tbuckley/cabot-search huggingface dataset:
Abstract 1988: A bi-directional feedback loop between Wnt and ERK is important in maintaining the proliferative phenotype of normal human urothelial cells
Authors: Lisa A. Kirkwood, Nikolaos T. Georgopoulos, Jennifer Southgate
Journal: Cancer Research (2011)

Abstract Introduction: The urothelial lining of the bladder is ordinarily mitotically quiescent, but can rapidly regenerate in response to injury. This regenerative capacity is thought to be important in restoring urinary barrier function and offers a primary target for deregulation in cancer. Previous work in our laboratory has implicated autocrine EGFR activation in this process, but other regulatory pathways may be involved. Wnt signalling has been shown to be important in the renewal of a number of adult epithelial tissues, but to date, no conclusive evidence for a role for Wnt in urothelial regeneration has been demonstrated. In the absence of Wnt ligand, β-catenin is sequestered via the destruction complex. Activation of the canonical Wnt pathway by ligand, inactivates the destruction complex, allowing β-catenin to translocate to the nucleus and drive proliferation. The aim of this study was to assess whether Wnt signaling was functional in normal human urothelial (NHU) cells, and to analyze the effects of Wnt and downstream EGFR signaling on proliferation. Materials and Methods: NHU cells were grown as finite lifespan cell lines in proliferating cultures. Destruction complex antagonists were used to activate the Wnt pathway. Proliferation assays, immunofluorescence labeling and TOPFLASH luciferase reporter assays were used to assess NHU cell responses. Pathway crosstalk was analyzed using shRNA targeted to β-catenin, as well as antagonists of the EGFR signaling pathways. Results: Pharmacological inhibition of the destruction complex or activation of the Wnt pathway with exogenous Wnt ligand led to nuclear accumulation of β-catenin and an increase in TCF/LEF transcription factor activity. These effects were only apparent when autocrine EGFR signaling was blocked. Knockdown of β-catenin led to significant changes in p-ERK and p-AKT downstream signaling. Conclusion: Wnt signaling can be activated in NHU cells, verifying the presence of a functional pathway. Activation of the pathway is however masked by EGFR signaling, indicating pathway crosstalk. The effect of β-catenin knockdown on p-ERK and p-AKT indicates a bi-directional positive feedback loop between the Wnt and EGFR signaling cascades in NHU cells. This study identifies the Wnt signaling pathway as an important signaling cascade in regulating the regenerative phenotype of NHU cells and indicates at least two pathways that may be arrogated by urothelial cells during neoplastic transformation. 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 1988. doi:10.1158/1538-7445.AM2011-1988
SEDACIÓN CON PROPOFOL EN ECOENDOSCOPIA GUIADA POR ENDOSCOPISTAS PARA PACIENTES DE ALTO RIESGO. ANÁLISIS DE SEGURIDAD Y UTILIDAD
Authors: E Redondo Cerezo, J Martínez Cara, M Ojeda Hinojosa, A Matas Cobos, C González Artacho, V Martos Ruiz, D Sánchez Capilla, M López de Hierro, J de Teresa Galván
Journal: Endoscopy (2011)

Introducción: La sedación guiada por endoscopistas para pacientes de alto riesgo suele limitarse por dudas acerca de su seguridad, existiendo pocos estudios en este grupo de pacientes. Presentamos un estudio observacional, prospectivo en pacientes de alto riesgo.
Abstract 4351: Exposure to ionizing radiation causes long-term increase in serum estradiol and activation of PI3K-Akt signaling pathway in mouse mammary gland
Authors: Shubhankar Suman, Michael D. Johnson, Albert J. Fornace, Kamal Datta
Journal: Cancer Research (2012)

Abstract Purpose: Exposure to ionizing radiation is an established risk factor for breast cancer. Radiation exposure during infancy, childhood and adolescence confer the highest risk. Although radiation is a proven mammary carcinogen, it remains unclear where it acts in the complex multi-stage process of breast cancer development. In this study, we investigated the long-term pathophysiological effects of ionizing radiation at a dose (2Gy) relevant to fractionated radiotherapy. Methods and Materials: Adolescent (6 to 8 weeks old; n=10) female C57BL/6J mice were exposed to 2 Gy of total body ≤ radiation and the mammary glands were harvested and serum and urine samples were collected 2 and 12 months post-exposure. Molecular pathways involving estrogen receptor alpha (ERalpha) and phosphatidylinositol-3-OH kinase (PI3K)-Akt signaling were investigated by immunohistochemistry and western blot. Results: Serum estrogen and urinary levels of the oncogenic estrogen metabolite (16alphaOHE1) were significantly increased in irradiated animals. Immunostaining for the cellular proliferative marker Ki-67 and cyclin-D1 showed increased nuclear accumulation in sections of mammary glands from irradiated versus control mice. Marked increase in p85alpha, a regulatory sub-unit of the PI3K was associated with increase in Akt, phospho-Akt, phospho-BAD, phospho-mTOR, and c-Myc in irradiated samples. Persistent increase in nuclear ERalpha in mammary tissues at 2- and 12-month after radiation exposure was also observed. Conclusions: Taken together our data not only supports epidemiological observations associating radiation and breast cancer but it also for the first time specifies molecular events that could be involved in radiation-induced breast cancer. 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 4351. doi:1538-7445.AM2012-4351
Abstract 2092: Integrated genetic analysis of clear cell renal cell carcionoma
Authors: Yusuke Sato, Shigekatsu Mekawa, Yasunobu Nagata, Kenichi Yoshida, Aiko Sato, Yusuke Okuno, Yuichi Shiraishi, Tetsuichi Yoshizato, Hiromichi Suzuki, Masashi Sanada, Haruki Kume, Yukio Homma, Seishi Ogawa
Journal: Cancer Research (2012)

Abstract Renal cell carcinoma (RCC) is the most common form of adult kidney cancer and accounts for 2-3% of all adult malignancies, in which clear cell carcinoma accounts for more than 80% of the cases. As for the pathogenesis of clear cell RCC, inactivation of the VHL gene has been reported in 80% of clear cell RCC and more recently, frequent mutations of epigenetic regulators, including PBRM1, SETD2, KDM5C and UTX, have been demonstrated through high-throughput mutation studies, including PBRM1 has been demonstrated in ∼40% of the cases. Nevertheless, probably, our knowledge of the full spectrum of gene mutations in RCC is still incomplete. In this study, to obtain a better understanding of molecular pathogenesis of clear cell RCC, we performed an integrated genetic study of clear cell RCC, where a total of 93 paired specimens were analyzed by massively parallel sequencing of SureSelect (Agilent)-enriched whole exomes, SNP array-based copy number analysis (Affymetrix), as well as gene expression profiling (Agilent). In whole exome sequencing, 42 somatic mutations per sample were identified on average, which involved not only previously reported genes, but also a number of novel gene targets. Among these, mutations of genes involved in chromatin regulation or histone modification were preferentially found in advanced cases. To understand whole picture of gene mutations of epigenetic mechanism in clear cell RCC, mutation analysis of 85 genes involved in chromatin regulation or histone modification were performed in 180 cases using multiplexed barcode sequencing. A total of 201 somatic mutations were validated and 74% cases had at least one somatic mutation. PBRM1 mutations were found in 43% cases and SETD2 were mutated in 10% of cases. When comparing clinical picture with mutation status, SETD2 mutation was associated with the risk of metastasis, while PBRM1 mutations had no impact on prognosis. Our results showed that in clear cell RCC, multiple component of complexes involved in epigenetic regulation undergo gene mutations, confirming that deregulated epigenetic apparatus play important roles in pathogenesis of clear cell RCC. In this meeting, we will present the result of our integrated genetic analysis of RCC and discuss the genetic basis of RCC in terms of copy number alterations, gene mutations, as well as gene expression profiles. 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 2092. doi:1538-7445.AM2012-2092
A5.8 B Cell Depletion Therapy in a Cohort of Patients with Seropositive and Seronegative Rheumatoid Arthritis: Abstract A5.8 Table 1
Authors: ML Velloso Feijoo, R Martínez Pérez, L Mayordomo Gonzalez, JL Marenco de la Fuente
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> B cells play a crucial role in the pathogenesis of rheumatoid arthritis (RA). They are responsible for the autoantibodies formation such as rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibodies (anti-CCP) and the production of cytokines, act as antigen presenting cells and regulate T cell functions. Rituximab (RTX), murine monoclonal antibody which selectively targets CD20-positive B-cells, has proved to be an effective and safe therapy for active RA. Initially it was used in seropositive RA, but considering the other functions of B cells, it is logical to think that it is also useful in seronegative forms. <h3>Objective</h3> To evaluate the efficacy of RTX in our series of refractory seronegative and seropositive RA. <h3>Materials and Methods</h3> Baseline characteristics and disease activity markers at baseline, and after 3 and 6 months of treatment with RTX (1g × 2 weeks), were collected in 33 patients. A descriptive study was made; and the relations between variables were analysed statistically. <h3>Results</h3> The mean age was 52.06 ± 12.01 years, 75.8% female, 78.8% RF positive. The mean duration of illness was 7.70 ± 4.47 years. Thirty two patients (97%) had failed at least to one TNF antagonist. Most of the patients (84.8% 9) received RTX with methotrexate. The mean DAS28 at baseline was 5.7 ± 1.30; at 3 months decreased to 3.4 ± 1.22, and at 6 months to 4.15 ± 1.69 (p &lt; 0.0005). At 3 months, 88.9% reached good eular response, and 63.3% at 6 months. Remission was obtained in 17.2% at 3 months and in 16.7% at 6 months. It was also noted improvement in baseline HAQ, after 3 and 6 months (from 1.75 ± 0.767 to 0.96 ± 0.56 and 1.24 ± 0.70 respectively). No significant differences were found between decreases in DAS 28 at 3 and 6 months compared to baseline between RF seronegative and seropositive patients, neither in good eular response, remission percentages or HAQ improvement. The data are shown in the table. <h3>Discussion</h3> The efficacy and safety of RTX has been proved in several clinical trials. The presence of RF, low baseline functional disability and no more than one previous anti-TNF are predictors of good response to RTX, as has been recently published. Response rates in seronegative RA are slightly lower, although higher than placebo, as described in other publications. In conclussion, the experience of RTX treatment in our patients with seronegative RA is positive, in terms of efficacy, due to the action on B cells and their different roles, with no significant differences comparing to seropositive RA.
Control of recent community-based outbreaks of invasive meningococcal disease in men who have sex with men in Europe and the United States
Authors: D Weiss, J K Varma
Journal: Eurosurveillance (2013)

Preview this article: Control of recent community-based outbreaks of invasive meningococcal disease in men who have sex with men in Europe and the United States, Page 1 of 1 < Previous page | Next page > /docserver/preview/fulltext/eurosurveillance/18/28/art20522-en-1.gif
AB0401 Combined drug-rehabilitative treatment in rheumatoid arthritis
Authors: L. Di Gioia, C. Zincarelli, S. Iervolino, D.F. Vitale, N. Pappone
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Rheumatoid Arthritis may lead to structural alterations with severely impaired function. Biologic DMARDs reduce signs and symptoms, but fail in reducing the established joint damage and in improving impaired function. Recent reports show the efficacy of rehabilitative programs in RA patients, by affecting pain, stiffness and fatigue <h3>Objectives</h3> assess the effectivenessof a combined drug-rehabilitative treatment in ameliorating function and fatigue in RA patients <h3>Methods</h3> 40 RA patients treated with biologic DMARDs, with severely impaired function were enrolled. From the enrollment (T0) all subjects underwent to a 3-weeks rehabilitative program. They were followed-up at the end of treatment (T1), 3 (T2), 6 (T3) and at 9 (T4) months, evaluating: TJC, SJC, DAS-28, ERS, HAQ, GH and FACIT. <h3>Results</h3> all the outcomes significantly improved from T0 to T4 (Tab. 1). <h3>Conclusions</h3> the combined treatment is effective in reducing function impairment. This approach ameriorated joint pain, muscle-tone, and improved the resistance to fatigue, even if unmodifying the biologic DMARDs. These effects were kept over the time. FACIT resulted to be an independent variable from disease activity parameters. In conclusion, the combined treatment results in a durable improved function and resistance to fatigue regardless disease activity. <h3>References</h3> Harris ED Jr. Rheumatoid arthritis: pathophysiology and implications for therapy. N Eng J Med 1990; 322: 1277-1289 <h3>Disclosure of Interest</h3> None Declared
Abstract 948: IGF-I receptor expression is associated with stage and has therapeutic activity in human biliary tract cancers
Authors: Yasushi Adachi, Hiroyuki Yamamoto, Hirokazu Ohashi, Hiroaki Taniguchi, Katsuhiko Nosho, Hiromu Suzuki, Yoshiaki Arimura, Takao Endo, Kohzoh Imai, David P. Carbone, Yasuhisa Shinomura
Journal: Cancer Research (2012)

Abstract Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and progression of several cancers but the function of this pathway and its utility as a therapeutic target has not been well studied in biliary tract carcinomas. We investigated the immunohistochemical expression of elements of the IGF axis, matrilysin, overexpression of p53, and the methylation status of the IGFBP-3 promoter in 80 surgically resected biliary tract carcinomas. We also assessed the effect of IGF-IR blockade on signal transduction, proliferation, and survival in 3 biliary tract cancer cell lines using a new tyrosine kinase inhibitor, BMS-536924, and dominant negative IGF-IR (IGF-IR/dn). The effects of IGF-IR blockade was also studied in nude mouse xenografts models. IGF-I was expressed in 60% and IGF-II in 50% of tumors and high expression was associated with tumor size. IGF-IR was expressed in 69% of the cases and was associated to advanced stage and matrilysin expression. Hypermethylation of the IGFBP-3 promoter was detected in 41% and was inversely correlated with p53 expression. BMS-536924 blocked autophosphorylation of IGF-IR and both Akt and ERK activation by both IGF-I and insulin. BMS-536924 suppressed proliferation and tumorigenicity in vitro in a dose-dependent fashion. This inhibitor up-regulated chemotherapy-induced apoptosis in a dose dependent fashion. Moreover, IGF-IR blockade was effective against tumors in mice. IGF-IR might identify a subset of biliary tract cancers with a particularly aggressive phenotype and is a candidate therapeutic target in this disease. BMS-536924 may have significant therapeutic utility. 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 948. doi:1538-7445.AM2012-948
AB0510 Predicting Factors of Unfavorable Clinical Outcome in Lupus Nephritis
Authors: D. Kishimoto, Y. Kunishita, R. Kamiyama, K. Minegishi, M. Hama, R. Yoshimi, Y. Asami, Y. Kirino, A. Ueda, M. Takeno, Y. Ishigatsubo
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> There is accumulating evidence that pathological findings of the kidney are useful for predincting clinical outcomes, as Class IV in ISN/RPS classification of lupus nephritis (LN) is associated with progressive renal impairment. Tubulointerstitial inflammation (TI) is also implicated in deterioration of renal function. <h3>Objectives</h3> To determine pre-therapeutic features including pathological and laboratory findings which are associated with unfavorable clinical outcomes of LN. <h3>Methods</h3> We retrospectively analyzed date in 51 SLE patients (34.2 y.o. 48 female) who received renal biopsy between 2004 and 2013 in our department. The pathological findings were assessed by existence of crescent, glomerular sclerosis, TI and thrombi in addition to ISN/RPS classification. Pre-therapeutic laboratory data were reviewed. Therapeutic response (CR or non-CR) at 2 year were evaluated by SLICC renal activity and response index score (SLICC score). <h3>Results</h3> At the baseline, eGFR, proteinuria and SLICC score were 82.7±35.1ml/min, 1.68±2.15g/day and 4.9±4.6, respectively. The renal biopsy samples were classified into Class I/II/III/IV/V (1/5/16/25/4) according to ISN/RPS classification. Crescent, glomerular sclerosis, TI, and thrombi were found 23.5%, 58.8%, 60.8%, and 19.6%, respectively. As induction therapy, corticosteroids were given to all patients, whereas intravenous infusion with CY was used for 81.3% patients having ClassIII and IV. CR rate was not different among Class I to V. The presence of glomerular sclerosis and low level of eGFR were significantly associated with non-CR (p&lt;.05) at 2 years. Presence of crescent formation and thrombi were more frequently found in patients non-CR patients, whereas anti-phospholipid antibody was more common in CR patients, though the differences did not reach statistical significance. <h3>Conclusions</h3> The present study showed that ISN/RPS classification did not affect CR rate and that association of TI with non-CR unlike previous studies. These findings were presumably due to the fact that therapies were mainly determined according to previously identified prognostic factors. Rather, our data showed that severe glomerular damages shown by reduced GFR and glomerular sclerosis were related with unfavorable clinical outcomes. <h3>References</h3> Petri M, et al. Arthritis Rheum 2008;58(6):1784-1788 <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5411
Reply to Laleman and Van der Merwe
Authors: C. Fabbri, C. Luigiano, V. Cennamo, I. Tarantino
Journal: Endoscopy (2012)

In our discussion of this series of cases, we have been cautious, aware of the fact that currently the gold standard involves the use of plastic stents; indeed, our conclusion was “A larger prospective randomized study should be carried out to compare this technique with conventional drainage using plastic stents in order to validate these findings.”
Flexible training in cardiothoracic surgery
Authors: A. Merrick
Journal: BMJ (1997)

Women are still under represented in the surgical specialties, possibly because the training is not renowned for compatibility with family life. Cardiothoracic surgery's first flexible trainee, Anna Merrick, discusses part time working in an acute specialty 

Flexible training exists in order to allow fewer people to leave medicine and to allow personal fulfilment for those with wider interests and additional commitments. There are inadequate places for all who want to train less than full time. Flexible training is well established in many other specialties.

I was appointed as a career registrar at St George's Hospital just before Calman training was implemented in the specialty so I am an extra registrar. There have been flexible trainee anaesthetists within the department for some time so the concept of part time working was already accepted; only its application to cardiothoracic surgery was new. Although my role is not yet completely worked out I have found support and understanding from my fellow registrars, who treat me as an equal partner, and other medical staff, though my position is less well understood by nursing staff.

Cardiac surgery is a specialty renowned for long hours and intensity of workload. Historically it has attracted macho workaholics who apparently needed no sleep and never saw their families. This perception of cardiac surgeons was unintentionally fuelled by the BMJ letter last year signed by all cardiothoracic trainees, stating their desire to work 100 hours a week and requesting to be considered “less equal” than other surgical trainees.(1) It is probably not essential to be a hyperactive person who cannot fit into a nine to five routine in order to be a cardiac surgeon, but these were the characteristics of the pioneers of cardiac surgery. Different specialties attract people of different character so flexible trainees are likely to have the …
Limitations of Parathyroid Imaging With Tc-99m/Tl-201 Subtraction and Early/Delayed Tc-99m MIBI Imaging
Authors: CHRISTIAAN SCHIEPERS, HILDE VAN RIET, LUC MORTELMANS, MICHEL DE ROO
Journal: Clinical Nuclear Medicine (1996)

An 87-year-old woman with recurrent gastric ulcers was admitted with isolated hypercalcemia and thyroid enlargement. Serum PTH was 88.8 pg/mL (normal, 3-40 pg/mL) and ionized calcium 12.2 mg/dl (normal, 8.9-10.5 mg/dl). The patient was euthyroid. Ultrasonography showed a hyporeflective node in the thyroid bed, and CT showed a retrosternal goiter with trachea deviation. Dual-isotope scintigraphy and early/delayed Tc-99m MIBI imaging suggested a neoplasm. At surgery, a 1 cm left upper parathyroid adenoma and a benign microfollicular thyroid adenoma were found. Both examinations failed to detect the parathyroid adenoma, and incorrectly identified the right lobe mass as malignant.