tbuckley/cabot-search huggingface dataset:
Abstract 5066: Transformation of pancreatic epithelial cells by BrafV600E
Authors: Vicky Appleman, David Klimstra, Brian C. Lewis
Journal: Cancer Research (2010)

Abstract Pancreatic cancer is the 4th leading cause of cancer-related deaths in the United States, with an estimated 35,000 deaths expected in 2009. The vast majority of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC), and activating mutations in the KRAS oncogene are present in over 90% of these tumors. Interestingly, one third of all KRAS wild-type PDAC harbor activating mutations in the gene encoding the downstream Kras effector Braf. Yet, the roles of specific Kras-stimulated effector pathways in pancreatic tumor initiation and progression remain unclear. We therefore sought to determine the consequences of expressing an activated Braf molecule in primary pancreatic duct epithelial cells (PDECs). Expression of an activated BrafV600E mutant results in the activation of the Mek-Erk and PI3K-Akt signaling cascades as determined by phosphorylation of Erk on Thr202 and Akt on Ser473. Measurement of cell proliferation demonstrated that BrafV600E stimulates the proliferation of PDECs, albeit to a lesser extent than an activated KrasG12D mutant. Activated Braf also promotes the survival of PDECs after exposure to apoptotic stimuli such as cycloheximide treatment and ultraviolet irradiation. This survival is dependent on activation of both the Mek-Erk and PI3K-Akt signaling cascades, as inhibition of these pathways abrogated Braf-induced survival. Consistent with its ability to stimulate the proliferation and survival of PDECs, orthotopic transplantation of PDECs expressing BrafV600E, and deleted at the Ink4a/Arf and Trp53 tumor suppressor loci, resulted in tumor formation, albeit with delayed kinetics relative to KrasG12D expressing PDECs. Interestingly, cell lines derived from orthotopic tumors required the activation of the PI3K-Akt signaling axis, but not the Mek-Erk signaling pathway, for survival after exposure to apoptotic stimuli, suggesting differential roles for these pathways during pancreatic tumor initiation and progression. Thus, our studies provide evidence that activating Braf mutations lead to the transformation of pancreatic epithelial cells, and additionally suggest that downstream Ras effectors may play different roles during pancreatic tumor initiation and progression. 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 5066.
Prognostic Value Comparison Between 18F-FLT PET/CT and 18F-FDG PET/CT Volume-Based Metabolic Parameters in Patients with Head and Neck Cancer
Authors: Hiroshi Hoshikawa, Terushige Mori, Yuka Yamamoto, Takehito Kishino, Takashi Fukumura, Yasushi Samukawa, Nozomu Mori, Yoshihiro Nishiyama
Journal: Clinical Nuclear Medicine (2014)

Purpose The present study compared the potential of pretreatment 3′-deoxy-3′-[18F]-fluorothymidine (18F-FLT) uptake parameters and those of 18F-FDG to predict the clinical outcome of head and neck squamous cell carcinoma treated with chemoradiotherapy. Methods A total 53 patients undergoing pretreatment 18F-FLT PET/CT and 18F-FDG PET/CT from May 2006 to April 2013 were evaluated. The SUVmax, metabolic tumor volume (MTV), total lesion glycolysis, and total lesion proliferation (TLP) were determined semiquantitatively. Associations between clinical factors and PET/CT parameters and prognostic value were analyzed. Results In univariate analyses, 18F-FLT SUVmax, MTV, TLP, 18F-FDG MTV, and total lesion glycolysis correlated with locoregional control (P = 0.02, P = 0.0007, P = 0.0001, P = 0.007, and P = 0.013, respectively). Clinical T stage, 18F-FLT SUVmax, MTV, TLP, and 18F-FDG SUVmax correlated with overall survival (P = 0.012, P = 0.0057, P = 0.0018, P = 0.0012, and P = 0.047, respectively). On multivariate analyses, 18F-FLT TLP was an independent factor for locoregional control (P = 0.002; hazards ratio [HR], 5.13; 95% confidence interval [CI], 1.81-14.54), as were 18F-FLT SUVmax and MTV for overall survival (P = 0.021; HR, 3.47; 95% CI, 1.2–10.01 and P = 0.029; HR, 3.17; 95% CI, 1.12–8.95). Conclusions Pretreatment 18F-FLT PET/CT volume-based metabolic parameters are superior prognostic predictors to those of 18F-FDG PET/CT. 18F-FLT SUVmax and MTV can provide important prognostic information for patients with head and neck squamous cell carcinomas administered with chemoradiotherapy.
P223 One blood gas is not enough to assess a patient for LTOT--how to kiss goodbye to circa 10 million in England
Authors: C. Loutsios, G. Logan, C. Deeming, D. Powrie, A. Davison
Journal: Thorax (2010)

It is recommended in the recent NICE Clinical Guidelines on COPD (June 2010) that stable patients should be offered LTOT if the PaO<sub>2</sub> &lt;7.3 kPa or &gt;7.3 and &lt;8 kPa with associated features; assessment should be made by measuring arterial blood gases on two occasions at least 3 weeks apart in confirmed stable COPD with optimum management. This was the criteria for entry in the MRC and NOTT LTOT trials. This is currently our practice. It has also been recently suggested as part of the COPD National Strategy that only one measurement of blood gases may be necessary. The annual spend on tariffs including LTOT in England in 2006 was £35 500 000. 38 patients were started on LTOT by the South East Essex Oxygen Service in 1 year from March 2009. In addition 11 stable COPD patients had a blood gas measurement in respiratory outpatients and had a PaO<sub>2</sub> &lt;7.3 kPa (Mean 6.79 SD 0.4) and when repeated by the oxygen team was above 7.3 kPa. These patients therefore did not meet the criteria for LTOT. One patient subsequently did meet the criteria within the year. This suggests that at least an extra 28% of patients would have been prescribed LTOT if only one initial blood gas below 7.3 kPa was used to assess for eligibility for LTOT. This could produce an extra spend of approximately £10 million on LTOT if extrapolated across the whole of England. These results suggest that there is considerable variability in PaO<sub>2</sub> in hypoxic patients over time. These results also support the current NICE Clinical Guideline which recommends two measurements of arterial blood gases at least 3 weeks apart should be made before prescribing oxygen. This was the evidence base for starting LTOT in randomised controlled trials.
Characterization of <i>PTEN</i> allelic status in a series of sporadic breast carcinomas demonstrating loss of 10q23.3 region by array-CGH.
Authors: F Bonnet, M Lafitte, G MacGrogan, M Longy, N Sevenet
Journal: Cancer Research (2009)

Abstract Abstract #4072 Background: Since its characterization, PTEN gene seems to play an increasing major role in the breast tumor development. Recently, various studies demonstrated that inactivation of PTEN is more and more detected in sporadic breast carcinomas and that the way of inactivation seems to be gross gene rearrangement rather than deleterious point mutation. Furthermore, because PTEN is an essential component of the PI3K signal transduction pathway, its complete molecular exploration should be done, since it has been demonstrated that PTEN loss-of-function is associated with herceptin resistance in HER2+-breast tumours.&amp;#x2028; Material and methods: A series of 135 sporadic invasive ductal carcinomas resected between 1989 and 1992 in Institut Bergonie, has been extensively studied for genomic profiling using array-CGH. A subgroup of 27 tumours demonstrated allelic imbalance at the locus 10q23.3, targeting the BAC containing the genomic sequence of PTEN was characterized. Genomic DNA and total RNA from those 27 tumours, and 11 other tumours demonstrating IHC PTEN intensity decreased or absent, were used for PTEN point mutation (dHPLC following by sequence of the variants) and gross gene rearrangement (QMP-SF) screening. Total RNA was used for qRT-PCR with specific assays for PTEN, and/or confirmation of the impact of point mutation at the transcript level.&amp;#x2028; Results: 6 PTEN gene point mutations for 5 tumours, 15 biallelic and 10 monoallelic gross PTEN gene rearrangements were detected. All but one of the 27 tumours demonstrating deletion of 10q23.3 by array-CGH were confirmed with other molecular techniques. Some of the tumours with IHC PTEN decreased or absent demonstrated decreased quantity of transcript regarding to a tumour control. All the results of the extensive molecular PTEN exploration will be presented.&amp;#x2028; Discussion : We clearly characterized a subgroup of sporadic breast carcinomas demonstrating biallelic inactivation of PTEN gene either by gross gene rearrangement alone or by the combination of gross gene rearrangement and point mutation. All these molecular events are deleterious leading to a loss-of-function of PTEN protein. In our study, a high percentage of sporadic breast carcinomas demonstrated PTEN inactivation (80% of the subgroup; 15% of the 135 breast carcinomas). Those results demonstrated that inactivation of PTEN is a key step in overall breast carcinogenesis and not only restricted to BRCA1-mutated tumours. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4072.
Abstract 965: Mechanistic studies of a dietary combination in cancer prevention: The effects of manganese superoxide dismutase on tumor suppressor gene activation
Authors: Delira F. Robbins, Kerri Morris, Yunfeng Zhao
Journal: Cancer Research (2010)

Abstract Mechanistic Studies of a Dietary Combination in Cancer Prevention: The Effects of MnSOD on Tumor Suppressor Gene Activation Reactive oxygen species can act as signaling transduction molecules modulating various pathways, such as the PI3K/Akt pathway. It is known that this pathway is constitutively activated in tumorigenesis contributing to protein synthesis, cell cycle progression, migration and survival. However, the PI3K/Akt pathway is negatively regulated by the major tumor suppressor protein PTEN. PTEN has dual specificity phosphatase activity regulating Akt phosphorylation as a lipid phosphatase; as well as, regulating cyclin D1 expression as a protein phosphotase. However, these are the roles of cytoplasmic PTEN. Recently, the nuclear roles of PTEN have received significant attention. Nuclear PTEN plays a major role in maintaining cellular homeostasis and stability by contributing to chromosome stability, DNA repair and cell cycle arrest. Previous studies have shown that PTEN nuclear localization is mediated by oxidative stress and may play a role in p53 stabilization. Nevertheless, MnSOD is considered to be a novel tumor suppressor gene. MnSOD has been defined as a nuclear encoded primary antioxidant enzyme localized in the mitochondria. We have shown in previous studies that the dietary combination Protandim reduced tumor incidence and multiplicity via the synergistic induction of superoxide dismutase enzymes. It has been shown that overexpression of MnSOD in in vivo models can suppress tumor formation via modulation of AP-1 binding. Therefore, it is imperative to look at how MnSOD may affect the process of apoptosis and the activation of tumor suppressor genes involved (i.e. PTEN and p53). Using our in vivo models (wildtype, MnSOD knockout, non-transgenic and MnSOD transgenic mice), we investigated how modulation of MnSOD expression may affect PTEN-mediated p53 stabilization, and how this contributes to chemoprevention. In addition, we explored how mutations in p53 may affect the PTEN-p53 interaction and its effects on tumor promotion via a gene transfection approach. 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 965.
Autonomic Insufficiency in Uremia as a Cause of Hemodialysis-Induced Hypotension
Authors: Edward S. Kersh, S. Jack Kronfield, Allen Unger, Robert W. Popper, Stephen Cantor, Keith Cohn
Journal: New England Journal of Medicine (1974)

Eight patients with chronic uremia who had suffered hypotensive episodes during hemodialysis were studied hemodynamically. To evaluate autonomic function we used the Valsalva maneuver and the heart-rate increment after amyl-nitrite-induced fall in arterial pressure. Two uremic patients had normal autonomic function, normal peroneal-nerve conduction, and the normal compensatory response to hypotension of hemodialysis: a rise in systemic resistance and in heart rate. The six others had evidence of autonomic dysfunction, depressed peroneal-nerve conduction and, during hemodialysis-induced hypotension, a fall in total systemic resistance and fixed heart rate. The hypotension did not improve in the second group of patients after volume expansion but did respond to administration of norepinephrine. Thus, autonomic insufficiency appears to occur in chronic uremia, is probably due to the generalized neuropathy seen in this state, and may contribute to the pathogenesis of hemodialysis-induced hypotension. (N Engl J Med 290:650–653, 1974)
PTH-144 Bowel Screening in Welsh Prisons
Authors: H Heard, S Darwin
Journal: Gut (2013)

<h3>Introduction</h3> The aim of the bowel screening programme in Wales is to reduce mortality from bowel cancer by 15% in the population invited for screening by 2020. Some groups of the population are difficult to reach, particularly if they are not registered with a General Practitioner (G.P.). Not all prisoners are registered with a G.P. and a task and finish group was established to develop strategies to identify and invite prisoners for screening. <h3>Methods</h3> Contact was made with governors and health care staff at the five prisons in Wales and an education programme provided for prison staff. Data sharing agreements were developed and agreed for each prison. Protocols and care pathways were developed for screening prisoners comprising of a slightly modified service model to the standard bowel screening programme. A pilot was established in 2 prisons and the service model modified in response to issues. It was agreed that contact with prisoners would be through health care staff. There are around 110 prisoners within the eligible age range in Welsh prisons and during the pilot prison healthcare staff notified BSW of eligible prisoners. Invitations and test kits were sent in batches to the prisoner via the medical centre where staff arranged for prisoners to be offered the opportunity to participate. Test kits were returned individually and results issued to the health care staff who disseminated them to individual prisoners. Should a prisoner have a positive test result, arrangements will be made with prison healthcare staff for telephone assessment to be undertaken by a Specialist Screening Practitioner (SSP). Prior arrangement with the prison will ensure that the prisoner is brought to the medical centre to undergo this assessment. Consideration has to be given to posting of bowel preparation medication and for prisoners who needed to undergo colonoscopy. Collaboration with prison staff was needed to ensure prisoners were given equal opportunity to participate in the programme without breaching prison security policies. <h3>Results</h3> The pilot was established in two prisons and is currently being rolled out in another. Uptake has been encouraging and a complete data set for the pilot phase will be presented in June. To date all prisoners who participated have received negative results and the positive pathway has not yet been tested. Challenges encountered included engagement of the healthcare teams within prisons due to staffing levels and varying viewpoints towards health care and the concept of informed choice and consent. <h3>Conclusion</h3> By engaging and developing this service within Welsh prisons, BSW has extended its population based screening programme to a vulnerable group and are committed to formal evaluation and service improvement where necessary. <h3>Disclosure of Interest</h3> None Declared.
P2-11-10: Low Toll-Like Receptor 9 Expression Is Required for the Aggressive Behavior of Triple Negative Breast Cancer Cells in Hypoxia.
Authors: KS Selander, J Tuomela, J Sandholm, P Karihtala, C Pressey, J Ilvesaro, K Vuopala, JH Kauppila, S Kauppila, KW Harris, D Graves, A Jukkola-Vuorinen
Journal: Cancer Research (2011)

Abstract Toll-like receptor-9 (TLR9) is a cellular DNA-receptor and a member of the innate immune system which is widely expressed in breast cancers. Although synthetic TLR9-ligands stimulate breast cancer cell invasion in vitro, through down-regulation of tissue inhibitor of matrix metalloproteinase-3 (TIMP-3), the role of this protein in breast or other cancer pathophysiology is unclear. We discovered that low tumor TLR9 expression is associated with a significantly shortened breast cancer specific survival among patients with triple negative tumors, but not among those with ER+ tumors. We further discovered that hypoxia induces TLR9 expression in breast cancer cells in vitro and in vivo. Although the triple negative TLR9 siRNA MDA-MB-231 breast cancer cells (with lower TLR9 expression) were less invasive than control siRNA cells in normoxia, these cells became highly aggressive in hypoxia and they formed significantly larger tumors than corresponding control cells in an orthotopic model in vivo. Further in vitro experiments revealed that the removal of TLR9 expression through siRNA significantly potentiated the hypoxia-induced invasive capacity of the triple negative MDA-MB-231 cells, but not that of the ER+ T47-D cells. Low TLR9 expression in hypoxia resulted also in complete disappearance of TIMP-3 in the MDA-MB-231 cells, but not in the ER+ T47-D cells. Taken together, these studies suggest that low TLR9 expression has different effects on the behavior of triple negative and ER+ breast cancer cells in hypoxia; triple negative cells become more invasive under these conditions, possibly through loss of endogenous invasion inhibitors, such as TIMP-3. Furthermore, these studies suggest that low TLR9 expression in triple negative breast cancers may serve as a novel prognostic factor and help characterize the group of patients that are at a high risk of relapse. Finally, our results suggest that any treatments or factors that lower TLR9 expression or induce hypoxia in residual or metastatic triple negative breast cancer cells, might actually induce their spread. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-11-10.
Reimbursement Influences Choice of Cancer Therapy
Authors: L. Fintor
Journal: JNCI Journal of the National Cancer Institute (1991)

Journal Article Reimbursement Influences Choice of Cancer Therapy Get access Lou Fintor Lou Fintor Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 83, Issue 22, 20 November 1991, Pages 1606–1608, https://doi.org/10.1093/jnci/83.22.1606 Published: 20 November 1991
AB0809 Proteinuria in systemic sclerosis: Reversal by ACE inhibition
Authors: J. Schuster, P. Moinzadeh, C. Kurschat, T. Benzing, T. Krieg, M. Weber, N. Hunzelmann
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> In systemic sclerosis (SSc) kidney damage is a major clinical problem which can lead to a deleterious outcome. In diabetes mellitus, early detection of proteinuria and treatment with angiotensin converting enzyme inhibitors (ACE) inhibitors has been shown to slow progression of kidney disease and to improve prognosis. <h3>Objectives</h3> To investigate the spontaneous course of proteinuria and the effects of ACE inhibitor therapy in SSc patients. <h3>Methods</h3> Proteinuria was determined in SSc patients with urine protein electrophoresis. SSc patients with proteinuria (n=31) were followed over a median of 12 months. <h3>Results</h3> Of all 31 patients with pathologic urine protein electrophoresis investigated in this study 9 patients (29%) had additional microalbuminuria and 4 patients (12, 9%) showed increased total urinary protein. ACE inhibitor treatment was subsequently given to 23 patients. 8 patients remained untreated for various reasons. Proteinuria resolved in 74% of patients treated with ACE inhibitors, whereas in the untreated group remission was observed only in 25% (p=0,014). Improvement of proteinuria was predominantly achieved in patients with recently diagnosed proteinuria, short disease duration and low level of inflammation <h3>Conclusions</h3> In patients with SSc and proteinuria, initiation of ACE inhibitor therapy resulted in a significant decrease of proteinuria. <h3>Disclosure of Interest</h3> None Declared
Aging, Health Risks, and Cumulative Disability
Authors: A J Vita, R B Terry, H B Hubert, J F Fries
Journal: New England Journal of Medicine (1998)

Persons with lower health risks tend to live longer than those with higher health risks, but there has been concern that greater longevity may bring with it greater disability. We performed a longitudinal study to determine whether persons with lower potentially modifiable health risks have more or less cumulative disability.We studied 1741 university alumni who were surveyed first in 1962 (average age, 43 years) and then annually starting in 1986. Strata of high, moderate, and low risk were defined on the basis of smoking, body-mass index, and exercise patterns. Cumulative disability was determined with a health-assessment questionnaire and scored on a scale of 0 to 3. Cumulative disability from 1986 to 1994 (average age in 1994, 75 years) or death was the measure of lifetime disability.Persons with high health risks in 1962 or 1986 had twice the cumulative disability of those with low health risks (disability index, 1.02 vs. 0.49; P<0.001). The results were consistent among survivors, subjects who died, men, and women and for both the last year and the last two years of observation. The onset of disability was postponed by more than five years in the low-risk group as compared with the high-risk group. The disability index for the low-risk subjects who died was half that for the high-risk subjects in the last one or two years of observation.Smoking, body-mass index, and exercise patterns in midlife and late adulthood are predictors of subsequent disability. Not only do persons with better health habits survive longer, but in such persons, disability is postponed and compressed into fewer years at the end of life.
Sialylated Sugars in Breast Milk Help Gut Microbes Promote Infant Growth
Authors: Tracy Hampton
Journal: JAMA (2016)

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PERCUTANEOUS VENO-ARTERIAL EXTRACORPOREAL MEMBRANE OXYGENATION FOR PATIENTS PRESENTING WITH REFRACTORY CARDIOGENIC SHOCK DUE TO ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION
Authors: Yader Sandoval, Kyle Anderson, Ivan Chavez, Ross Garberich, David Hildebrandt, Katarzyna Hryniewicz
Journal: Journal of the American College of Cardiology (2015)