tbuckley/cabot-search huggingface dataset:
ET-56 * SENSITIZATION OF GLIOBLASTOMA CELLS TO IRRADIATION BY MODULATING THE GLUCOSE METABOLISM
Authors: H. Shen, E. Hau, P. Dilda, K. McDonald
Journal: Neuro-Oncology (2014)

Since adjuvant radiotherapy significantly reduces the mortality and increases median survival in patients with glioblastoma (GBM), the radioresistance of GBM cells and targets to modify their radiation tolerance are of significant interest. High glycolytic states of tumor cells are known to correlate strongly with radioresistance, thus the concept of metabolic targeting needs to be investigated in combination with radiotherapy. Dichloroacetate (DCA), currently being used to treat lactic acidosis, can modify tumor metabolism by activating mitochondrial activity to force glycolytic tumor cells into oxidative phosphorylation. DCA alone demonstrated modest anti-tumor effects on both in vitro and in vivo models of GBM. However, we herein describe a better efficacy when DCA is combined with radiotherapy. An enhanced inhibition of clonogenicity of a panel of GBM cells was observed when DCA was combined with irradiation. Further mechanistic investigation revealed that i) DCA sensitized GBM cells to irradiation by inducing the cell cycle arrest at G2/M phase, the most radiosensitive cell cycle phase; ii) DCA reduced mitochondrial reserve capacity, a measure of the ability of cells to resist oxidative stress; iii) DCA and irradiation synergistically boosted the oxidative stress and iv) induced DNA damage in GBM cells at a higher rate compared to each therapy alone. Metabolically, we observed that the glycolysis in GBM cells was induced post-irradiation by stabilizing the hypoxia inducible factor (HIF)-1α, which in turn activated its direct target pyruvate dehydrogenase kinase 1 (PDK1). This irradiation-induced glycolytic metabolism was blocked by the addition of DCA when the combination was administered. In conclusion, this study provides the proof of concept that DCA can effectively sensitize GBM cells to irradiation by modulating the metabolic state of tumor cells. These findings warrant further evaluation of the combination of DCA and radiotherapy in vivo using GBM xenografts.
Use of next-generation sequencing (NGS) to identify actionable genomic alterations (GA) in diverse solid tumor types: The Foundation Medicine (FMI) experience with 2,200+ clinical samples.
Authors: Vincent A. Miller, Jeffrey S. Ross, Kai Wang, Siraj M. Ali, Geoff Otto, John Curran, Norma Alonzo Palma, Roman Yelensky, Sean Downing, Phil Stephens, Doron Lipson, Gary A. Palmer
Journal: Journal of Clinical Oncology (2013)

11020 Background: ST oncology has been transformed by the linkage of GA with targeted therapeutics. Unfortunately, most STs still have no target detected by clinically available assays. More comprehensive testing platforms are needed to determine GA in ST and thus broaden treatment options. We developed a ST NGS diagnostic assay, optimized for routine clinical FFPE specimens including core and fine needle biopsies and malignant effusions, and analyzed &gt; 2,200 patients’ tumors in a CLIA-certified lab (Foundation Medicine). Methods: Hybridization capture of 3,320 exons from 182 cancer-related genes and 37 introns of 14 genes commonly rearranged in cancer was applied to ≥ 50ng of DNA extracted from 2,200+ consecutive FFPE tumor specimens and sequenced to high unique coverage. GA (base substitutions, small indels, rearrangements, copy number alterations) were categorized as “actionable” if directly linked to a clinically available targeted treatment option or a mechanism-driven clinical trial. Results: 2,112/2,221 (95%) of specimens (most common 1° sites: lung 18%, breast 14%, colon 7%, other 34%) were successfully profiled (mean coverage 1134X). Alterations were reported in 155/182 (85%) of genes. Seventy-six percent of cases harbored ≥1 actionable GA, mean 1.6 (range 0-16); sixty-two percent harbored at least one actionable GA not assayed by available tumor-type specific tests or hotspot panels. This approach has led to novel insights into advanced cancer including: 13 novel, potentially druggable kinase gene fusions; alterations in known drug targets (e.g. ALK, EGFR, ERRB2, KIT, MET, PDGFR α and β, RAF1 and RET) in novel tumor types and new mechanisms of resistance to approved targeted therapies. Several patients demonstrated dramatic responses to treatment with targeted therapies directed against these alterations. Conclusions: Comprehensive NGS genomic profiling was successful in profiling &gt;2,200 unselected clinical cases, identified actionable alterations in 76% of cases and provided additional treatment options for 62% of patients targeting alterations in genes not assayed by available hotspot panels.
914 INCIDENCE OF END STAGE LIVER DISEASE (ESLD) AND CAUSES OF DEATHS IN A COHORT OF HIV/HCV INFECTED PATIENTS IN FRANCE HEPAVIH ANRS C013’
Authors: E. Pambrun, M.A. Loko, M. Winnock, P. Sogni, K. Lacombe, P. Morlat, F. Dabis, D. Salmon
Journal: Journal of Hepatology (2012)
Abstract P6-15-15: MM-111 - A Novel Bispecific Antibody Targeting HER-2/HER-3 Z Heterodimer: Safety and Tolerability in a First-In Human Phase I/II Study in Patients with Refractory HER2-Positive (HER-2+) Cancers
Authors: M Beeram, CS Denlinger, AW Tolcher, LJ Goldstein, A Patnaik, K Papadopoulos, J Murray, C McDonagh, K Andreas, C Niyikiza, VM. Moyo
Journal: Cancer Research (2010)

Abstract Background: The ErbB2/ErbB3 oncogenic heterodimer is the most potent ErbB receptor pairing with respect to strength of interaction, receptor tyrosine phosphorylation, and downstream signaling through mitogen activated protein kinase and phosphoinositide-3 kinase pathways. ErbB3 signaling has emerged as an important mechanism of resistance to ErbB2 (HER-2) targeted agents in clinical use (Sergina et al Nature 2007, Garrett et al SABCS 2009 abstract 63). MM-111 is a novel bispecific antibody fusion protein that specifically targets the ErbB2/ErbB3 heterodimer and abrogates ligand binding. In preclinical models of HER-2+ gastric, breast, ovarian and lung cancers, MM-111 inhibits ligand-induced ErbB3 phosphorylation, cell cycle progression, and tumor growth. This first-inhuman phase 1-2 study evaluates the safety and tolerability of MM-111 and preliminarily explores efficacy in HER-2+ advanced breast cancer (ABC). The safety data obtained during the Phase 1 dose escalation portion of this study provide the basis of this report. Methods: Patients (pts) with histologically confirmed HER-2+ advanced solid tumors progressing or recurring on standard therapy; aged ≥18 years; ECOG PS ≥2 and adequate organ function were eligible for phase I. Pts with stable CNS lesions were also eligible. A Modified Fibonacci schema was used for dose escalation in Phase I. Primary endpoints for Phase 1 were determination of maximum tolerated dose/maximum feasible dose while secondary endpoints included determination of dose-limiting toxicity, adverse events, and pharmacokinetic (PK) and immunogenicity profiles of MM-111. MM-111 was administered intravenously weekly in 4-week cycles. Results: 12 pts (11 ABC and 1 gastric cancer) were treated: median age 59 (range 36-82), median PS 1 (range 0-1), 11♂:1♀, median numberof prior therapies 7 (3-12). A total 19 courses (median 2; range 1-2) of therapy was administered at 4 dose-levels (3 mg/kg, 6mg/kg, 12mg/kg and 20 mg/kg respectively). Common adverse events reported included pain (n=7) fatigue (n=4), dyspepsia (n = 3) and pyrexia (n = 3). There were no treatment interruptions due to adverse events. No dose limiting toxicities were observed and there has been no evidence of cardiotoxicity or immunogenicity to date. PK data indicate dose proportionality at the dose-levels explored and supports weekly dosing. Conclusions: MM-111 is well tolerated at the doses levels studied and the PK profile suggests that weekly dosing is feasible. Enrollment to phase II is anticipated to commence shortly. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-15.
AB1196 Paediatric autoimmune neuropsychiatric disorder associated with group a streptococcal infection (PANDAS): Cardiac and articular involvement
Authors: S. Pieropan, D. Biasi, G. Barausse, M. Facci, S. Tonetta, V. Ravagnani, A. Carletto, F. Boscaini, A. Boner, G. Sidoti, S. Adami, L. Zoccante
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> PANDAS is a syndrome characterized by obsessive-compulsive disorder (OCD) and/or tic disorder with symptom exacerbations in children after group A β-hemolytic streptococcal (GAS) infections. No cardiac nor articular involvement is present as in the case of Sydenham Chorea. Antinuclear antibodies and nuclear basal involvement at brain MR may be encountered. <h3>Objectives</h3> We evaluated the possible misdiagnosed cardiac and articular involvement in 30 children affected by PANDAS and regularly assessed at an out-patient ambulatory in the period from 2007 to 2011. <h3>Methods</h3> 30 children affected by PANDAS according the Swedo SA diagnostic criteria were evaluated at the out-patient ambulatory of the Rhematologic and Neuropsichiatric departments of Verona’s University Hospital in the period from 2007 to 2011; thorough cardiologic evaluation encompassing ECG and echocardiogram was performed <h3>Results</h3> mean age of the 30 young patients (M:F 23:7) was 7±3 years; all had sierologic evidence of previous streptococcal infection; ECG was normal in all the cases as well as cardiac echogram with the exception of 2 cases of trivial mitral regurgitation without structural valvular alterations; no patient was affected by perferic arthritis, arthargias nor morning stiffness. <h3>Conclusions</h3> the absence of cardiac or articular involvement in PANDAS patients, as evidenced in this study, confirms its differential diagnosis with Sydenham Chorea <h3>Disclosure of Interest</h3> None Declared
AB0143 Angiotensin receptor type 1 and endothelin receptor type a on immune cells mediate migration and the expression of il-8 and ccl18 when stimulated by autoantibodies from systemic sclerosis patients
Authors: J. Guenther, A. Kill, M. O. Becker, E. Siegert, M. Radic, G. Riemekasten
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Agonistic autoantibodies against the angiotensin II receptor type 1 (AT1R) and the endothelin receptor type A (ETAR) have been identified in patients suffering from systemic sclerosis (SSc). <h3>Objectives</h3> Here we examined the expression of the AT1R and the ETAR in human immune cells and the pathological effects mediated through these receptors by the corresponding autoantibodies (Aabs). <h3>Methods</h3> AT1R and ETAR protein expression on peripheral blood T cells, B cells, and monocytes of healthy individuals and SSc patients were analyzed using flow cytometry. Messenger ribonucleic acid (mRNA) expression of both receptors in peripheral blood mononuclear cells (PBMCs) from healthy donors was examined by real-time polymerase chain reaction (PCR). In addition, PBMCs from healthy donors were stimulated <i>in vitro</i> with affinity-purified immunoglobulin G (IgG) fractions from SSc patients containing Aabs against the AT1R and the ETAR, and with IgG from healthy donors serving as control. Alterations in cell surface marker expression, cytokine secretion and chemotactic motility were analyzed using flow cytometry, ELISA, and chemotaxis assays, respectively. Results were correlated with characteristics and clinical findings of the IgG donors. <h3>Results</h3> Both AT1R and ETAR were expressed on peripheral lymphocytes and monocytes in humans. The protein expression of both receptors was decreased in SSc patients when compared to healthy donors and correlated negatively with disease duration. In addition, IgG fractions of SSc patients containing Aabs against the AT1R and the ETAR induced T cell migration in an anti-AT1R and anti-ETAR Aab level-dependent manner. Moreover, IgG of SSc patients was capable of stimulating PBMCs to produce more IL-8 and CCL18 than IgG of healthy donors. All effects could be significantly abrogated by the application of selective AT1R and ETAR antagonists. Statistical analysis revealed a negative correlation between SSc IgG-induced IL-8 concentrations and disease duration, between SSc IgG-induced CCL18 concentrations and the time since the onset of lung fibrosis as well as an association of CCL18 concentrations with vascular complications of the corresponding SSc IgG donors. <h3>Conclusions</h3> In this study we demonstrate the expression of both, AT1R and ETAR, on human peripheral T cells, B cells and monocytes. Moreover, we found signs for a chronic activation of peripheral immune cells from SSc patients. The inflammatory and profibrotic effects upon Aab stimulation of PBMCs <i>in vitro</i>, and their associations with clinical findings suggest a role for autoantibody-mediated activation of immune cells mediated through the AT1R and ETAR in the pathogenesis or even the onset of the disease. <h3>Disclosure of Interest</h3> None Declared
Regulatory Updates: Oregon Reform, California Media, And Passive Smoking Dangers
Authors: C. Vanchieri
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Regulatory Updates: Oregon Reform, California Media, And Passive Smoking Dangers Get access Cori Vanchieri Cori Vanchieri Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 17, 2 September 1992, Pages 1313–1314, https://doi.org/10.1093/jnci/84.17.1313 Published: 02 September 1992
INCIDENCE AND ONE YEAR OUTCOME OF PERIOPERATIVE ATRIAL ARRHYTHMIA IN THE ELDERLY FOLLOWING HIP FRACTURE SURGERY
Authors: Bhanu Gupta, Rachel C. Steckelberg, Lisa Kirkland, Dirk Larson, Paul Huddleston, R. Scott Wright, Jeanne Huddleston
Journal: Journal of the American College of Cardiology (2015)
P736P2Y6 deficiency limits vascular inflammation and atherosclerosis in mice
Authors: P Stachon, A Peikert, N Michel, D Wolf, B Dufner, N Hoppe, C Bode, M Idzko, A Zirlik
Journal: Cardiovascular Research (2014)

Objective: Nucleotides such as ATP, ADP, UTP, and UDP serve as pro- inflammatory danger signals via purinergic receptors upon their release to the extracellular space by activated or dying cells. UDP binds to the P2Y6 receptor and propagates vascular inflammation by inducing the expression of chemokines such as MCP-1, IL-8 and adhesion molecules such as VCAM-1 and ICAM-1. Thus, P2Y6 contributes to leukocyte recruitment and inflammation in conditions such as allergic asthma or sepsis. Since atherosclerosis is a chronic inflammatory disease driven by leukocyte recruitment to the vessel wall we hypothesized a role of P2Y6 in atherogenesis.
FRI0196 Comparison between ultrasonographic and clinical disease activity of rheumatoid arthritis in patients two years treated with anti tnf biological therapy
Authors: S. Z. Prodanovic, G. Radunovic, S. Zivojinovic, S. Seric, N. Damjanov, M. Zlatanovic
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> To compare disease activity in patients with rheumatoid arthritis (RA) after two years treatment with anti TNF therapy estimated by ultrasound and clinical examination (US) of 28 joints. <h3>Methods</h3> A total 30 RA pts. after anti TNF (Etanercept) treatment lasting for two years, were enrolled in study. Seventy three percent (22/30) of pts. were female, the mean age of patients was 52.7±9.4 yr. The mean duration of the disease was 132±94.0 months. Ultrasound examination of 28 joints included in DAS 28 was performed by Esaote My Lab 70 machine equipped 8-18 MHz linear probe. The total number of 840 joints were examined. The presence of joint effusion and Power Doppler (PD) signal was assessed qualitatively, (present or not). The simultaneous presence of joint effusion and PD signal at the same joint, were considered as ultrasonographic sign of disease activity. RA disease activity was assessed by DAS-28. All pts. were completed HAQ. Structural joint damage was evaluated by Sharp/van der Heijde method. The pts. with RA remission (the value of DAS-28&lt;2.6) and low (the value of DAS-28 3.2≥ 2.6) disease activity were further analyzed. The data were analyzed in SPSS system. <h3>Results</h3> The mean value of DAS 28 was 3.4±1.4, HAQ 0.5±0.5 and Sharp/van der Heijde score 101.1±63.4.5. The pts. had 5.5 joints with effusion and 1.2 joints with positive PD signal in average by US in opposite to 1.4 swollen and 2.7 painful joints in average by clinical examination. Only one patient had no evidence of joint effusion while thirteen (43%) had no PD signal presence by ultrasound examination in contrast to fifteen (50%) pts. without swollen and twelve (40%) pts. without painful joints by clinical examination. Nineteen (57.5%) pts. had ultrasonographic sign of disease activity. Six pts. were found with DAS 28 remission. The frequency of ultrasonographic evidence of disease activity was present at 33.3% of pts. in contrast to 62.5% of pts.with value of DAS&gt;2.6. The difference was not statistically significant (p=0.360). Thirteen pts. were found with low disease activity according to DAS 28. The frequency of ultrasonographic evidence of disease activity was present at 62% of pts. in opposite to 53 % of pts.with very active RA. The difference was not statistically significant (p=0.721). <h3>Conclusions</h3> Despite signs of RA remission or low disease activity according to DAS 28, patients had some evidence of joint inflammation confirmed by ultrasound after two years of treatment with anti TNF therapy. <h3>Disclosure of Interest</h3> None Declared
PWE-198 Outcomes for Patients undergoing Mesenteric Angiography for Acute Severe Gastrointestinal Bleeds in an Intensive Care unit of a Tertiary Hospital
Authors: F Phillips, T Rahman
Journal: Gut (2013)

<h3>Introduction</h3> In acute severe gastrointestinal bleeding, endoscopy has a failure rate of 10–30% in detecting active bleeders and achieving haemostasis. Further aggressive treatment may be necessary and mesenteric angiography has the advantage of being both a therapeutic and diagnostic modality. Previous outcome data on patients undergoing angiography report a normal angiogram in 52% (due to the intermittent nature of bleeds), with lower rebleed rates than in those with positive extravasation, but a higher mortality. Where there was positive extravasation and subsequent embolization, a rebleed rate of 9–47% is reported, with a surgery rate of 0–35% and 30 day mortality of 3–27%. We would like to report our department’s experience of the outcomes of acute severe gastrointestinal bleeds requiring mesenteric angiography. <h3>Methods</h3> Over a 5 year study period between 2006–2011 in the general intensive care unit of St George’s Hospital, patients were included if they had had a non-variceal acute severe gastrointestinal bleed that required mesenteric angiography after failed endoscopy. Retrospective data was collected on patient demographics, endoscopic findings, angiographic findings, embolization, rates of rebleeding, number of packed red blood cells (PRBC) transfused, hospital stay, and mortality at 30 days. <h3>Results</h3> 26 patients were included, 18 male and 8 female. Overall, each patient needed an average of 22.2 units of PRBCs; rebleeding occurred in 28.9%; surgery was performed in 6 patients (including 4 colectomies); 30 day mortality was 35% (n = 9) and 90-day motality was 50% (n = 13). Subgroup analysis showed that for the 18 patients with positive angiographic findings and subsequent embolization, 10 had positive endoscopic findings (4 gastric ulcers, 5 duodenal ulcers, 1 Dieulefoy lesion) whilst 8 had inconclusive findings at endoscopy. For this group, an average of 18 units PRBCs were transfused, the rebleed rate was 35%, subsequent surgery was performed in 24%, 30 day mortality was 44% (n = 8) and 90 day mortality 54% (n = 10). For the 8 patients (27%) with a negative angiography, all had a negative endoscopy. Only 13% required surgery (n = 1), an average of 11 units was transfused, the rebleed rate was 13% (n = 1), 30 day mortality 13% (n = 1) and 90 day mortality 38% (n = 3). <h3>Conclusion</h3> Overall, this group of patients needing angiography have a very high risk of mortality. Only 31% of our patients had a normal angiogram, suggesting a more astute selection of cases. Interestingly, for those with a negative angiography, the rates of rebleeding and surgery were lower than in the positive extravasation group, but the mortality is also lower, a finding in contrast to previous studies. <h3>Disclosure of Interest</h3> None Declared.
P3-09-06: Changes of Serum Vitamin D According to the Breast Cancer Treatment.
Authors: HJ Kim, OV Yi, BS Koh, JH Yu, JW Lee, BH Son, SH Ahn
Journal: Cancer Research (2011)

Abstract Background: Vitamin D deficiency is associated with increased breast cancer risk and decreased breast cancer survival. The purpose of this study was to determine the effect of breast cancer adjuvant treatment to the vitamin D status, as measured by the serum hydroxyvitamin D (25OHD) in breast cancer patients. Patients and Methods: For 589 patients who was diagnosed as a non metastatic breast cancer in 2009 at the asan medical center, blood was prospectively analyzed in batches for serum 25 OHD level at basal and at 6 and 12month. We excluded the patients who took a vitamin D supplementation and got a neoadjuvant chemotherapy. Vitamin D sufficiency was defined as serum as 30ng/ml or greater, insufficiency as 20 to 29 ng/ml and insufficiency as less than 20ng/ml. Results: At baseline, mean serum 25OHD was greater in summer (April to Oct) than Winter(Nov to May) (28.2ng/ml vs 32.9ng/ml respectively, p=0.000). The patients who did not get a chemotherapy and antihormonal therapy as baseline, the patient with chemotherapy showed decreased serum 25OHD level than who without chemotherapy in 6 month but not in 12 month (p=0.003, vs p=0.156 respectively). The patients who had taken anti-hormonal therapy showed significant increasing serum 25OHD in 6 month and 12 months (p=0.000 both). For the patients who got both chemotherapy and anti-hormonal therapy, the changes of serum 25OHD level is smaller than the patients who got a chemotherapy only. For the patients who got a chemotherapy, 57% of patients were vitamin D sufficient at baseline, but 27% of patients in 6 month and 49% in 12 month (p=0.001). Conclusion: Vitamin D status was worsen during chemotherapy but recovered after chemotherapy. Anti hormonal therapy make the serum vitamin D level increased. The translational research about the effect of chemotherapy and anti-hormonal therapy to the vitamin D status should be warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-09-06.
GE-35 * THE THERAPEUTIC CHANGES OF ATYPICAL TERATOID/RHABDOID TUMOR IN MOLECULAR CHARACTERS
Authors: M. Suzuki, A. Kondo, I. Ogino, J. Fujimura, S. Sakaguchi, M. Miyajima, H. Arai
Journal: Neuro-Oncology (2014)

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor in early childhood. Though it is widely known that over 90% of tumors show loss of INI1 nuclear staining histologically, at this point comprehended molecular analysis of this tumor has not been done. In this report, we investigate the differences between primary tumor, recurrent tumor post induction chemotherapy, and the tumor post radiation therapy in the profiling of expression genes. MATERIALS AND METHODS: We had 3 cases of AT/RT patients who had several surgical interventions. Using these tumor tissues, we investigated the changes between primary and recurrent tumors, histological and molecular biologically with a commercially utilized SNP array system. (OncoScan, FFPE Assay Kit, Affymetrix) The data were analyzed with a commercially utilized software (Nexus Express Software). RESULTS: We have made copy number analysis and mutation study in cancer specific genes. Several common changes in molecular sense can be seen after interventions, such as specific drug treatments and radiation therapy. CONCLUSION: Our study may show how this tumor acquires the resistance to conventional therapies. Further study is needed to identify the malignant characters of this tumor.