tbuckley/cabot-search huggingface dataset:
HINT1 inhibits proteasome-mediated degradation of p21CIP1 and p27KIP1
Authors: Bo Cen, Haiyang Li, I. Bernard Weinstein
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

413 

Previous studies in our laboratory indicated that HINT1, a member of the evolutionary conserved family of histidine triad proteins, functions as a haplo-insufficient tumor suppressor in mice. Thus, with aging Hint1 deleted mice display an increase in various spontaneous tumors and these mice have a marked increase in susceptibility to induction of gastric tumors by the carcinogen NMBA. Furthermore, both Hint1 +/- and Hint1 -/- mice display a marked increase in the induction of both mammary and ovarian tumors by the carcinogen DMBA (Su,T. et al., Proc. Natl. Acad. Sci. USA 100,7824-7829,2003; Li, H. et al., Oncogene 25,713-721,2006). Several tumor suppressors exect their effects by perturbing cell cycle regulation. Therefore, in the present study we examined possible effects of HINT1 on expression of the cyclin-dependent kinase inhibitors p21CIP1 and p27KIP1. These two proteins were of particular interest since their levels are often reduced in a variety of human cancers. Indeed, we found that overexpression of HINT1 in SW480 human colon cancer cells caused a marked increase (about 3-fold) in cellular levels of both p21CIP1 and p27KIP1 proteins, whereas transfection with a Hint1 RNAi construct decreased the levels of both of these proteins. However, RT-PCR assays indicated that neither HINT1 overexpression nor Hint1 RNAi affected the mRNA levels of p21CIP1 and p27KIP1 in SW480 cells. Furthermore, in transient transfection assays co-transfection with Hint1 did not stimulate p21CIP1 promoter-luciferase or p27KIP1 promoter-luciferase reporter activity. Taken together with the RT-PCR assays, these results indicate that the increased cellular levels of the p21CIP1 and p27KIP1 proteins induced by HINT1 occur at a posttranscriptional level. Assays done in the presence of cycloheximide indicated that overexpression of HINT1 in SW480 cells extended the half lives of both the p21CIP1 and p27KIP1 proteins. Treatment of SW480 cells with the proteasome inhibitor MG132 increased cellular levels of p21CIP1 and p27KIP1 and this effect was augmented by overexpression of HINT1, while Hint1 RNAi impaired MG132 induced upregulation of p21CIP1 and p27KIP1. Co-immunoprecipitation assays indicated that HINT1 does not bind directly to p21CIP1 or p27KIP1. Taken together, our results suggest that HINT1 may play a role in cell cycle regulation by inhibiting proteasome-mediated degradation of p21CIP1 and p27KIP1. Studies are in progress to determine the precise biochemical mechanism. These effects of HINT1 may contribute to its tumor suppressor activity.
Abstract 15934: Common Genetic Variants of Apolipoprotein E and Apolipoprotein E Receptor 2 Have Differential Impact on Endothelial Function
Authors: Victoria Ulrich, Ivan Yuhanna, Ken Chambliss, Robert D Gerard, Meaghan Waltmann, James Cash, David Hui, Chieko Mineo, Philip W Shaul
Journal: Circulation (2013)

Cardiovascular disease (CVD) risk is greater in individuals harboring the apolipoprotein E4 (apoE) allele versus apoE3, and in those with the Apolipoprotein E receptor 2 (ApoER2) variant ApoER2-R95...
P0178 : Sarcopenia and malnutrition predict early post-liver transplantation outcomes independently of the meld score: implications for organ allocation
Authors: M. Kalafateli, K. Mantzoukis, C.Y. Yau, A.O. Mohammad, S. Arora, S. Rodrigues, M. de Vos, K. Papadimitriou, D. Thorburn, J. O'Beirne, D. Patch, M. Pinzani, M.Y. Morgan, B. Agarwal, D. Yu, A.K. Burroughs, E.A. Tsochatzis
Journal: Journal of Hepatology (2015)
Abstract A04: PI3K regulation of RAC1 is required for Kras-induced pancreatic tumorigenesis
Authors: Kenneth K. Takeuchi, Eileen Carpenter, Claire Wu, Christopher J. Halbrook, Richard Z. Lin, Howard C. Crawford
Journal: Cancer Research (2015)

Abstract Nearly all pancreatic ductal adenocarcinomas are caused by oncogenic mutations in the KRAS gene. Pharmacological inhibition of mutant KRAS has thus far been unsuccessful in the clinical setting, precipitating a need to understand the pathways downstream of KRAS which may prove more easily targeted with small molecule inhibitors. Here we show that PI3K p110α is absolutely required for pancreatic tumorigenesis while p110β is dispensable for this process. Surprisingly, ablation of p110α does not impair the ability of KRAS to activate AKT, demonstrating that AKT activation is not sufficient for transformation. Instead we find that p110α is required for robust activation of RAC1, a small GTPase required for pancreatic metaplasia. Consistent with this, our data show that p110α is necessary for regulating epithelial expression and activation of RAC-GEFs including Vav1, Tiam1 and Ect2. Ultimately, these results define the mechanistic role of p110α in pancreatic tumorigenesis and suggest selective inhibition of this PI3K isoform as a promising therapeutic approach to treating patients with pancreas cancer. Citation Format: Kenneth K. Takeuchi, Eileen Carpenter, Claire Wu, Christopher J. Halbrook, Richard Z. Lin, Howard C. Crawford. PI3K regulation of RAC1 is required for Kras-induced pancreatic tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A04.
Abstract 14742: MicroRNA-30 Mediates Shear Stress-Induced Anti-Inflammatory Properties of Endothelial Cells via Angiopoietin-2
Authors: Shemsi Demolli, Carmen Doebele, David Kaluza, Stefanie Dimmeler, Reinier A Boon
Journal: Circulation (2013)

Laminar blood flow exerts high shear stress on the endothelium, which is known to prevent local atherosclerosis formation and inhibits inflammatory pathways in endothelial cells (ECs). MicroRNAs (m...
Denosumab for the treatment of giant cell tumor (GCT) of bone: Final results from a proof-of-concept, phase II study
Authors: D. M. Thomas, S. Chawla, K. Skubitz, A. Staddon, R. Henshaw, J. Blay, J. Smith, Z. Ye, M. Roudier, S. Jun
Journal: Journal of Clinical Oncology (2009)

10510 Background: GCT of bone is a primary osteolytic bone tumor with low metastatic potential that is associated with significant skeletal morbidity. GCT is rich in stromal cells that express RANKL, a key mediator of osteoclast activation. In this open-label, study, we investigated whether denosumab, a fully human monoclonal antibody against RANKL, could have a potential therapeutic effect on giant cell histology for patients with GCT. Methods: In this single-arm study, 37 patients with measurable or unresectable GCT received denosumab 120 mg subcutaneously once monthly with loading doses on days 8 and 15 of month 1. The primary endpoint was the proportion of patients with a tumor response (≥90% elimination of giant cells or no radiographic progression of the target lesion) at week 25 as assessed by histology and CT or MRI. A sample size of 35 patients was planned. All 37 enrolled patients were evaluated for safety; 35 were eligible for efficacy evaluation (2 had insufficient histology or radiology data). Results: Thirty of 35 patients (86%; 95% CI 70%-95%) had a tumor response: 20 of 20 by histology and 10 of 15 by radiology. Of 31 patients with data for assessments of clinical benefit, 26 (84%%; 95% CI 66%-95%) reported reduced pain or improvement in functional status. Bone repair was reported in 9 patients (29%; 95% CI 14%-48%). Suppression of the bone turnover markers urinary N-telopeptide and serum C-telopeptide was seen as early as 28 days after the first dose and sustained for the duration of the study. Adverse events (AEs) were reported in 33 patients (89%). One death due to surgical complications (not treatment-related) occurred on-study. No patient experienced treatment-related serious AEs or developed anti-denosumab antibodies. Conclusions: In this study, 86% of patients with measurable or unresectable GCT experienced a tumor response with denosumab. Further clinical trials of denosumab as a new therapy for GCT are warranted. [Table: see text]
National Outcomes of Cataract Extraction
Authors: Jonathan C. Javitt, James M. Tielsch, Joseph K. Canner, Margaret M. Kolb, Alfred Sommer, Earl P. Steinberg, Earl P. Steinberg, Marilyn Bergner, Alfred Sommer, Gerard F. Anderson, Eric B. Bass, Joseph Canner, Alan M. Gittelsohn, Jonathan C. Javitt, Margaret M. Kolb, Marcia Legro, Neil R. Powe, Oliver P. Schein, Phoebe Sharkey, Donald M. Steinwachs, Debra Street, James M. Tielsch, Donald Doughman, Merton Flom, Thomas Harbin, Harry Knopf, Thomas Lewis, Stephen Obstbaum, Denis O'Day, Walter Stark, Arlo Terry, C. Pat Wilkinson
Journal: Ophthalmology (1992)

The authors studied 57,103 randomly selected Medicare beneficiaries who underwent extracapsular cataract extraction in 1986 or 1987 to determine the possible association between performance of neodymium (Nd):YAG laser capsulotomy and the risk of subsequent retinal break or detachment.Cases of cataract surgery were identified from Medicare claims submitted in 1986 and 1987 and were followed through the end of 1988. Episodes of cataract surgery, posterior capsulotomy, and retinal complications were ascertained based on procedure and diagnosis codes listed in physician bills and hospital discharge records. Lifetable and Cox's proportional hazards models were used to analyze the risk of retinal detachment or break in patients undergoing and not undergoing capsulotomy during the period of observation.Of the 57,103 persons identified as having undergone extracapsular cataract extraction in 1986 or 1987, 13,709 subsequently underwent Nd:YAG laser capsulotomy between 1986 and 1988. A total of 337 persons had aphakic or pseudophakic retinal detachments between 1986 and 1988 and an additional 194 underwent repair of a retinal break. Proportional hazards modeling shows a 3.9-fold increase in the risk of retinal break or detachment among those who underwent capsulotomy (95% confidence interval: 2.89 to 5.25). Younger patient age, male sex, and white race also were associated with increased risk of retinal complications after extracapsular cataract extraction.The authors conclude that there is a statistically significant increase in the risk of retinal detachment or break in those patients who undergo capsulotomy after cataract extraction. Therefore, capsulotomy should be deferred until the patient's impairment caused by capsular opacification warrants the increased risk of retinal complications associated with performance of capsulotomy.
A new surveillance system for undiagnosed serious infectious illness for the London 2012 Olympic and Paralympic Games
Authors: E Heinsbroek, B Said, H Kirkbride, Collective On behalf of the HPA USII Steering Group
Journal: Eurosurveillance (2012)

A new surveillance system was developed to detect possible new or emerging infections presenting as undiagnosed serious infectious illness (USII) for use during the London 2012 Olympic and Paralympic Games. Designated clinicians in sentinel adult and paediatric intensive care units (ICU/PICUs) reported USII using an online reporting tool or provided a weekly nil notification. Reported cases were investigated for epidemiological links. A pilot study was undertaken for six months between January and July 2011 to evaluate the feasibility and acceptability of the system. In this six-month period, 5 adults and 13 children were reported by six participating units (3 ICUs, 3 PICUs). Of these 18 patients, 12 were reported within four days after admission to an ICU/PICU. Nine patients were subsequently diagnosed and were thus excluded from the surveillance. Therefore, only nine cases of USII were reported. No clustering was identified. On the basis of the pilot study, we conclude that the system is able to detect cases of USII and is feasible and acceptable to users. USII surveillance has been extended to a total of 19 sentinel units in London and the south-east of England during the London 2012 Olympic and Paralympic Games.
Curcumin suppresses growth of cervical cancer cells
Authors: Lisa C. Flowers, Kenyatta W. Stephens, Ruo Pan Huang, Sulma Mohammed
Journal: Cancer Research (2005)

4280  Bone is a favored location for several cancer metastases, especially for breast and prostate cancer and myeloma. Metastatic breast cancer cells can stimulate directly or indirectly osteoclast-mediated bone resorption, resulting in the increase of bone destruction. Breast cancer cells also secrete several factors, such as parathyroid hormone-related protein (PTHrP), interleukin-6 (IL-6) and IL-11. These factors stimulate stromal/osteoblastic cells to express osteoclastogenic factor. One key factor is the protein receptor activator of nuclear factor-kappa B ligand (RANKL), which is required to induce osteoclast formation and activity. Another factor, osteoprotegerin (OPG), is a soluble decoy receptor for RANKL and inhibits RANKL-induced osteoclastogenesis. The consequent bone resorption induces release of various growth factors from the bone matrix, such as TGF-I,II and IGF-I,II. The released growth factors stimulate cancer cell proliferation. This sequential process is called to ‘vicious cycle’. We investigated the inhibitory effect on the growth and PTHrP mRNA expression of human metastatic breast cancer cells, MDA-MB-231. We also examined the effects of Glycyrrhizae radix extract and isoliquiritigenin(ISL) on the expression of RANKL and OPG in human osteoblastic cells, hFOB1.19 treated with conditioned medium(CM) of MDA-MB-231 cells, CM-induced apoptosis of hFOB1.19 cells and RANKL-induced osteoclastogenesis in RAW264.7 cells, a murine monocytic cell line. We found that the extract of Glycyrrhizae radix and ISL inhibited the cell proliferation and induced apoptosis in MDA-MB-231 cells. ISL did not affect the expression of PTHrP mRNA. The mRNA level of RANKL was increased and the mRNA level of OPG was decreased in hFOB1.19 cells treated with CM, resulting in the increased RANKL/OPG mRNA ratio. The Glycyrrhizae radix extract and ISL significantly decreased the ratio of RANKL/OPG mRNA in hFOB1.19 cells treated with CM. The Glycyrrhizae radix extract and ISL also inhibited RANKL-induced osteoclast formation in RAW264.7 cells. These results suggest that the extract of Glycyrrhizae radix and ISL may block bone metastasis of breast cancer cells by inducing apoptosis of metastatic breast cancer cells, decreasing the ratio of RANKL/OPG mRNA in osteoblasts and inhibiting osteoclastogenesis. Based on these data, we investigated the molecular mechanisms underlying the effect of Glycyrrhizae radix extract and ISL on vicious cycle. In particular, we focused on COX-2 protein, which plays an important role for RANKL expression and osteoclastogenesis as well as metastasis.
Some New Experiments on Protection Against Whole-Body Irradiation&lt;xref ref-type="fn" rid="fn1"&gt;2&lt;/xref&gt;
Authors: A. Lacassagne, J.F. Duplan, N.P. BuuHoi
Journal: JNCI Journal of the National Cancer Institute (1955)

Some New Experiments on Protection Against Whole-Body Irradiation Get access A. Lacassagne, A. Lacassagne Laboratoire Pasteur de l'Institut du Radium, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar J-F. Duplan, J-F. Duplan Laboratoire Pasteur de l'Institut du Radium, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar N. P. Buu-Hoi N. P. Buu-Hoi Laboratoire Pasteur de l'Institut du Radium, Paris, France Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 15, Issue 4, February 1955, Pages 915–921, https://doi.org/10.1093/jnci/15.4.915 Published: 01 February 1955 Article history Received: 18 October 1954 Published: 01 February 1955
Treatment of body-dysmorphic disorder with serotonin reuptake blockers
Authors: Eric Hollander, Michael R. Liebowitz, Ronald Winchel, Almuth Klumker, Donald F. Klein
Journal: American Journal of Psychiatry (1989)

The authors describe five patients with body-dysmorphic disorder who responded preferentially to serotonin reuptake blockers. They review the literature, describe how patients with excessive concern about body abnormalities lie along a spectrum of doubt and certainty, and discuss similarities and differences between this disorder and obsessive-compulsive disorder.
Daclatasvir plus Sofosbuvir for HCV Infection
Authors: Harpal S Dhaliwal, Ram V Nampoothiri
Journal: New England Journal of Medicine (2014)

To the Editor: With regard to the article by Sulkowski et al. (Jan. 16 issue)1: a sustained virologic response that is defined as undetectable hepatitis C virus (HCV) RNA 24 weeks after the end of interferon-based therapy corresponds to a definitive cure of HCV in 99.1% of cases.2 A sustained virologic response that is defined as undetectable HCV RNA 12 weeks after treatment has a concordance of 99.0% with a sustained virologic response 24 weeks after treatment and hence is clinically equally relevant.3 It is well known that after a sustained virologic response, residual HCV RNA persists in mononuclear cells, lymphocytes, and macrophages.4,5 The definitions of a sustained virologic response at 12 weeks and at 24 weeks after treatment have been tested only in interferonbased regimens that are associated with longterm immunomodulation in treated patients, so that once suppressed, the virus remains so in the years to come, even without the drug. Data are lacking on the long-term relevance of these end points in patients who received interferonfree regimens that inhibit the virus by interfering with its life cycle without altering the immune responses (which could be helpful once the patient is no longer receiving the drugs). Similarly, the concept of a sustained virologic response is not applicable in patients with hepatitis B virus (HBV) and human immunodeficiency virus (HIV) infection, to whom oral drugs (that only inhibit viral replication) are administered on a long-term and usually lifelong basis.
Identification of novel subsets of CD133-positive glioblastoma cells with distinct differences in sensitivity to tyrosine kinase inhibitors
Authors: Xiaobing He, Daniel Hagerstrand, Saskia Hoefs, Goran Hesselager, Maja Bradic, Arne Ostman, Monica Nister
Journal: Cancer Research (2008)

4618   Glioblastoma multiforme (GBM) is a highly malignant brain tumor where improved treatments are urgently needed. Genetic and array-based studies suggest the existence of biologically distinct subsets. Experimental and clinical studies have indicated that PDGF and IGF1 receptor signaling contribute to the growth of some glioblastomas. Finally, recent studies have proposed the existence of CD133-positive GBM stem cells.  In this study, a panel of high grade human glioma cell cultures were analyzed first for gene expression profile and further for the expression of stem cell markers and different lineage markers recognizing astrocytes, oligodendrocytes, neurons and microglial cells by real-time RT-PCR. In parallel, the sensitivity to imatinib mesylate/STI571/Glivec and AEW541, two small molecular inhibitors targeting PDGF- and IGFI-receptors respectively, were also investigated.  11 out of 20 cultures displayed CD133 expression measured by real-time RT-PCR. These could be further divided into two subsets both by gene-expression signatures and different stem cell and lineage markers. Type I cultures displayed high expression of CXCR4, Sox2, EAAT1 and GFAP, and low level of CNP, PDGFRβ, CXCL12 and extracellular matrix proteins as compared to Type II. Further functional analysis by neurosphere assay revealed that Type I cells were better at neurosphere formation than Type II cells. Interestingly, these two subsets of CD133+ cultures displayed different sensitivities to PDGFR and IGFIR inhibitors. Type II cells were sensitive to either imatinib, AEW541 or both, while Type I cells were insensitive to both. However, when a combination treatment with imatinib and AEW541 was tested on Type I cells, a prominent growth inhibition was observed. Clinical significance of these subsets was indicated by the coordinated expression of Type I and Type II “markers” in human glioblastoma samples.  In summary, two novel subsets of CD133-positive human glioma cultures could be identified and distinct differences between the two subsets with regard to sensitivity to AEW541 and imatinib were demonstrated. One of these subsets, which displayed high level of CXCR4, Sox2, EAAT1 and GFAP expression, was more prone to form neurospheres, was resistant to treatment with PDGFR and IGFIR inhibitors individually but showed sensitivity to combination treatment. The findings suggest continued studies to evaluate these novel potential treatment options for GBM based on targeting of CD133-positive cancer stem cells.
If a woman has not had a thrombotic event in years of use she is unlikely to have one now
Authors: J. Guillebaud
Journal: BMJ (1995)

south Wales, and our list size is 5600.All con- sultations in this context were initiated by patients.We routinely code clinical information during consultations on our computer database; this facilitates audit of clinical practice.When a patient is advised about contraception a Read code (6777: contraception counselling) is recorded.Over the 10 weeks before the "pill scare" on 19 October the code for contraception counselling was recorded 18 times (average 1-8 times a week).Over the three weeks after the announcement the code was recorded (week by week) 30, 28, and 27 times (average 28-3).If it is assumed that these figures are reflected throughout England and Wales the effect on general practitioners' workload nationally can be estimated and perhaps costed.