tbuckley/cabot-search huggingface dataset:
Abstract 5727: Competitive inhibition of mTOR results in tumor specific radiosensitization
Authors: Thomas J. Hayman, Heekyong Bae, Kevin Camphausen, Philip J. Tofilon
Journal: Cancer Research (2012)

Abstract Translational control of gene expression has been implicated as a component of the cellular response to ionizing radiation (IR). The mammalian target of rapamycin (mTOR) is a critical kinase in the regulation of translation. mTOR exists in two distinct complexes: mTORC1 and mTORC2. mTORC1 regulates 4E-BP1 and p70-s6k, whereas mTORC2 regulates several AGC kinases including AKT. Most studies of mTOR have focused on the use of the allosteric inhibitor rapamycin and its analogs, which incompletely inhibit mTORC1 and do not inhibit mTORC2. In contrast, newly developed competitive mTOR inhibitors (e.g. PP242) inhibit mTORC1 output more completely and inhibit mTORC2. In the study described here, we compared the effects of rapamycin and PP242 on cellular radiosensitivity using a clonogenic assay. In two tumor cell lines originating from different histologies, U251 and MDA-MB-231, PP242 treatment 1h before irradiation increased radiosensitivity with DEFs (dose enhancement factors at 0.1 surviving fraction) of 1.52 and 1.34 respectively, whereas rapamycin had no effect. However, PP242 had no effect on the radiosensitivity of the normal human fibroblast cell line, MRC9. PP242 treatment of U251 cells resulted in a dose-dependent increase in radiosensitivity. Furthermore, addition of PP242 immediately, 1, or 6h after IR resulted in increased radiosensitivity with DEFs of 1.60, 1.50, and 1.26, respectively. To investigate the mechanism of this radiosensitization U251 cells were treated with PP242, irradiated (2Gy) and stained for γH2AX, a marker of DNA double strand breaks (DSBs). PP242 exposure significantly delayed the dispersal of radiation-induced γH2AX foci, consistent with an inhibition of DSB repair. Under conditions of clonogenic survival, exposure of U251 or MDA-MB-231 cells to 2Gy resulted in no detectable increase in mTOR output. PP242 treatment of both tumor lines resulted in complete inhibition of mTORC1/2 output whereas rapamycin only partially inhibited mTORC1 and did not inhibit mTORC2. m7-GTP batch chromatography showed PP242 induced a decrease in cap-bound eIF4G and an increase in cap-bound 4E-BP1, while rapamycin slightly increased 4E-BP1 binding and had no effect on eIF4G binding. Consistent with the effects on cap-complex formation, PP242 treatment caused a considerably greater decrease in polysome abundance than rapamycin. These results suggest that competitive inhibitors of mTOR, in contrast to rapalogs, induce tumor selective radiosensitization. Moreover, the mechanism appears to involve the inhibition of DSB repair and the suppression of translation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5727. doi:1538-7445.AM2012-5727
Pregnancy and the Risk of Stroke
Authors: Steven J. Kittner, Barney J. Stern, Barbara R. Feeser, J. Richard Hebel, David A. Nagey, David W. Buchholz, Christopher J. Earley, Constance J. Johnson, Richard F. Macko, Michael A. Sloan, Robert J. Wityk, Marcella A. Wozniak
Journal: New England Journal of Medicine (1996)

It is widely believed that pregnancy increases the risk of stroke, but there are few data available to quantify that risk.
GMC sees 15% fall in applications for GP training
Authors: G. Iacobucci
Journal: BMJ (2014)

The number of applications to enter general practice training in the United Kingdom fell by 15% this year, a new report by the General Medical Council has disclosed.

The State of Medical Education and Practice in the UK 2014 1 said that the number of applications dropped from 6031 in 2013 to 5100 in 2014, and it reported “considerable variation in the supply of trained GPs across different parts of the UK.” The GMC added that the burnout being felt by the current GP workforce may have contributed to the fall in applications to …
Obama vows to fully implement Affordable Care Act despite opposition
Authors: M. McCartney
Journal: BMJ (2013)

Arguing that access to healthcare is not a privilege but a right, President Barack Obama has vowed to fully implement his 2010 Patient Protection and Affordable Care Act.

The president made the remarks on Friday 10 May as his administration pressed ahead with implementation of the act in the face of weak public support and stiff Republican opposition. …
NT-23 * PHASE 1/2A STUDY OF GLUTATHIONE PEGYLATED LIPOSOMAL DOXORUBICIN (2B3-101) IN BREAST CANCER PATIENTS WITH BRAIN METASTASES (BCBM) OR RECURRENT HIGH GRADE GLIOMAS (HGG)
Authors: B. M. Kerklaan, A. Jager, P. Aftimos, V. Dieras, S. Altintas, C. Anders, M. Arnedos, H. Gelderblom, P. Soetekouw, W. Gladdines, P. Gaillard, C. de Sousa, A. Awada, J. Schellens, M. van Linde, D. Brandsma
Journal: Neuro-Oncology (2014)

BACKGROUND: Without active delivery across the blood-brain barrier, the efficacy of doxorubicin is limited in the treatment of brain tumors. 2B3-101 was developed as a brain-targeted doxorubicin product. In preclinical studies, 2B3-101 showed a 5-fold increased delivery of doxorubicin to the brain and improved survival of mice with HGG, compared to Caelyx®. METHODS: This open-label study assessed the safety, tolerability, MTD, PK and anti-tumor activity of 2B3-101. For this analysis, 30 HGG and 25 BCBM patients were included who received a 2B3-101 starting dose of 40-70 mg/m2 q21d (n = 35) or 60 mg/m2 q28d (n = 20 all HGG). Treatment continued until disease progression or unacceptable toxicity. Anti-tumor activity was assessed by RANO in HGG or RECIST 1.1 in BCBM patients. RESULTS: As of 30-May-2014, 172 cycles (range 1-10) of 2B3-101 were administrated, 4 HGG and 2 BCBM patients are still on treatment. 2B3-101 was tolerated up to a dose-intensity of 15 mg/m2/wk. Cycle 1 MTD was not reached. Phase 2a doses were selected based upon tolerability after repeated dosing. Most frequent reported treatment emergent AEs ≥ grade 2 were: neutropenia (41%), palmar-plantar erythrodysesthesia (PPE) (39%), fatigue (36%), stomatitis (21%), and infusion-reaction (20%). Notable grade 3–4 AEs were neutropenia (26%) and PPE (14%). All were transient and manageable with standard medication or dose delays. Dose reductions were required in 25% of the patients. 2B3-101 showed no neuro-or cardiotoxicity. In 25 evaluable HGG patients, 52% had SD as best response and 3-months PFS rate of 40%. 3 patients had intracranial response of ≥ 20%. In 23 evaluable BCBM patients, 9% had PR and 48% SD as overall best response with 3-months PFS rate of 48%. 4 patients had intracranial response of ≥ 20%. CONCLUSIONS: 2B3-101 is safe, well tolerated and shows promise as a potential treatment option for progressive HGG and BCBM patients.
SP0102 Toward new diagnostic criteria for macrophage activation syndrome in systemic juvenile idiopathic arthritis
Authors: A. Ravelli
Journal: Annals of the Rheumatic Diseases (2013)

Macrophage activation syndrome (MAS) is a severe, potentially fatal complication of systemic juvenile idiopathic arthritis (sJIA) with features of hemophagocytosis, leading to coagulopathy, pancytopenia, and liver and central nervous system dysfunction. MAS is overt in about 10% of children with sJIA but may occur subclinically in another 30-40% of patients. The diagnosis of MAS in sJIA can be challenging because it may mimic a flare of the underlying disease or be confounded with an infectious complication or a medication side effect. So far, universally agreed upon diagnostic criteria for MAS are not available. A multinational collaborative effort is under way that is aimed to generate new criteria for diagnosing MAS as a complication of sJIA. The first step of the project has led to the identification of, by means of a Delphi survey, the clinical, laboratory and histopathologic features of MAS that were felt to be most important by a large sample of international pediatric rheumatologists with experience with MAS in children with sJIA. The following 9 features were selected by more than 50% of the respondents and were given most frequently the highest ranks: falling platelet count, hyperferritinemia, evidence of macrophage hemophagocytosis in the bone marrow, increased serum liver enzymes, falling leukocyte count, persistent continuous fever ≥38°C, falling ESR, hypofibrinogenemia, and hypertriglyceridemia. In the second phase of the project, which is ongoing, investigators were asked to record data related to the clinical, laboratory and histopathologic features of their own patients with sJIA-associated MAS and of patients with 2 “confusable” conditions (that is, conditions that may mimic MAS clinically), represented by instances of active sJIA without evidence of MAS or non-sJIA patients with febrile systemic infections requiring hospitalization. By the middle of January 2011, data describing a total of 272 patients with MAS, 378 patients with active sJIA without MAS, and 322 non-sJIA patients with acute febrile infections had been entered in the study website (powered by the Pediatric Rheumatology International Trials Organization, PRINTO) by 76 investigators from 27 countries. The final set of criteria is meant to be established in a consensus conference of experts using a combination of statistical and consensus formation techniques. The ultimate goal of the project is to develop a core set of criteria that is both highly sensitive and specific. These criteria will assist physicians in MAS diagnosis in children with sJIA and enable quick institution of appropriate therapy. <h3>Disclosure of Interest</h3> None Declared
Case 64-1961
Journal: New England Journal of Medicine (1961)

Presentation of Case A forty-four-year-old woman entered the hospital because of pain in the abdomen and dysuria. Eleven years before admission the patient began to experience intermittent attacks of frequency of urination, dysuria and lower abdominal pain. The first episode followed the repair of a cystocele, rectocele and lacerated cervix after a normal pregnancy, which was the third and last. Six years before entry a subtotal hysterectomy was performed, and it was noted that the cecum was bound to the right uterine cornu by a dense fibrous adhesion. Two years later the cervical stump was removed because of prolapse. The . . .
Abstract 4345: FGFR1, a new FISH biomarker, may predict recurrence of prostate cancer after prostatectomy
Authors: Ying Zhang, Katerina Pestova, Jing Du, Ping Liu, Lela Buckingham, Tracey Colpitts
Journal: Cancer Research (2015)

Abstract Background: To identify prostate cancer (CaP) with high recurrence risk after Radical Prostatectomy (RP) is a challenge. FGFR1 (Fibroblast Growth Factor Receptor 1) plays a critical role in prostate development and tumorigenesis. In this study, we explored the possibility of using FGFR1 fluorescence in situ hybridization (FISH) to predict recurrence after RP in the Formalin fixed paraffin embedded (FFPE) tissue from CaP patients. Methods: FFPE histological specimens from 52 RP cases were evaluated with FGFR1 (8p12) / CEP 8 probe mix. While 32 of the 52 patients recurred within 5 years (PSA progression or death of disease), and 20 remained disease-free with 8 to 15 years. Median age of patients was 62 with Gleason Score range from 4 to 9. Percent of FGFR1 gain and FGFR1 loss per specimen, as well as mean number of FGFR1 signals per specimen were calculated. CEP8 was used as a control to assess hybridization quality. Statistical analysis (Cox Proportional Hazards model) was conducted using SAS 9.2. Results: Survival analysis demonstrated that percent FGFR1 loss in a specimen could identify recurrent CaP with the Harzard Ratio (HR) of 3.34 (p = 0.0011), which indicated that the risk of recurrence for FGFR1 loss-positive group is 3.34 times than that for FGFR1 loss-negative group. On the other hand, survival analysis of the percent FGFR1 gain showed that FGFR1 gain (amplification) is favorable for survival with HR of 0.36 (p = 0.0043), which indicated that the risk of recurrence for FGFR1 gain-positive group is 0.36 times than that for FGFR1 gain-negative group. By using mean FGFR1 signals per specimen in the Kaplan-Meier analysis, the patient specimens stratified into three distinct groups (overall logrank p = 0.0011): normal for FGFR1, FGFR1 gain (more favorable outcome), and FGFR1 loss (highest risk of recurrence). Conclusions: This study shows the utility of FGFR1 copy number abnormalities in CaP. Our results indicate that gain and loss of FGFR1 may have a different effect on disease recurrence. Therefore, FGFR1 FISH may provide predictive value for CaP recurrence in post RP patients, either by itself, or as an adjunct to the currently clinical prognostic indicators. Citation Format: Ying Zhang, Katerina Pestova, Jing Du, Ping Liu, Lela Buckingham, Tracey Colpitts. FGFR1, a new FISH biomarker, may predict recurrence of prostate cancer after prostatectomy. [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 4345. doi:10.1158/1538-7445.AM2015-4345
CYSTATIN C- AND CREATININE-BASED DEFINITIONS OF CONTRAST-INDUCED NEPHROPATHY AFTER CORONARY ANGIOGRAPHY OR PERCUTANEOUS CORONARY INTERVENTION
Authors: Yong Liu, Hualong Li, Li-Wen Li, Ning Tan, Shiqun Chen, Pingyan Chen, Jianbin Zhao, Jiyan Chen
Journal: Journal of the American College of Cardiology (2016)
Abstract 4172: MiR-215 expression in tumor tissue and in vitro effects of its replacement in colorectal cancer.
Authors: Petra Faltejskova, Marek Svoboda, Jitka Mlcochova, Klara Srutova, Pavel Fabian, Rostislav Vyzula, Ondrej Slaby
Journal: Cancer Research (2013)

Abstract Background: MicroRNAs (miRNAs) constitute a robust regulatory network with post-transcriptional regulatory efficiency for almost one half of human coding genes, including oncogenes and tumor suppressors. Methods: We determined the expression profile of 667 miRNAs in colorectal cancer (CRC) tissues and paired non-tumoral tissues and identified 42 differentially expressed miRNAs. One of the most significantly altered miRNAs was miR-215, significantly down-regulated in tumor tissue. We chose miR-215 for further validation on an independent cohort of 125 clinically characterized CRC patients and for in vitro functional studies on DLD1, HCT116 and HT29 cell lines. Results: MiR-215 was proved to be significantly decreased in CRC tumor tissues (p&amp;lt;0.0001) and to be negatively correlated with clinical stage (p&amp;lt;0.0001) and tumor grade (p=0.04). In vitro analyses showed that ectopic expression of miR 215 decreases viability in DLD1 (p=0.05) and HCT116 (p=0,05) cells, increases apoptosis in HCT116 (p=0.005), promotes cell cycle arrest (inhibited G1/S transition) in HCT-116 colon cancer cells (p=0.01) and decreases migration in DLD1 (p=0.05) and HT-29 cells (p=0.05). We further confirmed transcription factor HOXB9 as direct target of miR-215 on the mRNA and protein level. Conclusions: These findings indicate that miR 215 play an important role in CRC as tumor suppressor and contributes to CRC pathogenesis. Supported by Internal Grant Agency of Czech Ministry of Health, grant numbers: NT13549-4/2012 a NT13860 4/2012. Citation Format: Petra Faltejskova, Marek Svoboda, Jitka Mlcochova, Klara Srutova, Pavel Fabian, Rostislav Vyzula, Ondrej Slaby. MiR-215 expression in tumor tissue and in vitro effects of its replacement in colorectal cancer. [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 4172. doi:10.1158/1538-7445.AM2013-4172
PWE-251 District general hospital experience of optimising treatment outcome on thiopurines by co-prescription of allopurinol in patients with inflammatory bowel disease
Authors: S Cherian, A Gera, V Saxena, A Loganayagam
Journal: Gut (2012)

<h3>Introduction</h3> Numerous patients, especially those with elevated thiopurine methyltransferase (TPMT) activity, selectively methylate thiopurine drugs, generating high levels of methylated metabolites and low thioguanine nucleotides. This pattern of metabolism is related to hepatotoxicity and non-response to therapy. Co-prescription of thiopurines (TP) (at 25% of standard dose) with allopurinol (xanthine oxidase inhibitor) seems to avoid this problem, optimising both metabolite profile and clinical response. British experience on the use of this combination therapy (CT) remains limited. In this study we report a district general hospital (DGH) experience for the indications of toxicity (mainly hepatic) and very high TPMT activity in patients with inflammatory bowel disease (IBD). <h3>Methods</h3> Retrospective notes review of patients at a district general hospital treated with CT using 25% dose of TP and 100 mg allopurinol was undertaken. Particular attention was paid to whether CT overcame the specific problem that prevented thiopurine monotherapy <h3>Results</h3> 15 patients (age 24–77 yrs, male=6, Crohn9s=6, ulcerative colitis=9) were identified. All 15 patients were on an oral five amino salicylic acid preparation and 12 patients had previously been on a TP. Two patients with fibrotic stricture and one patient with hepatic steatosis were excluded from the analysis. Of those patients receiving co-prescription for side effects (four hepatoxicity and five others: rash, nausea, headache, fatigue), 78% were able to tolerate CT with complete resolution of liver function abnormality where relevant. Clinical remission was achieved in 100% of the patients who tolerated CT. In the three patients where CT was commenced for very high TPMT activity, 1 (33%) developed non-specific side effects (headache, nausea) leading to discontinuation of therapy and 2 (67%) achieved clinical remission. <h3>Conclusion</h3> CT with low-dose TP and allopurinol avoids hepatotoxicity and improves chances for clinical remission. CT may also prevent other side effects. CT should be fully utilised in a DGH for hepatoxicity and other side effects. Using CT as first line in those with high TPMT activity remains questionable and requires further scrutiny in a prospective study. <h3>Competing interests</h3> None declared.
Abstract 2988: DOK2 suppression by methylation induces platinum resistance via suppression of apoptosis in ovarian cancer cells.
Authors: Elena Lum, Michele Vigliotti, Nilanjana Banerjee, Noelle Cutter, Sitharthan Kamalakaran, Kazimierz Wrzeszczynski, Sohail Khan, Nevenka Dimitrova, Douglas Levine, Robert Lucito
Journal: Cancer Research (2013)

Abstract Ovarian cancers are highly heterogeneous and while chemotherapy is the preferred treatment, many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur will become resistant. Recent evidence suggests that epigenetic deregulation may be a key factor in the onset and maintenance of chemoresistance. To examine the ovarian epigenome, we first analyzed a set of 43 primary ovarian tumors and 9 normal ovarian samples. Since therapy response is a significant issue for ovarian cancer patients we analyzed the epigenetic differences that segregate with platinum response. We then associated expression data to identify genes with expression changes potentially altered by promoter methylation to generate a list of candidate platinum resistance genes. Next, we developed a tissue culture carboplatin resistance screen to determine which candidates functionally affect resistance. The screen utilized pools of shRNAs of the candidate genes to identify genes that when repressed allowed survival from carboplatin treatment, in order to validate that our epigenetics screen identified genes involved in resistance. Of the genes identified in the screen we further characterized one gene, docking protein 2 (DOK2), an adapter protein downstream of tyrosine kinase, to determine if we could elucidate what mechanism was used to increase resistance. Our analysis determined that loss of DOK2 decreased the level of apoptosis in response to carboplatin. In addition, we determined that in cells with reduced DOK2, the level of anoikis was decreased, a mechanism of possible importance in ovarian cancer where there is a large number of cells floating in ascites. Functional analysis of the DOK2 genes ability to affect resistance validates this approach to finding genes involved in carboplatin resistance. Citation Format: Elena Lum, Michele Vigliotti, Nilanjana Banerjee, Noelle Cutter, Sitharthan Kamalakaran, Kazimierz Wrzeszczynski, Sohail Khan, Nevenka Dimitrova, Douglas Levine, Robert Lucito. DOK2 suppression by methylation induces platinum resistance via suppression of apoptosis in ovarian cancer cells. [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 2988. doi:10.1158/1538-7445.AM2013-2988
The Effect of Atherosclerosis on the Vasomotor Response of Coronary Arteries to Mental Stress
Authors: Alan C. Yeung, Vladimir I. Vekshtein, David S. Krantz, Joseph A. Vita, Thomas J. Ryan, Peter Ganz, Andrew P. Selwyn
Journal: New England Journal of Medicine (1991)

Mental stress can cause angina in patients with coronary artery disease, but Its effects on coronary vasomotion and blood flow are poorly understood. Because atherosclerosis affects the reactivity of coronary arteries to various stimuli, such as exercise, we postulated that atherosclerosis might also influence the vasomotor response of coronary arteries to mental stress.
Abstract 946: Interaction between smoking and obesity and the risk of developing breast cancer among postmenopausal women: The Women's Health Initiative Observational Study
Authors: Juhua Luo, Kimberly Horn, Judith K. Ockene, Michael S. Simon, Marcia L. Stefanick, Elisa Tong, Karen L. Margolis
Journal: Cancer Research (2011)

Abstract Background: Recent studies suggest that smoking increases breast cancer risk, and obesity is an established risk factor for postmenopausal breast cancer. Since there is a complex relation between smoking, weight and fat distribution, we hypothesized that the effect of smoking on breast cancer risk may be modified by obesity among postmenopausal women. Methods: 76,628 women with no previous history of cancer aged 50-79 enrolled in the Women's Health Initiative Observational Study were recruited at 40 centers across the United States from 1993 to 1998, and were followed up through 2009. Cox proportional hazards regression models estimated hazard ratios (HRs) for invasive breast cancer risk associated with smoking, stratified by obesity status, and adjusting for other breast cancer risk factors. Interactions between obesity status and different metrics of smoking were tested by entering multiplicative interaction terms into the model. Results: 3,378 incident cases of invasive breast were identified. A significant association between smoking and breast cancer risk was noted in non-obese women, but not in obese women defined by BMI &amp;gt; 30 (p for interaction=0.047). A significantly higher breast cancer risk was observed in non-obese women with long duration of smoking, but not in obese women (p for interaction = 0.03). Similar results were obtained when obesity status was defined by waist circumference &amp;gt; 88 cm. Conclusion: Our study suggests the effect of smoking on breast cancer risk was modified by obesity among post-menopausal women. The modification effect did not differ by general vs. abdominal obesity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 946. doi:10.1158/1538-7445.AM2011-946