tbuckley/cabot-search huggingface dataset:
Abstract 4045: c-Met inhibition synergistically enhances death receptor-induced apoptosis via upregulation of DR5 in papillary thyroid cancer
Authors: Prashant Bavi, Rong Bu, Azhar R. Hussain, Maqbool Ahmed, Saravanan Thangavel, Saif Al-Sobhi, Abdulrahman Al-Nuaim, Tarek Amin, Mohammed Ahmed, Shahab Uddin, Khawla S. Al-Kuraya
Journal: Cancer Research (2011)

Abstract The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in variety of human malignancies. Previously we have shown that c-Met was overexpressed in Middle Eastern Papillary Thyroid Cancer (PTC) and significantly associated with poor prognoses. In this study, we investigated the functional link between c-Met/AKT signaling pathway and Dearth Receptor 5 (DR5) in a large cohort of PTC patient samples, a panel of PTC cell lines, and xenografts in a NUDE mouse model by using tissue microarray, MTT, flow cytometry and DNA fragmentation assays and western blotting. Immunohistochemistry staining showed a significant association of p-Met with DR5 in PTC patient samples. The PHA665752, an inhibitor of c-met tyrosine kinase, inhibited cell proliferation and induced apoptosis in a dose dependent manner in all cell lines studied. PHA665752 treatment resulted in dephosphorylation of c-Met, AKT and its downstream effector molecules FOXO1, GSK-3 and pBad. Additionally, treatment of PTC cell lines with PHA665752 resulted in activation of caspases-9 and 3, cleavage PARP and apoptosis. Moreover, HGF, a ligand of c-Met, stimulated the growth of all PTC cell lines via activation of c-MET and AKT. In addition, pre-treatment of PTC cell line with PHA665752 abrogated the HGF stimulated growth and activation of c-met and AKT further suggesting the critical role of c-met and AKT pathway in PTC pathogenesis. Furthermore, c-Met inhibitor PHA665752 up-regulated DR5 expression in PTC cell line cells, and synergistically potentiated death receptor-induced apoptosis with TRAIL. Finally, co-treatment with PHA665752 and TRAIL causes more pronounced effect on PTC xenograft tumor growth in NUDE mice. Our data suggest that c-Met/HGF pathway may be a potential target for therapeutic intervention for treatment of PTC with c-Met inhibitor alone or in combination of conventionally therapeutic agents. 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 4045. doi:10.1158/1538-7445.AM2011-4045
Abstract 5175: L1 stimulation of human glioma cell motility correlates with FAK activation
Authors: Muhua Yang, Yupei Li, Magdy I. Boulos, Deni S. Galileo
Journal: Cancer Research (2010)

Abstract Our previous studies showed the expression and proteolysis of neural adhesion molecule L1 (CD171) in human glioma cell lines and human glioma surgical samples. The proteolysis of this molecule was suggested to autocrine stimulate glioma cell motility through binding to integrin receptors (Yang et al., 2009). To further investigate the mechanism of this stimulation, in this study, a lentivirally introduced shRNA was used to attenuate L1 expression in human glioma T98G cells (T98G/shL1 cells), which resulted in 95% decreased expression compared to empty vector infected control cells. L1 attenuated cells exhibited 50% decreased cell motility compared to control cells as shown by time lapse microscopy and the quantitative “Super Scratch” assay. These slower T98G/shL1 cells showed a 68% decrease in FAK activity and an approximately 36% increase in focal complex size compared to control cells. These results suggest that T98G/shL1 cells had decreased focal complex turnover, which resulted in their slower migration. Conditioned media containing the L1 ectodomain was made from CHO cells infected with a lentiviral vector expressing the human L1 ectodomain sequence. Adding L1 conditioned media 1) rescued the cell motility in T98G/shL1 cells and 2) increased cell motility in U118 cells (a grade III human glioma cell line lacking of endogenous L1 expression) by 30% compared to the control cells. These results support a model for stimulation of glioma cell motility through the L1 ectodomain after ADAM10 proteolysis (Yang et al., 2009). In order to examine L1 function in glioma cell invasion into brain tissue, a novel embryonic chick model was used. Injection of GFP labeled T98G cells and dissociated cells from human glioma surgical samples into embryonic chick brains resulted in extensive invasion after 4 days, and this in vivo system is being used to study L1 function in glioma cell invasion. Confocal microscopy of immunostained tissue sections revealed that cell surface L1 was missing in cells located at the margin of the tumor as opposed to cells in the tumor mass. These results are consistent with our previous finding that L1 was expressed on the surfaces of confluent T98G cells in culture, but was lost from the cell surface along the edge of a scratch into which cells migrated. These studies suggest a general mechanism where the L1 ectodomain autocrine stimulates glioma cell motility and invasion by binding to integrin receptors, which activates FAK and thereby increases turnover of focal complexes. Supported by NIH INBRE. 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 5175.
Abstract 4957: Mixed Lineage Kinase 3 mediates vanadium-induced cell death in cancer cells
Authors: Velusamy Rangasamy, Gautam Sondarva, Sushan Tuladhar, Basabi Rana, Ajay Rana
Journal: Cancer Research (2012)

Abstract Vanadium is a transition metal and occurs naturally in a variety of minerals. In mammals, vanadium has been shown to promote cancer cell death and can also mimic insulin action, most probably through the inhibition of cellular tyrosine phosphatase and subsequent activation of signaling pathways. The mechanism by which vanadium causes cancer cell death is still not known. Interestingly, it has been shown that various mitogen activated protein kinase (MAPK) members are activated upon vanadium treatment. However, the contribution of any specific MAPK member that mediates vanadium-induced cell death has not been clearly delineated. It has been reported that JNK is activated by vanadium and therefore we investigated the role of Mixed Lineage Kinase 3 (MLK3) on vanadium-induced cell death. MLK3 is a MAP3K member that is known to specifically activate JNK pathway. We have earlier reported that MLK3 activation promotes cell death in cancer and neuronal cells. Our results demonstrated that endogenous MLK3 was activated by vanadium and MLK3 was highly phosphorylated on tyrosine residues. We also identified Src as a tyrosine kinase that phosphorylated MLK3 on specific tyrosine residues and phosphorylation of these tyrosine residues by Src was essential for MLK3 activation. Vanadium-induced cancer cell death was mediated by MLK3 or MLKs, because CEP-1347, a pan MLK inhibitor, prevented this cell death. Furthermore, the tyrosine phospho-deficient mutants of MLK3 also prevented vanadium-induced cell death. Interestingly, the activity of Src was seen to be in parallel with MLK3 kinase activity in human primary breast tumors. Taken together, our data demonstrate that tyrosine phosphorylation of MLK3 by oncogenic Src leads to MLK3 activation, which subsequently promotes vanadium-induced cell death in cancer cells. Our results also implicate a paradoxical pro-apoptotic role of Src in cancer cells, and thus it is conceivable that in tumors where both Src and MLK3/MLKs activities are higher, targeting of this axis might promote cell death. 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 4957. doi:1538-7445.AM2012-4957
Improving Access and Mobility — The Interstate Medical Licensure Compact
Authors: Humayun J. Chaudhry, Lisa A. Robin, Eric M. Fish, Donald H. Polk, J. Daniel Gifford
Journal: New England Journal of Medicine (2015)

An Interstate Medical Licensure Compact released last year provides a mechanism for managing the portability of physicians' medical licenses to improve access to care. Many state boards have voted to support it, and related legislation is gaining ground in multiple states.
MARFAN SYNDROME RELATED TO TGFβR2 MUTATION AND SUDDEN DEATH: A ROLE FOR ABNORMAL VENTRICULAR REPOLARIZATION RELATED ARRHYTHMIAS?
Authors: Fabrice Extramiana, Olivier Milleron, Sandy Elbitar, Arianna Uccelini, Gabriel Delorme, Florence Arnoult, Isabelle Denjoy, Maud Langeois, Myrtille Spentchian, Veronique Fressart, Pierre Maison-Blanche, Patrick De Jode, Marianne Abifadel, Antoine Leenhardt, Catherine Boileau, Guillaume Jondeau
Journal: Journal of the American College of Cardiology (2016)
VPB's — The Benign and the Malignant
Authors: Michael Lesch
Journal: New England Journal of Medicine (1977)

Angiographic evaluation of patients with coronary-artery disease has demonstrated that the two major determinants of mortality in the chronic phases of this disease are the extent of atherosclerosis within the coronary arterial tree (i.e., involvement of one, two or three coronary vessels) and the degree of ventricular dysfunction resultant from the atherosclerotic process.1 Thus, patients with single-vessel disease and normal ventricular function are known to have mortality rates identical to disease-free cohorts matched for age whereas a markedly increased mortality is experienced by patients with three-vessel disease and severe ventricular dysfunction.In contrast, during the most acute manifestation of coronary . . .
PARE0002 Patient osteoporosis information leaflet “the bone thief, how to stop him”
Authors: J.-N. Dachicourt, C. Bonnet, C.L. Benhamou, R. Ghozlan, F. Alliot Launois, C. Cardon, L. Carton, T. Thomas, P. Tauveron, L. Grange
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Osteoporosis is a real matter or public health affecting more than 1 woman out of 3 and 1 man out of 12 (1). Over 50 years old, at least 1 woman out of 3 and 1 man out of 8 will suffer from an osteoporotic-caused fracture (2). Osteoporosis is a heavy-consequence pathology as every thighbone-upper-end-fracture leads to an average 21 days of hospitalization, 21% of patients die within three months, with a twice higher mortality rate amongst men. Silent before fracture happens, this pathology is commonly under-treated and under-diagnosed. <h3>Objectives</h3> The public has to realize how serious it is and large scale screening tests must take place to improve care. Aflar, created in 1928 and state-approved for its public utility, has a mission of improval of care for all rheumatic and musculo-skeletal disorders, among them osteoporosis. It is the only french association representing osteoporosis patients. It aims at supporting public information about the disease. Aflar has decided to create a leaflet in partnership with GRIO in order to help french population take conscience of osteoporosis. <h3>Methods</h3> To conceive this new public information tool on osteoporosis, a physical brainstorming meeting took place, as well as two phone conferences about redaction. Patients members of AFLAR were included, as well as AFLAR and GRIO recognized experts. They all participated equally to the conception and the redaction. The goal was to determine the key messages to improve care of osteoporosis and therefore its screening and its treatment. <h3>Results</h3> We offer a triptycal A4 leaflet answering major questions in an attractive way: I'm young, am I concerned ? hy is it a problem if it doesn't cause pain ? How do I know about my bones health ? What is osteoporosis ? What can I do to prevent it ? At the end, an validation quizz helps take conscience of one's own knowledge. <h3>Conclusions</h3> This document, innovative in its conception including patients, is to become a leading information tool on osteoporosis for the french population. Created for the public, it's been elaborated with AFLAR patients and GRIO experts. It is the first in a new series of tools respecting modern conception and fabrication standards, placing the patient at the heart of the editorial process. <h3>References</h3> Dargent-Molina P. Epidémiologie de l'ostéoporose. Médecine thérapeutique 3 (1997):5-12. Dargent-Molina P. Epidémiologie et facteurs de risque de l'ostéoporose. La Revue de Médecine Interne 25 (2004) S517-S525. <h3>Disclosure of Interest</h3> None Declared
PTU-059 Adalimumab Therapy Reduces Hospitalization and Colectomy Rates in Patients with Ulcerative Colitis among Initial Responders
Authors: B G Feagan, W J Sandborn, M Skup, M Yang, A Lazar, R B Thakkar, J Chao, P M Mulani
Journal: Gut (2013)

<h3>Introduction</h3> Two double-blind, placebo-controlled trials (ULTRA 1 and 2) revealed that adalimumab (ADA) therapy significantly reduces hospitalisation and non-significantly decreases colectomy rates in patients with moderate to severe ulcerative colitis (UC).<sup>1</sup> <h3>Methods</h3> We assessed the effect of an ADA 160/80/40 mg treatment regimen on risk reduction of all-cause and UC-related hospitalisation and colectomy in these 2 trials among initial ADA responders. The pooled dataset included 963 patients (480 ADA, 483 placebo [PBO]). Hospitalization and colectomy events were based on safety reports reviewed by 2 gastroenterologists who were blinded to treatment. Conservatively, hospitalizations from initial ADA non-responders (per Mayo score at Week 8) through Week 8 were counted, but were censored after Week 8 to reflect the clinical practise pattern of continuing treatment in initial ADA responders. Risk and number of hospitalizations were compared between groups using person-year (PY)–based incidence rates (IRs) and Poisson regression, respectively; Z-scores were used to assess statistical differences.2 <h3>Results</h3> 35% and 34% reductions in the number of patients hospitalised and number of hospitalizations for any reason, respectively, were observed with ADA therapy vs. PBO (<b>table</b>, <i>P</i> &lt; 0.05 for both comparisons). When UC-related hospitalizations were compared, reductions for rate (50%) and number (54%) of hospitalizations were both statistically significant, too. <h3>Conclusion</h3> Initial ADA-responders had a significantly lower risk for UC-related and all-cause hospitalisation compared with PBO. Reduction of all-cause hospitalisation is unique for ADA compared with any other anti–tumour necrosis factor agent. A non-significantly lower colectomy rate in patients receiving ADA vs. those receiving PBO was also observed. <h3>Disclosure of Interest</h3> B. Feagan Grant/Research Support from: AbbVie, Consultant for: AbbVie, W. Sandborn Grant/Research Support from: AbbVie, Consultant for: AbbVie, Conflict with: AbbVie, M. Skup Shareholder of: AbbVie, Employee of: AbbVie, M. Yang Shareholder of: AbbVie, Employee of: AbbVie, A. Lazar Shareholder of: AbbVie, Employee of: AbbVie, R. Thakkar Shareholder of: AbbVie, Employee of: AbbVie, J. Chao Shareholder of: AbbVie, Employee of: AbbVie, P. Mulani Shareholder of: AbbVie, Employee of: AbbVie <h3>References</h3> Feagan BG, <i>et al.</i> Presentation OP209, UEGW, Stockholm, Sweden. October 22–26, 2011. Miettinen O. <i>Am J Epidemiol</i><i>.</i> 1976; 103:226–35.
Cutaneous Necrosis Associated with Cold Agglutinins
Authors: Antonia Jeskowiak, Tobias Goerge
Journal: New England Journal of Medicine (2013)

A 31-year-old woman presented with multiple necrotic skin lesions on her nose, ears, and legs that had developed over a few days. The lesions had begun as erythematous-bluish macules that soon became bullous and subsequently developed into thick necrotic plaques.
Abstract 3255: Tetrahydropyridine derivatives: Novel and potent histone demethylase LSD1 inhibitors
Authors: Patrick S. Callery, Wisut Wichitnithad, Elizabeth Borysiewicz, Gregory W. Konat, Gregory W. Konat
Journal: Cancer Research (2011)

Abstract Flavin-dependent histone demethylases play an important role in epigenetic gene regulation. The most studied enzyme, LSD1 (KDM1), catalyzes the oxidative demethylation of methylated Lys4 of histone H3. Known LSD1 inhibitors also inhibit other flavin-dependent enzymes, in particular monoamine oxidase (MAO). Therefore, selective inhibition of LSD1 is a significant drug discovery target. We designed, synthesized and evaluated in vitro a series of eleven N-substituted tetrahydropyridines as inhibitors of flavin-dependent enzymes. Complete chemical structures of the compounds used will be disclosed at the time of presentation. The inhibition of LSD1 was measured in rat glioma C6 cells. Briefly, cells grown in serum-free medium were treated with the inhibitors for 24 h, and the level of Lys4 dimethylated form of histone H3 was measured by immunoblot. MAO A activity was determined using human recombinant enzyme with kynuramine as substrate. The most selective among the inhibitors showed low nanomolar potency toward LSD1 and weak inhibition of MAO A. The observed high potency and substrate selectivity justifies further evaluation of the drug discovery potential of the tetrahydropyridine scaffold. 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 3255. doi:10.1158/1538-7445.AM2011-3255
Differential Diagnosis of Oliguria in Aged Patients
Authors: I. Norman Sporn, Ruben G. Lancestremere, Solomon Papper
Journal: New England Journal of Medicine (1962)

A DECREASE in extracellular-fluid or blood volume may result in oliguria by the following mechanisms: diminished renal perfusion, without associated damage to the renal tubular cells; or acute tubular insufficiency, with or without necrosis of the tubular cells.¶ 2 It is of clinical importance to differentiate these two mechanisms, since in the first fluidreplacement therapy may prevent the development of tubular insufficiency.2 3 4 In some cases it may be difficult, if not impossible, to establish the proper diagnosis on the basis of history, physical examination, urinalysis or urine volume. In such circumstances it has been emphasized that the concentration of total solutes . . .
Facial Angiofibromas Associated with Tuberous Sclerosis
Authors: Heather Klein Hamilton, Viseslav Tonkovic-Capin
Journal: New England Journal of Medicine (2011)

A 29-year-old woman presented with a long-standing history of yellow-orange papules on her nose and cheeks, skin-colored papules at the proximal nail fold of several toes, and a skin-colored plaque on her back. These findings were diagnosed as facial angiofibromas, periungual fibromas, and a shagreen patch, respectively. They are characteristic of tuberous sclerosis, an autosomal dominant disorder in which mutations in tumor suppressor gene TSC1 or TSC2 result in the formation of benign hamartomas throughout the body. Previous computed tomography of the brain had shown such hamartomas in the patient. Almost all patients with this condition have at least one . . .
P06 Role of serum hyaluronic acid in predicting mortality in patients with chronic liver disease
Authors: N. Plevris, N. C. Mcavoy, P. C. Hayes
Journal: Gut (2011)

<h3>Introduction</h3> Currently liver biopsies are used to assess extent of liver fibrosis and provide prognostic information in liver disease. Hyaluronic acid (HA) is a non-invasive serum marker that has been shown to correlate well with different degrees of hepatic fibrosis. Despite this the prognostic abilities of HA still remain to be established. <h3>Aim</h3> In this study we aim to establish the relationship between levels of serum HA and survival, as well as determine the sensitivity and specificity of HA for predicting death in patients with chronic liver disease of varying aetiology. <h3>Method</h3> Patients seen at the department of hepatology, Royal Infirmary of Edinburgh between 1995 and 2010 who had serum HA levels measured were followed up for death from the date of HA measurement until the 1 November 2010 by examination of clinical records on TRAK (NHS Lothian). The cumulative probability for survival from liver related death and overall deaths at 1-, 5- and 8-year follow-up was determined. Receiver operating characteristic (ROC) curves were generated to assess the sensitivity and specificity of HA levels at predicting liver-related death at 1, 3 and 5 years. <h3>Results</h3> HA levels were available for 632 patients. The median follow-up time (from HA measurement to death or ‘last known alive’) was 2.7 years (range 0.0–8.0; IQR 0.9–4.4). Survival analysis showed that HA levels &gt;400 μg/l are associated with a significantly lower probability of survival from liver related death compared to patients with values of &lt;100 μg/l and 100–400 μg/l at 1 year (88%, p&lt;0.01), 5 years (68%, p&lt;0.001) and 8 years (49%, p&lt;0.05). In addition, the probability of survival from liver related death at 8 years was also significantly less in patients with HA value of 100–400 μg/l compared to patients with HA &lt;100 μg/l (83%, p&lt;0.05). Similar results were observed when assessing probability of survival from overall deaths. The unadjusted area under the ROC curve for predicting liver related mortality for HA at 1-, 3- and 5 years was 0.89 (CI 95% 0.84 to 0.94), 0.85 (CI 95% 0.79 to 0.91) and 0.79 (CI 95% 0.71 to 0.87) respectively. Optimum cut-off value for 1-, 3-and 5 year for predicting liver death was 326 μg/l (88% sensitivity/79% specificity), 267 μg/l (74% sensitivity/79% specificity) and 203 μg/l (71% sensitivity/72% specificity) respectively. <h3>Conclusion</h3> In this study we have shown that patients with high levels of serum HA have an increased liver and all cause mortality. In addition, HA levels are both sensitive as well as specific at determining liver related mortality. This highlights the potential use of HA as a non-invasive marker for prognosis in patients with chronic liver disease of varying aetiology.
Case 42-1993
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely, David B. Smith, Christopher P. Stowell, Nancy L. Harris
Journal: New England Journal of Medicine (1993)

Presentation of CaseA 62-year-old woman was admitted to the hospital because of nausea, vomiting, and jaundice two weeks after an aortic valvuloplasty.The patient had had a heart murmur “since birth,” for which she was followed annually, and had remained free of symptoms.Eleven months before entry, evaluation revealed splenomegaly. Laboratory tests were performed (Table 1). Three months before admission laboratory tests were performed (Table 1 and Table 2). A biopsy specimen of the bone marrow was normal, with adequate megakaryocytes. A computed tomographic scan of the abdomen and pelvis, obtained after the intravenous injection of contrast material, revealed marked splenomegaly, . . .