tbuckley/cabot-search huggingface dataset:
Abstract 3460: Inhibition of c-met radio-sensitizes in breast cancer brain metastatic cancer
Authors: Heekyoung Yang, Juyoun Jin, Misuk Kim, Kang Ho Kim, Donggeon Kim, Wonyoung Kang, Hyewon Lee, Kyeung Min Joo, Do-Hyun Nam
Journal: Cancer Research (2012)

Abstract Ionizing radiation (IR) is a critical component in the treatments of breast cancer patients with all stages of the disease and a gold standard modality in patients with multiple brain metastasis, demonstrating improved overall survival (OS) in recent meta-analysis. However, the problem of recurrent or persistent disease exists due to tumor radio-resistance, and the development of distant metastasis after IR has presented a major obstacle to treatment. We investigated which molecule could be targeted for radio-sensitization. We found that c-Met over-expression and activation of downstream-signaling were induced in response to IR in a panel of human breast cancer cells by q-PCR, FACS, and Western blot analysis. The radio-sensitizing effect of c-Met silencing in vitro showed that increased c-Met activity is required for radio-resistance. In addition, c-Met inhibition combined with IR showed synergistic antitumor response including improved tumor regression and lengthened overall survival in breast cancer orthotopic and experimental brain metastasis xenograft models. Our preclinical findings establish a basis for a novel strategy to target the HGF/c-Met pathway with radiation when treating primary and brain metastatic breast cancer and possibly other c-Met pathway dependent cancers. 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 3460. doi:1538-7445.AM2012-3460
Submucosal endoscopy with mucosal resection (SEMR): a new hybrid technique of endoscopic submucosal dissection
Authors: K. Takizawa, C. Gostout, M. Knipschield
Journal: Endoscopy (2013)

In Western countries endoscopic submucosal dissection (ESD) has not prevailed because of training issues and a target patient population. We identified the ability to transform the submucosa into a free working space within which one could potentially undermine mucosal disease and perform en bloc excision "from the inside out" to the lumen, a direction which should also increase the safety of excising tissues. The same submucosal working space could also allow the overlying intact mucosa to serve as a protective flap during natural orifice transluminal endoscopic surgery (NOTES) access to body cavities, or the performance of achalasia myotomy. Submucosal endoscopy with mucosal safety valve flap (SEMF) was pushed ahead of our initial resection investigations due to the rapid evolution of NOTES experiences [1] [2]. With resumed animal experiments, we returned to our original plan, modifying SEMF into submucosal endoscopy with mucosal resection (SEMR), which may offer added safety, simplification, and ease for mucosal resection [3] [4].
Abstract SY11-03: Circulating tumor DNA as a non-invasive diagnostic and research tool.
Authors: Nitzan Rosenfeld
Journal: Cancer Research (2013)

Abstract In patients with solid malignancies, cell-free DNA carrying tumor-specific sequences can be found in body fluids such as blood plasma. This circulating tumor DNA (ctDNA) contains representation of the entire cancer genome, broken down into short mutation-carrying fragments, whose relative levels vary in response to treatment and progression. Different approaches to the study of ctDNA can work together to provide a window for noninvasive analysis of the cancer genome and its dynamics. Quantification of ctDNA levels may be useful as a prognostic biomarker and to assess response to treatment. When cancer overcomes treatment and progresses, the fraction of mutant alleles in plasma DNA can reach levels of 10%~20% or more, which makes it possible to study cancer evolution noninvasively by whole-genome or exome analysis of plasma DNA. Sensitivity and resistance to targeted therapies are often associated with known mutations in hotspot loci or genes. In advanced cancer patients, the status of pre-defined mutations can be analyzed noninvasively using circulating plasma DNA as a liquid biopsy. Targeted sequencing of limited regions in circulating DNA can allow identification of de novo mutations, even when these are present as rare fragments. This also facilitates parallel quantification of multiple mutations in plasma, which can indicate the relative systemic burden of different mutations or clones. Routine monitoring for sensitizing and resistance-conferring mutations may provide a framework for rational adaptive cancer therapy, providing real-time information on mutation levels to guide treatment against the most aggressive or treatable clones. Citation Format: Nitzan Rosenfeld. Circulating tumor DNA as a non-invasive diagnostic and research tool. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY11-03. doi:10.1158/1538-7445.AM2013-SY11-03
Limited Usefulness of Alkaline Diuresis and Peritoneal Dialysis in Pentobarbital Intoxication
Authors: H. A. Bloomer
Journal: New England Journal of Medicine (1965)

RECENT clinical studies have demonstrated that osmotic diuresis, with or without urinary alkalinization, will accelerate the renal excretion of drug in patients with barbiturate intoxication.1 2 3 4 5 When the intoxication is due to a long acting barbiturate — for example, phenobarbital — urinary excretion plays a major part in drug disposal. The augmented excretion achieved with this regimen is of sufficient magnitude to accelerate the fall in plasma barbiturate concentration and shorten the duration of coma.1 , 3 The claim that a similar beneficial effect can be obtained when coma is due to a short acting barbiturate such as pentobarbital or secobarbital is less . . .
Abstract 1885: Dietary stearate reduces abdominal fat, serum leptin and glucose and increases MCP-1
Authors: Ming-Che T. Shen, Lynda M. Evans, Eric C. Toline, Renee A. Desmond, Siegal P. Gene, Robert W. Hardy
Journal: Cancer Research (2010)

Abstract Stearate is a dietary, long-chain saturated fatty acid (C18:0) that has been shown to decrease breast cancer cell proliferation, migration, and invasion in vitro and reduce tumor growth and metastasis in vivo. Obesity, or excess adipose tissue, is a risk factor for breast cancer. Our overall hypothesis is that dietary stearate inhibits breast cancer by decreasing body fat. Our goal was to determine whether there was an association between dietary stearate and adipose tissue. Four groups of 10 athymic nude mice each were each fed one of four different diets for 18 weeks (6% corn oil - low fat diet, 17% stearate diet, 17% corn oil diet, or 17% safflower oil diet). Body composition was assessed by nuclear magnetic resonance (NMR) and dual energy X-ray absorptionmetry (DXA). Serum concentrations of glucose, insulin, leptin, adiponectin, interleukin-6, and monocyte chemoattractant protein-1 (MCP-1) were also determined. In a repeated measures model assessing the relationship between groups, for fat and lean mass over time the following differences were found: the stearate group had significantly reduced body fat compared to the low fat and the corn oil groups (p&amp;lt;0.001); mice on the high fat diets (stearate, corn oil, and safflower oil) had a significantly increased lean body mass compared to the low fat group (p=0.009, 0.012, and 0.022 respectively). Postmortem measurement revealed no significant changes in organ weight (brain, heart/lungs, liver, and kidney) among the four diet groups. However dietary stearate had less abdominal fat than the other diets although only the low fat - stearate difference was significant (low fat-stearate *p= 0.0043. corn oil-stearate p= 0.0565, and safflower-stearate p= 0.0636). Serum glucose and leptin concentrations were significantly reduced in the stearate diet mice (glucose, p&amp;lt;0.039, stearate vs all other diets, leptin, p&amp;lt;0.015, stearate vs low fat and corn oil diets). Serum MCP-1 was increased in stearate diet mice compared to either the low fat or safflower oil mice (p&amp;lt;0.019). Significant differences were not observed with the other analytes. Studies have suggested that glucose and leptin have cancer promoting effects, while MCP-1 may promote or inhibit breast cancer. Overall these data support our hypothesis that dietary stearate decreases body fat and that this decrease in body fat may be related to stearate inhibition of breast cancer. 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 1885.
TR-06 * COMBINATORIAL PATHWAY TARGETING APPROACHES FOR BRAF-FUSIONS ASSOCIATED WITH PEDIATRIC LOW-GRADE GLIOMAS
Authors: A. Waanders, A. Silva, S.-S. Chen, H. Han, Y. Zhu, K. Boucher, P. Jain, T. Fierst, N. Choudhari, S. Mueller, D. Haas-Kogan, P. Storm, A. Resnick
Journal: Neuro-Oncology (2015)

INTRODUCTION: Activating BRAF-fusion mutations occur frequently in pediatric low-grade gliomas (PLGGs). We have previously shown targeting of KIAA1549-BRAF fusion by PLX4720, the research analog of vemurafenib, results in paradoxical activation of the mitogen activated protein kinase (MAPK) signal cascade. We hypothesized that BRAF-fusions could be targeted by downstream MEK inhibitors (MEKi), and that combinatorial targeting of BRAF-fusions could also prevent acquired resistance to single agent therapy. METHODS: BRAF-fusions were screened with a selection of clinically relevant MEKi and with PLX8394, a second-generation RAF inhibitor, in vitro in cell culture and soft agar. BRAF V600E and RAS mutant cells were also screened for comparison. MEKi/PLX8394 resistant BRAF-fusion cell lines were generated in vitro and interrogated by sequencing, immunoblotting, and RNA-seq analysis to identify potential co-targets. Combinatorial therapy was then tested in vitro and in vivo to confirm efficacy. RESULTS: BRAF-fusions in PLGGs can be targeted by MEKi and by the pan-RAF inhibitor PLX8394. AZD6244, MEK162, GDC0623, and GDC0973 all inhibited downstream ERK phosphorylation; however, GSK1120212 more robustly inhibited MAPK activation in the BRAF-fusion, BRAF V600E, and RAS mutant cells. Interestingly, the MEKi/PLX8394 resistant BRAF-fusion cells all showed activation of phosphatidylinositol 3-kinase (PI3K) pathway. BRAF-fusion parental cells were screened with RAD001, a targeted mTOR inhibitor, resulting in modest downstream inhibition. Co-targeting of the parental BRAF-fusions with GSK1120212 and RAD001 resulted in robust inhibition of down-stream signaling and in significant tumor inhibition, and prevented acquired resistance to targeted inhibition. CONCLUSION: Our work demonstrates that BRAF-fusion oncogenes can be effectively targeted with GSK1120212 as single agent but even more robustly with GSK1120212 and RAD001 co-targeting. This provides preclinical rationale for treating PLGGs harboring BRAF-fusion oncogenes with combinatorial MEK and mTOR inhibitors in clinical trial.
Abstract 3637: Loss of prostate derived Ets (E-twenty six) transcription factor (PDEF) predicts patients at the highest risk of metastatic prostate cancer
Authors: Andrew C. Haller, Carl Morrison, Wei Tan, Rochelle Payne-Ondracek, Willie Underwood, Michael Poch, Lili Tian, James Mohler, Fengzhi Li
Journal: Cancer Research (2012)

Abstract PSA has ability to detect prostate cancer (CaP) at an early stage, but many CaP tumors are slow to progress, and many patients are overtreated for a disease that will not become life-threatening. Since there remains no reliable way to distinguish indolent from aggressive disease, doctors who advise and patients on active surveillance worry about progression to incurable disease. Therefore, new prognostic tools must be developed to identify patients with potentially metastatic, life threatening CaP. Prostate derived Ets transcription factor (PDEF) has shown to be a master negative regulator of transcriptional networks controlling migration and invasion in many cancer tissues, including CaP. Therefore we studied the expression of PDEF in radical prostatectomy specimens to determine retrospectively whether PDEF expression is predictive of clinical outcome. Patients’ tumor PDEF expression was determined by immunohistochemical staining of a 724 patient tissue microarray (TMA). CaP patients were stratified into groups based on PDEF expression (high, mid, low, null) and a Cox proportional hazards model was used to compare clinical outcomes. Univariate analysis showed that loss of PDEF expression significantly increased risk of metastatic disease (HR = 5.38, PDEF mid; to HR = 43.48, PDEF null; p=0.0059), although it did not correlate with incidence of biochemical failure detected using the American Urological Association (AUA) or National Comprehensive Cancer Network (NCCN) definitions. This result was confirmed in the Kaplan-Meier survival analysis that showed that patients whose CaP were PDEF low/null had significantly shorter metastases-free survival (p=0.0151). Multivariate analysis also demonstrated CaP with low/null PDEF expression were associated with increased risk of developing metastatic disease (HR = 6.21/10.53), although it was not statistically significant, in part due to the low incidence of patients with metastatic disease in the TMA. Therefore, we studied PDEF and vimentin (stem-like marker, repressed by PDEF) tumor expression in a cohort of patients matched for Gleason score, stage, age, and follow-up who developed metastatic disease versus those who did not. Patients that developed metastatic disease had a significantly lower PDEF (3.9 vs 1.7, p&amp;lt;0.0001) and higher vimentin (0.43 vs. 4.1, p&amp;lt;0.0001) expression compared to matched controls. We propose that intact PDEF expression in CaP can be used to distinguish patients who are suitable for active surveillance from those who require aggressive treatment. 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 3637. doi:1538-7445.AM2012-3637
P4-11-22: Familial History of Cancer among Breast Cancer Women under 36 yr. in Rio De Janeiro, Brazil.
Authors: S Koifman, GPJ Ortega, RJ Koifman
Journal: Cancer Research (2011)

Abstract Background. Antecedents of familial history of cancer (FHC) have been reported as an important feature observed among young women with breast cancer (BC). Objective. To explore the distribution of FHC in a sample of young women with BC in Brazil. Methods. Antecedents of FHC were obtained by a face to face interview carried out with 224 BC cases 20–35 yr., and 246 age-frequency matched controls, enrolled in a hospital-based case control study carried out along 1996–2006 in Rio de Janeiro, Brazil. Unconditional logistic regression was performed and BC odds ratios adjusted for age and education (adj. OR) were obtained according to FHC characteristics (parenthood degree, age of diagnosis and amount of relatives with cancer). Results. BC antecedents among 1 st degree relatives was 5.4% among BC cases and 1.2% of controls (p=0.01). The adj. OR for BC among 1st degree relatives was 4.3, 95% CI 1.2−15.8. Comparatively to families without BC antecedents, an adj. OR =2.4, 95% CI 1.4−4.1 was observed for those with 1 reported BC case, and an adj. OR = 3.7, 95% CI 1.0–14.0 for those with 2 or more BC cases (p trend =0.0002). A similar trend was verified according to all other cancer sites (p-trend &amp;lt; 0.0001). The reported median age of BC diagnosis in the 1st generation (proband grand-mothers) was 76 yr., being 45 yr. at the 2nd generation (proband mothers), and 38,4 yr. at the 3rd (proband sisters). A similar trend along generations was also verified for other cancer sites among case relatives, respectively, 69 yr., 58 yr. ***, and 45 yr. The mean age of diagnosis among the cases offspring was 6.7 yr. (standard deviation, SD = 0.6) and 12.0 yr. (SD = 1.4) among the controls descents (p&amp;lt; 0.01). Brain cancer reported among case relatives was 6.0 fold higher than among control relatives (3.7 fold higher for ovarian cancer, and 3.2 higher for skin cancer). Discussion. The observed results reveal that cancer risks among relatives of young women with BC are either higher for BC or other selected cancer sites. The observed decline along successive generations on the age at diagnosis of BC and other tumors is suggestive of recent genetic-environmental interaction in the studied sample of young women with BC in Brazil. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-22.
P2-19-01: Impact of Zoledronic Acid on Fractures, Bone Mineral Density and Bone Remodeling in the AZURE Trial (BIG 01–04).
Authors: R Coleman, E Woodward, L Turner, H Marshall, M Collinson, D Dodwell, C Davies, R Bell, D Cameron, J Brown
Journal: Cancer Research (2011)

Abstract Background: The AZURE trial was designed to determine whether the addition of zoledronic acid (ZOL) to standard adjuvant therapy improves disease free survival (DFS) in patients (pts) with stage II/III breast cancer. Although in a recent analysis after 752 events and a median follow-up of 59 months no difference in overall DFS was seen between ZOL and control pts, significant benefits were seen in women &amp;gt;5years post menopause. Here, we report the impact of ZOL on fractures in the main study, and on bone mineral density (BMD) and bone remodeling evaluated within a sub-study. Materials and methods: 3360 pts were randomized to receive (neo) adjuvant chemotherapy (CT) and/or endocrine therapy with (n=1681) or without (n=1678) up to 19 doses of ZOL 4mg over 5 years. Pts with osteoporosis and those using bisphosphonates, either at baseline or in the previous year, were excluded from study entry. BMD was assessed in 228 patients within a sub-study; 40 of these also underwent quantitative bone scanning (QBS), a novel imaging technique that yields values for 99mTc-MDP/HMDP whole skeleton plasma clearance (Kbone) as a surrogate for the rate of bone remodeling and enables assessment of specific regions of interest within the skeleton. Results: Fractures occurred in 152 (4.5%) pts; 60 (3.6%) ZOL pts compared with 92 (5.5%) control (CTRL) pts (difference −1.9%; 95%CI −3.3%, −0.5%). The difference in fracture incidence appeared early and persisted throughout the follow-up period. Fifty-six (86.2%) of the fractures in the ZOL group and 68 (61.8%) in the CTRL group occurred in the absence of, or prior to a DFS event. The fracture rates before disease recurrence were similar at 3.0% (51 pts) in the ZOL group and 3.4% (57 pts) in the CTRL group (difference −0.4%; 95%CI −1.6%, 0.8%). In contrast, 2.1% (8 ZOL pts) and 9.1% (34 CTRL pts) experienced a fracture after a DFS event (difference −6.9%; 95% CI −10.2%, −3.7%). For pts with a DFS event, the majority of fractures occurred after a skeletal recurrence; 87.5% (7 of 8) ZOL and 88.2% (30 of 34) CTRL pts. BMD Z-scores at completion of protocol treatment were higher in patients treated with ZOL. Kbone was lower in ZOL patients (26.5 vs 29.8 ml min−1 using 99mTc-MDP and 34.3 vs 39.3 ml min−1 with 99mTc-HMDP). Expressed as a percentage of whole skeleton clearance, regional values in the mandible were similar 1.15% (ZOL) vs. 1.22% (CTRL). Conclusions: Adjuvant ZOL given in the schedule studied in AZURE reduced the fracture rate in patients who developed recurrence of breast cancer. BMD was higher and the rate of bone remodeling less in patients treated with ZOL. Further follow-up will determine the duration and clinical relevance of these effects on bone health. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-19-01.
A6.14 Semaphorin 3A, an immunoregulator and potential biomarker for disease severity in systemic sclerosis
Authors: Z Vadasz, D Rimar, E Toubi
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Introduction</h3> Semaphorin 3A (sema3A) plays a regulatory role in immune responses, mainly affecting the activation of regulatory T cells. It has been found to correlate with disease activity in rheumatoid arthritis and systemic lupus erythematosus (SLE). <h3>Aim</h3> To investigate the expression of sema3A in patients with systemic sclerosis (SSc) compared to healthy controls and SLE disease controls and to correlate its expression with clinical characteristics. <h3>Methods</h3> 27 SSc patients, 42 SLE patients and 18 healthy controls were enrolled. Serum level of sema3A was measured by ELISA and expression of sema3A on regulatory T cells was evaluated by FACS analysis. SSc patients were evaluated for demographics, clinical manifestations, routine laboratory results, nailfold videocapillaroscopy patterns, pulmonary function tests, echocardiograms, modified Rodnan skin score (mRSS) and disease activity and severity scores. <h3>Results</h3> Serum levels of semaphorin 3A were lower in SSc compared to healthy controls 14.38 ± 5.7 ng/ml vs. 27.14 ± 8.4 ng/ml, p &lt; 0.0001 and similar to SLE 15.7 ± 4.3 ng/ml. The expression of semaphorin 3A on regulatory T cells was also lower in SSc compared to healthy controls 61.7 ± 15.7% vs. 88.7 ± 3. 7% (p &lt; 0.0001). Semaphorin 3A serum level inversely correlated with the duration of disease; r = -0.4, p = 0.036 and with low C4 level r = 0.66 p = 0.026. SCL-70 antibody positivity was associated with a lower semaphorin 3A level in serum (difference in mean of 3.44 p = 0.06). <h3>Conclusion</h3> Sema3A expression is low in SSc serum and more specifically on regulatory T cells. This may help explain the reduced activation of regulatory T cells in SSc, contributes to our understanding of the pathogenesis of the disease and may serve as a future target for treatment.
Reply to Castells et al.
Authors: Cesare Hassan, Jean-Marc Dumonceau
Journal: Endoscopy (2014)

The letter by Castells et al. appropriately focuses on the integration between adenomatous and serrated lesions when scheduling postpolypectomy surveillance. In theory, there are at least two possibilities when dealing with patients with two different types of lesions. The first is to generate an evidence-based ranking among the different histological types, in order to classify the patient according to the highest-ranking lesion. For instance, it could be proposed that patients with coexisting adenomatous and serrated lesions should always be classified according to the adenomatous component, down-grading the serrated component. Indeed, the relationship between the features of the adenoma (size, villous component, grade of dysplasia) and the risk of metachronous advanced neoplasia has been well validated, irrespective of the additional presence of serrated polyps. As the Authors admit, there is scarce literature, if any, supporting a higher risk of metachronous advanced neoplasia in those with coexisting lesions compared with those with only adenomas. Thus, by adding a re-stratification of the adenomatous component based on the coexisting serrated component would only dilute the moderate degree of certainty related to the adenomatous component in the first place.