tbuckley/cabot-search huggingface dataset:
Flurbiprofen benzylnitrate (FBN) inhibits the growth of various human cancer cells in vitro and prevents intestinal carcinogenesis in Min (APCMin/+) mice
Authors: Khosrow Kashfi, Galina Borodulina
Journal: Cancer Research (2007)

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

111 

Introduction: Nitric oxide-releasing nonsteroidal antiinflammatory drugs (NO-NSAIDs) are potentially an important class of chemopreventive agents against cancer. They consist of a traditional NSAID attached to an NO releasing moiety through a chemical spacer. It had previously been shown that an aromatic spacer enhanced the potency of a particular NO-NSAID compared to an aliphatic spacer (JPET 312:978-988, 2005). Hence, we synthesized an NO-releasing arylpropionic acid NSAID, comprising an aromatic spacer and evaluated it against several human cancer cell lines as well as an animal model of colon carcinogenesis.

Methods: FBN: synthesized, purified, NMR and mass spectrometry verified by us; human cancer cell lines: HT-29 (colon, COX-1 and -2 positive); HCT 15 (colon, COX null); MIA PaCa-2 (pancreas, COX null); BxPc-3 (pancreas, COX-1 and -2 positive); A549 (lungs); A-431 ( skin); LNCaP (prostate); MCF-7 (breast); SSC-25 (tongue squamous cell carcinoma); and HeLa, Caski (cervix). Cell growth: MTT; cell cycle phase distribution: flow cytometry; apoptosis: subdiploid (sub-G0/G1) peak in DNA content histograms; proliferation: PCNA. In vivo: six-week-old female C57BL/6J APCMin/+ mice and the corresponding C57BL/6J+/+ wild type mice (N = 10 animals/group). Each mouse was treated via oral administration by gavage as follows: group 1 , wild type controls treated with vehicle; group 2 , wild type controls treated with FBN (100 mg/kg/day); group 3 , Min mice treated with vehicle; group 4 , Min mice treated with FBN (100 mg/kg/day). After 21 days of treatment all animals were euthanized and their small intestine was dissected. Tumors were counted under a magnifying lens.

Results: FBN inhibits the growth of colon, pancreas, lung, skin, prostate, breast, tongue and cervical cancer cells, being up to 20-fold more potent than flurbiprofen. This effect is due to: a) cell kinetics: inhibition of proliferation (PCNA), b) induction of apoptosis (multiple criteria) and c) in general blocking the G1 to S cell cycle transition. Animal studies: there were no signs of overt toxicity including gastrointestinal toxicity from FBN. The number of tumors were reduced by 95.6% (number of tumors in controls = 32.1 ± 6.4; treated animals = 1.4 ± 2.8, p < 0.001, mean ± SD).

Conclusions: These findings establish a strong inhibitory effect of FBN in various human cancer lines, an effect which is modulated through parameters important in determining cellular mass. Our findings also show a strong inhibitory effect in intestinal carcinogenesis in the Min mouse. Taken altogether, these data suggest that FBN merits further evaluation as a chemopreventive and potentially chemotherapeutic agent.
Vaccines and the world of child health
Authors: None The Lancet
Journal: The Lancet (2009)

For those in developed countries the few vaccinations of our early years are a distant memory. It is easy to take for granted not only the invisible and longlasting protective veil that vaccinations draw against potentially fatal infectious diseases, but also the public health transformation wrought by vaccines and other interventions in the past century. Our enviable life expectancy and economic success both depend on them.
The Addition of Bortezomib to Standard Chemotherapy for Pediatric Acute Myeloid Leukemia Has Increased Toxicity without Therapeutic Benefit: A Report from the Children's Oncology Group
Authors: Richard Aplenc, Soheil Meshinchi, Lillian Sung, Todd A. Alonzo, Jessica Pollard, Robert Gerbing, Susana C. Raimondi, Betsy A. Hirsch, Michael R. Loken, Laura Winter, Samir B. Kahwash, John K Choi, John E Levine, E. Anders Kolb, Alan S. Gamis
Journal: Blood (2016)
The economic burden of physical inactivity: a systematic review and critical appraisal
Authors: Ding Ding, Tracy Kolbe-Alexander, Binh Nguyen, Peter T Katzmarzyk, Michael Pratt, Kenny D Lawson
Journal: British Journal of Sports Medicine (2017)

Objective To summarise the literature on the economic burden of physical inactivity in populations, with emphases on appraising the methodologies and providing recommendations for future studies. Design Systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO registration number CRD42016047705). Data sources Electronic databases for peer-reviewed and grey literature were systematically searched, followed by reference searching and consultation with experts. Eligibility criteria Studies that examined the economic consequences of physical inactivity in a population/population-based sample, with clearly stated methodologies and at least an abstract/summary written in English. Results Of the 40 eligible studies, 27 focused on direct healthcare costs only, 13 also estimated indirect costs and one study additionally estimated household costs. For direct costs, 23 studies used a population attributable fraction (PAF) approach with estimated healthcare costs attributable to physical inactivity ranging from 0.3% to 4.6% of national healthcare expenditure; 17 studies used an econometric approach, which tended to yield higher estimates than those using a PAF approach. For indirect costs, 10 studies used a human capital approach, two used a friction cost approach and one used a value of a statistical life approach. Overall, estimates varied substantially, even within the same country, depending on analytical approaches, time frame and other methodological considerations. Conclusion Estimating the economic burden of physical inactivity is an area of increasing importance that requires further development. There is a marked lack of consistency in methodological approaches and transparency of reporting. Future studies could benefit from cross-disciplinary collaborations involving economists and physical activity experts, taking a societal perspective and following best practices in conducting and reporting analysis, including accounting for potential confounding, reverse causality and comorbidity, applying discounting and sensitivity analysis, and reporting assumptions, limitations and justifications for approaches taken. We have adapted the Consolidated Health Economic Evaluation Reporting Standards checklist as a guide for future estimates of the economic burden of physical inactivity and other risk factors.
EphB2 and EphB4 receptors forward signaling promotes SDF-1-induced endothelial cell chemotaxis and branching remodeling
Authors: Ombretta Salvucci, Maria de la Luz Sierra, Jose A Martina, Peter J McCormick, Giovanna Tosato
Journal: Cancer Research (2007)

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

2146 

The complex molecular mechanisms that drive endothelial cell movement and the formation of new vessels are poorly understood and require further investigation. Eph receptor tyrosine kinases and their membrane-anchored ephrin ligands regulate cell movements mostly by cellâ\#8364;“cell contact, whereas the G-proteinâ\#8364;“ coupled receptor CXCR4 and its unique SDF-1 chemokine ligand regulate cell movement mostly through soluble gradients. By using biochemical and functional approaches, we investigated how ephrinB and SDF-1 orchestrate endothelial cell movement and morphogenesis into capillary-like structures. We describe how endogenous EphB2 and EphB4 signaling are required for the formation of extracellular matrixâ\#8364;“dependent capillarylike structures in primary human endothelial cells. We further demonstrate that EphB2 and EphB4 activation enhance SDF-1â\#8364;“induced signaling and chemotaxis that are also required for extracellular matrixâ\#8364;“dependent endothelial cell clustering. These results support a model in which SDF-1 gradients first promote endothelial cell clustering and then EphB2 and EphB4 critically contribute to subsequent cell movement and alignment into cordlike structures. This study reveals a requirement for endogenous Eph signaling in endothelial cell morphogenic processes, uncovers a novel link between EphB forward signaling and SDF-1â\#8364;“induced signaling, and demonstrates a mechanism for cooperative regulation of endothelial cell movement.
P02.03 Real-world treatment patterns in glioblastoma multiforme (GBM)
Authors: K. Byrne, J. Waller, J. Piercy, J. Shaw, H. Dastani
Journal: Neuro-Oncology (2017)

Objectives: To understand real-world utilization of treatments for GBM. METHODOLOGY: Real-world data were collected through a cross-sectional survey administered to physicians in Canada, France, Germany, and the UK between May and July 2016. Physicians provided data for eight consecutive patients receiving treatment for GBM regarding disease history, characteristics, and treatment patterns. Summary statistics were reported and differences assessed using chi-square tests. Results: A total of 161 physicians (Canada, 29; France, 52; Germany, 50; and UK, 30) provided information for 1,235 GBM patients (Canada, 195; France, 400; Germany, 400; and UK, 240). Nearly half (45%) of all patients presented with stable disease, while 28% were classified as progressing and the remaining 28% as responding to treatment. Forty-five percent of patients had experienced a recurrence. Methylation status was evaluated in 70% of patients with 59% of these showing gene promoter methylation. Approximately two-thirds (67%) of patients had undergone surgery of whom 88% had been operated on prior to initiation of drug treatment. More than three-quarters of patients had received treatment with radiotherapy Ninety percent of patients received first-line treatment with temozolomide (TMZ), while the remainder were treated with bevacizumab (BEV) (5%); a procarbazine, lomustine, and vincristine (PCV) regimen (4%); or irinotecan (IRI) (1%). 613 patients received second-line therapy of whom 36% were treated with BEV (alone or in regimen), 22% with TMZ or PCV, and 13% with IRI. BEV use varied among countries with a prevalence of 49% in France, 38% in Germany, 35% in Canada, and 10% in the UK (p <0.001). Use of BEV in second line was higher among patients with progressive disease than those with stable disease (43% vs. 28%, p<0.001). However, there was no difference in BEV use between patients with progressed or treatment-responsive disease (43% vs. 35%, p=0.188). Similarly, there was no difference in the prevalence of second-line BEV use between patients with or without gene promoter methylation (40% in each group, p=0.962). Only 45 patients received third-line therapy of whom 51% were treated with BEV (alone or in regimen), 16% IRI, 13% TMZ, and 4% PCV. By country, the prevalence of BEV use varied with 62% in France, 55% in Canada, 50% in Germany, and 17% in the UK. CONCLUSION: Real-world data collected in Canada, France, Germany, and the UK indicate that TMZ is the most commonly used first-line treatment for GBM, whereas BEV is most commonly prescribed in second and later lines. The high prevalence of BEV use underscores the need for more effective therapies.
Impact of rituximab on the course of low-grade follicular lymphoma.
Authors: Jairam Krishnamurthy, Fausto R. Loberiza, Martin Bast, Pavankumar Tandra, Vijaya Raj Bhatt, Gregory Bociek, Philip Jay Bierman, Julie Vose, James O. Armitage
Journal: Journal of Clinical Oncology (2013)

8572 Background: Rituximab has revolutionized the treatment of lymphomas and has been shown to improve clinical outcomes in patients with follicular lymphoma. Our study evaluated the progression free survival (PFS) and overall survival (OS) in patients with grades I and II follicular lymphoma when rituximab was used as initial therapy, as salvage or if no rituximab was used. Methods: Patients with grades I and II follicular lymphoma treated between June 1981 and January 2010 were included. Disease and treatment related variables were compared based on type of treatment (No rituximab-Group I, rituximab as salvage-Group II, Rituximab as initial treatment-Group III) using the Kruswal Wallis or chi-square tests. Univariate probabilities of PFS and OS were estimated using the Kaplan Meier method. Multivariate analyses were performed using Cox proportional hazards regression analysis to evaluate differences in risk of treatment failure and mortality in the three groups while adjusting for covariates. Results: There were 226 patients in group I, 84 in group II and 110 in group III. Significant differences were found in some of the disease and treatment related variables. Univariate analysis is shown in the Table. The relative risk of treatment failure for group II was 0.82 (p=0.26) and 2.63 (p=0.0001) respectively in the first 10 years and after 10 years while it was 0.52 (p=0.0003) and 3.97 (p=0.001) respectively for group III in the first 10 years and after 10 years. The relative risk of mortality in group II was 0.63 (p=0.008) and group III was 0.32 (p&lt;0.0001). Conclusions: Overall survival for patients with low grade follicular lymphoma is significantly improved when rituximab is used as initial treatment or as salvage when compared with no rituximab. [Table: see text]
Abstract 257: PP2Cm Regulation Links Branched Chain Amino Acid with Hypertrophy Response
Authors: Meiyi Zhou, Zhihua Wang, Darwin Jeyaraj, Bangfen Pan, Ying Huang, Yuanyang Yuan, Mukesh Jain, Yibin Wang, Haipeng Sun
Journal: Circulation Research (2012)

[Introduction] Branched Chain Amino Acids (BCAAs), including leucine, isoleucine, and valine, modulate mTOR activity that controls protein synthesis and cell growth. PP2Cm is a mitochondrial protein phosphatase that regulates the rate limiting step of BCAA degradation. Loss of PP2Cm leads to BCAA accumulation. [Hypothesis] PP2Cm downregulation by hypertrophic signal impairs BCAA catabolism and thus hypertrophy response in heart. [Methods and Results] High level of PP2Cm is expressed in heart through all development stages. PP2Cm expression was reduced in hypertrophic heart induced by pressure overload, corresponding with increase of BCAA level and mTOR activity. KLF15 and microRNA22 are both key regulators of hypertrophy. It has been shown that hypertrophy signal s upregulated microRNA22 while decreasing KLF15 expression. We found that KLF15 increased PP2Cm promoter activity and miRNA22 regulated PP2Cm mRNA level and protein expression via 3’UTR . Together, our data indicated that hypertrophy inducers down-regulates KLF15 while increasing miRNA22, resulting in decreased PP2Cm level and thus repressed BCAA catabolism, which in turn can impact on mTOR mediated signaling and activity. [Conclusions] Pathological stress may affect the expression of PP2Cm and influence the outcome of hypertrophic response, suggesting an important role of BCAA nutrient and PP2Cm expression in heart.
P01.09 In vitro Assessment of apoptosis and cell cycle arrest by metformin in GBM
Authors: L. Eagles, F. Rowther
Journal: Neuro-Oncology (2017)

Introduction: The repurposing of existing medication could be an efficient method of developing new therapies for glioblastoma multiform (GBM). Metformin is currently the most common antidiabetic drug treatment for type 2 diabetes in the world. Over the last ten years, multiple studies have demonstrated anti-proliferative effects against a range of tumour types although the mechanisms of action have yet to be identified. Previously, we have determined the ID50 value of metformin on a panel of 13 GBM patient- derived short-term cultures and the U251MG cell line and shown that response to metformin is significantly associated with p53 status. In this study, we investigated the ability of metformin to induce apoptosis, cell cycle arrest and autophagy in GBM in vitro. Materials and methods: Flow cytometry was carried out using 5 GBM patient- derived short-term cultures, the U251MG cell line and normal human astrocytes (NHA) treated with ID50 concentrations of metformin in media containing either 3mM or 6mM glucose. Early apoptosis was assessed using FITC Annexin V staining every 24 hours over a time course of 96 hours. Caspase 3/7 expression was determined using Promega Caspase-Glo at 72 and 96 hours. Cell cycle response was measured after 96 hours by staining with propidium iodide on ethanol fixed cells. Results: No significant increase in early apoptosis was observed in any cell culture. FITC Annexin V staining showed that in all cultures significant changes to the live cell population occurred after 72 hours of drug treatment (P= 0.0016 to 0.0323) and early apoptosis was not induced in any culture regardless of glucose level (p>0.05). Reduction of glucose in treatment media caused a significant (p= 0.0113 to 0.0467) increase in cell death at 72 hours irrespective of p53 status. Similarly, metformin did not induce significant changes in caspase activity or increases in apoptotic cell death measured by cell cycle analysis (p>0.05). However, an increase in the G2/M phase population after 96 hours of metformin treatment was observed in three p53 compromised cultures (IN859, IN1979 and U251MG) indicating possible cell cycle arrest. Conclusions: This study indicates that unlike in other cancers, metformin does not utilize apoptotic pathways to induce cell death in GBM. The availability of glucose in the growth media has a direct impact on cell survival and viability during exposure to metformin. The G2/M cell cycle arrest is also different to results seen in other cancer types, showing the variability in response to metformin treatment. These results suggest that metformin’s main mechanism could be related to the availability of glucose, cellular stress and cell cycle arrest.
Abstract 173: Clonal Analysis Reveals Limited Proliferative Capacity of Mature Cardiomyocytes during Embryonic Development.
Authors: Konstantina-Ioanna Sereti, Paniz Kamran, Shah R Ali, Josh Z Lee, Ali Subat, Humberto Contreras-Trujillo, Peng Zhao, Reza Ardehali
Journal: Circulation Research (2013)

There is growing evidence that supports the ability of the heart to generate new cardiomyocytes during development and in response to injury albeit at a very low rate. It still remains unclear whether the newly generated cells originate from cardiac progenitor/stem cells or from pre-existing cardiomyocytes that re-enter the cell cycle. Understanding the cellular mechanisms regulating new cardiomyocyte formation is imperative towards the development of novel clinical strategies. We assessed the hypothesis that the cardiomyocytes generated during cardiac development are derived from cardiac progenitor cells and to a lesser extent form proliferating cardiomyocytes. We performed clonal analysis of cardiomyocyte formation by utilizing a stochastic multicolor reporter system (Rainbow) that allows random labeling of cells with three fluorescent proteins upon Cre-mediated recombination. Rainbow mice were crossed to αMHC-CreER mice for selective marking of cardiomyocytes or to Actin-CreER mice where all types of cells can be labeled. We induced rare recombination events at embryonic day E12.5 and clonal expansion of labeled cells was retrospectively analyzed at different time-points from E15.5 to postnatal day P30. To determine at which developmental stage cardiac cells lose their ability to proliferate, recombination was induced at different time-points from early embryonic to postnatal life and analysis was performed at P30. For each time-point, data was collected from ten mice. In αMHC-CreER;Rainbow mice, we observed mainly single cell labeling, a few doublets and some rare four-cell clones. At the same time-points, Actin-CreER;Rainbow hearts exhibited a large number of clones ranging from doublets to clones of more than twenty cells. Interestingly, clone formation and expansion was reduced with age. In conclusion, our results indicate that αMHC-positive cardiomyocyte proliferation is limited during development. On the other hand, non-αMHC expressing cells exhibited clonal expansion suggesting the possible contribution of cardiac progenitors even during late cardiovascular development.
P08.03 In-vivo DCE-MRI for the discrimination between glioblastoma and radiation necrosis in rats
Authors: J. Bolcaen, B. Descamps, M. Acou, K. Deblaere, C. Van den Broecke, T. Boterberg, C. Vanhove, I. Goethals
Journal: Neuro-Oncology (2017)

Purpose: Discrimination between glioblastoma (GB) and radiation necrosis (RN) remains challenging using conventional MRI. However, a correct diagnosis is important for patient management. We hypothesised that based on differences in vascular properties, such as vascular density, vascular permeability, blood flow, composition of the extracellular and extravascular space and interstitial pressure, dynamic contrast-enhanced (DCE) MRI would allow to distinguish GB from RN. As such, in this study, the potential of semi-quantitative and quantitative analysis of DCE-MRI was investigated to differentiate GB from RN in rats. Procedures: F98 GB cells were inoculated in the rat brain. GB growth was seen on follow-up MRI 8–23 days post-inoculation (n=15). RN lesions developed 6–8 months post-irradiation (n=10). DCE-MRI was acquired using a fast low angle shot (FLASH) sequence. Regions of interest (ROIs) encompassed peripheral contrast-enhancement in GB (n=15) and RN (n=10) as well as central necrosis within these lesions (GB (n=4), RN (n=3)). DCE-MRI data were fitted to determine 4 function variables (amplitude A, offset from zero C, wash-in rate k and wash-out rate D) as well as maximal intensity (ImaxF) and time-to-peak (TTPF). Secondly, maps of semi-quantitative and quantitative parameters (extended Tofts model) were created using Olea sphere (O). Semi-quantitative DCE-MRI parameters included wash-inO, wash-outO, area under the curve (AUCO), maximal intensity (ImaxO) and time-to-peak (TTPO). Quantitative parameters included the rate constant plasma to extravascular-extracellular space (EES) (Ktrans), the rate constant EES to plasma (Kep), plasma volume (Vp) and EES volume (Ve). All (semi-)quantitative parameters were compared between GB and RN using the Mann-Whitney U test and ROC analysis was performed. Results: Wash-in rates (k and wash-inO) were significantly higher in GB compared to RN (p=0.016 and p=0.041, respectively). Wash-out rate (D) was only significantly higher in GB using curve fitting (p=0.014). TTPF and TTPO were significantly lower in GB compared to RN (p=0.001 and p < 0.001, respectively). The highest sensitivity (93%) and specificity (90%) was obtained for TTPO by applying a threshold of 415 s. Ktrans, Kep, Vp and Ve were not significantly different between GB and RN. Conclusions: Based on our results in a rat model, DCE-MRI may be useful to discriminate GB from RN. Wash-in rates (k and wash-inO), TTPF and TTPO, which can be derived from a 5-min DCE-MRI acquisition, are able to distinguish GB from RN while other quantitative and semi-quantitative parameters are not. Whether DCE-MRI will also be able to differentiate GB from RN in humans must be further explored.