tbuckley/cabot-search huggingface dataset:
P5-05-04: Bipshenol-A Modulates Estrogen Receptor Alpha and Compromises Tamoxifen-Induced Apoptosis.
Authors: III WH Goodson, MG Luciani, A Sayeed, I Jaffee, II DH Moore, SH Dairkee
Journal: Cancer Research (2011)

Abstract BACKGROUND: Antiestrogens are important for treatment and prevention of breast cancer. Such drugs influence multiple pathways involved in regulation of cell survival — including apoptosis. In previous work, exposure of human, benign, high-risk donor breast epithelial cells (HRBECs) to the xenoestrogen (XE) bisphenol-A (BPA) induced gene expression changes predicting disruption of apoptotic signaling (Dairkee et al, Cancer Research 2008). Therefore, we hypothesized that antiestrogenic, pro-apoptotic effects of tamoxifen are likely modulated under the influence of XEs. Because the environmental XE, BPA is routinely detected in a large percentage of random human blood samples, we employed functional tests to determine whether BPA interferes with tamoxifen-induced apoptosis in XE-exposed HRBECs. METHODS: With IRB approval and written informed consent, HRBECs were obtained by random periareolar fine needle aspiration (RPFNA) from women who were high risk on the basis of personal or family history of breast cancer, breast density, or high-risk histology. Primary HRBEC cultures were treated for one week with a low concentrations of BPA corresponding to levels reported in human body fluids. Estrogen Receptor (ER)-α and -β were measured by Western blot (n=6). Altered response to tamoxifen toxicity was measured by analyzing quantitative changes in the Annexin V-positive apoptotic cell population (n=8). RESULTS: After one-week exposure to BPA, ER-α increased in six of six cases, ER-β decreased in 5 of 6 cases, and we observed a 25 percent reduction in tamoxifen-induced apoptosis. Prior exposure to BPA at the high concentration range detected in the human population reduced tamoxifen efficacy by 50 percent. There was a dose response of evasion of apoptosis to increasing concentrations of BPA (P&amp;lt;0.001, two-sided test for slope fixed effect in a linear mixed effects regression). Prior exposure to another XE, methylparaben (MP), caused a similar dose-dependent decline in tamoxifen-induced apoptosis (p&amp;lt;0.001). CONCLUSION: BPA and MP, in a range of concentrations measured in humans, prevent tamoxifen-induced apoptotic cell death. For BPA this involves upregulation of ER-α and downregulation of ER-β. Because these XEs are widespread in the American population, they may play a role in limiting the prophylactic and therapeutic efficacy of tamoxifen and other hormone-based therapies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-05-04.
Low Glutamine Levels during Critical Illness — Adaptive or Maladaptive?
Authors: Greet Van den Berghe
Journal: New England Journal of Medicine (2013)

Glutamine is the most abundant nonessential free amino acid in a healthy human body.1 It is synthesized de novo, predominantly in skeletal muscle. Low glutamine levels, which have been detected in patients during critical illness, have been associated with a poor outcome.2,3 Loss of muscle mass, with no evident up-regulation of glutamine synthesis, has been inferred to contribute to insufficient glutamine production.4,5 Thus, apparent glutamine deficiency, brought about by the increased glutamine requirements of immune cells, enterocytes, and hepatocytes, is thought to occur and has led to the idea that glutamine is a “conditionally essential” amino acid during . . .
A6.16 Harmonisation of eleven flow cytometers for multi-colour analyses of a large cohort of patients in the context of the european imi project "precisesads"
Authors: JO Pers, L Le Lann, C Marañon, N Barbarroja, D Alvarez, E Trombetta, V Gerl, A Zuber, T Cantaert, E Neves, K Kniesch, J Ducreux, C Jamin
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background and objectives</h3> The "Molecular Reclassification to Find Clinically Useful Biomarkers for Systemic Autoimmune Diseases" (PRECISESADS) IMI project will study 2,500 individuals affected by SADs into clusters of molecular, instead of clinical entities. Among extensive OMICS approaches, patients will get flow cytometry analyses using 9 panels of Abs, containing 8 different multi-stained markers, that will be performed in 11 various centres equipped with different flow cytometers (Canto II, Aria III, Fortessa, Verse, Navios or Gallios). The aim of this work was to establish a method to harmonised all the cytometers to be able to compared the overall data. <h3>Materials and methods</h3> VersaComp capture beads (Beckman Coulter) were used for the mirroring of the 11 flow cytometers. Rainbow <i>8</i>-<i>peak beads </i>(Beckman Coulter) were used to settle internal quality control for each machine. Duraclone tubes (Beckman Coulter) containing dried Ab cocktail were used for the multi-colour staining of the blood samples. <h3>Results</h3> A Navios has been chosen as the internal reference to fix the MFIs of the 8 different fluorochrome-conjugated Abs (FITC, PE, PC5.5, PC7, APC, APC-AF750, PB and KrO) using the VersaComp Ab capture beads. The 10 other centres have then fixed their own PMT values to reach the same MFIs using the same conjugated Abs. Thereafter, each centre acquired the Rainbow <i>8</i>-<i>peak beads to determine their own internal QC. One blood sample has been dispatched in all centres and has been concomitantly stained with the </i>Duraclone tubes (Beckman Coulter)<i>. Frequencies of cell subsets and MFIs of markers have been compared and found similar between centres.</i> <h3>Conclusions</h3> The prerequisite of the integration of the flow cytometry informations in bioinformatical and biostatistical analyses of the OMICS data is a fine inter-cytometer harmonisation. This procedure has been succesfully achieved getting a very close sensitivity for all flow cytometers. The inclusion of patients can now be confidently performed, knowing that the comparison of the flow cytometry data will be workable. Identification of specific molecular signatures in patients with SADs should finally enable clinicians to tailor individual therapies. (This work has received support from EU/EFPIA Innovative Medicines Initiative Joint Undertaking PRECISESADS grant n°115565).
HIGH DENSITY LIPOPROTEIN CHOLESTEROL EFFLUX CAPACITY AS A NOVEL RISK MARKER FOR INCIDENT ATHEROSCLEROTIC CARDIOVASCULAR DISEASE INDEPENDENT OF FAMILY HISTORY OR PREVALENT CORONARY CALCIUM IN A MULTI-ETHNIC POPULATION-BASED STUDY
Authors: Purav Mody, Andre Paixao, Amit Khera, Colby Ayers, James de Lemos, Anand Rohatgi
Journal: Journal of the American College of Cardiology (2015)
AT-08 * RADIOTHERAPY WITH VS WITHOUT TEMOZOLOMIDE IN OLDER PATIENTS WITH GLIOBLASTOMA
Authors: N. Arvold, M. Cefalu, Y. Wang, C. Zigler, D. Schrag, F. Dominici
Journal: Neuro-Oncology (2014)

BACKGROUND: A randomized trial of glioblastoma patients aged ≤70 years demonstrated that adding temozolomide (TMZ) to radiotherapy (RT) improved overall survival (OS). We examined whether adding TMZ to RT was associated with improved OS in older glioblastoma patients. METHODS: We performed a retrospective cohort study of 1,718 Medicare beneficiaries aged ≥65 years with glioblastoma diagnosed in a SEER region who received ≥10 daily fractions of RT between 2005-2009, or between 1995-1999 before TMZ was available. Patients were categorized into 3 cohorts based on diagnosis year and treatment received within 3 months of diagnosis: 1) 2005-2009 and TMZ/RT, 2) 2005-2009 and RT only, or 3) 1995-1999 and RT only. Associations between treatment group and OS were compared using Cox proportional hazards models and propensity score analyses, controlling for baseline patient characteristics. RESULTS: Median survival estimates were 9.4 (IQR, 5.2-17.0) months for TMZ/RT, 7.9 (IQR, 4.7-15.0) months for RT in 2005-2009, and 7.7 (IQR, 4.9-11.8) months for RT in 1995-1999. Two-year survival probabilities were 12.4% for TMZ/RT, 7.6% for RT in 2005-2009, and 3.3% for RT in 1995-1999. Propensity score-adjusted models showed decreased mortality risk for TMZ/RT compared to RT in 2005-2009 (AHR, 0.88; 95% CI, 0.79-0.98) and to RT in 1995-1999 (AHR, 0.70; 95% CI, 95% CI, 0.56-0.87). Subgroup and sensitivity analyses showed no significant advantage to TMZ/RT compared to RT in 2005-2009 among patients receiving long-course RT (≥27 fractions; AHR, 0.89; 95% CI, 0.79-1.01). CONCLUSIONS: Concurrent TMZ was associated with a small survival benefit among older glioblastoma patients receiving RT, but no significant survival benefit was observed among patients who received standard long-course RT.
Patient Accrual Is Up for High-Priority Trials
Authors: J. A. Steele, J. Glover
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article Patient Accrual Is Up for High-Priority Trials Get access Julie A. Steele, Julie A. Steele Search for other works by this author on: Oxford Academic PubMed Google Scholar Janet Glover Janet Glover Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 2, 16 January 1991, Pages 87–88, https://doi.org/10.1093/jnci/83.2.87 Published: 16 January 1991
Abstract 849: Autophagic cell death response to benzyl isothiocyanate exposure in human breast cancer cells is mediated by FoxO1
Authors: Dong Xiao, Ajay Bommareddy, Shivendra V. Singh
Journal: Cancer Research (2011)

Abstract Benzyl isothiocyanate (BITC), a constituent of edible cruciferous vegetables (e.g., gardencress), is empowered to prevent chemically-induced cancers as well as oncogene-driven spontaneous mammary cancer development in rodent models. Furthermore, BITC treatment effectively inhibits growth of cultured as well as xenografted human breast cancer cells. However, the mechanisms underlying cancer chemopreventive responses to BITC are not fully understood. We now demonstrate, for the first time, that BITC causes FoxO1-mediated autophagic cell death in human breast cancer cells. Exposure of MDA-MB-231 (an estrogen-independent cell line with mutant p53) and MCF-7 (an estrogen-receptor positive cell line with wild-type p53) human breast cancer cells to BITC resulted in autophagy characterized by appearance of double-membrane structures judged by transmission electron microscopy, formation of acidic vesicular organelles evidenced by microscopy following staining with lysosomotropic agent acridine orange, cleavage of LC3 evidenced by immunoblotting, and punctuate localization of LC3. Interestingly, a spontaneously immortalized and non-tumorigenic human mammary epithelial cell line (MCF-10A) was resistant to autophagy induction by BITC. BITC-mediated growth inhibition and apoptotic cell death resulting from 6 hour treatment was significantly attenuated in the presence of autophagy inhibitor 3-methyladenineand (3-MA; a phosphatidylinositol 3-phosphate kinase inhibitor) and bafilomycin A1 (an inhibitor of vacuolar type H+-ATPase). On the other hand, growth inhibition and apoptotic DNA fragmentation resulting from 24 hour exposure to BITC was not prevented by either 3-MA or bafilomycin A. Furthermore, inhibition of MDA-MB-231 xenograft growth in female athymic mice by BITC administration (2.5 and 7.5 µmol BITC/mouse by i.p. injection) correlated with cleavage of LC3. BITC-induced autophagy was accompanied by induction of FoxO1. Moreover, RNA interference of FoxO1 conferred significant protection against BITC-mediated growth inhibition and autophagy. In conclusion, these results indicate that autophagy is an early event in growth inhibition by BITC against human breast cancer cells, which culminates into apoptotic cell death following longer exposures (e.g., 24 hours). This investigation was supported by the USPHS grant RO1 CA129347-04, awarded by the National Cancer Institute. 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 849. doi:10.1158/1538-7445.AM2011-849
OC-050 The frequency of gastrointestinal haemorrhage in patients treated for acute coronary syndromes: an observational study: Abstract OC-050
Authors: K J Monahan, N I A N McNeil, J Arnold, T Orchard
Journal: Gut (2010)

<h3>Introduction</h3> Antiplatelet and antithrombotic therapy for acute coronary syndromes may increase the risk of gastrointestinal and other haemorrhagic events. The aim of this study was to compare the frequency of bleeding events, and consequent morbidity and mortality among patients treated for acute coronary syndromes and a control group of hospital inpatients. <h3>Methods</h3> Design: Observational cross-sectional study performed in Ealing Hospital NHS Trust, UK, used from 1 December 2004 to 28 February 2005. The treatment group consisted of 111 inpatients diagnosed with acute coronary syndrome and treated with standard anti-thrombotic medication. A control group of 106 patients was admitted during the same period. The main outcome measure was the incidence of bleeding events within 30 days. Haemoglobin concentration was monitored. <h3>Results</h3> A significant increase in haemorrhage was found in the group treated for acute coronary syndrome (OR 10.6, 95% CI 4.3 to 26.4), predominantly upper GI haemorrhage (OR 9.3, 95% CI 2.7 to 32.0). Bleeding events occurred in 42 patients in the treatment group (∼38%) and 6 patients in the control group. The treatment group were also more likely to develop anaemia as inpatients (OR 4.93, 95% CI 2.65 to 9.2). Examination of serial haemoglobins indicated that 56 patients became newly anaemic and that there was an overall drop in haemoglobin of over 12.3% (p=0.0005). Eleven patients died with major bleeds, contributing as a major cause of mortality in 3 patients (2 gastrointestinal and 1 intracranial), although this difference was not significant. <h3>Conclusion</h3> We have demonstrated a greater incidence of GI and other system haemorrhage than that reported in many of the major trials for treatment of acute coronary syndromes. This calls in to question the current recommendations for the use of proton pump inhibitors in such patients, a recent matter of much controversy due to the interactions of these drugs with clopidogrel.
Abstract 1664: Maternal embryonic leucine aipper kinase (MELK) is a critical regulator of proliferation and is independently prognostic in estrogen receptor-negative breast cancer
Authors: Karrie Wheatley, Corey Speers, Anna Tsimelzon, Krystal Sexton, Susan Hilsenbeck, Jenny Chang, Powel Brown
Journal: Cancer Research (2011)

Abstract Background: Molecularly targeted therapies such as tamoxifen, aromatase inhibitors, and trastuzumab are useful for the treatment of breast cancer. However, these targeted therapies do not treat all breast cancers, especially estrogen receptor alpha (ER)-negative, progesterone receptor (PR)-negative, HER2-negative (“triple-negative”) breast cancer. Our lab previously used gene expression profiling of human breast cancers to identify kinases overexpressed in ER-negative breast cancers. One of the kinases highly expressed in a poor prognosis group of triple negative breast cancers is maternal embryonic leucine-zipper kinase (MELK). The purpose of this study was to demonstrate that MELK expression is upregulated in ER-negative breast cancers, and to test the hypothesis that MELK is a critical regulator of ER-negative breast cancer cell growth. Methods: RNA from breast cancer cell lines and 60 human breast tumors was isolated for Q-PCR analysis of MELK. To determine if MELK regulates cell proliferation, ER-positive and ER-negative breast cancer cell lines were transfected with siRNA targeting MELK. Cells were replated 36 hours after transfection in 96-well plates at a density of 2,000/well. Cell number was measured by the MTS assay every day for 6 days. To determine if MELK levels are independently prognostic, we performed uni- and multivariate Cox regression analysis, including all available biological characteristics of the tumor in the model. Results: MELK mRNA levels were significantly higher (p&amp;lt;0.02) in ER-negative breast cancers (20.2 ± 7 fold) compared to ER-positive breast cancers (5.0 ± 2 fold). In 6 of 7 ER-negative cell lines, MELK knockdown suppressed growth (≥50% growth inhibition) compared to cells transfected with control siRNA. MELK knockdown had little to no effect on growth of the 3 ER-positive cell lines tested. Importantly, in a multivariate Cox proportional hazards model, high MELK expression was shown to be independently associated with a poor prognosis, [HR=1.19 95% CI: (1.05, 1.36) p=0.007]. Current studies are focused on understanding how MELK regulates ER-negative cell growth, using ER-negative cell lines stably expressing an inducible dominant negative MELK protein. Conclusions: MELK is highly expressed in ER-negative breast cancer, essential for ER-negative breast cancer cell growth, and is independently prognostic. These findings suggest that MELK is a promising target for the treatment of ER-negative breast cancer. Supported by a Susan G. Komen for the Cure Promise Grant. (KG081694). 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 1664. doi:10.1158/1538-7445.AM2011-1664
Urinary Bladder Leiomyosarcoma
Authors: William Makis, Rajan Rakheja, Ayoub Nahal, Marc Hickeson, Robert Lisbona
Journal: Clinical Nuclear Medicine (2013)

A 28-year-old woman with a history of prior bilateral retinoblastoma presented with general fatigue, anemia, and a urinary bladder mass seen on abdominal ultrasound and CT. She was referred for a staging 18F-FDG PET/CT, which showed an intensely FDG-avid bladder mass that was biopsied to reveal a leiomyosarcoma, with no evidence of metastases, which guided her management. 18F-FDG PET/CT is routinely used in the evaluation of leiomyosarcomas; however, its use in the staging of a leiomyosarcoma of the urinary bladder has not been previously described in the literature. This case highlights the usefulness of PET/CT in the staging of this rare tumor.
Chronic Neurologic Manifestations of Lyme Disease
Authors: Eric L. Logigian, Richard F. Kaplan, Allen C. Steere
Journal: New England Journal of Medicine (1990)

Lyme disease, caused by the tick-borne spirochete Borrelia burgdorferi, is associated with a wide variety of neurologic manifestations. To define further the chronic neurologic abnormalities of Lyme disease, we studied 27 patients (age range, 25 to 72 years) with previous signs of Lyme disease, current evidence of immunity to B. burgdorferi, and chronic neurologic symptoms with no other identifiable cause. Eight of the patients had been followed prospectively for 8 to 12 years after the onset of infection.
UTILIDAD DE LA BIOPSIA ENDOSCÓPICA EN EL SEGUIMIENTO DE LOS PACIENTES CON ESÓFAGO DE BARRETT
Authors: A Rodríguez D'Jesús, H Córdova, J Llach, JM Bordas, À Ginès, M Pellisé, O Sendino, A Cárdenas, M Aceituno, B González, G Fernández-Esparrach
Journal: Endoscopy (2010)

Introducción: La endoscopia con obtención de biopsias aleatorias es la técnica estándar para el diagnóstico y seguimiento de los pacientes con esófago de Barrett (EB).
FDA will not regulate most mobile medical apps
Authors: M. McCarthy
Journal: BMJ (2013)

The US Food and Drug Administration will leave most mobile medical applications unregulated while it focuses its oversight on apps that present the greatest risk of harming patients should they not work as intended, the agency said on Monday 23 September.

“Some mobile apps carry minimal risks to consumers or patients, but others can carry significant risks if they do not operate correctly,” said Jeffrey Shuren, director of the FDA’s Center for Devices and Radiological Health, in a …
Abstract 2768: Development of a tubulin fractionation assay for the evaluation of “on target” activity of tubulin targeting agents in clinical PBMC samples
Authors: Clayton A. Matthews, David Bibby, Annabell F. Leske, Andrew J. Harvey, Gabriel Kremmidiotis
Journal: Cancer Research (2010)

Abstract The novel agent, BNC105, is a tubulin polymerization inhibitor which acts as a vascular disruption agent (VDA). BNC105 exhibits 100-fold selectivity for activated endothelial cells compared to quiescent endothelial cells, providing a large differential between effects on cancer vasculature and normal vasculature. We developed a tubulin fractionation assay that enables evaluation of tubulin polymerisation changes in peripheral blood mononuclear cell samples (PBMCs) obtained from patients treated with BNC105. The assay capitalizes on the mass differences between polymerized and depolymerised tubulin to separate each fraction in a density gradient by ultracentrifugation. Experimental conditions during the extraction process were optimised to maintain the polymerisation state of tubulin. This optimisation was carried out in cell lines and PBMCs from healthy volunteers. Critical parameters include temperature, GTP concentration, DMSO concentration, pH, and buffer density. Tubulin monomer and polymer extracts were resolved using SDS-PAGE and transferred onto nitrocellulose membranes followed by detection using βI tubulin specific antibodies. The tubulin bands were analysed by densitometry and normalized to an actin loading control. Following exposure of cell lines or PBMCs to tubulin polymerisation inhibitors for a period of 60 minutes, the depolymerised tubulin fraction increased, while the polymerised tubulin fraction decreased. Conversely, exposure to tubulin polymerizing agents caused a greater proportion of tubulin to appear in the polymerized fraction. We used this method to evaluate the tubulin polymerisation status in PBMC samples obtained from cancer patients treated with BNC105. Samples were obtained prior to dosing and at 1, 2, 3-5, 7, and 24 hours post-dosing. Based on the data obtained, BNC105 treatment caused an 80% reduction in the polymerised tubulin fraction at the 1, 2 and 3-5 hour sampling time points. The amount of tubulin in the polymerised fraction returned to pre-dose levels by the 7 hour post-dose time point. The pharmacokinetic profile of BNC105 shows a steep curve reaching Cmax at around 20 minutes post-administration, followed by plasma clearance with no BNC105 detectable after the 7 hour time point. The pharmacokinetics of BNC105 supports our tubulin depolymerisation data with respect to response time and the subsequent recovery period. These results were reproducible, and have shown a similar pattern in all patients tested to date. 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 2768.
Studies on Primary Hyperoxaluria
Authors: Elizabeth W. Frederick, Mitchell T. Rabkin, Robert H. Richie, Lloyd H. Smith
Journal: New England Journal of Medicine (1963)

PRIMARY hyperoxaluria, a recently described genetic disorder of oxalate metabolism, is characterized clinically by recurrent calcium oxalate nephrolithiasis and nephrocalcinosis. The disease usually appears in early childhood, with progression of renal damage to death in uremia.1 2 3 Calcium oxalate deposits may be demonstrable in extrarenal tissues at post-mortem examination, a pathologic condition termed oxalosis. The occasional occurrence of primary hyperoxaluria in siblings has suggested its transmission as an autosomal recessive trait although no defect in persons assumed to be heterozygotes has been found. A clinically similar but milder disorder has been reported in a few adults.4 , 5 The true incidence of derangements . . .