tbuckley/cabot-search huggingface dataset:
Abstract 5538: Direct inhibition of ERK1/2 by VTX-11e leads to increased induction of apoptosis in a subset of pancreatic cancer cell lines as compared to MEK1/2 inhibition by selumetinib (AZD6244).
Authors: Anne M. Miermont, Holger Pflicke, Hannah Guan, Harshini Chinnasamy, Craig Thomas, Udo Rudloff
Journal: Cancer Research (2013)

Abstract Background: Intense efforts to improve current molecular therapy in pancreatic ductal adenocarcinoma (PDAC) have focused on suppression of the MAPK/ERK1/2 pathway. Inhibitors of MEK1/2, downstream target of the frequently mutated RAS oncogene, are currently in development. Recently, results of a phase II clinical trial revealed that selumetinib, a second-generation MEK1/2 inhibitor, has not yielded its promising preclinical efficacy in PDAC patients. A novel Extracellular Signal Regulated Kinase 1/2 (ERK1/2) inhibitor, VTX-11e, has been recently developed as a potent and selective inhibitor of ERK1/2. In this study, we evaluated the effects of VTX-11e on cell growth and apoptosis in pancreatic cancer cell lines and compared VTX-11e to selumetinib. Methods: Fifty percent Growth Inhibition (GI50) and Lethal Dose (LD) were determined at 72 hours in 65 PDAC cell lines with increasing concentrations of VTX-11e or selumetinib. Apoptosis was quantified by Annexin V/PI following VTX-11e or selumetinib treatment at increasing concentrations at 24 and 72 hours and 7 days. Elk1 phosphorylation levels were determined by Western Blotting as a well-established readout for downstream MAPK pathway output. Results: More than a third of VTX-11e-treated PDAC lines showed GI50 concentrations of ≤2μM. LD drug response curves of cell lines treated with VTX-11e showed cell death induction at lower concentrations than selumetinib in close to half the cell lines tested. This finding was confirmed by assessment of apoptosis by the AnnexinV/PI assay. We demonstrated that VTX-11e induced significant increased apoptosis in a subset of the PDAC lines compared to selumetinib, leading to as much as 50% apoptotic cells. Furthermore, VTX-11e and selumetinib suppressed phosphorylation of downstream target Elk1 equally. Conclusion: Our results show that the novel ERK1/2 inhibitor VTX-11e leads to a significant increase in apoptosis as compared to the MEK1/2 inhibitor selumetinib in a subset of pancreatic cancer cell lines. This finding suggests that targeting ERK1/2 directly may be a more effective therapeutic strategy than targeting upstream MEK1/2 in some PDAC. Current studies are ongoing to determine the differential mechanism of action between VTX-11e and selumetinib. Citation Format: Anne M. Miermont, Holger Pflicke, Hannah Guan, Harshini Chinnasamy, Craig Thomas, Udo Rudloff. Direct inhibition of ERK1/2 by VTX-11e leads to increased induction of apoptosis in a subset of pancreatic cancer cell lines as compared to MEK1/2 inhibition by selumetinib (AZD6244). [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 5538. doi:10.1158/1538-7445.AM2013-5538
LONG-TERM OUTCOMES AND AORTIC VALVE MOTION AFTER REIMPLANTATION TECHNIQUES OF VALVE SPARING AORTIC ROOT REPLACEMENT, USING GRAFTS WITH PSEUDOSINUSES OF VALSALVA
Authors: Haruo Yamauchi, Kan Nawata, Tomoko Nakao, Masao Daimon, Takayuki Kawata, Megumi Hirokawa, Osamu Kinoshita, Yoshifumi Itoda, Mitsutoshi Kimura, Issei Komuro, Minoru Ono
Journal: Journal of the American College of Cardiology (2016)
Abstract 5095: Differential sensitivity to dietary restriction in xenograft models harboring PI3K pathway mutations in nude mice
Authors: Travis Gulledge, Amber R. Blackwell, Robert J. Mullin, Beth A. Hollister, Lynn A. Cheatham
Journal: Cancer Research (2010)

Abstract The inhibitory effect of dietary restriction on the growth of human tumors has been well established. Recent evidence exploring the molecular mechanisms underlying this observation has been accumulating and supports a strong link with the PI3K/PTEN signaling pathway. Despite these recent advances, there remains a significant gap in our understanding of this observation. We have investigated the effects of dietary restriction on tumor growth in nude mouse xenografts of human tumor cell lines containing mutations in either PI3K or PTEN. In these experiments, dietary restriction was started after mean tumor size had reached between 60-100mg and continued until control groups reached endpoint (1000-2000mg). Diet restriction was achieved by feeding the experimental group a vitamin and nutrient enriched chow at a 20-40% reduction in overall amount relative to control groups. Our findings suggest that while activation of the PI3K/PTEN pathway may afford some resistance to dietary restriction, there may be other underlying mechanisms involved. 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 5095.
Abstract 5272: A novel organotypic 3D invasion platform to advance anticancer drug development
Authors: Johanna M. Tuomela, Jani Seppänen, Jenni Bernoulli, Sirpa Salo, Tuula Salo, Jussi Halleen
Journal: Cancer Research (2012)

Abstract Tumor cell invasion is traditionally studied in three-dimensional (3D) organotypic models composed of type I collagen and fibroblasts, where various cell types and the extracellular matrix in the tumor microenvironment (TME) affects tumor cell behavior. As both molecular and cellular components of TME are cardinal participants in tumor progression, special attention should be addressed in the growth environment. As there is urgent need for more predictive models to be utilized in drug discovery and development, organotypic 3D in vitro assay provides an applicable platform. We characterized a novel organotypic model based on human uterine leiomyoma tissue to be used in drug development. To evaluate the general applicability of the myoma model, human tongue squamous cell carcinoma cells (HSC-3) and human triple negative breast cancer cells (MDA-MB-231(SA)-GFP) were cultured on top of human uterine leiomyoma tissue. Organotypic sections were examined by immunohistochemical stainings against cytokeratin and GFP, where invasion area and depth were measured. The organotypic myoma model also gives opportunity for ELISA, RIA and Western blotting analysis of the culture media. The used cell lines were found to invade in highly distinct patterns. This organotypic 3D myoma model provides a potent tool for analyzing the behavior of tumor cells. Moreover, we conclude that established organotypic 3D in vitro platform gives remarkable advantages to screen potential therapeutic options by producing totally new commercially usable models and innovative treatment approaches that target both the cancer cells and the TME components. 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 5272. doi:1538-7445.AM2012-5272
Assessment of competence in ERCP
Authors: Lars Konge, Lars Svendsen, Peter Vilmann
Journal: Endoscopy (2015)

As endoscopists performing ERCP and researchers in assessment of endoscopic procedures we enjoyed reading the paper by Ekkelenkamp et al. concerning the learning curve for ERCP [1]. We totally agree with the authors that basic competency should not be established on the basis of number of procedures performed, but would like to point out some weaknesses in relying on self-assessment by the trainees. A review of studies comparing self-assessment with observed measures of competence found that physicians had a limited ability to accurately self-assess [2], and a recent study regarding colonoscopic polypectomy found a weak correlation between self-assessment and assessors’ scores [3]. Unfortunately, the deficient accuracy of self-assessment makes it unsuitable as a guide to improving performance, and false optimism about one’s actual competence can be dangerous [4].
Technics for Minimizing Trauma to the Tracheobronchial Tree after Tracheotomy
Authors: Fred Plum, Marcelle F. Dunning
Journal: New England Journal of Medicine (1956)

OBSTRUCTION of the upper respiratory airway due to laryngopharyngeal paralysis is frequent in acute poliomyelitis, extensive polyneuritis, head injuries, myasthenic crises or coma induced by drug poisoning. Coughing force is impaired, and cough reflexes are often depressed. A tracheotomy relieves the upper respiratory obstruction, but the tracheobronchial tree must then be aspirated directly through the tracheotomy to keep the lower airway patent. Under these circumstances, tracheobronchial secretions often increase markedly during the first few hours after tracheotomy. Blood-tinged aspirate is sometimes observed for several days after surgery when repeated suctioning is carried out. Tracheobronchitis often ensues. Antibiotic-resistant bacterial pathogens are . . .
Cell Proliferation and Chemical Carcinogenesis: Conference Summary and Future Directions
Authors: James A. Swenberg
Journal: Environmental Health Perspectives (1993)

Although it has been acknowledged for many years that cell proliferation is essential for carcinogenesis, this is the first meeting to directly focus on its role in carcinogenesis in a comprehensive manner.Many of the critical issues were outlined by Dr. Melnick in his opening remarks.Of particular interest is what data can be brought to bear on the recent controversies regarding the role of cell proliferation in studies of nongenotoxic carcinogens tested at maximum tolerated doses (MTD), and can cell proliferation alone be a cause of cancer?The symposium talks and poster presentations have been comprehensive and highly illumi- nating.It is impossible to truly summarize such a meeting, but I will try to place some of the major issues in perspective.Speakers at this meeting have frequently referred to the multistep process of carcinogenesis.Many chemical carcinogens require metabolic activation to produce reactive electrophiles.Genotoxic agents directly dam- age DNA, whereas other chemicals may generate free radicals and indirectly damage DNA.In addition, spontaneous or background damage to DNA is always present.None of this DNA damage becomes a muta- tion unless cell replication takes place.This cell replication can be the de novo replication of a particular tis- sue or cell type, it can be modulated either up or down by toxicity, or it may be influenced by exposure to exogenous agents such as promoters.After fixation of such damage in the form of mutations at critical sites in the genome, we have the very first step in carcinogenesis, the initiated cell.In the past, we have focused primarily on point mutations; however, it is now known that chromosomal changes, such as insertions,
Abstract LB-56: LGR5 is differentially expressed in hepato-gastrointestinal tumors
Authors: Eva Simon, Diana Petke, Christine Böger, Viktoria Warneke, Michael Behrens, Christoph Rocken
Journal: Cancer Research (2011)

Abstract Background: The orphan G-protein-coupled receptor (GPCR) and Wnt-target protein LGR5 was recently identified as a stem cell marker for cells with intestinal differentiation. In this study we generated a polyclonal anti-LGR5 antibody to investigate protein expression in various hepato-gastrointestinal carcinomas and its correlation with clinico-pathological patient characteristics. Materials and Methods: Differential expression of LGR5 was studied on transcriptional (real time-polymerase chain reaction) and translational level (immunohistochemistry) in carcinomas and corresponding normal mucosal specimens comprising seven different primary tumor sites, i.e. oesophagus, pancreas, stomach, liver, colon and rectum. The putative clinico-pathological relevance of LGR5-expression in terms of patient survival was studied in tissue micro arrays obtained from a cohort of 488 gastric carcinomas. Results: We succeeded to establish and characterize a highly specific antibody that recognizes the C-terminal tail of LGR5. LGR5 was differentially expressed on transcriptional and translational level in adenocarcinomas of the oesophagus, pancreas, stomach, colon, rectum, hepatocellular and cholangiocellular carcinoma of the liver compared with the adjacent non-neoplastic tissue. However, in gastric cancer tissue microarrays the expression of LGR5 had no impact on patient survival. Nevertheless, expression of LGR5 by endothelial cells of tumor vessels correlated significantly with the tumor type and tumor grade. Conclusion: Our results substantiate the significance of LGR5 on the biology of hepato-gastrointestinal carcinomas and provide evidence for its function as potential stem cell marker and candidate therapeutic target in the stomach. With our anti-LGR5 antibody we now have a useful tool for detection and further analyzes of LGR5 biological function. 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 LB-56. doi:10.1158/1538-7445.AM2011-LB-56
Ineffectiveness of capsule endoscopy and total double-balloon enteroscopy to elicit the cause of obscure overt gastrointestinal bleeding: think GIST!
Authors: I. Jovanovic, Z. Krivokapic, N. Menkovic, M. Krstic, K. Mönkemüller
Journal: Endoscopy (2011)

A 55-year-old healthy woman was admitted because of a 2-month history of recurrent melena. Two previous esophagogastroduodenoscopies (EGD) and colonoscopies were negative. On admission the patient was hemodynamically stable. Her hemoglobin concentration was 8.6 g/dL. Physical examination was unremarkable. An emergency repeat EGD was negative. Capsule endoscopy revealed fresh blood, a suspicious submucosal lesion but no mucosal erosions in the jejunum ([Fig. 1]).
Endoscopic ultrasound-guided fine-needle aspiration for the differential diagnosis of intraductal papillary mucinous neoplasms and size stratification for surveillance
Authors: Abdurrahman Kadayifci, William Brugge
Journal: Endoscopy (2014)

We read with great interest the paper by Kamata et al. published in the January issue of Endoscopy [1]. The authors examined (1) the incidence of pancreatic ductal adenocarcinomas (PDACs) concomitant to or derived from branch duct intraductal papillary mucinous neoplasm (IPMN), and (2) the usefulness of endoscopic ultrasound (EUS) relative to other imaging methods for detecting these tumors. They found that IPMN-concomitant PDACs were quite often detected at diagnosis and during follow-up, and that EUS plays an important role in management as it allows detection of small carcinomas at an early stage. We think the results make an important contribution to the current knowledge on the topic. However, there are some points that need to be clarified and discussed further.
Unusual Metastases of Thyroid Cancer to Mediastinal Blood Vessels
Authors: Hong Yun Ma, Renee Moadel, Leonard M. Freeman
Journal: Clinical Nuclear Medicine (2014)

Poorly differentiated thyroid cancer is a rare thyroid cancer, accounts for approximately 5% of all thyroid cancer cases, and is associated with a poor prognosis. It commonly metastasizes to regional lymph nodes, lung, and bones. We present a patient with poorly differentiated thyroid cancer with unusual extensive spread to mediastinal blood vessels.
SAT0309 Strontium Ranelate Prevents Radiological Progression in Patients with Primary Knee Osteoarthritis
Authors: J. Reginster, F. Berenbaum, P. Nash, O. Zamani, M. Cohen-Solal, G. Bianchi, J. Branco, F. Navarro, C. Cooper
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objectives</h3> Strontium ranelate (SrRan) has demonstrated a structure-modifying activity associated with symptomatic improvement in patients with knee osteoarthritis (OA) the SEKOIA study). The aim of this analysis was to describe the proportion of patients in whom radiological OA progression was prevented in each treatment group, when considering different cut-offs of JSN. <h3>Methods</h3> SEKOIA study included patients with symptomatic primary knee OA (Kellgren and Lawrence [KL] grade 2 or 3, joint space width [JSW] 2.5–5 mm) randomly allocated to SrRan 1 or 2 g/day, or placebo. Primary endpoint was radiographic change in JSW of the medial tibiofemoral compartment from baseline to LOCF. JSW was measured yearly using a validated computer-assisted centralised reading method. Patients with no relevant radiological OA progression were defined as those with a JSW loss between baseline and End, lower than 0.1 mm (JSN ≥-0.1 mm), or 0.2 mm (JSN ≥-0.2 mm) or 0.3 mm (JSN≥-0.3 mm). Patients who withdrew from the study were counted as non-responder patients. SrRan 1g and SrRan 2g treatment groups were compared to placebo using a chi² test. <h3>Results</h3> ITT set included 1371 (82%) patients. Age was 63±7 years, BMI was 30±5 kg/m2, JSW was 3.5±0.8 mm. 61% were KL II. 69% were female. A significantly greater proportion of patients in both SrRan groups had no radiological progression as compared to placebo: 40.5% and 44.1% vs. 32.8% of responders respectively (p=0.006 and p=0.003) when applying the 0.3 mm threshold. In other words, the proportion of responders compared to placebo increased by 24% and 34% in the SrRan 1g and 2g groups respectively, with a number of patients needed to be treated (NNT) of 13 and 9 respectively. Similar differences between groups were observed for responders at additional JSN cut-offs: <h3>Conclusions</h3> Treatment with SrRan is associated with a significantly greater number of patients without OA radiological progression over 3 years. <h3>Disclosure of Interest</h3> J. Reginster Consultant for: Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GSK, Roche, Merckle, Nycomed, NPS, Theramex, UCB, Paid instructor for: Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis, Servier, Roche, GlaxoSmithKline, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Theramex, Nycomed, Novo-Nordisk, F. Berenbaum Grant/research support from: Servier, P. Nash Grant/research support from: Servier, Paid instructor for: Servier, O. Zamani: None Declared, M. Cohen-Solal: None Declared, G. Bianchi Grant/research support from: Servier, J. Branco Grant/research support from: Servier, F. Navarro: None Declared, C. Cooper Consultant for: Amgen, ABBH, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Shire, Servier, Paid instructor for: Amgen, ABBH, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Shire, Servier
Art, science and randomization
Authors: Kamran Abbasi
Journal: Journal of the Royal Society of Medicine (2011)

As I write, a television pundit describes the London riots as a ‘random’ act. Random is a word that people tend to use randomly, without a definite plan or purpose. Medicine, which some have called a science, would offer a reasonably prominent spot to random and its many derivatives, such as randomization, in a word cloud of conversations at vivas and journal clubs.

But science doesn't come naturally to most clinicians and neither do the finer points of randomized controlled trials – and those befuddled clinicians range from medical students and junior doctors to professors and journal editors. Applying received wisdom and an instinctive feel for doing the right thing (art) remain more natural skills than applying hard logic (science). That doesn't mean we execute either approach well, and indeed a balance of the two is probably the essence of good medical practice.

Clinicians, it seems, are increasingly unlikely to win a Nobel Prize in Medicine. According to Hutan Ashrafian and colleagues, clinicians accounted for 79% of medical scientists to win a Nobel Prize in the first 30 years of the awards; a figure that has dropped to 26% in the last 30 (JRSM 2011;104:387–9). Focus is on basic biological mechanisms of medical discovery instead of translation of scientific discoveries to wider clinical use.

Is this even a problem? Medicine has changed. Clinicians were once taught at length about the scientific method and the philosophy of science. Today, technological advances and our greater understanding of the human body offer us much else to fill the heads of students and trainees. We have guidelines and algorithms, polices and patient charters plenty enough to learn. Science has become a specialist subject. For most clinicians, there is no value in being able to distinguish a frequentist from a Bayesian. No benefit in understanding the science in the healing arts.

Clinical medicine is a messy business, and Ashrafian and colleagues argue for special dispensation. Constructing a flawless scientific study to evaluate translational innovation is such an immense challenge that those who interpret Alfred Nobel's wishes should be mindful of the difficulties.

In the meantime, some might view medicine as more art than science but many medical researchers consider the application of the scientific method to the messy world of clinical medicine a fascinating and essential challenge. To these gurus, a riot is no more random than the purpose of randomization in a clinical trial is a purely statistical construct. In case I've lost you, Ian Chalmers will help you understand how the landmark 1948 MRC trial of streptomycin used allocation based on random numbers to minimize allocation bias, enable like to be compared with like, and fulfil a clinical need (JRSM 2011;104:383–6).
654 A NEW CLASSIFICATION OF PRIMARY LIVER CARCINOMAS BASED ON THEIR POSSIBLE CELLULAR ORIGIN
Authors: M. Komuta, V. Vandecaveye, O. Olivier, F. De Keyzer, W. Lalemen, C. Verslype, W. Van Steenbergen, J. Pirenne, F. Nevens, R. Aerts, B. Topal, T. Roskams
Journal: Journal of Hepatology (2013)