tbuckley/cabot-search huggingface dataset:
The Metabolism of Pyrazoloacridine (NSC 366140) by Cytochromes P450 and Flavin Monooxygenase in Human Liver Microsomes
Authors: Joel M. Reid, Denise L. Walker, Jennifer K. Miller, Linda M. Benson, Andrew J. Tomlinson, Stephen Naylor, April L. Blajeski, Patricia M. LoRusso, Matthew M. Ames
Journal: Clinical Cancer Research (2004)

Pyrazoloacridine (PZA) is an experimental antitumor agent presently under investigation for treatment of solid tumors on the basis of its unique mechanism of action and selectivity for human solid tumor xenograft in mice. Using capillary electrophoresis coupled with electrospray ionization mass spectrometry, we have identified three oxidative PZA metabolites, 9-desmethyl-PZA, N-demethyl-PZA, and PZA N-oxide. The cytochrome p450 (CYP) isoforms involved in PZA metabolism were characterized by studies with CYP chemical inhibitors, correlation of marker activities for selected CYPs with formation of the metabolites using a human liver panel, and PZA metabolism by cDNA-expressed CYPs. 9-Desmethyl-PZA formation was catalyzed by CYP1A2, whereas N-demethyl-PZA formation was catalyzed by CYP3A4. PZA N-oxide formation was catalyzed by flavin monooxygenase (FMO) rather than CYP, as determined by studies with chemical inhibitors of FMO and metabolism by cDNA-expressed human flavin monooxygenase. After administration of [10b-(14)C]PZA to mice, six urinary metabolites were detected by high-performance liquid chromatography UV and radiochromatograms including 9-desmethyl-PZA, N-demethyl-PZA, and PZA N-oxide. Trace concentrations of 9-desmethyl-PZA and PZA N-oxide were detected in mouse plasma. PZA N-oxide and N-demethyl-PZA were detected in urine from patients after PZA administration. PZA, 9-desmethyl-PZA, and PZA N-oxide inhibited growth of A375 human melanoma cells. IC(50) values were 0.17, 0.11, and 7.0 micro M, respectively, for the three molecules.
A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer
Authors: H. Oettle, D. Richards, R.K. Ramanathan, J.L. van Laethem, M. Peeters, M. Fuchs, A. Zimmermann, W. John, D. Von Hoff, M. Arning, H.L. Kindler
Journal: Annals of Oncology (2005)
Management of patients with delusional parasitosis in a joint dermatology/ liaison psychiatry clinic
Authors: R. Healy, R. Taylor, S. Dhoat, E. Leschynska, A.P. Bewley
Journal: British Journal of Dermatology (2009)

Journal Article Management of patients with delusional parasitosis in a joint dermatology/ liaison psychiatry clinic Get access R. Healy, R. Healy Departments of Dermatology and Liaison Psychiatry, Bart's and the London NHS Trust, Whitechapel, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar R. Taylor, R. Taylor Departments of Dermatology and Liaison Psychiatry, Bart's and the London NHS Trust, Whitechapel, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar S. Dhoat, S. Dhoat Departments of Dermatology and Liaison Psychiatry, Bart's and the London NHS Trust, Whitechapel, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar E. Leschynska, E. Leschynska Departments of Dermatology and Liaison Psychiatry, Bart's and the London NHS Trust, Whitechapel, London, U.K. Search for other works by this author on: Oxford Academic Google Scholar A.P. Bewley A.P. Bewley Departments of Dermatology and Liaison Psychiatry, Bart's and the London NHS Trust, Whitechapel, London, U.K. Correspondence: Anthony Bewley. E‐mail: anthony.bewley@bartsandthelondon.nhs.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 161, Issue 1, 1 July 2009, Pages 197–199, https://doi.org/10.1111/j.1365-2133.2009.09183.x Published: 01 July 2009
Reflux related hospital admissions after fundoplication in children with neurological impairment: retrospective cohort study
Authors: R. Srivastava, J. G Berry, M. Hall, E. C Downey, M. O'Gorman, J M. Dean, D. C Barnhart
Journal: BMJ (2009)

<b>Objective</b> To examine the impact of fundoplication on reflux related hospital admissions for children with neurological impairment. <b>Design</b> Retrospective, observational cohort study. <b>Setting </b>42 children’s hospitals in the United States. <b>Participants</b> 3721 children with neurological impairment born between 2000 and 2005 who had at least one hospital admission at a study hospital before their fundoplication. <b>Intervention</b> Fundoplication. <b>Main outcome measures</b> Incident rate ratio for reflux related hospital admissions, defined as the post-fundoplication admission rate divided by the pre-fundoplication admission rate. <b>Results</b> Of the 955 285 children born during the study period, 144 749 (15%) had neurological impairment. Of these, 27 720 (19%) were diagnosed as having gastro-oesophageal reflux disease, of whom 6716 (24%) had a fundoplication. Of these, 3721 (55%) had at least one previous hospital admission and were included in the study cohort. After fundoplication, hospital admissions decreased for any reflux related cause (incident rate ratio 0.69, 95% confidence interval 0.67 to 0.72; P&lt;0.01), aspiration pneumonia (0.71, 0.62 to 0.81; P&lt;0.01), gastro-oesophageal reflux disease (0.60, 0.57 to 0.63; P&lt;0.01), and mechanical ventilation (0.40, 0.37 to 0.43; P&lt;0.01), after adjustment for other patient and hospital related factors that may influence reflux related hospital admissions. Hospital admissions increased for asthma (incident rate ratio 1.52, 1.38 to 1.67; P&lt;0.01) and remained constant for pneumonia (1.07, 0.98 to 1.17; P=0.16). <b>Conclusions </b>Children with neurological impairment who have fundoplication had reduced short term reflux related hospital admissions for aspiration pneumonia, gastro-oesophageal reflux disease, and mechanical ventilation. However, admissions for pneumonia remained constant and those for asthma increased after fundoplication. Comparative effectiveness data for other treatments (such as gastrojejunal feeding tubes) are unknown.
The Right Brain Hypothesis for Obesity
Authors: Miguel Alonso-Alonso, Alvaro Pascual-Leone
Journal: JAMA (2007)

THE PREVALENCE OF OBESITY CONTINUES TO INcrease exponentially worldwide. In the United States, where the majority of the adult population is at least overweight, this condition accounts for an economic burden in billions of dollars per year. Despite increased awareness and determined efforts, the epidemic remains uncontrolled and constitutes a global public health problem. Moreover, the current state of knowledge may not include critical aspects of the etiology of obesity.
Inhibition of Transforming Growth Factor-β1 Signaling Attenuates Ataxia Telangiectasia Mutated Activity in Response to Genotoxic Stress
Authors: Julia Kirshner, Michael F. Jobling, Maria Jose Pajares, Shraddha A. Ravani, Adam B. Glick, Martin J. Lavin, Sergei Koslov, Yosef Shiloh, Mary Helen Barcellos-Hoff
Journal: Cancer Research (2006)

Abstract Ionizing radiation causes DNA damage that elicits a cellular program of damage control coordinated by the kinase activity of ataxia telangiectasia mutated protein (ATM). Transforming growth factor β (TGFβ)-1, which is activated by radiation, is a potent and pleiotropic mediator of physiologic and pathologic processes. Here we show that TGFβ inhibition impedes the canonical cellular DNA damage stress response. Irradiated Tgfβ1 null murine epithelial cells or human epithelial cells treated with a small-molecule inhibitor of TGFβ type I receptor kinase exhibit decreased phosphorylation of Chk2, Rad17, and p53; reduced γH2AX radiation-induced foci; and increased radiosensitivity compared with TGFβ competent cells. We determined that loss of TGFβ signaling in epithelial cells truncated ATM autophosphorylation and significantly reduced its kinase activity, without affecting protein abundance. Addition of TGFβ restored functional ATM and downstream DNA damage responses. These data reveal a heretofore undetected critical link between the microenvironment and ATM, which directs epithelial cell stress responses, cell fate, and tissue integrity. Thus, Tgfβ1, in addition to its role in homoeostatic growth control, plays a complex role in regulating responses to genotoxic stress, the failure of which would contribute to the development of cancer; conversely, inhibiting TGFβ may be used to advantage in cancer therapy. (Cancer Res 2006; 66(22): 10861-9)
Antihypertensive effect of the GABA receptor agonist muscimol in spontaneously hypertensive rats. Role of the sympathoadrenal axis.
Authors: T Unger, H Becker, R Dietz, D Ganten, R E Lang, R Rettig, A Schömig, N A Schwab
Journal: Circulation Research (1984)

The antihypertensive action of central GABA-ergic stimulation was investigated in conscious stroke prone spontaneously hypertensive rats. Injection of the potent GABA agonist muscimol (0.01-1 microgram) into the lateral brain ventricle (icv) lowered mean arterial blood pressure (192.1 +/- 8.4 mm Hg) dose-dependently in stroke prone spontaneously hypertensive rats with a maximal fall of -52.7 +/- 5 mm Hg lasting for about 90 minutes. This was accompanied by bradycardia and sedation. Pretreatment with atropine (2 mg/kg, ip, or 15 micrograms/kg, icv) did not significantly influence the muscimol-induced fall in mean arterial pressure. In normotensive (109.3 +/- 1.9 mm Hg) Wistar-Kyoto controls, the maximal decrease in mean arterial pressure was -12.1 +/- 1.6 mm Hg from 109.3 +/- 1.9 mm Hg, and the duration of the effect was much less than in stroke prone spontaneously hypertensive rats, Following 1 microgram muscimol, icv, plasma noradrenaline did not fall significantly in stroke prone spontaneously hypertensive and Wistar-Kyoto rats, but in stroke prone spontaneously hypertensive rats, plasma adrenaline was fully suppressed (from 118.1 +/- 24.2 to 22.8 +/- 5.7 pg/ml) throughout the depressor response. The efferent sympathetic nervous activity as directly recorded from the n. splanchnicus was similar in conscious stroke prone spontaneously hypertensive and Wistar-Kyoto rats, and was moderately reduced in both strains by 1 microgram muscimol, icv.(ABSTRACT TRUNCATED AT 250 WORDS)
SIRT1 Is Essential for Oncogenic Signaling by Estrogen/Estrogen Receptor α in Breast Cancer
Authors: Selvakumar Elangovan, Sabarish Ramachandran, Narayanan Venkatesan, Sudha Ananth, Jaya P. Gnana-Prakasam, Pamela M. Martin, Darren D. Browning, Patricia V. Schoenlein, Puttur D. Prasad, Vadivel Ganapathy, Muthusamy Thangaraju
Journal: Cancer Research (2011)

The NAD-dependent histone deacetylase silent information regulator 1 (SIRT1) is overexpressed and catalytically activated in a number of human cancers, but recent studies have actually suggested that it may function as a tumor suppressor and metastasis inhibitor in vivo. In breast cancer, SIRT1 stabilization has been suggested to contribute to the oncogenic potential of the estrogen receptor α (ERα), but SIRT1 activity has also been associated with ERα deacetylation and inactivation. In this study, we show that SIRT1 is critical for estrogen to promote breast cancer. ERα physically interacted and functionally cooperated with SIRT1 in breast cancer cells. ERα also bound to the promoter for SIRT1 and increased its transcription. SIRT1 expression induced by ERα was sufficient to activate antioxidant and prosurvival genes in breast cancer cells, such as catalase and glutathione peroxidase, and to inactivate tumor suppressor genes such as cyclin G2 (CCNG2) and p53. Moreover, SIRT1 inactivation eliminated estrogen/ERα-induced cell growth and tumor development, triggering apoptosis. Taken together, these results indicated that SIRT1 is required for estrogen-induced breast cancer growth. Our findings imply that the combination of SIRT1 inhibitors and antiestrogen compounds may offer more effective treatment strategies for breast cancer.
Association of Episodic Physical and Sexual Activity With Triggering of Acute Cardiac Events
Authors: Issa J. Dahabreh
Journal: JAMA (2011)

Evidence has suggested that physical and sexual activity might be triggers of acute cardiac events.To assess the effect of episodic physical and sexual activity on acute cardiac events using data from case-crossover studies.MEDLINE and EMBASE (through February 2, 2011) and Web of Science (through October 6, 2010).Case-crossover studies investigating the association between episodic physical or sexual activity and myocardial infarction (MI) or sudden cardiac death (SCD).Two reviewers extracted descriptive and quantitative information from each study. We calculated summary relative risks (RRs) using random-effects meta-analysis and absolute event rates based on US data for the incidence of MI and SCD. We used the Fisher P value synthesis method to test whether habitual physical activity levels modify the triggering effect and meta-regression to quantify the interaction between habitual levels of physical activity and the triggering effect.We identified 10 studies investigating episodic physical activity, 3 studies investigating sexual activity, and 1 study investigating both exposures. The outcomes of interest were MI (10 studies), acute coronary syndrome (1 study), and SCD (3 studies). Episodic physical and sexual activity were associated with an increase in the risk of MI (RR = 3.45; 95% confidence interval [CI], 2.33-5.13, and RR = 2.70; 95% CI, 1.48-4.91, respectively). Episodic physical activity was associated with SCD (RR = 4.98; 95% CI, 1.47-16.91). The effect of triggers on the absolute rate of events was limited because exposure to physical and sexual activity is infrequent and their effect is transient; the absolute risk increase associated with 1 hour of additional physical or sexual activity per week was estimated as 2 to 3 per 10,000 person-years for MI and 1 per 10,000 person-years for SCD. Habitual activity levels significantly affected the association of episodic physical activity and MI (P < .001), episodic physical activity and SCD (P < .001), and sexual activity and MI (P = .04); in all cases, individuals with lower habitual activity levels had an increased RR for the triggering effect. For every additional time per week an individual was habitually exposed to physical activity, the RR for MI decreased by approximately 45%, and the RR for SCD decreased by 30%.Acute cardiac events were significantly associated with episodic physical and sexual activity; this association was attenuated among persons with high levels of habitual physical activity.
Renal and segmental pancreatic grafting with draining of exocrine secretion and initial continuous intravenous cyclosporin A in a patient with insulin-dependent diabetes and renal failure
Authors: R Y Calne, D J G White, K Rolles, T J Duffy, T Kass
Journal: BMJ (1982)

A patient with renal failure and insulin-dependent diabetes received renal and segmental pancreatic allografts from the same donor, with exocrine drainage of the pancreas being directed into the bowel. An attempt was made to maintain the serum concentrations of cyclosporin A between 300 and 1000 μg/l to avoid serious nephrotoxicity and rejection. Considerable difficulty was experienced in controlling the serum concentrations even with continuous intravenous infusion. When the concentrations were maintained between 300 and 1000 μg/l function in both allografts was satisfactory. At seven months the patient required no insulin and had good renal function. He was not receiving corticosteroids.
Prospective study of α-fetoprotein in cirrhotic patients monitored for development of hepatocellular carcinoma
Authors: Hiroko Oka, Akihiro Tamori, Tetsuo Kuroki, Kenzo Kobayashi, Sukeo Yamamoto
Journal: Hepatology (1994)

The usefulness of measurements of serum α-fetoprotein elevation for diagnosis of the development of hepatocellular carcinoma was evaluated by a prospective study of 260 patients with cirrhosis. Hepatocellular carcinoma was found in 55 patients during the 5-yr follow-up, excluding 7 found to have hepatocellular carcinoma in the first 6 mo. The cumulative incidence of hepatocellular carcinoma was 26 in the 185 patients who had α-fetoprotein levels below 20 ng/ml at the time of entry and 46 in the 68 patients who had α-fetoprotein levels of 20 ng/ml or more but below 200 ng/ml. In 169 of the patients, serum levels of α-fetoprotein were assayed regularly for at least 2 yr. The incidence of hepatocellular carcinoma development in the 36 patients who had repeated transient increases in α-fetoprotein to above 100 ng/ml was 36. This was significantly higher than the incidence in the 99 patients who had α-fetoprotein levels consistently below 20 ng/ml. Thus patients who had α-fetoprotein levels of 20 ng/ml or more, who had transient increases in α-fetoprotein or who had both should be treated as being in a super-high-risk group for hepatocellular carcinoma. Frequent and careful examination by ultrasonography of such patients is recommended. (Hepatology 1994;19:61-66).
Professional Uncertainty and Disempowerment Responding to Ethnic Diversity in Health Care: A Qualitative Study
Authors: Joe Kai, Jackie Beavan, Christina Faull, Lynne Dodson, Paramjit Gill, Angela Beighton
Journal: PLoS Medicine (2007)

While ethnic disparities in health and health care are increasing, evidence on how to enhance quality of care and reduce inequalities remains limited. Despite growth in the scope and application of guidelines on "cultural competence," remarkably little is known about how practising health professionals experience and perceive their work with patients from diverse ethnic communities. Using cancer care as a clinical context, we aimed to explore this with a range of health professionals to inform interventions to enhance quality of care.We conducted a qualitative study involving 18 focus groups with a purposeful sample of 106 health professionals of differing disciplines, in primary and secondary care settings, working with patient populations of varying ethnic diversity in the Midlands of the UK. Data were analysed by constant comparison and we undertook processes for validation of analysis. We found that, as they sought to offer appropriate care, health professionals wrestled with considerable uncertainty and apprehension in responding to the needs of patients of ethnicities different from their own. They emphasised their perceived ignorance about cultural difference and were anxious about being culturally inappropriate, causing affront, or appearing discriminatory or racist. Professionals' ability to think and act flexibly or creatively faltered. Although trying to do their best, professionals' uncertainty was disempowering, creating a disabling hesitancy and inertia in their practice. Most professionals sought and applied a knowledge-based cultural expertise approach to patients, though some identified the risk of engendering stereotypical expectations of patients. Professionals' uncertainty and disempowerment had the potential to perpetuate each other, to the detriment of patient care.This study suggests potential mechanisms by which health professionals may inadvertently contribute to ethnic disparities in health care. It identifies critical opportunities to empower health professionals to respond more effectively. Interventions should help professionals acknowledge their uncertainty and its potential to create inertia in their practice. A shift away from a cultural expertise model toward a greater focus on each patient as an individual may help.
Beyond 30-Day Mortality
Authors: Margaret L. Schwarze, Karen J. Brasel, Anne C. Mosenthal
Journal: JAMA Surgery (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
Functional Proteomic Screen Identifies a Modulating Role for CD44 in Death Receptor–Mediated Apoptosis
Authors: Robert S. Hauptschein, Kevin E. Sloan, Claudia Torella, Roya Moezzifard, Maryann Giel-Moloney, Carol Zehetmeier, Christine Unger, Leodevico L. Ilag, Daniel G. Jay
Journal: Cancer Research (2005)

Abstract Apoptotic evasion is a hallmark of cancer and its resistance to chemotherapeutic drugs. Identification of cellular proteins that mediate apoptotic programs is a critical step toward the development of therapeutics aimed at overcoming apoptosis resistance. We developed an innovative high-throughput screen to identify proteins that modulate Fas ligand–mediated apoptosis using fluorophore-assisted light inactivation (HTS-FALIpop). The FALI protein knockdown strategy was coupled to a caspase activity assay with the ability to detect both proapoptotic and antiapoptotic surface molecules expressed by HT-1080 human fibrosarcoma cells. FALI of the Fas receptor (Fas/CD95) using a fluorescein-conjugated anti-Fas antibody abrogated Fas ligand–mediated caspase activation. Ninety-six single-chain variable fragment antibodies (scFv), selected for binding to the surface of HT-1080 cells, were screened by HTS-FALIpop. Three of the scFvs caused decreases in caspase induction after FALI of their protein targets. One of the targets of these positive scFvs was identified as CD44 and was validated by performing FALI using a CD44-specific monoclonal antibody, which resulted in similar protection from Fas apoptosis. CD44-targeted FALI was antiapoptotic in multiple human cancer cell lines, including both Fas signaling type I and II cells, and was also protective against other ligands of the tumor necrosis factor death receptor family. FALI of CD44 inhibited formation and activation of the death-inducing signaling complex, suggesting that CD44 regulates Fas at the cell surface. This mechanism of death receptor regulation represents a novel means of apoptosis modulation that could be exploited by pharmacologic agents.