tbuckley/cabot-search huggingface dataset:
PWE-171 Assessing The Utility Of Key Mri Parameters In Characterising The Mode Of Action Of A Proven Effective Laxative, Ispaghula
Authors: K Murray, L Marciani, G Major, C Hoad, E Cox, A Silos-Santiago, C Kurtz, M Kaviani, JA Paul, P Gowland, J Johnston, R Spiller
Journal: Gut (2014)

<h3>Introduction</h3> Half of the patients who suffer from chronic constipation are dissatisfied with their treatments, which has initiated a recent surge in novel treatments. Assessing the efficacy of these treatments requires techniques that are patient acceptable and non-invasive and allow characterisation of the underlying mode of action. This study assessed the utility of key parameters likely to give insight into laxatives’ mode of action including: colonic volumes, transit, ascending colon water content (ACWC) and small bowel water content (SBWC) by means of a randomised double-blind, placebo-controlled, crossover study (RCT) of a known effective laxative, ispaghula. <h3>Methods</h3> 16 healthy volunteers (24 ± 4 years old, BMI 23 ± 4 kg m<sup>-2</sup>) participated in this three-way RCT. They took either 21 g/day of ispaghula, 10.5 g/day of ispaghula or a placebo daily on days 1–6. On day 5 they swallowed 5 transit marker pills (TMP) filled with a dilute MR contrast agent and on day 6 were scanned serially for 7 h. The TMPs were assigned a weighted average position score (WAPS) based on their location in the bowel. Protocol compliance was assessed and 9 subjects were included in the per protocol analysis. <h3>Results</h3> (mean AUC±SEM, n = 9) Relative to the placebo, 21 g/day but not 10.5 g/day of ispaghula increased the ACWC (Figure 1) significantly (11 ± 4 L.min vs. 1.0 ± 0.5 L.min, p &lt; 0.001), while SBWC (Figure 2) was increased significantly by both doses (68 ± 15 L.min vs placebo 25 ± 6 L.min, p= &lt; 0.01), and (49 ± 11 L.min, p= &lt; 0.05) respectively. Both doses significantly increased the total colon volume, and there was a significant increase in colon volume at fasted baseline measurement. Ascending colon T1 was also increased by the 21 g/day dose (p &lt; 0.01), but 24 h WAPS for transit were not significantly changed by treatment. <h3>Conclusion</h3> The volume of water in both the ascending colon and the small bowel are significantly increased by ispaghula and could be useful biomarkers of a laxative effect. Ispaghula also increased colonic volumes and ascending colon T1 without altering transit times, suggesting it or its metabolites does not stimulate motility. These MRI methods could be readily used in assessing the mode of action of a range of novel agents in constipated patients will provide unique information on the mechanisms of action. <h3>Disclosure of Interest</h3> None Declared.
Abstract 3918: PEA3 is a novel transcriptional activator of Notch-1 and Notch-4 in breast cancer: Opportunity for a new combination strategy
Authors: Anthony G. Clementz, Paola Rizzo, Lucio Miele, Clodia Osipo
Journal: Cancer Research (2010)

Abstract Women diagnosed with triple-negative breast cancer have the worst overall prognosis and frequently present with metastatic tumors. To date, there are no targeted therapies available to combat this aggressive form of breast cancer due to the lack of expression of well-known targets such as ERα, PR, or HER2/neu. Therefore, there is an immediate need to identify novel targets that are responsible for the proliferation, survival, and invasive phenotype. Notch-1 and Notch-4, both potent breast oncogenes, are overexpressed in triple-negative breast cancers-associated with the poorest overall survival. PEA3 (polyomavirus enhancer activator 3), a member of the Ets family of transcription factors, is overexpressed in triple-negative breast cancer and also correlates with aggressive behavior and poor overall survival. Here, we provide new evidence for transcriptional regulation of Notch in triple negative breast cancer and other subtypes of breast cancer. With focus on triple-negative breast cancer cells (MDA-MB-231), our results show that PEA3 is a transcriptional activator of both Notch-1 and Notch-4 as determined by using a PEA3 siRNA and measuring both transcripts and proteins. Chromatin immunoprecipitation confirmed enrichment of PEA3 within the promoter regions of both Notch-1 and Notch-4. Notch-1 recruitment appears to be AP-1 independent, whereas PEA3 recruitment on the Notch-4 promoter is dependent upon c-JUN. Furthermore, results showed that either c-Jun or Fra-1 were required for Notch-4 transcription while c-FOS was a repressor. Importantly, the combined inhibition of Notch signaling (via a gamma-secretase inhibitor, GSI) and PEA3 (via siRNA) arrested the cells in G1, decreased cell viability, reduced tumorgenicity in vitro, and increased apoptosis. Taken together, our results indicate that PEA3 is a novel transcriptional activator of both Notch-1 and Notch-4. PEA3-mediated Notch-1 transcription is AP-1 independent while Notch-4 transcription requires both PEA3 and AP-1 most probably composed of the c-Jun: Fra-1 complex. Moreover, both PEA3 and Notch signaling are essential for proliferation and survival of MDA-MB-231 breast cancer cells. Thus, dual targeting of both PEA3 and Notch pathways might provide a new therapeutic strategy for triple-negative breast cancer as well as additional therapeutic targeting in other breast cancer subtypes. 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 3918.
Streptococcal Infections of Skin and Soft Tissues
Authors: Alan L. Bisno, Dennis L. Stevens
Journal: New England Journal of Medicine (1996)

Streptococcus pyogenes (group A in the Lancefield classification) is one of the most common human pathogens. Although this ubiquitous organism is responsible for a wide array of illnesses, most attention has focused on its relation to acute pharyngitis, because of the frequency of that condition and its potential for inciting acute rheumatic fever. The recent resurgence of invasive group A streptococcal infections,1,2 however, is a reminder that the pathogen can cause a variety of skin and soft-tissue infections, some of which are severe and even life-threatening.Streptococcal PyodermaPyoderma, or impetigo, is a localized, purulent infection of the . . .
Abstract 5078: Response-guided anti-angiogenic therapy for hepatocellular carcinoma recurrence with clinically available safety agent.
Authors: Hitoshi Yoshiji, Ryuichi Noguchi, Kosuke Kaji, Yosuke Aihara, Tadashi Namisaki, Kei Moriya, Akitoshi Douhara, Mitsuteru Kitade, Hiroshi Fukui
Journal: Cancer Research (2013)

Abstract The incidence of hepatocellular carcinoma (HCC) is increasing not only in Asia but also in Europe and United States. Since the high-risk group of either primary or secondary HCC development seems to be clearer than in the other types of tumors, it is likely that chemopreventive agents will be beneficial in improving the prognosis of HCC. No chemopreventive agent, however, has been approved against HCC yet. Since neovascularization plays a pivotal role in HCC, an angiostatic agent is considered as one of the promising approaches. Although an anti-angiogenic agent, sorafenib has approved for advanced heparocellular carcinoma (HCC), most of patients show adverse effects in liver cirrhosis. Insulin resistance (IR) is reportedly involved in the progression of HCC partly mediated with neovascularization. The aim of this study was to develop the response-guided anti-angiogenic therapy with a clinically used safe agent; branched-chain amino acid (BCAA), which reportedly possess anti-angiogenic and IR improving activities, for the cumulative recurrence of HCC after curative therapy. BCAA (Livact; 12 g/day) was administered after the curative therapy for HCC, and 60-month follow-up revealed that the BCAA markedly inhibited the cumulative recurrence of HCC under the condition of IR along with suppression of VEGF. Chronological studies reveled that the VEGF and AFP-L3 were significantly decreased in patients without recurrence at 6 and 12 months after the treatment, respectively. The soluble VEGFR (sVEGFR)-2 was significantly suppressed only in patients without recurrence, whereas sVEGFR-1 was not. A marked suppression of sVEGFR-2 could be achieved within only three months after the treatment. Collectively, since BCAA is widely and safely used in the clinical practice to treat the patients with chronic liver diseases, BCAA may represent a new strategy for secondary chemoprevention for the HCC patients with IR. Moreover, our findings suggest that sVEGFR-2 could become a useful response-guided predictive marker of anti-angiogenic therapy against HCC by BCAA under the condition of IR. Citation Format: Hitoshi Yoshiji, Ryuichi Noguchi, Kosuke Kaji, Yosuke Aihara, Tadashi Namisaki, Kei Moriya, Akitoshi Douhara, Mitsuteru Kitade, Hiroshi Fukui. Response-guided anti-angiogenic therapy for hepatocellular carcinoma recurrence with clinically available safety agent. [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 5078. doi:10.1158/1538-7445.AM2013-5078
AB1032 The Frequency of Risk Factors of Complications Associated with Nsaids: Cross-Sectional Study
Authors: A. Karateev, T. Popkova
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> NSAIDs are effective for control of the main symptoms of rheumatic diseases (RD) and they are widely used in clinical practice. However, NSAIDs can cause serious gastrointestinal (GI) and cardiovascular (CV) complications. Prevention of these complications based on an evaluation of risk factors. <h3>Objectives</h3> To evaluate the presence of risk factors in patients requiring NSAID. <h3>Methods</h3> We conducted a cross-sectional population study. In this study, 2021 physicians from 9 countries of former USSR within 2 weeks interviewed at least 10 patients who need treatment by NSAID. Inclusion criterions were the presence of severe musculoskeletal pain (&gt;40 mm VAS) or the use of NSAIDs at the time of investigation. Data were obtained from 21 185 patients, 57.5% of women and 42.5% men, age 50.5±14.1 years, mostly with back pain (56.6%) and osteoarthritis (23.5%). The average intensity of pain (VAS) was 62.2±25.2 mm. <h3>Results</h3> History of GI bleeding was found in 1.7%, history of peptic ulcer in 11.3%, 25.3% had dyspepsia, age over 65 years in 16.8%, the use of low-dose aspirin in 20.0%. The total number of patients at high risk of GI complications was 29.0%. The following proportion of patients met CV risk factors: myocardial infarction or stroke in 7.4%, IHD in 17.6%, hypertension in 36.5%, and diabetes in 7.8%. The total number of patients with high CV risk (without SCORE evaluation) was 23.0%. Many patients at high risk who have used NSAIDs did not receive effective prevention. Among patients with history of peptic ulcer only 70.3% used gastroprotective medications and among patients with history of CV events only 66.2% used low-dose aspirin. <h3>Conclusions</h3> These data suggest that significant proportion of patients with RD who needs active analgesic therapy has serious risk of CV and GI complications. This limits the use of NSAIDs and determines the need for effective prevention or alternative methods of analgesia. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.3785
Abstract A28: The link between the metabolic effects of nuclear receptor (NR) modulators and anticarcinogenic properties on leukemia cancer cells can be revealed through studying the Warburg effect
Authors: Ramy R. Attia, Jaeki Min, R. Kiplin Guy
Journal: Cancer Research (2011)

Abstract The Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by aerobic oxidation of pyruvate in mitochondria. Genetic studies in humans and rodents support the notion that metabolic enzymes controlling glucose metabolism can directly contribute to carcinogenesis. Current knowledge of nuclear receptor (NR) signaling networks indicates that NRs control a wide variety of metabolic processes by regulating the expression of genes encoding key enzymes, transporters, and other proteins involved in metabolic homeostasis. Thus, a better understanding of the mechanistic links between cellular metabolism control by NRs and cancer cells' growth control may ultimately lead to better treatments for human cancer. We created a library of 134 NR modulators including compounds targeting the estrogen receptor (ER), androgen receptor (AR), farnesoid X receptor (FXR), peroxisome proliferator-activated receptor (PPAR), retinoic acid receptor (RAR), retinoid X receptor (RXR), glucocorticoid receptor (GR), mineralocorticoid receptor (MR), liver X receptor (LXR), thyroid receptor (TR), and pregnane X receptor (PXR). We used high-throughput assays to measure cell viability, apoptosis, and cell proliferation of leukemic cell lines after treatment with this library. Afterwards, compounds which highly induced apoptosis and inhibited cell proliferation were picked for further investigation of their mechanism of action. We linked the effect of those compounds on apoptosis to their effect on lactate levels. In addition, we tested the effect of these compounds on the activity of pyruvate dehydrogenase complex (PDC) which catalyzes the irreversible oxidative decarboxylation of pyruvate into acetyl-CoA an important step in commitment of glucose into full oxidation rather than glycolysis, PDH dipstick assay was used for this purpose. Of the 134 nuclear receptors modulators that we have tested, nine compounds induced significant apoptosis in Jurkat cells. These compounds mainly targeted ER and RAR. On the other hand, only six compounds from this list significantly reduced the lactate levels in Jurkat cells. Finally, the compounds modulating the RAR pathway were the only compounds that showed significant effects on PDC activity. This work may open a door to further explore the RAR modulators as strong potential anticarcinogenic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A28.
FRACTIONAL FLOW RESERVE IN PATIENTS WITH ANGINA IN THE ABSENCE OF OBSTRUCTIVE CORONARY ARTERY DISEASE: IS THERE SUCH A THING AS NORMAL CORONARY ARTERIES?
Authors: Takumi Kimura, William Fearon, Yuhei Kobayashi, Kozo Okada, Kojiro Miki, Vedant Pargaonkar, Paul Yock, Peter Fitzgerald, Yasuhiro Honda, Alan Yeung, Jennifer Tremmel
Journal: Journal of the American College of Cardiology (2016)
Catecholamine metabolism during heroin use
Authors: J J Schildkraut, R E Meyer, P J Orsulak, S M Mirin, M Roffman, P A Platz, E Grab, M E Randall, M McDougle
Journal: American Journal of Psychiatry (1977)

The authors examined urinary levels of catecholamines and metabolites during a 10-day period of heroin use in 9 subjects. Catecholamine and metabolite excretion increased over baseline values on the first day of heroin use, but markedly different patterns of change emerged later. In contrast to the significant increase in normetanephrine and decrease in metanephrine excretion in all 9 subjects during heroin use, only 4 subjects showed an increase in 3-methoxy-4-hydroxyphenyl glycol (MHPG) excretion. Moreover, it appeared that the increase in MHPG excretion in this subgroup began on the day before heroin administration, which suggests the possibility of an anticipatory or conditioned response.
S78 Do Tuberculosis Cases Managed By Clinicians With Average Annual Caseloads Below 10 Have Poorer Treatment Outcomes?
Authors: H. Stagg, H. Thomas, D. Pedrazzoli, L. Anderson, I. Abubakar, C. Merle
Journal: Thorax (2014)

<h3>Introduction and objectives</h3> The 2007 Department of Health Tuberculosis Toolkit advises that clinicians should not be solely managing tuberculosis (TB) cases if their average caseload is less than 10 per year. A systematic evaluation of whether these guidelines are being followed, and how effective such a threshold is, has not been undertaken in the UK. <h3>Methods</h3> All UK TB cases notified 2003–2011 were extracted from Public Health England’s Enhanced Tuberculosis Surveillance system. Mean caseload for each clinician was calculated over the preceding year and three years by using case notification date. 12 month TB treatment outcomes were categorised as unfavourable or good/neutral.<sup>1,2</sup> Cases without clinician information and resistant to rifampicin were excluded, the latter due to UK recommendations on the length of treatment. The proportion of cases managed by clinicians with a caseload under 10 was analysed, then random effects logistic regression utilised to determine the relationship between caseload and treatment outcomes, adjusting for clustering by clinician and confounding. <h3>Results</h3> 74,550 TB cases were notified 2003–11. The proportion of TB cases seen by a clinician who had a low caseload (less than 10) in the preceding year declined gradually 2004–11 (42 to 28%), with no apparent acceleration post-Toolkit. Univariate modelling demonstrated very strong evidence of increased odds of an unfavourable treatment outcome among cases seen by a clinician who had a low caseload over the preceding three years (cluster-specific odds ratio 1.23 (95% confidence interval 1.14–1.33), p-value &lt;0.001); this relationship was upheld in a model adjusted for demographic, temporal and clinical confounders (1.14 (1.05–1.23), &lt;0.001; 44,184 cases), and additionally when a sensitivity analysis was performed looking at second assigned clinician, if present. <h3>Conclusions</h3> Our analysis indicates that TB cases managed by clinicians with a mean caseload of under 10 over the preceding three years have increased odds of an unfavourable treatment outcome. However other factors, such as the number of clinicians managing TB cases in the hospital overall, should potentially be taken into account for policy recommendations. <h3>References</h3> Ditah, <i>Thorax</i> 2008;63:440–446 Anderson, <i>Euro Surveill</i>. 2013;18(40):pii=20601
Abstract 5383: Overexpression of the vitamin D catabolizing enzyme CYP24A1 is caused by gene amplification and results in highly proliferative colorectal tumors.
Authors: Julia Höbaus, Abhishek Aggarwal, Doris M. Hummel, Ursula Thiem, Irfete Fetahu, Ildiko Mesteri, Enikö Kallay
Journal: Cancer Research (2013)

Abstract Vitamin D insufficiency increases risk of colorectal cancer. Vitamin D is produced photochemically in the skin, thus, low sunlight exposure results in vitamin D insufficiency. Vitamin D is further processed in the liver to its storage form calcidiol (25-OH vitamin D3). Calcidiol can be activated by 1α-hydroxylation to the secosteroid hormone calcitriol (1α,25-OH vitamin D3). Although systemic levels of bioactive calcitriol are regulated by the kidneys, almost every tissue can synthesize and degrade calcitriol. Tissue calcitriol acts in an autocrine/paracrine manner and controls proliferation, apoptosis, and differentiation. In colorectal cancer, the calcidiol and calcitriol-degrading enzyme CYP24A1 is substantially overexpressed both on mRNA and protein level. High CYP24A1 levels markedly reduce the half-life of vitamin D metabolites, likely reducing the anti-tumorigenic effects of calcitriol in the tumor. The causes and consequences of this overexpression are not fully understood. Here, we investigated gene amplification of the CYP24A1 locus (20q13.2) as a possible cause of CYP24A1 overexpression and increased proliferation as a consequence thereof. Quantitative real time PCR assays showed that approximately 60% of colorectal tumors carry CYP24A1 gene amplification (n=127). This gene amplification correlated with increased mRNA expression (ρ=0.38, p&amp;lt;0.001). Aberrantly high CYP24A1 expression may reduce the anti-proliferative actions of calcitriol and lead to increased proliferation. In our colorectal cancer cohort, CYP24A1 mRNA expression correlated with expression of several proliferation markers (e.g. CDC6 ρ=0.60, p&amp;lt;0.001). In conclusion, our data suggest that CYP24A1 gene amplification results in increased mRNA expression in colorectal tumors. Further, high CYP24A1 expression correlates with increased proliferation, possibly caused by an inhibition of the anti-proliferative effects of calcitriol. Tumor specific inhibition of CYP24A1 may provide a future strategy to restore local vitamin D levels and its anti-tumorigenic activities. Citation Format: Julia Höbaus, Abhishek Aggarwal, Doris M. Hummel, Ursula Thiem, Irfete Fetahu, Ildiko Mesteri, Enikö Kallay. Overexpression of the vitamin D catabolizing enzyme CYP24A1 is caused by gene amplification and results in highly proliferative colorectal tumors. [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 5383. doi:10.1158/1538-7445.AM2013-5383
Epilogue: The Peril and the Promise of Comparative Effectiveness Research in Oncology
Authors: Gary H. Lyman, Mark Levine
Journal: Journal of Clinical Oncology (2012)

Article Tools REVIEW ARTICLES Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2012.45.9800 Journal of Clinical Oncology - published online before print October 15, 2012 PMID: 23071238 Epilogue: The Peril and the Promise of Comparative Effectiveness Research in Oncology Gary H. LymanxGary H. LymanSearch for articles by this author , Mark LevinexMark LevineSearch for articles by this author Show More Gary H. Lyman, Duke University and the Duke Cancer Institute, Durham, NC; and Mark Levine, McMaster University, Hamilton, Ontario, Canada. https://doi.org/10.1200/JCO.2012.45.9800 Full Text PDF Figures and Tables "Epilogue: The Peril and the Promise of Comparative Effectiveness Research in Oncology." Journal of Clinical Oncology, 30(34), p. 4282© 2012 by American Society of Clinical Oncology
Quantifying Leukocyte and Thrombocyte Suppression–Recovery After Re-186 HEDP for Bone Metastases
Authors: RICHARD P. SPENCER
Journal: Clinical Nuclear Medicine (2000)

Using a standard quantity of Re-186 HEDP, for therapy of osseous metastases from carcinoma of the breast, Palmedo and associates reported leukocyte and thrombocyte responses at 4 and 8 weeks. These were analyzed by dividing results into categories, based on the numeric initial values. Thrombocytes at 8 weeks exceeded pretreatment values in 10 of 18 cases. This "over-rebound" was also found in 7 of 19 leukocyte responses. The ability to predict thrombocyte-leukocyte response, in most cases, was linked to the initial hematologic values. If coupled with data on the status of bone marrow, this may allow the quantity of therapeutic radiopharmaceutical used to be increased or decreased without irreversibly compromising hematopoietic responses.