tbuckley/cabot-search huggingface dataset:
Cyclin D1 Is a Direct Target of JAG-Mediated Notch Signaling in Breast Cancer.
Authors: M. Reedijk, M. Reedijk, M. Reedijk, B. Cohen, M. Shimizu, N. Ng, Y. Bukhman, J. Pan, J. Dering
Journal: Cancer Research (2009)

Abstract We have previously demonstrated that expression of the Notch ligand, JAG1 is associated with the basal breast cancer phenotype and disease recurrence. Herein we report on a genomics approach to elucidate mechanisms downstream of JAG1 that promote breast cancer growth. In a survey of 46 breast cancer cell lines we found that triple negative (TN; basal and mesenchymal ER-, PR- and Her2-negative) lines express JAG1 at significantly higher levels than do HER2+ or luminal (ER+) Her2- cell lines. The TN breast cancer cell lines HCC1143 and MDA MB231, which express JAG1 and demonstrate growth inhibition with RNA interference-induced down-regulation of JAG1, were selected for further study. We used microarray profiling of tumor cells transfected with JAG1 siRNA to identify JAG1-regulated genes. Differentially expressed genes (p ≤ 0.005; fold change ≥ 1.5) were identified for further study. Among the JAG1-regulated genes identified, cyclin D1 was found to be a direct target of NOTCH1 and NOTCH3. We show that JAG1 down-regulation results in reduced cyclin D1 expression, reduced direct binding of Notch to the cyclin D1 promoter, and inhibition of cell cycle progression through the cyclin D1-dependant G1/S check-point. Furthermore, we show that cyclin D1 and JAG1 expression correlate in basal breast cancer expression data sets. These data suggest a model whereby JAG1 promotes cyclin D1-mediated proliferation of TN breast cancer cells. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2150.
Intrasphincteric Botulinum Toxin for the Treatment of Achalasia
Authors: Pankaj J. Pasricha, William J. Ravich, Thomas R. Hendrix, Samuel Sostre, Bronwyn Jones, Anthony N. Kalloo
Journal: New England Journal of Medicine (1995)

Achalasia is a disorder of swallowing in which the lower esophageal sphincter fails to relax. We report the use of botulinum toxin, a paralytic agent, for the treatment of this condition.
The Enzymatic Defect in Variegate Porphyria
Authors: David A. Brenner, Joseph R. Bloomer
Journal: New England Journal of Medicine (1980)

Fecal protoporphyrin is increased in patients with variegate porphyria, even during clinical remission, suggesting an enzymatic defect in the terminal portion of the heme biosynthetic pathway. We measured the activities of protoporphyrinogen oxidase, which catalyzes the oxidation of protoporphyrinogen to protoporphyrin, and heme synthase, which catalyzes the chelation of iron to protoporphyrin, in cultured skin fibroblasts from five normal controls and five patients with variegate porphyria. Heme synthase activity was shown to be normal in variegate porphyria cells by direct assay in cell sonicates and indirect assay in intact cells. Protoporphyrinogen oxidase activity, however, was reduced to 43 per cent of normal in sonicates of variegate porphyria cells (0.90±0.13 vs. 2.12±0.25 nmol of protoporphyrin per milligram of protein per hour [mean ±S.E.M.] [P<0.005]). We conclude that protoporphyrinogen oxidase activity is deficient in variegate porphyria. Fecal protoporphyrin may increase because an excess amount of protoporphyrinogen is excreted into bile and subsequently auto-oxidized to protoporphyrin. (N Engl J Med. 1980; 302:765–9.)
AB0622 Heart conduction disturbances in patients treated with antimalarials:
Authors: I. Pérez-Martín, C. Bejerano, E. Peirό, R. Blanco, M. Agudo, V.M. Martínez-Taboada, M.A. González-Gay
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Chloroquine and Hydroxichloroquine are well-known anti-malarial drugs used in the management of several rheumatologic diseases, in particular in patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). Apart from the ophthalmologic complication, these drugs are considered to be relatively safe drugs. However, their prolonged use may be associated with other complications, including heart rhythm problems such as heart block. <h3>Methods</h3> We reviewed the medical records of a series of patients seen at the outpatient Rheumatology Clinic of a University Hospital, who required prolonged anti-malarial drug therapy. In the present study we aimed to identify the alterations in the heart conduction system as well as the conditions associated to these abnormalities. <h3>Results</h3> From a series of 212 patients treated with antimalarials, 154 (72.64%) were diagnosed with RA, 57 (26.88%) with SLE and 1 with Still disease. We disclosed 9 patients (6 females/3 males) who experienced heart conduction disturbances. The mean age at time of the diagnosis of the cardiac conduction disturbances was 61.3±17.2 years (range 20-81). The mean duration of the disease before the onset of these heart complications was 90±52 (18- 204) months. SLE was the disease more frequently associated with these complications (5 patients) followed by RA (3 cases) and Still disease (1 case). Two of 9 who suffered the heart complication had abnormal kidney function with a clearance ≤40mg/dl. Chloroquine and hydroxichloroquine were administrated in a single dose of 250 mg/daily and 200 mg/twice daily respectively. The mean weight of the patients was 66, 33 kg ± 7,28 (51-75).The weight-adjusted dose for the chloroquine were 3.87±0.5 mg/kg (3.47-4.9) and 5.9±0.55 (5.3-6.3) for the hydroxichloroquine. Before the onset of antimalarial therapy only 2 of the patients had abnormal ECG (atrial fibrillation (AF) and right bundle-branch block respectively). Following anti-malarial drug therapy the following heart conduction disturbances were observed: 5 atrioventricular blocks (2 associated with right bundle-branch block and other one with left bundle-branch), 2 right bundle-branch block, 1 left bundle-branch block, 1 blocked AF associated with right bundle-branch. Seven of these patients required pacemaker. <h3>Conclusions</h3> We must be aware of the potential risk of having heart conduction disturbances following prolonged used of anti-malarial drugs. <h3>Disclosure of Interest</h3> None Declared
Case 17-2013
Authors: Jose C. Florez, Jo-Anne O. Shepard, Richard L. Kradin
Journal: New England Journal of Medicine (2013)

A 56-year-old woman with diabetes mellitus was admitted to this hospital because of hyperglycemia and chest pain. Approximately 4 years earlier, a chest radiograph showed a solitary pulmonary nodule in the right upper lobe. Diagnostic tests were performed.
Abstract 1604: Treatment with Pequi (<i>Caryocar brasiliense Camb</i>) fruit pulp oil decrease the DNA damage caused by chemical carcinogenesis in experimental model of lung cancer.
Authors: Natália B. Colombo, Edwin Roger Parra, César koppe Grisolia, Marcia Hage, Maristela P. Rangel, Vera Luíza Capelozzi
Journal: Cancer Research (2012)

Abstract Background: It is well known that a daily consumption of foods that are rich in antioxidants prevents the oxidative damage caused by reactive species (ROS), including DNA damage, and can reduce the risk of cancer, atherosclerosis and other degenerative diseases. The pulp of Caryocar brasiliense Camb, most known as pequi, is a Brazilian fruit that has high levels of antoxidants properties, such as vitamin C, carotenoids, phenolic compounds like flavonoids, saponins and tannins, and essential oils. The aim of this study was to evaluate the action of the pequi oil in the DNA damage in experimental model of lung cancer induced by the urethane. Material and Methods: Male BALB/c mice (n=14) received by gavage 0,5μL/mg/day of pequi oil (CBC oil) during 75 days. After 15 days of the beginning of the gavage, 10 of these animals received two doses of 1,5g/kg intraperitoneal of urethane (Urethane + CBC oil). Urethane animals (n=4) were only submitted to two doses of 1,5g/kg intraperitoneal of urethane (urethane group). After these 75 days, lung tissues were submitted to histological and biochemical analysis by comet assay method to evaluated the DNA damage. The DNA damage was quantificate by image analysis. Results: The lung parenchyma from the urethane groups without oil and with oil showed neoplasic formations induced by the chemical carcinogenesis in contrast with oil control group. The image analysis of the comet assay showed a statistical significant diminish of the DNA damage cells in the urethane oil group when compared with urethane control group (p=0.001). The decreased DNA damage was very similar that we obtained in the oil control group. Conclusion: We conclude that the different antioxidant components found in the pequi oil diminish the DNA damage in the mouse lung after chemical carcinogenesis, suggesting that this type of strategies may have a greater impact in lung cancer treatment. Financial Support: FAPESP, CNPq 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 1604. doi:1538-7445.AM2012-1604
Abstract LB-20: Transcriptionally inactive PAX3-FKHR fails to induce ARMS cells differentiation
Authors: Mathivanan Jothi, Charles Keller, Asoke K Mal
Journal: Cancer Research (2010)

Abstract Alveolar rhabdomyosarcoma (ARMS) is an aggressive muscle cancer of childhood and believed to arise from committed muscle progenitor cells that have arrested during the process of skeletal muscle differentiation. One of the most established genetic signatures in ARMS is the presence of chimeric aberrant transcription factor PAX3-FKHR generated by fusion of PAX3 and FKHR genes. The stronger transcriptional activity of this fusion PAX3-FKHR protein has previously been attributed to the deregulation of genes, which are known to be associated with tumorigenesis and suppression of skeletal muscle differentiation. Currently, we are investigating the relative contribution of PAX3-FKHR's transcriptional activity in abrogating ARMS cells differentiation using mouse ARMS cells as an in vitro model differentiation readout system. Here, we show that transactivation potential of PAX3-FKHR is declined in mouse ARMS cells that have been induced to differentiate by growing these cells in mitogens-deficient in vitro differentiation-permissible condition. Moreover, this diminished activity of PAX3-FKHR is not due to the alteration of its sub-cellular localization or changes in the level of either mRNA or protein in these ARMS cells. Results also show the lack of muscle-specific gene activation in these ARMS cells despite the reduced transcriptional activity of PAX3-FKHR under condition of differentiation. We also observed that decrease in transcriptional activity of PAX3-FKHR is coincided with the activation of PI3/AKT pathway. The results further show that blockade of PI3/AKT pathway sustains the transcriptional activity of PAX3-FKHR whereas forced activation of AKT inhibits this activity. Together, our results signify that transcriptionally inactive PAX3-FKHR by AKT is incompetent to induce mouse ARMS cells differentiation. 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 LB-20.
A Type I Insulin-Like Growth Factor Receptor Kinase Inhibitor (PQIP) Enhances the Cytotoxicity of Doxorubicin in Human Cancer Cell Lines.
Authors: X. Zeng, E. Buck, D. Yee
Journal: Cancer Research (2009)

Abstract The type-I insulin like growth factor (IGF-IR) is either activated and/or overexpressed in a wide range of tumor types and contributes to tumorigenicity, proliferation, survival, metastasis and drug resistance. Disruption of IGF-IR signaling alone or in combination with other cytotoxic agents has emerged as an important strategy in cancer therapy. Our laboratory has shown that sequentially combining doxorubicin with anti-IGF-IR antibodies significantly enhances the response of chemotherapy, while the opposite sequence causes cells resistant to chemotherapy. Here, we show that a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP) inhibited IGF-IR and insulin receptor (IR) kinase activity and proliferation in MCF-7 and MDA435/LCC6 cell lines. Moreover, PQIP treatment blocked both IGF-I and insulin stimulated activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase in both cell lines. At doses that inhibited monolayer cell growth, the compound also inhibited cell motility, blocked IGF-I stimulated S-phase progression and induced autophage; at higher doses, it also caused PARP cleavage. Combining PQIP with doxorubicin significantly enhanced cytotoxicity but did not further enhance doxorubicin-induced PARP cleavage in monolayer cell growth. Furthermore, our sequencing studies showed that combining PQIP with doxorubicin simultaneously or doxorubicin followed by PQIP significantly inhibited the anchorage-independent growth in both MCF-7 and MDA435/LCC6 cells. In contrast, pre-treatment with PQIP followed by doxorubicin did not enhance the cytotoxicity of doxorubicin in anchorage-independent growth, which is similar as anti-IGF-IR antibodies in combination with doxorubicin. In summary, these results suggest that the IGF-IR tyrosine kinase inhibitor PQIP can be used alone or in combination with chemotherapy to enhance cytotoxicity of human tumor cell lines, and the timing of IGF-IR inhibition may affect responses to doxorubicin. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6110.
Abstract 2600: HMGB1, a potential new target for mesothelioma therapy
Authors: Sandro Jube, Zeyana Rivera, Giovanni Gaudino, Harvey I. Pass, Marco E. Bianchi, Michele Carbone, Haining Yang
Journal: Cancer Research (2011)

Abstract Malignant mesothelioma (MM) is a very aggressive cancer that causes 2000-3000 deaths annually in the U.S. and is resistant to current therapies. Diagnosis frequently occurs at a late stage of disease progression and median survival from time of diagnosis is about 1 year. Therefore, novel therapeutic strategies are urgently needed. We found previously that High-Mobility Group Box 1 protein (HMGB1), a known pro-inflammatory cytokine, induces tumor necrosis factor-alpha (TNF-α) secretion, potentiates survival of asbestos-exposed primary human mesothelial cells (HM) and enables HM malignant transformation, which leads to the initiation of MM. We show here that HMGB1 is also critical in the maintenance and progression of established MM. We found that HMGB1 is highly expressed in MM tissues and its levels in MM patients’ sera are significantly higher than in those of healthy individuals (P &amp;lt; 0.0001). MM tumor cells over-express HMGB1 in both the nucleus and cytoplasm. Instead, normal HM only express nuclear HMGB1 at significantly lower level than MM cells. The main receptor of HMGB1, receptor for advanced glycation end products (RAGE), is also upregulated in MM cells compared to HM. MM cells release biologically active HMGB1 into extra-cellular space, and the interaction with its receptors induces cell proliferation and chemo-attractant activity on MM cells. Moreover, the interference with HMGB1 activity by using specific HMGB1 inhibitors, such as BoxA and HMGB1 neutralizing monoclonal antibodies, leads to MM cell death. HMGB1 inhibitors impair MM cells migration, invasion, wound healing and also colony formation in soft agar. Our results strongly suggest that HMGB1 can be a novel target for mesothelioma therapy. 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 2600. doi:10.1158/1538-7445.AM2011-2600
Abstract P1-10-07: Preferences for Gender of Surgeon among Women with Breast Cancer
Authors: DH Freed
Journal: Cancer Research (2010)

Abstract Background: Hospitals have aggressively recruited and marketed women breast surgeons without evidence that women with breast cancer prefer them. Research about preferences could improve future decision making, with positive effects on patient satisfaction and health outcomes, hospital clinical and financial performance, and surgeon supply and workload distribution. The purpose of this study was to develop a grounded theory of preferences for gender of surgeon among women with breast cancer that is based upon exploratory research guided by two principal research questions: 1. What are the major categories to emerge from interviews with women with breast cancer about preferences for gender of surgeon? 2. How do women with breast cancer form preferences for gender of surgeon? Material and Methods: A university-based survey research unit conducted semi-structured, random digit dialing telephone interviews with 12 Rockland County, NY women age 40-80 regarding factors of importance, including gender, when they actually or prospectively considered what surgeon to visit for breast cancer care. The researcher then used principles of thematic analysis to systematically categorize and make sense of interview data. Institutional review board approvals and multiple methods of verification were both provided for. Results: Women recited both evaluative criteria used to compare surgeons and determinant attributes actually used to differentiate among choices, but gender did not emerge spontaneously in either case. Four categories did emerge: surgeon, hospital, clinical scenario, and office practice. A central category described the relationship between women's preferences and surgeons’ attributes: hierarchy of effects among women's beliefs, feelings, and behaviors. Women informed their preferences through a deliberate, well-informed process of active research, not stereotypes. Discussion: Gender may act to mediate preferences once other threshold categories are accounted for. Future research using quantitative methods is feasible. Hospitals that seek to promote breast surgery services should first, become valued information resources; and second, recruit and market surgeons according to competence and not gender as a principal criterion. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-10-07.
Improving the recruitment and retention of doctors
Authors: J. Harvey, H. Davison, H. Bichovsky
Journal: BMJ (1998)

Poor working conditions in the NHS are the main cause of “wastage” of doctors. Jane Harvey, Helen Davison, and Hilary Bichovsky report from the Don't Waste Doctors project.

Don't Waste Doctors is an innovative, Manchester based project set up to respond to the North West region's crisis in the recruitment and retention of doctors: in October 1995, 32% of senior house officer posts in the North West Region remained unfilled after interview. Since it started in 1995, Don't Waste Doctors has had a double remit: to conduct research and to act practically.

Don't Waste Doctors's practical work has centred on establishing new, less than full time (LTFT) posts in the North West region. With money from the task force to meet the requirements of the new deal, Don't Waste Doctors worked in conjunction with Manchester and Merseyside postgraduate departments and local NHS trusts to create nine new pilot LTFT training posts. These differ from traditional flexible training posts in that they are substantive not supernumerary. This means that funding and educational approval are attached to the post rather than the trainee and that they are available through open competition at trust level. There were bids from 15 NHS trusts for 24 posts, and funding was allocated to the nine posts that combined the greatest new deal needs with a good training environment. It is hoped that these posts will act as an example for other NHS trusts looking at developing more family friendly and flexible working patterns. Some trusts have taken up this idea even without extra funding.

Don't Waste Doctors has also identified a need for retraining posts, particularly for doctors who have not worked for several years. Two retraining posts for junior doctors were set up that provided initial intensive consultant supervision until the doctor had gained sufficient …
SAT0285 Progranulin-Neutralizing Autoantibodies in Psoriatic Arthritis
Authors: G. Assmann, S. Zinke, M. Zaks, C. Pfoehler, D. Preuss, M. Pfreundschuh, L. Thurner
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Psoriatic arthritis (PsA) is a distinctive inflammatory arthritis that may develop in 5-40% of individuals suffering from psoriasis. We recently described progranulin autoantibodies (PGRN-Abs) in the sera of patients with different autoimmune diseases including seronegative polyarthritis [Ref. 1]. <h3>Objectives</h3> In the present study we investigated the occurrence of PGRN-Abs in PsA. <h3>Methods</h3> PGRN-Abs were determined in 260 patients with PsA, 100 patients with psoriasis without arthritic manifestations and 97 healthy controls using a recently described ELISA. PGRN plasma levels were determined from subgroups by a commercially available ELISA-kit. <h3>Results</h3> PGRN-Abs were detected in 50/260 (19.23%) patients with PsA, but in 0/100 patients with psoriasis without arthritic manifestations (*p=0.0001) [Figure 1]. PGRN-Abs were significantly more frequent in PsA patients with enthesitis (21.3 vs. 14.7%) or dactylitis (21.8 vs. 15.4%). PGRN-Abs were also more frequent in PsA patients receiving treatment with TNF-α-blockers than in patients treated without TNF-α-blockers (20.8 vs. 17.4%; p=0.016). PGRN plasma levels were significantly lower in PGRN-Ab-positive patients with PsA than in healthy controls and patients with psoriasis without arthritic manifestations (p&lt;0.001), indicating a neutralizing effect of PGRN-Abs. <h3>Image/graph</h3> <h3>Conclusions</h3> PGRN-Ab is a serological marker present in a subgroup of patients with PsA, but absent in patients without arthritic manifestations. Its restriction to patients with PsA suggests that PGRN-Ab might not only be useful as a diagnostic and prognostic marker, but may be involved in the pathogenesis of the arthritic process in a subgroup of patients with PsA. <h3>References</h3> Thurner L, Preuss KD, Fadle N, Regitz E, Klemm P, Zaks M, Kemele M, Hasenfus A, Csernok E, Gross WL, Pasquali JL, Martin T, Bohle RM, Pfreundschuh M. Progranulin antibodies in autoimmune diseases. J Autoimmun. 2012 Nov 11. doi:pii: S0896-8411(12)00130-8. 10.1016/j.jaut.2012.10.003. [Epub ahead of print] <h3>Disclosure of Interest</h3> None Declared
FDG-Anorectic Parathyroid Carcinoma With FDG-Avid Bone Metastasis on PET/CT Images
Authors: Mei Li, Hankui Lu, Yunchao Gao
Journal: Clinical Nuclear Medicine (2013)

A 53-year-old man complained of aggravated left hip pain of more than 2 months. Whole-body (18)F-FDG PET/CT revealed only 1 hypermetabolic lesion in the left ilium. Histopathologic examination of the lesion suggested metastatic disease. Blood tests documented mildly elevated blood calcium and parathyroid hormone. Subsequent neck ultrasonography, contrast-enhanced CT, and dual-phase scintigraphy with (99m)Tc-MIBI showed a right parathyroid tumor, which was confirmed to be a parathyroid carcinoma postoperatively. We report a case of parathyroid carcinoma rarely encountered with a FDG-negative primary but a FDG-positive metastasis on PET/CT images.