tbuckley/cabot-search huggingface dataset:
Abstract SY24-03: Targeting IAP proteins in cancer: From molecular mechanism to therapeutic application.
Authors: Simone Fulda
Journal: Cancer Research (2013)

Abstract Evasion of apoptosis is a hallmark of human cancers and contributes to tumor formation and progression as well as resistance to current cancer therapies, which largely rely on intact cell death pathways in cancer cells. Apoptosis resistance can be caused by aberrant expression of antiapoptotic proteins, for example, Inhibitor of Apoptosis“ (IAP) proteins, which are expressed at high levels in many human cancers. Since IAP proteins block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases, they present promising therapeutic targets. Among the therapeutic approaches that have been developed to target IAP proteins, the most widely used strategy is based on mimicking the IAP-binding motif of second mitochondria- derived activator of caspase (SMAC), which functions as an endogenous IAP antagonist. Alternative strategies include transcriptional repression and the use of antisense oligonucleotides. Current and future perspectives on neutralizing IAP proteins for therapeutic intervention in human cancers will be discussed. Citation Format: Simone Fulda. Targeting IAP proteins in cancer: From molecular mechanism to therapeutic application. [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 SY24-03. doi:10.1158/1538-7445.AM2013-SY24-03
The Value of Interictal Brain SPECT in Epilepsy Patients Without Mesial-Temporal Sclerosis
Authors: ALAN SIEGEL, PETRA LEWIS, ADRIAN M. SIEGEL
Journal: Clinical Nuclear Medicine (2002)

Purpose Most of the literature concerning interictal SPECT brain scanning in patients with seizures has involved the evaluation of those with temporal lobe epilepsy. The authors' aim was to determine the utility of interictal SPECT in patients with neocortical epilepsy. Materials and Methods Eighty-four patients with neocortical epilepsy were evaluated with 95 interictal SPECT scans and magnetic resonance imaging (MRI). Results Fifty-four percent of studies with normal MRI findings had SPECT images without regions of hypoperfusion. Sixty-one percent of patients with abnormal MRI results had matching defects visible on SPECT images. Fourteen scans (only 24%) had focal hypoperfusion by SPECT and no obvious matching MRI finding. Conclusions Interictal SPECT, without a comparison ictal study, is of potentially limited value in localizing neocortical seizure foci. SPECT findings usually match MRI findings. Interictal SPECT, however, may still be of value in confirming abnormalities detected by ictal examination.
Adeno-Associated Virus Mediates Long-Term Gene Transfer and Delivery of Chondroprotective IL-4 to Murine Synovium
Authors: Shohei Watanabe, Tomoyuki Imagawa, Gregory P. Boivin, Guangping Gao, James M. Wilson, Raphael Hirsch
Journal: Molecular Therapy (2000)

<h2>Abstract</h2> Treatments for rheumatoid arthritis and other inflammatory arthropathies are often ineffective at preventing joint destruction. Long-term genetic modification of the cells lining the joint space (synoviocytes) in vivo represents a potential method for the treatment of these chronic conditions. However, a vector capable of efficiently transducing synoviocytes <i>in vivo</i> for a persistent period has not been available. The present report describes the genetic modification of synoviocytes in vivo using recombinant adeno-associated virus. High-titer adeno-associated virus encoding the gene for <i>Escherichia coli</i> β-galactosidase was injected into the knee joints of mice. Synovial tissues were then examined for β-galactosidase transgene expression by <i>in situ</i> staining and by fluorometry. High-efficiency, persistent transgene expression was observed in the synovium with no evidence of vector-induced inflammation. Expression was observed for at least 7 months and was higher in arthritic than nonarthritic mice. Gene transfer of murine IL-4 to the joints of mice with collagen-induced arthritis led to detectable levels of IL-4 in the joint and protection from articular cartilage destruction. These data suggest that adeno-associated virus may be a useful vector for gene delivery to the synovium for the treatment of inflammatory arthropathies.
Abstract 3805: Single cell evolution of AKT pathway activation drives T-cell acute lymphoblastic leukemia relapse.
Authors: Jessica S. Blackburn, Sali Liu, Kimberly Dobrinski, Jayme Ranalli, Sarah Martinez, Charles Lee, David Langenau
Journal: Cancer Research (2013)

Abstract The aggressive and unpredictable behavior of relapsed T-cell acute lymphoblastic leukemia (T-ALL) presents a major clinical challenge, with &amp;gt;70% of children and &amp;gt;90% of adults unable to survive relapsed disease. Relapsed T-ALL often acquires mutations that are not found in the primary malignancy. It is these new mutations that allow clones to survive treatment and drive relapse growth. In order to identify the genes and pathways responsible for T-ALL relapse, we have developed a transgenic zebrafish model of relapsed T-ALL where single fluorescently-labeled leukemic cells are transplanted into genetically identical recipient fish and functionally assessed for differences in relapse growth. Using serial transplantation of single T-ALL cells and &amp;gt;6,000 recipient animals, we have followed single-cell evolution of T-ALL and identified critical drivers of relapse. These experiments showed that 6 of 49 individual T-ALL cells significantly increased their ability to form relapse over time. Analysis of T-ALL clones pre- and post-evolution showed that AKT pathway activation was correlated with increased relapse potential. Subsequent studies utilizing transgenic zebrafish that over-expressed activated AKT in developing T-ALL demonstrated that AKT signaling increased relapse potential 10-fold. Transgenic epistatic experiments revealed that AKT signaling plays two distinct roles in T-ALL relapse: the AKT/mTORC1 pathway directly enhanced relapse potential, while AKT mediated stabilization of the Myc protein increased T-ALL aggressiveness. Moreover, small molecule inhibition of AKT signaling reduced T-ALL relapse potential in vivo by 25-fold and synergized with Dexamethasone, a common cytotoxic chemotherapy, to significantly enhance cell killing in both zebrafish and human T-ALL. Activation of AKT signaling is associated with poor prognosis and drug resistance in human T-ALL, which, together with our work, suggests that AKT will be a useful molecular target in the treatment of T-ALL. Our experiments have documented the functional heterogeneity of single leukemic cells and identified AKT as a critical driver of T-ALL aggression, relapse formation, and insensitivity to therapy. These are first studies performed in any model to follow single cell evolution as it relates to relapse, opening new and exciting avenues of study to uncover genetic pathways that drive cancer malignancy. Citation Format: Jessica S. Blackburn, Sali Liu, Kimberly Dobrinski, Jayme Ranalli, Sarah Martinez, Charles Lee, David Langenau. Single cell evolution of AKT pathway activation drives T-cell acute lymphoblastic leukemia relapse. [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 3805. doi:10.1158/1538-7445.AM2013-3805
P90 -1 antitrypsin (a1AT) polymers cause extreme hepatocyte ageing
Authors: M. Mela, S. Davies, S. Verma, P. Tachtatzis, E. Miranda, D. A. Lomas, N. Coleman, G. Alexander
Journal: Gut (2011)

Introduction a1AT, synthesised predominantly in the liver, is the archetypal inhibitor of the serpin protein family. a1AT deficiency is a common inherited disorder; Glu342Lys substitution causes abnormal folding of mutant protein, which may polymerise and aggregate in the endoplasmic reticulum. a1AT aggregates are the histological hallmark of a1AT-related liver disease but it is unclear how aggregates induce liver injury. Aim To determine whether hepatocytes containing polymerised-a1AT (pa1AT) had accelerated ageing manifest as shortened telomeres. Method Liver biopsy sections were studied from 60 patients with a1AT- related liver disease with a broad spectrum of fibrosis, recruited from the Cambridge metabolic liver clinic (30 were homozygous and 30 heterozygous). Comparison was made with sections from 20 age and sex matched time zero biopsies obtained at liver transplant. Mean hepatocyte telomere length, a reflection of age, was measured by quantitative fluorescent in situ hybridisation (QFISH) with a PNA Cy5 probe. Nuclei were identified with DAPI, hepatocytes with antibody against hepar-1 and pa1AT with specific mouse monoclonal antibody (2C1). Images were obtained and analysed using the Olympus ScanR software system ([Abstract P90 figure 1][1]). Statistical analysis used Graph Pad Prism. ![Abstract P90 Figure 1][2]</img> Abstract P90 Figure 1 QFISH image which highlights the a1AT polymers (shown as bright white speckles), surrounding some of the affected hepatocytes. Results Hepatocyte nuclei were larger in patients with both homozygous and heterozygous a1AT deficiency (p=0.002) and had shorter telomeres (p<0.0001) than age and sex matched controls. Homozygous patients had shorter hepatocyte telomeres than heterozygous patients (p=0.003). Hepatocyte nuclei in both homozygous and heterozygous a1AT deficiency were larger in cells with pa1AT compared to neighbouring cells without pa1AT (p=0.002). Hepatocyte telomeres were far shorter in cells that contained pa1AT than neighbouring hepatocytes without pa1AT (p<0.0001, [Abstract P90 figure 2][3]). Hepatocytes with pa1AT showed additional telomere shortening with increased age (p=0.0002). Fibrosis stage was related to telomere shortening- telomeres shortened as the stage of fibrosis increased. ![Abstract P90 Figure 2][2]</img> Abstract P90 Figure 2 Hepatocyte telomere length in patients with a1AT deficiency with or without polymerised a1AT. Conclusion Senescence, characterised by increased nuclear size and shortened telomeres, was present in hepatocytes from patients with both homozygous and heterozygous a1AT related liver disease. The novel 2C1 antibody showed that these markers of senescence were even more marked in cells expressing pa1AT. The steps between pa1AT expression and accelerated senescence are a clear target for therapeutic intervention. [1]: #F1 [2]: pending:yes [3]: #F2
P1308 HEPATOPROTECTIVE EFFECTS OF NGM282 COMPARED TO OBETICHOLIC ACID AND BEZAFIBRATE IN MOUSE MODELS OF CHOLESTASIS
Authors: J. Luo, B. Ko, C. To, D. Lindhout, L. Ling, J.L. Chen, T. Parsons, S. Rossi, A. DePaoli, H. Tian
Journal: Journal of Hepatology (2014)
AB0372 Safety of hydroxychloroquine in pregnant women with systemic lupus erythematosus and rheumatoid arthritis.
Authors: G. Hakobyan, V. Vardanyan
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The use of the hydroxychloroquine(HCQ) in pregnancy is controversial. The current practice of discontinuing these medications because of pregnancy makes little sense as the half-life of these medications is so long. Patients with autoimmune diseases, especially with systemic lupus erythematosus (SLE) have increased fetal wastage and one of the factors known to contribute to this fetal wastage is disease activity. It is also known that discontinuing the HCQ can precipitate flares of disease in lupus patients. Mothers and their potential offspring are therefore at risk for flares of disease and pregnancy failure if these medications are discontinued because of pregnancy. <h3>Objectives</h3> To determine the safety for both mother and fetus of HCQ, in pregnant patients with SLE and rheumatoid arthritis (RA) who continued antimalarial drugs throughout pregnancy. <h3>Methods</h3> We studied 30 case histories of pregnant women (22 with SLE, and 8 - with RA), all of whom took hydroxychloroquine (Plaquenil) throughout pregnancy. All 30 pregnancies, resulted in 30 live births (18 full term and 12 preterm). <h3>Results</h3> No congenital abnormalities occurred and mean follow-up of 1 year (range 10-48 months) revealed no abnormalities in these children. Temporary discontinuation of HCQ for 1-2 months in 9 pregnancies precipitated a flare of disease (SLE or RA), documented both clinically and serologically, which required administration of glucocorticoids in relatively high doses. <h3>Conclusions</h3> It is safer to continue hydroxychloroquine rather than to discontinue this drug simply because of pregnancy. <h3>References</h3> Mok CC, Wong RW. Pregnancy in systemic lupus erythematosus. Postgrad Med J. 2001 Mar;77(905):157-65. <h3>Disclosure of Interest</h3> None Declared
O102 PROLIFERATION OF HBV-INFECTED HUMAN HEPATOCYTES IN HUMANIZED MICE PROMOTES THE OCCURRENCE OF VIRAL INTEGRATIONS WITHIN THE HOST GENOME
Authors: L. Allweiss, T. Volz, K. Giersch, A.W. Lohse, J. Petersen, M. Lütgehetmann, M. Dandri
Journal: Journal of Hepatology (2014)
Observations on a Family Epidemic of Infectious Hepatitis
Authors: Henry G. Kunkel, Charles L. Hoagland
Journal: New England Journal of Medicine (1947)

AN epidemic of infectious hepatitis occurring in 9 of 10 children in a single family was followed for five months in New York City. Such a high incidence of the disease in a group is unique in itself; in addition, these cases offered special information on four separate aspects of the disease — namely, epidemiology, the comparative value of certain liver-function tests, the occurrence of spider angiomas in the acute stage of infectious hepatitis and the incidence of subicteric cases.All members of the family were observed in the Outpatient Department of the Rockefeller Hospital, where liver-function tests were performed . . .
Roswell Park: The Phoenix Rises In Buffalo
Authors: N. Volkers
Journal: JNCI Journal of the National Cancer Institute (1992)

Journal Article Roswell Park: The Phoenix Rises In Buffalo Get access Nancy Volkers Nancy Volkers Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 84, Issue 20, 21 October 1992, Pages 1548–1550, https://doi.org/10.1093/jnci/84.20.1548 Published: 21 October 1992
Hammer Names Members Of Special Committee On Drug Regulation
Authors: M. Hampton
Journal: JNCI Journal of the National Cancer Institute (1988)

Journal Article Hammer Names Members Of Special Committee On Drug Regulation Get access Maree Hampton Maree Hampton Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 80, Issue 20, 21 December 1988, Page 1591, https://doi.org/10.1093/jnci/80.20.1591 Published: 21 December 1988
Did introduction of pneumococcal vaccines in the Netherlands decrease the need for respiratory antibiotics in children? Analysis of 2002 to 2013 data
Authors: G Gefenaite, M J Bijlsma, H J Bos, E Hak
Journal: Eurosurveillance (2014)

To estimate the effect of the introduction of the 7- and 10-valentpneumococcal vaccines in 2006 and 2011, respectively in the Netherlands, we assessed respiratory antibiotic use in one to nine year-old children between 2002 and 2013. Seasonal autoregressive integrated moving-average models were applied to estimate the percentage reduction in respiratory antibiotic use. When compared with the pre-vaccination period, the proportion of respiratory antibiotic prescriptions fell by 4.94% (95% CI: 4.63 to 5.26) and 9.02% (95% CI: 2.83 to 14.82) after the introduction of the 7-valent vaccine in children aged three and four years, respectively. After the introduction of the 10-valent vaccine, we observed a reduction of 13.04% (95% CI: 2.76 to 22.23), 20.31% (95% CI: 13.50 to 26.58), 16.92% (95% CI: 3.07 to 28.80), 22.34% (95% CI: 3.73 to 37.35), 23.75% (95% CI: 2.37 to 40.44) in two, three, four, six and seven year-old children, respectively. Thus, our results indicate a reduction in respiratory antibiotic prescriptions in young children after introduction of the pneumococcal vaccines. As only children in our study population aged one and two years born after March 2011 had received the 10-valent vaccine, the effects of the 10-valent vaccine in children aged three to nine years likely reflect the effects of the 7-valent vaccine and herd immunity.
AB0690 Pulmonary arterial hypertension (PAH) in a cohort of systemic lupus erythematosus (SLE)
Authors: M.M. Bianchi, P. Santo, P. Estrada, L. Lόpez, M. Aparicio, J. Narváez, J. Valverde, J. Nolla
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> PAH is a rare complication of SLE and the prevalence varies among the different studies and diagnostic method employed. The clinical course of PAH is asymptomatic until advanced stages and therefore has poor outcome (1). <h3>Objectives</h3> The aim of this study is to estimate the prevalence of PAH in a cohort of SLE patients and evaluate if Raynaud's phenomenon (RP) and certain antibodies constitute risk factors for developing PAH. <h3>Methods</h3> Asymptomatic SLE patients (who fulfilled ACR criteria for SLE) were recruited in a rheumatology unit of a hospital in Barcelona, Spain. We assessed clinical features of SLE, presence of antiphospholipid syndrome, interstitial lung disease, pulmonary embolism, autoantibody profile and history of RP. Transthoracic echocardiography (TTE) was performed to all SLE patients to estimate the pulmonary artery pressures. PAH was defined as systolic pulmonary artery pressure (sPAP) ≥36 mmHg according to current guidelines (2). <h3>Results</h3> 49 SLE patients were evaluated with TTE and none had PAH. We separated two groups according to sPAP ≤30 and sPAP between ≥31 to 35 mmHg; not finding any differences between the clinical features of the 2 groups. <h3>Conclusions</h3> PAH is a serious complication with very low prevalence in SLE patients. In our SLE cohort none of our patients developed PAH. Also, we failed to prove any association with RP in the group with higher sPAP. Finally, with our study we may conclude that routine screening with TTE in asymptomatic SLE patients is not justified due to the very low prevalence of PAH in our SLE population. <h3>References</h3> Sánchez O, Sitbon O, Jaïs X, Simonneau G, Humbert M. Immunosuppressive therapy in connective tissue diseases-associated pulmonary arterial hypertension. Chest 2006; 130:182-9. Galiè N, Torbicki A et al. Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J. 2004; 25:2243-78. <h3>Disclosure of Interest</h3> None Declared
Epidemiology and clinical relevance of mutations in postpolycythemia vera and postessential thrombocythemia myelofibrosis: A study on 359 patients of the AGIMM group
Authors: Giada Rotunno, Annalisa Pacilli, Valentina Artusi, Elisa Rumi, Margherita Maffioli, Federica Delaini, Giada Brogi, Tiziana Fanelli, Alessandro Pancrazzi, Daniela Pietra, Isabella Bernardis, Clara Belotti, Lisa Pieri, Emanuela Sant'Antonio, Silvia Salmoiraghi, Daniela Cilloni, Alessandro Rambaldi, Francesco Passamonti, Tiziano Barbui, Rossella Manfredini, Mario Cazzola, Enrico Tagliafico, Alessandro M. Vannucchi, Paola Guglielmelli
Journal: American Journal of Hematology (2016)

Transformation to secondary myelofibrosis (MF) occurs as part of the natural history of polycythemia vera (PPV‐MF) and essential thrombocythemia (PET‐MF). Although primary (PMF) and secondary MF are considered similar diseases and managed similarly, there are few studies specifically focused on the latter. The aim of this study was to characterize the mutation landscape, and describe the main clinical correlates and prognostic implications of mutations, in a series of 359 patients with PPV‐MF and PET‐MF. Compared with PV and ET, the JAK2 V617F and CALR mutated allele burden was significantly higher in PPV‐MF and/or PET‐MF, indicating a role for accumulation of mutated alleles in the process of transformation to MF. However, neither the allele burden nor the type of driver mutation influenced overall survival (OS), while absence of any driver mutation (triple negativity) was associated with significant reduction of OS in PET‐MF, similar to PMF. Of the five interrogated subclonal mutations ( ASXL1, EZH2, SRSF2, IDH1, and IDH2 ), that comprise a prognostically detrimental high molecular risk (HMR) category in PMF, only SRSF2 mutations were associated with reduced survival in PET‐MF, and no additional mutation profile with prognostic relevance was highlighted. Overall, these data indicate that the molecular landscape of secondary forms of MF is different from PMF, suggesting that unknown mutational events might contribute to the progression from chronic phase disease to myelofibrosis. These findings also support more extended genotyping approaches aimed at identifying novel molecular abnormalities with prognostic relevance for patients with PPV‐MF and PET‐MF. Am. J. Hematol. 91:681–686, 2016. © 2016 Wiley Periodicals, Inc.
Endoscopic Ultrasonography is Associated with Improved Survival in Patients with Esophageal Cancer
Authors: A Das, A Chak, M Sivk, J Payes, G Cooper
Journal: Endoscopy (2006)

Endoscopic ultrasonography (EUS) staging is used for management of esophageal cancer but its effect on the outcome of patients is unknown. Objective: To study the association of receipt of EUS and overall survival in a cohort of patients with esophageal cancer. Methods: All persons 65 years or older, who were diagnosed with esophageal cancer between January 1994 and December 1999 in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database were identified. Relevant demographic, cancer specific information and EUS procedural information was extracted. Results: 2,830 patients with esophageal cancer (48% squamous cell cancer) were eligible for analysis. Only 303 (10.7%) patients underwent a EUS examination. Median survival in patients who underwent EUS evaluation was higher than those who did not [485 (Inter-quartile range, 213–984) and 184 (Inter-quartile range, 62–457) days, p=0.001]. Patients who had EUS evaluation were more likely to undergo esophageal resection (21.1% vs. 14.7%, p=0.01) and more likely to have received adjuvant therapy (11.2% vs. 6.7%, p=0.008). When adjusted for age at diagnosis, race, gender, co-morbidity, histology, and tumor stage, receipt of EUS was associated with a reduced risk of death (relative hazard=0.594, 95% CI 0.52–0.68, p=0.001). Conclusion: Receipt of EUS in patients with esophageal cancer is independently associated with improved survival, possibly because of improved stage-appropriate management such as use of adjuvant therapy and surgical resection.