesis. Deletion or reduced expression of ING4 has been shown in a number of human malignancies, including breast cancer. We found ING4 to be deleted in 15% of estrogen receptor-positive (ER+) breast cancers, implicating a role for ING4 as a tumor suppressor in estrogen-driven breast cancer. In addition, we showed that over-expression of ING4 abrogated, whereas ING4 knock-down enhanced, estrogen-dependent cell growth of MCF7 ER+ breast cancer cells, indicating a suppressive function of ING4 in estrogen-dependent cell growth. The molecular mechanisms of ING4 in ER+ breast cancers have not yet been elucidated. Using a bacterial two-hybrid screen, we identified CCAR1 (Cell-Cycle and Apoptosis Regulatory Protein 1) as an ING4 binding protein. Subsequently, we validated interactions between ING4 and CCAR1 in 293T and MCF7 cells using co-immunoprecipitation assays. CCAR1 had previously been shown to be a co-activator of the estrogen receptor (ER) complex that is required for estrogen-dependent cell growth and gene transcription in ER+ breast cancer cells (Kim JH, Yang CK, Heo K, Roeder RG, An W, and Stallcup MR, 2008). Taken together, these results suggested that ING4 may interact with the ER-complex and implicated a role for ING4 in the ER-mediated cellular processes. Here we show that ING4 co-immunoprecipitates with estrogen receptor-alpha (ERα) and the co-activator AIB1 in MCF7 and T47D ER+ breast cancer cells, demonstrating ER:ING4 interactions in cells. Treatment with 17β-estradiol (E2) reduced ING4:ER interactions. These results suggested that ING4 may not be a co-factor in the estrogen-bound active ER-complex, supporting our hypothesis that ING4 plays a role in the modulation of the ER-complex. Strikingly, tamoxifen treatment greatly enhanced ING4 association with ERα, suggesting that tamoxifen stabilizes ER:ING4 interactions and/or ING4 has a greater binding affinity to the tamoxifen-bound ER-complex. It is possible that ING4 plays a role in the recruitment of co-repressors to the tamoxifen-bound ER-complex. These results implicate a role for ING4 in tamoxifen response. We conclude that ING4 may function as a tumor suppressor in ER+ breast cancers by binding to the ER-complex and modulating estrogen-dependent cellular processes including cell proliferation and gene transcription. 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 4024. doi:10.1158/1538-7445.AM2011-4024
Guidelines Recommended for Sponsored Research Agreements
Authors: N. S. Larsen
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Guidelines Recommended for Sponsored Research Agreements Get access Natalie S. Larsen Natalie S. Larsen Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 5, 2 March 1994, Pages 333–335, https://doi.org/10.1093/jnci/86.5.333 Published: 02 March 1994
SAT0108 Arthritis with childhood onset in adult patients
Authors: N. Muravieva, Y. Muraviev
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Despite active therapy in adult patients with childhood onset arthritis, the aim of therapy is not always achieved, which explains non satisfactory outcomes. <h3>Objectives</h3> To analysis of database of adults with childhood onset arthritis. <h3>Methods</h3> Analysis of database for the 9-years period of observation (2003-2011 years). <h3>Results</h3> Database contains information about 190 adult patients with the age of disease onset was 8.3±4.7 years: 142 women, 48 men in the age from 17 to 64 (mean 24.9±8.1) years, disease duration from 1 to 50 (mean 16.7±8.3) years. Disease activity (according to DAS28) was found in 88.9% of patients (I – in 122, II – in 38, III – in 9), non-medicamental remission - in 21 patients. I radiological stage was stated in 4, II – in 100, III – in 47, IV – in 39 patients. The majority of patients (91.6%) had the II functional class, 4 patients move in wheel-chair. Disease-modifying anti-rheumatic drugs (DMARDs) receive 83% patients: methotrexate – 83 (the duration use of 9.0±4.1 years, 30 patients take it for more than 10 years), leflunomide – 35, other DMARDs (sulphasalazine, hydroxychloroquine, cyclosporine, azathioprine) – 40 patients. Never took DMARDs 32 patients. 20 patients receive biological agents. Glucocorticoids (GC) were prescribed to 106 patients, 64% patients continue taking them, 39 patients - for more than 10 years. Aseptic bone necrosis was diagnosed in 43 patients, the majority of patients (83.7%) had used GC; while 70 patients who took GC did not develop aseptic bone necrosis. 54 patients on GC-therapy demonstrated osteoporosis, while 4 patients with osteopenia never had receive GC. Bone fractures were diagnosed in 7 patients on GC-therapy: hip – in 4, forearm – in 2, metatarsal bones – in 1. Nanism was found in 26, primary amenorrhea – in 11, secondary amenorrhea – in 2 patients. Steroid cataract was found in 7 patients, steroid diabetes – in 1 patient. <h3>Conclusions</h3> The activity of the disease and serious complications is observed in the majority of adults with childhood onset arthritis, which necessitates further studies, aimed at therapy optimization. <h3>Disclosure of Interest</h3> None Declared
Abstract 4206: Utilizing a Drosophila high throughput screening technology for cancer drug discovery
Authors: Elena M. Gracheva, Eduardo J. Martinez, Jill Thompson, Dominick Thompson, Ross L. Cagan
Journal: Cancer Research (2010)

Abstract MEDROS has developed unique high-throughput 96-well drug screening methods to model human diseases in the context of a whole organism, the fruit fly Drosophila melanogaster. Our approach is designed to address disease complexity and whole animal drug pharmacology, aspects poorly addressed by in vitro or cell screening methods. Here we focus on cancer, a complex disease that will benefit from the powerful tools available in Drosophila. We have designed a cancer fly model where the human oncogenes Ras and Src, centrally important in a variety of major human cancers, are targeted together to the retinal epithelium. We utilize inducible systems to calibrate their activation, generating reliably metastatic tumors that progress in a manner that is readily screened. In one iteration, these ‘tumors’ lead to organismal lethality that we have developed into a robust high-throughput screen. The kinase inhibitor Sorafenib rescued this phenotype, allowing flies to survive to adulthood and providing important validation of our screening platform. In a second iteration we permit Ras and Src to more mildly transform the eye epithelium to generate a ‘rough’ or ‘tumorous’ eye. We demonstrate that these phenotypes provide a second, more sensitive assay of Ras/Src oncogenic activity; again, Sorafenib rescued these cancer-like phenotypes. This work has important implications regarding novel drug screening methods for cancer and provides useful insights about the metastatic process. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4206.
Hemostatic effect of oxidized regenerated cellulose in an experimental gastric mucosal resection model
Authors: Jacobo Velázquez-Aviña, Klaus Mönkemüller, Paulo Sakai, Marianny Sulbaran, Carlos Chávez-Vargas, Eduardo Montalvo Javé, Sergio Sobrino-Cossío
Journal: Endoscopy (2014)

<b>Background and study aim:</b> The endoscopic hemostatic therapies currently available do not always result in hemostasis of gastrointestinal bleeding. Oxidized regenerated cellulose (ORC) mesh is a widely available surgical hemostatic material. The aim of this study was to evaluate the hemostatic efficacy of ORC in experimental gastric hemorrhage after endoscopic resection. <b>Methods:</b> This was a prospective, two-stage experimental, Phase I, proof-of-concept study. In Stage 1, eight gastric mucosal lesions were created in anticoagulated rabbits and treated with ORC (closed or open pores). In Stage 2, the endoscopic introduction and application of ORC mesh pieces were evaluated in a porcine model of endoscopic submucosal dissection (ESD). <b>Results:</b> In Stage 1, hemostasis was achieved in all lesions. Hemostasis was achieved more rapidly with closed-pore than open-pore ORC (24.5 vs. 66.5 seconds) (<i>P</i> < 0.01). At 24 hours, all lesions showed persistent hemostasis. There were no episodes of rebleeding, complications, or mortality. In Stage 2, the endoscopic introduction of ORC pieces and application with a biopsy forceps were feasible in all ESD lesions. <b>Conclusions:</b> ORC was an effective hemostatic agent for bleeding lesions following mucosal resection in anticoagulated rabbits. Closed-pore ORC achieved hemostasis faster than open-pore ORC. Endoscopic introduction and release of ORC were feasible.
AI-01 * ARE WE USING TOO MUCH BEVACIZUMAB IN OUR GBM PATIENTS?
Authors: A. Ajlan, P. Thomas, R. Thomas, S. Nagpal, L. Recht
Journal: Neuro-Oncology (2014)

INTRODUCTION: Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below MTD. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of at least 10mg/kg every other week (5mg/week), there has not been any study to our knowledge that this is optimal in terms of minimizing side effects. METHODS: We assessed charts from 59 patients treated at Stanford who received BEV for glioblastoma to survey the incidence of complications relative to the dose of medication/week. All patients were treated with standard upfront chemoradiation. The BEV dose was calculated per week. The toxicity was graded based on the NCI CTCAE, version 4.03. RESULTS: 52 patients received BEV for progression; the others received it as an added upfront treatment to control mass effect during irradiation. The median overall survival was 15 months (2-87). The dose ranged from 1.6 to 10/mg/kg/week with a median of 3.3mg/kg/week. The rate of BEV serious related adverse events was 13.5% (n = 8/59). Compared to a 20% incidence of Grade 3 toxicities in patients receiving > 3.0mg/kg/wk (8/40), no toxicity was seen in patients administered lower doses (0/19), (P < 0.05). The rates of grade 3 related toxicity, or higher, were 12% (n = 3/25) in patients received 3-4 mg/kg/week, 33% (n = 3/9)in patients received 4-5mg/kg/week, and 33%(n = 2/6) in patients received >5mg/kg/week. No differences in survival were noted as a function of dose. CONCLUSION: Lower rates of serious BEV related toxicities are noted when lower dosages are used. Furthermore, besides these findings being clinically significant, there is also an added economic benefit to using lower amounts of this very expensive medicine. Further work aimed at optimizing BEV dosage is justified.