tbuckley/cabot-search huggingface dataset:
Activating transcription factor 3 (ATF3) stabilizes p53 in genotoxic response
Authors: Chunhong Yan, Tsonwin Hai, Douglas Boyd
Journal: Cancer Research (2005)

3658   Transcription initiation in eukaryotes is a tightly regulated, multi-step process. One important aspect is the interaction of various transcription factors with histone acetyltransferase (HAT) complexes. For example, the HATs p300, CBP and PCAF function as coactivators of the tumor suppressor protein p53, and transcriptional activity of p53 correlates with p53 acetylation by HATs. But p300 and CBP also play roles in promoting beta-catenin-dependent transcription that results in cellular proliferation. Thus, transcription factors with very different roles in the cell require the activity of HAT complexes. The precise mechanisms that define access of transcription factors to HAT complexes have not been defined. As components of HAT complexes, the ADA2 and ADA3 proteins (Alteration/Deficiency in Activation) are likely to play important roles in this process, since yeast and mammalian ADA2 and ADA3 proteins have been shown to function as adaptor or docking proteins for transcription factors. For example, our laboratory’s previous work showed that hADA3 physically interacts with p53 in human cells and is required for full transcriptional activity of p53. We have now established that hADA2 also interacts with p53 through coimmunoprecipitation of over-expressed hADA2 and p53. We demonstrated that coexpressed hADA2 and hADA3 coimmunoprecipitate significantly more p53 than either one alone, indicating that hADA2 and hADA3 may stabilize each other, as well as their interaction with p53. Furthermore, we showed that hADA2 and hADA3 interact with proliferation-inducing beta-catenin by coimmunoprecipitation of over-expressed hADA2, hADA3 and beta-catenin. These results suggest that p53 and beta-catenin (together with the DNA binding proteins LEF or TCF) may have to compete for hADA2 and hADA3 in order to transactivate their target genes. Preliminary results indicate that p53 and beta-catenin indeed interfere with each other in coimmunoprecipitation experiments with hADA2 and hADA3. Additional experiments are currently confirming this finding and are exploring the functional consequences of this competition. The discovery that p53, beta-catenin and, likely, other transcription factors may have to compete for access to HAT complexes by interacting with both hADA2 & hADA3 is intriguing because it provides a novel mechanism by which cell proliferation, differentiation or apoptosis may be regulated. p53 activation through cellular stress may not only lead to activation of p53 target genes, but may simultaneously reduce beta-catenin activity by reducing beta-catenin access to HAT complexes. Likewise, abnormally increased beta-catenin activity in human cancers may blunt the p53 pathway by limiting access of wild-type p53 to HAT complexes.
Correlation of a tivozanib response biomarker identified in a preclinical model with clinical activity in a phase II study in renal cell carcinoma (RCC).
Authors: M. O. Robinson, J. Lin, B. Feng, X. Sun, W. Rideout, M. I. Chiu, B. Esteves, M. Al-Adhami, W. Slichenmyer, P. Bhargava
Journal: Journal of Clinical Oncology (2010)

e13564 Background: A population-based, genetically engineered breast tumor model comprising 107 tumors was developed, characterized, and used to test the efficacy of tivozanib, a VEGFR-1, 2, and 3 kinase inhibitor that has shown clinical activity in RCC (ASCO 2009, abstract #5032). Methods: Propagated HER2/INK4A(−/−) murine breast tumor isolates were dosed daily with 5mpk tivozanib, tumor volume measurements were taken twice weekly, followed by histological characterization of tumors at end of study. Hypoxia markers were also monitored in a subset. Bioinformatics analysis of RNA microarray expression profiles identified a gene signature associated with resistance. Immunohistochemical (IHC) analysis using a murine myeloid marker was also conducted on pretreatment samples to correlate the gene based marker with the myeloid IHC marker. IHC using a human myeloid marker was conducted on available formalin fixed paraffin embedded tumor samples Results: Tivozanib treatment of 25 propagated murine tumors identified both sensitive and resistant tumors among the population (40% responders, 60% resistant). Bioinformatics analysis of pre-treatment tumor microarray data identified a 42 gene resistance signature representing components of hematopoietic gene expression. IHC quantitation of myeloid markers in the tumors identified the presence of infiltrating myeloid cells, whose percentage composition in the tumor correlated with both the 42 gene signature and resistance to tivozanib. Examination of both the signature and myeloid infiltration in human tumor samples indicated that this resistant phenotype is present in a significant subset of all human tumor datasets examined. IHC analysis of infiltrating myeloid cells in 21 patient samples demonstrated a significant correlation between the percent myeloid cell composition in the tumors and maximum tumor shrinkage by RECIST. Conclusions: These observations define two distinct angiogenesis mechanisms in both murine and human solid tumors and demonstrate the utility of this population based preclinical model in predicting response in humans. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AVEO No significant financial relationships to disclose.
Blood Pressure Control and Recurrence of Intracerebral Hemorrhage
Authors: Simone Vidale, Claudio Pini, Marco Arnaboldi
Journal: JAMA (2016)

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 HomeNew OnlineCurrent IssueFor Authors 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) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
PTU-285 Early in-patient management of alcohol-related liver disease: results of a liver care bundle to improve quality of care
Authors: I Huang-Doran, C Mason, M Mcphail, S Peake, K Monahan, C Collins
Journal: Gut (2015)

<h3>Introduction</h3> The incidence of Alcohol Related Liver Disease (ARLD) is rising in the UK, as is its associated mortality. A recent National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report highlighted recurring deficiencies in the care of ARLD in UK hospitals and the British Gastroenterological Society provided guidance in the treatment of these patients during acute hospital admissions. <h3>Method</h3> Between 1 August 2013 and 31 October 2013, consecutive admissions of patients with ARLD to a district general hospital were identified from discharge and mortality data. A liver care bundle (LCB) using NCEPOD recommendations was generated and case notes analysed prior to institution of this LCB and re-audited following its inception from 1 April 2014 to 31 July 2014. Electronic referrals to specialist gastroenterology and dieticians formed part of the LCB as well as a checklist of actions for the admitting physician. <h3>Results</h3> 20 patients (median age 51 (28–67) years) were identified initially with ARLD, of which 13 (65%) were male. Median Model for End-stage Liver Disease (MELD) score was 14 (range 6–35). Post LCB institution a further cohort of 25 patients studied was matched for age (59 (32–79) years, sex (13/25 (52% male) and MELD score (13 (6–40)). Inpatient mortality was 7/20 (35%) prior and 2/23 (9%) post LCB (p = 0.065). All patients were screened for ongoing alcohol use and in 65% a withdrawal regime was prescribed. Only 1/20 (5%) had dietician input in the first 48 h rising to 11/25 (44%) post LCB institution (p &lt; 0.001). In all patients with ascites in the presence of acute kidney injury, diuretics were discontinued in both cohorts. In 92% of cases of ascites, diagnostic parascentesis was performed, however blood cultures were performed on admission in only 6/20 (30%) initially rising to 40% post LCB. 13/20 of patients (65%) had consultant review within 12 h pre LCB with 18/25 (72%) post LCB. The proportion of patients receiving specialist review by a gastroenterologist within 72 h rose from 45% to 54% following LCB use. <h3>Conclusion</h3> Instituting a liver care bundle for the management of alcohol related liver disease at our centre improved both the quality of care and outcome from patients admitted during acute decompensation, particularly related to early specialist review. Initiation of bundles of care in liver disease requires close collaboration between specialist medical services and allied health professionals such as dieticians to optimise patient care. <h3>Disclosure of interest</h3> None Declared.
Registry results and high-dose therapy.
Authors: P M Ravdin, N S Callander, G N Hortobagyi
Journal: Journal of Clinical Oncology (1998)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1998.16.1.387 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 9440768 Registry results and high-dose therapy. P M RavdinxP M RavdinSearch for articles by this author , N S CallanderxN S CallanderSearch for articles by this author , G N HortobagyixG N HortobagyiSearch for articles by this author https://doi.org/10.1200/JCO.1998.16.1.387 PDF "Registry results and high-dose therapy.." Journal of Clinical Oncology, 16(1), pp. 387–388© 1998 by American Society of Clinical Oncology
Abstract 1161: Metformin has an inhibitory effect on cell proliferation but does not induce death in colorectal cancer
Authors: Angela Mogavero, Maria Valeria Maiorana, Claudia Bertan, Fabio Bozzi, Marco A. Pierotti, Manuela Gariboldi
Journal: Cancer Research (2015)

Abstract Metformin, a widely used and well-tolerated antidiabetic drug, may reduce cancer risk and improve prognosis of certain malignancies. In vitro and in vivo studies on several cancer models have evaluated the potential antitumorigenic effects of metformin and many clinical trials are looking to its use for suppressing tumor growth. However, the mechanism for its anti-cancer effect remains uncertain and needs to be clarified. Here we investigated the anti-cancer activity of metformin on colorectal cancer growth by treating three colorectal cancer cell lines, HT29, HCT116, HCT116p53-/-, with the drug. We found that, at a dose of 5mM, metformin reduced cell proliferation in all the colorectal cancer cells analyzed, as shown by BrdU incorporation assays. Metformin induced cell cycle arrest in G0/G1 phase that was accompanied by a strong decrease of cyclin D1, c-Myc expression, and inhibition of pRB phosphorylation. The antiproliferative activity of the drug resulted mediated by suppression of mTOR and IGF-1/AKT pathways. In particular, we observed inactivation of mTOR and of its downstream targets S6 and 4EBP1, both in an AMPK dependent and independent way, and also downregulation of the activity of IGF1R. We analysed the biological mechanisms by which metformin inhibited cell proliferation by evaluating its ability to induce apoptosis, autophagy or senescence, as observed in other cancer cell lines. Unexpectedly, we found that metformin did not stimulate any of these mechanisms in colorectal cancer cells. In support of these results, a colony formation assay showed that metformin did not arrest growth of cells, but only slowed down cell ability of forming colonies. Our findings highlight that metformin inhibits the proliferation of colorectal cancer cell lines as a consequence of promoting cell cycle arrest in the G0/G1 phase, but does not induce cell death. Further investigations are needed to better elucidate the mechanisms altered by the drug in colorectal cancer and caution should be used when treating cancer patients with metformin. Citation Format: Angela Mogavero, Maria Valeria Maiorana, Claudia Bertan, Fabio Bozzi, Marco A. Pierotti, Manuela Gariboldi. Metformin has an inhibitory effect on cell proliferation but does not induce death in colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1161. doi:10.1158/1538-7445.AM2015-1161
Induction and Properties of Aryl Hydrocarbon Hydroxylase in Bovine Pancreatic Ducts&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: M W Kahng, R T Jones, B F Trump
Journal: JNCI Journal of the National Cancer Institute (1979)

Inducibility and characteristics of aryl hydrocarbon hydroxylase (AHH) in cultured bovine pancreatic ducts were studied by the fluorometric method. AHH was present and inducible in all the pancreatic ducts studied when they were exposed to 20 microgram benz[a]anthracene (BA)/ml medium. AHH activity in the control tissue ranged from 1.0 to 3.0 U/mg DNA, whereas the activity in the BA-treated tissue was 4.2--28.5 U/mg DNA, which resulted in the induction of 5- to 18-fold activity. At 12 hours of BA exposure, AHH activity in the treated tissue was 12-fold that in the control tissue and continued to increase to 15-, 19-, and 31-fold that in the control tissue at 24, 48, and 72 hours, respectively. The BA-induced AHH activity had a broad pH optimum between 7.1 and 7.7, and the maximum activity was found at pH 7.4. The AHH activity was linear with respect to the incubation time up to 30 minutes. The effect of the benzo[a]pyrene concentration on AHH activity was studied on the BA-induced enzyme. The apparent Michaelis constant for the substrate was 0.5 microM, and the maximum velocity was 8.6 U/mg DNA. BA-induced AHH activity was inhibited 65% by 100 microM 7,8-benzoflavone, whereas the control enzyme activity was stimulated 100% by the same concentration of 7,8-benzoflavone.
Abstract 13079: Evaluation of Ventricular Volume and Mass using 4D echocardiography on a Fetal-Sized Heart: An in vivo study
Authors: Meihua Zhu, Eriko Shimada, Cole Streiff, Sumito Kimura, Muhammad Ashraf, David J Sahn
Journal: Circulation (2013)

Background: Ventricular volume and mass are often used to aid diagnosis and assessment of cardiac disorders as well as evaluation of the treatment of defects. This study evaluated the feasibility and accuracy of non-gated full volume 4D echocardiography in determining ventricular volume and mass using an in vivo fetal heart model. Methods: Five open chest instrumented rabbits were studied. Four sonomicrometry (sono) crystals were implanted on the left ventricular (LV) surface of the heart to acquire volume (A). Full volume 4D image loops were acquired at each state with an X6-1 matrix probe on a Phillips IU22 ultrasound system. After acquiring baseline image data, each rabbit was subjected to saline bolus at two different volumes (2ml/kg; 4ml/kg); inferior vena cava (IVC) and ascending aorta (AAO) ligations were performed to simulate rapid changes in ventricular volume. Echo and sono data were acquired for each experimental state, allowing time for the heart to completely recover, and real baseline images...
Radiologic and pathologic response to trabectedin (T) in myxoid liposarcomas (MLS): An exploratory study in 7 patients
Authors: R. G. Sanfilippo, F. Grosso, E. Pennacchioli, C. Morosi, M. Fiore, E. Virdis, J. Jimeno, S. Pilotti, P. G. Casali, A. Gronchi
Journal: Journal of Clinical Oncology (2008)

10594 Background: To describe patterns of radiologic and pathologic response in a series of 7 patients with advanced MLS patients following treatment with trabectedin (T). Methods: Since September 2002, 32 patients (pts) with recurrent/metastatic MLS received T within an expanded access program. As of June 2007, 7 pts (5 male and 2 female) were selected for surgery having obtained response or prolonged tumor control. Surgery was complete in all. Radiologic response according to RECIST and pathologic response were studied. Pathologic response was defined by the percentage of cell component and vascular network loss, and scored as 0≤10%; 1=10-<50%; 2=50-<90%; 3≥90%; the presence of a mature component and coagulative necrosis were recorded. Results: Median age at T start was 47 yrs. Four pts had abdominal metastases and 3 had locally advanced recurrence to the thigh (one of them with a cardiac metastasis). The median number of T courses was 13 (range, 5–17). Three pts reached PR, 2 SD and 2 MR. A decrease in tumor density was documented in all cases. The regression score of cellular and vascular component, respectively, was as follows: 3+3 with mature cell component in 1 pt with SD and 1 pt with MR; 2+3 in 1 pt with MR, 2+2 in 2 pts with PR and 1 pt with SD, 2+1 in 1 pt with PR. At a median follow-up of 22 months, all patients are free from disease. Conclusions: Major pathologic responses were found in patients with minor or no tumor shrinkage, but decrease in tumor density. This confirms that radiologic tissue responses correspond to pathologic responses. PFS was prolonged in these responding pts after surgery. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration PharmaMar Zeltia PharmaMar Jansen Cilag PharmaMar
Phylogeographic Analyses of American Black Bears (<i>Ursus americanus</i>) Suggest Four Glacial Refugia and Complex Patterns of Postglacial Admixture
Authors: Emily E. Puckett, Paul D. Etter, Eric A. Johnson, Lori S. Eggert
Journal: Molecular Biology and Evolution (2015)

Studies of species with continental distributions continue to identify intraspecific lineages despite continuous habitat. Lineages may form due to isolation by distance, adaptation, divergence across barriers, or genetic drift following range expansion. We investigated lineage diversification and admixture within American black bears (Ursus americanus) across their range using 22 k single nucleotide polymorphisms and mitochondrial DNA sequences. We identified three subcontinental nuclear clusters which we further divided into nine geographic regions: Alaskan (Alaska-East), eastern (Central Interior Highlands, Great Lakes, Northeast, Southeast), and western (Alaska-West, West, Pacific Coast, Southwest). We estimated that the western cluster diverged 67 ka, before eastern and Alaskan divergence 31 ka; these divergence dates contrasted with those from the mitochondrial genome where clades A and B diverged 1.07 Ma, and clades A-east and A-west diverged 169 ka. We combined estimates of divergence timing with hindcast species distribution models to infer glacial refugia for the species in Beringia, Pacific Northwest, Southwest, and Southeast. Our results show a complex arrangement of admixture due to expansion out of multiple refugia. The delineation of the genomic population clusters was inconsistent with the ranges for 16 previously described subspecies. Ranges for U. a. pugnax and U. a. cinnamomum were concordant with admixed clusters, calling into question how to order taxa below the species level. Additionally, our finding that U. a. floridanus has not diverged from U. a. americanus also suggests that morphology and genetics should be reanalyzed to assess taxonomic designations relevant to the conservation management of the species.
Euthanasia and Assisted Suicide of Patients With Psychiatric Disorders in the Netherlands 2011 to 2014
Authors: Scott Y. H. Kim, Raymond G. De Vries, John R. Peteet
Journal: JAMA Psychiatry (2016)

<h3>Importance</h3> Euthanasia or assisted suicide (EAS) of psychiatric patients is increasing in some jurisdictions such as Belgium and the Netherlands. However, little is known about the practice, and it remains controversial. <h3>Objectives</h3> To describe the characteristics of patients receiving EAS for psychiatric conditions and how the practice is regulated in the Netherlands. <h3>Design, Setting, and Participants</h3> This investigation reviewed psychiatric EAS case summaries made available online by the Dutch regional euthanasia review committees as of June 1, 2015. Two senior psychiatrists used directed content analysis to review and code the reports. In total, 66 cases from 2011 to 2014 were reviewed. <h3>Main Outcomes and Measures</h3> Clinical and social characteristics of patients, physician review process of the patients' requests, and the euthanasia review committees' assessments of the physicians' actions. <h3>Results</h3> Of the 66 cases reviewed, 70% (n = 46) were women. In total, 32% (n = 21) were 70 years or older, 44% (n = 29) were 50 to 70 years old, and 24% (n = 16) were 30 to 50 years old. Most had chronic, severe conditions, with histories of attempted suicides and psychiatric hospitalizations. Most had personality disorders and were described as socially isolated or lonely. Depressive disorders were the primary psychiatric issue in 55% (n = 36) of cases. Other conditions represented were psychotic, posttraumatic stress or anxiety, somatoform, neurocognitive, and eating disorders, as well as prolonged grief and autism. Comorbidities with functional impairments were common. Forty-one percent (n = 27) of physicians performing EAS were psychiatrists. Twenty-seven percent (n = 18) of patients received the procedure from physicians new to them, 14 of whom were physicians from the End-of-Life Clinic, a mobile euthanasia clinic. Consultation with other physicians was extensive, but 11% (n = 7) of cases had no independent psychiatric input, and 24% (n = 16) of cases involved disagreement among consultants. The euthanasia review committees found that one case failed to meet legal due care criteria. <h3>Conclusions and Relevance</h3> Persons receiving EAS for psychiatric disorders in the Netherlands are mostly women and of diverse ages, with complex and chronic psychiatric, medical, and psychosocial histories. The granting of their EAS requests appears to involve considerable physician judgment, usually involving multiple physicians who do not always agree (sometimes without independent psychiatric input), but the euthanasia review committees generally defer to the judgments of the physicians performing the EAS.