tbuckley/cabot-search huggingface dataset:
Elderly patients with fluoropyrimidine-resistant advanced colorectal cancer (CRC) derive similar benefit without excessive toxicity when treated with irinotecan monotherapy
Authors: G. Stewart, I. Chau, A. R. Norman, O. Katopodis, C. Topham, G. Middleton, M. Hill, P. Ross, J. Oates, D. Cunningham
Journal: Journal of Clinical Oncology (2004)

3622 Background: Elderly and performance status (PS) 2 patients are perceived to tolerate irinotecan poorly and currently these patients are recommended to have a reduced starting dose (300mg/m2 once every 3 weeks) as monotherapy. The aims of this analysis are to compare toxicity and survival according to age, PS, sex and prior radical pelvic radiotherapy (RT). Methods: Between 1997 and 2003, 339 eligible patients with advanced CRC progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospectively registered in a multicentre randomised trial. All patients commenced irinotecan at 350mg/m2 once every 3 weeks. The primary endpoints were overall survival and an irinotecan-specific toxicity composite endpoint (TCE) defined as the occurrence of grade 3 or 4 diarrhoea, neutropenia, febrile neutropenia, fever, infection or nausea & vomiting. Results: Of the 339 patients, 72 (21%) were aged ≥70, 41 (12%) were PS 2, 201 (59%) were males and 51 (15%) had prior RT. There were no differences in proportions of patients developing TCE by age (<70 vs. ≥70: 37.8% vs. 45.8%; p=0.218), performance status (0–1 vs. 2–3: 39.3% vs. 41.5%; p=0.943) or prior RT (RT vs. no RT: 45.1% vs. 38.5%; p=0.377). Time to occurrence of TCE was also similar by age (log rank p=0.222) and PS (p=0.424). Males experienced more toxicity than females (44.3% vs. 32.6%; p=0.031), but this became non-significant after controlling for other co-variates (p=0.06). Patients aged ≥70 had similar objective responses (11.1% vs. 9%; p=0.585) and survival (median 9.4 vs. 9 months; p=0.74) compared to younger patients. Performance status (p=0.092) and gender (p=0.512) were not significant prognostic factors in multivariate analysis. Conclusions: Elderly patients derive the same benefit without experiencing more toxicity with second line irinotecan treatment for advanced CRC. Our data do not support the recommendations to give reduced starting dose to the elderly and PS 2 patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis Aventis
Abstract 2174: A high-throughput, high-content assay for the discovery of new inhibitors of DNA double-strand break repair
Authors: Yulia Surovtseva, Vikram Jairam, Ranjini Sundaram, Ranjit Bindra, Seth Herzon
Journal: Cancer Research (2016)

Abstract DNA repair pathways are being intensively investigated as targets for chemotherapeutic interventions. Despite the immense interest in this area, few whole-cell screens for the discovery of DNA repair inhibitors have been described. We have developed an automated, whole-cell, high-throughput assay for the unbiased discovery of inhibitors of the non-homologous end joining (NHEJ) and homologous recombination HR) repair pathways, the two primary pathways that ameliorate DNA double-strand breaks. Our assay enables indirect measurement of DNA repair activity by monitoring the kinetics of γH2AX and 53BP1 foci resolution after treatment with ionizing radiation (IR) and candidate DNA damage response (DDR) inhibitor. We also have developed a unique platform of secondary assays to rank-order the potency of lead compounds and gain insights into their mechanism of action. In addition to hit validation and rigorous exclusion of false-positive hits, our follow-up platform includes orthogonal assays for measuring mutagenic NHEJ and HR repair activity, as well as high-throughput assays for quantitative analysis of cell viability and cell cycle. Notably, both our primary and secondary assays are fully-automated and may be applied to screen large libraries of compounds. We validated our high-throughput assay using known DDR and DNA damage checkpoint inhibitors, and applied this screen toward the evaluation of 2,366 structurally-diverse small molecules with known bioactivity. Vorinostat and quercetin, compounds known to possess DDR inhibitory activity, were identified in the screen, supporting the sensitivity of our approach. Notably, the screen also lead to the identification of cardiac glycosides, natural products in clinical use for the treatment of heart failure and atrial arrhythmia, as potent inhibitors of DNA double-strand break repair. Many studies have noted the anticancer properties of the cardiac glycosides, but the basis of this activity has remained a “black box”. Our data suggest an explanation for this long-standing unsolved problem, and argue that this activity should be taken into consideration when evaluating other clinical applications of these agents. Because these compounds are already approved for use in humans, we believe they are excellent candidates for repurposing as chemo and radiosensitizers. Citation Format: Yulia Surovtseva, Vikram Jairam, Ranjini Sundaram, Ranjit Bindra, Seth Herzon. A high-throughput, high-content assay for the discovery of new inhibitors of DNA double-strand break repair. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2174.
Arterial load and ventricular-arterial coupling: physiologic relations with body size and effect of obesity
Authors: Julio Chirinos Medina, Ernst Rietzschel, Marc De Buyzere, Dirk De Bacquer, Thierry Gillebert, Patrick Segers
Journal: Circulation (2009)

Background: Accurate quantification of arterial function is crucial to distinguishing disease states from normal variants. Data regarding methods to scale arterial load to body size in humans are needed. 
Methods: We studied 2365 adults aged 35–55 years free of overt cardiovascular disease enrolled in the Asklepios study. We assessed arterial hemodynamics and ventricular-vascular coupling with carotid tonometry and Doppler echocardiography. To define normal (physiologic) relationships between hemodynamic indices and body size, we used non-linear regression to analyze a selected reference subsample (n=612) with normal weight (body mass index 18 –25 kg/m2), waist circumference and metabolic parameters. 
Results: Most arterial hemodynamic indices demonstrated important relationships with body size, which were frequently allometric (non-linear, Table). Allometric indexation using appropriate powers (but not ratiometric indexation) eliminated the relationships between indices of arterial load and body size in normal subjects. In the entire sample (n=2365), the adverse effects of obesity on arterial load and end-systolic ventricular stiffening were clearly demonstrated only after appropriate allometric indexation. After adjustment for age and gender, a progressive increase in indexed systemic vascular resistance, effective arterial and ventricular end-systolic elastance and a decrease in total arterial compliance were seen from normal weight to obesity (P<0.0001). 
Conclusions: Arterial load relates to body size in an allometric fashion, calling for scaling with the use of appropriate powers. Obesity exerts adverse effects on arterial load and ventricular stiffening that go beyond the normal relationship with body size. Our study provides, for the first time, data for appropriate allometric normalization for arterial load in humans.
Abstract 220: Role of ECM Stiffness in Microvascular Inflammation
Authors: Kaustabh Ghosh, Harry Scott, Xiao Yang, Soroush Ardekani
Journal: Circulation Research (2013)

Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) is a critical regulator of inflammation as it inhibits leukocyte adhesion to vessel endothelium. Notably, reduced eNOS activity/NO bioavailability and chronic inflammation are key features, and often major determinants, of atherosclerosis and diabetic cardiovascular complications. Past approaches aimed at normalizing eNOS activity have focused primarily on the role of soluble, genetic or shear stress-mediated physical factors. However, extracellular matrix (ECM) mechanics also plays a crucial role in endothelial cell (EC) activation and function. Importantly, tissue mechanics is altered in both atherosclerosis and diabetes that are marked by chronic inflammation and impaired eNOS activity. Thus, we investigated whether there exists a causal relationship between ECM stiffness and eNOS/NO-dependent endothelial inflammation. To test this hypothesis, we cultured ECs on fibronectin-coated elastic substrates of varying stiffness (220 Pa/soft, 1000 Pa/intermediate and 4000 Pa/stiff). EC mechanosensitivity was first confirmed by quantifying the density of actin cytoskeletal filaments, which increased with increasing ECM stiffness. EC-leukocyte adhesion (inflammation) on these substrates, however, followed a biphasic trend where ECs on both 220 Pa (soft) and 4000 Pa (stiff) substrates exhibited greater leukocyte adhesion than those cultured on intermediate 1000 Pa substrates. This biphasic effect of ECM stiffness on endothelial inflammation correlated inversely with levels of eNOS-activation and NO production on these substrates. Consistent with these data, NF-kB activation was enhanced on 220 Pa and 4000 Pa while being suppressed on 1000 Pa substrates. Preliminary data implicate differential levels of calcium influx via mechanosensitive calcium ion channels in this ECM stiffness-dependent eNOS activation and endothelial inflammation. These new findings can potentially lead to superior cardiovascular disease management as they identify ECM stiffness both as a novel therapeutic target for immunomodulatory strategies as well as a key physical design criterion for the development of instructive biomaterials for cardiovascular tissue engineering.
Image quality of a novel light-emitting diode (LED)-illuminated colonoscope
Authors: Sho Sasaki, Jun Nishikawa, Hideo Yanai, Munetaka Nakamura, Junichi Nishimura, Atsushi Goto, Shu Kiyotoki, Mari Saito, Kouichi Hamabe, Ryo Tanabe, Yohei Nakamura, Hiroshi Tokiyama, Shinichi Hashimoto, Takeshi Okamoto, Shingo Higaki, Satoshi Kurai, Hiroyuki Ogihara, Yoshihiko Hamamoto, Isao Sakaida
Journal: Endoscopy (2016)

Light-emitting diodes (LEDs) are used widely for their high luminous efficiency and durability. We developed a novel prototype high definition endoscope with white LEDs and evaluated the image quality it produced against a commercial endoscope with conventional light source.The specifications of both colonoscopes were identical, except for the LED light source at the tip of the prototype. We examined 20 patients with rectal or sigmoid colon lesions and the image quality was evaluated in 40 images (one image from the LED colonoscope and one from the conventional colonoscope for each lesion) by three endoscopists. We additionally evaluated the 17 videos recorded with the LED colonoscope that were available. Image quality, mucosal and vascular color, and luminous distribution and intensity were scored on a 5-point scale.The mean score for vascular color given by one evaluator was significantly higher using the LED colonoscope than using the conventional colonoscope. The mean scores for mucosal color and luminous intensity from another evaluator were significantly lower with the LED colonoscope than with the conventional colonoscope. There were no significant differences in the luminous distribution scores for any of the evaluators. The image quality of the videos was evaluated as being similar with both colonoscopes.Image quality from the LED and conventional colonoscopes were similar, although the luminous intensity of the LEDs is inferior to that of the conventional light source at the present time.
Median Absolute Lymphocyte Count Independently Predicts Survival of Elderly Patients with Diffuse Large B-Cell Lymphoma Treated with R-Chemotherapy: Analysis of 651 Patients Included In the Czech Lymphoma Project
Authors: Vit Prochazka, Marek Trneny, David Salek, David Belada, Tomas Kozak, Tomas Papajik, Robert Pytlik, Ingrid Vasova, Alice Sykorova, Milada Jankovska, Katerina Kubackova, Martin Brejcha, Milan Matuska, Katarina Petrakova, Jan Pirnos, J. Nepomucka, David Starostka, Milan Lysy, Vit Campr, Ludmila Boudova, Marie Trnkova, Marketa Petrova
Journal: Blood (2010)
Abstract 4686: Intermittent exposure to EGFR tyrosine kinase inhibitors selects lessEGFRT790M mutant clones than continuous exposure in lung cancer cell lines
Authors: Youngjoo Lee, Kyoung-Yeon Kim
Journal: Cancer Research (2016)

Abstract Background: Drug-resistant cell lines are essential tools for investigating the mechanisms of resistance to molecular-targeted anti-cancer drugs. However, little is known about how to establish clinically relevant drug-resistant cell lines. Our study examined the impact of a drug-free period on the establishment of a cell line with clinically relevant resistance to molecular-targeted drugs. Methods: We used PC-9 cells, a lung cancer cell line carrying EGFR mutation, because this is a validated target for EGFR tyrosine kinase inhibitors (TKI). PC-9 cells were intermittently or continuously exposed to increasing concentrations of gefitinib (0.01 μM to 1.0 μM) and the emergence of the most common acquired resistance mutation in EGFR, T790M, was determined. Results: T790M was detected at a 25-fold lower drug concentration in cells continuously exposed to gefitinib (PC-9/GRc) than in cells intermittently exposed to gefitinib (PC-9/GRi) (0.04 μM vs 1.0 μM, respectively). The mutation frequencies at those drug concentrations were 19.8% and 8.0% in PC-9/GRc and PC-9/GRi cells, respectively. After drug-free culture for 8 weeks, resistance to gefitinib decreased in the PC-9/GRi cells but not in the PC-9/GRc cells. In the PC-9/GRc cells, the frequency of the T790M mutation was consistently about 20% from 0.04 μM to 1.0 μM of gefitinib. In the PC-9/GRc cells, the T790M mutation was detected in all single-cell clones, at frequencies ranging from 7.0% to 37.0%, with a median of 19.5% (95% confidence interval, 17.3%-20.9%). Conclusion: Intermittent exposure to EGFR-TKIs reduces the emergence of the EGFR T790M mutation in a lung cancer cell line. Citation Format: Youngjoo Lee, Kyoung-Yeon Kim. Intermittent exposure to EGFR tyrosine kinase inhibitors selects less EGFR T790M mutant clones than continuous exposure in lung cancer cell lines. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4686.
Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality
Authors: Mingyang Song, Teresa T. Fung, Frank B. Hu, Walter C. Willett, Valter D. Longo, Andrew T. Chan, Edward L. Giovannucci
Journal: JAMA Internal Medicine (2016)

Defining what represents a macronutritionally balanced diet remains an open question and a high priority in nutrition research. Although the amount of protein may have specific effects, from a broader dietary perspective, the choice of protein sources will inevitably influence other components of diet and may be a critical determinant for the health outcome.
Study of the effect of novel anticancer agent oncamex on gene expression profiles of preclinical breast cancer models.
Authors: Carlos Martinez-Perez, Arran Turnbull, Carol Ward, Peter Mullen, James Meehan, Edward J Jarman, Graeme Cook, Patrick IT Thomson, Colin J Campbell, Donald McPhail, David Harrison, Simon Langdon
Journal: Journal of Clinical Oncology (2016)

e14071 Background: Clinical trials now underway will assess the use of flavonoids (natural polyphenols) as anticancer agents. Previous work has shown the promising antitumor activity of Oncamex (a novel myricetin-derived flavonoid with redox properties and mitochondrial targeting) on preclinical breast cancer models and suggested the role of reactive oxygen species (ROS) modulation in these effects. Methods: We evaluated the effect at gene level of Oncamex treatment (10µM for 6 h) in cell lines representing ER+, antiestrogen-resistant and triple negative breast cancers. RNA was extracted, amplified, labeled and hybridised to Illumina microarrays for gene expression analysis (GEA). Results: Oncamex produced a strong induction of apoptosis in all models through caspase activation and modulation of the Bcl-2 family: down-regulating antiapoptotic genes (BCL2, BIRC6) and up-regulating proapoptotic genes (BNIP3, BNIP3L, CRADD). Oncamex also up-regulated caspase co-activator APAF1 and proapoptotic transcription factor FOXO3. Cell cycle was inhibited at gene level by down-regulating expression of cyclins (CCND1, CCNB1) and up-regulating checkpoint genes (CDK7, RAS1). Interestingly, Oncamex also reduced expression of mitochondrial transmembrane proteins (TOMM40, TIMM23) and NFkB-related genes linked to proliferation and progression (BCL3, IL1A, IL1R1, AKT1). These novel results have led us to a new mechanistic model: due to its mitochondrial targeting, Oncamex disrupts mitochondrial redox homeostasis and membrane integrity, leading to initiation of intrinsic apoptosis through cytochrome C release and caspase activation. Conclusions: New GEA results have shown the proapoptotic and antiproliferative effect of Oncamex at gene expression level. We have formulated a novel mechanistic model by which Oncamex effectively induces intrinsic mitochondria-dependent apoptosis. GEA results suggest Oncamex works not only at protein level, but also induces transcriptional changes. Other mechanisms may be involved which directly inhibit proliferation at gene expression level, possibly through NFkB modulation. Current work will validate and expand this model using RT-PCR and western blot.
Abstract 1920: miR-211 directly targets pyruvate dehydrogenase kinase 4 to inhibit cellular growth and glucose metabolism in triple negative breast cancer
Authors: Maheedhara R. Guda, Swapna Asuthkar, Soumen Das, Sudipta Seal, Andrew J. Tsung, Kiran K. Velpula
Journal: Cancer Research (2016)

Abstract Deregulated metabolism and aerobic glycolysis are common to many kinds of tumors including, breast cancers driven by a plethora of transcription factors. One such is hypoxia-inducible factor-1α (HIF-1α) known to drive the expression of glycolytic target genes. Here, we identify PDK4 (pyruvate dehydrogenase kinase 4) as a key regulator of HIF-1α signaling. In triple-negative human breast cancer (TNBC) cell lines, we investigated the contribution of PDK4 and HIF-1α to experimental tumor growth, core glucose metabolism and ionizing radiation effects. When these TNBC cells were exposed to 4, 6 and 8Gy treatment, we observed a linear increase in the expression levels of PDK4 and HIF-1α genes. In this study we also report that miR-211, a microRNA predicted to target PDK4 is suppressed in TNBC patient specimens as evidenced by in situ hybridization analysis. The expression levels of PDK4, HIF-1α and RICTOR were reduced with miR-211 over expression while the levels of PDH and FH were observed to be increased. Further, we observed that miR-211 conjugated to cerium oxide nanoparticles (nanoceria) showed increased cytotoxicity. Similar effects were observed when these TNBCs were treated with 5mM DCA, a potent metabolic inhibitor of PDK. Combinatory suppression of PDK4 and HIF-1α exerted synergistic inhibition of lactate released suggesting of reversal of aerobic glycolysis. Alternatively, TCGA datasets were predictive of patient survival, with a PDK4/miR-211 signature robustly predicting poor patient prognosis. Overall, our findings suggest that combined targeting of PDK4 signaling cascade with miR-211 and DCA in combination specifically regulate core glucose metabolism in TNBC. Citation Format: Maheedhara R. Guda, Swapna Asuthkar, Soumen Das, Sudipta Seal, Andrew J. Tsung, Kiran K. Velpula. miR-211 directly targets pyruvate dehydrogenase kinase 4 to inhibit cellular growth and glucose metabolism in triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1920.
Abstract 1051: Activation of PI3K pathway in breast cancer associates with tumor phospholipid fatty acid composition
Authors: Nawale Hajjaji, Flavie Arbion, Alain Fautrel, Claire Villalva, Lucie Karayan-Tapon, Marie-Lise Jourdan
Journal: Cancer Research (2016)

Abstract Background Ever since the discovery of the PI3K/Akt/mTOR pathway key role in breast cancer resistance, several molecules have been developed to target this pathway. However, mechanisms of resistance restrain their efficacy. An in-depth understanding of the interactions of PI3K pathway is essential to improve its blockade and avoid resistance. Preclinical studies reported that lipid composition of cancer cells altered the activation of PI3K pathway, thus suggesting another possible molecular interaction with lipid metabolism. The aim of this study was to analyze the relationship between the activation of PI3K pathway and tumor lipid composition in breast cancer patients. Methods Frozen and formalin-fixed paraffin-embedded tumor specimens were retrieved for 50 French patients with stage I to III primary breast cancer treated uniformly with surgery, adjuvant chemotherapy, radiation therapy and endocrine therapy. The tumor specimens were analyzed for PIK3CA gene mutation, PTEN protein expression by immunohistochemistry, and pAktS473, pAktT308, mTOR, pS6K, and S6RP by protein array. Tumor total fatty acid (FA) and phospholipid FA compositions were analysed using mass spectroscopy. Pearson test was used for correlation analyses. Results Mean age was 53 years. All tumors were ER or PR positive and HER-2 negative, and 76% were node positive. PI3K mutation was observed in 14% of cases, and 34% were PTEN negative or had low PTEN expression. Mean tumor satured fatty acid (SFA) level was 33.78 mol%, monounsaturated FA (MUFA) level was 46.46 mol%, n-6 polyunsaturated FA (PUFA) level was 18.08 mol%, and n-3 PUFA level was 1.68 mol%. Large and high grade tumors had a higher SFA content. MUFA rich tumors were frequently low grade. There was a positive correlation between d18:1/C20:0 ceramide level and Akt, mTOR and p70S6K expression. mTOR expression also correlated with 18:0 lysophosphatidylserine (lysoPS), 36:1 PS, 38:3 PS, 38:5 PS, 40:5 PS, 40:6 PS, 34:0 phosphatidylcholine (PC), 34:1 PC, and 38:3 PC. Conclusions Our results show that SFA associated with a more aggressive tumor phenotype and that PI3K pathway activation significantly correlated with fatty acid composition of specific tumor phospholipids. These results suggest a potential role of tumor lipid metabolism in PI3K pathway activation. Citation Format: Nawale Hajjaji, Flavie Arbion, Alain Fautrel, Claire Villalva, Lucie Karayan-Tapon, Marie-Lise Jourdan. Activation of PI3K pathway in breast cancer associates with tumor phospholipid fatty acid composition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1051.